CA2460625A1 - Structural and cytoskeleton-associated proteins - Google Patents

Abstract

Various embodiments of the invention provide human structural and cytoskelet on- associated proteins (SCAP) and polynucleotides which identify and encode SCA P. Embodiments of the invention also provide expression vectors, host cells, antibodies, agonists, and antagonists. Other embodiments provide methods for diagnosing, treating, or preventing disorders associated with aberrant expression of SCAP.

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STRUCTURAL AND CYTOSKELETON-ASSOCIATED PROTEINS
TECHNICAL FIELD
The invention relates to novel nucleic acids, structural and cytoskeleton-associated proteins encoded by these nucleic acids, and to the use of these nucleic acids and proteins in the diagnosis, treatment, and prevention of cell proliferative disorders, viral infections, neurological disorders, and heart and skeletal muscle disorders. The invention also relates to the assessment of the effects of exogenous compounds on the expression of nucleic acids and structural and cytoskeleton-associated proteins.
BACKGROUND OF THE INVENTION
The cytoskeleton is a cytoplasmic network of protein fibers that mediate cell shape, structure, and movement. The cytoskeleton supports the cell membrane and forms tracks along which organelles and other elements move in the cytosol. The cytoskeleton is a dynamic structure that allows cells to adopt various shapes and to carry out directed movements.
Major cytoskeletal fibers include the microtubules, the microfilaments, and the intermediate filaments.
Motor proteins, including myosin, dynein, and kinesin, drive movement of or along the fibers.
The motor protein dynamin drives the formation of membrane vesicles. Accessory or associated proteins modify the structure or activity of the fibers while cytoskeletal membrane anchors connect the fibers to the cell membrane.
Microtubules and Associated Proteins Tubulins Microtubules, cytoskeletal fibers with a diameter of about 24 nm, have multiple roles in the cell. Bundles of microtubules form cilia and flagella, which are whip-like extensions of the cell membrane that are necessary for sweeping materials across an epithelium and for swimming of sperm, respectively. Marginal bands of microtubules in red blood cells and platelets are important for these cells' pliability. Organelles, membrane vesicles, and proteins are transported in the cell along tracks of microtubules. For example, microtubules run through nerve cell axons, allowing bi-directional transport of materials and membrane vesicles between the cell body and the nerve terminal. Failure to supply the nerve terminal with these vesicles blocks the transmission of neural signals. Microtubules are also critical to chromosomal movement during cell division. Both stable and short-lived populations of microtubules exist in the cell.
Microtubules are polymers of GTP-binding tubulin protein subunits. Each subunit is a heterodimer of a- and ~3- tubulin, multiple isoforms of which exist. The hydrolysis of GTP is linked to the addition of tubulin subunits at the end of a microtubule. The subunits interact head to tail to form protofilaments; the protofilaments interact side to side to form a microtubule. A microtubule is polarized, one end ringed with a-tubulin and the other with (3-tubulin, and the two ends differ in their rates of assembly. Generally, each microtubule is composed of 13 protofilaments although 11 or 15 protofilament-microtubules are sometimes found. Cilia and flagella contain doublet microtubules.
Microtubules grow from specialized structures known as centrosomes or microtubule-organizing centers (MTOCs). MTOCs may contain one or two centrioles, which are pinwheel arrays of triplet microtubules. The basal body, the organizing center located at the base of a cilium or flagellum, contains one centriole. Gamma tubulin present in the MTOC is important for nucleating the polymerization of a- and (3- tubulin heterodimers but does not polymerize into microtubules. The protein pericentrin is found in the MTOC and has a role in microtubule assembly.
Microtubule-Associated Proteins Microtubule-associated proteins (MAPs) have roles in the assembly and stabilization of microtubules. One major family of MAPS, assembly MAPs, can be identified in neurons as well as non-neuronal cells. Assembly MAPS are responsible for cross-linking microtubules in the cytosol.
These MAPS are organized into two domains: a basic microtubule-binding domain and an acidic projection domain. The projection domain is the binding site for membranes, intermediate filaments, or other microtubules. Based on sequence analysis, assembly MAPS can be further grouped into two types: Type I and Type II. Type I MAPS, which include MAP1A and MAP1B, are large, filamentous molecules that co-purify with microtubules and are abundantly expressed in brain and testes. Type I
MAPS contain several repeats of a positively-charged amino acid sequence motif that binds and neutralizes negatively charged tubulin, leading to stabilization of microtubules. MAP1A and MAP1B
are each derived from a single precursor polypeptide that is subsequently proteolytically processed to generate one heavy chain and one light chain.
Another light chain, LC3, is a 16.4 kDa molecule that binds MAP1A, MAP1B, and microtubules. It is suggested that LC3 is synthesized from a source other than the MAP1A or MAP1B transcripts, and that the expression of LC3 may be important in regulating the microtubule binding activity of MAP1A and MAP1B during cell proliferation (Mann, S.S. et al. (1994) J. Biol.
Chem. 269:11492-11497).
Type II MAPS, which include MAP2a, MAP2b, MAP2c, MAP4, and Tau, are characterized by three to four copies of an 18-residue sequence in the microtubule-binding domain. MAP2a, MAP2b, and MAP2c are found only in dendrites, MAP4 is found in non-neuronal cells, and Tau is found in axons and dendrites of nerve cells. Alternative splicing of the Tau mRNA leads to the existence of multiple forms of Tau protein. Tau phosphorylation is altered in neurodegenerative disorders such as Alzheimer's disease, Pick's disease, progressive supranuclear palsy, corticobasal degeneration, and familial frontotemporal dementia and Parkinsonism linked to chromosome 17. The altered Tau phosphorylation leads to a collapse of the microtubule network and the formation of intraneuronal Tau aggregates (Spillantini, M.G. and M. Goedert (1998) Trends Neurosci. 21:428-433).
Another microtubule associated protein, STOP (stable tubule only polypeptide), is a S calmodulin-regulated protein that regulates stability (Denarier, E. et al.
(1998) Biochem. Biophys.
Res. Common. 24:791-796). In order for neurons to maintain conductive connections over great distances, they rely upon axodendritic extensions, which in turn are supported by microtubules.
STOP proteins function to stabilize the microtubular network. STOP proteins are associated with axonal microtubules, and are also abundant in neurons (Guillaud, L. et al.
(1998) J. Cell Biol.
142:167-179). STOP proteins are necessary for normal neurite formation, and have been observed to stabilize microtubules, in vitro, against cold-, calcium-, or drug-induced dissassembly (Margolis, R.L.
et al. (1990) EMBO 9:4095-502).
Microfilaments and Associated Proteins Actins Microfilaments, cytoskeletal filaments with a diameter of about 7-9 nm, are vital to cell locomotion, cell shape, cell adhesion, cell division, and muscle contraction.
Assembly and disassembly of the microfilaments allow cells to change their morphology.
Microfilaments are the polymerized form of actin, the most abundant intracellular protein in the eukaryotic cell. Human cells contain six isoforms of actin. The three a-actins are found in different kinds of muscle, nonmuscle (3-actin and nonmuscle y-actin are found in nonmuscle cells, and another y-actin is found in intestinal smooth muscle cells. G-actin, the monomeric form of actin, polymerizes into polarized, helical F-actin filaments, accompanied by the hydrolysis of ATP to ADP. Actin filaments associate to form bundles and networks, providing a framework to support the plasma membrane and determine cell shape. These bundles and networks are connected to the cell membrane. In muscle cells, thin filaments containing actin slide past thick filaments containing the motor protein myosin during contraction. A family of actin-related proteins exist that are not part of the actin cytoskeleton, but rather associate with microtubules and dynein.
Actin-Associated Proteins Actin-associated proteins have roles in cross-linking, severing, and stabilization of actin filaments and in sequestering actin monomers. Several of the actin-associated proteins have multiple functions. Bundles and networks of actin filaments are held together by actin cross-linking proteins.
These proteins have two actin-binding sites, one for each filament. Short cross-linking proteins promote bundle formation while longer, more flexible cross-linking proteins promote network formation. Actin-interacting proteins (AIPs) participate in the regulation of actin filament organization. Other actin-associated proteins such as TARA, a novel F-actin binding protein, function in a similar capacity by regulating actin cytoskeletal organization.
Calmodulin-like calcium-binding domains in actin cross-linking proteins allow calcium regulation of cross-linking. Group I
cross-linking proteins have unique actin-binding domains and include the 30 kD
protein, EF-la, fascin, and scrum. Group II cross-linking proteins have a 7,000-MW actin-binding domain and include villin and dematin. Group III cross-linking proteins have pairs of a 26,000-MW actin-binding domain and include fimbrin, spectrin, dystrophin, ABP 120, and filamin.
Severing proteins regulate the length of actin filaments by breaking them into short pieces or by blocking their ends. Severing proteins include gCAP39, severin (fragmin), gelsolin, and villin.
Capping proteins can cap the ends of actin filaments, but cannot break filaments. Capping proteins include CapZ and tropomodulin. The proteins thymosin and profilin sequester actin monomers in the cytosol, allowing a pool of unpolymerized actin to exist. The actin-associated proteins tropomyosin, troponin, and caldesmon regulate muscle contraction in response to calcium.
Microtubule and actin filament networks cooperate in processes such as vesicle and organelle transport, cleavage furrow placement, directed cell migration, spindle rotation, and nuclear migration.
Microtubules and actin may coordinate to transport vesicles, organelles, and cell fate determinants, or transport may involve targeting and capture of microtubule ends at cortical actin sites. These cytoskeletal systems may be bridged by myosin-kinesin complexes, myosin-CLIP170 complexes, formin-homology (FH) proteins, dynein, the dynactin complex, Kar9p, coronin, ERM proteins, and ketch repeat-containing proteins (for a review, see Goode, B.L. et al. (2000) Curr. Opin. Cell Biol.
12:63-71). The ketch repeat is a motif originally observed in the ketch protein, which is involved in formation of cytoplasmic bridges called ring canals. A variety of mammalian and other ketch family proteins have been identified. The ketch repeat domain is believed to mediate interaction with actin (Robinson, D.N. and L. Cooley (1997) J. Cell Biol. 138:799-810).
ADF/cofilins are a family of conserved 15-18 kDa actin-binding proteins that play a role in cytokinesis, endocytosis, and in development of embryonic tissues, as well as in tissue regeneration and in pathologies such as ischemia, oxidative or osmotic stress. LIM kinase 1 downregulates ADF
(Carlier, M.F. et al. (1999) J. Biol. Chem. 274:33827-33830).
LIM is an acronym of three transcription factors, Lin-1 l, Isl-1, and Mec-3, in which the motif was first identified. The LIM domain is a double zinc-finger motif that mediates the protein-protein interactions of transcription factors, signaling, and cytoskeleton-associated proteins (Roof, D.J. et al.
(1997) J. Cell Biol. 138:575-588). These proteins are distributed in the nucleus, cytoplasm, or both (Brown, S. et al. (1999) J. Biol. Chem. 274:27083-27091). Recently, ALP
(actinin-associated LIM
protein) has been shown to bind alpha-actinin-2 (Bouju, S. et al. (1999) Neuromuscul. Disord. 9:3-10).
The Frabin protein is another example of an actin-filament binding protein (Obaishi, H. et al.

(1998) J. Biol. Chem. 273:18697-18700). Frabin (FGDl-related F-actin-binding protein) possesses one actin-filament binding (FAB) domain, one Dbl homology (DH) domain, two pleckstrin homology (PH) domains, and a single cysteine-rich FYVE ( Fablp, YOTB, Vaclp, and EEAl (early endosomal antigen 1)) domain. Frabin has shown GDP/GTP exchange activity for Cdc42 small G protein (Cdc42), and indirectly induces activation of Rac small G protein (Rac) in intact cells. Through the activation of Cdc42 and Rac, Frabin is able to induce formation of both filopodia- and lamellipodia-like processes (Ono, Y. et al. (2000) Oncogene 19:3050-3058).
The Rho family of small GTP-binding proteins are important regulators of actin-dependent cell functions including cell shape change, adhesion, and motility. The Rho family consists of three major subfamilies: Cdc42, Rac, and Rho. Rho family members cycle between GDP-bound inactive and GTP-bound active forms by means of a GDP/GTP exchange factor (GEF) (Umikawa, M. et al.
(1999) J. Biol. Chem. 274:25197-25200). The Rho GEF family is crucial for microfilament organization.
Nebulin-related Proteins Nebulin is a large sarcomeric protein that interacts with actin filaments in skeletal muscle (Wang, K. et al. (1996) J. Biol. Chem. 271:4304-4314). Nebulin contains 185 or more copies of a 35-residue module that has a consensus sequence and a predicted a-helical structure. The 35-residue module comprises an actin-binding domain. In the central region of nebulin, the 35-residue modules exhibit a seven module super-repeat pattern. This super-repeat pattern is not present in the C-terminal 100 kDa region of nebulin. The N-terminal region of nebulin contains 8 linker modules and an 8 kDa acidic domain. The C-terminal region is distinct and contains an SH3 domain.
Within the sarcomere, nebulin is oriented with its C-terminus located at the Z-line, and its N-terminus at the pointed slow-growing end of thin filaments in the acto-myosin overlap region.
Nebulin exists as different isoforms which range in size from 600-900 kDa (Kruger, M. et al.
(1991) J. Cell. Biol. 115:97-107). The size of nebulin is tissue- and species-specific and is developmentally regulated. Based on the observation that isoform size correlates with the length of thin filaments in skeletal muscle, nebulin is proposed to play a role as a molecular ruler that regulates the length of thin filaments. Each nebulin 35-residue module may associate with one actin monomer;
thus, isoforms with different numbers of modules could determine the length of thin filaments. The N-terminal region of nebulin interacts with tropomodulin, which may assist in this function (McElhinny, A.S. et al. (2001) J. Biol. Chem. 276:583-592). Tropomodulin caps actin at the pointed end of thin filaments and maintains filament length by preventing actin monomer dissociation or addition.
Nebulin is absent from cardiac muscle, but related proteins with nebulin-like modules may provide similar functions. Nebulette, for example, is specifically expressed in heart and has a C-terminal region containing twenty-three 35-residue nebulin-like modules (Moncman, C.L. and K.
Wang (2000) J. Muscle Res. Cell Motil. 21:153-169; Millevoi, S. et al. (1998) J. Mol. Biol. 282:111-123). The domain structure of nebulette is similar to nebulin, though it is a smaller protein of only 107 kDa. It has an acidic N-terminal domain, a repeat domain containing nebulin-like modules, a linker domain, and an SH3 domain. The repeat domain of nebulette is about one-tenth the size of that of nebulin. The 35-residue modules of nebulette have a consensus motif, and a subfamily of modules 15-22 share a conserved motif. Unlike nebulin, nebulette modules do not display a super-repeat pattern. Nebulette binds to actin as well as other sarcomeric proteins including myosin, calmodulin, tropomyosin, troponin, and cc-actinin (Moncman, C.L. and K. Wang (1999) Cell Motil. Cytoskeleton 44:1-22). The orientation of nebulette in the sarcomere is analogous to that of nebulin with its C-terminus at the Z-line and its N-terminus in the I-band.
Nebulin-related anchoring protein (N-RAP) is expressed in cardiac and skeletal muscle (Luo, G. et al. ( 1997) Cell Motil. Cytoskeleton 38:75-90). It is a 133 kDa protein found at the ends of myofibrils at muscle myotendon junctions and intercalated disks. The C-terminal region of N-RAP
has 27 copies of the 35-residue nebulin-like modules. Seventeen of the modules are organized in a super-repeat pattern. The N-terminal region contains a cysteine-rich LIM
domain. LIM domains bind two zinc ions in two adjacent zinc finger-like structures and are known to mediate protein-protein interactions. N-RAP may mediate interactions between actin filaments of myofibrils and other sarcomeric proteins. N-RAP binds to actin, talin, and vinculin (Luo, G.
et al. (1999) Biochemistry 38:6135-6143). It interacts with actin and vinculin through its super-repeat region and with talin through its LIM domain. Talin and vinculin are also located at myotendon junctions and together with N-RAP may provide a link between actin filaments of the myofibril and the sarcolemma and transmit tension from the myofibril to the extracellular matrix.
Mutations of sarcomeric proteins are associated with muscle weakness and disease (Laing, N.G. (1999) Curr. Opin. Neurol. 12:513-518). Autosomal recessive nemaline myopathy in some cases is caused by nebulin deficiency (Pelin, K. et al. (1999) Proc. Natl.
Acad. Sci. 96:2305-2310).
The disease is characterized by the presence of nemaline bodies in muscle fibers. The nemaline bodies contain proteins normally associated with the Z disc and thin filament.
Defects in nebulin apparently perturb interactions among sarcomeric proteins and result in the pathological aggregation of proteins in nemaline bodies.
Intermediate Filaments and Associated Proteins Intermediate filaments (IFs) are cytoskeletal fibers with a diameter of about 10 nm, intermediate between that of microfilaments and microtubules. IFs serve structural roles in the cell, reinforcing cells and organizing cells into tissues. IFs are particularly abundant in epidermal cells and in neurons. IFs are extremely stable, and, in contrast to microfilaments and microtubules, do not function in cell motility.
Five types of IF proteins are known in mammals. Type I and Type II proteins are the acidic and basic keratins, respectively. Heterodimers of the acidic and basic keratins are the building blocks of keratin IFs. Keratins are abundant in soft epithelia such as skin and cornea, hard epithelia such as nails and hair, and in epithelia that line internal body cavities. Mutations in keratin genes lead to epithelial diseases including epidermolysis bullosa simplex, bullous congenital ichthyosiform erythroderma (epidermolytic hyperkeratosis), non-epidermolytic and epidermolytic palmoplantar keratoderma, ichthyosis bullosa of Siemens, pachyonychia congenita, and white sponge nevus. Some of these diseases result in severe skin blistering. (See, e.g., Wawersik, M.
et al. (1997) J. Biol. Chem.
272:32557-32565; and Corden L.D. and W.H. McLean (1996) Exp. Dermatol. 5:297-307.) Type III IF proteins include desmin, glial fibrillary acidic protein, vimentin, and peripherin.
Desmin filaments in muscle cells link myofibrils into bundles and stabilize sarcomeres in contracting muscle. Glial fibrillary acidic protein filaments are found in the glial cells that surround neurons and astrocytes. Vimentin filaments are found in blood vessel endothelial cells, some epithelial cells, and mesenchymal cells such as fibroblasts, and are commonly associated with microtubules. Vimentin filaments may have roles in keeping the nucleus and other organelles in place in the cell. Type IV IFs include the neurofilaments and nestin. Neurofilaments, composed of three polypeptides, NF-L, NF-M, and NF-H, are frequently associated with microtubules in axons.
Neurofilaments are responsible for the radial growth and diameter of an axon, and ultimately for the speed of nerve impulse transmission. Changes in phosphorylation and metabolism of neurofilaments are observed in neurodegenerative diseases including amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease (Julien, J.P. and W.E. Mushynski (1998) Prog. Nucleic Acid Res. Mol. Biol.
61:1-23). Type V IFs, the lamins, are found in the nucleus where they support the nuclear membrane.
1Fs have a central a-helical rod region interrupted by short nonhelical linker segments. The rod region is bracketed, in most cases, by non-helical head and tail domains.
The rod regions of intermediate filament proteins associate to form a coiled-coil dimer. A highly ordered assembly process leads from the dimers to the IFs. Neither ATP nor GTP is needed for IF
assembly, unlike that of microfilaments and microtubules.
IF-associated proteins (IFAPs) mediate the interactions of IFs with one another and with other cell structures. IFAPs cross-link IFs into a bundle, into a network, or to the plasma membrane, and may cross-link IFs to the microfilament and microtubule cytoskeleton.
Microtubules and IFs are particularly closely associated. IFAPs include BPAG1, plakoglobin, desmoplakin I, desmoplakin II, plectin, ankyrin, filaggrin, and lamin B receptor.
Cytoskeletal-Membrane Anchors Cytoskeletal fibers are attached to the plasma membrane by specific proteins.
These attachments are important for maintaining cell shape and for muscle contraction. In erythrocytes, the spectrin-actin cytoskeleton is attached to the cell membrane by three proteins, band 4.1, ankyrin, and adducin. Defects in this attachment result in abnormally shaped cells which are more rapidly degraded by the spleen, leading to anemia. In platelets, the spectrin-actin cytoskeleton is also linked to the membrane by ankyrin; a second actin network is anchored to the membrane by filamin. In muscle cells the protein dystrophin links actin filaments to the plasma membrane; mutations in the dystrophin gene lead to Duchenne muscular dystrophy.
Focal adhesions Focal adhesions are specialized structures in the plasma membrane involved in the adhesion of a cell to a substrate, such as the extracellular matrix (ECM). Focal adhesions form the connection between an extracellular substrate and the cytoskeleton, and affect such functions as cell shape, cell motility and cell proliferation. Transmembrane integrin molecules form the basis of focal adhesions.
Upon ligand binding, integrins cluster in the plane of the plasma membrane.
Cytoskeletal linker proteins such as the actin binding proteins a-actinin, talin, tensin, vinculin, paxillin, and filamin are recruited to the clustering site. Key regulatory proteins, such as Rho and Ras family proteins, focal adhesion kinase, and Src family members are also recruited. These events lead to the reorganization of actin filaments and the formation of stress fibers. These intracellular rearrangements promote further integrin-ECM interactions and integrin clustering. Thus, integrins mediate aggregation of protein complexes on both the cytosolic and extracellular faces of the plasma membrane, leading to the assembly of the focal adhesion. Many signal transduction responses are mediated via various adhesion complex proteins, including Src, FAK, paxillin, and tensin. (For a review, see Yamada, K.M. and B. Geiger, (1997) Curr. Opin. Cell Biol. 9:76-85.) IFs are also attached to membranes by cytoskeletal-membrane anchors. The nuclear lamina is attached to the inner surface of the nuclear membrane by the lamin B receptor.
Vimentin IFs are attached to the plasma membrane by ankyrin and plectin. Desmosome and hemidesmosome membrane junctions hold together epithelial cells of organs and skin. These membrane junctions allow shear forces to be distributed across the entire epithelial cell layer, thus providing strength and rigidity to the epithelium. IFs in epithelial cells are attached to the desmosome by plakoglobin and desmoplakins. The proteins that link IFs to hemidesmosomes are not known.
Desmin IFs surround the sarcomere in muscle and are linked to the plasma membrane by paranemin, synemin, and ankyrin.
Motor Proteins Myosin-related Motor Proteins Myosins are actin-activated ATPases, found in eukaryotic cells, that couple hydrolysis of ATP with motion. Myosin provides the motor function for muscle contraction and intracellular movements such as phagocytosis and rearrangement of cell contents during mitotic cell division (cytokinesis). The contractile unit of skeletal muscle, termed the sarcomere, consists of highly ordered arrays of thin actin-containing filaments and thick myosin-containing filaments.
Crossbridges form between the thick and thin filaments, and the ATP-dependent movement of myosin heads within the thick filaments pulls the thin filaments, shortening the sarcomere and thus the muscle fiber.
Myosins are composed of one or two heavy chains and associated light chains.
Myosin heavy chains contain an amino-terminal motor or head domain, a neck that is the site of light-chain binding, and a carboxy-terminal tail domain. The tail domains may associate to form an a-helical coiled coil.
Conventional myosins, such as those found in muscle tissue, are composed of two myosin heavy-chain subunits, each associated with two light-chain subunits that bind at the neck region and play a regulatory role. Unconventional myosins, believed to function in intracellular motion, may contain either one or two heavy chains and associated light chains. There is evidence for about 25 myosin heavy chain genes in vertebrates, more than half of them unconventional.
Dynein-related Motor Proteins Dyneins are (-) end-directed motor proteins which act on microtubules. Two classes of dyneins, cytosolic and axonemal, have been identified. Cytosolic dyneins are responsible for translocation of materials along cytoplasmic microtubules, for example, transport from the nerve terminal to the cell body and transport of endocytic vesicles to lysosomes. As well, viruses often take advantage of cytoplasmic dyneins to be transported to the nucleus and establish a successful infection (Sodeik, B. et al. (1997) J. Cell Biol. 136:1007-1021). Virion proteins of herpes simplex virus 1, for example, interact wiih the cytoplasmic dynein intermediate chain (Ye, G.J. et al. (2000) J. Virol.
74:1355-1363). Cytoplasmic dyneins are also reported to play a role in mitosis. Axonemal dyneins are responsible for the beating of flagella and cilia. Dynein on one microtubule doublet walks along the adjacent microtubule doublet. This sliding force produces bending that causes the flagellum or cilium to beat. Dyneins have a native mass between 1000 and 2000 kDa and contain either two or three force-producing heads driven by the hydrolysis of ATP. The heads are linked via stalks to a basal domain which is composed of a highly variable number of accessory intermediate and light chains. Cytoplasmic dynein is the largest and most complex of the motor proteins.
Kinesin-related Motor Proteins Kinesins are (+) end-directed motor proteins which act on microtubules. The prototypical kinesin molecule is involved in the transport of membrane-bound vesicles and organelles. This function is particularly important for axonal transport in neurons. Kinesin is also important in all cell types for the transport of vesicles from the Golgi complex to the endoplasmic reticulum. This role is critical for maintaining the identity and functionality of these secretory organelles.
Kinesins define a ubiquitous, conserved family of over 50 proteins that can be classified into at least 8 subfamilies based on primary amino acid sequence, domain structure, velocity of movement, and cellular function. (Reviewed in Moore, J.D. and S.A. Endow (1996) Bioessays 18:207-219; and Hoyt, A.M. (1994) Curr. Opin. Cell Biol. 6:63-68.) The prototypical kinesin molecule is a heterotetramer comprised of two heavy polypeptide chains (KHCs) and two light polypeptide chains (KLCs). The KHC subunits are typically referred to as "kinesin." KHC is about 1000 amino acids in length, and KLC is about 550 amino acids in length. Two KHCs dimerize to form a rod-shaped molecule with three distinct regions of secondary structure. At one end of the molecule is a globular motor domain that functions in ATP hydrolysis and microtubule binding. Kinesin motor domains are highly conserved and share over 70% identity. Beyond the motor domain is an a-helical coiled-coil region which mediates dimerization. At the other end of the molecule is a fan-shaped tail that associates with molecular cargo. The tail is formed by the interaction of the KHC C-termini with the two KLCs.
Members of the more divergent subfamilies of kinesins are called kinesin-related proteins (KRPs), many of which function during mitosis in eukaryotes (Hoyt, supra).
Some KRPs are required for assembly of the mitotic spindle. In vivo and in vitro analyses suggest that these KRPs exert force on microtubules that comprise the mitotic spindle, resulting in the separation of spindle poles. Phosphorylation of KRP is required for this activity. Failure to assemble the mitotic spindle results in abortive mitosis and chromosomal aneuploidy, the latter condition being characteristic of cancer cells. In addition, a unique KRP, centromere protein E, localizes to the kinetochore of human mitotic chromosomes and may play a role in their segregation to opposite spindle poles.
Dynamin-related Motor Proteins Dynamin is a large GTPase motor protein that functions as a "molecular pinchase,"
generating a mechanochemical force used to sever membranes. This activity is important in forming clathrin-coated vesicles from coated pits in endocytosis and in the biogenesis of synaptic vesicles in neurons. Binding of dynamin to a membrane leads to dynamin's self-assembly into spirals that may act to constrict a flat membrane surface into a tubule. GTP hydrolysis induces a change in conformation of the dynamin polymer that pinches the membrane tubule, leading to severing of the membrane tubule and formation of a membrane vesicle. Release of GDP and inorganic phosphate leads to dynamin disassembly. Following disassembly the dynamin may either dissociate from the membrane or remain associated to the vesicle and be transported to another region of the cell. Three homologous dynamin genes have been discovered, in addition to several dynamin-related proteins.
Conserved dynamin regions are the N-terminal GTP-binding domain, a central pleckstrin homology domain that binds membranes, a central coiled-coil region that may activate dynamin's GTPase activity, and a C-terminal proline-rich domain that contains several motifs that bind SH3 domains on other proteins. Some dynamin-related proteins do not contain the pleckstrin homology domain or the to proline-rich domain. (See McNiven, M.A. (1998) Cell 94:151-154; Scaife, R.M.
and R.L. Margolis (1997) Cell. Signal. 9:395-401.) The cytoskeleton is reviewed in Lodish, H. et al. (1995) Molecular Cell Biolo~y, Scientific American Books, New York NY.
Expression profiling Microarrays are analytical tools used in bioanalysis. A microarray has a plurality of molecules spatially distributed over, and stably associated with, the surface of a solid support.
Microarrays of polypeptides, polynucleotides, and/or antibodies have been developed and find use in a variety of applications, such as gene sequencing, monitoring gene expression, gene mapping, bacterial identification, drug discovery, and combinatorial chemistry.
One area in particular in which microarrays find use is in gene expression analysis. Array technology can provide a simple way to explore the expression of a single polymorphic gene or the expression profile of a large number of related or unrelated genes. When the expression of a single gene is examined, arrays are employed to detect the expression of a specific gene or its variants.
When an expression profile is examined, arrays provide a platform for identifying genes that are tissue specific, are affected by a substance being tested in a toxicology assay, are part of a signaling cascade, carry out housekeeping functions, or are specifically related to a particular genetic predisposition, condition, disease, or disorder.
Colon cancer Colorectal cancer is the fourth most common cancer and the second most common cause of cancer death in the United States with approximately 130,000 new cases and 55,000 deaths per year.
Colon and rectal cancers share many environmental risk factors and both are found in individuals with specific genetic syndromes. (See Potter, JD ( 1999) J Natl Cancer Institute 91:916-932 for a review of colorectal cancer.) Colon cancer is the only cancer that occurs with approximately equal frequency in men and women, and the five-year survival rate following diagnosis of colon cancer is around 55% in the United States (Ries et al. (1990) National Institutes of Health, DHHS Publ No.
(NIH)90-2789).
Colon cancer is causally related to both genes and the environment. Several molecular pathways have been linked to the development of colon cancer, and the expression of key genes in any of these pathways may be lost by inherited or acquired mutation or by hypermethylation. There is a particular need to identify genes for which changes in expression may provide an early indicator of colon cancer or a predisposition for the development of colon cancer.
For example, it is well known that abnormal patterns of DNA methylation occur consistently in human tumors and include, simultaneously, widespread genomic hypomethylation and localized areas of increased methylation. In colon cancer in particular, it has been found that these changes occur early in tumor progression such as in premalignant polyps that precede colon cancer. Indeed, DNA methyltransferase, the enzyme that performs DNA methylation, is significantly increased in histologically normal mucosa from patients with colon cancer or the benign polyps that precede cancer, and this increase continues during the progression of colonic neoplasms (Wafik, S et al.
(1991) Proc Natl Acad Sci USA 88:3470-3474). Increased DNA methylation occurs in G+C rich areas of genomic DNA termed "CpG islands" that are important for maintenance of an "open"
transcriptional conformation around genes, and that hypermethylation of these regions results in a "closed" conformation that silences gene transcription. It has been suggested that the silencing or downregulation of differentiation genes by such abnormal methylation of CpG
islands may prevent differentiation in immortalized cells (Anteguera, F. et al. ( 1990) Cell 62:503-514).
Familial Adenomatous Polyposis (FAP) is a rare autosomal dominant syndrome that precedes colon cancer and is caused by an inherited mutation in the adenomatous polyposis coli (APC) gene.
FAP is characterized by the early development of multiple colorectal adenomas that progress to cancer at a mean age of 44 years. The APC gene is a part of the APC-(3-catenin-Tcf (T-cell factor) pathway. Impairment of this pathway results in the loss of orderly replication, adhesion, and migration of colonic epithelial cells that results in the growth of polyps. A
series of other genetic changes follow activation of the APC-13-catenin-Tcf pathway and accompanies the transition from normal colonic mucosa to metastatic carcinoma. These changes include mutation of the K-Ras proto-oncogene, changes in methylation patterns, and mutation or loss of the tumor suppressor genes p53 and Smad4/ DPC4. While the inheritance of a mutated APC gene is a rare event, the loss or mutation of APC and the consequent effects on the APC-f3-catenin-Tcf pathway is believed to be central to the majority of colon cancers in the general population.
Hereditary nonpolyposis Colorectal Cancer (HNPCC) is another inherited autosomal dominant syndrome with a less well defined phenotype than FAP. HNPCC, which accounts for about 2% of colorectal cancer cases, is distinguished by the tendency to early onset of cancer and the development of other cancers, particularly those involving the endometrium, urinary tract, stomach and biliary system. HNPCC results from the mutation of one or more genes in the DNA mis-match repair (MMR) pathway. Mutations in two human MMR genes, MSH2 and MLH1, are found in a large majority of HNPCC families identified to date. The DNA MMR pathway identifies and repairs errors that result from the activity of DNA polymerase during replication.
Furthermore, loss of MMR
activity contributes to cancer progression through accumulation of other gene mutations and deletions, such as loss of the BAX gene which controls apoptosis, and the TGFf3 receptor II gene which controls cell growth. Because of the potential for irreparable damage to DNA in an individual with a DNA MMR defect, progression to carcinoma is more rapid than usual.
Although ulcerative colitis is a minor contributor to colon cancer, affected individuals have about a 20-fold increase in risk for developing cancer. Progression is characterized by loss of the p53 gene which may occur early, appearing even in histologically normal tissue.
The progression of the disease from ulcerative colitis to dysplasia/carcinoma without an intermediate polyp state suggests a high degree of mutagenic activity resulting from the exposure of proliferating cells in the colonic mucosa to the colonic contents.
Almost all colon cancers arise from cells in which the estrogen receptor (ER) gene has been silenced. The silencing of ER gene transcription is age related and linked to hypermethylation of the ER gene (Issa, J-P J et al. (1994) Nature Genetics 7:536-540). Introduction of an exogenous ER gene into cultured colon carcinoma cells results in marked growth suppression. The connection between loss of the ER protein in colonic epithelial cells and the consequent development of cancer has not been established.
Clearly there are a number of genetic alterations associated with colon cancer and with the development and progression of the disease, particularly the downregulation or deletion of genes, that potentially provide early indicators of cancer development, and which may also be used to monitor IS disease progression or provide possible therapeutic targets. The specific genes affected in a given case of colon cancer depend on the molecular progression of the disease.
Identification of additional genes associated with colon cancer and the precancerous state would provide more reliable diagnostic patterns associated with the development and progression of the disease.
The present invention provides for a composition comprising a plurality of cDNAs for use in detecting changes in expression of genes encoding proteins associated with colon cancer. Such a composition satisfies a need in the art by providing a set of differentially expressed genes which may be used entirely or in part in the diagnosis, prognosis or treatment of colon cancer.
Colon cancer evolves through a multi-step process whereby pre-malignant colonocytes undergo a relatively defined sequence of events leading to tumor formation.
Several factors participate in the process of tumor progression and malignant transformation including genetic factors, mutations, and selection. Despite efforts to characterize the molecular events leading to colon cancer, the process of tumor development and progression has not been delineated. To identify genes differentially expressed in colon cancer, gene expression patterns in normal and tumor tissues were compared. Matched normal and tumor samples from the same individual were compared by competitive hybridization. This process eliminates some of the individual variation due to genetic background, and enhances differences due to the disease process.
The C3A line is a clonal derivative of the Hep G2 hepatoma cell line isolated from a 15-year old male with liver tumor, which was selected for its strong contact inhibition of growth. The use of a clonal population enhances the reproducibility of the cells. The C3A line expresses insulin receptor and insulin-like growth factor II receptor. Progesterone is a naturally-occurring progestin. In the body, it is synthesized in the ovaries, testes, placenta, and adrenal cortex.
Beclomethasone is a synthetic glucocorticoid that is used for treating steroid-dependent asthma, relieving symptoms associated with allergic or nonallergic (vasomotor) rhinitis, or for preventing recurrent nasal polyps following surgical removal. The anti-inflammatory and vasoconstrictive effects of intranasal beclomethasone are 5,000 times greater than those produced by hydrocortisone.
Glucocorticoids are naturally-occurring hormones that prevent or suppress inflammation and immune responses when administered at pharmacological doses. At the molecular level, unbound glucocorticoids readily cross cell membranes and bind with high affinity to specific cytoplasmic receptors. Subsequent to binding, transcription and, ultimately, protein synthesis are affected.
Medroxypro~esterone (MAH) is a synthetic progestin with a pharmacological activity about 15 times greater than progesterone.
Budesonide (Bude) is a corticosteroid used to control symptoms associated with allergic rhinitis or asthma. Budesonide has high topical anti-inflammatory activity but low systemic activity.
Prednisone is a corticosteroid that is metabolized in the liver to its active form, prednisolone.
Prednisone is approximately four times more potent as a glucocorticoid than hydrocortisone.
Prednisone is intermediate between hydrocortisone and dexamethasone in duration of action.
Dexamethasone (DEX) is a synthetic glucocorticoid used as an anti-inflammatory or immunosuppressive agent. Due to its greater ability to reach the central nervous system, DEX is approximately 20-30 times more potent than hydrocortisone and 5-7 time more potent than prednisone. Lastly, betamethasone is a synthetic glucocorticoid used as an anti-inflammatory or immunosuppressive agent.
Osteosarcoma Osteosarcoma is the most common malignant bone tumor in children.
Approximately 30-40% of patients with non-metastatic disease relapse following therapy.
Currently, there is no prognostic factor that can be used at the time of initial diagnosis to predict which patients will have a high risk of relapse.
Alzheimer's Disease Alzheimer's disease is a progressive neurodegenerative disorder that is characterized by the formation of senile plaques and neurofibrillary tangles containing amyloid beta peptide. These plaques are found in limbic and association cortices of the brain. The hippocampus is part of the limbic system and plays an important role in learning and memory. In subjects with Alzheimer's disease, accumulating plaques damage the neuronal architecture in limbic areas and eventually cripple the memory process. Approximately twenty million people worldwide suffer with dementia that results from Alzheimer's disease. The disease can affect individuals as young as 30 years of age.
It can be familial or sporadic. Familial Alzheimer's disease was once thought to be strictly an autosomal dominant trait, but this view is changing as more genetic determinants are isolated. For example, some normal allelic variants of apolipoprotein E (ApoE), which is found in senile plaques, can either protect against, or increase the risk of, the disease (Strittmatter et al. ( 1993) Proc Natl Acad Sci 90:1977-1981).
Mutations in four genes predispose an individual to Alzheimer's disease: ApoE, amyloid precursor protein (APP), presenilin-1, and presenilin-2 (Selkoe (1999) Nature 399:A23-A31). The e4 allele of the ApoE gene confers increased risk for late onset Alzheimer's disease. (3-amyloid protein (A(3) is the major component of senile plaques, and it is normally formed when (3- and y- secretases cleave APP. In Alzheimer's disease patients, large quantities of A~i are generated and accumulate extracellularly in these neuropathological plaques. Efforts to understand the mechanism underlying A(3 deposition have recently focused on the APP-cleaving secretases. Two yeast aspartyl proteases have been shown to process APP in vitro (Zhang et al. ( 1997) Biochim Biophys Acta 1359:110-122).
The secretases are intramembrane-cleaving aspartyl proteases (Wolfe et al.
(1999) Biochemistry 38:4720-4727). The presenilin-1 gene is a candidate for the y-secretase that cleaves the APP carboxyl terminus. Presenilin can be coimmunoprecipitated with APP, and mutations in the presenilin genes increase production of the 42-amino acid peptide form of A(3. These missense point mutations result in a particularly aggressive, early onset form of the disease (Haas and DeStrooper ( 1999) Science 286:916-919).
The proteases BACE1 and BACE2 (~3-site APP cleaving enzymes 1 and 2), which appear to be (3-secretases, are potential therapeutic targets because of their ability to cleave APP. BACEl is an aspartyl protease with ~i-secretase activity which cleaves APP to produce A(3 peptide in vitro (Vasser et al. (1999) Science 286:735-741). It is expressed at moderate levels across all brain regions and is concentrated in neurons but not in glia. BACE2 has 52% amino acid identity with BACE1 (Saunders et al. (1999) Science 286:1255a). Whereas BACE1 maps to the long arm of chromosome 11, BACE2 maps to the Down syndrome region of chromosome 21 (Acquati et al. (2000) 468: 59-64;
Saunders et al. sera). Middle-aged Down syndrome patients have enhanced (3-amyloid deposits.
The amino terminals of A(3 peptides appear to be cleaved heterogeneously, indicating that there may be several (3-secretases involved in APP processing (Vasser (1999) Science 286:735-741).
Associations between Alzheimer's disease and many other genes and proteins have been reported. Fetal Alzheimer antigen (FALZ) and synuclein a (SNCA) are found in brain plaques and tangles. Inheritance of some gene polymorphisms is also linked to increased risk of developing the disease. For example, a polymorphism in the gene encoding (32-macroglobulin, a protein that can act as a protease inhibitor, is associated with increased risk for developing a late-onset form of Alzheimer's disease.
Breast cancer Breast cancer is the most frequently diagnosed type of cancer in American women and the IS

second most frequent cause of cancer death. The lifetime risk of an American woman developing breast cancer is 1 in 8, and one-third of women diagnosed with breast cancer die of the disease. A
number of risk factors have been identified, including hormonal and genetic factors. One genetic defect associated with breast cancer results in a loss of heterozygosity (LOH) at multiple loci such as p53, Rb, BRCA1, and BRCA2. Another genetic defect is gene amplification involving genes such as c-myc and c-erbB2 (Her2-neu gene). Steroid and growth factor pathways are also altered in breast cancer, notably the estrogen, progesterone, and epidermal growth factor (EGF) pathways. Breast cancer evolves through a multi-step process whereby premalignant mammary epithelial cells undergo a relatively defined sequence of events leading to tumor formation. An early event in tumor development is ductal hyperplasia. Cells undergoing rapid neoplastic growth gradually progress to invasive carcinoma and become metastatic to the lung, bone, and potentially other organs. Variables that may influence the process of tumor progression and malignant transformation include genetic factors, environmental factors, growth factors, and hormones.
Lun cancer Lung cancer is the leading cause of cancer death for men and the second leading cause of cancer death for women in the U.S. Lung cancers are divided into four histopathologically distinct groups. Three groups (squamous cell carcinoma, adenocarcinoma, and large cell carcinoma) are classified as non-small cell lung cancers (NSCLCs). The fourth group of cancers is referred to as small cell lung cancer (SCLC). Deletions on chromosome 3 are common in this disease and are thought to indicate the presence of a tumor suppressor gene in this region.
Activating mutations in K-ras are commonly found in lung cancer and are the basis of one of the mouse models for the disease.
Ovarian cancer Ovarian cancer is the leading cause of death from a gynecologic cancer. The majority of ovarian cancers are derived from epithelial cells, and 70% of patients with epithelial ovarian cancers present with late-stage disease. As a result, the long-term survival rates for this disease is very low.
Identification of early-stage markers for ovarian cancer would significantly increase the survival rate.
Genetic variations involved in ovarian cancer development include mutation of p53 and microsatellite instability. Gene expression patterns likely vary when normal ovary is compared to ovarian tumors.
Prostate cancer As with most tumors, prostate cancer develops through a multistage progression ultimately resulting in an aggressive tumor phenotype. The initial step in tumor progression involves the hyperproliferation of normal luminal and/or basal epithelial cells. Androgen responsive cells become hyperplastic and evolve into early-stage tumors. Although early-stage tumors are often androgen sensitive and respond to androgen ablation, a population of androgen independent cells evolve from the hyperplastic population. These cells represent a more advanced form of prostate tumor that may become invasive and potentially become metastatic to the bone, brain, or lung.
A variety of genes may be differentially expressed during tumor progression. For example, loss of heterozygosity (LOH) is frequently observed on chromosome 8p in prostate cancer. Fluorescence in situ hybridization (FISH) revealed a deletion for at least 1 locus on 8p in 29 (69%) tumors, with a significantly higher frequency of the deletion on 8p21.2-p21.1 in advanced prostate cancer than in localized prostate cancer, implying that deletions on 8p22-p21.3 play an important role in tumor differentiation, while 8p21.2-p2l.l deletion plays a role in progression of prostate cancer (Oba, K. et al. (2001) Cancer Genet. Cytogenet. 124: 20-26).
Osteoarthritis Osteoarthritis (OA) is a debilitating joint disease involving focal cartilage loss. Several studies indicate a major genetic component can be involved in causing OA.
Estimates of inheritability from twin studies of radiographic OA of the hand, knee and hip range from 36% to 68%
(MacGregor, A.J. and Spector, T.D. ( 1999) Rheumatology 38:583-560). Several interleukin and interleukin-associated genes are located at 2q 12-q22 (Leppavouri, J. et al. ( 1999) Am. J. Hum. Genet.
65:1060-1067). Interleukins regulate a number of enzymes that degrade the cartilage extracellular matrix, and the expression of certain interleukin genes, including IL-1(3, is altered in OA joint tissue (Elson, C.J. et al. (1998) Br. J. Rheum. 37:106-107.
There is a need in the art for new compositions, including nucleic acids and proteins, for the diagnosis, prevention, and treatment of cell proliferative disorders, viral infections, neurological disorders, and heart and skeletal muscle disorders.
SUMMARY OF THE INVENTION
Various embodiments of the invention provide purified polypeptides, structural and cytoskeleton-associated proteins, referred to collectively as 'SCAP' and individually as 'SCAP-1,' 'SCAP-2,' 'SCAP-3,' 'SCAP-4,' 'SCAP-5,' 'SCAP-6,' 'SCAP-7,' 'SCAP-8,' 'SCAP-9,' 'SCAP-10,' 'SCAP-11,' 'SCAP-12,' 'SCAP-13,' 'SCAP-14,' 'SCAP-15,' 'SCAP-16,' 'SCAP-17,' 'SCAP-18,' 'SCAP-19,' 'SCAP-20,' 'SCAP-21,' 'SCAP-22,' 'SCAP-23,' 'SCAP-24,' 'SCAP-25,' 'SCAP-26,' 'SCAP-27,' 'SCAP-28,' 'SCAP-29,' 'SCAP-30,' 'SCAP-31,' 'SCAP-32,' 'SCAP-33,' 'SCAP-34,' 'SCAP-35,' 'SCAP-36,' 'SCAP-37,' 'SCAP-38,' 'SCAP-39,' 'SCAP-40,' 'SCAP-41,' 'SCAP-42,' 'SCAP-43,' 'SCAP-44,' 'SCAP-45,' 'SCAP-46,' 'SCAP-47,' 'SCAP-48,' 'SCAP-49,' 'SCAP-50,' and 'SCAP-51' and methods for using these proteins and their encoding polynucleotides for the detection, diagnosis, and treatment of diseases and medical conditions.
Embodiments also provide methods for utilizing the purified structural and cytoskeleton-associated proteins and/or their encoding polynucleotides for facilitating the drug discovery process, including determination of 1~

efficacy, dosage, toxicity, and pharmacology. Related embodiments provide methods for utilizing the purified structural and cytoskeleton-associated proteins and/or their encoding polynucleotides for investigating the pathogenesis of diseases and medical conditions.
An embodiment provides an isolated polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-51, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical or at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ ID
NO:1-51, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-51, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID
NO:1-51. Another embodiment provides an isolated polypeptide comprising an amino acid sequence of SEQ ID NO:1-51. .
Still another embodiment provides an isolated polynucleotide encoding a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ )D NO:1-51, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical or at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ >D NO:1-51, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ >D NO:1-51, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ >D NO:1-51. In another embodiment, the polynucleotide encodes a polypeptide selected from the group consisting of SEQ ID NO:1-51. In an alternative embodiment, the polynucleotide is selected from the group consisting of SEQ ID N0:52-102.
Still another embodiment provides a recombinant polynucleotide comprising a promoter sequence operably linked to a polynucleotide encoding a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ll~ NO:1-51, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical or at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-51, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ )D NO:1-51, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ
ID NO:1-51. Another embodiment provides a cell transformed with the recombinant polynucleotide.
Yet another embodiment provides a transgenic organism comprising the recombinant polynucleotide.
Another embodiment provides a method for producing a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-51, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical or at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-51, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-51, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ
>D NO:1-51. The method comprises a) culturing a cell under conditions suitable for expression of the polypeptide, wherein said cell is transformed with a recombinant polynucleotide comprising a promoter sequence operably linked to a polynucleotide encoding the polypeptide, and b) recovering the polypeptide so expressed.
Yet another embodiment provides an isolated antibody which specifically binds to a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-51, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical or at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-51, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ
ID NO:1-51, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-51.
Still yet another embodiment provides an isolated polynucleotide selected from the group consisting of a) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID N0:52-102, b) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 90% identical or at least about 90% identical to a polynucleotide sequence selected from the group consisting of SEQ ID N0:52-102, c) a polynucleotide complementary to the polynucleotide of a), d) a polynucleotide complementary to the polynucleotide of b), and e) an RNA equivalent of a)-d). In other embodiments, the polynucleotide can comprise at least about 20, 30, 40, 60, 80, or 100 contiguous nucleotides.
Yet another embodiment provides a method for detecting a target polynucleotide in a sample, said target polynucleotide being selected from the group consisting of a) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID N0:52-102, b) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 90% identical or at least about 90% identical to a polynucleotide sequence selected from the group consisting of SEQ ID
N0:52-102, c) a polynucleotide complementary to the polynucleotide of a), d) a polynucleotide complementary to the polynucleotide of b), and e) an RNA equivalent of a)-d).
The method comprises a) hybridizing the sample with a probe comprising at least 20 contiguous nucleotides comprising a sequence complementary to said target polynucleotide in the sample, and which probe specifically hybridizes to said target polynucleotide, under conditions whereby a hybridization complex is formed between said probe and said target polynucleotide or fragments thereof, and b) detecting the presence or absence of said hybridization complex. In a related embodiment, the method can include detecting the amount of the hybridization complex. In still other embodiments, the probe can comprise at least about 20, 30, 40, 60, 80, or 100 contiguous nucleotides.
Still yet another embodiment provides a method for detecting a target polynucleotide in a sample, said target polynucleotide being selected from the group consisting of a) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ
)D N0:52-102, b) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 90% identical or at least about 90% identical to a polynucleotide sequence selected from the group consisting of SEQ >D
N0:52-102, c) a polynucleotide complementary to the polynucleotide of a), d) a polynucleotide complementary to the polynucleotide of b), and e) an RNA equivalent of a)-d).
The method comprises a) amplifying said target polynucleotide or fragment thereof using polymerase chain reaction amplification, and b) detecting the presence or absence of said amplified target polynucleotide or fragment thereof. In a related embodiment, the method can include detecting the amount of the amplified target polynucleotide or fragment thereof.
Another embodiment provides a composition comprising an effective amount of a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-51, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical or at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ )D NO:1-51, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ
)D NO: l-51, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-51, and a pharmaceutically acceptable excipient.
In one embodiment, the composition can comprise an amino acid sequence selected from the group consisting of SEQ ID NO:1-51. Other embodiments provide a method of treating a disease or condition associated with decreased or abnormal expression of functional SCAP, comprising administering to a patient in need of such treatment the composition.
Yet another embodiment provides a method for screening a compound for effectiveness as an agonist of a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-51, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical or at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ >D NO:1-51, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ
ID NO:1-51, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ >D NO:1-51. The method comprises a) exposing a sample comprising the polypeptide to a compound, and b) detecting agonist activity in the sample. Another embodiment provides a composition comprising an agonist compound identified by the method and a pharmaceutically acceptable excipient. Yet another embodiment provides a method of treating a disease or condition associated with decreased expression of functional SCAP, comprising administering to a patient in need of such treatment the composition.
Still yet another embodiment provides a method for screening a compound for effectiveness as an antagonist of a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ 1D NO:1-51, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical or at least about 90%
identical to an amino acid sequence selected from the group consisting of SEQ
>D NO:1-51, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ >D NO:1-51, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-51. The method comprises a) exposing a sample comprising the polypeptide to a compound, and b) detecting antagonist activity in the sample. Another embodiment provides a composition comprising an antagonist compound identified by the method and a pharmaceutically acceptable excipient. Yet another embodiment provides a method of treating a disease or condition associated with overexpression of functional SCAP, comprising administering to a patient in need of such treatment the composition.
Another embodiment provides a method of screening for a compound that specifically binds to a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ >D NO:1-51, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical or at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ 1D NO:1-51, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ
)17 NO:1-51, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ff~ NO:1-51. The method comprises a) combining the polypeptide with at least one test compound under suitable conditions, and b) detecting binding of the polypeptide to the test compound, thereby identifying a compound that specifically binds to the polypeptide.
Yet another embodiment provides a method of screening for a compound that modulates the activity of a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ )D NO:1-51, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical or at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ >D NO:1-51, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ
ID NO:1-51, and d) an immunogenic fragment of a polypeptide having an amino acid sequence 2l selected from the group consisting of SEQ )D NO:1-51. The method comprises a) combining the polypeptide with at least one test compound under conditions permissive for the activity of the polypeptide, b) assessing the activity of the polypeptide in the presence of the test compound, and c) comparing the activity of the polypeptide in the presence of the test compound with the activity of the polypeptide in the absence of the test compound, wherein a change in the activity of the polypeptide in the presence of the test compound is indicative of a compound that modulates the activity of the polypeptide.
Still yet another embodiment provides a method for screening a compound for effectiveness in altering expression of a target polynucleotide, wherein said target polynucleotide comprises a polynucleotide sequence selected from the group consisting of SEQ >D N0:52-102, the method comprising a) exposing a sample comprising the target polynucleotide to a compound, b) detecting altered expression of the target polynucleotide, and c) comparing the expression of the target polynucleotide in the presence of varying amounts of the compound and in the absence of the compound.
Another embodiment provides a method for assessing toxicity of a test compound, said method comprising a) treating a biological sample containing nucleic acids with the test compound;
b) hybridizing the nucleic acids of the treated biological sample with a probe comprising at least 20 contiguous nucleotides of a polynucleotide selected from the group consisting of i) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ
ID N0:52-102, ii) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 90% identical or at least about 90% identical to a polynucleotide sequence selected from the group consisting of SEQ >D
N0:52-102, iii) a polynucleotide having a sequence complementary to i)> iv) a polynucleotide complementary to the polynucleotide of ii), and v) an RNA equivalent of i)-iv). Hybridization occurs under conditions whereby a specific hybridization complex is formed between said probe and a target polynucleotide in the biological sample, said target polynucleotide selected from the group consisting of i) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID N0:52-102, ii) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 90% identical or at least about 90% identical to a polynucleotide sequence selected from the group consisting of SEQ ID N0:52-102, iii) a polynucleotide complementary to the polynucleotide of i)> iv) a polynucleotide complementary to the polynucleotide of ii), and v) an RNA equivalent of i)-iv). Alternatively, the target polynucleotide can comprise a fragment of a polynucleotide selected from the group consisting of i)-v) above; c) quantifying the amount of hybridization complex; and d) comparing the amount of hybridization complex in the treated biological sample with the amount of hybridization complex in an untreated biological sample, wherein a difference in the amount of hybridization complex in the treated biological sample is indicative of toxicity of the test compound.

BRIEF DESCRIPTION OF THE TABLES
Table 1 summarizes the nomenclature for full length polynucleotide and polypeptide embodiments of the invention.
Table 2 shows the GenBank identification number and annotation of the nearest GenBank homolog, and the PROTEOME database identification numbers and annotations of PROTEOME
database homologs, for polypeptide embodiments of the invention. The probability scores for the matches between each polypeptide and its homolog(s) are also shown.
Table 3 shows structural features of polypeptide embodiments, including predicted motifs and domains, along with the methods, algorithms, and searchable databases used for analysis of the polypeptides.
Table 4 lists the cDNA and/or genomic DNA fragments which were used to assemble polynucleotide embodiments, along with selected fragments of the polynucleotides.
Table 5 shows representative cDNA libraries for polynucleotide embodiments.
Table G provides an appendix which describes the tissues and vectors used for construction of the cDNA libraries shown in Table 5.
Table 7 shows the tools, programs, and algorithms used to analyze polynucleotides and polypeptides, along with applicable descriptions, references, and threshold parameters.
Table 8 shows single nucleotide polymorphisms found in polynucleotide sequences of the invention, along with allele frequencies in different human populations.
DESCRIPTION OF THE INVENTION
Before the present proteins, nucleic acids, and methods are described, it is understood that embodiments of the invention are not limited to the particular machines, instruments, materials, and methods described, as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the invention.
As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to "a host cell" includes a plurality of such host cells, and a reference to "an antibody" is a reference to one or more antibodies and equivalents thereof known to those skilled in the art, and so forth.
Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs.
Although any machines, materials, and methods similar or equivalent to those described herein can be used to practice or test the present invention, the preferred machines, materials and methods are now described. All publications mentioned herein are cited for the purpose of describing and disclosing the cell lines, protocols, reagents and vectors which are reported in the publications and which might be used in connection with various embodiments of the invention. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.
DEFINITIONS
"SOAP" refers to the amino acid sequences of substantially purified SCAP
obtained from any species, particularly a mammalian species, including bovine, ovine, porcine, murine, equine, and human, and from any source, whether natural, synthetic, semi-synthetic, or recombinant.
The term "agonist" refers to a molecule which intensifies or mimics the biological activity of SCAP. Agonists may include proteins, nucleic acids, carbohydrates, small molecules, or any other compound or composition which modulates the activity of SCAP either by directly interacting with SCAP or by acting on components of the biological pathway in which SCAP
participates.
An "allelic variant" is an alternative form of the gene encoding SCAP. Allelic variants may result from at least one mutation in the nucleic acid sequence and may result in altered mRNAs or in polypeptides whose structure or function may or may not be altered. A gene may have none, one, or many allelic variants of its naturally occurring form. Common mutational changes which give rise to allelic variants are generally ascribed to natural deletions, additions, or substitutions of nucleotides.
Each of these types of changes may occur alone, or in combination with the others, one or more times in a given sequence.
"Altered" nucleic acid sequences encoding SCAP include those sequences with deletions, insertions, or substitutions of different nucleotides, resulting in a polypeptide the same as SCAP or a polypeptide with at least one functional characteristic of SCAP. Included within this definition are polymorphisms which may or may not be readily detectable using a particular oligonucleotide probe of the polynucleotide encoding SCAP, and improper or unexpected hybridization to allelic variants, with a locus other than the normal chromosomal locus for the polynucleotide encoding SCAP. The encoded protein may also be "altered," and may contain deletions, insertions, or substitutions of amino acid residues which produce a silent change and result in a functionally equivalent SCAP.
Deliberate amino acid substitutions may be made on the basis of one or more similarities in polarity, charge, solubility, hydrophobicity, hydrophilicity, and/or the amphipathic nature of the residues, as long as the biological or immunological activity of SCAP is retained. For example, negatively charged amino acids may include aspartic acid and glutamic acid, and positively charged amino acids may include lysine and arginine. Amino acids with uncharged polar side chains having similar hydrophilicity values may include: asparagine and glutamine; and serine and threonine. Amino acids with uncharged side chains having similar hydrophilicity values may include:
leucine, isoleucine, and valine; glycine and alanine; and phenylalanine and tyrosine.
The terms "amino acid" and "amino acid sequence" can refer to an oligopeptide, a peptide, a polypeptide, or a protein sequence, or a fragment of any of these, and to naturally occurring or synthetic molecules. Where "amino acid sequence" is recited to refer to a sequence of a naturally occurring protein molecule, "amino acid sequence" and like terms are not meant to limit the amino acid sequence to the complete native amino acid sequence associated with the recited protein molecule.
"Amplification" relates to the production of additional copies of a nucleic acid.
Amplification may be carried out using polymerase chain reaction (PCR) technologies or other nucleic acid amplification technologies well known in the art.
The term "antagonist" refers to a molecule which inhibits or attenuates the biological activity of SCAP. Antagonists may include proteins such as antibodies, anticalins, nucleic acids, carbohydrates, small molecules, or any other compound or composition which modulates the activity of SCAP either by directly interacting with SCAP or by acting on components of the biological pathway in which SCAP participates.
The term "antibody" refers to intact immunoglobulin molecules as well as to fragments thereof, such as Fab, F(ab')Z, and Fv fragments, which are capable of binding an epitopic determinant.
Antibodies that bind SCAP polypeptides can be prepared using intact polypeptides or using fragments containing small peptides of interest as the immunizing antigen. The polypeptide or oligopeptide used to immunize an animal (e.g., a mouse, a rat, or a rabbit) can be derived from the translation of RNA, or synthesized chemically, and can be conjugated to a carrier protein if desired. Commonly used carriers that are chemically coupled to peptides include bovine serum albumin, thyroglobulin, and keyhole limpet hemocyanin (KLH). The coupled peptide is then used to immunize the animal.
The term "antigenic determinant" refers to that region of a molecule (i.e., an epitope) that makes contact with a particular antibody. When a protein or a fragment of a protein is used to immunize a host animal, numerous regions of the protein may induce the production of antibodies which bind specifically to antigenic determinants (particular regions or three-dimensional structures on the protein). An antigenic determinant may compete with the intact antigen (i.e., the immunogen used to elicit the immune response) for binding to an antibody.
The term "aptamer" refers to a nucleic acid or oligon~cleotide molecule that binds to a specific molecular target. Aptamers are derived from an in vitro evolutionary process (e.g., SELEX
(Systematic Evolution of Ligands by EXponential Enrichment), described in U.S.
Patent No.
5,270,163), which selects for target-specific aptamer sequences from large combinatorial libraries.
Aptamer compositions may be double-stranded or single-stranded, and may include deoxyribonucleotides, ribonucleotides, nucleotide derivatives, or other nucleotide-like molecules.

The nucleotide components of an aptamer may have modified sugar groups (e.g., the 2'-OH group of a ribonucleotide may be replaced by 2'-F or 2'-NHZ), which may improve a desired property, e.g., resistance to nucleases or longer lifetime in blood. Aptamers may be conjugated to other molecules, e.g., a high molecular weight carrier to slow clearance of the aptamer from the circulatory system.
Aptamers may be specifically cross-linked to their cognate ligands, e.g., by photo-activation of a cross-linker (Brody, E.N. and L. Gold (2000) J. Biotechnol. 74:5-13).
The term "intramer" refers to an aptamer which is expressed in vivo. For example, a vaccinia virus-based RNA expression system has been used to express specific RNA
aptamers at high levels in the cytoplasm of leukocytes (Blind, M. et al. (1999) Proc. Natl. Acad. Sci.
USA 96:3606-3610).
The term "spiegelmer" refers to an aptamer which includes L-DNA, L-RNA, or other left-handed nucleotide derivatives or nucleotide-like molecules. Aptamers containing left-handed nucleotides are resistant to degradation by naturally occurring enzymes, which normally act on substrates containing right-handed nucleotides.
The term "antisense" refers to any composition capable of base-pairing with the "sense"
(coding) strand of a polynucleotide having a specific nucleic acid sequence.
Antisense compositions may include DNA; RNA; peptide nucleic acid (PNA); oligonucleotides having modified backbone linkages such as phosphorothioates, methylphosphonates, or benzylphosphonates;
oligonucleotides having modified sugar groups such as 2'-methoxyethyl sugars or 2'-methoxyethoxy sugars; or oligonucleotides having modified bases such as 5-methyl cytosine, 2'-deoxyuracil, or 7-deaza-2'-deoxyguanosine. Antisense molecules may be produced by any method including chemical synthesis or transcription. Once introduced into a cell, the complementary antisense molecule base-pairs with a naturally occurring nucleic acid sequence produced by the cell to form duplexes which block either transcription or translation. The designation "negative" or "minus" can refer to the antisense strand, and the designation "positive" or "plus" can refer to the sense strand of a reference DNA molecule.
The term "biologically active" refers to a protein having structural, regulatory, or biochemical functions of a naturally occurring molecule. Likewise, "immunologically active" or "immunogenic"
refers to the capability of the natural, recombinant, or synthetic SCAP, or of any oligopeptide thereof, to induce a specific immune response in appropriate animals or cells and to bind with specific antibodies.
"Complementary" describes the relationship between two single-stranded nucleic acid sequences that anneal by base-pairing. For example, 5'-AGT-3' pairs with its complement, 3'-TCA-5'.
A "composition comprising a given polynucleotide" and a "composition comprising a given polypeptide" can refer to any composition containing the given polynucleotide or polypeptide.. The composition may comprise a dry formulation or an aqueous solution.
Compositions comprising polynucleotides encoding SCAP or fragments of SCAP may be employed as hybridization probes.
The probes may be stored in freeze-dried form and may be associated with a stabilizing agent such as a carbohydrate. In hybridizations, the probe may be deployed in an aqueous solution containing salts (e.g., NaCI), detergents (e.g., sodium dodecyl sulfate; SDS), and other components (e.g., Denhardt's solution, dry milk, salmon sperm DNA, etc.).
"Consensus sequence" refers to a nucleic acid sequence which has been subjected to repeated DNA sequence analysis to resolve uncalled bases, extended using the XL-PCR kit (Applied Biosystems, Foster City CA) in the 5' and/or the 3' direction, and resequenced, or which has been assembled from one or more overlapping cDNA, EST, or genomic DNA fragments using a computer program for fragment assembly, such as the GELVIEW fragment assembly system (Accelrys, Burlington MA) or Phrap (University of Washington, Seattle WA). Some sequences have been both extended and assembled to produce the consensus sequence.
"Conservative amino acid substitutions" are those substitutions that are predicted to least interfere with the properties of the original protein, i.e., the structure and especially the function of the protein is conserved and not significantly changed by such substitutions.
The table below shows amino acids which may be substituted for an original amino acid in a protein and which are regarded as conservative amino acid substitutions.
Original Residue Conservative Substitution Ala Gly, Ser Arg His, Lys Asn Asp, Gln, His Asp Asn, Glu Cys Ala, Ser Gln Asn, Glu, His Glu Asp, Gln, His Gly Ala His Asn, Arg, Gln, Glu Ile Leu, Val Leu Ile, Val Lys Arg, Gln, Glu Met Leu, Ile Phe His, Met, Leu, Trp, Tyr Ser Cys, Thr Thr Ser, Val Trp Phe, Tyr Tyr His, Phe, Trp Val Ile, Leu, Thr Conservative amino acid substitutions generally maintain (a) the structure of the polypeptide backbone in the area of the substitution, for example, as a beta sheet or alpha helical conformation, (b) the charge or hydrophobicity of the molecule at the site of the substitution, and/or (c) the bulk of the side chain.

A "deletion" refers to a change in the amino acid or nucleotide sequence that results in the absence of one or more amino acid residues or nucleotides.
The term "derivative" refers to a chemically modified polynucleotide or polypeptide.
Chemical modifications of a polynucleotide can include, for example, replacement of hydrogen by an alkyl, acyl, hydroxyl, or amino group. A derivative polynucleotide encodes a polypeptide which retains at least one biological or immunological function of the natural molecule. A derivative polypeptide is one modified by glycosylation, pegylation, or any similar process that'retains at least one biological or immunological function of the polypeptide from which it was derived.
A "detectable label" refers to a reporter molecule or enzyme that is capable of generating a measurable signal and is covalently or noncovalently joined to a polynucleotide or polypeptide.
"Differential expression" refers to increased or upregulated; or decreased, downregulated, or absent gene or protein expression, determined by comparing at least two different samples. Such comparisons may be carried out between, for example, a treated and an untreated sample, or a diseased and a normal sample.
"Exon shuffling" refers to the recombination of different coding regions (exons). Since an exon may represent a structural or functional domain of the encoded protein, new proteins may be assembled through the novel reassortment of stable substructures, thus allowing acceleration of the evolution of new protein functions.
A "fragment" is a unique portion of SCAP or a polynucleotide encoding SCAP
which can be identical in sequence to, but shorter in length than, the parent sequence. A
fragment may comprise up to the entire length of the defined sequence, minus one nucleotide/amino acid residue. For example, a fragment may comprise from about 5 to about 1000 contiguous nucleotides or amino acid residues. A
fragment used as a probe, primer, antigen, therapeutic molecule, or for other purposes, may be at least 5, 10, 15, 16, 20, 25, 30, 40, 50, 60, 75, 100, 150, 250 or at least 500 contiguous nucleotides or amino acid residues in length. Fragments may be preferentially selected from certain regions of a molecule.
For example, a polypeptide fragment may comprise a certain length of contiguous amino acids selected from the first 250 or S00 amino acids (or first 25% or 50%) of a polypeptide as shown in a certain defined sequence. Clearly these lengths are exemplary, and any length that is supported by the specification, including the Sequence Listing, tables, and figures, may be encompassed by the present embodiments.
A fragment of SEQ ID N0:52-102 can comprise a region of unique polynucleotide sequence that specifically identifies SEQ >D N0:52-102, for example, as distinct from any other sequence in the genome from which the fragment was obtained. A fragment of SEQ m N0:52-102 can be employed in one or more embodiments of methods of the invention, for example, in hybridization and amplification technologies and in analogous methods that distinguish SEQ 1D
N0:52-102 from 2s related polynucleotides. The precise length of a fragment of SEQ ~ N0:52-102 and the region of SEQ ID N0:52-102 to which the fragment corresponds are routinely determinable by one of ordinary skill in the art based on the intended purpose for the fragment.
A fragment of SEQ ll~ NO:1-51 is encoded by a fragment of SEQ >D N0:52-102. A
fragment of SEQ ID NO:1-51 can comprise a region of unique amino acid sequence that specifically identifies SEQ ID NO:1-51. For example, a fragment of SEQ 1D NO:1-51 can be used as an immunogenic peptide for the development of antibodies that specifically recognize SEQ ID NO:1-51.
The precise length of a fragment of SEQ )D NO:1-51 and the region of SEQ ID
NO:1-51 to which the fragment corresponds can be determined based on the intended purpose for the fragment using one or more analytical methods described herein or otherwise known in the art.
A "full length" polynucleotide is one containing at least a translation initiation codon (e.g., methionine) followed by an open reading frame and a translation termination codon. A "full length"
polynucleotide sequence encodes a "full length" pol.ypeptide sequence.
"Homology" refers to sequence similarity or, alternatively, sequence identity, between two or more polynucleotide sequences or two or more polypeptide sequences.
The terms "percent identity" and "% identity," as applied to polynucleotide sequences, refer to the percentage of identical residue matches between at least two polynucleotide sequences aligned using a standardized algorithm. Such an algorithm may insert, in a standardized and reproducible way, gaps in the sequences being compared in order to optimize alignment between two sequences, and therefore achieve a more meaningful comparison of the two sequences.
Percent identity between polynucleotide sequences may be determined using one or more computer algorithms or programs known in the art or described herein. For example, percent identity can be determined using the default parameters of the CLUSTAL V algorithm as incorporated into the MEGALIGN version 3.12e sequence alignment program. This program is part of the LASERGENE software package, a suite of molecular biological analysis programs (DNASTAR, Madison WI). CLUSTAL V is described in Higgins, D.G. and P.M. Sharp (1989;
CABIOS 5:151-153) and in Higgins, D.G. et al. (1992; CABIOS 8:189-191). For pairwise alignments of polynucleotide sequences, the default parameters are set as follows: Ktuple=2, gap penalty=5, window=4, and "diagonals saved"=4. The "weighted" residue weight table is selected as the default.
Alternatively, a suite of commonly used and freely available sequence comparison algorithms which can be used is provided by the National Center for Biotechnology Information (NCBI) Basic Local Alignment Search Tool (BLAST) (Altschul, S.F. et al. (1990) J. Mol.
Biol. 215:403-410), which is available from several sources, including the NCBI, Bethesda, MD, and on the Internet at http://www.ncbi.nlm.nih.govBLAST/. The BLAST software suite includes various sequence analysis programs including "blastn," that is used to align a known polynucleotide sequence with other polynucleotide sequences from a variety of databases. Also available is a tool called "BLAST 2 Sequences" that is used for direct pairwise comparison of two nucleotide sequences. "BLAST 2 Sequences" can be accessed and used interactively at http://www.ncbi.nlm.nih.gov/gorf/bl2.html.
The "BLAST 2 Sequences" tool can be used for both blastn and blastp (discussed below). BLAST
programs are commonly used with gap and other parameters set to default settings. For example, to compare two nucleotide sequences, one may use blastn with the "BLAST 2 Sequences" tool Version 2Ø12 (April-21-2000) set at default parameters. Such default parameters may be, for example:
Matrix: BLOSUM62 Reward for match: 1 Penalty for mismatch: -2 Open Cap: 5 and Extension Gap: 2 penalties Gap x drop-off.' S0 Expect: 10 Word Size: I1 Filter: on Percent identity may be measured over the length of an entire defined sequence, for example, as defined by a particular SEQ ID number, or may be measured over a shorter length, for example, over the length of a fragment taken from a larger, defined sequence, for instance, a fragment of at least 20, at least 30, at least 40, at least 50, at least 70, at least 100, or at least 200 contiguous nucleotides. Such lengths are exemplary only, and it is understood that any fragment length supported by the sequences shown herein, in the tables, figures, or Sequence Listing, may be used to describe a length over which percentage identity may be measured.
Nucleic acid sequences that do not show a high degree of identity may nevertheless encode similar amino acid sequences due to the degeneracy of the genetic code. It is understood that changes in a nucleic acid sequence can be made using this degeneracy to produce multiple nucleic acid sequences that all encode substantially the same protein.
The phrases "percent identity" and "% identity," as applied to polypeptide sequences, refer to the percentage of identical residue matches between at least two polypeptide sequences aligned using a standardized algorithm. Methods of polypeptide sequence alignment are well-known. Some alignment methods take into account conservative amino acid substitutions.
Such conservative substitutions, explained in more detail above, generally preserve the charge and hydrophobicity at the site of substitution, thus preserving the structure (and therefore function) of the polypeptide. The phrases "percent similarity" and "% similarity," as applied to polypeptide sequences, refer to the percentage of residue matches, including identical residue matches and conservative substitutions, between at least two polypeptide sequences aligned using a standardized algorithm. In contrast, conservative substitutions are not included in the calculation of percent identity between polypeptide sequences.
Percent identity between polypeptide sequences may be determined using the default parameters of the CLUSTAL V algorithm as incorporated into the MEGALIGN
version 3.12e sequence alignment program (described and referenced above). For pairwise alignments of polypeptide sequences using CLUSTAL V, the default parameters are set as follows: Ktuple=1, gap penalty=3, window=5, and "diagonals saved"=5. The PAM250 matrix is selected as the default residue weight table.
Alternatively the NCBI BLAST software suite may be used. For example, for a pairwise comparison of two polypeptide sequences, one may use the "BLAST 2 Sequences"
tool Version 2Ø12 (April-21-2000) with blastp set at default parameters. Such default parameters may be, for example:
Mcatrix: BLOSUM62 Open Gap: 11 and Extension Gap: I penalties Gap x drop-off. 50 Expect.' 10 Word Size: 3 Filter. on Percent identity may be measured over the length of an entire defined polypeptide sequence, for example, as defined by a particular SEQ ID number, or may be measured over a shorter length, for example, over the length of a fragment taken from a larger, defined polypeptide sequence, for instance, a fragment of at least 15, at least 20, at least 30, at least 40, at least S0, at least 70 or at least 150 contiguous residues. Such lengths are exemplary only, and it is understood that any fragment length supported by the sequences shown herein, in the tables, figures or Sequence Listing, may be used to describe a length over which percentage identity may be measured.
"Human artificial chromosomes" (HACs) are linear microchromosomes which may contain DNA sequences of about 6 kb to 10 Mb in size and which contain all of the elements required for chromosome replication, segregation and maintenance.
The term "humanized antibody" refers to an antibody molecule in which the amino acid sequence in the non-antigen binding regions has been altered so that the antibody more closely resembles a human antibody, and still retains its original binding ability.
"Hybridization" refers to the process by which a polynucleotide strand anneals with a complementary strand through base pairing under defined hybridization conditions. Specific hybridization is an indication that two nucleic acid sequences share a high degree of complementarity. Specific hybridization complexes form under permissive annealing conditions and remain hybridized after the "washing" step(s). The washing steps) is particularly important in determining the stringency of the hybridization process, with more stringent conditions allowing less non-specific binding, i.e., binding between pairs of nucleic acid strands that are not perfectly matched. Permissive conditions for annealing of nucleic acid sequences are routinely determinable by one of ordinary skill in the art and may be consistent among hybridization experiments, whereas wash conditions may be varied among experiments to achieve the desired stringency, and therefore hybridization specificity. Permissive annealing conditions occur, for example, at 68°C in the presence of about 6 x SSC, about 1% (w/v) SDS, and about 100 ~.g/ml sheared, denatured salmon sperm DNA.
Generally, stringency of hybridization is expressed, in part, with reference to the temperature under which the wash step is carried out. Such wash temperatures are typically selected to be about 5°C to 20°C lower than the thermal melting point (T",) for the specific sequence at a defined ionic strength and pH. The T", is the temperature (under defined ionic strength and pH) at which 50% of the target sequence hybridizes to a perfectly matched probe. An equation for calculating Tm and conditions for nucleic acid hybridization are well known and can be found in Sambrook, J. and D.W.
Russell (2001; Molecular Cloning: A Laboratory Manual, 3rd ed., vol. 1-3, Cold Spring Harbor Press, Cold Spring Harbor NY, ch. 9).
High stringency conditions for hybridization between polynucleotides of the present invention include wash conditions of 68°C in the presence of about 0.2 x SSC and about 0.1% SDS, for 1 hour. Alternatively, temperatures of about 65°C, 60°C, 55°C, or 42°C may be used. SSC
concentration may be varied from about 0.1 to 2 x SSC, with SDS being present at about 0.1%.
Typically, blocking reagents are used to block non-specific hybridization.
Such blocking reagents include, for instance, sheared and denatured salmon sperm DNA at about 100-200 p,g/ml. Organic solvent, such as formamide at a concentration of about 35-50% v/v, may also be used under particular circumstances, such as for RNA:DNA hybridizations. Useful variations on these wash conditions will be readily apparent to those of ordinary skill in the art. Hybridization, particularly under high stringency conditions, may be suggestive of evolutionary similarity between the nucleotides. Such similarity is strongly indicative of a similar role for the nucleotides and their encoded polypeptides.
The term "hybridization complex" refers to a complex formed between two nucleic acids by virtue of the formation of hydrogen bonds between complementary bases. A
hybridization complex may be formed in solution (e.g., Cot or Rot analysis) or formed between one nucleic acid present in solution and another nucleic acid immobilized on a solid support (e.g., paper, membranes, filters, chips, pins or glass slides, or any other appropriate substrate to which cells or their nucleic acids have been fixed).
The words "insertion" and "addition" refer to changes in an amino acid or polynucleotide sequence resulting in the addition of one or more amino acid residues or nucleotides, respectively.
"Immune response" can refer to conditions associated with inflammation, trauma, immune disorders, or infectious or genetic disease, etc. These conditions can be characterized by expression of various factors, e.g., cytokines, chemokines, and other signaling molecules, which may affect cellular and systemic defense systems.
An "immunogenic fragment" is a polypeptide or oligopeptide fragment of SCAP
which is capable of eliciting an immune response when introduced into a living organism, for example, a mammal. The term "immunogenic fragment" also includes any polypeptide or oligopeptide fragment of SCAP which is useful in any of the antibody production methods disclosed herein or known in the art.
The term "microarray" refers to an arrangement of a plurality of polynucleotides, polypeptides, antibodies, or other chemical compounds on a substrate.
The terms "element" and "array element" refer to a polynucleotide, polypeptide, antibody, or other chemical compound having a unique and defined position on a microarray.
The term "modulate" refers to a change in the activity of SCAP. For example, modulation may cause an increase or a decrease in protein activity, binding characteristics, or any other biological, functional, or immunological properties of SCAP.
The phrases "nucleic acid" and "nucleic acid sequence" refer to a nucleotide, oligonucleotide, polynucleotide, or any fragment thereof. These phrases also refer to DNA or RNA of genomic or synthetic origin which may be single-stranded or double-stranded and may represent the sense or the antisense strand, to peptide nucleic acid (PNA), or to any DNA-like or RNA-like material.
"Operably linked" refers to the situation in which a first nucleic acid sequence is placed in a functional relationship with a second nucleic acid sequence. For instance, a promoter is operably linked to a coding sequence if the promoter affects the transcription or expression of the coding sequence. Operably linked DNA sequences may be in close proximity or contiguous and, where necessary to join two protein coding regions, in the same reading frame.
"Peptide nucleic acid" (PNA) refers to an antisense molecule or anti-gene agent which comprises an oligonucleotide of at least about 5 nucleotides in length linked to a peptide backbone of amino acid residues ending in lysine. The terminal lysine confers solubility to the composition.
PNAs preferentially bind complementary single stranded DNA or RNA and stop transcript elongation, and may be pegylated to extend their lifespan in the cell.
"Post-translational modification" of an SCAP may involve lipidation, glycosylation, phosphorylation, acetylation, racemization, proteolytic cleavage, and other modifications known in the art. These processes may occur synthetically or biochemically. Biochemical modifications will vary by cell type depending on the enzymatic milieu of SCAP.

"Probe" refers to nucleic acids encoding SCAP, their complements, or fragments thereof, which are used to detect identical, allelic or related nucleic acids. Probes are isolated oligonucleotides or polynucleotides attached to a detectable label or reporter molecule. Typical labels include radioactive isotopes, ligands, chemiluminescent agents, and enzymes. "Primers" are short nucleic acids, usually DNA oligonucleotides, which may be annealed to a target polynucleotide by complementary base-pairing. The primer may then be extended along the target DNA strand by a DNA polymerise enzyme. Primer pairs can be used for amplification (and identification) of a nucleic acid, e.g., by the polymerise chain reaction (PCR).
Probes and primers as used in the present invention typically comprise at least 15 contiguous nucleotides of a known sequence. In order to enhance specificity, longer probes and primers may also be employed, such as probes and primers that comprise at least 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, or at least 150 consecutive nucleotides of the disclosed nucleic acid sequences. Probes and primers may be considerably longer than these examples, and it is understood that any length supported by the specification, including the tables, figures, and Sequence Listing, may be used.
Methods for preparing and using probes and primers are described in, for example, Sambrook, J. and D.W. Russell (2001; Molecular Clonin~~A Laboratory Manual, 3rd ed., vol. 1-3, Cold Spring Harbor Press, Cold Spring Harbor NY), Ausubel, F.M. et al. (1999;
Short Protocols in Molecular Biolo~y, 4''' ed., John Wiley & Sons, New York NY), and Innis, M. et al. (1990; PCR
Protocols, A Guide to Methods and Applications, Academic Press, San Diego CA).
PCR primer pairs can be derived from a known sequence, for example, by using computer programs intended for that purpose such as Primer (Version 0.5, 1991, Whitehead Institute for Biomedical Research, Cambridge MA).
Oligonucleotides for use as primers are selected using software known in the art for such purpose. For example, OLIGO 4.06 software is useful for the selection of PCR
primer pairs of up to 100 nucleotides each, and for the analysis of oligonucleotides and larger polynucleotides of up to 5,000 nucleotides from an input polynucleotide sequence of up to 32 kilobases.
Similar primer selection programs have incorporated additional features for expanded capabilities. For example, the PrimOU primer selection program (available to the public from the Genome Center at University of Texas South West Medical Center, Dallas TX) is capable of choosing specific primers from megabase sequences and is thus useful for designing primers on a genome-wide scope. The Primer3 primer selection program (available to the public from the Whitehead Institute/MTT Center for Genome Research, Cambridge MA) allows the user to input a "mispriming library," in which sequences to avoid as primer binding sites are user-specified. Primer3 is useful, in particular, for the selection of oligonucleotides for microarrays. (The source code for the latter two primer selection programs may also be obtained from their respective sources and modified to meet the user's specific needs.) The PrimeGen program (available to the public from the UK Human Genome Mapping Project Resource Centre, Cambridge UK) designs primers based on multiple sequence alignments, thereby allowing selection of primers that hybridize to either the most conserved or least conserved regions of aligned nucleic acid sequences. Hence, this program is useful for identification of both unique and conserved oligonucleotides and polynucleotide fragments. The oligonucleotides and polynucleotide fragments identified by any of the above selection methods are useful in hybridization technologies, for example, as PCR or sequencing primers, microarray elements, or specific probes to identify fully or partially complementary polynucleotides in a sample of nucleic acids. Methods of oligonucleotide selection are not limited to those described above.
A "recombinant nucleic acid" is a nucleic acid that is not naturally occurring or has a sequence that is made by an artificial combination of two or more otherwise separated segments of sequence. This artificial combination is often accomplished by chemical synthesis or, more commonly, by the artificial manipulation of isolated segments of nucleic acids, e.g., by genetic engineering techniques such as those described in Sambrook and Russell (supra). The term recombinant includes nucleic acids that have been altered solely by addition, substitution, or deletion of a portion of the nucleic acid. Frequently, a recombinant nucleic acid may include a nucleic acid sequence operably linked to a promoter sequence. Such a recombinant nucleic acid may be part of a vector that is used, for example, to transform a cell.
Alternatively, such recombinant nucleic acids may be part of a viral vector, e.g., based on a vaccinia virus, that could be use to vaccinate a mammal wherein the recombinant nucleic acid is expressed, inducing a protective immunological response in the mammal.
A "regulatory element" refers to a nucleic acid sequence usually derived from untranslated regions of a gene and includes enhancers, promoters, introns, and 5' and 3' untranslated regions (UTRs). Regulatory elements interact with host or viral proteins which control transcription, translation, or RNA stability.
"Reporter molecules" are chemical or biochemical moieties used for labeling a nucleic acid, amino acid, or antibody. Reporter molecules include radionuclides; enzymes;
fluorescent, chemiluminescent, or chromogenic agents; substrates; cofactors; inhibitors;
magnetic particles; and other moieties known in the art.
An "RNA equivalent," in reference to a DNA molecule, is composed of the same linear sequence of nucleotides as the reference DNA molecule with the exception that all occurrences of the nitrogenous base thymine are replaced with uracil, and the sugar backbone is composed of ribose instead of deoxyribose.
The term "sample" is used in its broadest sense. A sample suspected of containing SCAP, nucleic acids encoding SCAP, or fragments thereof may comprise a bodily fluid;
an extract from a cell, chromosome, organelle, or membrane isolated from a cell; a cell; genomic DNA, RNA, or cDNA, in solution or bound to a substrate; a tissue; a tissue print; etc.
The terms "specific binding" and "specifically binding" refer to that interaction between a protein or peptide and an agonist, an antibody, an antagonist, a small molecule, or any natural or synthetic binding composition. The interaction is dependent upon the presence of a particular structure of the protein, e.g., the antigenic determinant or epitope, recognized by the binding molecule. For example, if an antibody is specific for epitope "A," the presence of a polypeptide comprising the epitope A, or the presence of free unlabeled A, in a reaction containing free labeled A
and the antibody will reduce the amount of labeled A that binds to the antibody.
The term "substantially purified" refers to nucleic acid or amino acid sequences that are removed from their natural environment and are isolated or separated, and are at least about 60% free, preferably at least about 75% free, and most preferably at least about 90%
free from other components with which they are naturally associated.
A "substitution" refers to the replacement of one or more amino acid residues or nucleotides by different amino acid residues or nucleotides, respectively.
"Substrate" refers to any suitable rigid or semi-rigid support including membranes, filters, chips, slides, wafers, fibers, magnetic or nonmagnetic beads, gels, tubing, plates, polymers, microparticles and capillaries. The substrate can have a variety of surface forms, such as wells, trenches, pins, channels and pores,. to which polynucleotides or polypeptides are bound.
A "transcript image" or "expression profile" refers to the collective pattern of gene expression by a particular cell type or tissue under given conditions at a given time.
"Transformation" describes a process by which exogenous DNA is introduced into a recipient cell. Transformation may occur under natural or artificial conditions according to various methods well known in the art, and may rely on any known method for the insertion of foreign nucleic acid sequences into a prokaryotic or eukaryotic host cell. The method for transformation is selected based on the type of host cell being transformed and may include, but is not limited to, bacteriophage or viral infection, electroporation, heat shock, lipofection, and particle bombardment. The term "transformed cells" includes stably transformed cells in which the inserted DNA is capable of replication either as an autonomously replicating plasmid or as part of the host chromosome, as well as transiently transformed cells which express the inserted DNA or RNA for limited periods of time.
A "transgenic organism," as used herein, is any organism, including but not limited to animals and plants, in which one or more of the cells of the organism contains heterologous nucleic acid introduced by way of human intervention, such as by transgenic techniques well known in the art. The nucleic acid is introduced into the cell, directly or indirectly by introduction into a precursor of the cell, by way of deliberate genetic manipulation, such as by microinjection or by infection with a recombinant virus. In another embodiment, the nucleic acid can be introduced by infection with a recombinant viral vector, such as a lentiviral vector (Lois, C. et al. (2002) Science 295:868-872). The term genetic manipulation does not include classical cross-breeding, or in vitro fertilization, but rather is directed to the introduction of a recombinant DNA molecule. The transgenic organisms contemplated in accordance with the present invention include bacteria, cyanobacteria, fungi, plants and animals. The isolated DNA of the present invention can be introduced into the host by methods known in the art, for example infection, transfection, transformation or transconjugation. Techniques for transferring the DNA of the present invention into such organisms are widely known and provided in references such as Sambrook and Russell (supra).
A "variant" of a particular nucleic acid sequence is defined as a nucleic acid sequence having at least 40% sequence identity to the particular nucleic acid sequence over a certain length of one of the nucleic acid sequences using blastn with the "BLAST 2 Sequences" tool Version 2Ø9 (May-07-1999) set at default parameters. Such a pair of nucleic acids may show, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% or greater sequence identity over a certain defined length. A variant may be described as, for example, an "allelic" (as defined above), "splice," "species," or "polymorphic" variant. A
splice variant may have significant identity to a reference molecule, but will generally have a greater or lesser number of polynucleotides due to alternate splicing of exons during mRNA processing. The corresponding polypeptide may possess additional functional domains or lack domains that are present in the reference molecule. Species variants are polynucleotides that vary from one species to another. The resulting polypeptides will generally have significant amino acid identity relative to each other. A
polymorphic variant is a variation in the polynucleotide sequence of a particular gene between individuals of a given species. Polymorphic variants also may encompass "single nucleotide polymorphisms" (SNPs) in which the polynucleotide sequence varies by one nucleotide base. The presence of SNPs may be indicative of, for example, a certain population, a disease state, or a propensity for a disease state.
A "variant" of a particular polypeptide sequence is defined as a polypeptide sequence having at least 40% sequence identity or sequence similarity to the particular polypeptide sequence over a certain length of one of the polypeptide sequences using blastp with the "BLAST 2 Sequences" tool Version 2Ø9 (May-07-1999) set at default parameters. Such a pair of polypeptides may show, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% or greater sequence identity or sequence similarity over a certain defined length of one of the polypeptides.

THE INVENTION
Various embodiments of the invention include new human structural and cytoskeleton-associated proteins (SCAP), the~polynucleotides encoding SCAP, and the use of these compositions for the diagnosis, treatment, or prevention of cell proliferative disorders, viral infections, neurological disorders, and heart and skeletal muscle disorders.
Table 1 summarizes the nomenclature for the full length polynucleotide and polypeptide embodiments of the invention. Each polynucleotide and its corresponding polypeptide are correlated to a single Incyte project identification number (Incyte Project ID). Each polypeptide sequence is denoted by both a polypeptide sequence identification number (Polypeptide SEQ
ID NO:) and an Incyte polypeptide sequence number (Incyte Polypeptide ID) as shown. Each polynucleotide sequence is denoted by both a polynucleotide sequence identification number (Polynucleotide SEQ
ID NO:) and an Incyte polynucleotide consensus sequence number (Incyte Polynucleotide ID) as shown. Column 6 shows the Incyte ID numbers of physical, full length clones corresponding to the polypeptide and polynucleotide sequences of the invention. The full length clones encode polypeptides which have at least 95% sequence identity to the polypeptide sequences shown in column 3.
Table 2 shows sequences with homology to the polypeptides of the invention as identified by BLAST analysis against the GenBank protein (genpept) database and the PROTEOME
database.
Columns 1 and 2 show the polypeptide sequence identification number (Polypeptide SEQ >D NO:) and the corresponding Incyte polypeptide sequence number (Incyte Polypeptide ID) for polypeptides of the invention. Column 3 shows the GenBank identification number (GenBank ID
NO:) of the nearest GenBank homolog and the PROTEOME database identification numbers (PROTEOME )D
NO:) of the nearest PROTEOME database homologs. Column 4 shows the probability scores for the matches between each polypeptide and its homolog(s). Column 5 shows the annotation of the GenBank and PROTEOME database homolog(s) along with relevant citations where applicable, all of which are expressly incorporated by reference herein.
Table 3 shows various structural features of the polypeptides of the invention. Columns 1 and 2 show the polypeptide sequence identification number (SEQ >D NO:) and the corresponding Incyte polypeptide sequence number (Incyte Polypeptide ID) for each polypeptide of the invention.
Column 3 shows the number of amino acid residues in each polypeptide. Column 4 shows potential phosphorylation sites and potential glycosylation sites, as determined by the MOTIFS program of the GCG sequence analysis software package (Accelrys, Burlington MA), as well as amino acid residues comprising signature sequences, domains, and motifs. Column 5 shows analytical methods for protein structure/function analysis and in some cases, searchable databases to which the analytical methods were applied.

Together, Tables 2 and 3 summarize the properties of polypeptides of the invention, and these properties establish that the claimed polypeptides are structural and cytoskeleton-associated proteins.
For example, SEQ 117 N0:3 is 23% identical, from residue R80 to residue M1045, to Oryctolagus cuniculus trichohyalin, an intermediate filament-associated protein (GenBank ID g1747) as determined by the Basic Local Alignment Search Tool (BLAST). (See Table 2.) The BLAST
probability score is 3.1E-57, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance. SEQ ID N0:3 is localized to the cell envelope, where it binds to and cross-links keratin intermediate filaments, possibly acting as a scaffold protein in anchoring keratin intermediate filaments to the cell envelope, and is a trychohyalin, as determined by BLAST analysis using the PROTEOME database. SEQ ID N0:3 also contains a Zinc forger C-x8-C-x5-C-x3-H type domain as determined by searching for statistically significant matches in the hidden Markov model (HMM)-based PFAM database of conserved protein family domains. (See Table 3.) Data from further BLAST analyses of the PRODOMO and DOMO databases provide corroborative evidence that SEQ ID N0:3 is a trychohyalin.
As another example, SEQ )D N0:8 is 82% identical, from residue Ml to residue Q1064, and 81% identical, from residue D1070 to residue P1490, to murine myosin-VIIb (GenBank B7 g13506797) as determined by the Basic Local Alignment Search Tool (BLAST).
(See Table 2.) The BLAST probability score is 0.0, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance. SEQ ID N0:8 is localized to the myosin region, has MY07A
function, and is a cytoskeletal motor protein, as determined by BLAST analysis using the PROTEOME database. SEQ )D N0:8 also contains an IQ calmodulin-binding motif domain, a MyTH4 domain, and a myosin head (motor) domain as determined by searching for statistically significant matches in the hidden Markov model (HMM)-based PFAM database of conserved protein family domains. (See Table 3.) Data from BLIMPS, BLAST-PRODOM, BLAST-DOMO, and MOTIFS analyses provide further corroborative evidence that SEQ >D N0:8 is a cytoskeleton associated protein.
As another example, SEQ ID N0:12 is 99% identical, from residue M1 to residue K1253, to human myosin VI (GenBank ID g9280816) as determined by the Basic Local Alignment Search Tool (BLAST). (See Table 2.) The BLAST probability score is 0, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance. SEQ ID N0:12 is localized to the cytoplasm, has motor protein function, and is a Class VI myosin, as determined by BLAST analysis using the PROTEOME database. SEQ ID N0:12 also contains a myosin head domain as determined by searching for statistically significant matches in the hidden Markov model (HMM)-based PFAM
database of conserved protein family domains. (See Table 3.) Data from BLIMPS, MOTIFS, and further BLAST analyses provide further corroborative evidence that SEQ ll~
N0:12 is a myosin VI.

As another example, SEQ ID N0:22 is 97% identical, from residue M1 to residue N1006, to rat myosin I (GenBank ff~ g3724141) as determined by the Basic Local Alignment Search Tool (BLAST). (See Table 2.) The BLAST probability score is 0.00, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance. SEQ ID N0:22 is localized to the cytoplasm region, has motor protein, ATPase, and hydrolase function and is a myosin protein, as determined by BLAST analysis using the PROTEOME database. SEQ ID N0:22 also contains a myosin head domain as determined by searching for statistically significant matches in the hidden Markov model (HMM)-based PFAM database of conserved protein family domains.
(See Table 3.) Data from BLIMPS, BLAST, and MOTIFS analyses provide further corroborative evidence that SEQ
ID N0:22 is a myosin molecule.
As another example, SEQ ID N0:29 is 26% identical, from residue H34 to residue L589, to mouse actin-binding protein (GenBank ~ g2282582) as determined by the Basic Local Alignment Search Tool (BLAST). (See Table 2.) The BLAST probability score is 3.7e-49, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance. SEQ ID N0:29 also has homology to human ENC1, which is a nuclear matrix-associated phosphoprotein that is specifically expressed in primary neurons and interacts with the active form of Retinoblastoma p110(RB) protein during neuronal differentiation, as determined by BLAST
analysis using the PROTEOME database. SEQ ID N0:29 also contains a BTB/POZ and a Kelch motif domain as determined by searching for statistically significant matches in the hidden Markov model (HMM)-based PFAM database of conserved protein family domains. (See Table 3.) Data from BLIMPS and further BLAST analyses provide corroborative evidence that SEQ ID N0:29 is an actin-binding protein.
As another example, SEQ >D N0:39 is 77% identical, from residue Ml to residue 6983, to human microtubule-associated protein 4 (GenBank ID g641916) as determined by the Basic Local Alignment Search Tool (BLAST). (See Table 2.) The BLAST probability score is 0.0, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance. SEQ
ID N0:39 also has homology to microtubule-associated protein 4 as determined by BLAST analysis using the PROTEOME database. SEQ 1D N0:39 also contains a Tau and MAP, tubulin-binding protein domain as determined by searching for statistically significant matches in the hidden Markov model (HMM)-based PFAM database of conserved protein family domains. (See Table 3.) Data from BLIMPS, MOTIFS, and PROFILESCAN analyses provide further corroborative evidence that SEQ 1D N0:39 is a microtubule-associated protein.
As another example, SEQ >D NO:51 is 99% identical, from residue Q43 to residue F334, to human alpha-actin (GenBank )D g28330) as determined by the Basic Local Alignment Search Tool (BLAST). (See Table 2.) The BLAST probability score is.1.6e-176, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance. SEQ ID
NO:51 also has homology to proteins that are localized to the cytoplasm and are members of the muscle-specific actin family, as determined by BLAST analysis using the PROTEOME database. SEQ ID
NO:51 also contains an actin domain as determined by searching for statistically significant matches in the hidden Markov model (HMM)-based PFAM database of conserved protein family domains.
(See Table 3.) Data from BLIMPS, BLAST, MOTIFS, and PROFILESCAN analyses provide further corroborative evidence that SEQ >D NO:51 is an actin.
SEQ >D NO:1-2, SEQ ID N0:4-7, SEQ ID N0:9-1 l, SEQ ID N0:13-21, SEQ >D N0:23-28, SEQ ID N0:30-38, and SEQ >D N0:40-50 were analyzed and annotated in a similar manner. The algorithms and parameters for the analysis of SEQ >Z7 NO: l-51 are described in Table 7.
As shown in Table 4, the full length polynucleotide embodiments were assembled using cDNA sequences or coding (exon) sequences derived from genomic DNA, or any combination of these two types of sequences. Column 1 lists the polynucleotide sequence identification number (Polynucleotide SEQ )D NO:), the corresponding Incyte polynucleotide consensus sequence number (Incyte >D) for each polynucleotide of the invention, and the length of each polynucleotide sequence in basepairs. Column 2 shows the nucleotide start (5') and stop (3') positions of the cDNA and/or genomic sequences used to assemble the full length polynucleotide embodiments, and of fragments of the polynucleotides which are useful, for example, in hybridization or amplification technologies that identify SEQ )D N0:52-102 or that distinguish between SEQ )D N0:52-102 and related polynucleotides.
The polynucleotide fragments described in Column 2 of Table 4 may refer specifically, for example, to Incyte cDNAs derived from tissue-specific cDNA libraries or from pooled cDNA
libraries. Alternatively, the polynucleotide fragments described in column 2 may refer to GenBank cDNAs or ESTs which contributed to the assembly of the full length polynucleotides. In addition, the polynucleotide fragments described in column 2 may identify sequences derived from the ENSEMBL
(The Sanger Centre, Cambridge, UK) database (i.e., those sequences including the designation "ENST"). Alternatively, the polynucleotide fragments described in column 2 may be derived from the NCBI RefSeq Nucleotide Sequence Records Database (i.e., those sequences including the designation "NM" or "NT") or the NCBI RefSeq Protein Sequence Records (i.e., those sequences including the designation "NP"). Alternatively, the polynucleotide fragments described in column 2 may refer to assemblages of both cDNA and Genscan-predicted exons brought together by an "exon stitching" algorithm. For example, a polynucleotide sequence identified as FL_XXXXXX_N, NZ_YYYYY Nj NQ represents a "stitched" sequence in which XXXXXX
is the identification number of the cluster of sequences to which the algorithm was applied, and YYYYY is the number of the prediction generated by the algorithm, and N,,z,3,.., if present, represent specific exons that may have been manually edited during analysis (See Example V).
Alternatively, the polynucleotide fragments in column 2 may refer to assemblages of exons brought together by an "exon-stretching" algorithm. For example, a polynucleotide sequence identified as FLXXXXXX~AAA_gBBBBB_1 N is a "stretched" sequence, with XXXXXX being the Incyte project identification number, gAAAAA being the GenBank identification number of the human genomic sequence to which the "exon-stretching" algorithm was applied, gBBBBB
being the GenBank identification number or NCBI RefSeq identification number of the nearest GenBank protein homolog, and N referring to specific exons (See Example V). In instances where a RefSeq sequence was used as a protein homolog for the "exon-stretching" algorithm, a RefSeq identifier (denoted by "NM," "NP," or "NT") may be used in place of the GenBank identifier (i.e., gBBBBB).
Alternatively, a prefix identifies component sequences that were hand-edited, predicted from genomic DNA sequences, or derived from a combination of sequence analysis methods. The following Table lists examples of component sequence prefixes and corresponding sequence analysis methods associated with the prefixes (see Example IV and Example V).
Prefix Type of analysis and/or examples of programs GNN, GFG,Exon prediction from genomic sequences using, for example, ENST GENSCAN (Stanford University, CA, USA) or FGENES

(Computer Genomics Group, The Sanger Centre, Cambridge, UK).

GBI Hand-edited analysis of genomic sequences.

FL Stitched or stretched genomic sequences (see Example V).

INCY Full length transcript and exon prediction from mapping of EST

sequences to the genome. Genomic location and EST composition data are combined to predict the exons and resulting transcript.

In some cases, Incyte cDNA coverage redundant with the sequence coverage shown in Table 4 was obtained to confirm the final consensus polynucleotide sequence, but the relevant Incyte cDNA
identification numbers are not shown.
Table 5 shows the representative cDNA libraries for those full length polynucleotides which were assembled using Incyte cDNA sequences. The representative cDNA library is the Incyte cDNA
library which is most frequently represented by the Incyte cDNA sequences which were used to assemble and confirm the above polynucleotides. The tissues and vectors which were used to construct the cDNA libraries shown in Table 5 are described in Table 6.
Table 8 shows single nucleotide polymorphisms (SNPs) found in polynucleotide sequences of the invention, along with allele frequencies in different human populations.
Columns I and 2 show the polynucleotide sequence identification number (SEQ ID NO:) and the corresponding Incyte project identification number (P)D) for polynucleotides of the invention.
Column 3 shows the Incyte identification number for the EST in which the SNP was detected (EST >D), and column 4 shows the identification number for the SNP (SNP )D). Column 5 shows the position within the EST sequence at which the SNP is located (EST SNP), and column 6 shows the position of the SNP within the full-y length polynucleotide sequence (CB 1 SNP). Column 7 shows the allele found in the EST sequence.
Columns 8 and 9 show the two alleles found at the SNP site. Column 10 shows the amino acid encoded by the codon including the SNP site, based upon the allele found in the EST. Columns 11-14 show the frequency of allele 1 in four different human populations. An entry of n/d (not detected) indicates that the frequency of allele 1 in the population was too low to be detected, while n/a (not available) indicates that the allele frequency was not determined for the population .
The invention also encompasses SCAP variants. Various embodiments of SCAP
variants can have at least about 80%, at least about 90%, or at least about 95% amino acid sequence identity to the SCAP amino acid sequence, and can contain at least one functional or structural characteristic of SCAP.
Various embodiments also encompass polynucleotides which encode SCAP. In a particular embodiment, the invention encompasses a polynucleotide sequence comprising a sequence selected from the group consisting of SEQ 117 N0:52-102, which encodes SCAP. The polynucleotide sequences of SEQ ID N0:52-102, as presented in the Sequence Listing, embrace the equivalent RNA
sequences, wherein occurrences of the nitrogenous base thymine are replaced with uracil, and the sugar backbone is composed of ribose instead of deoxyribose.
The invention also encompasses variants of a polynucleotide encoding SCAP. In particular, such a variant polynucleotide will have at least about 70%, or alternatively at least about 85%, or even at least about 95% polynucleotide sequence identity to a polynucleotide encoding SOAP. A
particular aspect of the invention encompasses a variant of a polynucleotide comprising a sequence selected from the group consisting of SEQ )D N0:52-102 which has at least about 70%, or alternatively at least about 85%, or even at least about 95% polynucleotide sequence identity to a nucleic acid sequence selected from the group consisting of SEQ ID N0:52-102.
Any one of the polynucleotide variants described above can encode a polypeptide which contains at least one functional or structural characteristic of SCAP.
In addition, or in the alternative, a polynucleotide variant of the invention is a splice variant of a polynucleotide encoding SCAP. A splice variant may have portions which have significant sequence identity to a polynucleotide encoding SCAP, but will generally have a greater or lesser number of polynucleotides due to additions or deletions of blocks of sequence arising from alternate splicing of exons during mRNA processing. A splice variant may have less than about 70%, or alternatively less than about 60%, or alternatively less than about 50%
polynucleotide sequence identity to a polynucleotide encoding SCAP over its entire length; however, portions of the splice variant will have at least about 70%, or alternatively at least about 85%, or alternatively at least about 95%, or alternatively 100% polynucleotide sequence identity to portions of the polynucleotide encoding SCAP. For example, a polynucleotide comprising a sequence of SEQ ID
N0:59 and a ' polynucleotide comprising a sequence of SEQ ID N0:60 are splice variants of each other; and a polynucleotide comprising a sequence of SEQ ID N0:90 and a polynucleotide comprising a sequence of SEQ 117 N0:95 are splice variants of each other. Any one of the splice variants described above can encode a polypeptide which contains at least one functional or structural characteristic of SCAP.
It will be appreciated by those skilled in the art that as a result of the degeneracy of the genetic code, a multitude of polynucleotide sequences encoding SCAP, some bearing minimal similarity to the polynucleotide sequences of any known and naturally occurring gene, may be produced. Thus, the invention contemplates each and every possible variation of polynucleotide sequence that could be made by selecting combinations based on possible codon choices. These combinations are made in accordance with the standard triplet genetic code as applied to the polynucleotide sequence of naturally occurring SCAP, and all such variations are to be considered as being specifically disclosed.
Although polynucleotides which encode SOAP and its variants are generally capable of hybridizing to polynucleotides encoding naturally occurring SCAP under appropriately selected conditions of stringency, it may be advantageous to produce polynucleotides encoding SCAP or its derivatives possessing a substantially different codon usage, e.g., inclusion of non-naturally occurring codons. Codons may be selected to increase the rate at which expression of the peptide occurs in a particular prokaryotic or eukaryotic host in accordance with the frequency with which particular codons are utilized by the host. Other reasons for substantially altering the nucleotide sequence encoding SCAP and its derivatives without altering the encoded amino acid sequences include the production of RNA transcripts having more desirable properties, such as a greater half-life, than transcripts produced from the naturally occurring sequence.
The invention also encompasses production of polynucleotides which encode SCAP
and SCAP derivatives, or fragments thereof, entirely by synthetic chemistry. After production, the synthetic polynucleotide may be inserted into any of the many available expression vectors and cell systems using reagents well known in the art. Moreover, synthetic chemistry may be used to introduce mutations into a polynucleotide encoding SCAP or any fragment thereof.
Embodiments of the invention can also include polynucleotides that are capable of hybridizing to the claimed polynucleotides, and, in particular, to those having the sequences shown in SEQ ID N0:52-102 and fragments thereof, under various conditions of stringency (Wahl, G.M. and S.L. Berger ( 1987) Methods Enzymol. 152:399-407; Kimmel, A.R. ( 1987) Methods Enzymol.

152:507-511). Hybridization conditions, including annealing and wash conditions, are described in "Definitions."
Methods for DNA sequencing are well known in the art and may be used to practice any of the embodiments of the invention. The methods may employ such enzymes as the Klenow fragment of DNA polymerase I, SEQUENASE (US Biochemical, Cleveland OH), Taq polymerase (Applied Biosystems), thermostable T7 polymerase (Amersham Biosciences, Piscataway NJ), or combinations of polymerases and proofreading exonucleases such as those found in the ELONGASE amplification system (Invitrogen, Carlsbad CA). Preferably, sequence preparation is automated with machines such as the MICROLAB 2200 liquid transfer system (Hamilton, Reno NV), PTC200 thermal cycler (MJ
Research, Watertown MA) and ABI CAT~L.YST 800 thermal cycler (Applied Biosystems).
Sequencing is then carried out using either the ABI 373 or 377 DNA sequencing system (Applied Biosystems), the MEGABACE 1000 DNA sequencing system (Amersham Biosciences), or other systems known in the art. The resulting sequences are analyzed using a variety of algorithms which are well known in the art (Ausubel et al., supra, ch. 7; Meyers, R.A. (1995) Molecular Biology and BiotechnoloQV, Wiley VCH, New York NY, pp. 856-853).
The nucleic acids encoding SCAP may be extended utilizing a partial nucleotide sequence and employing various PCR-based methods known in the art to detect upstream sequences, such as promoters and regulatory elements. For example, one method which may be employed, restriction-site PCR, uses universal and nested primers to amplify unknown sequence from genomic DNA within a cloning vector (Sarkar, G. (1993) PCR Methods Applic. 2:318-322).
Another method, inverse PCR, uses primers that extend in divergent directions to amplify unknown sequence from a circularized template. The template is derived from restriction fragments comprising a known genomic locus and surrounding sequences (Triglia, T. et al. ( 1988) Nucleic Acids Res. 16:8186). A
third method, capture PCR, involves PCR amplification of DNA fragments adjacent to known sequences in human and yeast artificial chromosome DNA (Lagerstrom, M. et al.
(1991) PCR
Methods Applic. 1:111-119). In this method, multiple restriction enzyme digestions and ligations .
may be used to insert an engineered double-stranded sequence into a region of unknown sequence before performing PCR. Other methods which may be used to retrieve unknown sequences are known in the art (Parker, J.D. et al. (1991) Nucleic Acids Res. 19:3055-3060).
Additionally, one may use PCR, nested primers, and PROMOTERFINDER libraries (Clontech, Palo Alto CA) to walk genomic DNA. This procedure avoids the need to screen libraries and is useful in finding intron/exon junctions. For all PCR-based methods, primers may be designed using commercially available software, such as OLIGO 4.06 primer analysis software (National Biosciences, Plymouth MN) or another appropriate program, to be about 22 to 30 nucleotides in length, to have a GC content of about 50% or more, and to anneal to the template at temperatures of about 68°C to 72°C.

When screening for full length cDNAs, it is preferable to use libraries that have been size-selected to include larger cDNAs. In addition, random-primed libraries, which often include sequences containing the 5'regions of genes, are preferable for situations in which an oligo d(T) library does not yield a full-length cDNA. Genomic libraries may be useful for extension of sequence into 5' non-transcribed regulatory regions.
Capillary electrophoresis systems which are commercially available may be used to analyze the size or confirm the nucleotide sequence of sequencing or PCR products. In particular, capillary sequencing may employ flowable polymers for electrophoretic separation, four different nucleotide-specific, laser-stimulated fluorescent dyes, and a charge coupled device camera for detection of the emitted wavelengths. Output/light intensity may be converted to electrical signal using appropriate software (e.g., GENOTYPER and SEQUENCE NAVIGATOR, Applied Biosystems), and the entire process from loading of samples to computer analysis and electronic data display may be computer controlled. Capillary electrophoresis is especially preferable for sequencing small DNA fragments which may be present in limited amounts in a particular sample.
In another embodiment of the invention, polynucleotides or fragments thereof which encode SCAP may be cloned in recombinant DNA molecules that direct expression of SCAP, or fragments or functional equivalents thereof, in appropriate host cells. Due to the inherent degeneracy of the genetic code, other polynucleotides which encode substantially the same or a functionally equivalent polypeptides may be produced and used to express SCAP.
The polynucleotides of the invention can be engineered using methods generally known in the art in order to alter SCAP-encoding sequences for a variety of purposes including, but not limited to, modification of the cloning, processing, and/or expression of the gene product. DNA shuffling by random fragmentation and PCR reassembly of gene fragments and synthetic oligonucleotides may be used to engineer the nucleotide sequences. For example, oligonucleotide-mediated site-directed mutagenesis may be used to introduce mutations that create new restriction sites, alter glycosylation patterns, change codon preference, produce splice variants, and so forth.
The nucleotides of the present invention may be subjected to DNA shuffling techniques such as MOLECULARBREEDING (Maxygen Inc., Santa Clara CA; described in U.S. Patent No.

5,837,458; Chang, C.-C. et al. (1999) Nat. Biotechnol. 17:793-797; Christians, F.C. et al. (1999) Nat.
Biotechnol. 17:259-264; and Crameri, A. et al. (1996) Nat. Biotechnol. 14:315-319) to alter or improve the biological properties of SCAP, such as its biological or enzymatic activity or its ability to bind to other molecules or compounds. DNA shuffling is a process by which a library of gene variants is produced using PCR-mediated recombination of gene fragments. The library is then subjected to selection or screening procedures that identify those gene variants with the desired properties. These preferred variants may then be pooled and further subjected to recursive rounds of DNA shuffling and selection/screening. Thus, genetic diversity is created through "artificial"
breeding and rapid molecular evolution. For example, fragments of a single gene containing random point mutations may be recombined, screened, and then reshuffled until the desired properties are optimized. Alternatively, fragments of a given gene may be recombined with fragments of homologous genes in the same gene family, either from the same or different species, thereby maximizing the genetic diversity of multiple naturally occurring genes in a directed and controllable manner.
In another embodiment, polynucleotides encoding SCAP may be synthesized, in whole or in part, using one or more chemical methods well known in the art (Caruthers, M.H. et al. ( 1980) Nucleic Acids Symp. Ser. 7:215-223; Horn, T. et al. (1980) Nucleic Acids Symp.
Ser. 7:225-232).
Alternatively, SCAP itself or a fragment thereof may be synthesized using chemical methods known in the art. For example, peptide synthesis can be performed using various solution-phase or solid-phase techniques (Creighton, T. (1984) Proteins, Structures and Molecular Properties, WH
Freeman, New York NY, pp. 55-60; Roberge, J.Y. et al. (1995) Science 269:202-204). Automated synthesis may be achieved using the ABI 431A peptide synthesizer (Applied Biosystems).
Additionally, the amino acid sequence of SCAP, or any part thereof, may be altered during direct synthesis and/or combined with sequences from other proteins, or any part thereof, to produce a variant polypeptide or a polypeptide having a sequence of a naturally occurring polypeptide.
The peptide may be substantially purified by preparative high performance liquid chromatography (Chiez, R.M. and F.Z. Regnier (1990) Methods Enzymol. 182:392-421). The composition of the synthetic peptides may be confirmed by amino acid analysis or by sequencing (Creighton, supra, pp. 28-53).
In order to express a biologically active SCAP, the polynucleotides encoding SCAP or derivatives thereof may be inserted into an appropriate expression vector, i.e., a vector which contains the necessary elements for transcriptional and translational control of the inserted coding sequence in a suitable host. These elements include regulatory sequences, such as enhancers, constitutive and inducible promoters, and 5' and 3' untranslated regions in the vector and in polynucleotides encoding SCAP. Such elements may vary in their strength and specificity. Specific initiation signals may also be used to achieve more efficient translation of polynucleotides encoding SCAP. Such signals include the ATG initiation codon and adjacent sequences, e.g. the Kozak sequence. In cases where a polynucleotide sequence encoding SCAP and its initiation codon and upstream regulatory sequences are inserted into the appropriate expression vector, no additional transcriptional or translational control signals may be needed. However, in cases where only coding sequence, or a fragment thereof, is inserted, exogenous translational control signals including an in-frame ATG initiation codon should be provided by the vector. Exogenous translational elements and initiation codons may be of various origins, both natural and synthetic. The efficiency of expression may be enhanced by the inclusion of enhancers appropriate for the particular host cell system used (Scharf, D. et al. ( 1994) Results Probl. Cell Differ. 20:125-162).
Methods which are well known to those skilled in the art may be used to construct expression vectors containing polynucleotides encoding SCAP and appropriate transcriptional and translational control elements. These methods include in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic recombination (Sambrook and Russell, supra, ch. 1-4, and 8; Ausubel et al., suprn, ch. l, 3, and 15).
A variety of expression vector/host systems may be utilized to contain and express polynucleotides encoding SCAP. These include, but are not limited to, microorganisms such as bacteria transformed with recombinant bacteriophage, plasmid, or cosmid DNA
expression vectors;
yeast transformed with yeast expression vectors; insect cell systems infected with viral expression vectors (e.g., baculovirus); plant cell systems transformed with viral expression vectors (e.g., cauliflower mosaic virus, CaMV, or tobacco mosaic virus, TMV) or with bacterial expression vectors (e.g., Ti or pBR322 plasmids); or animal cell systems (Sambrook and Russell, supra; Ausubel et al., supra; Van Heeke, G. and S.M. Schuster (1989) J. Biol. Chem. 264:5503-5509;
Engelhard, E.K. et al.
(1994) Proc. Natl. Acad. Sci. USA 91:3224-3227; Sandig, V. et al. (1996) Hum.
Gene Ther. 7:1937-1945; Takamatsu, N. (1987) EMBO J. 6:307-31 l; The McGraw Hill Yearbook of Science and Technolo~y (1992) McGraw Hill, New York NY, pp. 191-196; Logan, J. and T.
Shenk (1984) Proc.
Natl. Acad. Sci. USA 81:3655-3659; Harrington, J.J. et al. (1997) Nat. Genet.
15:345-355).
Expression vectors derived from retroviruses, adenoviruses, or herpes or vaccinia viruses, or from various bacterial plasmids, may be used for delivery of polynucleotides to the targeted organ, tissue, or cell population (Di Nicola, M. et al. (1998) Cancer Gen. Ther. 5:350-356;
Yu, M. et al. (1993) Proc. Natl. Acad. Sci. USA 90:6340-6344; Buller, R.M. et al. (1985) Nature 317:813-815; McGregor, D.P. et al. ( 1994) Mol. Immunol. 31:219-226; Verma, LM. and N. Somia ( 1997) Nature 389:239-242). The invention is not limited by the host cell employed.
In bacterial systems, a number of cloning and expression vectors may be selected depending upon the use intended for polynucleotides encoding SCAP. For example, routine cloning, subcloning, and propagation of polynucleotides encoding SCAP can be achieved using a multifunctional E. coli vector such as PBLUESCRIPT (Stratagene, La Jolla CA) or PSPORT 1 plasmid (Invitrogen).
Ligation of polynucleotides encoding SCAP into the vector's multiple cloning site disrupts the lacZ
gene, allowing a colorimetric screening procedure for identification of transformed bacteria containing recombinant molecules. In addition, these vectors may be useful for in vitro transcription, dideoxy sequencing, single strand rescue with helper phage, and creation of nested deletions in the cloned sequence (Van Heeke, G. and S.M. Schuster (1989) J. Biol. Chem.
264:5503-5509). When large quantities of SCAP are needed, e.g. for the production of antibodies, vectors which direct high level expression of SCAP may be used. For example, vectors containing the strong, inducible SP6 or T7 bacteriophage promoter may be used.
Yeast expression systems may be used for production of SCAP. A number of vectors containing constitutive or inducible promoters, such as alpha factor, alcohol oxidase, and PGH
promoters, may be used in the yeast Saccharomyces cerevisiae or Pichia pastoris. In addition, such vectors direct either the secretion or intracellular retention of expressed proteins and enable integration of foreign polynucleotide sequences into the host genome for stable propagation (Ausubel et al., supra; Bitter, G.A. et al. (1987) Methods Enzymol. 153:516-544;
Scorer, C.A. et al. (1994) Bio/Technology 12:181-184).
Plant systems may also be used for expression of SCAP. Transcription of polynucleotides encoding SCAP may be driven by viral promoters, e.g., the 35S and 19S
promoters of CaMV used alone or in combination with the omega leader sequence from TMV (Takamatsu, N.
(1987) EMBO J.

6:307-311). Alternatively, plant promoters such as the small subunit of RUBISCO or heat shock promoters may be used (Coruzzi, G. et al. (1984) EMBO J. 3:1671-1680; Broglie, R. et al. (1984) Science 224:838-843; Winter, J. et al. (1991) Results Probl. Cell Differ.
17:85-105). These constructs can be introduced into plant cells by direct DNA transformation or pathogen-mediated transfection (The McGraw Hill Yearbook of Science and Technolo~y (1992) McGraw Hill, New York NY, pp. 191-196).
In mammalian cells, a number of viral-based expression systems may be utilized. In cases where an adenovirus is used as an expression vector, polynucleotides encoding SCAP may be ligated into an adenovirus transcription/translation complex consisting of the late promoter and tripartite leader sequence. Insertion in a non-essential E1 or E3 region of the viral genome may be used to obtain infective virus which expresses SCAP in host cells (Logan, J. and T.
Shenk ( 1984) Proc. Natl.
Acad. Sci. USA 81:3655-3659). In addition, transcription enhancers, such as the Rous sarcoma virus (RSV) enhancer, may be used to increase expression in mammalian host cells.
SV40 or EBV-based vectors may also be used for high-level protein expression.
Human artificial chromosomes (HACs) may also be employed to deliver larger fragments of DNA than can be contained in and expressed from a plasmid. HACs of about 6 kb to 10 Mb are constructed and delivered via conventional delivery methods (liposomes, polycationic amino polymers, or vesicles) for therapeutic purposes (Harrington, J.J. et al.
(1997) Nat. Genet. 15:345-355).
For long term production of recombinant proteins in mammalian systems, stable expression of SCAP in cell lines is preferred. For example, polynucleotides encoding SCAP
can be transformed into cell lines using expression vectors which may contain viral origins of replication and/or 3S endogenous expression elements and a selectable marker gene on the same or on a separate vector.

Following the introduction of the vector, cells may be allowed to grow for about 1 to 2 days in enriched media before being switched to selective media. The purpose of the selectable marker is to confer resistance to a selective agent, and its presence allows growth and recovery of cells which successfully express the introduced sequences. Resistant clones of stably transformed cells may be propagated using tissue culture techniques appropriate to the cell type.
Any number of selection systems may be used to recover transformed cell lines.
These include, but are not limited to, the herpes simplex virus thymidine kinase and adenine phosphoribosyltransferase genes, for use in tk- and apY cells, respectively (Wigler, M. et al. (1977) Cell 11:223-232; Lowy, I. et al. ( 1980) Cell 22:817-823). Also, antimetabolite, antibiotic, or herbicide resistance can be used as the basis for selection. For example, dhfr confers resistance to methotrexate; neo confers resistance to the aminoglycosides neomycin and G-418; and als and pat confer resistance to chlorsulfuron and phosphinotricin acetyltransferase, respectively (Wigler, M. et al. (1980) Proc. Natl. Acad. Sci. USA 77:3567-3570; Colbere-Garapin, F. et al.
(1981) J. Mol. Biol.
150:1-14). Additional selectable genes have been described, e.g., trpB and hisD, which alter cellular requirements for metabolites (Hartman, S.C. and R.C. Mulligan (1988) Proc.
Natl. Acad. Sci. USA
85:8047-8051). Visible markers, e.g., anthocyanins, green fluorescent proteins (GFP; Clontech), (3-glucuronidase and its substrate (3-glucuronide, or luciferase and its substrate luciferin may be used.
These markers can be used not only to identify transformants, but also to quantify the amount of transient or stable protein expression attributable to a specific vector system (Rhodes, C.A. (1995) Methods Mol. Biol. 55:121-131).
Although the presence/absence of marker gene expression suggests that the gene of interest is also present, the presence and expression of the gene may need to be confirmed. For example, if the sequence encoding SCAP is inserted within a marker gene sequence, transformed cells containing polynucleotides encoding SCAP can be identified by the absence of marker gene function.
Alternatively, a marker gene can be placed in tandem with a sequence encoding SCAP under the control of a single promoter. Expression of the marker gene in response to induction or selection usually indicates expression of the tandem gene as well.
In general, host cells that contain the polynucleotide encoding SCAP and that express SCAP
may be identified by a variety of procedures known to those of skill in the art. These procedures include, but are not limited to, DNA-DNA or DNA-RNA hybridizations, PCR
amplification, and protein bioassay or immunoassay techniques which include membrane, solution, or chip based technologies for the detection and/or quantification of nucleic acid or protein sequences.
Immunological methods for detecting and measuring the expression of SCAP using either specific polyclonal or monoclonal antibodies are known in the art. Examples of such techniques include enzyme-linked immunosorbent assays (ELISAs), radioimmunoassays (RIAs), and fluorescence activated cell sorting (FACS). A two-site, monoclonal-based immunoassay utilizing monoclonal antibodies reactive to two non-interfering epitopes on SCAP is preferred, but a competitive binding assay may be employed. These and other assays are well known in the art (Hampton, R. et al. (1990) Serological Methods, a Laboratory Manual, APS
Press, St. Paul MN, Sect.
IV; Coligan, J.E. et al. (1997) Current Protocols in Immunolo~y, Greene Pub.
Associates and Wiley-Interscience, New York NY; Pound, J.D. (1998) Immunochemical Protocols, Humana Press, Totowa NJ).
A wide variety of labels and conjugation techniques are known by those skilled in the art and may be used in various nucleic acid and amino acid assays. Means for producing labeled hybridization or PCR probes for detecting sequences related to polynucleotides encoding SCAP
include oligolabeling, nick translation, end-labeling, or PCR amplification using a labeled nucleotide.
Alternatively, polynucleotides encoding SCAP, or any fragments thereof, may be cloned into a vector for the production of an mRNA probe. Such vectors are known in the art, are commercially available, and may be used to synthesize RNA probes in vitro by addition of an appropriate RNA polymerase such as T7, T3, or SP6 and labeled nucleotides. These procedures may be conducted using a variety of commercially available kits, such as those provided by Amersham Biosciences, Promega (Madison WI), and US Biochemical. Suitable reporter molecules or labels which may be used for ease of detection include radionuclides, enzymes, fluorescent, chemiluminescent, or chromogenic agents, as well as substrates, cofactors, inhibitors, magnetic particles, and the like.
Host cells transformed with polynucleotides encoding SCAP may be cultured under conditions suitable for the expression and recovery of the protein from cell culture. The protein produced by a transformed cell may be secreted or retained intracellularly depending on the sequence and/or the vector used. As will be understood by those of skill in the art, expression vectors containing polynucleotides which encode SCAP may be designed to contain signal sequences which direct secretion of SCAP through a prokaryotic or eukaryotic cell membrane.
In addition, a host cell strain may be chosen for its ability to modulate expression of the inserted polynucleotides or to process the expressed protein in the desired fashion. Such modifications of the polypeptide include, but are not limited to, acetylation, carboxylation, glycosylation, phosphorylation, lipidation, and acylation. Post-translational processing which cleaves a "prepro" or "pro" form of the protein may also be used to specify protein targeting, folding, and/or activity. Different host cells which have specific cellular machinery and characteristic mechanisms for post-translational activities (e.g., CHO, HeLa, MDCK, HEK293, and WI38) are available from the American Type Culture Collection (ATCC, Manassas VA) and may be chosen to ensure the correct modification and processing of the foreign protein.
In another embodiment of the invention, natural, modified, or recombinant polynucleotides 5~

encoding SCAP may be ligated to a heterologous sequence resulting in translation of a fusion protein in any of the aforementioned host systems. For example, a chimeric SCAP
protein containing a heterologous moiety that can be recognized by a commercially available antibody may facilitate the screening of peptide libraries for inhibitors of SCAP activity. Heterologous protein and peptide moieties may also facilitate purification of fusion proteins using commercially available affinity matrices. Such moieties include, but are not limited to, glutathione S-transferase (GST), maltose binding protein (MBP), thioredoxin (Trx), calmodulin binding peptide (CBP), 6-His, FLAG, c-myc, and hemagglutinin (HA). GST, MBP, Trx, CBP, and 6-His enable purification of their cognate fusion proteins on immobilized glutathione, maltose, phenylarsine oxide, calmodulin, and metal-chelate resins, respectively. FLAG, c-myc, and hemagglutinin (HA) enable immunoaffinity purification of fusion proteins using commercially available monoclonal and polyclonal antibodies that specifically recognize these epitope tags. A fusion protein may also be engineered to contain a proteolytic cleavage site located between the SCAP encoding sequence and the heterologous protein sequence, so that SCAP may be cleaved away from the heterologous moiety following purification. Methods for fusion protein expression and purification are discussed in Ausubel et al.
(supra, ch. 10 and 16). A
variety of commercially available kits may also be used to facilitate expression and purification of fusion proteins.
In another embodiment, synthesis of radiolabeled SCAP may be achieved in vitro using the TNT rabbit reticulocyte lysate or wheat germ extract system (Promega). These systems couple transcription and translation of protein-coding sequences operably associated with the T7, T3, or SP6 promoters. Translation takes place in the presence of a radiolabeled amino acid precursor, for example, 35S-methionine.
SCAP, fragments of SCAP, or variants of SCAP may be used to screen for compounds that specifically bind to SCAP. One or more test compounds may be screened for specific binding to SCAP. In various embodiments, 1, 2, 3, 4, 5, 10, 20, 50, 100, or 200 test compounds can be screened for specific binding to SCAP. Examples of test compounds can include antibodies, anticalins, oligonucleotides, proteins (e.g., ligands or receptors), or small molecules.
In related embodiments, variants of SCAP can be used to screen for binding of test compounds, such as antibodies, to SCAP, a variant of SCAP, or a combination of SOAP and/or one or more variants SCAP. In an embodiment, a variant of SCAP can be used to screen for compounds that bind to a variant of SCAP, but not to SCAP having the exact sequence of a sequence of SEQ ID
NO:1-51. SCAP variants used to perform such screening can have a range of about 50% to about 99% sequence identity to SCAP, with various embodiments having 60%, 70%, 75%, 80%, 85%, 90%, and 95% sequence identity.
In an embodiment, a compound identified in a screen for specific binding to SCAP can be closely related to the natural ligand of SCAP, e.g., a ligand or fragment thereof, a natural substrate, a structural or functional mimetic, or a natural binding partner (Coligan, J.E.
et al. (1991) Current Protocols in Immunology 1(2):Chapter 5). In another embodiment, the compound thus identified can be a natural ligand of a receptor SCAP (Howard, A.D. et al. (2001) Trends Pharmacol. Sci.22:132-140; Wise, A. et al. (2002) Drug Discovery Today 7:235-246).
In other embodiments, a compound identified in a screen for specific binding to SCAP can be closely related to the natural receptor to which SCAP binds, at least a fragment of the receptor, or a fragment of the receptor including all or a portion of the ligand binding site or binding pocket. For example, the compound may be a receptor for SCAP which is capable of propagating a signal, or a decoy receptor for SCAP which is not capable of propagating a signal (Ashkenazi, A. and V.M. Divit (1999) Curr. Opin. Cell Biol. 11:255-260; Mantovani, A. et al. (2001) Trends Immunol. 22:328-336).
The compound can be rationally designed using known techniques. Examples of such techniques include those used to construct the compound etanercept (ENBREL; Amgen Inc., Thousand Oaks CA), which is efficacious for treating rheumatoid arthritis in humans.
Etanercept is an engineered p75 tumor necrosis factor (T1VF) receptor dimer linked to the Fc portion of human IgG, (Taylor, P.C.
et al. (2001) Curr. Opin. Immunol. 13:611-616).
In one embodiment, two or more antibodies having similar or, alternatively, different specificities can be screened for specific binding to SCAP, fragments of SCAP, or variants of SCAP.
The binding specificity of the antibodies thus screened can thereby be selected to identify particular fragments or variants of SCAP. In one embodiment, an antibody can be selected such that its binding specificity allows for preferential identification of specific fragments or variants of SCAP. In another embodiment, an antibody can be selected such that its binding specificity allows for preferential diagnosis of a specific disease or condition having increased, decreased, or otherwise abnormal production of SCAP.
In an embodiment, anticalins can be screened for specific binding to SCAP, fragments of SCAP, or variants of SCAP. Anticalins are ligand-binding proteins that have been constructed based on a lipocalin scaffold (Weiss, G.A. and H.B. Lowman (2000) Chem. Biol. 7:8177-8184; Skerra, A.
(2001) J. Biotechnol. 74:257-275). The protein architecture of lipocalins can include a beta-barrel having eight antiparallel beta-strands, which supports four loops at its open end. These loops form the natural ligand-binding site of the lipocalins, a site which can be re-engineered in vitro by amino acid substitutions to impart novel binding specificities. The amino acid substitutions can be made using methods known in the art or described herein, and can include conservative substitutions (e.g., substitutions that do not alter binding specificity) or substitutions that modestly, moderately, or significantly alter binding specificity.
In one embodiment, screening for compounds which specifically bind to, stimulate, or inhibit SCAP involves producing appropriate cells which express SCAP, either as a secreted protein or on the cell membrane. Preferred cells can include cells from mammals, yeast, Drosophila, or E. coli.
Cells expressing SCAP or cell membrane fractions which contain SCAP are then contacted with a test compound and binding, stimulation, or inhibition of activity of either SCAP or the compound is analyzed.
An assay may simply test binding of a test compound to the polypeptide, wherein binding is detected by a fluorophore, radioisotope, enzyme conjugate, or other detectable label. For example, the assay may comprise the steps of combining at least one test compound with SCAP, either in solution or affixed to a solid support, and detecting the binding of SCAP to the compound.
Alternatively, the assay may detect or measure binding of a test compound in the presence of a labeled competitor. Additionally, the assay may be carried out using cell-free preparations, chemical libraries, or natural product mixtures, and the test compounds) may be free in solution or affixed to a solid support.
An assay can be used to assess the ability of a compound to bind to its natural ligand and/or to inhibit the binding of its natural ligand to its natural receptors.
Examples of such assays include radio-labeling assays such as those described in U.S. Patent No. 5,914,236 and U.S. Patent No.
6,372,724. In a related embodiment, one or more amino acid substitutions can be introduced into a polypeptide compound (such as a receptor) to improve or alter its ability to bind to its natural ligands (Matthews, D.J. and J.A. Wells. (1994) Chem. Biol. 1:25-30). In another related embodiment, one or more amino acid substitutions can be introduced into a polypeptide compound (such as a ligand) to improve or alter its ability to bind to its natural receptors (Cunningham, B.C. and J.A. Wells (1991) Proc. Natl. Acad. Sci. USA 88:3407-3411; Lowman, H.B. et al. (1991) J. Biol.
Chem. 266:10982-10988).
SCAP, fragments of SCAP, or variants of SCAP may be used to screen for compounds that modulate the activity of SCAP. Such compounds may include agonists, antagonists, or partial or inverse agonists. In one embodiment, an assay is performed under conditions permissive for SCAP
activity, wherein SCAP is combined with at least one test compound, and the activity of SCAP in the presence of a test compound is compared with the activity of SCAP in the absence of the test compound. A change in the activity of SCAP in the presence of the test compound is indicative of a compound that modulates the activity of SCAP. Alternatively, a test compound is combined with an in vitro or cell-free system comprising SCAP under conditions suitable for SCAP activity, and the assay is performed. In either of these assays, a test compound which modulates the activity of SCAP
may do so indirectly and need not come in direct contact with the test compound. At least one and up to a plurality of test compounds may be screened.
In another embodiment, polynucleotides encoding SCAP or their mammalian homologs may be "knocked out" in an animal model system using homologous recombination in embryonic stem (ES) cells. Such techniques are well known in the art and are useful for the generation of animal models of human disease (see, e.g., U.S. Patent No. 5,175,383 and U.S. Patent No. 5,767,337). For example, mouse ES cells, such as the mouse 129/SvJ cell line, are derived from the early mouse embryo and grown in culture. The ES cells are transformed with a vector containing the gene of interest disrupted by a marker gene, e.g., the neomycin phosphotransferase gene (neo; Capecchi, M.R.
(1989) Science 244:1288-1292). The vector integrates into the corresponding region of the host genome by homologous recombination. Alternatively, homologous recombination takes place using the Cre-IoxP system to knockout a gene of interest in a tissue- or developmental stage-specific manner (Marth, J.D. (1996) Clin. Invest. 97:1999-2002; Wagner, K.U. et al.
(1997) Nucleic Acids Res. 25:4323-4330). Transformed ES cells are identified and microinjected into mouse cell blastocysts such as those from the C57BL/6 mouse strain. The blastocysts are surgically transferred to pseudopregnant dams, and the resulting chimeric progeny are genotyped and bred to produce heterozygous or homozygous strains. Transgenic animals thus generated may be tested with potential therapeutic or toxic agents.
Polynucleotides encoding SCAP may also be manipulated in vitro in ES cells derived from human blastocysts. Human ES cells have the potential to differentiate into at least eight separate cell lineages including endoderm, mesoderm, and ectodermal cell types. These cell lineages differentiate into, for example, neural cells, hematopoietic lineages, and cardiomyocytes (Thomson, J.A. et al.
(1998) Science 282:1145-1147).
Polynucleotides encoding SCAP can also be used to create "knockin" humanized animals (pigs) or transgenic animals (mice or rats) to model human disease. With knockin technology, a region of a polynucleotide encoding SCAP is injected into animal ES cells, and the injected sequence integrates into the animal cell genome. Transformed cells are injected into blastulae, and the blastulae are implanted as described above. Transgenic progeny or inbred lines are studied and treated with potential pharmaceutical agents to obtain information on treatment of a human disease.
Alternatively, a mammal inbred to overexpress SCAP, e.g., by secreting SCAP in its milk, may also serve as a convenient source of that protein (Janne, J. et al. (1998) Biotechnol. Annu. Rev. 4:55-74).
THERAPEUTICS
Chemical and structural similarity, e.g., in the context of sequences and motifs, exists between regions of SCAP and structural and cytoskeleton-associated proteins.
In addition, the expression of SCAP is closely associated with brain tissue including posterior cingulate, brain stem tissue, colon cancer and osteosarcoma, fetal liver tissue, dendritic cells derived from umbilical cord, stomach tissue, tumor-associated ileum tissue, jejunum tissue, small intestine tissue, testicular tissue, inferior parietal cortex tissue, diseased breast tissue, sigmoid colon tissue, forearm muscle tissue, tibial muscle tissue, atrium tissue, peritoneal tumor tissue, epithelial cell tissue, osteoblast tissue, fetal spleen tissue prostate tumor, and in a primary osteogenic sarcoma cell line (ATCC HTB-85). In addition, examples of tissues expressing SCAP can be found in Table 6 and can also be found in Example XI. Therefore, SCAP appears to play a role in cell proliferative disorders, viral infections, neurological disorders, and heart and skeletal muscle disorders. In the treatment of disorders associated with increased SCAP expression or activity, it is desirable to decrease the expression or activity of SCAP. In the treatment of disorders associated with decreased SOAP
expression or activity, it is desirable to increase the expression or activity of SCAP.
Therefore, in one embodiment, SCAP or a fragment or derivative thereof may be administered to a subject to treat or prevent a disorder associated with decreased expression or activity of SCAP. Examples of such disorders include, but are not limited to, a cell proliferative disorder such as actinic keratosis, arteriosclerosis, atherosclerosis, bursitis, cirrhosis, hepatitis, mixed connective tissue disease (MCTD), myelofibrosis, paroxysmal nocturnal hemoglobinuria, polycythemia vera, psoriasis, primary thrombocythemia, and a cancer including adenocarcinoma, leukemia, lymphoma, melanoma, myeloma, sarcoma, teratocarcinoma, and, in particular, a cancer of the adrenal gland, bladder, bone, bone marrow, brain, breast, cervix, gall bladder, ganglia, gastrointestinal tract, heart, kidney, liver, lung, muscle, ovary, pancreas, parathyroid, penis, prostate, salivary glands, skin, spleen, testis, thymus, thyroid, and uterus; a viral infection such as those caused by adenoviruses (acute respiratory disease, pneumonia), arenaviruses (lymphocytic choriomeningitis), bunyaviruses (Hantavirus), coronaviruses (pneumonia, chronic bronchitis), hepadnaviruses (hepatitis), herpesviruses (herpes simplex virus, varicella-zoster virus, Epstein-Barr virus, cytomegalovirus), flaviviruses (yellow fever), orthomyxoviruses (influenza), papillomaviruses (cancer), paramyxoviruses (measles, mumps), picornoviruses (rhinovirus, poliovirus, coxsackie-virus), polyomaviruses (BK virus, JC virus), poxviruses (smallpox), reovirus (Colorado tick fever), retroviruses (human immunodeficiency virus, human T lymphotropic virus), rhabdoviruses (rabies), rotaviruses (gastroenteritis), and togaviruses (encephalitis, rubella); and a neurological disorder such as epilepsy, ischemic cerebrovascular disease, stroke, cerebral neoplasms, Alzheimer's disease, Pick's disease, Huntington's disease, dementia, Parkinson's disease and other extrapyramidal disorders, amyotrophic lateral sclerosis and other motor neuron disorders, progressive neural muscular atrophy, retinitis pigmentosa, hereditary ataxias, multiple sclerosis and other demyelinating diseases, bacterial and viral meningitis, brain abscess, subdural empyema, epidural abscess, suppurative intracranial thrombophlebitis, myelitis and radiculitis, viral central nervous system disease, a prion disease including kuru, Creutzfeldt-Jakob disease, and Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia, nutritional and metabolic diseases of the nervous system, neurofibromatosis, tuberous sclerosis, cerebelloretinal hemangioblastomatosis, encephalotrigeminal syndrome, mental retardation and other developmental disorders of the central nervous system, cerebral palsy, neuroskeletal disorders, autonomic nervous system disorders, cranial nerve disorders, spinal cord diseases, muscular dystrophy and other neuromuscular disorders, peripheral nervous system disorders, dermatomyositis and polymyositis, inherited, metabolic, endocrine, and toxic myopathies, myasthenia gravis, periodic paralysis, mental disorders including mood, anxiety, and schizophrenic disorders, seasonal affective disorder (SAD), akathesia, amnesia, catatonia, diabetic neuropathy, tardive dyskinesia, dystonias, paranoid psychoses, postherpetic neuralgia, and Tourette's disorder;
[from pf-1310] and a heart and skeletal muscle disorder such as cardiomyopathy, myocarditis, Duchenne's muscular dystrophy, Becker's muscular dystrophy, myotonic dystrophy, central core disease, nemaline myopathy, centronuclear myopathy, lipid myopathy, mitochondrial myopathy, infectious myositis, polymyositis, dermatomyositis, inclusion body myositis, thyrotoxic myopathy, and ethanol myopathy.
In another embodiment, a vector capable of expressing SCAP or a fragment or derivative thereof may be administered to a subject to treat or prevent a disorder associated with decreased expression or activity of SCAP including, but not limited to, those described above.
In a further embodiment, a composition comprising a substantially purified SCAP in conjunction with a suitable pharmaceutical carrier may be administered to a subject to treat or prevent a disorder associated with decreased expression or activity of SCAP including, but not limited to, those provided above.
In still another embodiment, an agonist which modulates the activity of SCAP
may be administered to a subject to treat or prevent a disorder associated with decreased expression or activity of SCAP including, but not limited to, those listed above.
In a further embodiment, an antagonist of SCAP may be administered to a subject to treat or prevent a disorder associated with increased expression or activity of SCAP.
Examples of such disorders include, but are not limited to, those cell proliferative disorders, viral infections, neurological disorders, and heart and skeletal muscle disorders described above. In one aspect, an antibody which specifically binds SCAP may be used directly as an antagonist or indirectly as a targeting or delivery mechanism for bringing a pharmaceutical agent to cells or tissues which express SCAP.
In an additional embodiment, a vector expressing the complement of the polynucleotide encoding SCAP may be administered to a subject to treat or prevent a disorder associated with increased expression or activity of SCAP including, but not limited to, those described above.
In other embodiments, any protein, agonist, antagonist, antibody, complementary sequence, or vector embodiments may be administered in combination with other appropriate therapeutic agents. Selection of the appropriate agents for use in combination therapy may be made by one of 5~

ordinary skill in the art, according to conventional pharmaceutical principles. The combination of therapeutic agents may act synergistically to effect the treatment or prevention of the various disorders described above. Using this approach, one may be able to achieve therapeutic efficacy with lower dosages of each agent, thus reducing the potential for adverse side effects.
An antagonist of SCAP may be produced using methods which are generally known in the art. In particular, purified SCAP may be used to produce antibodies or to screen libraries of pharmaceutical agents to identify those which specifically bind SCAP.
Antibodies to SCAP may also be generated using methods that are well known in the art. Such antibodies may include, but are not limited to, polyclonal, monoclonal, chimeric, and single chain antibodies, Fab fragments, and fragments produced by a Fab expression library. In an embodiment, neutralizing antibodies (i.e., those which inhibit dimer formation) can be used therapeutically. Single chain antibodies (e.g., from camels or llamas) may be potent enzyme inhibitors and may have application in the design of peptide mimetics, and in the development of immuno-adsorbents and biosensors (Muyldermans, S. (2001) J.
Biotechnol. 74:277-302).
For the production of antibodies, various hosts including goats, rabbits, rats, mice, camels, dromedaries, llamas, humans, and others may be immunized by injection with SCAP or with any fragment or oligopeptide thereof which has immunogenic properties. Depending on the host species, various adjuvants may be used to increase immunological response. Such adjuvants include, but are not limited to, Freund's, mineral gels such as aluminum hydroxide, and surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, KLH, and dinitrophenol.
Among adjuvants used in humans, BCG (bacilli Calmette-Guerin) and Corynebacterium parvum are especially preferable.
It is preferred that the oligopeptides, peptides, or fragments used to induce antibodies to SCAP have an amino acid sequence consisting of at least about 5 amino acids, and generally will consist of at least about 10 amino acids. It is also preferable that these oligopeptides, peptides, or fragments are substantially identical to a portion of the amino acid sequence of the natural protein.
Short stretches of SCAP amino acids may be fused with those of another protein, such as KLH, and antibodies to the chimeric molecule may be produced.
Monoclonal antibodies to SCAP may be prepared using any technique which provides for the production of antibody molecules by continuous cell lines in culture. These include, but are not limited to, the hybridoma technique, the human B-cell hybridoma technique, and the EBV-hybridoma technique (Kohler, G. et al. (1975) Nature 256:495-497; Kozbor, D. et al.
(1985) J. Immunol.
Methods 81:31-42; Cote, R.J. et al. ( 1983) Proc. Natl. Acad. Sci. USA 80:2026-2030; Cole, S.P. et al.
( 1984) Mol. Cell Biol. 62:109-120).
In addition, techniques developed for the production of "chimeric antibodies,"
such as the splicing of mouse antibody genes to human antibody genes to obtain a molecule with appropriate antigen specificity and biological activity, can be used (Morrison, S.L. et al. (1984) Proc. Natl. Acad.
Sci. USA 81:6851-6855; Neuberger, M.S. et al. (1984) Nature 312:604-608;
Takeda, S. et al. (1985) Nature 314:452-454). Alternatively, techniques described for the production of single chain antibodies may be adapted, using methods known in the art, to produce SCAP-specific single chain antibodies. Antibodies with related specificity, but of distinct idiotypic composition, may be generated by chain shuffling from random combinatorial immunoglobulin libraries (Burton, D.R.
(1991) Proc. Natl. Acad. Sci. USA 88:10134-10137).
Antibodies may also be produced by inducing in vivo production in the lymphocyte population or by screening immunoglobulin libraries or panels of highly specific binding reagents as disclosed in the literature (Orlandi, R. et al. (1989) Proc. Natl. Acad. Sci.
USA 86:3833-3837; Winter, G. et al. (1991) Nature 349:293-299).
Antibody fragments which contain specific binding sites for SCAP may also be generated.
For example, such fragments include, but are not limited to, F(ab~2 fragments produced by pepsin digestion of the antibody molecule and Fab fragments generated by reducing the disulfide bridges of the F(ab~2 fragments. Alternatively, Fab expression libraries may be constructed to allow rapid and easy identification of monoclonal Fab fragments with the desired specificity (Huse, W.D. et al. (1989) Science 246:1275-1281).
Various immunoassays may be used for screening to identify antibodies having the desired specificity. Numerous protocols for competitive binding or immunoradiometric assays using either polyclonal or monoclonal antibodies with established specificities are well known in the art. Such immunoassays typically involve the measurement of complex formation between SCAP and its specific antibody. A two-site, monoclonal-based immunoassay utilizing monoclonal antibodies reactive to two non-interfering SCAP epitopes is generally used, but a competitive binding assay may also be employed (Pound, supra).
Various methods such as Scatchard analysis in conjunction with radioimmunoassay techniques may be used to assess the affinity of antibodies for SCAP. Affinity is expressed as an association constant, K", which is defined as the molar concentration of SCAP-antibody complex divided by the molar concentrations of free antigen and free antibody under equilibrium conditions.
The K;, determined for a preparation of polyclonal antibodies, which are heterogeneous in their affinities for multiple SCAP epitopes, represents the average affinity, or avidity, of the antibodies for SCAP. The K~ determined for a preparation of monoclonal antibodies, which are monospecific for a particular SCAP epitope, represents a true measure of affinity. High-affinity antibody preparations with K~ ranging from about 109 to 10'Z L/mole are preferred for use in immunoassays in which the SCAP-antibody complex must withstand rigorous manipulations. Low-affinity antibody preparations with K~ ranging from about 106 to 10' L/mole are preferred for use in immunopurification and similar procedures which ultimately require dissociation of SCAP, preferably in active form, from the antibody (Catty, D. ( 1988) Antibodies, Volume I: A Practical Approach, IRL
Press, Washington DC;
Liddell, J.E. and A. Cryer (1991) A Practical Guide to Monoclonal Antibodies, John Wiley & Sons, New York NY).
The titer and avidity of polyclonal antibody preparations may be further evaluated to determine the quality and suitability of such preparations for~certain downstream applications. For example, a polyclonal antibody preparation containing at least 1-2 mg specific antibody/ml, preferably 5-10 mg specific antibody/ml, is generally employed in procedures requiring precipitation of SCAP-antibody complexes. Procedures for evaluating antibody specificity, titer, and avidity, and guidelines for antibody quality and usage in various applications, are generally available (Catty, supra; Coligan et al., supra).
In another embodiment of the invention, polynucleotides encoding SCAP, or any fragment or complement thereof, may be used for therapeutic purposes. In one aspect, modifications of gene IS expression can be achieved by designing complementary sequences or antisense molecules (DNA, RNA, PNA, or modified oligonucleotides) to the coding or regulatory regions of the gene encoding SCAP. Such technology is well known in the art, and antisense oligonucleotides or larger fragments can be designed from various locations along the coding or control regions of sequences encoding SCAP (Agrawal, S., ed. (1996) Antisense Therapeutics, Humana Press, Totawa NJ).
In therapeutic use, any gene delivery system suitable for introduction of the antisense sequences into appropriate target cells can be used. Antisense sequences can be delivered intracellularly in the form of an expression plasmid which, upon transcription, produces a sequence complementary to at least a portion of the cellular sequence encoding the target protein (Slater, J.E. et al. (1998) J. Allergy Clin. Immunol. 102:469-475; Scanlon, K.J. et al. (1995) 9:1288-1296).
Antisense sequences can also be introduced intracellularly through the use of viral vectors, such as retrovirus and adeno-associated virus vectors (Miller, A.D. (1990) Blood 76:271; Ausubel et al., supra; Uckert, W. and W. Walther (1994) Pharmacol. Ther. 63:323-347). Other gene delivery mechanisms include liposome-derived systems, artificial viral envelopes, and other systems known in the art (Rossi, J.J. (1995) Br. Med. Bull. 51:217-225; Boado, R.J. et al.
(1998) J. Pharm. Sci.
87:1308-1315; Morris, M.C. et al. (1997) Nucleic Acids Res. 25:2730-2736).
In another embodiment of the invention, polynucleotides encoding SCAP may be used for somatic or germline gene therapy. Gene therapy may be performed to (i) correct a genetic deficiency (e.g., in the cases of severe combined immunodeficiency (SC>D)-X1 disease characterized by X-linked inheritance (Cavazzana-Calvo, M. et al. (2000) Science 288:669-672), severe combined immunodeficiency syndrome associated with an inherited adenosine deaminase (ADA) deficiency (Blaese, R.M. et al. (1995) Science 270:475-480; Bordignon, C. et al. (1995) Science 270:470-475), cystic fibrosis (Zabner, J. et al. (1993) Cell 75:207-216; Crystal, R.G. et al. (1995) Hum. Gene Therapy 6:643-666; Crystal, R.G. et al. (1995) Hum. Gene Therapy 6:667-703), thalassamias, familial hypercholesterolemia, and hemophilia resulting from Factor VIII or Factor IX
deficiencies (Crystal, R.G. (1995) Science 270:404-410; Verma, LM. and N. Somia (1997) Nature 389:239-242)), (ii) express a conditionally lethal gene product (e.g., in the case of cancers which result from unregulated cell proliferation), or (iii) express a protein which affords protection against intracellular parasites (e.g., against human retroviruses, such as human immunodeficiency virus (HIV) (Baltimore, D.
(1988) Nature 335:395-396; Poeschla, E. et al. (1996) Proc. Natl. Acad. Sci.
USA 93:11395-11399), hepatitis B or C virus (HBV, HCV); fungal parasites, such as Candida albicans and Paracoccidioides brasiliensis; and protozoan parasites such as Plasmodium falciparum and Trypanosoma cruzi). In the case where a genetic deficiency in SCAP expression or regulation causes disease, the expression of SCAP from an appropriate population of transduced cells may alleviate the clinical manifestations caused by the genetic deficiency.
In a further embodiment of the invention, diseases or disorders caused by deficiencies in SOAP are treated by constructing mammalian expression vectors encoding SCAP
and introducing these vectors by mechanical means into SCAP-deficient cells. Mechanical transfer technologies for use with cells in vivo or ex vitro include (i) direct DNA microinjection into individual cells, (ii) ballistic gold particle delivery, (iii) liposome-mediated transfection, (iv) receptor-mediated gene transfer, and (v) the use of DNA transposons (Morgan, R.A. and W.F. Anderson (1993) Annu. Rev.
Biochem. 62:191-217; Ivics, Z. (1997) Cell 91:501-510; Boulay, J.-L. and H.
Recipon (1998) Curr.
Opin. Biotechnol. 9:445-450).
Expression vectors that may be effective for the expression of SCAP include, but are not limited to, the PCDNA 3.1, EPITAG, PRCCMV2, PREP, PVAX, PCR2-TOPOTA vectors s; 25 (Invitrogen, Carlsbad CA), PCMV-SCRIPT, PCMV-TAG, PEGSH/PERV
(Stratagene, La Jolla CA), and PTET-OFF, PTET-ON, PTRE2, PTRE2-LUC, PTK-HYG (Clontech, Palo Alto CA).
SCAP may be expressed using (i) a constitutively active promoter, (e.g., from cytomegalovirus (CMV), Rous sarcoma virus (RSV), SV40 virus, thymidine kinase (TK), or (3-actin genes), (ii) an inducible promoter (e.g., the tetracycline-regulated promoter (Gossen, M. and H. Bujard (1992) Proc. Natl.
Acad. Sci. USA 89:5547-5551; Gossen, M. et al. (1995) Science 268:1766-1769;
Rossi, F.M.V. and H.M. Blau (1998) Curr. Opin. Biotechnol. 9:451-456), commercially available in the T-REX plasmid (Invitrogen)); the ecdysone-inducible promoter (available in the plasmids PVGRXR and PIND;
Invitrogen); the FK506/rapamycin inducible promoter; or the RU486/mifepristone inducible promoter (Rossi, F.M.V. and H.M. Blau, supra)), or (iii) a tissue-specific promoter or the native promoter of the endogenous gene encoding SCAP from a normal individual.

Commercially available liposome transformation kits (e.g., the PERFECT LIPID
TRANSFECTION KIT, available from Invitrogen) allow one with ordinary skill in the art to deliver polynucleotides to target cells in culture and require minimal effort to optimize experimental parameters. In the alternative, transformation is performed using the calcium phosphate method (Graham, F.L. and A.J. Eb (1973) Virology 52:456-467), or by electroporation (Neumann, E. et al.
(1982) EMBO J. 1:841-845). The introduction of DNA to primary cells requires modification of these standardized mammalian transfection protocols.
In another embodiment of the invention, diseases or disorders caused by genetic defects with respect to SCAP expression are treated by constructing a retrovirus vector consisting of (i) the polynucleotide encoding SCAP under the control of an independent promoter or the retrovirus long terminal repeat (LTR) promoter, (ii) appropriate RNA packaging signals, and (iii) a Rev-responsive element (RRE) along with additional retrovirus cis-acting RNA sequences and coding sequences required for efficient vector propagation. Retrovirus vectors (e.g., PFB and PFBNEO) are commercially available (Stratagene) and are based on published data (Riviere, I. et al. (1995) Proc.
Natl. Acad. Sci. USA 92:6733-6737), incorporated by reference herein. The vector is propagated in an appropriate vector producing cell line (VPCL) that expresses an envelope gene with a tropism for receptors on the target cells or a promiscuous envelope protein such as VSVg (Armentano, D. et al.
(1987) J. Virol. 61:1647-1650; Bender, M.A. et al. (1987) J. Virol. 61:1639-1646; Adam, M.A. and A.D. Miller (1988) J. Virol. 62:3802-3806; Dull, T. et al. (1998) J. Virol.
72:8463-8471; Zufferey, R.
et al. (1998) J. Virol.-72:9873-9880). U.S. Patent No. 5,910,434 to Rigg ("Method for obtaining retrovirus packaging cell lines producing high transducing efficiency retroviral supernatant") discloses a method for obtaining retrovirus packaging cell lines and is hereby incorporated by reference. Propagation of retrovirus vectors, transduction of a population of cells (e.g., CD4+ T-cells), and the return of transduced cells to a patient are procedures well known to persons skilled in the art of gene therapy and have been well documented (Ranga, U. et al. (1997) J. Virol. 71:7020-7029; Bauer, G. et al. (1997) Blood 89:2259-2267; Bonyhadi, M.L. (1997) J.
Virol. 71:4707-4716;
Ranga, U. et al. (1998) Proc. Natl. Acad. Sci. USA 95:1201-1206; Su, L. (1997) Blood 89:2283-2290).
In an embodiment, an adenovirus-based gene therapy delivery system is used to deliver polynucleotides encoding SCAP to cells which have one or more genetic abnormalities with respect to the expression of SCAP. The construction and packaging of adenovirus-based vectors are well known to those with ordinary skill in the art. Replication defective adenovirus vectors have proven to be versatile for importing genes encoding immunoregulatory proteins into intact islets in the pancreas (Csete, M.E. et al. (1995) Transplantation 27:263-268). Potentially useful adenoviral vectors are described in U.S. Patent No. 5,707,618 to Armentano ("Adenovirus vectors for gene therapy"), hereby incorporated by reference. For adenoviral vectors, see also Antinozzi, P.A. et al. (1999; Annu.
Rev. Nutr. 19:511-544) and Verma, LM. and N. Somia ( 1997; Nature 18:389:239-242).
In another embodiment, a herpes-based, gene therapy delivery system is used to deliver polynucleotides encoding SCAP to target cells which have one or more genetic abnormalities with respect to the expression of SCAP. The use of herpes simplex virus (HSV)-based vectors may be especially valuable for introducing SCAP to cells of the central nervous system, for which HSV has a tropism. The construction and packaging of herpes-based vectors are well known to those with ordinary skill in the art. A replication-competent herpes simplex virus (HSV) type 1-based vector has been used to deliver a reporter gene to the eyes of primates (Liu, X. et al.
(1999) Exp. Eye Res.
169:385-395). The construction of a HSV-1 virus vector has also been disclosed in detail in U.S.
Patent No. 5,804,413 to DeLuca ("Herpes simplex virus strains for gene transfer"), which is hereby incorporated by reference. U.5. Patent No. 5,804,413 teaches the use of recombinant HSV d92 which consists of a genome containing at least one exogenous gene to be transferred to a cell under the control of the appropriate promoter for purposes including human gene therapy.
Also taught by this patent are the construction and use of recombinant HSV strains deleted for ICP4, ICP27 and ICP22.
For HSV vectors, see also Goins, W.F. et al. (1999; J. Virol. 73:519-532) and Xu, H. et al. (1994;
Dev. Biol. 163:152-161). The manipulation of cloned herpesvirus sequences, the generation of recombinant virus following the transfection of multiple plasmids containing different segments of the large herpesvirus genomes, the growth and propagation of herpesvirus, and the infection of cells with herpesvirus are techniques well known to those of ordinary skill in the art.
In another embodiment, an alphavirus (positive, single-stranded RNA virus) vector is used to deliver polynucleotides encoding SCAP to target cells. The biology of the prototypic alphavirus, Semliki Forest Virus (SFV), has been studied extensively and gene transfer vectors have been based on the SFV genome (Garoff, H. and K.-J. Li (1998) Curr. Opin. Biotechnol.
9:464-469). During.
alphavirus RNA replication, a subgenomic RNA is generated that normally encodes the viral capsid proteins. This subgenomic RNA replicates to higher levels than the full length genomic RNA, resulting in the overproduction of capsid proteins relative to the viral proteins with enzymatic activity (e.g., protease and polymerase). Similarly, inserting the coding sequence for SCAP into the alphavirus genome in place of the capsid-coding region results in the production of a large number of SCAP-coding RNAs and the synthesis of high levels of SCAP in vector transduced cells. While alphavirus infection is typically associated with cell lysis within a few days, the ability to establish a persistent infection in hamster normal kidney cells (BHK-21) with a variant of Sindbis virus (SIN) indicates that the lytic replication of alphaviruses can be altered to suit the needs of the gene therapy application (Dryga, S.A. et al. (1997) Virology 228:74-83). The wide host range of alphaviruses will allow the introduction of SCAP into a variety of cell types. The specific transduction of a subset of cells in a population may require the sorting of cells prior to transduction.
The methods of manipulating infectious cDNA clones of alphaviruses, performing alphavirus cDNA and RNA
transfections, and performing alphavirus infections, are well known to those with ordinary skill in the art.
Oligonucleotides derived from the transcription initiation site, e.g., between about positions -10 and +10 from the start site, may also be employed to inhibit gene expression. Similarly, inhibition can be achieved using triple helix base-pairing methodology. Triple helix pairing is useful because it causes inhibition of the ability of the double helix to open sufficiently for the binding of polymerises, transcription factors, or regulatory molecules. Recent therapeutic advances using triplex DNA have been described in the literature (Gee, J.E. et al. (1994) in Huber, B.E. and B.I. Carr, Molecular and Immunologic Approaches, Futura Publishing, Mt. Kisco NY, pp. 163-177). A
complementary sequence or antisense molecule may also be designed to block translation of mRNA
by preventing the transcript from binding to ribosomes.
Ribozymes, enzymatic RNA molecules, may also be used to catalyze the specific cleavage of RNA. The mechanism of ribozyme action involves sequence-specific hybridization of the ribozyme molecule to complementary target RNA, followed by endonucleolytic cleavage.
For example, engineered hammerhead motif ribozyme molecules may specifically and efficiently catalyze endonucleolytic cleavage of RNA molecules encoding SCAP.
Specific ribozyme cleavage sites within any potential RNA target are initially identified by scanning the target molecule for ribozyme cleavage sites, including the following sequences: GUA, GUU, and GUC. Once identified, short RNA sequences of between 15 and 20 ribonucleotides, corresponding to the region of the target gene containing the cleavage site, may be evaluated for secondary structural features which may render the oligonucleotide inoperable.
The suitability of candidate targets may also be evaluated by testing accessibility to hybridization with complementary oligonucleotides using ribonuclease protection assays.
Complementary ribonucleic acid molecules and ribozymes may be prepared by any method known in the art for the synthesis of nucleic acid molecules. These include techniques for chemically synthesizing oligonucleotides such as solid phase phosphoramidite chemical synthesis. Alternatively, RNA molecules may be generated by in vitro and in vivo transcription ofDNA
molecules encoding SCAP. Such DNA sequences may be incorporated into a wide variety of vectors with suitable RNA
polymerise promoters such as T7 or SP6. Alternatively, these cDNA constructs that synthesize complementary RNA, constitutively or inducibly, can be introduced into cell lines, cells, or tissues.
RNA molecules may be modified to increase intracellular stability and half-life. Possible modifications include, but are not limited to, the addition of flanking sequences at the 5' and/or 3' ends of the molecule, or the use of phosphorothioate or 2' O-methyl rather than phosphodiesterase linkages within the backbone of the molecule. This concept is inherent in the production of PNAs and can be extended in all of these molecules by the inclusion of nontraditional bases such as inosine, queosine, and wybutosine, as well as acetyl-, methyl-, thio-, and similarly modified forms of adenine, cytidine, guanine, thymine, and uridine which are not as easily recognized by endogenous endonucleases.
In other embodiments of the invention, the expression of one or more selected polynucleotides of the present invention can be altered, inhibited, decreased, or silenced using RNA
interference (RNAi) or post-transcriptional gene silencing (PTGS) methods known in the art. RNAi is a post-transcriptional mode of gene silencing in which double-stranded RNA
(dsRNA) introduced into a targeted cell specifically suppresses the expression of the homologous gene (i.e., the gene bearing the sequence complementary to the dsRNA). This effectively knocks out or substantially reduces the expression of the targeted gene. PTGS can also be accomplished by use of DNA or DNA
fragments as well. RNAi methods are described by Fire, A. et al. (1998; Nature 391:806-811) and Gura, T. (2000; Nature 404:804-808). PTGS can also be initiated by introduction of a complementary segment of DNA into the selected tissue using gene delivery and/or viral vector delivery methods described herein or known in the art.
RNAi can be induced in mammalian cells by the use of small interfering RNA
also known as siRNA. SiRNA are shorter segments of dsRNA (typically about 21 to 23 nucleotides in length) that result in vivo from cleavage of introduced dsRNA by the action of an endogenous ribonuclease.
SiRNA appear to be the mediators of the RNAi effect in mammals. The most effective siRNAs appear to be 21 nucleotide dsRNAs with 2 nucleotide 3' overhangs. The use of siRNA for inducing RNAi in mammalian cells is described by Elbashir, S.M. et al. (2001; Nature 411:494-498).
SiRNA can either be generated indirectly by introduction of dsRNA into the targeted cell, or directly by mammalian transfection methods and agents described herein or known in the art (such as liposome-mediated transfection, viral vector methods, or other polynucleotide delivery/introductory methods). Suitable SiRNAs can be selected by examining a transcript of the target polynucleotide (e.g., mRNA) for nucleotide sequences downstream from the AUG start codon and recording the occurrence of each nucleotide and the 3' adjacent 19 to 23 nucleotides as potential siRNA target sites, with sequences having a 21 nucleotide length being preferred. Regions to be avoided for target siRNA sites include the 5' and 3' untranslated regions (UTRs) and regions near the start codon (within 75 bases), as these may be richer in regulatory protein binding sites. UTR-binding proteins and/or translation initiation complexes may interfere with binding of the siRNP
endonuclease complex. The selected target sites for siRNA can then be compared to the appropriate genome database (e.g., human, etc.) using BLAST or other sequence comparison algorithms known in the art. Target ' sequences with significant homology to other coding sequences can be eliminated from consideration.

The selected SiRNAs can be produced by chemical synthesis methods known in the art or by in vitro transcription using commercially available methods and kits such as the SILENCER siRNA
construction kit (Ambion, Austin TX).
In alternative embodiments, long-term gene silencing and/or RNAi effects can be induced in selected tissue using expression vectors that continuously express siRNA. This can be accomplished using expression vectors that are engineered to express hairpin RNAs (shRNAs) using methods known in the art (see, e.g., Brummelkamp, T.R. et al. (2002) Science 296:550-553; and Paddison, P.J.
et al. (2002) Genes Dev. 16:948-958). In these and related embodiments, shRNAs can be delivered to target cells using expression vectors known in the art. An example of a suitable expression vector for delivery of siRNA is the PSILENCER1.0-U6 (circular) plasmid (Ambion). Once delivered to the target tissue, shRNAs are processed in vivo into siRNA-like molecules capable of carrying out gene-specific silencing.
In various embodiments, the expression levels of genes targeted by RNAi or PTGS methods can be determined by assays for mRNA and/or protein analysis. Expression levels of the mRNA of a targeted gene, can be determined by northern analysis methods using, for example, the NORTHERNMAX-GLY kit (Ambion); by microarray methods; by PCR methods; by real time PCR
methods; and by other RNA/polynucleotide assays known in the art or described herein. Expression levels of the protein encoded by the targeted gene can be determined by Western analysis using standard techniques known in the art.
An additional embodiment of the invention encompasses a method for screening for a compound which is effective in altering expression of a polynucleotide encoding SCAP. Compounds which may be effective in altering expression of a specific polynucleotide may include, but are not limited to, oligonucleotides, antisense oligonucleotides, triple helix-forming oligonucleotides, transcription factors and other polypeptide transcriptional regulators, and non-macromolecular chemical entities which are capable of interacting with specific polynucleotide sequences. Effective compounds may alter polynucleotide expression by acting as either inhibitors or promoters of polynucleotide expression. Thus, in the treatment of disorders associated with increased SCAP
expression or activity, a compound which specifically inhibits expression of the polynucleotide encoding SCAP may be therapeutically useful, and in the treatment of disorders associated with decreased SCAP expression or activity, a compound which specifically promotes expression of the polynucleotide encoding SCAP may be therapeutically useful.
In various embodiments, one or more test compounds may be screened for effectiveness in altering expression of a specific polynucleotide. A test compound may be obtained by any method commonly known in the art, including chemical modification of a compound known to be effective in altering polynucleotide expression; selection from an existing, commercially-available or proprietary library of naturally-occurring or non-natural chemical compounds; rational design of a compound based on chemical and/or structural properties of the target polynucleotide;
and selection from a library of chemical compounds created combinatorially or randomly. A sample comprising a polynucleotide encoding SCAP is exposed to at least one test compound thus obtained. The sample may comprise, for example, an intact or permeabilized cell, or an in vitro cell-free or reconstituted biochemical system. Alterations in the expression of a polynucleotide encoding SCAP are assayed by any method commonly known in the art. Typically, the expression of a specific nucleotide is detected by hybridization with a probe having a nucleotide sequence complementary to the sequence of the polynucleotide encoding SCAP. The amount of hybridization may be quantified, thus forming the basis for a comparison of the expression of the polynucleotide both with and without exposure to one or more test compounds. Detection of a change in the expression of a polynucleotide exposed to a test compound indicates that the test compound is effective in altering the expression of the polynucleotide. A screen for a compound effective in altering expression of a specific polynucleotide can be carried out, for example, using a Schizosaccharomyces pombe gene expression system (Atkins, D. et al. (1999) U.S. Patent No. 5,932,435; Arndt, G.M. et al. (2000) Nucleic Acids Res.
28:E15) or a human cell line such as HeLa cell (Clarke, M.L. et al. (2000) Biochem. Biophys. Res.
Common. 268:8-13). A particular embodiment of the present invention involves screening a combinatorial library of oligonucleotides (such as deoxyribonucleotides, ribonucleotides, peptide nucleic acids, and modified oligonucleotides) for antisense activity against a specific polynucleotide sequence (Bruice, T.W. et al. (1997) U.S. Patent No. 5,686,242; Bruice, T.W.
et al. (2000) U.S.
Patent No. 6,022,691 ).
Many methods for introducing vectors into cells or tissues are available and equally suitable for use in vivo, in vitro, and ex vivo. For ex vivo therapy, vectors may be introduced into stem cells taken from the patient and clonally propagated for autologous transplant back into that same patient.
Delivery by transfection, by liposome injections, or by polycationic amino polymers may be achieved using methods which are well known in the art (Goldman, C.K. et al. (1997) Nat. Biotechnol. 15:462-466).
Any of the therapeutic methods described above may be applied to any subject in need of such therapy, including, for example, mammals such as humans, dogs, cats, cows, horses, rabbits, and monkeys.
An additional embodiment of the invention relates to the administration of a composition which generally comprises an active ingredient formulated with a pharmaceutically acceptable excipient. Excipients may include, for example, sugars, starches, celluloses, gums, and proteins.
Various formulations are commonly known and are thoroughly discussed in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing, Easton PA). Such compositions may consist of SCAP, antibodies to SCAP, and mimetics, agonists, antagonists, or inhibitors of SCAP.
In various embodiments, the compositions described herein, such as pharmaceutical compositions, may be administered by any number of routes including, but not limited to, oral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, intraventricular, pulmonary, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, or rectal means.
Compositions for pulmonary administration may be prepared in liquid or dry powder form.
These compositions are generally aerosolized immediately prior to inhalation by the patient. In the case of small molecules (e.g. traditional low molecular weight organic drugs), aerosol delivery of fast-acting formulations is well-known in the art. In the case of macromolecules (e.g. larger peptides and proteins), recent developments in the field of pulmonary delivery via the alveolar region of the lung have enabled the practical delivery of drugs such as insulin to blood circulation (see, e.g., Patton, J.S. et al., U.S. Patent No. 5,997,848). Pulmonary delivery allows administration without needle injection, and obviates the need for potentially toxic penetration enhancers.
Compositions suitable for use in the invention include compositions wherein the active ingredients are contained in an effective amount to achieve the intended purpose. The determination of an effective dose is well within the capability of those skilled in the art.
Specialized forms of compositions may be prepared for direct intracellular delivery of macromolecules comprising SCAP or fragments thereof. For example, liposome preparations containing a cell-impermeable macromolecule may promote cell fusion and intracellular delivery of the macromolecule. Alternatively, SCAP or a fragment thereof may be joined to a short cationic N-terminal portion from the HIV Tat-1 protein. Fusion proteins thus generated have been found to transduce into the cells of all tissues, including the brain, in a mouse model system (Schwarze, S.R. et al. (1999) Science 285:1569-1572).
For any compound, the therapeutically effective dose can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models such as mice, rats, rabbits, dogs, monkeys, or pigs. An animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.
A therapeutically effective dose refers to that amount of active ingredient, for example SCAP
or fragments thereof, antibodies of SCAP, and agonists, antagonists or inhibitors of SCAP, which ameliorates the symptoms or condition. Therapeutic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or with experimental animals, such as by calculating the EDSO (the dose therapeutically effective in 50% of the population) or LDSO (the dose lethal to 50% of the population) statistics. The dose ratio of toxic to therapeutic effects is the therapeutic index, which can be expressed as the LDSO/EDSO ratio. Compositions which exhibit large therapeutic indices are preferred. The data obtained from cell culture assays and animal studies are used to formulate a range of dosage for human use. The dosage contained in such compositions is preferably within a range of circulating concentrations that includes the EDSO
with little or no toxicity.
The dosage varies within this range depending upon the dosage form employed, the sensitivity of the patient, and the route of administration.
The exact dosage will be determined by the practitioner, in light of factors related to the subject requiring treatment. Dosage and administration are adjusted to provide sufficient levels of the active moiety or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, the general health of the subject, the age, weight, and gender of the subject, time and frequency of administration, drug combination(s), reaction sensitivities, and response to therapy. Long-acting compositions may be administered every 3 to 4 days, every week, or biweekly depending on the half-life and clearance rate of the particular formulation.
Normal dosage amounts may vary from about 0.1 ,ug to 100,000 ,ug, up to a total dose of about 1 gram, depending upon the route of administration. Guidance as to particular dosages and methods of delivery is provided in the literature and generally available to practitioners in the art.
Those skilled in the art will employ different formulations for nucleotides than for proteins or their inhibitors. Similarly, delivery of polynucleotides or polypeptides will be specific to particular cells, conditions, locations, etc.
DIAGNOSTICS
In another embodiment, antibodies which specifically bind SCAP may be used for the diagnosis of disorders characterized by expression of SCAP, or in assays to monitor patients being treated with SCAP or agonists, antagonists, or inhibitors of SCAP. Antibodies useful for diagnostic purposes may be prepared in the same manner as described above for therapeutics. Diagnostic assays for SCAP include methods which utilize the antibody and a label to detect SCAP
in human body fluids or in extracts of cells or tissues. The antibodies may be used with or without modification, and may be labeled by covalent or non-covalent attachment of a reporter molecule.
A wide variety of reporter molecules, several of which are described above, are known in the art and may be used.
A variety of protocols for measuring SOAP, including ELISAs, RIAs, and FACS, are known in the art and provide a basis for diagnosing altered or abnormal levels of SCAP expression. Normal or standard values for SCAP expression are established by combining body fluids or cell extracts taken from normal mammalian subjects, for example, human subjects, with antibodies to SCAP under conditions suitable for complex formation. The amount of standard complex formation may be quantitated by various methods, such as photometric means. Quantities of SOAP
expressed in subject, control, and disease samples from biopsied tissues are compared with the standard values.
Deviation between standard and subject values establishes the parameters for diagnosing disease.

In another embodiment of the invention, polynucleotides encoding SCAP may be used for diagnostic purposes. The polynucleotides which may be used include oligonucleotides, complementary RNA and DNA molecules, and PNAs. The polynucleotides may be used to detect and quantify gene expression in biopsied tissues in which expression of SCAP
may be correlated with disease. The diagnostic assay may be used to determine absence, presence, and excess expression of SCAP, and to monitor regulation of SCAP levels during therapeutic intervention.
In one aspect, hybridization with PCR probes which are capable of detecting polynucleotides, including genomic sequences, encoding SCAP or closely related molecules may be used to identify nucleic acid sequences which encode SCAP. The specificity of the probe, whether it is made from a highly specific region, e.g., the 5'regulatory region, or from a less specific region, e.g., a conserved motif, and the stringency of the hybridization or amplification will determine whether the probe identifies only naturally occurring sequences encoding SCAP, allelic variants, or related sequences.
Probes may also be used for the detection of related sequences, and may have at least 50%
sequence identity to any of the SCAP encoding sequences. The hybridization probes of the subject invention may be DNA or RNA and may be derived from the sequence of SEQ 117 N0:52-102 or from genomic sequences including promoters, enhancers, and introns of the SCAP
gene.
Means for producing specific hybridization probes for polynucleotides encoding SOAP
include the cloning of polynucleotides encoding SCAP or SOAP derivatives into vectors for the production of mRNA probes. Such vectors are known in the art, are commercially available, and may be used to synthesize RNA probes in vitro by means of the addition of the appropriate RNA
polymerases and the appropriate labeled nucleotides. Hybridization probes may be labeled by a variety of reporter groups, for example, by radionuclides such as 32P or 35S, or by enzymatic labels, such as alkaline phosphatase coupled to the probe via avidin/biotin coupling systems, and the like.
Polynucleotides encoding SCAP may be used for the diagnosis of disorders associated with expression of SCAP. Examples of such disorders include, but are not limited to, a cell proliferative disorder such as actinic keratosis, arteriosclerosis, atherosclerosis, bursitis, cirrhosis, hepatitis, mixed connective tissue disease (MCTD), myelofibrosis, paroxysmal nocturnal hemoglobinuria, polycythemia vera, psoriasis, primary thrombocythemia, and a cancer including adenocarcinoma, leukemia, lymphoma, melanoma, myeloma, sarcoma, teratocarcinoma, and, in particular, a cancer of the adrenal gland, bladder, bone, bone marrow, brain, breast, cervix, gall bladder, ganglia, gastrointestinal tract, heart, kidney, liver, lung, muscle, ovary, pancreas, parathyroid, penis, prostate, salivary glands, skin, spleen, testis, thymus, thyroid, and uterus; a viral infection such as those caused by adenoviruses (acute respiratory disease, pneumonia), arenaviruses (lymphocytic choriomeningitis), bunyaviruses (Hantavirus), coronaviruses (pneumonia, chronic bronchitis), hepadnaviruses (hepatitis), herpesviruses (herpes simplex virus, varicella-zoster virus, Epstein-Barr virus, ~o cytomegalovirus), flaviviruses (yellow fever), orthomyxoviruses (influenza), papillomaviruses (cancer), paramyxoviruses (measles, mumps), picornoviruses (rhinovirus, poliovirus, coxsackie-virus), polyomaviruses (BK virus, JC virus), poxviruses (smallpox), reovirus (Colorado tick fever), retroviruses (human immunodeficiency virus, human T lymphotropic virus), rhabdoviruses (rabies), rotaviruses (gastroenteritis), and togaviruses (encephalitis, rubella); and a neurological disorder such as epilepsy, ischemic cerebrovascular disease, stroke, cerebral neoplasms, Alzheimer's disease, Pick's disease, Huntington's disease, dementia, Parkinson's disease and other extrapyramidal disorders, amyotrophic lateral sclerosis and other motor neuron disorders, progressive neural muscular atrophy, retinitis pigmentosa, hereditary ataxias, multiple sclerosis and other demyelinating diseases, bacterial and viral meningitis, brain abscess, subdural empyema, epidural abscess, suppurative intracranial thrombophlebitis, myelitis and radiculitis, viral central nervous system disease, a prion disease including kuru, Creutzfeldt-Jakob disease, and Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia, nutritional and metabolic diseases of the nervous system, neurofibromatosis, tuberous sclerosis, cerebelloretinal hemangioblastomatosis, encephalotrigeminal syndrome, mental retardation and other developmental disorders of the central nervous system, cerebral palsy, neuroskeletal disorders, autonomic nervous system disorders, cranial nerve disorders, spinal cord diseases, muscular dystrophy and other neuromuscular disorders, peripheral nervous system disorders, dermatomyositis and polymyositis, inherited, metabolic, endocrine, and toxic myopathies, myasthenia gravis, periodic paralysis, mental disorders including mood, anxiety, and schizophrenic disorders, seasonal affective disorder (SAD), akathesia, amnesia, catatonia, diabetic neuropathy, tardive dyskinesia, dystonias, paranoid psychoses, postherpetic neuralgia, and Tourette's disorder;
[from pf-1310] and a heart and skeletal muscle disorder such as cardiomyopathy, myocarditis, Duchenne's muscular dystrophy, Becker's muscular dystrophy, myotonic dystrophy, central core disease, nemaline myopathy, centronuclear myopathy, lipid myopathy, mitochondrial myopathy, infectious myositis, polymyositis, dermatomyositis, inclusion body myositis, thyrotoxic myopathy, and ethanol myopathy. Polynucleotides encoding SCAP may be used in Southern or northern analysis, dot blot, or other membrane-based technologies; in PCR technologies;
in dipstick, pin, and multiformat ELISA-like assays; and in microarrays utilizing fluids or tissues from patients to detect altered SCAP expression. Such qualitative or quantitative methods are well known in the art.
In a particular embodiment, polynucleotides encoding SCAP may be used in assays that detect the presence of associated disorders, particularly those mentioned above. Polynucleotides complementary to sequences encoding SCAP may be labeled by standard methods and added to a fluid or tissue sample from a patient under conditions suitable for the formation of hybridization complexes. After a suitable incubation period, the sample is washed and the signal is quantified and compared with a standard value. If the amount of signal in the patient sample is significantly altered ~i in comparison to a control sample then the presence of altered levels of polynucleotides encoding SCAP in the sample indicates the presence of the associated disorder. Such assays may also be used to evaluate the efficacy of a particular therapeutic treatment regimen in animal studies, in clinical trials, or to monitor the treatment of an individual patient.
In order to provide a basis for the diagnosis of a disorder associated with expression of SCAP, a normal or standard profile for expression is established. This may be accomplished by combining body fluids or cell extracts taken from normal subjects, either animal or human, with a sequence, or a fragment thereof, encoding SCAP, under conditions suitable for hybridization or amplification. Standard hybridization may be quantified by comparing the values obtained from normal subjects with values from an experiment in which a known amount of a substantially purified polynucleotide is used. Standard values obtained in this manner may be compared with values obtained from samples from patients who are symptomatic for a disorder.
Deviation from standard values is used to establish the presence of a disorder.
Once the presence of a disorder is established and a treatment protocol is initiated, hybridization assays may be repeated on a regular basis to determine if the level of expression in the patient begins to approximate that which is observed in the normal subject.
The results obtained from successive assays may be used to show the efficacy of treatment over a period ranging from several days to months.
With respect to cancer, the presence of an abnormal amount of transcript (either under- or overexpressed) in biopsied tissue from an individual may indicate a predisposition for the development of the disease, or may provide a means for detecting the disease prior to the appearance of actual clinical symptoms. A more definitive diagnosis of this type may allow health professionals to employ preventative measures or aggressive treatment earlier, thereby preventing the development or further progression of the cancer.
Additional diagnostic uses for oligonucleotides designed from the sequences encoding SCAP
may involve the use of PCR. These oligomers may be chemically synthesized, generated enzymatically, or produced in vitro. Oligomers will preferably contain a fragment of a polynucleotide encoding SCAP, or a fragment of a polynucleotide complementary to the polynucleotide encoding SCAP, and will be employed under optimized conditions for identification of a specific gene or condition. Oligomers may also be employed under less stringent conditions for detection or quantification of closely related DNA or RNA sequences.
In a particular aspect, oligonucleotide primers derived from polynucleotides encoding SOAP
may be used to detect single nucleotide polymorphisms (SNPs). SNPs are substitutions, insertions and deletions that are a frequent cause of inherited or acquired genetic disease in humans. Methods of SNP detection include, but are not limited to, single-stranded conformation polymorphism (SSCP) and fluorescent SSCP (fSSCP) methods. In SSCP, oligonucleotide primers derived from polynucleotides encoding SCAP are used to amplify DNA using the polymerase chain reaction (PCR). The DNA may be derived, for example, from diseased or normal tissue, biopsy samples, bodily fluids, and the like. SNPs in the DNA cause differences in the secondary and tertiary structures of PCR products in single-stranded form, and these differences are detectable using gel electrophoresis in non-denaturing gels. In fSCCP, the oligonucleotide primers are fluorescently labeled, which allows detection of the amplimers in high-throughput equipment such as DNA
sequencing machines. Additionally, sequence database analysis methods, termed in silico SNP
(isSNP), are capable of identifying polymorphisms by comparing the sequence of individual overlapping DNA fragments which assemble into a common consensus sequence.
These computer-based methods filter out sequence variations due to laboratory preparation of DNA and sequencing errors using statistical models and automated analyses of DNA sequence chromatograms. In the alternative, SNPs may be detected and characterized by mass spectrometry using, for example, the high throughput MASSARRAY system (Sequenom, Inc., San Diego CA).
SNPs may be used to study the genetic basis of human disease. For example, at least 16 common SNPs have been associated with non-insulin-dependent diabetes mellitus.
SNPs are also useful for examining differences in disease outcomes in monogenic disorders, such as cystic fibrosis, sickle cell anemia, or chronic granulomatous disease. For example, variants in the mannose-binding lectin, MBL2, have been shown to be correlated with deleterious pulmonary outcomes in cystic fibrosis. SNPs also have utility in pharmacogenomics, the identification of genetic variants that influence a patient's response to a drug, such as life-threatening toxicity.
For example, a variation in N-acetyl transferase is associated with a high incidence of peripheral neuropathy in response to the anti-tuberculosis drug isoniazid, while a variation in the core promoter of the ALOXS gene results in diminished clinical response to treatment with an anti-asthma drug that targets the 5-lipoxygenase pathway. Analysis of the distribution of SNPs in different populations is useful for investigating genetic drift, mutation, recombination, and selection, as well as for tracing the origins of populations and their migrations (Taylor, J.G. et al. (2001) Trends Mol. Med. 7:507-512;
Kwok, P.-Y. and Z. Gu (1999) Mol. Med. Today 5:538-543; Nowotny, P. et al. (2001) Curr. Opin.
Neurobiol. 11:637-641).
Methods which may also be used to quantify the expression of SCAP include radiolabeling or biotinylating nucleotides, coamplification of a control nucleic acid, and interpolating results from standard curves (Melby, P.C. et al. (1993) J. Immunol. Methods 159:235-244;
Duplaa, C. et al. (1993) Anal. Biochem. 212:229-236). The speed of quantitation of multiple samples may be accelerated by running the assay in a high-throughput format where the oligomer or polynucleotide of interest is presented in various dilutions and a spectrophotometric or colorimetric response gives rapid quantitation.

In further embodiments, oligonucleotides or longer fragments derived from any of the polynucleotides described herein may be used as elements on a microarray. The microarray can be used in transcript imaging techniques which monitor the relative expression levels of large numbers of genes simultaneously as described below. The microarray may also be used to identify genetic variants, mutations, and polymorphisms. This information may be used to determine gene function, to understand the genetic basis of a disorder, to diagnose a disorder, to monitor progression/regression of disease as a function of gene expression, and to develop and monitor the activities of therapeutic agents in the treatment of disease. In particular, this information may be used to develop a pharmacogenomic profile of a patient in order to select the most appropriate and effective treatment regimen for that patient. For example, therapeutic agents which are highly effective and display the fewest side effects may be selected for a patient based on his/her pharmacogenomic profile.
In another embodiment, SCAP, fragments of SCAP, or antibodies specific for SCAP may be used as elements on a microarray. The microarray may be used to monitor or measure protein-protein interactions, drug-target interactions, and gene expression profiles, as described above.
A particular embodiment relates to the use of the polynucleotides of the present invention to generate a transcript image of a tissue or cell type. A transcript image represents the global pattern of gene expression by a particular tissue or cell type. Global gene expression patterns are analyzed by quantifying the number of expressed genes and their relative abundance under given conditions and at a given time (Seilhamer et al., "Comparative Gene Transcript Analysis," U.S.
Patent No. 5,840,484;
hereby expressly incorporated by reference herein). Thus a transcript image may be generated by hybridizing the polynucleotides of the present invention or their complements to the totality of transcripts or reverse transcripts of a particular tissue or cell type. In one embodiment, the hybridization takes place in high-throughput format, wherein the polynucleotides of the present invention or their complements comprise a subset of a plurality of elements on a microarray. The resultant transcript image would provide a profile of gene activity.
Transcript images may be generated using transcripts isolated from tissues, cell lines, biopsies, or other biological samples. The transcript image may thus reflect gene expression in vivo, as in the case of a tissue or biopsy sample, or in vitro, as in the case of a cell line.
Transcript images which profile the expression of the polynucleotides of the present invention may also be used in conjunction with in vitro model systems and preclinical evaluation of pharmaceuticals, as well as toxicological testing of industrial and naturally-occurring environmental compounds. All compounds induce characteristic gene expression patterns, frequently termed molecular fingerprints or toxicant signatures, which are indicative of mechanisms of action and toxicity (Nuwaysir, E.F. et al. (1999) Mol. Carcinog. 24:153-159; Steiner, S.
and N.L. Anderson (2000) Toxicol. Lett. 112-113:467-471). If a test compound has a signature similar to that of a compound with known toxicity, it is likely to share those toxic properties.
These fingerprints or signatures are most useful and refined when they contain expression information from a large number of genes and gene families. Ideally, a genome-wide measurement of expression provides the highest quality signature. Even genes whose expression is not altered by any tested compounds are important as well, as the levels of expression of these genes are used to normalize the rest of the expression data. The normalization procedure is useful for comparison of expression data after treatment with different compounds. While the assignment of gene function to elements of a toxicant signature aids in interpretation of toxicity mechanisms, knowledge of gene function is not necessary for the statistical matching of signatures which leads to prediction of toxicity (see, for example, Press Release 00-02 from the National Institute of Environmental Health Sciences, released February 29, 2000, available at http://www.niehs.nih.gov/oc/news/toxchip.htm). Therefore, it is important and desirable in toxicological screening using toxicant signatures to include all expressed gene sequences.
In an embodiment, the toxicity of a test compound can be assessed by treating a biological sample containing nucleic acids with the test compound. Nucleic acids that are expressed in the treated biological sample are hybridized with one or more probes specific to the polynucleotides of the present invention, so that transcript levels corresponding to the polynucleotides of the present invention may be quantified. The transcript levels in the treated biological sample are compared with levels in an untreated biological sample. Differences in the transcript levels between the two samples are indicative of a toxic response caused by the test compound in the treated sample.
Another embodiment relates to the use of the polypeptides disclosed herein to analyze the proteome of a tissue or cell type. The term proteome refers to the global pattern of protein expression in a particular tissue or cell type. Each protein component of a proteome can be subjected individually to further analysis. Proteome expression patterns, or profiles, are analyzed by quantifying the number of expressed proteins and their relative abundance under given conditions and at a given time. A profile of a cell's proteome may thus be generated by separating and analyzing the polypeptides of a particular tissue or cell type. In one embodiment, the separation is achieved using two-dimensional gel electrophoresis, in which proteins from a sample are separated by isoelectric focusing in the first dimension, and then according to molecular weight by sodium dodecyl sulfate slab gel electrophoresis in the second dimension (Steiner and Anderson, supra). The proteins are visualized in the gel as discrete and uniquely positioned spots, typically by staining the gel with an agent such as Coomassie Blue or silver or fluorescent stains. The optical density of each protein spot is generally proportional to the level of the protein in the sample. The optical densities of equivalently positioned protein spots from different samples, for example, from biological samples either treated or untreated with a test compound or therapeutic agent, are compared to identify any changes in protein spot density related to the treatment. The proteins in the spots are partially sequenced using, for example, standard methods employing chemical or enzymatic cleavage followed by mass spectrometry. The identity of the protein in a spot may be determined by comparing its partial sequence, preferably of at least 5 contiguous amino acid residues, to the polypeptide sequences of interest. In some cases, further sequence data may be obtained for definitive protein identification.
A proteomic profile may also be generated using antibodies specific for SCAP
to quantify the levels of SCAP expression. In one embodiment, the antibodies are used as elements on a microarray, and protein expression levels are quantified by exposing the microarray to the sample and detecting the levels of protein bound to each array element (Lueking, A. et al. (1999) Anal. Biochem. 270:103-111; Mendoze, L.G. et al. (1999) Biotechniques 27:778-788). Detection may be performed by a variety of methods known in the art, for example, by reacting the proteins in the sample with a thiol-or amino-reactive fluorescent compound and detecting the amount of fluorescence bound at each array element.
Toxicant signatures at the proteome level are also useful for toxicological screening, and should be analyzed in parallel with toxicant signatures at the transcript level. There is a poor correlation between transcript and protein abundances for some proteins in some tissues (Anderson, N.L. and J. Seilhamer ( 1997) Electrophoresis 18:533-537), so proteome toxicant signatures may be useful in the analysis of compounds which do not significantly affect the transcript image, but which alter the proteomic profile. In addition, the analysis of transcripts in body fluids is difficult, due to rapid degradation of mRNA, so proteomic profiling may be more reliable and informative in such cases.
In another embodiment, the toxicity of a test compound is assessed by treating a biological sample containing proteins with the test compound. Proteins that are expressed in the treated biological sample are separated so that the amount of each protein can be quantified. The amount of each protein is compared to the amount of the corresponding protein in an untreated biological sample. A difference in the amount of protein between the two samples is indicative of a toxic response to the test compound in the treated sample. Individual proteins are identified by sequencing the amino acid residues of the individual proteins and comparing these partial sequences to the polypeptides of the present invention.
In another embodiment, the toxicity of a test compound is assessed by treating a biological sample containing proteins with the test compound. Proteins from the biological sample are incubated with antibodies specific to the polypeptides of the present invention. The amount of protein recognized by the antibodies is quantified. The amount of protein in the treated biological sample is compared with the amount in an untreated biological sample. A
difference in the amount of protein between the two samples is indicative of a toxic response to the test compound in the treated sample.
Microarrays may be prepared, used, and analyzed using methods known in the art (Brennan, T.M. et al. (1995) U.S. Patent No. 5,474,796; Schena, M. et al. (1996) Proc.
Natl. Acad. Sci. USA
93:10614-10619; Baldeschweiler et al. (1995) PCT application W095/251116;
Shalom D. et al.
(1995) PCT application W095/35505; Heller, R.A. et al. (1997) Proc. Natl.
Acad. Sci. USA 94:2150-2155; Heller, M.J. et al. (1997) U.S. Patent No. 5,605,662). Various types of microarrays are well known and thoroughly described in Schena, M., ed. (1999; DNA Microarrays: A
Practical Approach, Oxford University Press, London).
In another embodiment of the invention, nucleic acid sequences encoding SCAP
may be used to generate hybridization probes useful in mapping the naturally occurring genomic sequence. Either coding or noncoding sequences may be used, and in some instances, noncoding sequences may be preferable over coding sequences. For example, conservation of a coding sequence among members of a mufti-gene family may potentially cause undesired cross hybridization during chromosomal mapping. The sequences may be mapped to a particular chromosome, to a specific region of a chromosome, or to artificial chromosome constructions, e.g., human artificial chromosomes (HACs), yeast artificial chromosomes (YACs), bacterial artificial chromosomes (BACs), bacterial P1 constructions, or single chromosome cDNA libraries (Harrington, J.J. et al.
(1997) Nat. Genet.
15:345-355; Price, C.M. (1993) Blood Rev. 7:127-134; Trask, B.J. (1991) Trends Genet. 7:149-154).
Once mapped, the nucleic acid sequences may be used to develop genetic linkage maps, for example, which correlate the inheritance of a disease state with the inheritance of a particular chromosome region or restriction fragment length polymorphism (RFLP) (Lander, E.S. and D.
Botstein (1986) Proc. Natl. Acad. Sci. USA 83:7353-7357).
Fluorescent in situ hybridization (FISH) may be correlated with other physical and genetic map data (Heinz-Ulrich, et al. (1995) in Meyers, supra, pp. 965-968). Examples of genetic map data can be found in various scientific journals or at the Online Mendelian Inheritance in Man (OMIM) World Wide Web site. Correlation between the location of the gene encoding SCAP on a physical map and a specific disorder, or a predisposition to a specific disorder, may help define the region of DNA associated with that disorder and thus may further positional cloning efforts.
In situ hybridization of chromosomal preparations and physical mapping techniques, such as linkage analysis using established chromosomal markers, may be used for extending genetic maps.
Often the placement of a gene on the chromosome of another mammalian species, such as mouse, may reveal associated markers even if the exact chromosomal locus is not known. This information is valuable to investigators searching for disease genes using positional cloning or other gene discovery techniques. Once the gene or genes responsible for a disease or syndrome have been crudely localized by genetic linkage to a particular genomic region, e.g., ataxia-telangiectasia to l 1q22-23, any sequences mapping to that area may represent associated or regulatory genes for further investigation (Gatti, R.A. et al. ( 1988) Nature 336:577-580). The nucleotide sequence of the instant invention may also be used to detect differences in the chromosomal location due to translocation, inversion, etc., among normal, carrier, or affected individuals.
In another embodiment of the invention, SCAP, its catalytic or immunogenic fragments, or oligopeptides thereof can be used for screening libraries of compounds in any of a variety of drug screening techniques. The fragment employed in such screening may be free in solution, affixed to a solid support, borne on a cell surface, or located intracellularly. The formation of binding complexes between SCAP and the agent being tested may be measured.
Another technique for drug screening provides for high throughput screening of compounds having suitable binding affinity to the protein of interest (Geysen, et al.
(1984) PCT application W084/03564). In this method, large numbers of different small test compounds are synthesized on a solid substrate. The test compounds are reacted with SCAP, or fragments thereof, and washed.
Bound SCAP is then detected by methods well known in the art. Purified SCAP
can also be coated directly onto plates for use in the aforementioned drug screening techniques.
Alternatively, non-neutralizing antibodies can be used to capture the peptide and immobilize it on a solid support.
In another embodiment, one may use competitive drug screening assays in which neutralizing antibodies capable of binding SCAP specifically compete with a test compound for binding SCAP. In this manner, antibodies can be used to detect the presence of any peptide which shares one or more antigenic determinants with SCAP.
In additional embodiments, the nucleotide sequences which encode SCAP may be used in any molecular biology techniques that have yet to be developed, provided the new techniques rely on properties of nucleotide sequences that are currently known, including, but not limited to, such properties as the triplet genetic code and specific base pair interactions.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
The disclosures of all patents, applications, and publications mentioned above and below, including U.S. Ser. No. 60/360,681, U.S. Ser. No. 60/328,931 U.S. Ser. No.
60/343,896, U.S. Ser. No.
60/346,308, U.S. Ser. No. 60/332,385, U.S. Ser. No. 60/340,776, and U.S. Ser.
No. 60/347,703, are hereby expressly incorporated by reference.
EXAMPLES
I. Construction of cDNA Libraries Incyte cDNAs were derived from cDNA libraries described in the LIFESEQ GOLD
database (Incyte Genomics, Palo Alto CA). Some tissues were homogenized and lysed in guanidinium isothiocyanate, while others were homogenized and lysed in phenol or in a suitable mixture of denaturants, such as TRIZOL (Invitrogen), a monophasic solution of phenol and guanidine isothiocyanate. The resulting lysates were centrifuged over CsCI cushions or extracted with chloroform. RNA was precipitated from the lysates with either isopropanol or sodium acetate and ethanol, or by other routine methods.
Phenol extraction and precipitation of RNA were repeated as necessary to increase RNA
purity. In some cases, RNA was treated with DNase. For most libraries, poly(A)+ RNA was isolated using oligo d(T)-coupled paramagnetic particles (Promega), OLIGOTEX latex particles (QIAGEN, Chatsworth CA), or an OLIGOTEX mRNA purification kit (QIAGEN). Alternatively, RNA was isolated directly from tissue lysates using other RNA isolation kits, e.g., the POLY(A)PURE mRNA
purification kit (Ambion, Austin TX).
In some cases, Stratagene was provided with RNA and constructed the corresponding cDNA
libraries. Otherwise, cDNA was synthesized and cDNA libraries were constructed with the UNIZAP
vector system (Stratagene) or SUPERSCRIPT plasmid system (Invitrogen), using the recommended procedures or similar methods known in the art (Ausubel et al., supra, ch. 5).
Reverse transcription was initiated using oligo d(T) or random primers. Synthetic oligonucleotide adapters were ligated to double stranded cDNA, and the cDNA was digested with the appropriate restriction enzyme or enzymes. For most libraries, the cDNA was size-selected (300-1000 bp) using SEPHACRYL S1000, SEPHAROSE CL2B, or SEPHAROSE CL4B column chromatography (Amersham Biosciences) or preparative agarose gel electrophoresis. cDNAs were ligated into compatible restriction enzyme sites of the polylinker of a suitable plasmid, e.g., PBLUESCRIPT plasmid (Stratagene), PSPORT1 plasmid (Invitrogen, Carlsbad CA), PCDNA2.1 plasmid (Invitrogen), PBK-CMV plasmid (Stratagene), PCR2-TOPOTA plasmid (Invitrogen), PCMV-ICIS plasmid (Stratagene), pIGEN (Incyte Genomics, Palo Alto CA), pRARE (Incyte Genomics), or pINCY (Incyte Genomics), or derivatives thereof.
Recombinant plasmids were transformed into competent E. coli cells including XL1-Blue, XL1-BIueMRF, or SOLR from Stratagene or DHSa, DH10B, or ElectroMAX DH10B from Invitrogen.
II. Isolation of cDNA Clones Plasmids obtained as described in Example I were recovered from host cells by in vivo excision using the UNIZAP vector system (Stratagene) or by cell lysis.
Plasmids were purified using at least one of the following: a Magic or WIZARD Minipreps DNA purification system (Promega);
an AGTC Miniprep purification kit (Edge Biosystems, Gaithersburg MD); and QIAWELL 8 Plasmid, QIAWELL 8 Plus Plasmid, QIAWELL 8 Ultra Plasmid purification systems or the R.E.A.L. PREP 96 plasmid purification kit from QIAGEN. Following precipitation, plasmids were resuspended in 0.1 ml of distilled water and stored, with or without lyophilization, at 4°C.
Alternatively, plasmid DNA was amplified from host cell lysates using direct link PCR in a high-throughput format (Rao, V.B. (1994) Anal. Biochem. 216:1-14). Host cell lysis and thermal cycling steps were carried out in a single reaction mixture. Samples were processed and stored in 384-well plates, and the concentration of amplified plasmid DNA was quantified fluorometrically using PICOGREEN dye (Molecular Probes, Eugene OR) and a FLUOROSKAN II
fluorescence scanner (Labsystems Oy, Helsinki, Finland).
III. Sequencing and Analysis Incyte cDNA recovered in plasmids as described in Example II were sequenced as follows.
Sequencing reactions were processed using standard methods or high-throughput instrumentation such as the ABI CATALYST 800 (Applied Biosystems) thermal cycler or the PTC-200 thermal cycler (MJ Research) in conjunction with the HYDRA microdispenser (Robbins Scientific) or the MICROLAB 2200 (Hamilton) liquid transfer system. cDNA sequencing reactions were prepared using reagents provided by Amersham Biosciences or supplied in ABI sequencing kits such as the ABI PRISM BIGDYE Terminator cycle sequencing ready reaction kit (Applied Biosystems).
Electrophoretic separation of cDNA sequencing reactions and detection of labeled polynucleotides were carried out using the MEGABACE 1000 DNA sequencing system (Amersham Biosciences); the ABI PRISM 373 or 377 sequencing system (Applied Biosystems) in conjunction with standard ABI
protocols and base calling software; or other sequence analysis systems known in the art. Reading frames within the cDNA sequences were identified using standard methods (Ausubel et al., supra, ch.

7). Some of the cDNA sequences were selected for extension using the techniques disclosed in Example VIII.
The polynucleotide sequences derived from Incyte cDNAs were validated by removing vector, linker, and poly(A) sequences and by masking ambiguous bases, using algorithms and programs based on BLAST, dynamic programming, and dinucleotide nearest neighbor analysis. The Incyte cDNA sequences or translations thereof were then queried against a selection of public databases such as the GenBank primate, rodent, mammalian, vertebrate, and eukaryote databases, and BLOCKS, PRINTS, DOMO, PRODOM; PROTEOME databases with sequences from Homo Sapiens, Rattus norvegicus, Mus musculus, Caenorhabditis elegans, Saccharomyces cerevisiae, Schizosaccharomyces pombe, and Candida albicans (Incyte Genomics, Palo Alto CA); hidden Markov model (HMM)-based protein family databases such as PFAM, INCY, and TIGRFAM (Haft, D.H. et al. (2001) Nucleic Acids Res. 29:41-43); and HMM-based protein domain databases such as SMART (Schultz, J. et al. (1998) Proc. Natl. Acad. Sci. USA 95:5857-5864;
Letunic, I. et al. (2002) Nucleic Acids Res. 30:242-244). (HMM is a probabilistic approach which analyzes consensus primary structures of gene families; see, for example, Eddy, S.R. (1996) Curr.
Opin. Struct. Biol.

6:361-365.) The queries were performed using programs based on BLAST, FASTA, BLIMPS, and HMMER. The Incyte cDNA sequences were assembled to produce full length polynucleotide sequences. Alternatively, GenBank cDNAs, GenBank ESTs, stitched sequences, stretched sequences, or Genscan-predicted coding sequences (see Examples IV and V) were used to extend Incyte cDNA
assemblages to full length. Assembly was performed using programs based on Phred, Phrap, and Consed, and cDNA assemblages were screened for open reading frames using programs based on GeneMark, BLAST, and FASTA. The full length polynucleotide sequences were translated to derive the corresponding full length polypeptide sequences. Alternatively, a polypeptide may begin at any of the methionine residues of the full length translated polypeptide. Full length polypeptide sequences were subsequently analyzed by querying against databases such as the GenBank protein databases (genpept), SwissProt, the PROTEOME databases, BLOCKS, PRINTS, DOMO, PRODOM, Prosite, hidden Markov model (HMM)-based protein family databases such as PFAM, INCY, and TIGRFAM; and HMM-based protein domain databases such as SMART. Full length polynucleotide sequences are also analyzed using MACDNASIS PRO software (MiraiBio, Alameda CA) and LASERGENE software (DNASTAR). Polynucleotide and polypeptide sequence alignments are generated using default parameters specified by the CLUSTAL algorithm as incorporated into the MEGALIGN multisequence alignment program (DNASTAR), which also calculates the percent identity between aligned sequences.
Table 7 summarizes the tools, programs, and algorithms used for the analysis and assembly of Incyte cDNA and full length sequences and provides applicable descriptions, references, and threshold parameters. The first column of Table 7 shows the tools, programs, and algorithms used, the second column provides brief descriptions thereof, the third column presents appropriate references, all of which are incorporated by reference herein in their entirety, and the fourth column presents, where applicable, the scores, probability values, and other parameters used to evaluate the strength of a match between two sequences (the higher the score or the lower the probability value, the greater the identity between two sequences).
The programs described above for the assembly and analysis of full length polynucleotide and polypeptide sequences were also used to identify polynucleotide sequence fragments from SEQ
ID N0:52-102. Fragments from about 20 to about 4000 nucleotides which are useful in hybridization and amplification technologies are described in Table 4, column 2.
IV. Identification and Editing of Coding Sequences from Genomic DNA
Putative structural and cytoskeleton-associated proteins were initially identified by running the Genscan gene identification program against public genomic sequence databases (e.g., gbpri and gbhtg). Genscan is a general-purpose gene identification program which analyzes genomic DNA
sequences from a variety of organisms (Burge, C. and S. Karlin (1997) J. Mol.
Biol. 268:78-94;

Burge, C. and S. Karlin (1998) Curr. Opin. Struct. Biol. 8:346-354). The program concatenates predicted exons to form an assembled cDNA sequence extending from a methionine to a stop codon.
The output of Genscan is a FASTA database of polynucleotide and polypeptide sequences. The maximum range of sequence for Genscan to analyze at once was set to 30 kb. To determine which of these Genscan predicted cDNA sequences encode structural and cytoskeleton-associated proteins, the encoded polypeptides were analyzed by querying against PFAM models for structural and cytoskeleton-associated proteins. Potential structural and cytoskeleton-associated proteins were also identified by homology to Incyte cDNA sequences that had been annotated as structural and cytoskeleton-associated proteins. These selected Genscan-predicted sequences were then compared by BLAST analysis to the genpept and gbpri public databases. Where necessary, the Genscan-predicted sequences were then edited by comparison to the top BLAST hit from genpept to correct errors in the sequence predicted by Genscan, such as extra or omitted exons.
BLAST analysis was also used to find any Incyte cDNA or public cDNA coverage of the Genscan-predicted sequences, thus providing evidence for transcription. When Incyte cDNA coverage was available, this information was used to correct or confirm the Genscan predicted sequence.
Full length polynucleotide sequences were obtained by assembling Genscan-predicted coding sequences with Incyte cDNA sequences and/or public cDNA sequences using the assembly process described in Example III. Alternatively, full length polynucleotide sequences were derived entirely from edited or unedited Genscan-predicted coding sequences.
V. Assembly of Genomic Sequence Data with cDNA Sequence Data "Stitched" Seguences Partial cDNA sequences were extended with exons predicted by the Genscan gene identification program described in Example IV. Partial cDNAs assembled as described in Example III were mapped to genomic DNA and parsed into clusters containing related cDNAs and Genscan exon predictions from one or more genomic sequences. Each cluster was analyzed using an algorithm based on graph theory and dynamic programming to integrate cDNA and genomic information, generating possible splice variants that were subsequently confirmed, edited, or extended to create a full length sequence. Sequence intervals in which the entire length of the interval was present on more than one sequence in the cluster were identified, and intervals thus identified were considered to be equivalent by transitivity. For example, if an interval was present on a cDNA and two genomic sequences, then all three intervals were considered to be equivalent. This process allows unrelated but consecutive genomic sequences to be brought together, bridged by cDNA
sequence. Intervals thus identified were then "stitched" together by the stitching algorithm in the order that they appear along their parent sequences to generate the longest possible sequence, as well as sequence variants.
Linkages between intervals which proceed along one type of parent sequence (cDNA to cDNA or sz genomic sequence to genomic sequence) were given preference over linkages which change parent type (cDNA to genomic sequence). The resultant stitched sequences were translated and compared by BLAST analysis to the genpept and gbpri public databases. Incorrect exons predicted by Genscan were corrected by comparison to the top BLAST hit from genpept. Sequences were further extended with additional cDNA sequences, or by inspection of genomic DNA, when necessary.
"Stretched" Sequences Partial DNA sequences were extended to full length with an algorithm based on BLAST
analysis. First, partial cDNAs assembled as described in Example III were queried against public databases such as the GenBank primate, rodent, mammalian, vertebrate, and eukaryote databases using the BLAST program. The nearest GenBank protein homolog was then compared by BLAST
analysis to either Incyte cDNA sequences or GenScan exon predicted sequences described in Example N. A chimeric protein was generated by using the resultant high-scoring segment pairs (HSPs) to map the translated sequences onto the GenBank protein homolog.
Insertions or deletions may occur in the chimeric protein with respect to the original GenBank protein homolog. The GenBank protein homolog, the chimeric protein, or both were used as probes to search for homologous genomic sequences from the public human genome databases. Partial DNA sequences were therefore "stretched" or extended by the addition of homologous genomic sequences. The resultant stretched sequences were examined to determine whether it contained a complete gene.
VI. Chromosomal Mapping of SCAP Encoding Polynucleotides The sequences which were used to assemble SEQ ID N0:52-102 were compared with sequences from the Incyte LIFESEQ database and public domain databases using BLAST and other implementations of the Smith-Waterman algorithm. Sequences from these databases that matched SEQ ID N0:52-I02 were assembled into clusters of contiguous and overlapping sequences using assembly algorithms such as Phrap (Table 7). Radiation hybrid and genetic mapping data available from public resources such as the Stanford Human Genome Center (SHGC), Whitehead Institute for Genome Research (WIGR), and Genethon were used to determine if any of the clustered sequences had been previously mapped. Inclusion of a mapped sequence in a cluster resulted in the assignment of all sequences of that cluster, including its particular SEQ ID NO:, to that map location.
Map locations are represented by ranges, or intervals, of human chromosomes.
The map position of an interval, in centiMorgans, is measured relative to the terminus of the chromosome's p-arm. (The centiMorgan (cM) is a unit of measurement based on recombination frequencies between chromosomal markers. On average; I cM is roughly equivalent to 1 megabase (Mb) of DNA in humans, although this can vary widely due to hot and cold spots of recombination.) The cM
distances are based on genetic markers mapped by Genethon which provide boundaries for radiation hybrid markers whose sequences were included in each of the clusters. Human genome maps and other resources available to the public, such as the NCBI "GeneMap'99" World Wide Web site (http://www.ncbi.nlm.nih.gov/genemap/), can be employed to determine if previously identified disease genes map within or in proximity to the intervals indicated above.
Association of SCAPpolynucleotides with osteoarthritis Markers that map to regions associated with particular diseases can be used to develop diagnostic and therapeutic tools. Disease association of a chromosome locus is expressed as lod (logarithm of odds) score. The lod score is the logarithm to base 10 of the odds in favor of linkage.
Linkage is defined as the tendency of two genes located on the same chromosome to be inherited together through meiosis (Genetics in Medicine, Fifth Edition, (1991) Thompson, M.W. et al., W.B.
Saunders Co. Philadelphia). A logarithm of the odds ratio for linkage (lod) score of 2 indicates a probability of 1 in 100 that the marker was found solely by chance in affected individuals. In a study of 48 families affected by osteoarthritis, Loughlin et al. (Rheumatology (2000) 39:377-381) identified D2S202 and D2S117 as two genetic markers with a multiple lod of 2.19 for linkage to OA of the hip.
Restriction fragment length polymorphism (RFLP) markers shown to be near regions of DNA known as sequence-tagged sites (STS), have been mapped to NT Contigs generated by the Human Genome Project using ePCR (Schuler, G.D. (1997) Genome Research 7: 541-550, and (1998) Trends Biotechnol. 16(11):456-9). Contigs containing regions of DNA with known disease-associated markers are therefore used to identify SCAP sequences that map to disease-associated regions of the genome.
Polynucleotdes encoding SCAP were mapped to NT Contigs. Contigs longer than 1Mb were broken into subcontigs of 1Mb length with overlaping sections of 100kb. A
preliminary step used a an algorithm, similar to MEGABLAST, to define the mRNA sequence /masked genomic DNA contig pairings. The cDNA/genomic pairings identified by the first algorithm were confirmed, and the SCAP polynucleotides mapped to DNA contigs, using SIM4 (Florea, L. et al.
(1998) Genome Res.

8:967-74, version May 2000) which had been optimized for high throughput processing and strand assignment confidence). The SIM4 output of the mRNA sequence/genomic contig pairs was further processed to determine the correct location of the SCAP polynucleotides on the genomic contig, as well as their strand identity.
SEQ ID N0:71 was mapped to NT Contig GBI:NT_005428 001.7 from Genbank release February, 2002, covering a 6.45 Mb region of the genome that also contains OA-associated genetic markers D2S202 and D2S72. The maximum distance between SEQ ID N0:71 and D2S202 and D2S72, therefore, is 6.45 Mb. Thus, SEQ ID N0:71 is in proximity with loci shown to consistently associate with OA.
VII. Analysis of Polynucleotide Expression Northern analysis is a laboratory technique used to detect the presence of a transcript of a gene and involves the hybridization of a labeled nucleotide sequence to a membrane on which RNAs from a particular cell type or tissue have been bound (Sambrook and Russell, supra, ch. 7; Ausubel et al., supra, ch. 4).
Analogous computer techniques applying BLAST were used to search for identical or related molecules in databases such as GenBank or LIFESEQ (Incyte Genomics). This analysis is much faster than multiple membrane-based hybridizations. In addition, the sensitivity of the computer search can be modified to determine whether any particular match is categorized as exact or similar.
The basis of the search is the product score, which is defined as:
BLAST Score x Percent Identity 5 x minimum {length(Seq. 1), length(Seq. 2)}
The product score takes into account both the degree of similarity between two sequences and the length of the sequence match. The product score is a normalized value between 0 and 100, and is calculated as follows: the BLAST score is multiplied by the percent nucleotide identity and the product is divided by (5 times the length of the shorter of the two sequences). The BLAST score is calculated by assigning a score of +5 for every base that matches in a high-scoring segment pair (HSP), and -4 for every mismatch. Two sequences may share more than one HSP
(separated by gaps). If there is more than one HSP, then the pair with the highest BLAST
score is used to calculate the product score. The product score represents a balance between fractional overlap and quality in a BLAST alignment. For example, a product score of 100 is produced only for 100%
identity over the entire length of the shorter of the two sequences being compared. A product score of 70 is produced either by 100% identity and 70% overlap at one end, or by 88% identity and 100% overlap at the other. A product score of 50 is produced either by 100% identity and 50%
overlap at one end, or 79%
identity and 100% overlap.
Alternatively, polynucleotides encoding SCAP are analyzed with respect to the tissue sources from which they were derived. For example, some full length sequences are assembled, at least in part, with overlapping Incyte cDNA sequences (see Example III). Each cDNA
sequence is derived from a cDNA library constructed from a human tissue. Each human tissue is classified into one of the following organ/tissue categories: cardiovascular system; connective tissue;
digestive system;
embryonic structures; endocrine system; exocrine glands; genitalia, female;
genitalia, male; germ cells; hemic and immune system; liver; musculoskeletal system; nervous system;
pancreas;
respiratory system; sense organs; skin; stomatognathic system;
unclassified/mixed; or urinary tract.
The number of libraries in each category is counted and divided by the total number of libraries across all categories. Similarly, each human tissue is classified into one of the following disease/condition categories: cancer, cell line, developmental, inflammation, neurological, trauma, cardiovascular, pooled, and other, and the number of libraries in each category is counted and divided by the total number of libraries across all categories. The resulting percentages reflect the tissue- and disease-specific expression of cDNA encoding SCAP. cDNA sequences and cDNA
library/tissue information are found in the LIFESEQ GOLD database (Incyte Genomics, Palo Alto CA).
VIII. Extension of SCAP Encoding Polynucleotides Full length polynucleotides are produced by extension of an appropriate fragment of the full length molecule using oligonucleotide primers designed from this fragment. One primer was synthesized to initiate 5' extension of the known fragment, and the other primer was synthesized to initiate 3' extension of the known fragment. The initial primers were designed using OLIGO 4.06 software (National Biosciences), or another appropriate program, to be about 22 to 30 nucleotides in length, to have a GC content of about 50% or more, and to anneal to the target sequence at temperatures of about 68°C to about 72°C. Any stretch of nucleotides which would result in hairpin structures and primer-primer dimerizations was avoided.
Selected human cDNA libraries were used to extend the sequence. If more than one extension was necessary or desired, additional or nested sets of primers were designed.
High fidelity amplification was obtained by PCR using methods well known in the art. PCR
was performed in 96-well plates using the PTC-200 thermal cycler (MJ Research, Inc.). The reaction mix contained DNA template, 200 nmol of each primer, reaction buffer containing MgZ+, (NH4)ZS04, and 2-mercaptoethanol, Taq DNA polymerise (Amersham Biosciences), ELONGASE
enzyme (Invitrogen), and Pfu DNA polymerise (Stratagene), with the following parameters for primer pair PCI A and PCI B: Step 1: 94°C, 3 min; Step 2: 94°C, 15 sec; Step 3: 60°C, 1 min; Step 4: 68°C, 2 min; Step 5: Steps 2, 3, and 4 repeated 20 times; Step 6: 68°C, 5 min;
Step 7: storage at 4°C. In the alternative, the parameters for primer pair T7 and SK+ were as follows: Step 1: 94°C, 3 min; Step 2:
94°C, 15 sec; Step 3: 57°C, 1 min; Step 4: 68°C, 2 min;
Step 5: Steps 2, 3, and 4 repeated 20 times;
Step 6: 68°C, 5 min; Step 7: storage at 4°C.
The concentration of DNA in each well was determined by dispensing 100 ~.1 PICOGREEN
quantitation reagent (0.25% (v/v) PICOGREEN; Molecular Probes, Eugene OR) dissolved in 1X TE
and 0.5 p,1 of undiluted PCR product into each well of an opaque fluorimeter plate (Corning Costar, Acton MA), allowing the DNA to bind to the reagent. The plate was scanned in a Fluoroskan II
(Labsystems Oy, Helsinki, Finland) to measure the fluorescence of the sample and to quantify the concentration of DNA. A 5 ~1 to 10 ~l aliquot of the reaction mixture was analyzed by electrophoresis on a 1 % agarose gel to determine which reactions were successful in extending the sequence.
The extended nucleotides were desalted and concentrated, transferred to 384-well plates, digested with CviJI cholera virus endonuclease (Molecular Biology Research, Madison WI), and sonicated or sheared prior to relegation into pUC 18 vector (Amersham Biosciences). For shotgun sequencing, the digested nucleotides were separated on low concentration (0.6 to 0.8%) agarose gels, fragments were excised, and agar digested with Agar ACE (Promega). Extended clones were relegated using T4 ligase (New England Biolabs, Beverly MA) into pUC 18 vector (Amersham Biosciences), treated with Pfu DNA polymerase (Stratagene) to fill-in restriction site overhangs, and transfected into competent E. coli cells. Transformed cells were selected on antibiotic-containing media, and individual colonies were picked and cultured overnight at 37°C in 384-well plates in LB/2x carb liquid media.
The cells were lysed, and DNA was amplified by PCR using Taq DNA polymerase (Amersham Biosciences) and Pfu DNA polymerase (Stratagene) with the following parameters: Step 1: 94°C, 3 min; Step 2: 94°C, 15 sec; Step 3: 60°C, 1 min; Step 4: 72°C, 2 min; Step 5: steps 2, 3, and 4 repeated 29 times; Step 6: 72°C, 5 min; Step 7: storage at 4°C. DNA was quantified by PICOGREEN reagent (Molecular Probes) as described above. Samples with low DNA
recoveries were reamplified using the same conditions as described above. Samples were diluted with 20%
dimethysulfoxide (1:2, v/v), and sequenced using DYENAMIC energy transfer sequencing primers and the DYENAMIC DIRECT kit (Amersham Biosciences) or the ABI PRISM BIGDYE
Terminator cycle sequencing ready reaction kit (Applied Biosystems).
In like manner, full length polynucleotides are verified using the above procedure or are used to obtain 5'regulatory sequences using the above procedure along with oligonucleotides designed for such extension, and an appropriate genomic library.
IX. Identification of Single Nucleotide Polymorphisms in SCAP Encoding Polynucleotides Common DNA sequence variants known as single nucleotide polymorphisms (SNPs) were identified in SEQ ID N0:52-102 using the LIFESEQ database (Incyte Genomics).
Sequences from the same gene were clustered together and assembled as described in Example III, allowing the identification of all sequence variants in the gene. An algorithm consisting of a series of filters was used to distinguish SNPs from other sequence variants. Preliminary filters removed the majority of basecall errors by requiring a minimum Phred quality score of 15, and removed sequence alignment errors and errors resulting from improper trimming of vector sequences, chimeras, and splice variants. An automated procedure of advanced chromosome analysis analysed the original chromatogram files in the vicinity of the putative SNP. Clone error filters used statistically generated algorithms to identify errors introduced during laboratory processing, such as those caused by reverse transcriptase, polymerase, or somatic mutation. Clustering error filters used statistically generated algorithms to identify errors resulting from clustering of close homologs or pseudogenes, or due to contamination by non-human sequences. A final set of filters removed duplicates and SNPs found in immunoglobulins or T-cell receptors.
s~

Certain SNPs were selected for further characterization by mass spectrometry using the high throughput MASSARRAY system (Sequenom, Inc.) to analyze allele frequencies at the SNP sites in four different human populations. The Caucasian population comprised 92 individuals (46 male, 46 female), including 83 from Utah, four French, three Venezualan, and two Amish individuals. The African population comprised 194 individuals (97 male, 97 female), all African Americans. The Hispanic population comprised 324 individuals (162 male, 162 female), all Mexican Hispanic. The Asian population comprised 126 individuals (64 male, 62 female) with a reported parental breakdown of 43% Chinese, 31% Japanese, 13% Korean, 5% Vietnamese, and 8% other Asian.
Allele frequencies were first analyzed in the Caucasian population; in some cases those SNPs which showed no allelic variance in this population were not further tested in the other three populations.
X. Labeling and Use of Individual Hybridization Probes Hybridization probes derived from SEQ ID N0:52-102 are employed to screen cDNAs, genomic DNAs, or mRNAs. Although the labeling of oligonucleotides, consisting of about 20 base pairs, is specifically described, essentially the same procedure is used with larger nucleotide fragments. Oligonucleotides are designed using state-of-the-art software such as OLIGO 4.06 software (National Biosciences) and labeled by combining 50 pmol of each oligomer, 250 ~Ci of [y 3zP] adenosine triphosphate (Amersham Biosciences), and T4 polynucleotide kinase (DuPont NEN, Boston MA). The labeled oligonucleotides are substantially purified using a supe~ne size exclusion dextran bead column (Amersham Biosciences). An aliquot containing 10' counts per minute of the labeled probe is used in a typical membrane-based hybridization analysis of human genomic DNA digested with one of the following endonucleases: Ase I, Bgl II, Eco RI, Pst I, Xba I, or Pvu II (DuPont NEN).
The DNA from each digest is fractionated on a 0.7% agarose gel and transferred to nylon membranes (Nytran Plus, Schleicher & Schuell, Durham NH). Hybridization is carried out for 16 hours at 40°C. To remove nonspecific signals, blots are sequentially washed at room temperature under conditions of up to, for example, 0.1 x saline sodium citrate and 0.5%
sodium dodecyl sulfate.
Hybridization patterns are visualized using autoradiography or an alternative imaging means and compared.
XI. Microarrays The linkage or synthesis of array elements upon a microarray can be achieved utilizing photolithography, piezoelectric printing (ink jet printing; see, e.g., Baldeschweiler et al., supra), mechanical microspotting technologies, and derivatives thereof. The substrate in each of the aforementioned technologies should be uniform and solid with a non-porous surface (Schena, M., ed.
(1999) DNA Microarrays: A Practical Approach, Oxford University Press, London). Suggested substrates include silicon, silica, glass slides, glass chips, and silicon wafers. Alternatively, a 8s procedure analogous to a dot or slot blot may also be used to arrange and link elements to the surface of a substrate using thermal, LTV, chemical, or mechanical bonding procedures.
A typical array may be produced using available methods and machines well known to those of ordinary skill in the art and may contain any appropriate number of elements (Schena, M. et al. (1995) Science 270:467-470;
Shalon, D. et al. (1996) Genome Res. 6:639-645; Marshall, A. and J. Hodgson (1998) Nat.
B iotechnol. 16:27-31 ).
Full length cDNAs, Expressed Sequence Tags (ESTs), or fragments or oligomers thereof may comprise the elements of the microarray. Fragments or oligomers suitable for hybridization can be selected using software well known in the art such as LASERGENE software (DNASTAR). The array elements are hybridized with polynucleotides in a biological sample. The polynucleotides in the biological sample are conjugated to a fluorescent label or other molecular tag for ease of detection. After hybridization, nonhybridized nucleotides from the biological sample are removed, and a fluorescence scanner is used to detect hybridization at each array element. Alternatively, laser desorbtion and mass spectrometry may be used for detection of hybridization.
The degree of complementarity and the relative abundance of each polynucleotide which hybridizes to an element on the microarray may be assessed. In one embodiment, microarray preparation-and usage is described in detail below.
Tissue or Cell Sample Preparation Total RNA is isolated from tissue samples using the guanidinium thiocyanate method and poly(A)+ RNA is purified using the oligo-(dT) cellulose method. Each poly(A)+
RNA sample is reverse transcribed using MMLV reverse-transcriptase, 0.05 pg/p.l oligo-(dT) primer (2lmer), 1X
first strand buffer, 0.03 units/p,l RNase inhibitor, S00 ~M dATP, 500 pM dGTP, 500 p.M dTTP, 40 p.M dCTP, 40 p,M dCTP-Cy3 (BDS) or dCTP-Cy5 (Amersham Biosciences). The reverse transcription reaction is performed in a 25 ml volume containing 200 ng poly(A)+ RNA with GEMBRIGHT kits (Incyte Genomics). Specific control poly(A)+ RNAs are synthesized by in vitro transcription from non-coding yeast genomic DNA. After incubation at 37°C for 2 hr, each reaction sample (one with Cy3 and another with Cy5 labeling) is treated with 2.5 ml of O.SM sodium hydroxide and incubated for 20 minutes at 85°C to the stop the reaction and degrade the RNA.
Samples are purified using two successive CHROMA SPIN 30 gel filtration spin columns (Clontech, Palo Alto CA) and after combining, both reaction samples are ethanol precipitated using 1 ml of glycogen (1 mg/ml), 60 ml sodium acetate, and 300 ml of 100% ethanol. The sample is then dried to completion using a SpeedVAC (Savant Instruments Inc., Holbrook NY) and resuspended in 14 p,1 SX
SSC/0.2% SDS.
Microarray Preparation Sequences of the present invention are used to generate array elements. Each array element is amplified from bacterial cells containing vectors with cloned cDNA inserts.
PCR amplification uses primers complementary to the vector sequences flanking the cDNA insert.
Array elements are amplified in thirty cycles of PCR from an initial quantity of 1-2 ng to a final quantity greater than 5 fig. Amplified array elements are then purified using SEPHACRYL-400 (Amersham Biosciences).
Purified array elements are immobilized on polymer-coated glass slides. Glass microscope slides (Corning) are cleaned by ultrasound in 0.1% SDS and acetone, with extensive distilled water washes between and after treatments. Glass slides are etched in 4%
hydrofluoric acid (VWR
Scientific Products Corporation (VWR), West Chester PA), washed extensively in distilled water, and coated with 0.05% aminopropyl silane (Sigma) in 95% ethanol. Coated slides are cured in a 110°C oven.
Array elements are applied to the coated glass substrate using a procedure described in U.S.
Patent No. 5,807,522, incorporated herein by reference. 1 ~,1 of the array element DNA, at an average concentration of 100 ng/~,1, is loaded into the open capillary printing element by a high-speed robotic apparatus. The apparatus then deposits about 5 n1 of array element sample per slide.
Microarrays are UV-crosslinked using a STRATALINKER UV-crosslinker (Stratagene).
Microarrays are washed at room temperature once in 0.2% SDS and three times in distilled water.
Non-specific binding sites are blocked by incubation of microarrays in 0.2%
casein in phosphate buffered saline (PBS) (Tropix, Inc., Bedford MA) for 30 minutes at 60°C
followed by washes in 0.2% SDS and distilled water as before.
Hybridization Hybridization reactions contain 9 ~,1 of sample mixture consisting of 0.2 p,g each of Cy3 and Cy5 labeled cDNA synthesis products in SX SSC, 0.2% SDS hybridization buffer.
The sample mixture is heated to 65°C for 5 minutes and is aliquoted onto the microarray surface and covered with an 1.8 cmz coverslip. The arrays are transferred to a waterproof chamber having a cavity just slightly larger than a microscope slide. The chamber is kept at 100% humidity internally by the addition of 140 ~.l of 5X SSC in a corner of the chamber. The chamber containing the arrays is incubated for about 6.5 hours at 60°C. The arrays are washed for 10 min at 45°C in a first wash buffer (1X SSC, 0.1% SDS), three times for 10 minutes each at 45°C in a second wash buffer (0.1X
SSC), and dried.
Detection Reporter-labeled hybridization complexes are detected with a microscope equipped with an Innova 70 mixed gas 10 W laser (Coherent, Inc., Santa Clara CA) capable of generating spectral lines at 488 nm for excitation of Cy3 and at 632 nm for excitation of CyS. The excitation laser light is focused on the array using a 20X microscope objective (Nikon, Inc., Melville NY). The slide containing the array is placed on a computer-controlled X-Y stage on the microscope and raster-scanned past the objective. The 1.8 cm x 1.8 cm array used in the present example is scanned with a resolution of 20 micrometers.
In two separate scans, a mixed gas multiline laser excites the two fluorophores sequentially.
Emitted light is split, based on wavelength, into two photomultiplier tube detectors (PMT 81477, Hamamatsu Photonics Systems, Bridgewater NJ) corresponding to the two fluorophores.
Appropriate filters positioned between the array and the photomultiplier tubes are used to filter the signals. The emission maxima of the fluorophores used are 565 nm for Cy3 and 650 nm for CyS.
Each array is typically scanned twice, one scan per fluorophore using the appropriate filters at the laser source, although the apparatus is capable of recording the spectra from both fluorophores simultaneously.
The sensitivity of the scans is typically calibrated using the signal intensity generated by a cDNA control species added to the sample mixture at a known concentration. A
specific location on the array contains a complementary DNA sequence, allowing the intensity of the signal at that location to be correlated with a weight ratio of hybridizing species of 1:100,000. When two samples from different sources (e.g., representing test and control cells), each labeled with a different fluorophore, are hybridized to a single array for the purpose of identifying genes that are differentially expressed, the calibration is done by labeling samples of the calibrating cDNA with the two fluorophores and adding identical amounts of each to the hybridization mixture.
The output of the photomultiplier tube is digitized using a 12-bit RTI-835H
analog-to-digital (A/D) conversion board (Analog Devices, Inc., Norwood MA) installed in an IBM-compatible PC
computer. The digitized data are displayed as an image where the signal intensity is mapped using a linear 20-color transformation to a pseudocolor scale ranging from blue (low signal) to red (high signal). The data is also analyzed quantitatively. Where two different fluorophores are excited and measured simultaneously, the data are first corrected for optical crosstalk (due to overlapping emission spectra) between the fluorophores using each fluorophore's emission spectrum.
A grid is superimposed over the fluorescence signal image such that the signal from each spot is centered in each element of the grid. The fluorescence signal within each element is then integrated to obtain a numerical value corresponding to the average intensity of the signal. The software used for signal analysis is the GEMTOOLS gene expression analysis program (Incyte Genomics). Array elements that exhibit at least about a two-fold change in expression, a signal-to-background ratio of at least about 2.5, and an element spot size of at least about 40%, are considered to be differentially expressed.
E~ression For example, in order to identify genes differentially expressed in colon cancer, gene expression patterns in normal and tumor tissues were compared. Matched normal and tumor samples from the same individual were compared by competitive hybridization. This process eliminates some of the individual variation due to genetic background, and enhances differences due to the disease process. SEQ 1D NO:55 was found to be downregulated at least two fold in one out of eight donors.
Therefore, SEQ ID NO:55 can be used in assays to detect colon cancer and in therapeutics.
In an alternate example, in order to determine some of the early gene expression changes involved in colon tumor formation that might reflect mutation of APC, polyps from an FAP patient were compared to normal colon tissue from the same patient. The purpose of this experiment was to identify genes affected by mutation of APC that may play a direct role in the development of colorectal cancer. SEQ >I7 NO:55 was found to be downregulated by two fold in the only patient tested. The experimental results held true when the experiment was repeated.
Therefore, SEQ m NO:55 can be used in assays for early detection of colorectal cancer and in therapeutics.
As another example, SEQ >D N0:61 and SEQ >D N0:67 showed differential expression in breast cancer tissue, as determined by microarray analysis. Histological and molecular evaluation of breast tumors has revealed that the development of breast cancer evolves through a multi-step process whereby pre-malignant mammary epithelial cells undergo a relatively defined sequence of events leading to tumor formation. Early in tumor development ductal hyperplasia is observed. Cells undergoing rapid neoplastic growth gradually progress to invasive carcinoma and become metastatic to the lung, bone and potentially other organs. Several factors, ranging from, but not limited to, environmental to genetic, influence tumor progression and malignant transformation.
In order to better determine the molecular and phenotypic characteristics associated with different stages of breast cancer, breast carcinoma cell lines at various stages of tumor progression were compared to primary human breast epithelial cells. The breast carcinoma cell lines include MCF7, a breast adenocarcinoma cell line derived from the pleural effusion of a 69-year-old female;
T-47D, a breast carcinoma cell line derived from a pleural effusion from a 54-year-old female with an infiltrating ductal carcinoma of the breast; Sk-BR-3, a breast adenocarcinoma cell line isolated from a malignant pleural effusion of a 43-year-old female; BT-20, a breast adenocarcinoma isolated in vitro from cells emigrating out of thin slices of a tumor mass isolated from a 74-year-old female; and MDA-mb-435S, a spindle shaped strain that evolved from a cell line isolated from the pleural effusion of a 31 year old female with metastatic, ductal adenocarcinoma of the breast. The primary mammary epithelial cell line HMEC was derived from normal human mammary tissue (Clonetics, San Diego, CA). All cell cultures were propagated in a chemically-defined medium, according to the supplier's recommendations and grown to 70-80% confluence prior to RNA
isolation. The microarray experiments showed that expression of SEQ ID N0:67 was decreased by at least two fold in all five breast carcinoma lines (MCF7, T-47D, Sk-BR-3, BT20, and MDA-mb-435S) relative to primary mammary epithelial cells, while expression of SEQ )D N0:61 was decreased by at least two-9z fold in all but the MDA-mb-4355 cell line. Therefore, SEQ ID N0:61 and SEQ ID
N0:67 are useful in diagnostic and staging assays for breast cancer and as potential biological markers and therapeutic agents in the treatment of breast cancer.
As another example, SEQ ID N0:62 showed differential expression in breast tumor tissue as compared to normal breast tissue isolated from the same donor, as determined by microarray analysis. Invasive lobular carcinoma tissue from a 43-year-old female was compared to normal breast tissue from the same donor (Huntsman Cancer Institute). The tumor was well differentiated and metastatic to 2 out of 13 lymph nodes. The expression of SEQ ID N0:62 was decreased by at least 2.5 fold in the tumor tissue as compared to the uninvolved breast tissue. Therefore, SEQ ID
N0:62 is useful in diagnostic assays for breast cancer and as a potential biological marker and therapeutic agent in the treatment of breast cancer.
As another example, SEQ ID N0:62 and SEQ ID N0:63 showed differential expression in lung cancer tissue, as determined by microarray analysis. Pair comparisons were performed in which tumor tissue was compared to normal tissue from the same donor. Expression of SEQ ID N0:62 was decreased more than 2.5 fold in moderately differentiated adenocarcinoma lung tissue from a 60-year-old donor, as compared to grossly uninvolved tissue from the same donor.
Expression of SEQ
ID N0:63 was decreased at least 2 fold in squamous cell carcinoma tissue, with 60% overt tumor cells, as compared to grossly uninvolved tissue from a 73-year-old male donor.
Therefore SEQ ID
N0:62 and SEQ ID N0:63 are useful in diagnostic assays for lung cancer and as potential biological markers and therapeutic agents in the treatment of lung cancer.
As another example, SEQ ID N0:67 showed differential expression in colon cancer tissue, as determined by microarray analysis. Colon cancer develops through a multistep process in which pre-malignant colonocytes undergo a relatively defined sequence of events that lead to tumor formation.
Factors that contribute to the process of tumor progression and malignant transformation include genetics, mutations, and selection. Matched normal and tumor samples from the same individual were compared to identify genes differentially expressed in colon cancer. The expression of SEQ ID
N0:67 was decreased at least two-fold in colon cancer tissue from a 73-year-old female donor, as compared to grossly uninvolved tissue from the same donor. Expression of SEQ
ID N0:67 was also decreased by at least two-fold in colon adenocarcinoma tissue as compared to normal tissue, isolated from a 56-year-old female diagnosed with poorly differentiated metastatic adenocarcinoma of possible ovarian origin. Therefore, SEQ ID N0:67 is useful in diagnostic assays for colon cancer and as a potential biological marker and therapeutic agent in the treatment of colon cancer.
As another example, SEQ ID N0:73 was differentially expressed in cancerous colon tissue compared to normal colon tissue. SEQ ID N0:73 was underexpressed by at least two-fold in colon tumor tissue as compared to normal colon tissue from the same donor.
Therefore, SEQ >D N0:73 is useful in diseases staging and in diagnostic assays for cell proliferative disorders, including colon cancer.
As another example, SEQ >D N0:77 was differentially expressed in normal human osteoblast tissue as compared to similar tissue from biopsy specimens, osteosarcoma tissues, primary cultures, or metastasized tissues. In comparison to expression of SEQ B7 N0:77 in normal osteoblasts, SEQ
ID N0:77 was underexpressed by at least two-fold in: chondroblastic bone tumor cells from an osteosarcoma, chondro-/osteoblastic bone tumor cells from an osteosarcoma of the femur, spindle cell bone tumor cells from the tibia, chondroblastic bone tumor tissue from an osteosarcoma of the femur, fibroblastic, chondroblastic, and chondro-/osteoblastic bone tumor tissue from an osteosarcoma of the femur, chondroblastic soft bone tumor tissue from an osteosarcoma of the femur, spindle cell soft bone tumor tissue from the tibia, chondro-/osteoblastic normal cartilage from a femur with osteosarcoma, lung tumor metastatic tissue from an osteosarcoma, and spindle cell of normal skeletal muscle from a patient with osteosarcoma. Therefore, SEQ ID
N0:77 is useful in disease staging and in diagnostic assays for cell proliferative disorders, including osteosarcomas.
As another example, SEQ ID N0:79 was differentially expressed in a liver tumor C3A line treated with various steroids as compared to untreated C3A cells. SEQ ID N0:79 was underexpressed by at least two-fold in the progesterone-treated C3A cells at all times points (1, 3, and 6 hours) for every dose (1, 10, and 100 ~M) as compared to untreated C3A
cells. SEQ )D N0:79 was underexpressed by at least two-fold in the beclometasone-treated C3A cells at all times points (l, 3, and 6 hours) for the two lowest doses (1 and 10 ~tM) as compared to untreated C3A cells. SEQ ID
N0:79 was underexpressed by at least two-fold in the MAH-treated C3A cells at all times points (1, 3, and 6 hours) for every dose (1, 10, and 100 ~M) as compared to untreated C3A cells. SEQ >Z7 N0:79 was underexpressed by at least two-fold in the bude-treated C3A cells at all times points (l, 3, and 6 hours) for every dose (l, 10, and 100 ~M) as compared to untreated C3A
cells. SEQ ID N0:79 was underexpressed by at least two-fold in the prednisone-treated C3A cells at all times points (1, 3, and 6 hours) for every dose (l, 10, and 100 ~M) as compared to untreated C3A
cells, with the exception of the 10 ~M dose at the 3 hour time point. SEQ m N0:79 was underexpressed by at least two-fold in the DEX-treated C3A cells at all times points (l, 3, and 6 hours) for every dose (1, 10, and 100 pM) as compared to untreated C3A cells, with the exception of the 10 ~tM dose at the 3 hour time point, and the 100 ~tM dose at the 1 and 3 hour time points. Lastly, SEQ
ID N0:79 was underexpressed by at least two-fold in the betamethasone-treated C3A cells at all times points (1, 3, and 6 hours) for every dose (1, 10, and 100 ~M) as compared to untreated C3A
cells, with the exception of the 1 p.M dose at the land 6 hour time points. Therefore, SEQ >D
N0:79 is useful in disease staging and diagnostic assays for liver disorders associated with steroid therapy.
For example, SEQ ID N0:93 showed decreased expression in brain tissue affected by Alzheimer's disease versus normal brain tissue, as determined by microarray analysis. Therefore, SEQ ID N0:93 is useful in monitoring treatment of, and diagnostic assays for, Alzheimer's disease and other neurological disorders.
As another example, SEQ >D N0:84, SEQ )D N0:90, SEQ 1D N0:93, and SEQ >D N0:95 showed decreased expression in breast carcinoma cells versus nonmalignant mammary epithelial cells, as determined by microarray analysis. Gene expression profiles of nonmalignant mammary epithelial cells were compared to gene expression profiles of various breast carcinoma lines at different stages of tumor progression. The cells were grown in defined serum-free H14 medium to 70-80% confluence prior to RNA harvest. Cell lines compared included: a) HMEC, a primary breast epithelial cell line isolated from a normal donor, b)MCF-10A, a breast mammary gland cell line isolated from a 36-year-old woman with fibrocystic breast disease, c)MCF7, a nonmalignant breast adenocarcinoma cell line isolated from the pleural effusion of a 69- year-old female, d)T-47D, a breast carcinoma cell line isolated from a pleural effusion obtained from a 54-year-old female with an infiltrating ductal carcinoma of the breast, e)Sk-BR-3, a breast adenocarcinoma cell line isolated from a malignant pleural effusion of a 43-year-old female, t)BT-20, a breast carcinoma cell line derived in vitro from cells emigrating out of thin slices of the tumor mass isolated from a 74-year-old female, g)MDA-mb-231, a breast tumor cell line isolated from the pleural effusion of a 51-year-old female, and h)MDA-mb-4355, a spindle-shaped strain that evolved from the parent line (435) isolated by R.
Cailleau from pleural effusion of a 31-year-old female with metastatic, ductal adenocarcinoma of the breast. Further, SEQ ID N0:84, SEQ )D N0:90, and SEQ m N0:95 showed decreased expression in a tumor from the right breast of a 43-year-old female diagnosed with invasive lobular carcinoma, versus grossly uninvolved breast tissue from the same donor (Huntsman Cancer Institute, Salt Lake City, UT). The tumor was well differentiated and metastatic to 2 out of 13 lymph nodes. Therefore, SEQ ID N0:84, SEQ ID N0:90, SEQ )D N0:93, and SEQ ID N0:95 are useful in monitoring treatment of, and diagnostic assays for, breast cancer and other cell proliferative disorders.
As another example, SEQ >D N0:89, SEQ m N0:90, and SEQ >D N0:95 showed decreased expression in tissue affected by lung adenocarcinoma versus normal lung tissue, as determined by microarray analysis. Moderately differentiated adenocarcinoma of the right lung was compared to grossly uninvolved lung tissue from a 60 year-old donor (Huntsman Cancer Institute). Therefore, SEQ m N0:89, SEQ )D N0:90, and SEQ >D N0:95 are useful in monitoring treatment of, and diagnostic assays for, lung cancer and other cell proliferative disorders.
As another example, SEQ ID N0:90 and SEQ >D N0:95 showed decreased expression in prostate carcinoma cells versus primary prostate epithelial cells, as determined by microarray analysis. Primary prostate epithelial cells were compared with prostate carcinomas representative of the different stages of tumor progression. Cell lines compared included:
a)PrEC, a primary prostate epithelial cell line isolated from a normal donor, b)DU 145, a prostate carcinoma cell line isolated from a metastatic site in the brain of 69-year old male with widespread metastatic prostate carcinoma, c)LNCaP, a prostate carcinoma cell line isolated from a lymph node biopsy of a 50-year-old male with metastatic prostate carcinoma, and d)PC-3, a prostate adenocarcinoma cell line isolated from a metastatic site in the bone of a 62- year-old male with grade IV prostate adenocarcinoma. Carcinoma cells grown under restrictive conditions were compared to normal PrECs grown under restrictive conditions. Therefore, SEQ ff~ N0:90 and SEQ ID N0:95 are useful in monitoring treatment of, and diagnostic assays for, prostate cancer and other cell proliferative disorders.
As another example, SEQ ID N0:102 showed differential expression associated with breast cancer, as determined by microarray analysis. The gene expression profile of a nonmalignant mammary epithelial cell line was compared to the gene expression profiles of a breast carcinoma line.
Hs 578T, a breast ductal carcinoma cell line, was isolated from a 74-year-old female with breast carcinoma, and compared to HMEC, a primary breast epithelial cell line isolated from a normal donor. Primary mammary epithelial cells (HMEC) were grown in basal media in the absence of growth factors and hormones for 24 hours prior to comparison with Hs578T
cells, grown either in basal media or under optimal growth conditions, in the presence of growth factors and nutrients. In both cases, the expression of SEQ ID N0:102 was increased by at least 2.5 fold in the Hs578T
carcinoma cell line as compared to the primary epithelial cell line.
Therefore, SEQ ID N0:102 is useful in diagnostic assays and disease staging assays for breast cancer and as a potential biological marker and therapeutic agent in the treatment of breast cancer.
In a further example, SEQ ID N0:102 showed differential expression associated with colon, lung and ovarian cancer, as determined by microarray analysis. In pair comparisons of matched normal and tumor tissue from five different donors (three colon, one lung and one ovary), the expression of SEQ ID N0:102 was downregulated by at least two-fold in colon tumor tissue, by at least 3.5-fold in lung adenocarcinoma tissue, and by at least 4.5-fold in ovarian tumor tissue.
Therefore SEQ ID N0:102 is also useful in diagnostic assays and disease staging assays for colon, lung and ovarian cancer and as a potential biological marker and therapeutic agent in the treatment of colon, lung and ovarian cancer.
In another example, SEQ ID N0:98 and SEQ ID N0:102 showed differential expression associated with prostate cancer, as determined by microarray analysis. Primary prostate epithelial cells were compared with prostate carcinomas representative of the different stages of tumor progression. Cell lines compared included: a) PrEC, a primary prostate epithelial cell line isolated from a normal donor, b) DU 145, a prostate carcinoma cell line isolated from a metastatic site in the brain of a 69-year old male with widespread metastatic prostate carcinoma, c) LNCaP, a prostate carcinoma cell line isolated from a lymph node biopsy of a 50-year-old male with metastatic prostate carcinoma, and d) PC-3, a prostate adenocarcinoma cell line isolated from a metastatic site in the bone of a 62- year-old male with grade N prostate adenocarcinoma. The expression of SEQ ID
N0:98 was decreased by at least two-fold in DU145, LNCaP and PC3 cell lines as compared to PrEC
cells. The expression of SEQ ID N0:102 was decreased by at least two-fold in the DU145 and LNCaP cell lines as compared to PrEC cells. Therefore, SEQ ID N0:98 and SEQ ID
N0:102 are useful in diagnostic assays and disease staging assays for prostate cancer and as potential biological markers and therapeutic agents in the treatment of prostate cancer.
XII. Complementary Polynucleotides Sequences complementary to the SCAP-encoding sequences, or any parts thereof, are used to detect, decrease, or inhibit expression of naturally occurring SCAP. Although use of oligonucleotides comprising from about 15 to 30 base pairs is described, essentially the same procedure is used with smaller or with larger sequence fragments. Appropriate oligonucleotides are designed using OLIGO
4.06 software (National Biosciences) and the coding sequence of SCAP. To inhibit transcription, a complementary oligonucleotide is designed from the most unique 5' sequence and used to prevent promoter binding to the coding sequence. To inhibit translation, a complementary oligonucleotide is designed to prevent ribosomal binding to the SCAP-encoding transcript.
XIII. Expression of SCAP
Expression and purification of SCAP is achieved using bacterial or virus-based expression systems. For expression of SCAP in bacteria, cDNA is subcloned into an appropriate vector containing an antibiotic resistance gene and an inducible promoter that directs high levels of cDNA
transcription. Examples of such promoters include, but are not limited to, the trp-lac (tac) hybrid promoter and the TS or T7 bacteriophage promoter in conjunction with the lac operator regulatory element. Recombinant vectors are transformed into suitable bacterial hosts, e.g., BL21(DE3).
Antibiotic resistant bacteria express SCAP upon induction with isopropyl beta-D-thiogalactopyranoside (IPTG). Expression of SOAP in eukaryotic cells is achieved by infecting insect or mammalian cell lines with recombinant Autographica californica nuclear polyhedrosis virus (AcMNPV), commonly known as baculovirus. The nonessential polyhedrin gene of baculovirus is replaced with cDNA encoding SCAP by either homologous recombination or bacterial-mediated transposition involving transfer plasmid intermediates. Viral infectivity is maintained and the strong polyhedrin promoter drives high levels of cDNA transcription. Recombinant baculovirus is used to infect Spodoptera frugiperda (Sf9) insect cells in most cases, or human hepatocytes, in some cases.
Infection of the latter requires additional genetic modifications to baculovirus (Engelhard, E.K. et al.
(1994) Proc. Natl. Acad. Sci. USA 91:3224-3227; Sandig, V. et al. (1996) Hum.
Gene Ther. 7:1937-1945 ).
In most expression systems, SCAP is synthesized as a fusion protein with, e.g., glutathione S-transferase (GST) or a peptide epitope tag, such as FLAG or 6-His, permitting rapid, single-step, affinity-based purification of recombinant fusion protein from crude cell lysates. GST, a 26-kilodalton enzyme from Schistosoma japonicum, enables the purification of fusion proteins on immobilized glutathione under conditions that maintain protein activity and antigenicity (Amersham Biosciences). Following purification, the GST moiety can be proteolytically cleaved from SCAP at specifically engineered sites. FLAG, an 8-amino acid peptide, enables immunoaffinity purification using commercially available monoclonal and polyclonal anti-FLAG antibodies (Eastman Kodak). 6-His, a stretch of six consecutive histidine residues, enables purification on metal-chelate resins (QIAGEN). Methods for protein expression and purification are discussed in Ausubel et al. (supra, ch. 10 and 16). Purified SCAP obtained by these methods can be used directly in the assays shown in Examples XVII and XVIII, where applicable.
XIV. Functional Assays SCAP function is assessed by expressing the sequences encoding SCAP at physiologically elevated levels in mammalian cell culture systems. cDNA is subcloned into a mammalian expression vector containing a strong promoter that drives high levels of cDNA
expression. Vectors of choice include PCMV SPORT plasmid (lnvitrogen, Carlsbad CA) and PCR3.1 plasmid (Invitrogen), both of which contain the cytomegalovirus promoter. 5-10 ug of recombinant vector are transiently transfected into a human cell line, for example, an endothelial or hematopoietic cell line, using either liposome formulations or electroporation. 1-2 ~g of an additional plasmid containing sequences encoding a marker protein are co-transfected. Expression of a marker protein provides a means to distinguish transfected cells from nontransfected cells and is a reliable predictor of cDNA expression from the recombinant vector. Marker proteins of choice include, e.g., Green Fluorescent Protein (GFP; Clontech), CD64, or a CD64-GFP fusion protein. Flow cytometry (FCM), an automated, laser optics-based technique, is used to identify transfected cells expressing GFP
or CD64-GFP and to evaluate the apoptotic state of the cells and other cellular properties. FCM
detects and quantifies the uptake of fluorescent molecules that diagnose events preceding or coincident with cell death. These events include changes in nuclear DNA content as measured by staining of DNA
with propidium iodide; changes in cell size and granularity as measured by forward light scatter and 90 degree side light scatter; down-regulation of DNA synthesis as measured by decrease in bromodeoxyuridine uptake; alterations in expression of cell surface and intracellular proteins as measured by reactivity with specific antibodies; and alterations in plasma membrane composition as measured by the binding of tluorescein-conjugated Annexin V protein to the cell surface. Methods in flow cytometry are discussed in Ormerod, M.G. (1994; Flow Cvtometry, Oxford, New York NY).
The influence of SOAP on gene expression can be assessed using highly purified populations of cells transfected with sequences encoding SCAP and either CD64 or CD64-GFP.
CD64 and CD64-GFP are expressed on the surface of transfected cells and bind to conserved regions of human immunoglobulin G (IgG). Transfected cells are efficiently separated from nontransfected cells using magnetic beads coated with either human IgG or antibody against CDG4 (DYNAL, Lake Success NY). mRNA can be purified from the cells using methods well known by those of skill in the art.
Expression of mRNA encoding SCAP and other genes of interest can be analyzed by northern analysis or microarray techniques.
XV. Production of SCAP Specific Antibodies SCAP substantially purified using polyacrylamide gel electrophoresis (PAGE;
see, e.g., Harrington, M.G. (1990) Methods Enzymol. 182:488-495), or other purification techniques, is used to immunize animals (e.g., rabbits, mice, etc.) and to produce antibodies using standard protocols.
Alternatively, the SCAP amino acid sequence is analyzed using LASERGENE
software (DNASTAR) to determine regions of high immunogenicity, and a corresponding oligopeptide is synthesized and used to raise antibodies by means known to those of skill in the art. Methods for selection of appropriate epitopes, such as those near the C-terminus or in hydrophilic regions are well described in the art (Ausubel et al., supra, ch. 11).
Typically, oligopeptides of about 15 residues in length are synthesized using an ABI 431A
peptide synthesizer (Applied Biosystems) using FMOC chemistry and coupled to KLH (Sigma-Aldrich, St. Louis MO) by reaction with N-maleimidobenzoyl-N-hydroxysuccinimide ester (MBS) to increase immunogenicity (Ausubel et al., supra). Rabbits are immunized with the oligopeptide-KLH
complex in complete Freund's adjuvant. Resulting antisera are tested for antipeptide and anti-SCAP
activity by, for example, binding the peptide or SCAP to a substrate, blocking with 1% BSA, reacting with rabbit antisera, washing, and reacting with radio-iodinated goat anti-rabbit IgG.
XVI. Purification of Naturally Occurring SCAP Using Specific Antibodies Naturally occurring or recombinant SCAP is substantially purified by immunoaffinity chromatography using antibodies specific for SCAP. An immunoaffinity column is constructed by covalently coupling anti-SCAP antibody to an activated chromatographic resin, such as CNBr-activated SEPHAROSE (Amersham Biosciences). After the coupling, the resin is blocked and washed according to the manufacturer's instructions.
Media containing SCAP are passed over the immunoaffinity column, and the column is washed under conditions that allow the preferential absorbance of SCAP (e.g., high ionic strength buffers in the presence of detergent). The column is eluted under conditions that disrupt antibody/SCAP binding (e.g., a buffer of pH 2 to pH 3, or a high concentration of a chaotrope, such as urea or thiocyanate ion), and SCAP is collected.
XVII. Identification of Molecules Which Interact with SCAP
SCAP, or biologically active fragments thereof, are labeled with '25I Bolton-Hunter reagent (Bolton, A.E. and W.M. Hunter (1973) Biochem. J. 133:529-539). Candidate molecules previously arrayed in the wells of a multi-well plate are incubated with the labeled SCAP, washed, and any wells with labeled SCAP complex are assayed. Data obtained using different concentrations of SCAP are used to calculate values for the number, affinity, and association of SCAP
with the candidate molecules.
Alternatively, molecules interacting with SCAP are analyzed using the yeast two-hybrid system as described in Fields, S. and O. Song (1989; Nature 340:245-246), or using commercially available kits based on the two-hybrid system, such as the MATCHMAKER system (Clontech).
SOAP may also be used in the PATHCALLING process (CuraGen Corp., New Haven CT) which employs the yeast two-hybrid system in a high-throughput manner to determine all interactions between the proteins encoded by two large libraries of genes (Nandabalan, K.
et al. (2000) U.S.
Patent No. 6,057,101).
XVIII. Demonstration of SCAP Activity A microtubule motility assay for SOAP measures motor protein activity. In this assay, recombinant SCAP is immobilized onto a glass slide or similar substrate. Taxol-stabilized bovine brain microtubules (commercially available) in a solution containing ATP and cytosolic extract are perfused onto the slide. Movement of microtubules as driven by SCAP motor activity can be visualized and quantified using video-enhanced light microscopy and image analysis techniques.
SCAP activity is directly proportional to the frequency and velocity of microtubule movement.
Alternatively, an assay for SCAP measures the formation of protein filaments in vitro. A
solution of SOAP at a concentration greater than the "critical concentration"
for polymer assembly is applied to carbon-coated grids. Appropriate nucleation sites may be supplied in the solution. The grids are negative stained with 0.7% (w/v) aqueous uranyl acetate and examined by electron microscopy. The appearance of filaments of approximately 25 nm (microtubules), 8 nm (actin), or 10 nm (intermediate filaments) is a demonstration of SCAP activity.
In another alternative, SCAP activity is measured by the binding of SCAP to protein filaments. 35S-Met labeled SCAP sample is incubated with the appropriate filament protein (actin, tubulin, or intermediate filament protein) and complexed protein is collected by immunoprecipitation using an antibody against the filament protein. The immunoprecipitate is then run out on SDS-PAGE
and the amount of SCAP bound is measured by autoradiography.
Various modifications and variations of the described compositions, methods, and systems of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. It will be appreciated that the invention provides novel and useful proteins, and their encoding polynucleotides, which can be used in the drug discovery process, as well as methods for using these compositions for the detection, diagnosis, and treatment of diseases and conditions.
too Although the invention has been described in connection with certain embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments.
Nor should the description of such embodiments be considered exhaustive or limit the invention to the precise forms disclosed. Furthermore, elements from one embodiment can be readily recombined with elements from one or more other embodiments. Such combinations can form a number of embodiments within the scope of the invention. It is intended that the scope of the invention be defined by the following claims and their equivalents.

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z <110> INCYTE GENOMICS, INC.
BECHA, Shanya D.
BHATIA, Umesh .
BLAKE, Julie J.
BOROWSKY, Mark L.
BURRILL, John D.
CHANG, Hsin-Ru CHAWLA, Narinder K.
ELLIOTT, Vicki S.
EMERLING, Brooke M.
FORSYTHE, Ian J.
GORVAD, Ann E.
GRIFFIN, Jennifer A.
HAFALIA, April J.A.
H0, Anne ISON, Craig H.
KABLE, Amy E.
KHARE, Reena LAL, Preeti G.
LEE, Sally LEE, Ernestine A.
LEE, Soo Yeun LEHR-MASON, Patricia M.
LI, Joana X.
LINDQUIST, Erika A.
LUO, Wen MARQUIS, Joseph P.
RAMKUMAR, Jayala}ani RICHARDSON, Thomas W.
SPRAGUE, William W.
SWARNAKAR, Anita TANG, Y. Tom WARREN, Bridget A.
YANG, Junming YUE, Henry ZEBARJADIAN, Yeganeh ZHENG, Wenjin <120> STRUCTURAL AND CYTOSKELETON-ASSOCIATED PROTEINS
<130> PF-1223 PCT
<140> To Be Assigned <141> Herewith <150> US 60/328,931 <151> 2001-10-12 <150> US 60/360,681 <151> 2001-10-19 <150> US 60/343,896 <151> 2001-11-02 <150> US 60/346,308 <151> 2001-11-09 <150> US 60/332,385 <151> 2001-11-16 <150> US 60/340,776 <151> 2001-12-07 <150> US 60/347,703 <151> 2002-01-11 <160> 102 <170> PERL Program <210> 1 <211> 1881 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 3644223CD1 <400> 1 Met Glu Lys Gly His Ser Leu Leu Lys Ser Ala Arg Glu Lys Gly Glu Arg Ala Val Lys Tyr Leu Glu Glu Gly Glu Ala Glu Arg Leu Arg Lys Glu Ile His Asp His Met Glu Gln Leu Lys Glu Leu Thr Ser Thr Val Arg Lys Glu His Met Thr Leu Glu Lys Gly Leu His Leu Ala Lys Glu Phe Ser Asp Lys Cys Lys Ala Leu Thr Gln Trp Ile.Ala Glu Tyr Gln Glu Ile Leu His Val Pro Glu Glu Pro Lys Met Glu Leu Tyr Glu Lys Lys Ala Gln Leu Ser Lys Tyr Lys Ser Leu Gln Gln Thr Val Leu Ser His Glu Pro Ser Val Lys Ser Val Arg Glu Lys Gly Glu Ala Leu Leu Glu Leu Val Gln Asp Val Thr Leu Lys Asp Lys Ile Asp Gln Leu Gln Ser Asp Tyr Gln Asp Leu Cys Ser Ile Gly Lys Glu His Val Phe Ser Leu Glu Ala Lys Val Lys Asp His Glu Asp Tyr Asn Ser Glu Leu Gln Glu Val Glu Lys Trp Leu Leu Gln Met Ser Gly Arg Leu Val Ala Pro Asp Leu Leu Glu Thr Ser Ser Leu Glu Thr Ile Thr Gln Gln Leu Ala His His Lys Ala Met Met Glu Glu Ile Ala Gly Phe Glu Asp Arg Leu Asn Asn Leu Gln Met Lys Gly Asp Thr Leu Ile Gly Gln Cys Ala Asp His Leu G1n Ala Lys Leu Lys Gln Asn Val His Ala His Leu Gln Gly Thr Lys Asp Ser Tyr Ser Ala Ile Cys Ser Thr Ala Gln Arg Met Tyr Gln Ser Leu Glu His Glu Leu Gln Lys His Val Ser Arg Gln Asp Thr Leu Gln Gln Cys Gln Ala Trp Leu Ser Ala Val Gln Pro Asp Leu Asp Pro Ser Pro Gln Pro Pro Leu Ser Arg Ala Glu Ala Ile Lys Gln Val Lys His Phe Arg Ala Leu Gln Glu Gln Ala Arg Thr Tyr Leu Asp Leu Leu Cys Ser Met Cys Asp Leu Ser Asn Ala Ser Val Lys Thr Thr Ala Lys Asp Ile Gln Gln Thr Glu Gln Thr Ile Glu Gln Arg Leu Val Gln Ala Gln Asn Leu Thr Gln Gly Trp Glu Glu Ile Lys His Leu Lys Ser Glu Leu Trp Ile Tyr Leu Gln Asp Ala Asp Gln Gln Leu Gln Asn Met Lys Arg Arg His Ser Glu Leu Glu Leu Asn Ile Ala Gln Asn Met Val Ser Gln Val Lys Asp Phe Val Lys Lys Leu Gln Ser Lys Gln Ala Ser Val Asn Thr Ile Ile Glu Lys Val Asn Lys Leu Thr Lys Lys Glu Glu Ser Pro Glu His Lys Glu Ile Asn His Leu Asn Asp Gln Trp Leu Asp Lea Cys Arg Gln Ser Asn Asn Leu Cys Leu Gln Arg Glu Glu Asp Leu Gln Arg Thr Arg Asp Tyr His Asp Cys Met Asn Val Val Glu Val Phe Leu Glu Lys Phe Thr Thr Glu Trp Asp Asn Leu Ala Arg Ser Asp Ala Glu Ser Thr Ala Val His Leu Glu Ala Leu Lys Lys Leu Ala Leu Ala Leu Gln Glu Arg Lys Tyr Ala Ile Glu Asp Leu Lys Asp Gln Lys Gln Lys Met Ile Glu His Leu Asn Leu Asp Asp Lys Glu Leu Val Lys Glu Gln Thr Ser His Leu Glu Gln Arg Trp Phe Gln Leu Glu Asp Leu Ile Lys Arg Lys Ile Gln Val Ser Val Thr Asn Leu Glu Glu Leu Asn Val Val Gln Ser Arg Phe Gln Glu Leu Met Glu Trp Ala Glu Glu Gln Gln Pro Asn Ile Ala Glu A1a Leu Lys Gln Ser Pro Pro Pro Asp Met Ala Gln Asn Leu Leu Met Asp His Leu Ala Ile Cys Ser Glu Leu Glu Ala Lys Gln Met Leu Leu Lys Ser Leu Ile Lys Asp Ala Asp Arg Val Met Ala Asp Leu Gly Leu Asn Glu Arg Gln Val Ile Gln Lys Ala Leu Ser Asp Ala Gln Ser His Val Asn Cys Leu Ser Asp Leu Val Gly Gln Arg Arg Lys Tyr Leu Asn Lys Ala Leu Ser Glu Lys Thr Gln Phe Leu Met Ala Val Phe Gln Ala Thr Ser Gln Ile Gln Gln His Glu Arg Lys Ile Met Phe Arg Glu His Ile Cys Leu Leu Pro Asp Asp Val Ser Lys Gln Val Lys Thr Cys Lys Ser Ala Gln Ala Ser Leu Lys Thr Tyr Gln Asn Glu Val Thr Gly Leu Trp Ala Gln Gly Arg Glu Leu Met Lys Glu Val Thr Glu Gln Glu Lys Ser Glu Val Leu Gly Lys Leu Gln Glu Leu Gln Ser Val Tyr Asp Ser Val Leu Gln Lys Cys Ser His Arg Leu Gln Glu Leu Glu Lys Asn Leu Val Ser Arg Lys His Phe Lys Glu Asp Phe Asp Lys Ala Cys His Trp Leu Lys Gln Ala Asp Ile Val Thr Phe Pro Glu Ile Asn Leu Met Asn Glu Ser Ser Glu Leu His Thr Gln Leu Ala Lys Tyr Gln Asn Ile Leu Glu Gln Ser Pro Glu Tyr Glu Asn Leu Leu Leu Thr Leu Gln Arg Thr Gly Gln Thr Ile Leu Pro Ser Leu Asn Glu Val Asp His Ser Tyr Leu Ser Glu Lys Leu Asn Ala Leu Pro Arg Gln Phe Asn Val Ile Val Ala Leu Ala Lys Asp Lys Phe Tyr Lys Val Gln Glu Ala Ile Leu Ala Arg Lys Glu Tyr Ala Ser Leu Ile Glu Leu Thr Thr Gln Ser Leu Ser Glu Leu Glu Ala Gln Phe Leu Arg Met Ser Lys Val Pro Thr Asp Leu Ala Val Glu Glu Ala Leu Ser Leu Gln Asp Gly Cys Arg Ala Ile Leu Asp Glu Val Ala Gly Leu Gly Glu Ala Val Asp Glu Leu Asn Gln Lys Lys Glu Gly Phe Arg Ser Thr Gly Gln Pro Trp Gln Pro Asp Lys Met Leu His Leu Val Thr Leu Tyr His Arg Leu Lys Arg Gln Thr Glu Gln Arg Val Ser Leu Leu Glu Asp Thr Thr Ser Ala Tyr Gln Glu His Glu Lys Met Cys Gln Gln Leu Glu Arg Gln Leu Lys Ser Val Lys Glu Glu Gln Ser Lys Val Asn Glu Glu Thr Leu Pro Ala Glu Glu Lys Leu Lys Met Tyr His Ser Leu Ala Gly Ser Leu Gln Asp Ser Gly Ile Val Leu Lys Arg Val Thr Ile His Leu Glu Asp Leu Ala Pro His Leu Asp Pro Leu Ala Tyr Glu Lys Ala Arg His Gln Ile Gln Ser Trp Gln Gly Glu Leu Lys Leu Leu Thr Ser Ala Ile Gly Glu Thr Val Thr Glu Cys Glu Ser Arg Met Val Gln Ser Ile Asp Phe Gln Thr Glu Met Ser Arg Ser Leu Asp Trp Leu Arg Arg Val Lys Ala Glu Leu Ser Gly Pro Val Tyr Leu Asp Leu Asn Leu Gln Asp Ile Gln Glu Glu Ile Arg Lys Ile Gln Ile His Gln Glu Glu Val Gln Ser Ser Leu Arg Ile Met Asn Ala Leu Ser His Lys Glu Lys Glu Lys Phe Thr Lys Ala Lys Glu Leu Ile Ser Ala Asp Leiz Glu His Ser Leu Ala Glu Leu Ser Glu Leu Asp Gly Asp Ile Gln Glu Ala Leu Arg Thr Arg Gln Ala Thr Leu Thr Glu Ile Tyr Ser Gln Cys Gln Arg Tyr Tyr Gln Val Phe Gln Ala Ala Asn Asp Trp Leu Glu Asp Ala Gln Glu Leu Leu Gln Leu Ala Gly Asn Gly Leu Asp Val Glu Ser Ala Glu Glu Asn Leu Lys Ser His Met Glu Phe Phe Ser Thr Glu Asp Gln Phe His Ser Asn Leu Glu Glu Leu His Ser Leu Val Ala Thr Leu Asp Pro Leu Ile Lys Pro Thr Gly Lys Glu Asp Leu Glu Gln Lys Val Ala Ser Leu Glu Leu Arg Ser Gln Arg Met Ser Arg Asp Ser Gly Ala Gln Val Asp Leu Leu Gln Arg Cys Thr Ala Gln Trp His Asp Tyr Gln Lys Ala Arg Glu Glu Val Ile Glu Leu Met Asn Asp Thr Glu Lys Lys Leu Ser Glu Phe Ser Leu Leu Lys Thr Ser Ser Ser His Glu Ala Glu Glu Lys Leu Ser Glu His Lys Ala Leu Val Ser Val Val Asn Ser Phe His Glu Lys Ile Val Ala Leu Glu Glu Lys Ala Ser Gln Leu Glu Lys Thr Gly Asn Asp Ala Ser Lys Ala Thr Leu Ser Arg Ser Met Thr Thr Val Trp Gln Arg Trp Thr Arg Leu Arg Ala Val Ala Gln Asp Gln Glu Lys Ile Leu Glu Asp Ala Val Asp Glu Trp Thr Gly Phe Asn Asn Lys Val Lys Lys Ala Thr Glu Met Ile Asp Gln Leu Gln Asp Lys Leu Pro Gly Ser Ser Ala Glu Lys Ala Ser Lys Ala Glu Leu Leu Thr Leu Leu Glu Tyr His Asp Thr Phe Val Leu Glu Leu Glu Gln Gln Gln Ser Ala Leu Gly Met Leu Arg Gln Gln Thr Leu Ser Met Leu Gln Asp Gly Ala Ala Pro Thr Pro Gly Glu Glu Pro Pro Leu Met Gln Glu Ile Thr Ala Met Gln Asp Arg Cys Leu Asn Met Gln Glu Lys Val Lys Thr Asn Gly Lys Leu Val Lys Gln Glu Leu Lys Asp Arg Glu Met Val Glu Thr Gln Ile Asn Ser Val Lys Cys Trp Val Gln Glu Thr Lys Glu Tyr Leu Gly Asn Pro Thr Ile Glu Ile Asp Ala Gln Leu Glu Glu Leu Gln Ile Leu Leu Thr Glu Ala Thr Asn His Arg Gln Asn Ile Glu Lys Met Ala Glu Glu Gln Lys Glu Lys Tyr Leu Gly Leu Tyr Thr Ile Leu Pro Ser Glu Leu Ser Leu Gln Leu Ala Glu Val Ala Leu Asp Leu Lys Ile Arg Asp Gln Ile Gln Asp Lys Ile Lys Glu Val Glu Gln Ser Lys Ala Thr Ser Gln Glu Leu Ser Arg Gln Ile Gln Lys Leu Ala Lys Asp Leu Thr Thr Ile Leu Thr Lys Leu Lys Ala Lys Thr Asp Asn Val Val Gln Ala Lys Thr Asp Gln Lys Val Leu Gly Glu Glu Leu Asp Gly Cys Asn Ser Lys Leu Met Glu Leu Asp Ala Ala Val Gln Lys Phe Leu Glu Gln Asn Gly Gln Leu Gly Lys Pro Leu Ala Lys Lys Ile Gly Lys Leu Thr Glu Leu His Gln Gln Thr Ile Arg Gln Ala Glu Asn Arg Leu Ser Lys Leu Asn Gln Ala Ala SerHis LeuGluGluTyr AsnGlu Met GluLeu IleLeu Leu Lys TrpIle GluLysAlaLys ValLeu Ala GlyThr IleAla His Trp AsnSer AlaSerGlnLeu ArgGlu Gln IleLeu HisGln Tyr Thr LeuLeu GluGluSerLys GluIle Asp GluLeu GluAla Ser Met ThrGlu LysLeuGlnTyr LeuThr Ser TyrCys ThrGlu Val Lys MetSer GlnGlnValAla GluLeu Gly GluThr GluGlu Arg Leu ArgGln MetIleLysIle ArgLeu Gln LeuGln AspAla Asn Ala LysAsp MetLysLysIle <210> 2 <211> 228 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 5284322CD1 <400> 2 Met Glu Arg Val Gly Cys Thr Leu Thr Thr Thr Tyr Ala His Pro Arg Pro Thr Pro Thr Asn Phe Leu Pro Ala Ile Ser Thr Met Ala Ser Ser Tyr Arg Asp Arg Phe Pro His Ser Asn Leu Thr His Ser Leu Ser Leu Pro Trp Arg Pro Ser Thr Tyr Tyr Lys Val Ala Ser Asn Ser Pro Ser Val Ala Pro Tyr Cys Thr Arg Ser Gln Arg Val Ser Glu Asn Thr Met Leu Pro Phe Val Ser Asn Arg Thr Thr Phe Phe Thr Arg Tyr Thr Pro Asp Asp Trp Tyr Arg Ser Asn Leu Thr Asn Tyr Gln Glu Ser Asn Thr Ser Arg His Asn Ser Glu Lys Leu Arg Val Asp Thr Ser Arg Leu Ile Gln Asp Lys Tyr Gln Gln Thr Arg Lys Thr Gln Ala Asp Thr Thr Gln Asn Leu Gly Glu Arg Val Asn Asp Ile Gly Phe Trp Lys Ser Glu Ile Ile His Glu Leu Asp Glu Met Ile Gly Glu Thr Asn Ala Leu Thr Asp Val Lys Lys Arg Leu Glu Arg Ala Leu Met Glu Thr Glu Ala Pro Leu Gln Val Ala Arg Glu Cys Leu Phe His Arg Glu Lys Arg Met Gly Ile Asp Leu Val His Asp Glu Val Glu Ala Gln Leu Leu Thr Ser Gln Gln Ser Val Pro Ala <210> 3 <211> 1564 <212> PRT

<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 7499423CD1 <400> 3 Met Ser Lys Ile Arg Arg Lys Val Thr Ala Glu Asn Thr Lys Thr Ile Ser Asp Ser Thr Ser Arg Arg Pro Ser Val Phe Glu Arg Leu Gly Pro Ser Thr Gly Ser Thr Ala Glu Thr Gln Cys Arg Asn Trp Leu Lys Thr Gly Asn Cys Leu Tyr Gly Asn Thr Cys Arg Phe Val His Gly Pro Ser Pro Arg Gly Lys Gly Tyr Ser Ser Asn Tyr Arg Arg Ser Pro Glu Arg Pro Thr Gly Asp Leu Arg Glu Arg Met Lys Asn Lys Arg Gln Asp Val Asp Thr Glu Pro Gln Lys Arg Asn Thr Glu Glu Ser Ser Ser Pro Val Arg Lys Glu Ser Ser Arg Gly Arg His Arg Glu Lys Glu Asp Ile Lys Ile Thr Lys Glu Arg Thr Pro 125 ' 130 135 Glu Ser Glu Glu Glu Asn Val Glu Trp Glu Thr Asn Arg Asp Asp Ser Asp Asn Gly Asp Ile Asn Tyr Asp Tyr Val His Glu Leu Ser Leu Glu Met Lys Arg Gln Lys Ile Gln Arg Glu Leu Met Lys Leu Glu Gln Glu Asn Met Glu Lys Arg Glu Glu Ile Ile Ile Lys Lys Glu Val Ser Pro Glu Val Val Arg Ser Lys Leu Ser Pro Ser Pro Ser Leu Arg Lys Ser Ser Lys Ser Pro Lys Arg Lys Ser Ser Pro Lys Ser Ser Ser Ala Ser Lys Lys Asp Arg Lys Thr Ser Ala Val Ser Ser Pro Leu Leu Asp Gln Gln Arg Asn Ser Lys Thr Asn Gln Ser Lys Lys Lys Gly Pro Arg Thr Pro Ser Pro Pro Pro Pro Ile Pro Glu Asp Ile Ala Leu Gly Lys Lys Tyr Lys Glu Lys Tyr Lys Val Lys Asp Arg Ile Glu Glu Lys Thr Arg Asp Gly Lys Asp Arg Gly Arg Asp Phe Glu Arg Gln Arg Glu Lys Arg Asp Lys Pro Arg Ser Thr Ser Pro Ala Gly Gln His His Ser Pro Ile Ser Ser Arg His His Ser Ser Ser Ser Gln Ser Gly Ser Ser Ile Gln Arg His Ser Pro Ser Pro Arg Arg Lys Arg Thr Pro Ser Pro Ser Tyr Gln Arg Thr Leu Thr Pro Pro Leu Arg Arg Ser Ala Ser Pro Tyr Pro Ser His Ser Leu Ser Ser Pro Gln Arg Lys Gln Ser Pro Pro Arg His Arg Ser Pro Met Arg Glu Lys Gly Arg His Asp His Glu Arg Thr Ser Gln Ser His Asp Arg Arg His Glu Arg Arg Glu Asp Thr Arg Gly Lys Arg Asp Arg Glu Lys Asp Ser Arg Glu Glu Arg Glu Tyr Glu Gln Asp Gln Ser Ser Ser Arg Asp His Arg Asp Asp Arg Glu Pro Arg Asp Gly Arg Asp Arg Arg Asp Ala Arg Asp Thr Arg Asp Arg Arg Glu Leu Arg Asp Ser Arg Asp Met Arg Asp Ser Arg Glu Met Arg Asp Tyr Ser Arg Asp Thr Lys Glu Ser Arg Asp Pro Arg Asp Ser Arg Ser Thr Arg Asp Ala His Asp Tyr Arg Asp Arg Glu Gly Arg Asp Thr His Arg Lys Glu Asp Thr Tyr Pro Glu Glu Ser Arg Ser Tyr Gly Arg Asn His Leu Arg Glu Glu Ser Ser Arg Thr Glu Ile Arg Asn Glu Ser Arg Asn Glu Ser Arg Ser Glu Ile Arg Asn Asp Arg Met Gly Arg Ser Arg Gly Arg Val Pro Glu Leu Pro Glu Lys Gly Ser Arg Gly Ser Arg Gly Ser Gln Ile Asp Ser His Ser Ser Asn Ser Asn Tyr His Asp Ser Trp Glu Thr Arg Ser Ser Tyr Pro Glu Arg Asp Arg Tyr Pro Glu Arg Asp Asn Arg Asp Gln Ala Arg Asp Ser Ser Phe Glu Arg Arg His Gly Glu Arg Asp Arg Arg Asp Asn Arg Glu Arg Asp Gln Arg Pro Ser Ser Pro Ile Arg His Gln Gly Arg Asn Asp Glu Leu Glu Arg Asp Glu Arg Arg Glu Glu Arg Arg Val Asp Arg Val Asp Asp Arg Arg Asp Glu Arg Ala Arg Glu Arg Asp Arg Glu Arg Glu Arg Asp Arg Glu Arg Glu Arg Glu Arg Glu Arg Glu Arg Asp Arg Glu Arg Glu Lys Glu Arg Glu Leu Glu Arg Glu Arg Ala Arg Glu Arg Glu Arg Glu Arg Glu Lys Glu Arg Asp Arg Glu Arg Asp Arg Asp Arg Asp His Asp Arg Glu Arg Glu Arg Glu Arg Glu Arg Asp Arg Glu Lys Glu Arg Glu Arg Glu Arg Glu Glu Arg Glu Arg Glu Arg Glu Arg Glu Arg Glu Arg Glu Arg Glu Arg Glu Arg Glu Arg Glu Arg Ala Arg Glu Arg Asp Lys Glu Arg Glu Arg Gln Arg Asp Trp Glu Asp Lys Asp Lys Gly Arg Asp Asp Arg Arg Glu Lys Arg Glu Glu Ile Arg Glu Asp Arg Asn Pro Arg Asp Gly His Asp Glu Arg Lys Ser Lys Lys Arg Tyr Arg Asn Glu Gly Ser Pro Ser Pro Arg Gln Ser Pro Lys Arg Arg Arg Glu His Ser Pro Asp Ser Asp Ala Tyr Asn Ser Gly Asp Asp Lys Asn Glu Lys His Arg Leu Leu Ser Gln Val Val Arg Pro Gln Glu Ser Arg Ser Leu Ser Pro Ser His Leu Thr Glu Asp Arg Gln Gly Arg Trp Lys Glu Glu Asp Arg Lys Pro Glu Arg Lys Glu Ser Ser Arg Arg Tyr Glu Glu Gln Glu Leu Lys Glu Lys Val Ser Ser Val Asp Lys Gln Arg Glu Gln Thr Glu Ile Leu Glu Ser Ser Arg Met Arg Ala Gln Asp Ile Ile Gly His His Gln Ser Glu Asp Arg Glu Thr Ser Asp Arg Ala His Asp Glu Asn Lys Lys Lys Ala Lys Ile Gln Lys Lys Pro Ile Lys Lys Lys Lys Glu Asp Asp Val Gly Ile Glu Arg Gly Asn Ile Glu Thr Thr Ser Glu Asp Gly Gln Val Phe Ser Pro Lys Lys Gly Gln Lys Lys Lys Ser Ile Glu Lys Lys Arg Lys Lys Ser Lys Gly Asp Ser Asp Ile Ser Asp Glu Glu Ala Ala Gln Gln Ser Lys Lys Lys Arg Gly Pro Arg Thr Pro Pro Ile Thr Thr Lys Glu Glu Leu Val Glu Met Cys Asn Gly Lys Asn Gly Ile Leu Glu Asp Ser Gln Lys Lys Glu Asp Thr Ala Phe Ser Asp Trp Ser Asp Glu Asp Val Pro Asp Arg Thr Glu Val Thr Glu Ala Glu His Thr Ala Thr Ala Thr Thr Pro Gly Ser Thr Pro Ser Pro Leu Ser Ser Leu Leu Pro Pro Pro Pro Pro Val Ala Thr Ala Thr Ala Thr Thr Val Pro Ala Thr Leu Ala Ala Thr Thr Ala Ala Ala Ala Thr Ser Phe Ser Thr Ser Ala Ile Thr Ile Ser Thr Ser Ala Thr Pro Thr Asn Thr Thr Asn Asn Thr Phe Ala Asn Glu Asp Ser His Arg Lys Cys His Arg Thr Arg Val Glu Lys Val Glu Thr Pro His Val Thr Ile Glu Asp Ala Gln His Arg Lys Pro Met Asp Gln Lys Arg Ser Ser Ser Leu Gly Ser Asn Arg Ser Asn Arg Ser His Thr Ser Gly Arg Leu Arg Ser Pro Ser Asn Asp Ser Ala His Arg Ser Gly Asp Asp Gln Ser Gly Arg Lys Arg Val Leu His Ser Gly Ser Arg Asp Arg Glu Lys Thr Lys Ser Leu Glu Ile Thr Gly Glu Arg Lys Ser Arg Ile Asp Gln Leu Lys Arg Gly Glu Pro Ser Arg Ser Thr Ser Ser Asp Arg Gln Asp Ser Arg Ser His Ser Ser Arg Arg Ser Ser Pro Glu Ser Asp Arg Gln Val His Ser Arg Ser Gly Ser Phe Asp Ser Arg Asp Arg Leu Gln Glu Arg Asp Arg Tyr Glu His Asp Arg Glu Arg Glu Arg Glu Arg Arg Asp Thr Arg Gln Arg Glu Trp Asp Arg Asp Ala Asp Lys Asp Trp Pro Arg Asn Arg Asp Arg Asp Arg Leu Arg Glu Arg Glu Arg Glu Arg Glu Arg Asp Lys Arg Arg Asp Leu Asp Arg Glu Arg Glu Arg Leu Ile Ser Asp Ser Val Glu Arg Asp Arg Asp Arg Asp Arg Asp Arg Thr Phe Glu Ser Ser Gln Ile Glu Ser Val Lys Arg Cys Glu Ala Lys Leu Glu Gly Glu His Glu Arg Asp Leu Glu Ser Thr Ser Arg Asp Ser Leu Ala Leu Asp Lys Glu Arg Met Asp Lys Asp Leu Gly Ser Val Gln Gly Phe Glu Asp Thr Asn Lys Ser Glu Arg Thr Glu Ser Leu Glu Ala Gly Asp Asp Glu Ser Lys Leu Asp Asp Ala His Ser Leu Gly Ser Gly Ala Gly Glu Gly Tyr Glu Pro Ile Ser Asp Asp Glu Leu Asp Glu Ile Leu Ala Gly Asp Ala Glu Lys Arg Glu Asp Gln Gln Asp Glu Glu Lys Met Pro Asp Pro Leu Asp Val Ile Asp Val Asp Trp Ser Gly Leu Met Pro Lys His Pro Lys Glu Pro Arg Glu Pro Gly Ala Ala Leu Leu Lys Phe Thr Pro Gly Ala Val Met Leu Arg Val Gly Ile Ser Lys Lys Leu Ala Gly Ser Glu Leu Phe Ala Lys Val Lys Glu Thr Cys Gln Arg Leu Leu Glu Lys Pro Lys Gly Ser Phe Ile Leu Leu <210> 4 <211> 282 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7502092CD1 <400> 4 Met Glu Asp Ser Gly Lys Thr Phe Ser Ser Glu Glu Glu Glu Ala Asn Tyr Trp Lys Asp Leu Ala Met Thr Tyr Lys Gln Arg Ala Glu Asn Thr Gln Glu Glu Leu Arg Glu Phe Gln Glu Gly Ser Arg Glu Tyr Glu Ala Glu Leu Glu Thr Gln Leu Gln Gln Ile Glu Thr Arg Asn Arg Asp Leu Leu Ser Glu Asn Asn Arg Leu Arg Met Glu Leu Glu Thr Ile Lys Glu Lys Phe Glu Val Gln His Ser Glu Gly Tyr Arg Gln Ile Ser Ala Leu Glu Asp Asp Leu Ala Gln Thr Lys Ala Ile Lys Asp Gln Leu Gln Lys Tyr Ile Arg Glu Leu Glu Gln Ala Asn Asp Asp Leu Glu Arg Ala Lys Arg Ala Thr Ile Met Ser Leu Glu Asp Phe Glu Gln Arg Leu Asn Gln Ala Ile Glu Arg Asn Ala Phe Leu Glu Ser Glu Leu Asp Glu Lys Glu Asn Leu Leu Glu Ser Val Gln Arg Leu Lys Asp Glu Ala Arg Asp Leu Arg Gln Glu Leu Ala Val Gln Gln Lys Gln Glu Lys Pro Arg Thr Pro Met Pro Ser Ser Val Glu Ala Glu Arg Thr Asp Thr Ala Val Gln Ala Thr Gly Ser Val Pro Ser Thr Pro Ile Ala His Arg Gly Pro Ser Ser Ser Leu Asn Thr Pro Gly Ser Phe Arg Arg Gly Thr Gly Val Gln Thr Arg Phe Leu Pro Glu Pro Arg Val Arg Ser Val Pro Lys Pro Asn Arg Trp Pro Ser Leu Trp Ala Glu Gln Gln Glu Gln Arg Trp Arg Gly Glu Thr Ala Lys Gln His Gln Arg Ala Phe Gly <210> 5 <211> 2063 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 7391923CD1 <400> 5 Met Gly Ser Gly Ala Ile Cys Trp Phe Asn Leu Arg Asp Val Gly Ser Gln Ala Pro Glu Asp Arg Trp Tyr Glu Ala Glu Lys Val Trp Leu Ala Gln Lys Asp Gly Phe Thr Leu Ala Thr Val Leu Lys Pro Asp Glu Gly Thr Ala Asp Leu Pro Ala Gly Arg Val Arg Leu Trp Ile Asp Ala Asp Lys Thr Ile Thr Glu Val Asp Glu Glu His Val His Arg Ala Asn Pro Pro Glu Leu Asp Gln Val Glu Asp Leu Ala Ser Leu Ile Ser Val Asn Glu Ser Ser Val Leu Asn Thr Leu Leu Gln Arg Tyr Lys Ala Gln Leu Leu His Thr Cys Thr Gly Pro Asp Leu Ile Val Leu Gln Pro Arg Gly Pro Ser Val Pro Ser Ala Gly Lys Val Pro Lys Gly Arg Arg Asp Gly Leu Pro Ala His Ile Gly Ser Met Ala Gln Arg Ala Tyr Trp Ala Leu Leu Asn Gln Arg Arg Asp Gln Ser Ile Val Ala Leu Gly Trp Ser Gly Ala Gly Lys Thr Thr Cys Cys Glu Gln Val Leu Glu His Leu Val Gly Met Ala Gly Ser Val Asp Gly Arg Val Ser Val Glu Lys Ile Arg Ala Thr Phe Thr Val Leu Arg Ala Phe Gly Ser Val Ser Met Ala His Ser Arg Ser Ala Thr Arg Phe Ser Met Val Met Ser Leu Asp Phe Asn Ala Thr Gly Arg Ile Thr Ala Ala Gln Leu Gln Thr Met Leu Leu Glu Lys Ser Arg Val Ala Arg Gln Pro Glu Gly Glu Ser Asn Phe Leu Val Phe Ser Gln Met Leu Ala Gly Leu Asp Leu Asp Leu Arg Thr Glu Leu Asn Leu His Gln Met Ala Asp Ser Ser Ser Phe Gly Met Gly Val Trp Ser Lys Pro Glu Asp Lys Gln Lys Ala Ala Ala Ala Phe Ala Gln Leu Gln Gly Ala Met Glu Met Leu Gly Ile Ser Glu Ser Glu Gln Arg Ala Val Trp Arg Val Leu Ala Ala Ile Tyr His Leu Gly Ala Ala Gly Ala Cys Lys Val Gly Arg Lys Gln Phe Met Arg Phe Glu Trp Ala Asn Tyr Ala Ala Glu Ala Leu Gly Cys Glu Tyr Glu Glu Leu Asn Thr Ala Thr Phe Lys His His Leu Arg Gln Ile Ile Gln Gln Met Thr Phe Gly Pro Ser Arg Trp Gly Leu Glu Asp Glu Glu Thr Ser Ser Gly Leu Lys Met Thr Gly Val Asp Cys Val Glu Gly Met Ala Ser Gly Leu Tyr Gln Glu Leu Phe Ala Ala Val Val Ser Leu Ile Asn Arg Ser Phe Ser Ser His His Leu Ser Met Ala Ser Ile Met Val Val Asp Ser Pro Gly Phe Gln Asn Pro Arg His Gln Gly Lys Asp Arg Ala Ala Thr Phe Glu Glu Leu Cys His Asn Tyr Thr His Glu Arg Leu Gln Leu Leu Phe Tyr Gln Arg Thr Phe Val Ser Thr Leu Gln Arg Tyr Gln Glu Glu Gly Val Pro Val Gln Phe Asp Leu Pro Asp Pro Ser Pro Gly Thr Thr Val Ala Val Val Asp Gln Asn Pro Ser Gln Val Arg Leu Pro Ala Gly Gly Gly Ala Gln Asp Ala Arg Gly Leu Phe Trp Val Leu Asp Glu Glu Val His Val Glu Gly Ser Ser Asp Ser Val Val Leu Glu Arg Leu Cys Ala Ala Phe Glu Lys Lys Gly Ala Gly Thr Glu Gly Ser Ser Ala Leu Arg Thr Cys Glu Gln Pro Leu Gln Cys Glu Ile Phe His Gln Leu Gly Trp Asp Pro Val Arg Tyr Asp Leu Thr Gly Trp Leu His Arg Ala Lys Pro Asn Leu Ser Ala Leu Asp Ala Pro Gln Val Leu His Gln Ser Lys Arg Glu Glu Leu Arg Ser Leu Phe Gln Ala Arg Ala Lys Leu Pro Pro Val Asp Arg Met Val Arg Arg Thr Phe Ala Ser Ser Leu Ala Ala Val Arg Arg Lys Ala Pro Cys Ser Gln Ile Lys Leu Gln Met Asp Ala Leu Thr Ser Met Ile Lys Arg Ser Arg Leu His Phe Ile His Cys Leu Val Pro Asn Pro Val Val Glu Ser Arg Ser Gly Gln Glu Ser Pro Pro Pro Pro Gln Pro Gly Arg Asp Lys Pro Gly Ala Gly Gly Pro Leu Ala Leu Asp Ile Pro Ala Leu Arg Val Gln Leu Ala Gly Phe His Ile Leu Glu Ala Leu Arg Leu His Arg Thr Gly Tyr Ala Asp His Met Gly Leu Thr Arg Phe Arg Arg Gln Phe Gln Val Leu Asp Ala Pro Leu Leu Lys Lys Leu Met Ser Thr Ser Glu Gly Ile Asp Glu Arg Lys Ala Val Glu Glu Leu Leu Glu Thr Leu Asp Leu Glu Lys Lys Ala Val Ala Val Gly His Ser Gln Val Phe Leu Lys Ala Gly Val Ile Ser Arg Leu Glu Lys Gln Arg Glu Lys Leu Val Ser Gln Ser Ile Val Leu Phe Gln Ala Ala Cys Lys Gly Phe Leu Ser Arg Gln Glu Phe Lys Lys Leu Lys Ile Arg Arg Leu Ala Ala Gln Cys Ile Gln Lys Asn Val Ala Val Phe Leu Ala Val Lys Asp Trp Pro Trp Trp Gln Leu Leu Gly Ser Leu Gln Pro Leu Leu Ser Ala Thr Ile Gly Thr Glu Gln Leu Arg Ala Lys Glu Glu Glu Leu Thr Thr Leu Arg Arg Lys Leu Glu Lys Ser Glu Lys Leu Arg Asn Glu Leu Arg Gln Asn Thr Asp Leu Leu Glu Ser Lys Ile Ala Asp Leu Thr Ser Asp Leu Ala Asp Glu Arg Phe Lys Gly Asp Val Ala Cys Gln Val Leu Glu Ser Glu Arg Ala Glu Arg Leu Gln Ala Phe Arg Glu Val Gln Glu Leu Lys Ser Lys His Glu Gln Val Gln Lys Lys Leu Gly Asp Val Asn Lys Gln Leu Glu Glu Ala Gln Gln Lys Ile Gln Leu Asn Asp Leu Glu Arg Asn Pro Thr Gly Gly Ala Asp Glu Trp Gln Met Arg Phe Asp Cys Ala Gln Met Glu Asn Glu Phe Leu Arg Lys Arg Leu Gln Gln Cys Glu Glu Arg Pro Asp Ser Glu Leu Thr Ala Arg Lys Glu Leu Glu Gln Lys Leu Gly Glu Leu Gln Ser Ala Tyr Asp Gly Ala Lys Lys Met Ala His Gln Leu Lys Arg Lys Cys His His Leu Thr Cys Asp Leu Glu Asp Thr Cys Val Leu Leu Glu Asn Gln Gln Ser Arg Asn His Glu Leu Glu Lys Lys Gln Lys Lys Phe Asp Leu Gln Leu Ala Gln Ala Leu Gly Glu Ser Val Phe Glu Lys Gly Leu Arg Glu Lys Val Thr Gln Glu Asn Thr Ser Val Arg Trp Glu Leu Gly Gln Leu Gln Gln Gln Leu Lys Gln Lys Glu Gln Glu Ala Ser Gln Leu Lys Gln Gln Val Glu Met Leu Gln Asp His Lys Arg Glu Leu Leu Gly Ser Pro Ser Leu Gly Glu Asn Cys Val Ala Gly Leu Lys Glu Arg Leu Trp Lys Leu Glu Ser Ser Ala Leu Glu Gln Gln Lys Ile Gln Ser Gln Gln Glu Asn Thr Ile Lys Gln Leu Glu Gln Leu Arg Gln Arg Phe Glu Leu Glu Ile Glu Arg Met Lys Gln Met His Gln Lys Asp Arg Glu Asp Gln Glu Glu Glu Leu Glu Asp Val Arg Gln Ser Cys Gln Lys Arg Leu His Gln Leu Glu Met Gln Leu Glu Gln Glu Tyr Glu Glu Lys Gln Met Val Leu His Glu Lys Gln Asp Leu Glu Gly Leu Ile Gly Thr Leu Cys Asp Gln Ile Gly His Arg Asp Phe Asp Val Glu Lys Arg Leu Arg Arg Asp Leu Arg Arg Thr His Ala Leu Leu Ser Asp Val Gln Leu Leu Leu Gly Thr Met Glu Asp Gly Lys Thr Ser Val Ser Lys Glu Glu Leu Glu Lys Val His Ser Gln Leu Glu Gln Ser Glu Ala Lys Cys Glu Glu Ala Leu Lys Thr Gln Lys Val Leu Thr Ala Asp Leu Glu Ser Met His Ser Glu Leu Glu Asn Met Thr Arg Asn Lys Ser Leu Val Asp Glu Gln Leu Tyr Arg Leu Gln Phe Glu Lys Ala Asp Leu Leu Lys Arg Ile Asp Glu Asp Gln Asp Asp Leu Asn Glu Leu Met Gln Lys His Lys Asp Leu Ile Ala Gln Ser Ala Ala Asp Ile Gly Gln Ile Gln Glu Leu Gln Leu Gln Leu Glu Glu Ala Lys Lys Glu Lys His Lys Leu Gln Glu Gln Leu Gln Val Ala Gln Met Arg Ile Glu Tyr Leu Glu Gln Ser Thr Val Asp Arg Ala Ile Val Ser Arg Gln Glu Ala Val Ile Cys Asp Leu Glu Asn Lys Thr Glu Phe Gln Lys Val Gln Ile Lys Arg Phe Glu Val Leu Val Ile Arg Leu Arg Asp Ser Leu Ile Lys Met Gly Glu Glu Leu Ser Gln Ala Ala Thr Ser Glu Ser Gln Gln Arg Glu Ser Ser Gln Tyr Tyr Gln Arg Arg Leu Glu Glu Leu Lys Ala Asp Met Glu Glu Leu Val Gln Arg Glu Ala Glu Ala Ser Arg Arg Cys Met Glu Leu Glu Lys Tyr Val Glu Glu Leu Ala Ala Val Arg Gln Thr Leu Gln Thr Asp Leu Glu Thr Ser Ile Arg Arg Ile Ala Asp Leu Gln Ala Ala Leu Glu Glu Val Ala Ser Ser Asp Ser Asp Thr Glu Ser Val Gln Thr Ala Val Asp Cys Gly Ser Ser Gly Arg Lys Glu Met Asp Asn Val Ser Ile Leu Ser Ser Gln Pro Glu Gly Ser Leu Gln Ser Trp Leu Ser Cys Thr Leu Ser Leu Ala Thr Asp Thr Met Arg Thr Pro Ser Arg Gln Ser Ala Thr Ser Ser Arg Ile Leu Ser Pro Arg Ile Asn Glu Glu Ala Gly Asp Thr Glu Arg Thr Gln Ser Ala Leu Ala Leu Ser Arg Ala Arg Ser Thr Asn Val His Ser Lys Thr Ser Gly Asp Lys Pro Val Ser Pro His Phe Val Arg Arg Gln Lys Tyr Cys His Phe Gly Asp Gly Glu Val Leu Ala Val Gln Arg Lys Ser Thr Glu Arg Leu Glu Pro Ala Ser Ser Pro Leu Ala Ser Arg Ser Thr Asn Thr Ser Pro Leu Ser Arg Glu Lys Leu Pro Ser Pro Ser Ala Ala Leu Ser Glu Phe Val Glu Gly Leu Arg Arg Lys Arg Ala Gln Arg Gly Gln Gly Ser Thr Leu Gly Leu Glu Asp Trp Pro Thr Leu Pro Ile Tyr Gln Thr Thr Gly Ala Ser Thr Leu Arg Arg Gly Arg Ala Gly Ser Asp Glu Gly Asn Leu Ser Leu Arg Val Gly Ala Lys Ser Pro Leu Glu Ile Glu Gly Ala Ala Gly Gly Leu Leu Arg Ser Thr Ser Leu Lys Cys Ile Ser Ser Asp Gly Val Gly Gly Thr Thr Leu Leu Pro Glu Lys Ser Lys Thr Gln Phe Ser Ser Cys Glu Ser Leu Leu Glu Ser Arg Pro Ser Met Gly Arg Lys Leu Ser Ser Pro Thr Thr Pro Arg Asp Met Leu Leu Ser Pro Thr Leu Arg Pro Arg Arg Arg Cys Leu Glu Ser Ser Val Asp Asp Ala Gly Cys Pro Asp Leu Gly Lys Glu Pro Leu Val Phe Gln Asn Arg Gln Phe Ala His Leu Met Glu Glu Pro Leu Gly Ser Asp Pro Phe Ser Trp Lys Leu Pro Ser_Leu Asp Tyr Glu Arg Lys Thr Lys Val Asp Phe Asp Asp Phe Leu Pro Ala Ile Arg Lys Pro Gln Thr Pro Thr Ser Leu Ala Gly Ser Ala Lys Gly Gly Gln Asp Gly Ser Gln Arg Ser Ser Ile His Phe Glu Thr Glu Glu Ala Asn Arg Ser Phe Leu Ser Gly Ile Lys Thr Ile Leu Lys Lys Ser Pro Glu Pro Lys Glu Asp Pro Ala His Leu Ser Asp Ser Ser Ser Ser Ser Gly Ser Ile Val Ser Phe Lys Ser Ala Asp Ser Ile Lys Ser Arg Pro Gly Ile Pro Arg Leu Ala Gly Asp Gly Gly Glu Arg Thr Ser Pro Glu Arg Arg Glu Pro Gly Thr Gly Arg Lys Asp Asp Asp Val Ala Ser Ile Met Lys Lys Tyr Leu Gln Lys <210> 6 <211> 646 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1390224CD1 <400> 6 Met Leu Ser Lys Glu Val Ser Cys Gln Glu Leu Lys Ala Glu Met Glu Ser Tyr Lys Glu Asn Asn Ala Arg Lys Ser Ser Leu Leu Thr Ser Leu Arg Asp Arg Val Gln Glu Leu Glu Glu Glu Ser Ala Ala Leu Ser Thr Ser Lys Ile Arg Thr Glu Ile Thr Ala His Ala Ala Ile Lys Glu Asn Gln Glu Leu Lys Lys Lys Val Val Glu Leu Asn Glu Lys Leu Gln Lys Cys Ser Lys Glu Asn Glu Glu Asn Lys Lys Gln Val Ser Lys Asn Cys Arg Lys His Glu Glu Phe Leu Thr Gln Leu Arg Asp Cys Leu Asp Pro Asp Glu Arg Asn Asp Lys Ala Ser Asp Glu Asp Leu Ile Leu Lys Leu Arg Asp Leu Arg Lys Glu Asn Glu Phe Val Lys Gly Gln Ile Val Ile Leu Glu Glu Thr Ile Asn Val His Glu Met Glu Ala Lys Ala Ser Arg Glu Thr Ile Met Arg Leu Ala Ser Glu Val Asn Arg Glu Gln Lys Lys Ala Ala Ser Cys Thr Glu Glu Lys Glu Lys Leu Asn Gln Asp Leu Leu Ser Ala Val Glu Ala Lys Glu Ala Leu Glu Arg Glu Val Lys Ile Phe Gln Glu Arg Leu Leu Ala Gly Gln Gln Val Trp Asp Ala Ser Lys Gln Glu Val Ser Leu Leu Lys Lys Ser Ser Ser Glu Leu Glu Lys Ser Leu Lys Ala Ser Gln Asp Ala Val Thr Thr Ser Gln Ser Gln Tyr Phe Ser Phe Arg Glu Lys Ile Ala Ala Leu Leu Arg Gly Arg Leu Ser Met Thr Gly Ser Thr Glu Asp Thr Ile Leu Glu Lys Ile Arg Glu Met Asp Ser Arg Glu Glu Ser Arg Asp Arg Met Val.Ser Gln Leu Glu Ala Gln Ile Ser Glu Leu Val Glu Gln Leu Gly Lys Glu Ser Gly Phe His Gln Lys Ala Leu Gln Arg Ala Gln Lys Ala Glu Asn Met Leu Glu Thr Leu Gln Gly Gln Leu Thr His Leu Glu Ala Glu Leu Val Ser Gly Gly Val Leu Arg Asp Asn Leu Asn Phe Glu Lys Gln Lys Tyr Leu Lys Phe Leu Asp Gln Leu Ser Gln Lys Met Lys Leu Asp Gln Met Ala Ala Glu Leu Gly Phe Asp Met Arg Leu Asp Val Val Leu Ala Arg Thr Glu Gln Leu Val Arg Leu Glu Ser Asn Ala Val Ile Glu Asn Lys Thr Ile Ala His Asn Leu Gln Arg Lys Leu Lys Thr Gln Lys Glu Arg Leu Glu Ser Lys Glu Leu His Met Ser Leu Leu Arg Gln Lys Ile Ala Gln Leu Glu Glu Glu Lys Gln Ala Arg Thr Ala Leu Val Val Glu Arg Asp Asn Ala His Leu Thr Ile Arg Asn Leu Gln Lys Lys Val Glu Arg Leu Gln Lys Glu Leu Asn Thr Cys Arg Asp Leu His Thr Glu Leu Lys Ala Lys Leu Ala Asp Thr Asn Glu Leu Lys Ile Lys Thr Leu Glu Gln Thr Lys Ala Ile Glu Asp Leu Asn Lys Ser Arg Asp Gln Leu Glu Lys Met Lys Glu Lys Ala Glu Lys Lys Leu Met Ser Val Lys Ser Glu Leu Asp Thr Thr Glu His Glu Ala Lys Glu Asn Lys Glu Arg Ala Arg Asn Met Ile Glu Val Val Thr Ser Glu Met Lys Thr Leu Lys Lys Ser Leu Glu Glu Ala Glu Lys Arg Glu Lys Gln Leu Ala Asp Phe Arg Glu Val Val Ser Gln Met Leu Gly Leu Asn Val Thr Ser Leu Ala Leu Pro Asp Tyr Glu Ile Ile Lys Cys Leu Glu Arg Leu Val His Ser His Gln His His Phe Val Thr Cys Ala Cys Leu Lys Asp Val Thr Thr Gly Gln Glu Arg His Pro Gln Gly His Leu Gln Leu Leu His <210> 7 <211> 837 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 7499649CD1 <400> 7 Met Val Gly Lys Ser Gln Gln Thr Asp Val Ile Glu Lys Lys Lys His Met Ala Ile Pro Lys Ser Ser Ser Pro Lys Ala Thr His Arg Ile Gly Asn Thr Ser Gly Ser Lys Gly Ser Tyr Ser Ala Lys Ala Tyr Glu Ser Ile Arg Val Ser Ser Glu Leu Gln Gln Thr Trp Thr Lys Arg Lys His Gly Gln Glu Met Thr Ser Lys Ser Leu Gln Thr Asp Thr Ile Val Glu Glu Lys Lys Glu Val Lys Leu Val Glu Glu Thr Val Val Pro Glu Glu Lys Ser Ala Asp Val Arg Glu Ala Ala Ile Glu Leu Pro Glu Ser Val Gln Asp Val Glu Ile Pro Pro Asn Ile Pro Ser Val Gln Leu Lys Met Asp Arg Ser Gln Gln Thr Ser Arg Thr Gly Tyr Trp Thr Met Met Asn Ile Pro Pro Val Glu Lys Val Asp Lys Glu Gln Gln Thr Tyr Phe Ser Glu Ser Glu Ile Val Val Ile Ser Arg Pro Asp Ser Ser Ser Thr Lys Ser Lys Glu Asp Ala Leu Lys His Lys Ser Ser Gly Lys Ile Phe Ala Ser Glu His Pro Glu Phe Gln Pro Ala Thr Asn Ser Asn Glu Glu Ile Gly Gln Lys Asn Ile Ser Arg Thr Ser Phe Thr Gln Glu Thr Lys Lys Gly Pro Pro Val Leu Leu Glu Asp Glu Leu Arg Glu Glu Val Thr Val Pro Val Val Gln Glu Gly Ser Ala Val Lys Lys Val Ala Ser Ala Glu Ile Glu Pro Pro Ser Thr Glu Lys Phe Pro Ala Lys Ile Gln Pro Pro Leu Val Glu Glu Ala Thr Ala Lys Ala Glu Pro Arg Pro Ala Glu Glu Thr His Val Gln Val Gln Pro Ser Thr Glu Glu Thr Pro Asp Ala Glu Ala Ala Thr Ala Val Ala Glu Asn Ser Val Lys Val Gln Pro Pro Pro Ala Glu Glu Ala Pro Leu Val Glu Phe Pro Ala Glu Ile Gln Pro Pro Ser Ala Glu Glu Ser Pro Ser Val Glu Leu Leu Ala Glu Ile Leu Pro Pro Ser Ala Glu Glu Ser Pro Ser Glu Glu Pro Pro Ala Glu Ile Leu Pro Pro Pro Ala Glu Lys Ser Pro Ser Val Glu Leu Leu Gly Glu Ile Arg Ser Pro Ser Ala Gln Lys Ala Pro Ile Glu Val Gln Pro Leu Pro Ala Glu Gly Ala Leu 395 400 , 405 Glu Glu Ala Pro Ala Lys Val Glu Pro Pro Thr Val Glu Glu Thr Leu Ala Glu Val Gln Pro Leu Leu Pro Glu Glu Ala Pro Arg Glu Glu Ala Arg Glu Leu Gln Leu Ser Thr Ala Met Glu Thr Pro Ala Glu Glu Ala Pro Thr Glu Phe Gln Ser Pro Leu Pro Lys Glu Thr Thr Ala Glu Glu Ala Ser Ala Glu Ile Gln Leu Leu Ala Ala Thr Glu Pro Pro Ala Asp Glu Thr Pro Ala Glu Ala Arg Ser Pro Leu Ser Glu Glu Thr Ser Ala Glu Glu Ala His Ala Glu Val Gln Ser Pro Leu Ala Glu Glu Thr Thr Ala Glu Glu Ala Ser Ala Glu Ile Gln Leu Leu Ala Ala Ile Glu Ala Pro Ala Asp Glu Thr Pro Ala Glu Ala Gln Ser Pro Leu Ser Glu Glu Thr Ser Ala Glu Glu Ala Pro Ala Glu Val Gln Ser Pro Ser Ala Lys Gly Val Ser Ile Glu Glu Ala Pro Leu Glu Leu Gln Pro Pro Ser Gly Glu Glu Thr Thr 575 580 ' 585 Ala Glu Glu Ala Ser Ala Ala Ile Gln Leu Leu Ala Ala Thr Glu Ala Ser Ala Glu Glu Ala Pro Ala Glu Val Gln Pro Pro Pro Ala Glu Glu Ala Pro Ala Glu Val Gln Pro Pro Pro Ala Glu Glu Ala Pro Ala Glu Val Gln Pro Pro Pro Ala Glu Glu Ala Pro Ala Glu Val Gln Pro Pro Pro Ala Glu Glu Ala Pro Ala Glu Val Gln Pro Pro Pro Ala Glu Glu Ala Pro Ala Glu Val Gln Pro Pro Pro Ala Glu Glu Ala Pro Ser Glu Val Gln Pro Pro Pro Ala Glu Glu Ala Pro Ala Glu Val Gln Ser Leu Pro Ala Glu Glu Thr Pro Ile Glu Glu Thr Leu Ala Ala Val His Ser Pro Pro Ala Asp Asp Val Pro Ala Glu Glu Ala Ser Val Asp Lys His Ser Pro Pro Ala Asp Leu Leu Leu Thr Glu Glu Phe Pro Ile Gly Glu Ala Ser Ala Glu Val Ser Pro Pro Pro Ser Glu Gln Thr Pro Glu Asp Glu Ala Leu Val Glu Asn Val Ser Thr Glu Phe Gln Ser Pro Gln Val Ala Gly Ile Pro Ala Val Lys Leu Gly Ser Val Val Leu Glu Gly Glu Ala Lys Phe Glu Glu Val Ser Lys Ile Asn Ser Val Leu Lys Asp Leu Ser Asn Thr Asn Asp Gly Gln Ala Pro Thr Leu Glu Ile Glu Ser Val Phe His Ile Glu Leu Lys Gln Arg Pro Pro Glu Leu <210> 8 <211> 1490 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7716792CD1 <400> 8 Met Ser Gly Phe Arg Leu Gly Asp His Val Trp Leu Glu Pro Pro Ser Thr His Lys Thr Gly Val Ala Ile Gly Gly Ile Ile Lys Glu Ala Lys Pro Gly Lys Val Leu Val Glu Asp Gly Glu Gly Lys Glu His Trp Ile Arg Ala Glu Asp Phe Gly Val Leu Ser Pro Met His Pro Asn Ser Val Gln Gly Val Asp Asp Met Ile Arg Leu Gly Asp Leu Asn Glu Ala Gly Met Val His Asn Leu Leu Ile Arg Tyr Gln Gln His Lys Ile Tyr Thr Tyr Thr Gly Ser Ile Leu Val Ala Val Asn Pro Phe Gln Val Leu Pro Leu Tyr Thr Leu Glu Gln Val Gln Leu Tyr Tyr Ser Arg His Met Gly Glu Leu Pro Pro His Val Phe Ala Ile Ala Asn Asn Cys Tyr Phe Ser Met Lys Arg Asn Lys Arg Asp Gln Cys Cys Ile Ile Ser Gly Glu Ser Gly Ala Gly Lys Thr Glu Thr Thr Lys Leu Ile Leu Gln Phe.Leu Ala Thr Ile Ser Gly Gln His Ser Trp Ile Glu Gln Gln Val Leu Glu Ala Asn Pro Ile Leu Glu Ala Phe Gly Asn Ala Lys Thr Ile Arg Asn Asp Asn Ser Ser Arg Phe Gly Lys Tyr Ile Asp Ile Tyr Phe Asn Pro Ser Gly Val Ile Glu Gly Ala Arg Ile Glu Gln Phe Leu Leu Glu Lys Ser Arg Val Cys Arg Gln Ala Pro Glu Glu Arg Asn Tyr His Ile Phe Tyr Tyr Met Leu Met Gly Val Ser Ala Glu Asp Lys Gln Leu Leu Ser Leu Gly Thr Pro Ser Glu Tyr His Tyr Leu Thr Met Gly Asn Cys Thr Ser Cys Glu Gly Leu Asn Asp Ala Lys Asp Tyr Ala His Ile Arg Ser Ala Met Lys Ile Leu Gln Phe Ser Asp Ser Glu Ser Trp Asp Val Ile Lys Leu Leu Ala Ala Ile Leu His Leu Gly Asn Val Gly Phe Met Ala Ser Val Phe Glu Asn Leu Asp Ala Ser Asp Val Met Glu Thr Pro Ala Phe Pro Thr Val Met Lys Leu Leu Glu Val Gln His Gln Glu Leu Arg Asp Cys Leu Ile Lys His Thr Ile Leu Ile Arg Gly Glu Phe Val Thr Arg Ser Leu Asn Ile Ala Gln Ala Ala Asp Arg Arg Asp Ala Phe Val Lys Gly Ile Tyr Gly His Leu Phe Leu Trp Ile Val Lys Lys Ile Asn Ala Ala Ile Phe Thr Pro Pro Ala Gln Asp Pro Lys Asn Val Arg Arg Ala Ile Gly Leu Leu Asp Ile Phe Gly Phe Glu Asn Phe Glu Asn Asn Ser Phe Glu Gln Leu Cys Ile Asn Phe Ala Asn Glu His Leu Gln Gln Phe Phe Val Gln His Val Phe Thr Met Glu Gln Glu Glu Tyr Arg Ser Glu Asn Ile Ser Trp Asp Tyr Ile His Tyr Thr Asp Asn Arg Pro Thr Leu Asp Leu Leu Ala Leu Lys Pro Met Ser Ile Ile Ser Leu Leu Asp Glu Glu Ser Arg Phe Pro Gln Gly Thr Asp Leu Thr Met Leu Gln Lys Leu Asn Ser Val His Ala Asn Asn Lys Ala Phe Leu Gln Pro Lys Asn Ile His Asp Ala Arg Phe Gly Ile Ala His Phe Ala Gly Glu Val Tyr Tyr Gln Ala Glu Gly Phe Leu Glu Lys Asn Arg Asp Val Leu Ser Thr Asp Ile Leu Thr Leu Val Tyr Ser Ser Lys Asn Lys Phe Leu Arg Glu Ile Phe Asn Leu Glu Leu Ala Glu Thr Lys Leu Gly His Gly Thr Ile Arg Gln Ala Lys Ala Gly Asn His Leu Phe Lys Ser Ala Asp Ser Asn Lys Arg Pro Ser Thr Leu Gly Ser Gln Phe Lys Gln Ser Leu Asp Gln Leu Met Lys Ile Leu Thr Asn Cys Gln Pro Tyr Phe Ile Arg Cys Ile Lys Pro Asn Glu Tyr Lys Lys Pro Leu Leu Phe Asp Arg Glu Leu Cys Leu Arg Gln Leu Arg Tyr Ser Gly Met Met Glu Thr Val His Ile Arg Lys Ser Gly Phe Pro Ile Arg Tyr Thr Phe Glu Glu Phe Ser Gln Arg Phe Gly Val Leu Leu Pro Asn Ala Met Arg Met Gln Leu Gln Gly Lys Leu Arg Gln Met Thr Leu Gly Ile Thr Asp Val Trp Leu Arg Thr Asp Lys Asp Trp Lys Ala Gly Lys Thr Lys Ile Phe Leu Arg Asp His Gln Asp Thr Leu Leu Glu Val Gln Arg Ser Gln Val Leu Asp Arg Ala Ala Leu Ser Ile Gln Lys Val Leu Arg Gly Tyr Arg Tyr Arg Lys Glu Phe Leu Arg Gln Arg Arg Ala Ala Val Thr Leu Gln Ala Trp Trp Arg Gly Tyr Cys Asn Arg Arg Asn Phe Lys Leu Ile Leu Val Gly Phe Glu Arg Leu Gln Ala Ile Ala Arg Ser Gln Pro Leu Ala Arg Gln Tyr Gln Ala Met Arg Gln Arg Thr Val Gln Leu Gln Ala Leu Cys Arg Gly Tyr Leu Val Arg Gln Gln Val Gln Ala Lys Arg Arg Ala Val Val Val Ile Gln Ala His Ala Arg Gly Met Ala Ala Arg Arg Asn Phe Gln Gln Arg Lys Ala Asn Ala Pro Leu Val Ile Pro Ala Glu Gly Gln Lys Ser Gln Gly Ala Leu Pro Ala Lys Lys Arg Arg Ser Ile Tyr Asp Thr Val Thr Asp Thr Glu Met Val Glu Lys Val Phe Gly Phe Leu Pro Ala Met Ile Gly Gly Gln Glu Gly Gln Ala Ser Pro His Phe Glu Asp Leu Glu Ser Lys Thr Gln Lys Leu Leu Glu Val Asp Leu Asp Thr Val Pro Met Ala Glu Glu Pro Glu Glu Asp Val Asp Gly Leu Ala Glu Tyr Thr Phe Pro Lys Phe Ala Val Thr Tyr Phe Gln Lys Ser Ala Ser His Thr His Ile Arg Arg Pro Leu Arg Tyr Pro Leu Leu Tyr His Glu Asp Asp Thr Asp Cys Leu Ala Ala Leu Val Ile Trp Asn Val Ile Leu Arg Phe Met Gly Asp Leu Pro Glu Pro Val Leu Tyr Ala Arg Ser Ser Gln Gln Gly Ser Ser Val Met Arg Gln Ile His Asp Thr Leu Gly Arg Glu His Gly Ala Gln Val Pro Gln His Ser Arg Ser Ala Gln Arg Ser Gly Cys Lys Asp Lys Gly Thr Lys Asp Ile Ser Ser Met Lys Leu Lys Arg Ser Ser Arg Ile Thr Gly Gln Val Ala Ser Gln Leu Asn Ile Gly Glu Glu Ala Leu Glu Pro Asp Gly Leu Gly Ala Asp Arg Pro Met Ser Asn Leu Glu Lys Val His Phe Ile Val Gly Tyr Ala Ile Leu Arg Pro Ser Leu Arg Asp Glu Ile Tyr Cys Gln Ile Cys Lys Gln Leu Ser Glu Asn Phe Lys Thr Ser Ser Leu Ala Arg Gly Trp Ile Leu Leu Ser Leu Cys Leu Gly Cys Phe Pro Pro Ser Glu Arg Phe Met Lys Tyr Leu Leu Asn Phe Ile Gly Gln Gly Pro Ala Thr Tyr Gly Pro Phe Cys Ala Glu Arg Leu Arg Arg Thr Tyr Ala Asn Gly Val Arg Ala Glu Pro Pro Thr Trp Leu Glu Leu Gln Ala Val Lys Ser Lys Lys His Ile Pro Ile Gln Val Ile Leu Ala Thr Gly Glu Ser Leu Thr Val Pro Val Asp Ser Ala Ser Thr Ser Arg Glu Met Cys Met His Ile Ala His Lys Gln Gly Leu Ser Asp His Leu Gly Phe Ser Leu Gln Val Ala Val Tyr Asp Lys Phe Trp Ser Leu Gly Ser Gly Arg Asp His Met Met Asp Ala Ile Ala Arg Cys Glu Gln Met Ala Gln Glu Arg Gly Glu Ser Gln Arg Gln Ser Pro Trp Arg Ile Tyr Phe Arg Lys Glu Phe Phe Thr Pro Trp His Asp Ser Arg Glu Asp Pro Val Ser Thr Glu Leu Ile Tyr Arg Gln Val Leu Arg Gly Val Trp Ser Gly Glu Tyr Ser Phe Glu Lys Glu Glu Glu Leu Val Glu Leu Leu Ala Arg His Cys Tyr Val Gln Leu Gly Ala Ser Ala Glu Ser Lys Ala Val Gln Glu Leu Leu Pro Ser Cys Ile Pro His Lys Leu Tyr Arg Thr Lys Pro Pro Asp Arg Trp Ala Ser Leu Val Thr Ala Ala Cys Ala Lys Ala Pro Tyr Thr Gln Lys Gln Val Thr Pro Leu Ala Val Arg Glu Gln Val Val Asp Ala Ala Arg Leu Gln Trp Pro Leu Leu Phe Ser Arg Leu Phe Glu Val Ile Thr Leu Ser Gly Pro Arg Leu Pro Lys Thr Gln Leu Ile Leu Ala Val Asn Trp Lys Gly Leu Cys Phe Leu Asp Gln Gln Glu Lys Met Leu Leu Glu Leu Ser Phe Pro Glu Val Met Gly Leu Ala Thr Asn Arg Cys Gly Pro <210> 9 <211> 2142 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 6824158CD1 <400> 9 Met Ser Gly Phe Arg Leu Gly Asp His Val Trp Leu Glu Pro Pro Ser Thr His Lys Thr Gly Val Ala Ile Gly Gly Ile Ile Lys Glu Ala Lys Pro Gly Lys Val Leu Val Glu Asp Gly Glu Gly Lys Glu His Trp Ile Arg Ala Glu Asp Phe Gly Val Leu Ser Pro Met His Pro Asn Ser Val Gln Gly Val Asp Asp Met Ile Arg Leu Gly Asp Leu Asn Glu Ala Gly'Met Val His Asn Leu Leu Ile Arg Tyr Gln Gln His Lys Ile Tyr Thr Tyr Thr Gly Ser Ile Leu Val Ala Val Asn Pro Phe Gln Val Leu Pro Leu Tyr Thr Leu Glu Gln Val Gln Leu Tyr Tyr Ser Arg His Met Gly Glu Leu Pro Pro His Val Phe Ala Ile Ala Asn Asn Cys Tyr Phe Ser Met Lys Arg Asn Lys Arg Asp Gln Cys Cys Ile Ile Ser Gly Glu Ser Gly Ala Gly Lys Thr Glu Thr Thr Lys Leu Ile Leu Gln Phe Leu Ala Thr Ile Ser Gly Gln His Ser Trp Ile Glu Gln Gln Val Leu Glu Ala Asn Pro Ile Leu Glu Ala Phe Gly Asn Ala Lys Thr Ile Arg Asn Asp Asn Ser Ser Arg Phe Gly Lys Tyr Ile Asp Ile Tyr Phe Asn Pro Ser Gly Val Ile Glu Gly Ala Arg Ile Glu Gln Phe Leu Leu Glu Lys Ser Arg Val Cys Arg Gln Ala Pro Glu Glu Arg Asn Tyr His Ile Phe Tyr Tyr Met Leu Met Gly Val Ser Ala Glu Asp Lys Gln Leu Leu Ser Leu Gly Thr Pro Ser Glu Tyr His Tyr Leu Thr Met Gly Asn Cys Thr Ser Cys Glu Gly Leu Asn Asp Ala Lys Asp Tyr Ala His Ile Arg Ser Ala Met Lys Ile Leu Gln Phe Ser Asp Ser Glu Ser Trp Asp Val Ile Lys Leu Leu Ala Ala Ile Leu His Leu Gly Asn Val Gly Phe Met Ala Ser Val Phe Glu Asn Leu Asp Ala Ser Asp Val Met Glu Thr Pro Ala Phe Pro Thr."Val Met Lys Leu Leu Glu Val Gln His Gln Glu Leu Arg Asp Cys Leu Ile Lys His Thr Ile Leu Ile Arg Gly Glu Phe Val Thr Arg Ser Leu Asn Ile Ala Gln Ala Ala Asp Arg Arg Asp Ala Phe Val Lys Gly Ile Tyr Gly His Pro Phe Leu Trp Ile Val Lys Lys Ile Asn Ala Ala Ile Phe Thr Pro Pro Ala Gln Asp Pro Lys Asn Val Arg Arg Ala Ile Gly Leu Leu Asp Ile Phe Gly Phe Glu Asn Phe Glu Asn Asn Ser Phe Glu Gln Leu Cys Ile Asn Phe Ala Asn Glu His Leu Gln Gln Phe Phe Val Gln His Val Phe Thr Met Glu Gln Glu Glu Tyr Arg Ser Glu Asn Ile Ser Trp Asp Tyr Ile His Tyr Thr Asp Asn Arg Pro Thr Pro Asp Leu Leu Ala Leu Lys Pro Met Ser Ile Ile Ser Leu Leu Asp Glu Glu Ser Arg Phe Pro Gln Gly Thr Asp Leu Thr Met Leu Gln Lys Leu Asn Ser Val His Ala Asn Asn Lys Ala Phe Leu Gln Pro Lys Asn Ile His Asp Ala Arg Phe Gly Ile Ala His Phe Ala Gly Glu Val Tyr Tyr Gln Ala Glu Gly Phe Leu Glu Lys Asn Arg Asp Val Leu Ser Thr Asp Ile Leu Thr Leu Val Tyr Ser Ser Lys Asn Lys Phe Leu Arg Glu Ile Phe Asn Leu Glu Leu Ala Glu Thr Lys Leu Gly His Gly Thr Ile Arg Gln Ala Lys Ala Gly Asn His Leu Phe Lys Ser Ala Asp Ser Asn Lys Arg Pro Ser Thr Leu Gly Ser Gln Phe Lys Gln Ser Leu Asp Gln Leu Met Lys Ile Leu Thr Asn Cys Gln Pro Tyr Phe Ile Arg Cys Ile Lys Pro Asn Glu Tyr Lys Lys Pro Leu Leu Phe Asp Arg Glu Leu Cys Leu Arg Gln Leu Arg Tyr Ser Gly Met Met Glu Thr Val His Ile Arg Lys Ser Gly Phe Pro Ile Arg Tyr Thr Phe Glu Glu Phe Ser Gln Arg Phe Gly Val Leu Leu Pro Asn Ala Met Arg Met Gln Leu Gln Gly Lys Leu Arg Gln Met Thr Leu Gly Ile Thr Asp Val Trp Leu Arg Thr Asp Lys Asp Trp Lys Ala Gly Lys Thr Lys Ile Phe Leu Arg Asp His Gln Asp Thr Leu Leu Glu Val Gln Arg Ser Gln Val Leu Asp Arg Ala Ala Leu Ser Ile Gln Lys Val Leu Arg Gly Tyr Arg Tyr Arg Lys Glu Phe Leu Arg Gln Arg Arg Ala Ala Val Thr Leu Gln Ala Trp Trp Arg Gly Tyr Cys Asn Arg Arg Asn Phe Lys Leu Ile Leu Val Gly Phe Glu Arg Leu Gln Ala Ile Ala Arg Ser Gln Pro Leu Ala Arg Gln Tyr Gln Ala Met Arg Gln Arg Thr Val Gln Leu Gln Ala Leu Cys Arg Gly Tyr Leu Val Arg Gln Gln Val Gln Ala Lys Arg Arg Ala Val Val Val Ile Gln Ala His Ala Arg Gly Met Ala Ala Arg Arg Asn Phe Gln Gln Arg Lys Ala Asn Ala Pro Leu Val Ile Pro Ala Glu Gly Gln Lys Ser Gln Gly Ala Leu Pro Ala Lys Lys Arg Arg Ser Ile Tyr Asp Thr Val Thr Asp Thr Glu Met Val Glu Lys Val Phe Gly Phe Leu Pro Ala Met Ile Gly Gly Gln Glu Gly Gln Ala Ser Pro His Phe Glu Asp Leu Glu Ser Lys Thr Gln Lys Leu Leu Glu Val Asp Leu Asp Thr Val Pro Met Ala Glu Glu Pro Glu Glu Asp Val Asp Gly Leu Ala Glu Tyr Thr Phe Pro Lys Phe Ala Val Thr Tyr Phe Gln Lys Ser Ala Ser His Thr His Ile Arg Arg Pro Leu Arg Tyr Pro Leu Leu Tyr His Glu Asp Asp Thr Asp Cys Leu Ala Ala Leu Val Ile Trp Asn Val Ile Leu Arg Phe Met Gly Asp Leu Pro Glu Pro Val Leu Tyr Ala Arg Ser Ser Gln Gln Gly Ser Ser Val Met Arg Gln Ile His Asp Thr Leu Gly Arg Glu His Gly Ala Gln Val Pro Gln His Ser Arg Ser Ala Gln Arg Ser Gly Cys Lys Asp Lys Gly Thr Lys Asp Ile Ser Ser Met Lys Leu Lys Arg Ser Ser Arg Ile Thr Gly Gln Val Ala Ser Gln Leu Asn Ile Gly Glu Glu Ala Leu Glu Pro Asp Gly Leu Gly Ala Asp Arg Pro Met Ser Asn Leu Glu Lys Val His Phe Ile Val Gly Tyr Ala Ile Leu Arg Pro Ser Leu Arg Asp Glu Ile Tyr Cys Gln Ile Cys Lys Gln Leu Ser Glu Asn Phe Lys Thr Ser Ser Leu Ala Arg Gly Trp Ile Leu Leu Ser Leu Cys Leu Gly Cys Phe Pro Pro Ser Glu Arg Phe Met Lys Tyr Leu Leu Asn Phe Ile Gly Gln Gly Pro Ala Thr Tyr Gly Pro Phe Cys Ala Glu Arg Leu Arg Arg Thr Tyr Ala Asn Gly Val Arg Ala Glu Pro Pro Thr Trp Leu Glu Leu Gln Ala Val Lys Ser Lys Lys-His Ile Pro Ile Gln Val Ile Leu Ala Thr Gly Glu Ser Leu Thr Val Pro Val Asp Ser Ala Ser Thr Ser Arg Glu Met Cys Met His Ile Ala His Lys Gln Gly Leu Ser Asp His Leu Gly Phe Ser Leu Gln Val Ala Val Tyr Asp Lys Phe Trp Ser Leu Gly Ser Gly Arg Asp His Met Met Asp Ala Ile Ala Arg Cys Glu Gln Met Ala Gln Glu Arg Gly Glu Ser Gln Arg Gln Ser Pro Trp Arg Ile Tyr Phe Arg Lys Glu Phe Phe Thr Pro Trp His Asp Ser Arg Glu Asp Pro Val Ser Thr Glu Leu Ile Tyr Arg Gln Val Leu Arg Gly Val Trp Ser Gly Glu Tyr Ser Phe Glu Lys Glu Glu Glu Leu Val Glu Leu Leu Ala Arg His Cys Tyr Val Gln Leu Gly Ala Ser Ala Glu Ser Lys Ala Val Gln Glu Leu Leu Pro Ser Cys Ile Pro His Lys Leu Tyr Arg Thr Lys Pro Pro Asp Arg Trp Ala Ser Leu Val Thr Ala Ala Cys Ala Lys Ala Pro Tyr Thr Gln Lys Gln Val Thr Pro Leu Ala Val Arg Glu Gln Val Val Asp Ala Ala Arg Leu Gln Trp Pro Leu Leu Phe Ser Arg Leu Phe Glu Val Ile Thr Leu Ser Gly Pro Arg Leu Pro Lys Thr Gln Leu Ile Leu Ala Val Asn Trp Lys Gly Leu Cys Phe Leu Asp Gln Gln Glu Lys Met Leu Leu Glu Leu Ser Phe Pro Glu Val Met Gly Leu Ala Thr Asn Arg Glu Ala Gln Gly Gly Gln Arg Leu Leu Leu Ser Thr Met His Glu Glu Tyr Glu Phe Val Ser Pro Ser Ser Val Ala Ile Ala Glu Leu Val Ala Leu Phe Leu Glu Gly Leu Lys Glu Arg Ser Ile Phe Ala Met Ala Leu Gln Asp Arg Lys Ala Thr Asp Asp Thr Thr Leu Leu Ala Phe Lys Lys Gly Asp Leu Leu Val Leu Thr Lys Lys Gln Gly Leu Leu Ala Ser Glu Asn Trp Thr Leu Gly Gln Asn Asp Arg Thr Gly Lys Thr Gly Leu Val Pro Met Ala Cys Leu Tyr Thr Ile Pro Thr Val Thr Lys Pro Ser Ala Gln Leu Leu Ser Leu Leu Ala Met Ser Pro Glu Lys Arg Lys Leu Ala Ala Gln Glu Gly Gln Phe Thr Glu Pro Arg Pro Glu Glu Pro Pro Lys Glu Lys Leu His Thr Leu Glu Glu Phe Ser Tyr Glu Phe Phe Arg Ala Pro Glu Lys Asp Met Val Ser Met Ala Val Leu Pro Leu Ala Arg Ala Arg Gly His Leu Trp Ala Tyr Ser Cys Glu Pro Leu Arg Gln Pro Leu Leu Lys Arg Val His Ala Asn Val Asp Leu Trp Asp Ile Ala Cys Gln Ile Phe Val Ala Ile Leu Arg Tyr Met Gly Asp Tyr Pro Ser Arg Gln Ala Trp Pro Thr Leu Glu Leu Thr Asp Gln Ile Phe Thr Leu Ala Leu Gln His Pro Ala Leu Gln Asp Glu Val Tyr Cys Gln Ile Leu Lys Gln Leu Thr His Asn Ser Asn Arg His Ser Glu Glu Arg Gly Trp Gln Leu Leu Trp Leu Cys Thr Gly Leu Phe Pro Pro Ser Lys Gly Leu Leu Pro His Ala Gln Lys Phe Ile Asp Thr Arg Arg Gly Lys Leu Leu Ala Pro Asp Cys Ser Arg Arg Ile Gln Lys Val Leu Arg Thr Gly Pro Arg Lys Gln Pro Pro His Gln Val Glu Val Glu Ala Ala Glu Gln Asn Val Ser Arg Ile Cys His Lys Ile Tyr Phe Pro Asn Asp Thr Ser Glu Met Leu Glu Val Val Ala Asn Thr Arg Val Arg Asp Val Cys Asp Ser Ile Ala Thr Arg Leu Gln Leu Ala Ser Trp Glu Gly Cys Ser Leu Phe Ile Lys Ile Ser Asp Lys Val Ile Ser Gln Lys Glu Gly Asp Phe Phe Phe Asp Ser Leu Arg 1880 1885 ' 1890 Glu Val Ser Asp Trp Val Lys Lys Asn Lys Pro Gln Lys Glu Gly Ala Pro Val Thr Leu Pro Tyr Gln Val Tyr Phe Met Arg Lys Leu Trp Leu Asn Ile Ser Pro Gly Lys Asp Val Asn Ala Asp Thr Ile Leu His Tyr His Gln Glu Leu Pro Lys Tyr Leu Arg Gly Phe His Lys Cys Ser Arg Glu Asp Ala Ile His Leu Ala Gly Leu Ile Tyr Lys Ala Gln Phe Asn Asn Asp Arg Ser Gln Leu Ala Ser Val Pro LysIleLeu ArgGluLeu ValProGlu LeuThr ArgLeu Asn Met SerSerGlu GluTrpLys LysSerIle LeuAla TyrAsp Leu Lys HisLysAsp LysThrVal GluGluAla ValAla PheLeu Lys Lys TrpIleCys ArgTrpPro ThrPheGly AlaPhe PheGlu Ser Val LysGlnThr SerGluPro SerTyrPro ValIle LeuIle Asp Ala IleAsnArg HisGlyVal LeuLeuIle ProLys ThrLys His Asp LeuLeuThr ThrTyrPro PheThrLys,IleSerSer TrpSer Ser GlySerThr TyrPheHis MetAlaLeu SerLeu GlyArg Gly Gly SerArgLeu LeuCysGlu ThrSerLeu TyrLys MetAsp Gly Asp LeuLeuThr SerTyrVal GlnGlnLeu SerAla MetAsn Leu Lys GlnArgGly SerLysAla ProAlaLeu SerThr Ala <210> 10 <211> 4649 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 7279022CD1 <400> 10 Met Ser Glu Pro Gly Gly Gly Gly Gly Glu Asp Gly Ser Ala Gly Leu Glu Val Ser Ala Val Gln Asn Val Ala Asp Val Ser Val Leu Gln Lys His Leu Arg Lys Leu Val Pro Leu Leu Leu Glu Asp Gly Gly Glu Ala Pro Ala Ala Leu Glu Ala Ala Leu Glu Glu Lys Ser Ala Leu Glu Gln Met Arg Lys Phe Leu Ser Asp Pro Gln Val His Thr Val Leu Val Glu Arg Ser Thr Leu Lys Glu Asp Val Gly Asp Glu Gly Glu Glu Glu Lys Glu Phe Ile Ser Tyr Asn Ile Asn Ile Asp Ile His Tyr Gly Val Lys Ser Asn Ser Leu Ala Phe Ile Lys Arg Thr Pro Val Ile Asp Ala Asp Lys Pro Val Ser Ser Gln Leu Arg Val Leu Thr Leu Ser Glu Asp Ser Pro Tyr Glu Thr Leu His Ser Phe Ile Ser Asn Ala Val Ala Pro Phe Phe Lys Ser Tyr Ile Arg Glu Ser Gly Lys Ala Asp Arg Asp Gly Asp Lys Met Ala Pro Ser Val Glu Lys Lys Ile Ala Glu Leu Glu Met Gly Leu Leu His Leu Gln Gln Asn Ile Glu Ile Pro Glu Ile Ser Leu Pro Ile His Pro Met Ile Thr Asn Val Ala Lys Gln Cys Tyr Glu Arg Gly Glu Lys Pro Lys Val Thr Asp Phe Gly Asp Lys Val Glu Asp Pro Thr Phe Leu Asn Gln Leu Gln Ser Gly Val Asn Arg Trp Ile Arg Glu Ile Gln Lys Val Thr Lys Leu Asp Arg Asp Pro Ala Ser Gly Thr Ala Leu Gln Glu Ile Ser Phe Trp Leu Asn Leu Glu Arg Ala Leu Tyr Arg Ile Gln Glu Lys Arg Glu Ser Pro Glu Val Leu Leu Thr Leu Asp Ile Leu Lys His Gly Lys Arg Phe His Ala Thr Val Ser Phe Asp Thr Asp Thr Gly Leu Lys Gln Ala Leu Glu Thr Val Asn Asp Tyr Asn Pro Leu Met Lys Asp Phe Pro Leu Asn Asp Leu Leu Ser Ala Thr Glu Leu Asp Lys Ile Arg Gln Ala Leu Val Ala Ile Phe Thr His Leu Arg Lys Ile Arg Asn Thr Lys Tyr Pro Ile Gln Arg Ala Leu Arg Leu Val Glu Ala Ile Ser Arg Asp Leu Ser Ser Gln Leu Leu Lys Val Leu Gly Thr Arg Lys Leu Met His Val Ala Tyr Glu Glu Phe Glu Lys Val Met Val Ala Cys Phe Glu Val Phe Gln Thr Trp Asp Asp Glu Tyr Glu Lys Leu Gln Val Leu Leu Arg Asp Ile Val Lys Arg Lys Arg Glu Glu Asn Leu Lys Met Val Trp Arg Ile Asn Pro Ala His Arg Lys Leu Gln Ala Arg Leu Asp Gln Met Arg Lys Phe Arg Arg Gln His Glu Gln Leu Arg Ala Val Ile Val Arg Val Leu Arg Pro Gln Val Thr Ala Val Ala Gln Gln Asn Gln Gly Glu Val Pro Glu Pro Gln Asp Met Lys Val Ala Glu Val Leu Phe Asp Ala Ala Asp Ala Asn Ala Ile Glu Glu Val Asn Leu Ala Tyr Glu Asn Val Lys Glu Val Asp Gly Leu Asp Val Ser Lys 530 535 ' 540 Glu Gly Thr Glu Ala Trp Glu Ala Ala Met Lys Arg Tyr Asp Glu Arg Ile Asp Arg Val Glu Thr Arg Ile Thr Ala Arg Leu Arg Asp Gln Leu Gly Thr Ala Lys Asn Ala Asn Glu Met Phe Arg Ile Phe Ser Arg Phe Asn Ala Leu Phe Val Arg Pro His Ile Arg Gly Ala Ile Arg Glu Tyr Gln Thr Gln Leu Ile Gln Arg Val Lys Asp Asp Ile Glu Ser Leu His Asp Lys Phe Lys Val Gln Tyr Pro Gln Ser Gln Ala Cys Lys Met Ser His Val Arg Asp Leu Pro Pro Val Ser Gly Ser Ile Ile Trp Ala Lys Gln Ile Asp Arg Gln Leu Thr Ala Tyr Met Lys Arg Val Glu Asp Val Leu Gly Lys Gly Trp Glu Asn His Val Glu Gly Gln Lys Leu Lys Gln Asp Gly Asp Ser Phe Arg Met Lys Leu Asn Thr Gln Glu Ile Phe Asp Asp Trp Ala Arg Lys Val Gln Gln Arg Asn Leu Gly Val Ser Gly Arg Ile Phe Thr Ile Glu Ser Thr Arg Val Arg Gly Arg Thr Gly Asn Val Leu Lys Leu Lys Val Asn Phe Leu Pro Glu Ile Ile Thr Leu Ser Lys Glu Val Arg Asn Leu Lys Trp Leu Gly Phe Arg Val Pro Leu Ala Ile Val Asn Lys Ala His Gln Ala Asn Gln Leu Tyr Pro Phe Ala Ile Ser Leu Ile Glu Ser Val Arg Thr Tyr Glu Arg Thr Cys Glu Lys Val Glu Glu Arg Asn Thr Ile Ser Leu Leu Val Ala Gly Leu Lys Lys Glu Val Gln Ala Leu Ile Ala Glu Gly Ile Ala Leu Val Trp Glu Ser Tyr Lys Leu Asp Pro Tyr Val Gln Arg Leu Ala Glu Thr Val Phe Asn Phe Gln Glu Lys Val Asp Asp Leu Leu Ile Ile Glu Glu Lys Ile Asp Leu Glu Val Arg Ser Leu Glu Thr Cys Met Tyr Asp His Lys Thr Phe Ser Glu Ile Leu Asn Arg Val Gln Lys Ala Val Asp Asp Leu Asn Leu His Ser Tyr Ser Asn Leu Pro Ile Trp Val Asn Lys Leu Asp Met Glu Ile Glu Arg Ile Leu Gly Val Arg Leu Gln Ala Gly Leu Arg Ala Trp Thr Gln Val Leu Leu Gly Gln Ala Glu Asp Lys Ala Glu Val Asp Met Asp Thr Asp Ala Pro Gln Val Ser His Lys Pro Gly Gly Glu Pro Lys Ile Lys Asn Val Val His Glu Leu Arg Ile Thr Asn Gln Val Ile Tyr Leu Asn Pro Pro Ile Glu Glu Cys Arg Tyr Lys Leu Tyr Gln Glu Met Phe Ala Trp Lys Met Val Val Leu Ser Leu Pro Arg Ile Gln Ser Gln Arg Tyr Gln Val Gly Val His Tyr Glu Leu Thr Glu Glu Glu Asn Phe Tyr Arg Asn Ala Leu Thr Arg Met Pro Asp Gly Pro Val Ala Leu Glu Glu Ser Tyr Ser Ala Val Met Gly Ile Val Ser Glu Val Glu Gln Tyr Val Lys Val Trp Leu Gln Tyr Gln Cys Leu Trp Asp Met Gln Ala Glu Asn Ile Tyr Asn Arg Leu Gly Glu Asp Leu Asn Lys Trp Gln Ala Leu Leu Val Gln Ile Arg Lys Ala Arg Gly Thr Phe Asp Asn Ala Glu Thr Lys Lys Glu Phe Gly Pro Val Val Ile Asp Tyr Gly Lys Val Gln Ser Lys Val Asn Leu Lys Tyr Asp Ser Trp His Lys Glu Val Leu Ser Lys Phe Gly Gln Met Leu Gly Ser Asn Met Thr Glu Phe His Ser Gln Ile Ser Lys Ser Arg Gln Glu Leu Glu Gln His Ser Val Asp Thr Ala Ser Thr Ser Asp Ala Val Thr Phe Ile Thr Tyr Val Gln Ser Leu Lys Arg Lys Ile Lys Gln Phe Glu Lys Gln Val Glu Leu Tyr Arg Asn Gly Gln Arg Leu Leu Glu Lys Gln Arg Phe Gln Phe Pro Pro Ser Trp Leu Tyr Ile Asp Asn Ile Glu Gly Glu Trp Gly Ala Phe Asn Asp Ile Met Arg Arg Lys Asp Ser Ala 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Ile Met Ala Leu Phe Asp Val Trp Ile Asp Val Gln Arg Arg Trp Val Tyr Leu Glu Gly Ile Phe Thr Gly Ser Ala Asp Ile Lys His Leu Leu Pro Val Glu Thr Gln Arg Phe Gln Ser Ile Ser Thr Glu Phe Leu Ala Leu Met Lys Lys Val Ser Lys Ser Pro Leu Val Met Asp Val Leu Asn Ile Gln Gly Val Gln Arg Ser Leu Glu Arg Leu Ala Asp Leu Leu Gly Lys Ile Gln Lys Ala Leu Gly Glu Tyr Leu Glu Arg Glu Arg Ser Ser Phe Pro Arg Phe Tyr Phe Val Gly Asp Glu Asp Leu Leu Glu Ile Ile Gly Asn Ser Lys Asn Val Ala Lys Leu Gln Lys His Phe Lys Lys Met Phe Ala Gly Val Ser Ser Ile Ile Leu Asn Glu Asp Asn Ser Val Val Leu Gly Ile Ser Ser Arg Glu Gly Glu Glu Val Met Phe Lys Thr Pro Val Ser Ile Thr Glu His Pro Lys Ile Asn Glu Trp Leu Thr Leu Val Glu Lys Glu Met Arg Val Thr Leu Ala Lys Leu Leu Ala Glu Ser Val Thr Glu Val Glu Ile Phe Gly Lys Ala Thr Ser Ile Asp Pro Asn Thr Tyr Ile Thr Trp Ile Asp Lys Tyr Gln Ala Gln Leu Val Val Leu Ser Ala Gln Ile Ala Trp Ser Glu Asn Val Glu Thr Ala Leu Ser Ser Met Gly Gly Gly Gly Asp Ala Ala Pro Leu His Ser Val Leu Ser Asn Val Glu Val Thr Leu Asn Val Leu Ala Asp Ser Val Leu Met Glu Gln Pro Pro Leu Arg Arg Arg Lys Leu Glu His Leu Ile Thr Glu Leu Val His Gln Arg Asp Val Thr Arg Ser Leu Ile Lys Ser Lys Ile Asp Asn Ala Lys Ser Phe Glu Trp Leu Ser Gln Met Arg Phe Tyr Phe Asp Pro Lys Gln Thr Asp Val Leu Gln Gln Leu Ser Ile Gln Met Ala Asn Ala Lys Phe Asn Tyr Gly Phe Glu Tyr Leu Gly Val Gln Asp Lys Leu Val Gln Thr Pro Leu Thr Asp Arg Cys Tyr Leu Thr Met Thr Gln Ala Leu Glu Ala Arg Leu Gly Gly Ser Pro Phe Gly Pro Ala Gly Thr Gly Lys Thr Glu Ser Val Lys Ala Leu Gly His Gln Leu Gly Arg Phe Val Leu Val Phe Asn Cys Asp Glu Thr Phe Asp Phe Gln Ala Met Gly Arg Ile Phe Val Gly Leu Cys Gln Val Gly Ala Trp Gly Cys Phe Asp Glu Phe Asn Arg Leu Glu Glu Arg Met Leu Ser Ala Val Ser Gln Gln Val Gln Cys Ile Gln Glu Ala Leu Arg Glu His Ser Asn Pro Asn Tyr Asp Lys Thr Ser Ala Pro Ile Thr Cys Glu Leu Leu Asn Lys Gln Val Lys Val Ser Pro Asp Met Ala Ile Phe Ile Thr Met Asn Pro Ala Tyr Ala Gly Arg Ser Asn Leu Pro Asp Asn Leu Lys Lys Leu Phe Arg Ser Leu Ala Met Thr Lys Pro Asp Arg Gln Leu Ile Ala Gln Val Met Leu Tyr Ser Gln Gly Phe Arg Thr Ala Glu Val Leu Ala Asn Lys Ile Val Pro Phe Phe 2015. 2020 2025 Lys Leu Cys Asp Glu Gln Leu Ser Ser Gln Ser His Tyr Asp Phe Gly Leu Arg Ala Leu Lys Ser Val Leu Val Ser Ala Gly Asn Val Lys Arg Glu Arg Ile Gln Lys Ile Lys Arg Glu Lys G1u Glu Arg Gly Glu Ala Val Asp Glu Gly Glu Ile Ala Glu Asn Leu Pro Glu Gln Glu Ile Leu Ile Gln Ser Val Cys Glu Thr Met Val Pro Lys Leu Val Ala Glu Asp Ile Pro Leu Leu Phe Ser Leu Leu Ser Asp Val Phe Pro Gly Val Gln Tyr His Arg Gly Glu Met Thr Ala Leu Arg Glu Glu Leu Lys Lys Val Cys Gln Glu Met Tyr Leu Thr Tyr Gly Asp Gly Glu Glu Val Gly Gly Met Trp Val Glu Lys Val Leu Gln Leu Tyr Gln Ile Thr Gln Ile Asn His Gly Leu Met Met Val Gly Pro Ser Gly Ser Gly Lys Ser Met Ala Trp Arg Val Leu Leu Lys Ala Leu Glu Arg Leu Glu Gly Val Glu Gly Val Ala His Ile Ile Asp Pro Lys Ala Ile Ser Lys Asp His Leu Tyr Gly Thr Leu Asp Pro Asn Thr Arg Glu Trp Thr Asp Gly Leu Phe Thr His Val Leu Arg Lys Ile Ile Asp Ser Val Arg Gly Glu Leu Gln Lys Arg Gln Trp Ile Val Phe Asp Gly Asp Val Asp Pro Glu Trp Val Glu Asn Leu Asn Ser Val Leu Asp Asp Asn Lys Leu Leu Thr Leu Pro Asn Gly Glu Arg Leu Ser Leu Pro Pro Asn Val Arg Ile Met Phe Glu Val Gln Asp Leu Lys Tyr Ala Thr Leu Ala Thr Val Ser Arg Cys Gly Met Val Trp Phe Ser Glu Asp Val Leu Ser Thr Asp Met Ile Phe Asn Asn Phe Leu Ala Arg Leu Arg Ser Ile Pro Leu Asp Glu Gly Glu Asp Glu Ala Gln Arg Arg Arg Lys Gly Lys Glu Asp Glu Gly Glu Glu Ala Ala Ser Pro Met Leu Gln Ile Gln Arg Asp Ala Ala Thr Ile Met Gln Pro Tyr Phe Thr Ser Asn Gly Leu Val Thr Lys Ala Leu Glu His Ala Phe Gln Leu Glu His Ile Met Asp Leu Thr Arg Leu Arg Cys Leu Gly Ser Leu Phe Ser Met Leu His Gln Ala Cys Arg Asn Val Ala Gln Tyr Asn Ala Asn His Pro Asp Phe Pro Met Gln Ile Glu Gln Leu Glu Arg Tyr Ile Gln Arg Tyr Leu Val Tyr Ala Ile Leu Trp Ser Leu Ser Gly Asp Ser Arg Leu Lys Met Arg Ala Glu Leu Gly Glu Tyr Ile Arg Arg Ile Thr Thr Val Pro 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Phe Tyr Thr Met Ser Gln Ser Val Phe Ser Ser Lys Ala Leu Gln Leu Gln Leu Trp Gly Thr Gly Phe Leu Phe Tyr Leu Leu Pro Thr Trp Ile Asn Ser Cys Leu Leu Pro Lys Cys Thr Cys Cys Ser Pro His Arg Leu Val Glu Asp.Glu Glu Arg Arg Trp Thr Asp Glu Asn Ile Asp Thr Val Ala Leu Lys His Phe Pro Asn Ile Asp Arg Glu Lys Ala Met Ser Arg Pro Ile Leu Tyr Ser Asn Trp Leu Ser Lys Asp Tyr Ile Pro Val Asp Gln Glu Glu Leu Arg Asp Tyr Val Lys Ala Arg Leu Lys Val Phe Tyr Glu Glu Glu Leu Asp Val Pro Leu Val Leu Phe Asn Glu Val Leu Asp His Val Leu Arg Ile Asp Arg Ile Phe Arg Gln Pro Gln Gly His Leu Leu Leu Ile Gly Val Ser Gly Ala Gly Lys Thr Thr Leu Ser Arg Phe Val Ala Trp Met Asn Gly Leu Ser Val Tyr Gln Ile Lys Val His Arg Lys Tyr Thr Gly Glu Asp Phe Asp Glu Asp Leu Arg Thr Val Leu Arg Arg Ser Gly Cys Lys Asn Glu Lys Ile Ala Phe Ile Met Asp Glu Ser Asn Val Leu Asp Ser Gly Phe Leu Glu Arg Met Asn Thr Leu Leu Ala Asn Gly Glu Val Pro Gly Leu Phe Glu Gly Asp Glu Tyr Ala Thr Leu Met Thr Gln 2960 2965 ,2970 Cys Lys Glu Gly Ala Gln Lys Glu Gly Leu Met Leu Asp Ser His Glu Glu Leu Tyr Lys Trp Phe Thr Ser Gln Val Ile Arg Asn Leu His Val Val Phe Thr Met Asn Pro Ser Ser Glu Gly Leu Lys Asp Arg Ala Ala Thr Ser Pro Ala Leu Phe Asn Arg Cys Val Leu Asn Trp Phe Gly Asp Trp Ser Thr Glu Ala Leu Tyr Gln Val Gly Lys Glu Phe Thr Ser Lys Met Asp Leu Glu Lys Pro Asn Tyr Ile Val Pro Asp Tyr Met Pro Val Val Tyr Asp Lys Leu Pro Gln Pro Pro Ser His Arg Glu Ala Ile Val Asn Ser Cys Val Phe Val His Gln Thr Leu His Gln Ala Asn Ala Arg Leu Ala Lys Arg Gly Gly Arg Thr Met Ala Ile Thr Pro Arg His Tyr Leu Asp Phe Ile Asn His Tyr Ala Asn Leu Phe His Glu Lys Arg Ser Glu Leu Glu Glu Gln Gln Met His Leu Asn Val Gly Leu Arg Lys Ile Lys Glu Thr Val Asp Gln Val Glu Glu Leu Arg Arg Asp Leu Arg Ile Lys Ser Gln Glu Leu Glu Val Lys Asn Ala Ala Ala Asn Asp Lys Leu Lys Lys Met Val Lys Asp Gln Gln Glu Ala Glu Lys Lys Lys Val Met Ser Gln Glu Ile Gln Glu Gln Leu His Lys Gln Gln Glu Val Ile Ala Asp Lys Gln Met Ser Val Lys Glu Asp Leu Asp Lys Val 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Leu Gln Gln Ala Asn Ile Gln Phe Arg Thr Asp Ile Ala Arg Thr Glu Tyr Leu Ser Asn Ala Asp Glu Arg Leu Arg Trp Gln Ala Ser Ser Leu Pro Ala Asp Asp Leu Cys Thr Glu Asn Ala Ile Met Leu Lys Arg Phe Asn Arg Tyr Pro Leu Ile Ile Asp Pro Ser Gly Gln Ala Thr Glu Phe Ile Met Asn Glu Tyr Lys Asp Arg Lys Ile Thr Arg Thr Ser Phe Leu Asp Asp Ala Phe Arg Lys Asn Leu Glu Ser Ala Leu Arg Phe Gly Asn Pro Leu Leu Val Gln Asp Val Glu Ser Tyr Asp Pro Val Leu Asn Pro Val Leu Asn Arg Glu Val Arg Arg Thr Gly Gly Arg Val Leu Ile Thr Leu Gly Asp Gln Asp Ile Asp Leu Ser Pro Ser Phe Val Ile Phe Leu Ser Thr Arg Asp Pro Thr Val Glu Phe Pro Pro Asp Leu Cys Ser Arg Val Thr Phe Val Asn Phe Thr Val Thr Arg Ser Ser Leu Gln Ser Gln Cys Leu Asn Glu Val Leu Lys Ala Glu Arg Pro Asp Val Asp Glu Lys Arg Ser Asp Leu Leu Lys Leu Gln Gly Glu Phe Gln Leu Arg Leu Arg Gln Leu Glu Lys Ser Leu Leu Gln Ala Leu Asn Glu Val Lys Gly Arg Ile Leu Asp Asp Asp Thr Ile Ile Thr Thr Leu Glu Asn Leu Lys Arg Glu Ala Ala Glu Val Thr Arg Lys Val Glu Glu Thr Asp Ile Val Met Gln Glu Val Glu Thr Val Ser Gln Gln Tyr Leu Pro Leu Ser Thr Ala Cys Ser Ser Ile Tyr Phe Thr Met Glu Ser Leu Lys Gln Ile His Phe Leu Tyr Gln Tyr Ser Leu Gln Phe Phe Leu Asp Ile Tyr His Asn Val Leu Tyr Glu Asn Pro Asn Leu Lys Gly Val Thr Asp His Thr Gln Arg Leu Ser Ile Ile Thr Lys Asp Leu Phe Gln Val Ala Phe Asn Arg Val Ala Arg Gly Met Leu His Gln Asp His Ile Thr Phe Ala Met Leu Leu Ala Arg Ile Lys Leu Lys Gly Thr Val Gly Glu Pro Thr Tyr Asp Ala Glu Phe Gln His Phe Leu Arg Gly Asn Glu Ile Val Leu Ser Ala Gly Ser Thr Pro Arg Ile Gln Gly Leu Thr Val Glu Gln Ala Glu Ala Val Gln Phe Gly Ile Trp Leu Asp Ser Ser Ser Pro Glu Gln Thr Val Pro Tyr Leu Trp Ser Glu Glu Thr Pro Ala Thr Pro Ile Gly Gln Ala Ile His Arg Leu Leu Leu Ile Gln Ala Phe Arg Pro Asp Arg Leu Leu Ala Met Ala His Met Phe Val Ser Thr Asn Leu Gly Glu Ser Phe Met Ser Ile Met Glu Gln Pro Leu Asp Leu Thr His Ile Val Gly Thr Glu Val Lys Pro Asn Thr Pro Val Leu Met Cys Ser Val Pro Gly Tyr Asp Ala Ser Gly His Val Glu Asp Leu Ala Ala Glu Gln Asn Thr Gln Ile Thr Ser Ile Ala Ile Gly Ser Ala Glu Gly Phe Asn Gln Ala Asp Lys Ala Ile Asn Thr Ala Val Lys Ser Gly Arg Trp Val Met Leu Lys Asn Val His Leu Ala Pro Gly Trp Leu Met Gln Leu Glu Lys Lys Leu His Ser Leu Gln Pro His Ala Cys Phe Arg Leu Phe Leu Thr Met Glu Ile Asn Pro Lys Val Pro Val Asn Leu Leu Arg Ala Gly Arg Ile Phe Val Phe Glu Pro Pro Pro Gly Val Lys Ala Asn Met Leu Arg Thr Phe Ser Ser Ile Pro Val Ser Arg Ile Cys Lys Ser Pro Asn Glu Arg Ala Arg Leu Tyr Phe Leu Leu Ala Trp Phe His Ala Ile Ile Gln Glu Arg Leu Arg Tyr Ala Pro Leu Gly Trp Ser Lys Lys Tyr Glu Phe Gly Glu Ser Asp Leu Arg Ser Ala Cys Asp Thr Val Asp Thr Trp Leu Asp Asp Thr Ala Lys Ala Ser Gly Arg Gln Asn Ile Ser Pro Asp Lys Ile Pro Trp Ser Ala Leu Lys Thr Leu Met Ala Gln Ser Ile Tyr Gly Gly Arg Val Asp Asn Glu Phe Asp Gln Arg Leu Leu Asn Thr Phe Leu Glu Arg Leu Phe Thr Thr Arg Ser Phe Asp Ser Glu Phe Lys Leu Ala Cys Lys Val Asp Gly His Lys Asp Ile Gln Met Pro Asp Gly Ile Arg Arg Glu Glu Phe Val Gln Trp Val Glu Leu Leu Pro Asp Thr Gln Thr Pro Ser Trp Leu Gly Leu Pro Asn Asn Ala Glu Arg Val Leu Leu Thr Thr Gln Gly Val Asp Met Ile Ser Lys Met Leu Lys Met Gln Met Leu Glu Asp Glu Asp Asp Leu Ala Tyr Ala Glu Thr Glu Lys Lys Thr Arg Thr Asp Ser Thr Ser Asp Gly Arg Pro Ala Trp Met Arg Thr Leu His Thr Thr Ala Ser Asn Trp Leu His Leu Ile Pro Gln Thr Leu Ser His Leu Lys Arg Thr Val Glu Asn Ile Lys Asp Pro Leu Phe Arg Phe Phe Glu Arg Glu Val Lys Met Gly Ala Lys Leu Leu Gln Asp Val Arg Gln Asp Leu Ala Asp Val Val Gln Val Cys Glu Gly Lys Lys Lys Gln Thr Asn Tyr Leu Arg Thr Leu Ile Asn Glu Leu Val Lys Gly Ile Leu Pro Arg Ser Trp Ser His Tyr Thr Val Pro Ala Gly Met Thr Val Ile Gln Trp Val Ser Asp Phe Ser Glu Arg Ile Lys Gln Leu Gln Asn Ile Ser Leu Ala Ala Ala Ser Gly Gly Ala Lys Glu Leu Lys Asn Ile His Val Cys Leu Gly Gly Leu Phe Val Pro Glu Ala Tyr Ile Thr Ala Thr Arg Gln Tyr Val Ala Gln A1a Asn Ser Trp Ser Leu Glu Glu Leu Cys Leu Glu Val Asn Val Thr Thr Ser Gln Gly Ala Thr Leu Asp Ala Cys Ser Phe Gly Val Thr Gly Leu Lys Leu Gln Gly Ala Thr Cys Asn Asn Asn Lys Leu Ser Leu Ser Asn Ala Ile Ser Thr Ala Leu Pro Leu Thr Gln Leu Arg Trp Val Lys Gln Thr Asn Thr Glu Lys Lys Ala Ser Val Val Thr Leu Pro Val Tyr Leu Asn Phe Thr Arg Ala Asp Leu Ile Phe Thr Val Asp Phe Glu Ile Ala Thr Lys Glu Asp Pro Arg Ser Phe Tyr Glu Arg Gly Gly Gly His Ala Pro Arg Ala Leu Leu Gly Thr Cys Leu Pro Val Ser Gly Gly Ser Met Gly Val Arg Lys Gly Ser Ala Ala Leu Gly Val Trp Ser Ser Ser Ala Ile Leu Glu Ser Ser Gly Tyr Val Pro Ser Ser Leu Ala Ser Arg Asp Thr Gly Pro Ala Gly His Phe Tyr Asp Lys Asn Gly Leu Lys Gly Val Leu Gly Ser Leu His Leu His Thr Glu Gly Arg Gln Gly Gly Trp Gln Glu Ala Glu Met Gly Val <210> 11 <211> 922 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 7503842CD1 <400> 11 Met Thr Thr Glu Val Gly Ser Val Ser Glu Val Lys Lys Asp Ser Ser Gln Leu Gly Thr Asp Ala Thr Lys Glu Lys Pro Lys Glu Val Ala Glu Asn Gln Gln Asn Gln Ser Ser Asp Pro Glu Glu Glu Lys Gly Ser Gln Pro Pro Pro Ala Ala Glu Ser Gln Ser Ser Leu Arg Arg Gln Lys Arg Glu Lys Glu Thr Ser Glu Ser Arg Gly Ile Ser Arg Phe Ile Pro Pro Trp Leu Lys Lys Gln Lys Ser Tyr Thr Leu Val Val Ala Lys Asp Gly Gly Asp Lys Lys Glu Pro Thr Gln Ala Val Val Glu Glu Gln Val Leu Asp Lys Glu Glu Pro Leu Pro Glu Glu Gln Arg Gln Ala Lys Gly Asp Ala Glu Glu Met Ala Gln Lys Lys Gln Glu Ile Lys Val Glu Val Lys Glu Glu Lys Pro Ser Val Ser Lys Glu Glu Lys Pro Ser Val Ser Lys Val Glu Met Gln Pro Thr Glu Leu Val Ser Lys Glu Arg Glu Glu Lys Val Lys Glu Thr Gln Glu Asp Lys Leu Glu Gly Gly Ala Ala Lys Arg Glu Thr Lys Glu Val Gln Thr Asn Glu Leu Lys Ala Glu Lys Ala Ser Gln Lys Val Thr Lys Lys Thr Lys Thr Val Gln Cys Lys Val Thr Leu Leu Asp Gly Thr Glu Tyr Ser Cys Asp Leu Glu Lys His Ala Lys Gly Gln Val Leu Phe Asp Lys Val Cys Glu His Leu Asn Leu Leu Glu Lys Asp Tyr Phe Gly Leu Leu Phe Gln Glu Ser Pro Glu Gln Lys Asn Trp Leu Asp Pro Ala Lys Glu Ile Lys Arg Gln Leu Arg Asn Leu Pro Trp Leu Phe Thr Phe Asn Val Lys Phe Tyr Pro Pro Asp Pro Ser Gln Leu Thr Glu Asp Ile Thr Arg Tyr Phe Leu Cys Leu Gln Leu Arg Gln Asp Ile Ala Ser Gly Arg Leu Pro Cys Ser Phe Val Thr His Ala Leu Leu Gly Ser Tyr Thr Leu Gln Ala Glu Leu Gly Asp Tyr Asp Pro Glu Glu His Gly Ser Ile Asp Leu Ser Glu Phe Gln Phe Ala Pro Thr Gln Thr Lys Glu Leu Glu Glu Lys Val Ala Glu Leu His Lys Thr His Arg Gly Leu Ser Pro Ala Gln Ala Asp Ser Gln Phe Leu Glu Asn Ala Lys Arg Leu Ser Met Tyr Gly Val Asp Leu His His Ala Lys Asp Ser Glu Gly Val Asp Ile Lys Leu Gly Val Cys Ala Asn Gly Leu Leu Ile Tyr Lys Asp Arg Leu Arg Ile Asn Arg Phe Ala Trp Pro Lys Ile Leu Lys Ile Ser Tyr Lys Arg Ser Asn Phe Tyr Ile Lys Val Arg Pro Ala Glu Leu Glu Gln Phe Glu Ser Thr Ile Gly Phe Lys Leu Pro Asn His Arg Ala Ala Lys Arg Leu Trp Lys Val Cys Val Glu His His Thr Phe Tyr Arg Leu Val Ser Pro Glu Gln Pro Pro Lys Ala Lys Phe Leu Thr Leu Gly Ser Lys Phe Arg Tyr Ser Gly Arg Thr Gln Ala Gln Thr Arg Gln Ala Ser Thr Leu Ile Asp Arg Pro Ala Pro His Phe Glu Arg Thr Ser Ser Lys Arg Val Ser Arg Ser Leu Asp Gly Ala Pro Ile Gly Val Met Asp Gln Ser Leu Met Lys Asp Phe Pro Gly Ala Ala Gly Glu Ile Ser Ala Tyr Gly Pro Gly Leu Val Ser Ile Ala Val Val Gln Asp Gly Asp Gly Arg Arg Glu Val Arg Ser Pro Thr Lys Ala Pro His Leu Gln Leu Ile Glu Gly Lys Lys Asn Ser Leu Arg Val Glu Gly Asp Asn Ile Tyr Val Arg His Ser Asn Leu Met Leu Glu Glu Leu Asp Lys Ala Gln Glu Asp Ile Leu Lys His Gln Ala Ser Ile Ser Glu Leu Lys Arg Asn Phe Met Glu Ser Thr Pro Glu Pro Arg Pro Asn Glu Trp Glu Lys Arg Arg Ile Thr Pro Leu Ser Leu Gln Thr Gln Gly Ser Ser His Glu Thr Leu Asn Ile Val Glu Glu Lys Lys Arg Ala Glu Val Gly Lys Asp Glu Arg Val Ile Thr Glu Glu Met Asn Gly Lys Glu Ile Ser Pro Gly Ser Gly Pro Gly Glu Ile Arg Lys Val Glu Pro Val Thr Gln Lys Asp Ser Thr Ser Leu Ser Ser Glu Ser Ser Ser Ser Ser Ser Glu Ser Glu Glu Glu Asp Val Gly Glu Tyr Arg Pro His His Arg Val Thr Glu Gly Thr Ile Arg Glu Glu Gln Glu Tyr Glu Glu Glu Val Glu Glu Glu Pro Arg Pro Ala Ala Lys Pro Pro Val Val Lys Thr Glu Met Val Thr Ile Ser Asp Ala Ser Gln Arg Thr Glu Ile Ser Thr Lys Glu Val Pro Ile Val Gln Thr Glu Thr Lys Thr Ile Thr Tyr Glu Ser Pro Gln Ile Asp Gly Gly Ala Gly Gly Asp Ser Gly Thr Leu Leu Thr Ala Gln Thr Ile Thr Ser Glu Ser Val Ser Thr Thr Thr Thr Thr His Ile Thr Lys Thr Val Lys Gly Gly Ile Ser Glu Thr Arg Ile Glu Lys Arg Ile Val Ile Thr Gly Asp Gly Asp Ile Asp His Asp Gln Ala Leu Ala Gln Ala Ile Arg Glu Ala Arg Glu Gln His Pro Asp Met Ser Val Thr Arg Val Val Val His Lys Glu Thr Glu Leu Ala Glu Glu Gly Glu Asp <210> 12 <211> 1253 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 7504194CD1 <400> 12 Met Glu Asp Gly Lys Pro Val Trp Ala Pro His Pro Thr Asp Gly Phe Gln Met Gly Asn Ile Val Asp Ile Gly Pro Asp Ser Leu Thr Ile Glu Pro Leu Asn Gln Lys Gly Lys Thr Phe Leu Ala Leu Ile Asn Gln Val Phe Pro Ala Glu Glu Asp Ser Lys Lys Asp Val Glu Asp Asn Cys Ser Leu Met Tyr Leu Asn Glu Ala Thr Leu Leu His Asn Ile Lys Val Arg Tyr Ser Lys Asp Arg Ile Tyr Thr Tyr Val Ala Asn Ile Leu Ile Ala Val Asn Pro Tyr Phe Asp Ile Pro Lys Ile Tyr Ser Ser Glu Ala Ile Lys Ser Tyr Gln Gly Lys Ser Leu Gly Thr Arg Pro Pro His Val Phe Ala Ile Ala Asp Lys Ala Phe Arg Asp Met Lys Val Leu Lys Met Ser Gln Ser Ile Ile Val Ser Gly Glu Ser Gly Ala Gly Lys Thr Glu Asn Thr Lys Phe Val Leu Arg Tyr Leu Thr Glu Ser Tyr Gly Thr Gly Gln Asp Ile Asp Asp Arg Ile Val Glu Ala Asn Pro Leu Leu Glu Ala Phe Gly Asn Ala Lys Thr Val Arg Asn Asn Asn Ser Ser Arg Phe Gly Lys Phe Val Glu Ile His Phe Asn Glu Lys Ser Ser Val Val Gly Gly Phe Val Ser His Tyr Leu Leu Glu Lys Ser Arg Ile Cys Val Gln Gly Lys Glu Glu Arg Asn Tyr His Ile Phe Tyr Arg Leu Cys Ala Gly Ala Ser Glu Asp Ile Arg Glu Lys Leu His Leu Ser Ser Pro Asp Asn Phe Arg Tyr Leu Asn Arg Gly Cys Thr Arg Tyr Phe Ala Asn Lys Glu Thr Asp Lys Gln Ile Leu Gln Asn Arg Lys Ser Pro Glu Tyr Leu Lys Ala Gly Ser Met Lys Asp Pro Leu Leu Asp Asp His Gly Asp Phe Ile Arg Met Cys Thr Ala Met Lys Lys Ile Gly Leu Asp Asp Glu Glu Lys Leu Asp Leu Phe Arg Val Val Ala Gly Val Leu His Leu Gly Asn Ile Asp Phe Glu Glu Ala Gly Ser Thr Ser Gly Gly Cys Asn Leu Lys Asn Lys Ser Ala Gln Ser Leu Glu Tyr Cys Ala Glu Leu Leu Gly Leu Asp Gln Asp Asp Leu Arg Val Ser Leu Thr Thr Arg Val Met Leu Thr Thr Ala Gly Gly Thr Lys Gly Thr Val Ile Lys Val Pro Leu Lys Val Glu Gln Ala Asn Asn Ala Arg Asp Ala Leu Ala Lys Thr Val Tyr Ser His Leu Phe Asp His Val Val Asn Arg Val Asn Gln Cys Phe Pro Phe Glu Thr Ser Ser Tyr Phe Ile Gly Val Leu Asp Ile Ala Gly Phe Glu Tyr Phe Glu His Asn Ser Phe Glu Gln Phe Cys Ile Asn Tyr Cys Asn Glu Lys Leu Gln Gln Phe Phe Asn Glu Arg Ile Leu Lys Glu Glu Gln Glu Leu Tyr Gln Lys Glu Gly Leu Gly Val Asn Glu Val His Tyr Val Asp Asn Gln Asp Cys Ile Asp Leu Ile Glu Ala Lys Leu Val Gly Ile Leu Asp Ile Leu Asp Glu Glu Asn Arg Leu Pro Gln Pro Ser Asp Gln His Phe Thr Ser Ala Val His Gln Lys His Lys Asp His Phe Arg Leu Thr Ile Pro Arg Lys Ser Lys Leu Ala Val His Arg Asn Ile Arg Asp Asp Glu Gly Phe Ile Ile Arg His Phe Ala Gly Ala Val Cys Tyr Glu Thr Thr Gln Phe Val Glu Lys Asn Asn Asp Ala Leu His Met Ser Leu Glu Ser Leu Ile Cys Glu Ser Arg Asp Lys Phe Ile Arg Glu Leu Phe Glu Ser Ser Thr Asn Asn Asn Lys Asp Thr Lys Gln Lys Ala Gly Lys Leu Ser Phe Ile Ser Val Gly Asn Lys Phe Lys Thr Gln Leu Asn Leu Leu Leu Asp Lys Leu Arg Ser Thr Gly Ala Ser Phe Ile Arg Cys Ile Lys Pro Asn Leu Lys Met Thr Ser His His Phe Glu Gly Ala Gln Ile Leu Ser Gln Leu Gln Cys Ser Gly Met Val Ser Val Leu Asp Leu Met Gln Gly Gly Tyr Pro Ser Arg Ala Ser Phe His Glu Leu Tyr Asn Met Tyr Lys Lys Tyr Met Pro Asp Lys Leu Ala Arg Leu Asp Pro Arg Leu Phe Cys Lys Ala Leu Phe Lys Ala Leu Gly Leu Asn Glu Asn Asp Tyr Lys Phe Gly Leu Thr Lys Val Phe Phe Arg Pro Gly Lys Phe Ala Glu Phe Asp Gln Ile Met Lys Ser Asp Pro Asp His Leu Ala Glu Leu Val Lys Arg Val Asn His Trp Leu Thr Cys Ser Arg Trp Lys Lys Val Gln Trp Cys Ser Leu Ser Val Ile Lys Leu Lys Asn Lys Ile Lys Tyr Arg Ala Glu Ala Cys Ile Lys Met Gln Lys Thr Ile Arg Met Trp Leu Cys Lys Arg Arg His Lys Pro Arg Ile Asp Gly Leu Val Lys Val Gly Thr Leu Lys Lys Arg Leu Asp Lys Phe Asn Glu 845 . 850 855 Val Val Ser Val Leu Lys Asp Gly Lys Pro Glu Met Asn Lys Gln Ile Lys Asn Leu Glu Ile Ser Ile Asp Thr Leu Met Ala Lys Ile Lys Ser Thr Met Met Thr Gln Glu Gln Ile Gln Lys Glu Tyr Asp Ala Leu Val Lys Ser Ser Glu Glu Leu Leu Ser Ala Leu Gln Lys Lys Lys Gln Gln Glu Glu Glu Ala Glu Arg Leu Arg Arg Ile Gln Glu Glu Met Glu Lys Glu Arg Lys Arg Arg Glu Glu Asp Glu Lys Arg Arg Arg Lys Glu Glu Glu Glu Arg Arg Met Lys Leu Glu Met Glu Ala Lys Arg Lys Gln Glu Glu Glu Glu Arg Lys Lys Arg Glu Asp Asp Glu Lys Arg Ile Gln Ala Glu Val Glu Ala Gln Leu Ala Arg Gln Lys Glu Glu Glu Ser Gln Gln Gln Ala Val Leu Glu Gln Glu Arg Arg Asp Arg Glu Leu Ala Leu Arg Ile Ala Gln Ser Glu Ala Glu Leu Ile Ser Asp Glu Ala Gln Ala Asp Leu Ala Leu Arg Arg Gly Pro Ala Val Leu Ala Thr Lys A1a Ala Ala Gly Thr Lys 1040 ~ 1045 1050 Lys Tyr Asp Leu Ser Lys Trp Lys Tyr Ala Glu Leu Arg Asp Thr Ile Asn Thr Ser Cys Asp Ile Glu Leu Leu Ala Ala Cys Arg Glu Glu Phe His Arg Arg Leu Lys Val Tyr His Ala Trp Lys Ser Lys Asn Lys Lys Arg Asn Thr Glu Thr Glu Gln Arg Ala Pro Lys Ser Val Thr Asp Tyr Ala Gln Gln Asn Pro Ala Ala Gln Ile Pro Ala Arg Gln Arg Glu Ile Glu Met Asn Arg Gln Gln Arg Phe Phe Arg Ile Pro Phe Ile Arg Pro Ala Asp Gln Tyr Lys Asp Pro Gln Ser Lys Lys Lys Gly Trp Trp Tyr Ala His Phe Asp Gly Pro Trp Ile Ala Arg Gln Met Glu Leu His Pro Asp Lys Pro Pro Ile Leu Leu Val Ala Gly Lys Asp Asp Met Glu Met Cys Glu Leu Asn Leu Glu Glu Thr Gly Leu Thr Arg Lys Arg Gly Ala Glu Ile Leu Pro Arg Gln Phe Glu Glu Ile Trp Glu Arg Cys Gly Gly Ile Gln Tyr Leu Gln Asn Ala Ile Glu Ser Arg Gln Ala Arg Pro Thr Tyr Ala Thr Ala Met Leu Gln Ser Leu Leu Lys <210> 13 <211> 428 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 1711872CD1 <400> 13 Met Ile Gln Glu Val Arg Lys Ala Val Leu Thr Ser Phe Arg Gly Ile Gly Gly Thr Ala Ser Leu Glu Glu Gly Pro Gln His Val Thr Val Leu Gln Leu Lys Arg Glu Leu Lys Lys Cys Gln Cys Val Leu 35 ~ 40 45 Ala Ala Asp Glu Val Val Phe Asn Gln Lys Glu Leu Glu Val Lys Glu Leu Lys Asn Gln Val Gln Met Met Val Gln Glu Asn Lys Gly His Ala Val Ser Leu Lys Glu Ala Gln Lys Val Asn Arg Leu Gln Asn Glu Lys Ile Ile Glu Gln Gln Leu Leu Val Asp Gln Leu Ser Glu Glu Leu Thr Lys Leu Asn Leu Ser Val Thr Ser Ser Ala Lys Glu Asn Cys Gly Asp Gly Pro Asp Ala Arg Ile Pro Glu Arg Arg Pro Tyr Thr Val Pro Phe Asp Thr His Leu Gly His Tyr Ile Tyr Ile Pro Ser Arg Gln Asp Ser Arg Lys Val His Thr Ser Pro Pro Met Tyr Ser Leu Asp Arg Ile Phe Ala Gly Phe Arg Thr Arg Ser Gln Met Leu Leu Gly His Ile Glu Glu Gln Asp Lys Val Leu His Cys Gln Phe Ser Asp Asn Ser Asp Asp Glu Glu Ser Glu Gly Gln Glu Lys Ser Gly Thr Arg Cys Arg Ser Arg Ser Trp Ile Gln Lys Pro Asp Ser Val Cys Ser Leu Val Glu Leu Ser Asp Thr Gln Asp Glu Thr Gln Lys Ser Asp Leu Glu Asn Glu Asp Leu Lys Ile Asp Cys Leu Gln Glu Ser Gln Glu Leu Asn Leu Gln Lys Leu Lys Asn Ser Glu Arg Ile Leu Thr Glu Ala Lys Gln Lys Met Arg Glu Leu Thr Ile Asn Ile Lys Met Lys Glu Asp Leu Ile Lys Glu Leu Ile Lys Thr Gly Asn Asp Ala Lys Ser Val Ser Lys Gln Tyr Ser Leu Lys Val Thr Lys Leu Glu His Asp Ala Glu Gln Ala Lys Val Glu Leu Ile Glu Thr Gln Lys Gln Leu Gln Glu Leu Glu Asn Lys Asp Leu Ser Asp Val Ala Met Lys Val Lys Leu Gln Lys Glu Phe Arg Lys Lys Met Asp Ala Ala Lys Leu Arg Val Gln Val Leu Gln Lys Lys Gln Gln Asp Ser Lys Lys Leu Ala Ser Leu Ser Ile Gln Asn Glu Lys Arg Ala Asn Glu Leu Glu Gln Ser Val Asp His Met Lys Tyr Gln Lys Ile Gln Leu Gln Arg Lys Thr Ile Lys Asn Arg Thr Gly Arg Arg Ser Lys Thr Glu Ser <210> 14 <211> 494 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 2639434CD1 <400> 14 Met Glu Gln Lys Glu Gly Lys Leu Ser Glu Asp Gly Thr Thr Val Ser Pro Ala Ala Asp Asn Pro Glu Met Ser Gly Gly Gly Ala Pro Ala Glu Glu Thr Lys Gly Thr Ala Gly Lys Ala Ile Asn Glu Gly Pro Pro Thr Glu Ser Gly Lys Gln Glu Lys Ala Pro Ala Glu Asp Gly Met Ser Ala Glu Leu Gln Gly Glu Ala Asn Gly Leu Asp Glu Val Lys Val Glu Ser Gln Arg Glu Ala Gly Gly Lys Glu Asp Ala Glu Ala Glu Leu Lys Lys Glu Asp Gly Glu Lys Glu Glu Thr Thr Val Gly Ser Gln Glu Met Thr Gly Arg Lys Glu Glu Thr Lys Ser Glu Pro Lys Glu Ala Glu Glu Lys Glu Ser Thr Leu Ala Ser Glu Lys Gln Lys Ala Glu Glu Lys Glu Ala Lys Pro Glu Ser Gly Gln Lys Ala Asp Ala Asn Asp Arg Asp Lys Pro Glu Pro Lys Ala Thr Val Glu Glu Glu Asp Ala Lys Thr Ala Ser Gln Glu Glu Thr Gly Gln Arg Lys Glu Cys Ser Thr Glu Pro Lys Glu Lys Ala Thr Asp Glu Glu Ala Lys Ala Glu Ser Gln Lys Ala Val Val Glu Asp Glu Ala Lys Ala Glu Pro Lys Glu Pro Asp Gly Lys Glu Glu Ala Lys His Gly Ala Lys Glu Glu Ala Asp Ala Lys Glu Glu Ala Glu Asp Ala Glu Glu Ala Glu Pro Gly Ser Pro Ser Glu Glu Gln Glu Gln Asp Val Glu Lys Glu Pro Glu Gly Gly Ala Gly Val Ile Pro Ser Ser Pro Glu Glu Trp Pro Glu Ser Pro Thr Gly Glu Gly His Asn Leu Ser Thr Asp Gly Leu Gly Pro Asp Cys Val Ala Ser Gly Gln Thr Ser Pro Ser Ala Ser Glu Ser Ser Pro Ser Asp Val Pro Gln Ser Pro Pro Glu Ser Pro Ser Ser Gly Glu Lys Lys Glu Lys Ala Pro Glu Arg Arg Val Ser Ala Pro Ala Arg Pro Arg Gly Pro Arg Ala Gln Asn Arg Lys Ala Ile Val Asp Lys Phe Gly Gly Ala Ala Ser Gly Pro Thr Ala Leu Phe Arg Asn Thr Lys Ala Ala Gly Ala Ala Ile Gly Gly Val Lys Asn Met Leu Leu Glu Trp Cys Arg Ala Met Thr Lys Lys Tyr Glu His Val Asp Ile Gln Asn Phe Ser Ser Ser Trp Ser Ser Gly Met Ala Phe Cys Ala Leu Ile His Lys Phe Phe Pro Asp Ala Phe Asp Tyr Ala Glu Leu Asp Pro Ala Lys Arg Arg His Asn Phe Thr Leu Ala Phe Ser Thr Ala Glu Lys Leu Ala Asp Cys Ala Gln Leu Leu Asp Val Asp Asp Met Val Arg Leu Ala Val Pro Asp Ser Lys Cys Val Tyr Thr Tyr Ile Gln Glu Leu Tyr Arg Ser Leu Val Gln Lys Gly Leu Val Lys Thr Lys Lys Lys <210> 15 <211> 354 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 3013578CD1 <400> 15 Met Glu Ala Ala Thr Ala Pro Glu Val Ala Ala Gly Ser Lys Leu Lys Val Lys Glu Ala Ser Pro Ala Asp Ala Glu Pro Pro Gln Ala Ser Pro Gly Gln Gly Ala Gly Ser Pro Thr Pro Gln Leu Leu Pro Pro Ile Glu Glu His Pro Lys Ile Trp Leu Pro Arg Ala Leu Arg Gln Thr Tyr Ile Arg Lys Val Gly Asp Thr Val Asn Leu Leu Ile Pro Phe Gln Gly Lys Pro Lys Pro Gln Ala Ile Trp Thr His Asp Gly Cys Ala Leu Asp Thr Arg Arg Val Ser Val Arg Asn Gly Glu Gln Asp Ser Ile Leu Phe Ile Arg Glu Ala Gln Arg Ala Asp Ser Gly Arg Tyr Gln Leu Arg Val Gln Leu Gly Gly Leu Glu Ala Thr Ala Thr Ile Asp Ile Pro Val Ile Glu Arg Pro Gly Pro Pro Gln Ser Ile Lys Leu Val Asp Val Trp Gly Leu Ser Ala Thr Leu Glu Trp Thr Pro Pro Gln Asp Thr Gly Asn Thr Ala Leu Leu Gly Tyr Thr Val Gln Lys Ala Asp Thr Lys Ser Gly Leu Trp Phe Thr Val Leu Glu His Tyr His Arg Thr Ser Cys Ile Val Ser Asp Leu Ile Ile Gly Asn Ser Tyr Ala Phe Arg Val Phe Ala Glu Asn Gln Cys Gly Leu Ser Glu Thr Ala Pro Ile Thr Thr Asp Leu Ala His Ile Gln Glu Ala Ala Thr Val Tyr Lys Thr Lys Gly Phe Ala Gln Arg Asp Phe Ser Glu Ala Pro Lys Phe Thr Gln Pro Leu Ala Asn Cys Thr Thr Val Thr Gly Tyr Asn Thr Gln Leu Phe Cys Cys Val Arg Ala Ser Pro Arg Pro Lys Ile Ile Trp Leu Lys Asn Lys Met Asp Ile Gln Gly Asn Pro Lys Tyr Arg Ala Leu Thr His Leu Gly Ile Cys Ser Leu Glu Ile Arg Lys Pro Gly Pro Phe Asp Gly Gly Ile Tyr Thr Cys Lys Ala Val Asn Pro Leu Gly Glu Ala Ser Val Asp Cys Arg Val Asp Val Lys Val Pro Asn <210> 16 <211> 625 <212> PRT
<213> Homo Sapiens <220>
<221> misC_feature <223> Incyte ID No: 7489954CD1 <400> 16 Met Ser His Gln Phe Ser Ser Gln Ser Ala Phe Ser Ser Met Ser Arg Arg Val Tyr Ser Thr Ser Ser Ser Ala Gly Ser Gly Gly Gly Ser Pro Ala Val Gly Ser Val Cys Tyr Ala Arg Gly Arg Cys Gly Gly Gly Gly Tyr Gly Ile His Gly Arg Gly Phe Gly Ser Arg Ser Leu Tyr Asn Leu Gly Gly Ser Arg Ser Ile Ser Ile Asn Leu Met Gly Arg Ser Thr Ser Gly Phe Cys Gln Gly Gly Gly Val Gly Gly Phe Gly Gly Gly Arg Gly Phe Gly Val Gly Ser Thr Gly Ala Gly Gly Phe Gly Gly Gly Gly Phe Gly Gly Ala Gly Phe Gly Thr Ser Asn Phe Gly Leu Gly Gly Phe Gly Pro Tyr Cys Pro Pro Gly Gly Ile Gln Glu Val Thr Ile Asn Gln Ser Leu Leu Glu Pro Leu His Leu Glu Val Asp Pro Glu Ile Gln Arg Ile Lys Ala Gln Glu Arg Glu Gln Ile Lys Thr Leu Asn Asn Lys Phe Ala Ser Phe Ile Asp Lys Val Arg Phe Leu Glu Gln Gln Asn Gln Val Leu Gln Thr Lys Trp Glu Leu Leu Gln Gln Met Asn Val Gly Thr Arg Pro Ile Asn Leu Glu Pro Ile Phe Gln Gly Tyr Ile Asp Ser Leu Lys Arg Tyr Leu Asp Gly Leu Thr Ala Glu Arg Thr Ser Gln Asn Ser Glu Leu Asn Asn Met Gln Asp Leu Val Glu Asp Tyr Lys Lys Lys Tyr Glu Asp Glu Ile Asn Lys Arg Thr Ala Ala Glu Asn Asp Phe Val Thr Leu Lys Lys Asp Val Asp Asn Ala Tyr Met Ile Lys Val Glu Leu Gln Ser Lys Val Asp Leu Leu Asn Gln Glu Ile Glu Phe Leu Lys Val Leu Tyr Asp Ala Glu Ile Ser Gln Ile His Gln Ser Val Thr Asp Thr Asn Val Ile Leu Ser Met Asp Asn Ser Arg Asn Leu Asp Leu Asp Ser Ile Ile Ala Glu Val Lys Ala Gln Tyr Glu Glu Ile Ala Gln Arg Ser Lys Glu Glu Ala Glu Ala Leu Tyr His Ser Lys Tyr Glu Glu Leu Gln Val Thr Val Gly Arg His Gly Asp Ser Leu Lys Glu Ile Lys Ile Glu Ile Ser Glu Leu Asn Arg Val Ile Gln Arg Leu Gln Gly Glu Ile Ala His Val Lys Lys Gln Cys Lys Asn Val Gln Asp Ala Ile Ala Asp Ala Glu Gln Arg Gly Glu His Ala Leu Lys Asp Ala Arg Asn Lys Leu Asn Asp Leu Glu Glu Ala Leu Gln Gln Ala Lys Glu Asp Leu Ala Arg Leu Leu Arg Asp Tyr Gln Glu Leu Met Asn Val Lys Leu Ala Leu Asp Val Glu Ile Ala Thr Tyr Arg Lys Leu Leu Glu Gly Glu Glu Cys Arg Met Ser Gly Asp Leu Ser Ser Asn Val Thr Val Ser Val Thr Ser Ser Thr Ile Ser Ser Asn Val Ala Ser Lys Ala Ala Phe Gly Gly Ser Gly Gly Arg Gly Ser Ser Ser Gly Gly Gly Tyr Ser Ser Gly Ser Ser Ser Tyr Gly Ser Gly Gly Arg Gln Ser Gly Ser Arg Gly Gly Ser Gly Gly Gly Gly Ser Ile Ser Gly Gly Gly Tyr Gly Ser Gly Gly Gly Ser Gly Gly Arg Tyr Gly Ser Gly Gly Gly Ser Lys Gly Gly Ser Ile Ser Gly Gly Gly Tyr Gly Ser Gly Gly Gly Lys His Ser Ser Gly Gly Gly Ser Arg Gly Gly Ser Ser Ser Gly Gly Gly Tyr Gly Ser Gly Gly Gly Gly Ser Ser Ser Val Lys Gly Ser Ser Gly Glu Ala Phe Gly Ser Ser Val Thr Phe Ser Phe Arg <210> 17 <211> 652 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 7502375CD1 <400> 17 Met Gly Gly Trp Lys Gly Pro Gly Gln Arg Arg Gly Lys Glu Gly Pro Glu Ala Arg Arg Arg Ala Ala Glu Arg Gly Gly Gly Gly Gly Gly Gly Gly Val Pro Ala Pro Arg Ser Pro Ala Arg Glu Pro Arg Pro Arg Ser Cys Leu Leu Leu Pro Pro Pro Trp Gly Ala Ala Met Thr Pro Asp Leu Leu Asn Phe Lys Lys Gly Trp Met Ser Ile Leu Asp Glu Pro Gly Glu Pro Pro Ser Pro Ser Leu Thr Thr Thr Ser Thr Ser Gln Trp Lys Lys His Trp Phe Val Leu Thr Asp Ser Ser Leu Lys Tyr Tyr Arg Asp Ser Thr Ala Glu Glu Ala Asp Glu Leu Asp Gly Glu Ile Asp Leu Arg Ser Cys Thr Asp Val Thr Glu Tyr Ala Val Gln Arg Asn Tyr Gly Phe Gln Ile His Thr Lys Asp Ala Val Tyr Thr Leu Ser Ala Met Thr Ser Gly Ile Arg Arg Asn Trp Ile Glu Ala Leu Arg Lys Thr Val Arg Pro Thr Ser Ala Pro Asp Val Thr Lys Leu Ser Asp Ser Asn Lys Glu Asn Ala Leu His Ser Tyr Ser Thr Gln Lys Gly Pro Leu Lys Ala Gly Glu Gln Arg Ala Gly Ser Glu Val Ile Ser Arg Gly Gly Pro Arg Lys Ala Asp Gly Gln Arg Gln Ala Leu Asp Tyr Val Glu Leu Ser Pro Leu Thr Gln Ala Ser Pro Gln Arg Ala Arg Thr Pro Ala Arg Thr Pro Asp Arg Leu Ala Lys Gln Glu Glu Leu Glu Arg Asp Leu Ala Gln Arg Ser Glu Glu Arg Arg Lys Trp Phe Glu Ala Thr Asp Ser Arg Thr Pro Glu Val Pro Ala Gly Glu Gly Pro Arg Arg Gly Leu Gly Ala Pro Leu Thr Glu Asp Gln Gln Asn Arg Leu Ser Glu Glu Ile Glu Lys Lys Trp Gln Glu Leu Glu Lys Leu Pro Leu Arg Glu Asn Lys Arg Val Pro Leu Thr Ala Leu Leu Asn Gln Ser Arg Gly Glu Arg Arg Gly Pro Pro Ser Asp Gly His Glu Ala Leu Glu Lys Glu Val Gln Ala Leu Arg Ala Gln Leu Glu Ala Trp Arg Leu Gln Gly Glu Ala Pro Gln Ser Ala Leu Arg Ser Gln Glu Asp Gly His Ile Pro Pro Gly Tyr Ile Ser Gln Glu Ala Cys Glu Arg Ser Leu Ala Glu Met Glu Ser Ser His Gln Gln Val Met Glu Glu Leu Gln Arg His His Glu Arg Glu Leu Gln Arg Leu Gln Gln Glu Lys Glu Trp Leu Leu Ala Glu Glu Thr Ala Ala Thr Ala Ser Ala Ile Glu Ala Met Lys Lys Ala Tyr Gln Glu Glu Leu Ser Arg Glu Leu Ser Lys Thr Arg Ser Leu Gln Gln Gly Pro Asp Gly Leu Arg Lys Gln His Gln Ser Asp Val Glu Ala Leu Lys Arg Glu Leu Gln Val Leu Ser Glu Gln Tyr Ser Gln Lys Cys Leu Glu Ile Gly Ala Leu Met Arg Gln Ala Glu Glu Arg Glu His Thr Leu Arg Arg Cys Gln Gln Glu Gly Gln Glu Leu Leu Arg His Asn Gln Glu Leu His Gly Arg Leu Ser Glu Glu Ile Asp Gln Leu Arg Gly Phe Ile Ala Ser Gln Gly Met Gly Asn Gly Cys Gly Arg Ser Asn Glu Arg Ser Ser Cys Glu Leu Glu Val Leu Leu Arg Val Lys Glu Asn Glu Leu Gln Tyr Leu Lys Lys Glu Val Gln Cys Leu Arg Asp Glu Leu Gln Met Met Gln Lys Asp Lys Arg Phe Thr Ser Gly Lys Tyr Gln Asp Val Tyr Val Glu Leu Ser His Ile Lys Thr Arg Ser Glu Arg Glu Ile Glu Gln Leu Lys Glu His Leu Arg Leu Ala Met Ala Ala Leu Gln Glu Lys Glu Ser Met Arg Asn Ser Leu Ala Glu <210> 18 <211> 408 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 7503411CD1 <400> 18 Met Lys Cys Glu His Cys Thr Arg Lys Glu Cys Ser Lys Lys Thr Lys Thr Asp Asp Gln Glu Asn Val Ser Ala Asp Ala Pro Ser Pro Ala Gln Glu Asn Gly Glu Lys Cys Asp Thr Ser Lys His Lys Val Leu Val Val Ser Val Cys Pro Gln Ser Leu Pro Tyr Phe Ala Ala Lys Phe Asn Leu Ser Val Thr Asp Ala Ser Arg Arg Leu Cys Gly Phe Leu Lys Ser Leu Gly Val His Tyr Val Phe Asp Thr Thr Ile Ala Ala Asp Phe Ser Ile Leu Glu Ser Gln Lys Glu Phe Val Arg Arg Tyr Arg Gln His Ser Glu Glu Glu Arg Thr Leu Pro Met Leu Thr Ser Ala Cys Pro Gly Trp Val Arg Tyr Ala Glu Arg Val Leu Gly Arg Pro Ile Thr Ala His Leu Cys Thr Ala Lys Ser Pro Gln Gln Val Met Gly Ser Leu Val Lys Asp Tyr Phe Ala Arg Gln Gln 155 ~ 160 165 Asn Leu Ser Pro Glu Lys Ile Phe His Val Ile Val Ala Pro Cys Tyr Asp Lys Lys Leu Glu Ala Leu Gln Glu Ser Leu Pro Pro Ala Leu His Gly Ser Arg Gly Ala Asp Cys Val Leu Thr Ser Gly Glu Ile Ala Gln Ile Met Glu Gln Gly Asp Leu Ser Val Arg Asp Ala Ala Val Asp Thr Leu Phe Gly Asp Leu Lys Glu Asp Lys Val Thr Arg His Asp Gly Ala Ser Ser Asp Gly His Leu Ala His Ile Phe Arg His Ala Ala Lys Glu Leu Phe Asn Glu Asp Val Glu Glu Val Thr Tyr Arg Ala Leu Arg Asn Lys Asp Phe Gln Glu Val Thr Leu Glu Lys Asn Gly Glu Val Val Leu Arg Phe Ala Ala Ala Tyr Gly Phe Arg Asn Ile Gln Asn Met Ile Leu Lys Leu Lys Lys Gly Lys Phe Pro Phe His Phe Val Glu Val Leu Ala Cys Ala Gly Gly Cys Leu Asn Gly Arg Gly Gln Ala Gln Thr Pro Asp Gly His Ala Asp Lys Ala Leu Leu Arg Gln Met Glu Gly Ile Tyr Ala Asp Ile Pro Val Arg Arg Pro Glu Ser Ser Ala His Val Gln Glu Leu Tyr Gln Glu Trp Leu Glu Gly Ile Asn Ser Pro Lys Ala Arg Glu Val Leu His Thr Thr Tyr Gln Ser Gln Glu Arg Gly Thr His Ser Leu Asp Ile Lys Trp <210> 19 <211> 250 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 7503546CD1 <400> 19 Met Gly Asp Ser Glu Met Ala Val Phe Gly Ala Ala Ala Pro Tyr Leu Arg Lys Ser Glu Lys Glu Arg Leu Glu Ala Gln Thr Arg Pro Phe Asp Leu Lys Lys Asp Val Phe Val Pro Asp Asp Lys Gln Glu Phe Val Lys Ala Lys Ile Val Ser Arg Glu Gly Gly Lys Val Thr Ala Glu Thr Glu Tyr Gly Lys Thr Val Thr Val Lys Glu Asp Gln Val Met Gln Gln Asn Pro Pro Lys Phe Asp Lys Ile Glu Asp Thr Ser Ala His Leu Glu Arg Met Lys Lys Asn Met Glu Gln Thr Ile Lys Asp Leu Gln His Arg Leu Asp Glu Ala Glu Gln Ile Ala Leu Lys Gly Gly Lys Lys Gln Leu Gln Lys Leu Glu Ala Arg Val Arg Glu Leu Glu Asn Glu Leu Glu Ala Glu Gln Lys Arg Asn Ala Glu Ser Val Lys Gly Met Arg Lys Ser Glu Arg Arg Ile Lys Glu Leu Thr Tyr Gln Thr Glu Glu Asp Arg Lys Asn Leu Leu Arg Leu Gln Asp Leu Val Asp Lys Leu Gln Leu Lys Val Lys Ala Tyr Lys Arg Gln Ala Glu Glu Ala Glu Glu Gln Ala Asn Thr Asn Leu Ser Lys Phe Arg Lys Val Gln His Glu Leu Asp Glu Ala Glu Glu Arg Ala Asp Ile Ala Glu Ser Gln Val Asn Lys Leu Arg Ala Lys Ser Arg Asp Ile Gly Thr Lys Gly Leu Asn Glu Glu <210> 20 <211> 1258 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 7504071CD1 <400> 20 Met Ala Gln Ser Lys Arg His Val Tyr Ser Arg Thr Pro Ser Gly 1 5 ~ 10 15 Ser Arg Met Ser Ala Glu Ala Ser Ala Arg Pro Leu Arg Val Gly Ser Arg Val Glu Val Ile Gly Lys Gly His Arg Gly Thr Val Ala Tyr Val Gly Ala Thr Leu Phe Ala Thr Gly Lys Trp Val Gly Val Ile Leu Asp Glu Ala Lys Gly Lys Asn Asp Gly Thr Val Gln Gly Arg Lys Tyr Phe Thr Cys Asp Glu Gly His Gly Ile Phe Val Arg Gln Ser Gln Ile Gln Val Phe Glu Asp Gly Ala Asp Thr Thr Ser Pro Glu Thr Pro Asp Ser Ser Ala Ser Lys Val Leu Lys Arg Glu Gly Thr Asp Thr Thr Ala Lys Thr Ser Lys Leu Pro Thr Arg Pro Ala Ser Thr Gly Val Ala Gly Ala Ser Ser Ser Leu Gly Pro Ser Gly Ser Ala Ser Ala Gly Glu Leu Ser Ser Ser Glu Pro Ser Thr Pro Ala Gln Thr Pro Leu Ala Ala Pro Ile Ile Pro Thr Pro Val Leu Thr Ser Pro Gly Ala Val Pro Pro Leu Pro Ser Pro Ser Lys Glu Glu Glu Gly Leu Arg Ala Gln Val Arg Asp Leu Glu Glu Lys Leu Glu Thr Leu Arg Leu Lys Arg Ala Glu Asp Lys Ala Lys Leu Lys Glu Leu Glu Lys His Lys Ile Gln Leu Glu Gln Val Gln Glu Trp Lys Ser Lys Met Gln Glu Gln Gln Ala Asp Leu Gln Arg Arg Leu Lys Glu Ala Arg Lys Glu Ala Lys Glu Ala Leu Glu Ala Lys Glu Arg Tyr Met Glu Glu Met Ala Asp Thr Ala Asp Ala Ile Glu Met Ala Thr Leu Asp Lys Glu Met Ala Glu Glu Arg Ala Glu Ser Leu Gln Gln Glu Val Glu Ala Leu Lys Glu Arg Val Asp Glu Leu Thr Thr Asp Leu Glu Ile Leu Lys Ala Glu Ile Glu Glu Lys Gly Ser Asp Gly Ala Ala Ser Ser Tyr Gln Leu Lys Gln Leu Glu Glu Gln Asn Ala Arg Leu Lys Asp Ala Leu Val Arg Met Arg Asp Leu Ser Ser Ser Glu Lys Gln Glu His Val Lys Leu Gln Lys Leu Met Glu Lys Lys Asn Gln Glu Leu Glu Val Val Arg Gln Gln Arg Glu Arg Leu Gln Glu Glu Leu Ser Gln Ala Glu Ser Thr Ile Asp Glu Leu Lys Glu Gln Val Asp Ala Ala Leu Gly Ala Glu Glu Met Val Glu Met Leu Thr Asp Arg Asn Leu Asn Leu Glu Glu Lys Val Arg Glu Leu Arg Glu Thr Val Gly Asp Leu Glu Ala Met Asn Glu Met Asn Asp Glu Leu Gln Glu Asn Ala Arg Glu Thr Glu Leu Glu Leu Arg Glu Gln Leu Asp Met Ala Gly Ala Arg Val Arg Glu Ala Gln Lys Arg Val Glu Ala Ala Gln Glu Thr Val Ala Asp Tyr Gln Gln Thr Ile Lys Lys Tyr Arg Gln Leu Thr Ala His Leu Gln Asp Val Asn Arg Glu Leu Thr Asn Gln Gln Glu Ala Ser Val Glu Arg Gln Gln Gln Pro Pro Pro Glu Thr Phe Asp Phe Lys Ile Lys Phe Ala Glu Thr Lys Ala His Ala Lys Ala Ile Glu Met Glu Leu Arg Gln Met Glu Val Ala Gln Ala Asn Arg His Met Ser Leu Leu Thr Ala Phe Met Pro Asp Ser Phe Leu Arg Pro Gly Gly Asp His Asp Cys Val Leu Val Leu Leu Leu Met Pro Arg Leu Ile Cys Lys Ala Glu Leu Ile Arg Lys Gln Ala Gln Glu Lys Phe Glu Leu Ser Glu Asn Cys Ser Glu Arg Pro Gly Leu Arg Gly Ala Ala Gly Glu Gln Leu Ser Phe Ala Ala Gly Leu Val Tyr Ser Leu Ser Leu Leu Gln Ala Thr Leu His Arg Tyr Glu His Ala Leu Ser Gln Cys Ser Val Asp Val Tyr Lys Lys Val Gly Ser Leu Tyr Pro Glu Met Ser Ala His Glu Arg Ser Leu Asp Phe Leu Ile Glu Leu Leu His Lys Asp Gln Leu Asp Glu Thr Val Asn Val Glu Pro Leu Thr Lys Ala Ile Lys Tyr Tyr Gln His Leu Tyr Ser Ile His Leu Ala Glu Gln Pro Glu Asp Cys Thr Met Gln Leu Ala Asp His Ile Lys Phe Thr Gln Ser Ala Leu Asp Cys Met Ser Val Glu Val Gly Arg Leu Arg Ala Phe Leu Gln Gly Gly Gln Glu Ala Thr Asp Ile Ala Leu Leu Leu Arg Asp Leu Glu Thr Ser Cys Ser Asp Ile Arg Gln Phe Cys Lys Lys Ile Arg Arg Arg Met Pro Gly Thr Asp Ala Pro Gly Ile Pro Ala Ala Leu Ala Phe Gly Pro Gln Val Ser Asp Thr Leu Leu Asp Cys Arg Lys His Leu Thr Trp Val Val Ala Val Leu Gln Glu Val Ala Ala Ala Ala Ala Gln Leu Ile Ala Pro Leu Ala Glu Asn Glu Gly Leu Leu Val Ala Ala Leu Glu Glu Leu Ala Phe Lys Ala Ser Glu Gln Ile Tyr Gly Thr Pro Ser Ser Ser Pro Tyr Glu Cys Leu Arg Gln Ser Cys Asn Ile Leu Ile Ser Thr Met Asn Lys Leu Ala Thr Ala Met Gln Glu Gly Glu Tyr Asp Ala Glu Arg Pro Pro Ser Lys Pro Pro Pro Val Glu Leu Arg Ala Ala Ala Leu Arg Ala Glu Ile Thr Asp Ala Glu Gly Leu Gly Leu Lys Leu Glu Asp Arg Glu Thr Val Ile Lys Glu Leu Lys Lys Ser Leu Lys Ile Lys Gly Glu Glu Leu Ser Glu Ala Asn Val Arg Leu Ser Leu Leu Glu Lys Lys Leu Asp Ser Ala Ala Lys Asp Ala Asp Glu Arg Ile Glu Lys Val Gln Thr Arg Leu Glu Glu Thr Gln Ala Leu Leu Arg Lys Lys Glu Lys Glu Phe Glu Glu Thr Met Asp Ala Leu Gln Ala Asp Ile Asp Gln Leu Glu Ala Glu Lys Ala Glu Leu Lys Gln Arg Leu Asn Ser Gln Ser Lys Arg Thr Ile Glu Gly Leu Arg Gly Pro Pro Pro Ser Gly Ile Ala Thr Leu Val Ser Gly Ile Ala Gly Glu Glu Gln Gln Arg Gly Ala Ile Pro Gly Gln Ala Pro Gly Ser Val Pro Gly Pro Gly Leu Val Lys Asp Ser Pro Leu Leu Leu Gln Gln Ile Ser Ala Met Arg Leu His Ile Ser Gln Leu Gln His Glu Asn Ser Ile Leu Lys Gly Ala Gln Met Lys Ala Ser Leu Ala Ser Leu Pro Pro Leu His Val Ala Lys Leu Ser His Glu Gly Pro Gly Ser Glu Leu Pro Ala Gly Ala Leu Tyr Arg Lys Thr Ser Gln Leu Leu Glu Thr Leu Asn Gln Leu Ser Thr His Thr His Val Val Asp Ile Thr Arg Thr Ser Pro Ala Ala Lys Ser Pro Ser Ala Gln Leu Met Glu Gln Val Ala Gln Leu Lys Ser Leu Ser Asp Thr Val Glu Lys Leu Lys Asp Glu Val Leu Lys Glu Thr Val Ser Gln Arg Pro Gly Ala Thr Val Pro Thr Asp Phe Ala Thr Phe Pro Ser Ser Ala Phe Leu Arg Ala Lys Glu Glu Gln Gln Asp Asp Thr Val Tyr Met Gly Lys Val Thr Phe Ser Cys Ala Ala Gly Phe Gly Gln Arg His Arg Leu Val Leu Thr Gln Glu Gln Leu His Gln Leu His Ser Arg Leu Ile Ser <210> 21 <211> 626 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 8041970CD1 <400> 21 Met Tyr Ala Phe Tyr Ser Leu Leu Ile Tyr Ile Phe Tyr Ser Leu Phe Arg Arg Asp Gly Gly Ala Ala Ala Ala Ala Glu Pro Gly Asp Pro Ala Gln Arg Ala Arg Lys Pro Arg Gly Arg Arg Arg Pro Asp Leu Pro Ala Pro Glu Leu Trp Thr Glu Leu Thr Gly Leu Ala Ala Ser Ser Glu Pro Glu Asp Gly Ser Glu Gly Ala Ala Glu Gly Arg Ala Ala Ala Val Ser Leu Glu Glu Ala Leu Leu Arg Leu Ala Glu Phe Leu Ser Val Gln Leu Gly Ala Glu Glu Ser Cys Gly Gly Pro Ala Asp Leu Gly Gln Ser Gly Glu Val Pro Ser Leu Leu Thr Val Thr Ser Gln Leu Leu Ala Leu Leu Ala Trp Leu Arg Ser Pro Arg Gly Arg Gln Ala Leu Leu Gln Gly Thr Gln Pro Ala Pro Arg Val Arg Pro Pro Ser Pro Asp Gly Ser Thr Ser Gln Glu Glu Ser Pro Ser His Phe Thr Ala Val Pro Gly Glu Pro Leu Gly Asp Glu Thr Gln Gly Gln Gln Pro Leu Gln Leu Glu Glu Asp G1n Arg Ala Trp Gln Arg Leu Glu Gln Leu Ile Leu Gly Gln Leu Glu Glu Leu Lys Gln Gln Leu Glu Gln Gln Glu Glu Glu Leu Gly Arg Leu Arg Leu Gly Val Gly Ala Thr Asp Ser Glu Lys Arg Val Gln His Leu Thr Leu Glu Asn Glu Ala Leu Lys Gln Ser Leu Ser Leu Met Arg Asp Leu Leu Leu His Trp Gly Pro Gly Pro Pro Ile Arg Ala Pro Gln Glu Glu Ala Glu Ala Leu Leu Glu Leu Gln Gly Arg Leu Gln Glu Ala Gln Asp Thr Thr Glu Ala Leu Arg Ala Gln Leu Gly Val Gln Glu Val Gln Leu Gln Gly Leu Gln Gly Ala Leu Gln Gln Leu Gln Gln Glu Thr Glu Gln Asn Cys Arg Arg Glu Leu Gln Gln Met His Gly Gln Leu Ala Gly Leu Arg Ala Arg Met Ala Ser Leu Arg Gln Gly Cys Gly Asp Leu Arg Gly Leu Val Ser Thr Phe Thr Gln Ser Cys Gln Gly Ser Leu Ser Glu Ala,Arg Gly Gln Val Ser Trp Ala Leu Gly Ala Leu Ser Ser Gly Gly Pro Gly Thr Gln Leu Pro Glu Gly Gln Gln Gly Pro Pro Ala Gly Cys Pro Gly Arg Leu Pro Glu Leu Lys Gly Asn Ile Arg Val Leu Cys Arg Leu Arg Pro Gly Thr Ser Ser Ser Leu Val Ser Val Glu Pro Gly Pro Gly Gly Thr Val Thr Thr Cys Tyr Arg Gly Arg His Arg Arg Phe Arg Leu Asp Trp Val Phe Pro Pro Asp Ala Ser Gln Glu Glu Val Phe Arg Glu Leu Glu Pro Ala Val Leu Ser Cys Leu Arg Gly Tyr Ser Val Cys Ile Phe Thr Tyr Gly Gln Thr Gly Thr Gly Lys Thr Tyr Ser Met Glu Gly Pro Pro Glu Asp Pro Gly Ile Val Pro Arg Ala Leu Gln Ser Leu Phe Arg Glu Met Gly Ala Gly Arg Gln His Arg Val Thr Leu Ser Met Val Glu Ile Tyr Asn Glu Ala Val Arg Asp Leu Leu Ala Pro Gly Pro Pro Glu Arg Leu Ala Val Arg Gln Gly Pro Glu Gly Gln Gly Gly Ile Gln Val Ala Gly Leu Thr His Trp Asp Val Pro Asn Leu Glu Thr Leu His Gln Met Leu Lys Leu Gly Arg Ser Asn Arg Ala Thr Ala Ala Thr Ala Met Asn Gln Arg Ser Ser Arg Ser His Ala Leu Val Thr Leu Thr Leu Arg Ala Ala Ser Pro Pro Arg Ala Pro Gly Thr Ala Gly Thr Thr Ala Gly Ala <210> 22 <211> 1006 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 2056295CD1 <400> 22 Met Ala Glu Gln Glu Ser Leu Glu Phe Gly Lys Ala Asp Phe Val Leu Met Asp Thr Val Ser Met Pro Glu Phe Met Ala Asn Leu Arg Leu Arg Phe Glu Lys Gly Arg Ile Tyr Thr Phe Ile Gly Glu Val Val Val Ser Val Asn Pro Tyr Lys Leu Leu Asn Ile Tyr Gly Arg Asp Thr Ile Glu Gln Tyr Lys Gly Arg Glu Leu Tyr Glu Arg Pro Pro His Leu Phe Ala Ile Ala Asp Ala Ala Tyr Lys Ala Met Lys 80 ' 85 90 Arg Arg Ser Lys Asp Thr Cys Ile Val Ile Ser Gly Glu Ser Gly Ala Gly Lys Thr Glu Ala Ser Lys Tyr Ile Met Gln Tyr Ile Ala Ala Ile Thr Asn Pro Ser Gln Arg Ala Glu Val Glu Arg Val Lys Asn Met Leu Leu Lys Ser Asn Cys Val Leu Glu Ala Phe Gly Asn Ala Lys Thr Asn Arg Asn Asp Asn Ser Ser Arg Phe Gly Lys Tyr Met Asp Ile Asn Phe Asp Phe Lys Gly Asp Pro Ile Gly Gly His Ile Asn Asn Tyr Leu Leu Glu Lys Ser Arg Val Ile Val Gln Gln Pro Gly Glu Arg Ser Phe His Ser Phe Tyr Gln Leu Leu Gln Gly Gly Ser Glu Gln Met Leu Arg Ser Leu His Leu Gln Lys Ser Leu Ser Ser Tyr Asn Tyr Ile His Val Gly Ala Gln Leu Lys Ser Ser Ile Asn Asp Ala Ala Glu Phe Arg Val Val Ala Asp Ala Met Lys Val Ile Gly Phe Lys Pro Glu Glu Ile Gln Thr Val Tyr Lys Ile Leu Ala Ala Ile Leu His Leu Gly Asn Leu Lys Phe Val Val Asp Gly Asp Thr Pro Leu Ile Glu Asn Gly Lys Val Val Ser Ile Ile Ala Glu Leu Leu Ser Thr Lys Thr Asp Met Val Glu Lys Ala Leu Leu Tyr Arg Thr Val Ala Thr Gly Arg Asp Ile Ile Asp Lys Gln His Thr Glu Gln Glu Ala Ser Tyr Gly Arg Asp Ala Phe Ala Lys Ala Ile Tyr Glu Arg Leu Phe Cys Trp Ile Val Thr Arg Ile Asn Asp Ile Ile Glu Val Lys Asn Tyr Asp Thr Thr Ile His Gly Lys Asn Thr Val Ile Gly Val Leu Asp Ile Tyr Gly Phe Glu Ile Phe Asp Asn Asn Ser Phe Glu Gln Phe Cys Ile Asn Tyr Cys Asn Glu Lys Leu Gln Gln Leu Phe Ile Gln Leu Val Leu Lys Gln Glu Gln Glu Glu Tyr Gln Arg Glu Gly Ile Pro Trp Lys His Ile Asp Tyr Phe Asn Asn Gln Ile Ile Val Asp Leu Val Glu Gln Gln His Lys Gly Ile Ile Ala Ile Leu Asp Asp Ala Cys Met Asn Val Gly Lys Val Thr Asp Glu Met Phe Leu Glu Ala Leu Asn Ser Lys Leu Gly Lys His Ala His Phe Ser Ser Arg Lys Leu Cys Ala Ser Asp Lys Ile Leu Glu Phe Asp Arg Asp Phe Arg Ile Arg His Tyr Ala Gly Asp Val Val Tyr Ser Val Ile Gly Phe Ile Asp Lys Asn Lys Asp Thr Leu Phe Gln Asp Phe Lys Arg Leu Met Tyr Asn Ser Ser Asn Pro Val Leu Lys Asn Met Trp Pro Glu Gly Lys Leu Ser Ile Thr Glu Val Thr Lys Arg Pro Leu Thr Ala Ala Thr Leu Phe Lys Asn Ser Met Ile Ala Leu Val Asp Asn Leu Ala Ser Lys Glu Pro Tyr Tyr Val Arg Cys Ile Lys Pro Asn Asp Lys Lys Ser Pro Gln Ile Phe Asp Asp Glu Arg Cys Arg His Gln Val Glu Tyr Leu Gly Leu Leu Glu Asn Val Arg Val Arg Arg Ala Gly Phe Ala Phe Arg Gln Thr Tyr Glu Lys Phe Leu His Arg Tyr Lys Met Ile Ser Glu Phe Thr Trp Pro Asn His Asp Leu Pro Ser Asp Lys Glu Ala Val Lys Lys Leu Ile Glu Arg Cys Gly Phe Gln Asp Asp Val Ala Tyr Gly Lys Thr Lys Ile Phe Ile Arg Thr Pro Arg Thr Leu Phe Thr Leu Glu Glu Leu Arg Ala Gln Met Leu Ile Arg Ile Val Leu Phe Leu Gln Lys Val Trp Arg Gly Thr Leu Ala Arg Met Arg Tyr Lys Arg Thr Lys Ala Ala Leu Thr Ile Ile Arg Tyr Tyr Arg Arg Tyr Lys Val Lys Ser Tyr Ile His Glu Val Ala Arg Arg Phe His Gly Val Lys Thr Met Arg Asp Tyr Gly Lys His Val Lys Trp Pro Ser Pro Pro Lys Val Leu Arg Arg Phe Glu Glu Ala Leu Gln Thr Ile Phe Asn Arg Trp Arg Ala Ser Gln Leu Ile Lys Ser Ile Pro Ala Ser Asp Leu Pro Gln Val Arg Ala Lys Val Ala Ala Val Glu Met Leu Lys Gly Gln Arg Ala Asp Leu Gly Leu Gln Arg Ala Trp Glu Gly Asn Tyr Leu Ala Ser Lys Pro Asp Thr Pro Gln Thr Ser Gly Thr Phe Val Pro Val Ala Asn Glu Leu Lys Arg Lys Asp Lys Tyr Met Asn Val Leu Phe Ser Cys His Val Arg Lys Val Asn Arg Phe Ser Lys Val Glu Asp Arg Ala Ile Phe Val Thr Asp Arg His Leu Tyr Lys Met Asp Pro Thr Lys Gln Tyr Lys Val Met Lys Thr Ile Pro Leu Tyr Asn Leu Thr Gly Leu Ser Val Ser Asn Gly Lys Asp Gln Leu Val Val Phe His Thr Lys Asp Asn Lys Asp Leu Ile Val Cys Leu Phe Ser Lys Gln Pro Thr His Glu Ser Arg Ile Gly Glu Leu Val Gly Val Leu Val Asn His Phe Lys Ser Glu Lys Arg His Leu Gln Val Asn Val Thr Asn Pro Val Gln Cys Ser Leu His Gly Lys Lys Cys Thr Val Ser Val Glu Thr Arg Leu Asn Gln Pro Gln Pro Asp Phe Thr Lys Asn Arg Ser Gly Phe Ile Leu Ser Val Pro Gly Asn <210> 23 <211> 379 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 70711963CD1 <400> 23 Met Tyr Asn Ile Lys Gln Ser Thr Asp Thr Lys Glu Ala Ala Ala Ile Glu Ala Arg Arg Asn Arg Glu Lys Glu Arg Gln Asn Arg Phe Phe Asn Val Arg Asn Arg Val Met Gly Val Asp Val Gln Ala Leu Asn Asn Gln Val Gly Asp Arg Lys Arg Arg Glu Ala Ala Glu Arg Ser Lys Glu Ala Ala Tyr Gly Thr Ser Gln Val Gln Tyr Asp Val Val Val Gln Met Leu Glu Lys Glu Glu Ala Asp Arg Thr Arg Gln Leu Ala Lys Lys Val Gln Glu Phe Arg Glu Gln Lys Gln Gln Leu Lys Asn Gly Arg Glu Phe Ser Leu Trp Asp Pro Gly Gln Val Trp Lys Gly Leu Pro Thr Tyr Leu Ser Tyr Ser Asn Thr Tyr Pro Gly Pro Ala Ser Leu Gln Tyr Phe Ser Gly Glu Asp Leu Asp Arg Asp Thr Arg Leu Arg Met Gln Gln Gly Gln Phe Arg Tyr Asn Leu Glu Arg Gln Gln Gln Glu Gln Gln Gln Ala Lys Val Asp Glu Asn Tyr Thr Asp Ala Leu Ser Asn Gln Leu Arg Leu Ala Met Asp Ala Gln Ala Thr His Leu Ala Arg Leu Glu Glu Ser Cys Arg Ala Ala Met Met Cys Ala Met Ala Asn Ala Asn Lys Ala Gln Ala Ala Val Gln Ala Gly Arg Gln Arg Cys Glu Arg Gln Arg Glu Gln Lys Ala Asn Leu Ala Glu Ile Gln His Gln Ser Thr Ser Asp Leu Leu Thr Glu Asn Pro Gln Val Ala Gln His Pro Met Ala Pro Tyr Arg Val Leu Pro Tyr Cys Trp Lys Gly Met Thr Pro Glu Gln Gln Ala Ala Ile Arg Lys Glu Gln Glu Val Gln Arg Ser Lys Lys Gln Ala His Arg Gln Ala Glu Lys Thr Leu Asp Thr Glu Trp Lys Ser Gln Thr Met Ser Ser Ala Gln Ala Val Leu Glu Leu Glu Glu Gln Glu Arg Glu Leu Cys Ala Val Phe Gln Arg Gly Leu Gly Ser Phe Asn Gln Gln Leu Ala Asn Glu Gln Lys Ala Gln Gln Asp Tyr Leu Asn Ser Val Ile Tyr Thr Asn Gln Pro Thr Ala Gln Tyr His Gln Gln Phe Asn Thr Ser Ser Arg <210> 24 <211> 490 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7374384CD1 <400> 24 Met Asn Lys Tyr Leu Gln Thr Lys Tyr Ala Gln Val Lys Ser Ile Leu Glu Arg Ser Lys Glu Glu Leu Ser Arg Thr Val Lys Cys Arg Asn Ala Ala Leu Lys Glu Ser Gln Lys Leu Lys Glu Asp Leu Glu Ala Val Glu Asp Arg Glu Asn Lys Lys Val Gly Asn Phe Gln Arg Gln Leu Ala Glu Ala Lys Glu Asp Asn Cys Lys Val Thr Ile Met Leu Glu Asn Val Leu Ala Ser His Ser Lys Met Gln Gly Ala Leu Glu Lys Val Gln Ile Glu Leu Gly Arg Arg Asp Ser Glu Ile Ala Gly Leu Lys Lys Glu Arg Asp Leu Asn Gln Gln Arg Val Gln Lys Leu Glu Ala Glu Val Asp Gln Trp Gln Ala Arg Met Leu Val Met Glu Asp Gln His Asn Ser Glu Ile Glu Ser Leu Gln Lys Ala Leu Gly Val Ala Arg Glu Asp Asn Arg Lys Leu Ala Met Ser Leu Glu Gln Ala Leu Gln Thr Asn Asn His Leu Gln Thr Lys Leu Asp His Ile Gln Glu Gln Leu Glu Ser Lys Glu Leu Glu Arg Gln Asn Leu Glu Thr Phe Lys Asp Arg Met Thr Glu Glu Ser Lys Val Glu Ala Glu Leu His Ala Glu Arg Ile Glu Ala Leu Arg Lys Gln Phe Gln Thr Glu Arg Glu Thr Thr Lys Lys Val Ala Gln Arg Glu Val Ala Glu Leu Lys Lys Ala Leu Asp Glu Ala Asn Phe Arg Ser Val Glu Val Ser Arg Thr Asn Arg Glu Leu Arg Gln Lys Leu Ala Glu Leu Glu Lys Ile Leu Glu Ser Asn Lys Glu Lys Ile Lys Asn Gln Lys Thr Gln Ile Lys Leu His Leu Ser Ala Lys Ala Asn Asn Ala Gln Asn Ile Glu Arg Met Lys Gln Ile Glu Lys Glu Leu Lys Gln Met Glu Leu Ile Lys Asp Gln Tyr Gln Lys Lys Asn Tyr Glu Gln Ser Leu Ser Ile Gln Arg Phe Val Cys Glu Met Thr Asn Leu Gln Lys Glu Met Gln Met Leu Ala Lys Ser Gln Tyr Asp Ala Ser Val Arg Asn Lys Gln Gln Glu Leu His Leu Glu Ala Glu Arg Lys Ile Arg Gln Glu Leu Glu Asn Arg Cys Gln Glu Leu Glu Glu Thr Val Arg His Leu Lys Lys Cys Lys Glu Ala Thr Glu Asn Thr Leu Lys Glu Ala Ser Val Glu Ser Glu Gln Ile Thr Ala Asn Leu Glu Glu Ala His Arg Trp Phe Lys His Arg Phe Asp Gly Leu Gln Leu Glu Leu Thr Lys Asn Arg Leu Gln Arg Pro Ser Gly Glu Asp Arg Trp Gln Glu Lys Asp Gln Asp Val Lys His Asp Val Met Ser Asn Gln Ser Val Leu His Arg Trp Glu Arg Lys Gln Asn Leu Arg Pro Met Pro Lys Lys Tyr His Ser Glu Val Gln Arg Lys <210> 25 <211> 99 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7503492CD1 <400> 25 Met Glu Asp Tyr Gln Ala Ala Glu Glu Ala Ile Glu Ser Ala Ile Gly Gly Asn Ala Tyr Gln His Ser Lys Val Asn Gln Trp Thr Thr Asn Val Val Glu Gln Thr Leu Ser Gln Leu Thr Lys Leu Gly Lys Pro Phe Lys Tyr Ile Val Thr Cys Val Ile Met Gln Lys Asn Gly Ala Gly Leu His Thr Ala Ser Ser Cys Phe Trp Asp Ser Ser Thr Asp Gly Ser Cys Thr Val Arg Trp Glu Asn Lys Thr Met Tyr Cys Ile Val Ser Ala Phe Gly Leu Ser Ile <210> 26 <211> 1103 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7503870CD1 <400> 26 Met Gly Glu Asn Glu Asp Glu Lys Gln Ala Gln Ala Gly Gln Val Phe Glu Asn Phe Val Gln Ala Ser Thr Cys Lys Gly Thr Leu Gln Ala Phe Asn Ile Leu Thr Arg His Leu Asp Leu Asp Pro Leu Asp His Arg Asn Phe Tyr Ser Lys Leu Lys Ser Lys Val Thr Thr Trp Lys Ala Lys Ala Leu Trp Tyr Lys Leu Asp Lys Arg Gly Ser His Lys Glu Tyr Lys Arg Gly Lys Ser Cys Thr Asn Thr Lys Cys Leu Ile Val Gly Gly Gly Pro Cys Gly Leu Arg Thr Ala Ile Glu Leu Ala Tyr Leu Gly Ala Lys Val Val Val Val Glu Lys Arg Asp Ser Phe Ser Arg Asn Asn Val Leu His Leu Trp Pro Phe Thr Ile His Asp Leu Arg Gly Leu Gly Ala Lys Lys Phe Tyr Gly Lys Phe Cys Ala Gly Ser Ile Asp His Ile Ser Ile Arg Gln Leu Gln Leu Ile Leu Phe Lys Val Ala Leu Met Leu Gly Val Glu Ile His Val Asn Val Glu Phe Val Lys Val Leu Glu Pro Pro Glu Asp Gln Glu Asn Gln Lys Ile Gly Trp Arg Ala Glu Phe Leu Pro Thr Asp His Ser Leu Ser Glu Phe Glu Phe Asp Val Ile Ile Gly Ala Asp Gly Arg Arg Asn Thr Leu Glu Gly Phe Arg Arg Lys Glu Phe Arg Gly Lys Leu Ala Ile Ala Ile Thr Ala Asn Phe Ile Asn Arg Asn Ser Thr Ala Glu Ala Lys Val Glu Glu Ile Ser Gly Val Ala Phe Ile Phe Asn Gln Lys Phe Phe Gln Asp Leu Lys Glu Glu Thr Gly Ile Asp Leu Glu Asn Ile Val Tyr Tyr Lys Asp Cys Thr His Tyr Phe Val Met Thr Ala Lys Lys Gln Ser Leu Leu Asp Lys Gly Val Ile Ile Asn Asp Tyr Ile Asp Thr Glu Met Leu Leu Cys Ala Glu Asn Val Asn Gln Asp Asn Leu Leu Ser Tyr Ala Arg Glu Ala Ala Asp Phe Ala Thr Asn Tyr Gln Leu Pro Ser Leu Asp Phe Ala Met Asn His Tyr Gly Gln Pro Asp Val Ala Met Phe Asp Phe Thr Cys Met Tyr Ala Ser Glu Asn Ala Ala Leu Val Arg Glu Arg Gln Ala His Gln Leu Leu Val Ala Leu Val Gly Asp Ser Leu Leu Glu Pro Phe Trp Pro Met Gly Thr Gly Cys Ala Arg Gly Phe Leu Ala Ala Phe Asp Thr Ala Trp Met Val Lys Ser Trp Asn Gln Gly Thr Pro Pro Leu Glu Leu Leu Ala Glu Arg Glu Ser Leu Tyr Arg Leu Leu Pro Gln Thr Thr Pro Glu Asn Ile Asn Lys Asn Phe Glu Gln Tyr Thr Leu Asp Pro Gly Thr Arg Tyr Pro Asn Leu Asn Ser His Cys Val Arg Pro His Gln Val Lys His Leu Tyr Ile Thr Lys Glu Leu Glu His Tyr Pro Leu Glu Arg Leu Gly Ser Val Arg Arg Ser Val Asn Leu Ser Arg Lys Glu Ser Asp Ile Arg Pro Ser Lys Leu Leu Thr Trp Cys Gln Gln Gln Thr Glu Gly Tyr Gln His Val Asn Val Thr Asp Leu Thr Thr Ser Trp Arg Ser Gly Leu Ala Leu Cys Ala Ile Ile His Arg Phe Arg Pro Glu Leu Ile Asn Phe Asp Ser Leu Asn Glu Asp Asp Ala Val Glu Asn Asn Gln Leu Ala Phe Asp Val Ala Glu Arg Glu Phe Gly Ile Pro Pro Val Thr Thr Gly Lys Glu Met Ala Ser Ala Gln Glu Pro Asp Lys Leu Ser Met Val Met Tyr Leu Ser Lys Phe Tyr Glu Leu Phe Arg Gly Thr Pro Leu Arg Pro Val Asp Ser Trp Arg Lys Asn Tyr Gly Glu Asn Ala Asp Leu Ser Leu Ala Lys Ser Ser Ile Ser Asn Asn Tyr Leu Asn Leu Thr Phe Pro Arg Lys Arg Thr Pro Arg Val Asp Gly Gln Thr Gly Glu Asn Asp Met Asn Lys Arg Arg Arg Lys Gly Phe Thr Asn Leu Asp Glu Pro Ser Asn Phe Ser Ser Arg Ser Leu Gly Ser Asn Gln Glu Cys Gly Ser Ser Lys Glu Gly Gly Asn Gln Asn Lys Val Lys Ser Met Ala Asn Gln Leu Leu Ala Lys Phe Glu Glu Ser Thr Arg Asn Pro Ser Leu Met Lys Gln Glu Arg Arg Val Ser Gly Ile Gly Lys Pro Val Leu Cys Ser Ser Ser Gly Pro Pro Val His Ser Cys Cys Pro Lys Pro Glu Glu Ala Thr Pro Ser Pro Ser Pro Pro Leu Lys Arg Gln Phe Pro Ser Val Val Val Thr Gly His Val Leu Arg Glu Leu Lys Gln Val Ser Ala Gly Ser Glu Cys Leu Ser Arg Pro Trp Arg Ala Arg Ala Lys Ser Asp Leu Gln Leu Gly Gly Thr Glu Asn Phe Ala Thr Leu Pro Ser Thr Arg Pro Arg Ala Gln Ala Leu Ser Gly Val Leu Trp Arg Leu Gln Gln Val Glu Glu Lys Ile Leu Gln Lys Arg Ala Gln Asn Leu Ala Asn Arg Glu Phe His Thr Lys Asn Ile Lys Glu Lys Ala Ala His Leu Ala Ser Met Phe Gly His Gly Asp Phe Pro Gln Asn Lys Leu Leu Ser Lys Gly Leu Ser His Thr His Pro Pro Ser Pro Pro Ser Arg Leu Pro Ser Pro Asp Pro Ala Ala Ser Ser Ser Pro Ser Thr Val Asp Ser Ala Ser Pro Ala Arg Lys Leu Thr Val Gly Lys Val Ser Ser Gly Ile Gly Ala Ala Ala Glu Val Leu Val Asn Leu Tyr Met Asn Asp His Arg Pro Lys Ala Gln Ala Thr Ser Pro Asp Leu Glu Ser Met Arg Lys Ser Phe Pro Leu Asn Leu GlyGlySer AspThrCys TyrPhe CysLys LysArg ValTyr Val MetGluArg LeuSerAla GluGly HisPhe PheHis ArgGlu Cys PheArgCys SerIleCys AlaThr ThrLeu ArgLeu AlaAla Tyr ThrPheAsp CysAspGlu GlyLys PheTyr CysLys ProHis Phe IleHisCys LysThrAsn SerLys GlnArg LysArg ArgAla Glu LeuLysGln GlnArgGlu GluGlu AlaThr TrpGln GluGln Glu AlaProArg ArgAspThr ProThr GluSer SerCys AlaVal Ala AlaIleGly ThrLeuGlu GlySer ProPro ValHis PheSer Leu ProValLeu HisProLeu LeuGly <210> 27 <211> 456 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7717376CD1 <400> 27 Met Asn Ser Ser Asp Glu Glu Lys Gln Leu Gln Leu Ile Thr Ser Leu Lys Glu Gln Ala Ile Gly Glu Tyr Glu Asp Leu Arg Ala Glu Asn Gln Lys Thr Lys Glu Lys Cys Asp Lys Ile Arg Gln Glu Arg Asp Glu Ala Val Lys Lys Leu Glu Glu Phe Gln Lys Ile Ser His Met Val Ile Glu Glu Val Asn Phe Met Gln Asn His Leu Glu Ile Glu Lys Thr Cys Arg Glu Ser Ala Glu Ala Leu Ala Thr Lys Leu Asn Lys Glu Asn Lys Thr Leu Lys Arg Ile Ser Met Leu Tyr Met Ala Lys Leu Gly Pro Asp Val Ile Thr Glu Glu Ile Asn Ile Asp Asp Glu Asp Ser Thr Thr Asp Thr Asp Gly Ala Ala Glu Thr Cys Val Ser Val Gln Cys Gln Lys Gln Ile Lys Glu Leu Arg Asp Gln Ile Val Ser Val Gln Glu Glu Lys Lys Ile Leu Ala Ile Glu Leu Glu Asn Leu Lys Ser Lys Leu Val Glu Val Ile Glu Glu Val Asn Lys Val Lys Gln Glu Lys Thr Val Leu Asn Ser Glu Val Leu Glu Gln Arg Lys Val Leu Glu Lys Cys Asn Arg Val Ser Met Leu Ala Val Glu Glu Tyr Glu Glu Met Gln Val Asn Leu Glu Leu Glu Lys Asp Leu Arg Lys Lys Ala Glu Ser Phe Ala Gln Glu Met Phe Ile Glu Gln Asn Lys Leu Lys Arg Gln Ser His Leu Leu Leu Gln Ser Ser Ile Pro Asp Gln Gln Leu Leu Lys Ala Leu Asp Glu Asn Ala Lys Leu Thr Gln Gln Leu Glu Glu Glu Arg Ile Gln His Gln Gln Lys Val Lys Glu Leu Glu Glu Gln Leu Glu Asn Glu Thr Leu His Lys Glu Ile His Asn Leu Lys Gln Gln Leu Glu Leu Leu Glu Glu Asp Lys Lys Glu Leu Glu Leu Lys Tyr Gln Asn Ser Glu Glu Lys Ala Arg Asn Leu Lys His Ser Val Asp Glu Leu Gln Lys Arg Val Asn Gln Ser Glu Asn Ser Val Pro Pro Pro Pro Pro Pro Pro Pro Pro Leu Pro Pro Pro Pro Pro Asn Pro Ile Arg Ser Leu Met Ser Met Ile Arg Lys Arg Ser His Pro Ser Gly Ser Gly Ala Lys Lys Glu Lys Ala Thr Gln Pro Glu Thr Thr Glu Glu Val Thr Asp Leu Lys Arg Gln Ala Val Glu Glu Met Met Asp Arg Ile Lys Lys Gly Val His Leu Arg Pro Val Asn Gln Thr Ala Arg Pro Lys Thr Lys Pro Glu Ser Ser Lys Gly Cys Glu Ser Ala Val Asp Glu Leu Lys Gly Ile Leu Ala Ser Gln <210> 28 <211> 701 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 7952550CD1 <400> 28 Met Glu Lys Lys Lys Ile Val Leu Glu Gln Glu Val Lys Thr Leu Asn Asp Ser Leu Lys Lys Val Glu Asn Lys Val Ser Ala Ile Val Asp Glu Lys Glu Asn Val Ile Lys Glu Val Glu Gly Lys Arg Ala Leu Leu Glu Ile Lys Glu Arg Glu His Asn Gln Leu Val Lys Leu Leu Glu Leu Ala Arg Glu Asn Glu Ala Thr Ser Leu Thr Glu Arg Gly Ile Leu Asp Leu Asn Leu Arg Asn Ser Leu Ile Asp Lys Gln Asn Tyr His Asp Glu Leu Ser Arg Lys Gln Arg Glu Lys Glu Arg Asp Phe Arg Asn Leu Arg Lys Met Glu Leu Leu Leu Lys Val Ser Trp Asp Ala Leu Arg Gln Thr Gln Ala Leu His Gln Arg Leu Leu Leu Glu Met Glu Ala Ile Pro Lys Asp Asp Ser Thr Leu Ser Glu Arg Arg Arg Glu Leu His Lys Glu Val Glu Val Ala Lys Arg Asn Leu Ala Gln Gln Lys Ile Ile Ser Glu Met Glu Ser Lys Leu Val Glu Gln Gln Leu Ala Glu Glu Asn Lys Leu Leu Lys Glu Gln Glu Asn Met Lys Glu Leu Val Val Asn Leu Leu Arg Met Thr Gln Ile Lys Ile Asp Glu Lys Glu Gln Lys Ser Lys Asp Phe Leu Lys Ala Gln Gln Lys Tyr Thr Asn Ile Val Lys Glu Met Lys Ala Lys Asp Leu Glu Ile Arg Ile His Lys Lys Lys Lys Cys Glu Ile Tyr Arg Arg Leu Arg Glu Phe Ala Lys Leu Tyr Asp Thr Ile Arg Asn Glu Arg Asn Lys Phe Val Asn Leu Leu His Lys Ala His Gln Lys Val Asn Glu Ile Lys Glu Arg His Lys Met Ser Leu Asn Glu Leu Glu Ile Leu Arg Asn Ser Ala Val Ser Gln Glu Arg Lys Leu Gln Asn Ser Met Leu Lys His Ala Asn Asn Val Thr Ile Arg Glu Ser Met Gln Asn Asp Val Arg Lys Ile Val Ser Lys Leu Gln Glu Met Lys Glu Lys Lys Glu Ala Gln Leu Asn Asn Ile Asp Arg Leu Ala Asn Thr Ile Thr Met Ile Glu Glu Glu Met Val Gln Leu Arg Lys Arg Tyr Glu Lys Ala Val Gln His Arg Asn Glu Ser Gly Val Gln Leu Ile Glu Arg Glu Glu Glu Ile Cys Ile Phe Tyr Glu Lys Ile Asn Ile Gln Glu Lys Met Lys Leu Asn Gly Glu Ile Glu Ile His Leu Leu Glu Glu Lys Ile Gln Phe Leu Lys Met Lys Ile Ala Glu Lys Gln Arg Gln Ile Cys Val Thr Gln Lys Leu Leu Pro Ala Lys Arg Ser Leu Asp Ala Asp Leu Ala Val Leu Gln Ile Gln Phe Ser Gln Cys Thr Asp Arg Ile Lys Asp Leu Glu Lys Gln Phe Val Lys Pro Asp Gly Glu Asn Arg Ala Arg Phe Leu Pro Gly Lys Asp Leu Thr Glu Lys Glu Met Ile Gln Lys Leu Asp Lys Leu Glu Leu Gln Leu Ala Lys Lys Glu Glu Lys Leu Leu Glu Lys Asp Phe Ile Tyr Glu Gln Val Ser Arg Leu Thr Asp Arg Leu Cys Ser Lys Thr Gln Gly Cys Lys Gln Asp Thr Leu Leu Leu Ala Lys Lys Met Asn Gly Tyr Gln Arg Arg Ile Lys Asn Ala Thr Glu Lys Met Met Ala Leu Val Ala Glu Leu Ser Met Lys Gln Ala Leu Thr Ile Glu Leu Gln Lys Glu Val Arg Glu Lys Glu Asp Phe Ile Phe Thr Cys Asn Ser Arg Ile Glu Lys Gly Leu Pro Leu Asn Lys Glu Ile Glu Lys Glu Trp Leu Lys Val Leu Arg Asp Glu Glu Met His Ala Leu Ala Ile Ala Glu Lys Ser Gln Glu Phe Leu Glu Ala Asp Asn Arg Gln Leu Pro Asn Gly Val Tyr Thr Thr Ala Glu Gln Arg Pro Asn Ala Tyr Ile Pro Glu Ala Asp Ala Thr Leu Pro Leu Pro Lys Pro Tyr Gly Ala Leu Ala Pro Phe Lys Pro Ser Glu Pro Gly Ala Asn Met Arg His Ile Arg Lys Pro Val Ile Lys Pro Val Glu Ile <210> 29 <211> 612 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 2412228CD1 <400> 29 Met Glu Leu Ala Met Asp Asn Ser Tyr Ala Phe Asn Gln Arg Ser Thr Cys Asn Gly Ile Pro Ser Glu Lys Lys Asn Asn Phe Leu Val Ser Glu Asp His Gly Gln Lys Ile Leu Ser Val Leu Gln Asn Phe Arg Glu Gln Asn Val Phe Tyr Asp Phe Lys Ile Ile Met Lys Asp Glu Ile Ile Pro Cys His Arg Cys Val Leu Ala Ala Cys Ser Asp Phe Phe Arg Ala Met Phe Glu Val Asn Met Lys Glu Arg Asp Asp Gly Ser Val Thr Ile Thr Asn Leu Ser Ser Lys Ala Val Lys Ala Phe Leu Asp Tyr Ala Tyr Thr Gly Lys Thr Lys Ile Thr Asp Asp Asn Val Glu Met Phe Phe Gln Leu Ser Ser Phe Leu Gln Val Ser Phe Leu Ser Lys Ala Cys Ser Asp Phe Leu Ile Lys Ser Ile Asn Leu Val Asn Cys Leu Gln Leu Leu Ser Ile Ser Asp Ser Tyr Gly Ser Thr Ser Leu Phe Asp His Ala Leu His Phe Val Gln His His Phe Ser Leu Leu Phe Lys Ser Ser Asp Phe Leu Glu Met Asn Phe Gly Val Leu Gln Lys Cys Leu Glu Ser Asp Glu Leu Asn Val Pro Glu Glu Glu Met Val Leu Lys Val Val Leu Ser Trp Thr Lys His Asn Leu Glu Ser Arg Gln Lys Tyr Leu Pro His Leu Ile Glu Lys Val Arg Leu His Gln Leu Ser Glu Glu Thr Leu Gln Asp Cys Leu Phe Asn Glu Glu Ser Leu Leu Lys Ser Thr Asn Cys Phe Asp Ile Ile Met Asp Ala Ile Lys Cys Val Gln Gly Ser Gly Gly Leu Phe Pro Asp Ala Arg Pro Ser Thr Thr Glu Lys Tyr Ile Phe Ile His Lys Thr Glu Glu Asn Gly Glu Asn Gln Tyr Thr Phe Cys Tyr Asn Ile Lys Ser Asp Ser Trp Lys Ile Leu Pro Gln Ser His Leu Ile Asp Leu Pro Gly Ser Ser Leu Ser Ser Tyr Gly Glu Lys Ile Phe Leu Thr Gly Gly Cys Lys Gly Lys Cys Cys Arg Thr Val Arg Leu His Ile Ala Glu Ser Tyr His Asp Ala Thr Asp Gln Thr Trp Cys Tyr Cys Pro Val Lys Asn Asp Phe Phe Leu Val Ser Thr Met Lys Thr Pro Arg Thr Met His Thr Ser Val Met Ala Leu Asp Arg Leu Phe Val Ile Gly Gly Lys Thr Arg Gly Ser Arg Asp Ile Lys Ser Leu Leu Asp Val Glu Ser Tyr Asn Pro Leu Ser Lys Glu Trp Ile Ser Val Ser Pro Leu Pro Arg Gly Ile Tyr Tyr Pro Glu Ala Ser Thr Cys Gln Asn Val Ile Tyr Val Leu Gly Ser Glu Val Glu Ile Thr Asp Ala Phe Asn Pro Ser Leu Asp Cys Phe Phe Lys Tyr Asn Ala Thr Thr Asp Gln Trp Ser Glu Leu Val Ala Glu Phe Gly Gln Phe Phe His Ala Thr Leu Ile Lys Ala Val Pro Val Asn Cys Thr Leu Tyr Ile Cys Asp Leu Ser Thr Tyr Lys Val Tyr Ser Phe Cys Pro Asp Thr Cys Val Trp Lys Gly Glu Gly Ser Phe Glu Cys Ala Gly Phe Asn Ala Gly Ala Ile Gly Ile Glu Asp Lys Ile Tyr Ile Leu Gly Gly Asp Tyr Ala Pro Asp Glu Ile Thr Asp Glu Val Gln Val Tyr His Ser Asn Arg Ser Glu Trp Glu Glu Val Ser Pro Met Pro Arg Ala Leu Thr Glu Phe Tyr Cys Gln Val Ile Gln Phe Asn Lys Tyr Arg Asp Pro Trp Phe Ser Asn Leu Cys Ala <210> 30 <211> 615 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7505714CD1 <400> 30 Met Ala Pro Gly Ala Ala Asp Ala Gln Ile Gly Thr Ala Asp Pro Gly Asp Phe Asp Gln Leu Thr Gln Cys Leu Ile Gln Ala Pro Ser Asn Arg Pro Tyr Phe Leu Leu Leu Gln Gly Tyr Gln Asp Ala Gln Asp Phe Val Val Tyr Val Met Thr Arg Glu Gln His Val Phe Gly Arg Gly Gly Asn Ser Ser Gly Arg Gly Gly Ser Pro Ala Pro Tyr Val Asp Thr Phe Leu Asn Ala Pro Asp Ile Leu Pro Arg His Cys Thr Val Arg Ala Gly Pro Glu His Pro Ala Met Val Arg Pro Ser Arg Gly Ala Pro Val Thr His Asn Gly Cys Leu Leu Leu Arg Glu Ala Glu Leu His Pro Gly Asp Leu Leu Gly Leu Gly Glu His Phe Leu Phe Met Tyr Lys Asp Pro Arg Thr Gly Gly Ser Gly Pro Ala Arg Pro Pro Trp Leu Pro Ala Arg Pro Gly Ala Thr Pro Pro Gly Pro Gly Trp Ala Phe Ser Cys Arg Leu Cys Gly Arg Gly Leu Gln Glu Arg Gly Glu Ala Leu Ala Ala Tyr Leu Asp Gly Arg Glu Pro Val Leu Arg Phe Arg Pro Arg Glu Glu Glu Ala Leu Leu Gly Glu Ile Val Arg Ala Ala Ala Ala Gly Ser Gly Asp Leu Pro Pro Leu Gly Pro Ala Thr Leu Leu Ala Leu Cys Val Gln His Ser Ala Arg Glu Leu Glu Leu Gly His Leu Pro Arg Leu Leu Gly Cys Leu Ala Arg Leu Ile Lys Glu Ala Val Trp Glu Lys Ile Lys Glu Ile Gly Asp Arg Gln Pro Glu Asn His Pro Glu Gly Val Pro Glu Val Pro Leu Thr Pro Glu Ala Val Ser Val Glu Leu Arg Pro Leu Met Leu Trp Met Ala Asn Thr Thr Glu Leu Leu Ser Phe Val Gln Glu Lys Val Leu Glu Met Glu Lys Glu Ala Asp Gln Glu Asp Pro Gln Leu Cys Asn Asp Leu Glu Leu Cys Asp Glu Ala Met Ala Leu Leu Asp Glu Val Ile Met Cys Thr Phe Gln Gln Ser Val Tyr Tyr Leu Thr Lys Thr Leu Tyr Ser Thr Leu Pro Ala Leu Leu Asp Ser Asn Pro Phe Thr Ala Gly Ala Glu Leu Pro Gly Pro Gly Ala Glu Leu Gly 380 385 ' 390 Ala Met Pro Pro Gly Leu Arg Pro Thr Leu Gly Val Phe Gln Ala Ala Leu Glu Leu Thr Ser Gln Cys Glu Leu His Pro Asp Leu Val Ser Gln Thr Phe Gly Tyr Leu Phe Phe Phe Ser Asn Ala Ser Leu Leu Asn Ser Leu Met Glu Arg Gly Gln Gly Arg Pro Phe Tyr Gln Trp Ser Arg Ala Val Gln Ile Arg Thr Asn Leu Asp Leu Val Leu Asp Trp Leu Gln Gly Ala Gly Leu Gly Asp Ile Ala Thr Glu Phe Phe Arg Lys Leu Ser Met Ala Val Asn Leu Leu Cys Val Pro Arg Thr Ser Leu Leu Lys Ala Ser Trp Ser Ser Leu Arg Thr Asp His Pro Thr Leu Thr Pro Ala Gln Leu His His Leu Leu Ser His Tyr Gln Leu Gly Pro Gly Arg Gly Pro Pro Ala Ala Trp Asp Pro Pro Pro Ala Glu Arg Glu Ala Val Asp Thr Gly Asp Ile Phe Glu Ser Phe Ser Ser His Pro Pro Leu Ile Leu Pro Leu Gly Ser Ser Arg Leu Arg Leu Thr Gly Pro Val Thr Asp Asp Ala Leu His Arg Glu Leu Arg Arg Leu Arg Arg Leu Leu Trp Asp Leu Glu Gln Gln Glu Leu Pro Ala Asn Tyr Arg His Gly Pro Pro Val Ala Thr Ser Pro <210> 31 <211> 1090 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 6922018CD1 <400> 31 Met Leu Lys Thr Glu Ser Ser Gly Glu Arg Thr Thr Leu Arg Ser Ala Ser Pro His Arg Asn Ala Tyr Arg Thr Glu Phe Gln Ala Leu Lys Ser Thr Phe Asp Lys Pro Lys Ser Asp Gly Glu Gln Lys Thr Lys Glu Gly Glu Gly Ser Gln Gln Ser Arg Gly Arg Lys Tyr Gly Ser Asn Val Asn Arg Ile Lys Asn Leu Phe Met Gln Met Gly Met Glu Pro Asn Glu Asn Ala Ala Val Ile Ala Lys Thr Arg Gly Lys Gly Gly His Ser Ser Pro Gln Arg Arg Met Lys Pro Lys Glu Phe Leu Glu Lys Thr Asp Gly Ser Val Val Lys Leu Glu Ser Ser Val Ser Glu Arg Ile Ser Arg Phe Asp Thr Met Tyr Asp Gly Pro Ser Tyr Ser Lys Phe Thr Glu Thr Arg Lys Met Phe Glu Arg Ser Val His Glu Ser Gly Gln Asn Asn Arg Tyr Ser Pro Lys Lys Glu Lys Ala Gly Gly Ser Glu Pro Gln Asp Glu Trp Gly Gly Ser Lys Ser Asn Arg Gly Ser Thr Asp Ser Leu Asp Ser Leu Ser Ser Arg Thr Glu Ala Val Ser Pro Thr Val Ser Gln Leu Ser Ala Val Phe Glu Asn Thr Asp Ser Pro Ser Ala Ile Ile Ser Glu Lys Ala Glu Asn Asn Glu Tyr Ser Val Thr Gly His Tyr Pro Leu Asn Leu Pro Ser Val Thr Val Thr Asn Leu Asp Thr Phe Gly His Leu Lys Asp Ser Asn Ser Trp Pro Pro Ser Asn Lys Arg Gly Val Asp Thr Glu Asp Ala His Lys Ser Asn Ala Thr Pro Val Pro Glu Val Ala Ser Lys Ser Thr Ser Leu Ala Ser Ile Pro Gly Glu Glu Ile Gln Gln Ser Lys Glu Pro Glu Asp Ser Thr Ser Asn Gln Gln Thr Pro Asp Ser Ile Asp Lys Asp Gly Pro Glu Glu Pro Cys Ala Glu Ser Lys Ala Met Pro Lys Ser Glu Ile Pro Ser Pro Gln Ser Gln Leu Leu Glu Asp Ala Glu Ala Asn Leu Val Gly Arg Glu Ala Ala Lys Gln Gln Arg Lys Glu Leu Ala Gly Gly Asp Phe Thr Ser Pro Asp Ala Ser Ala Ser Ser Cys Gly Lys Glu Val Pro Glu Asp Ser Asn Asn Phe Asp Gly Ser His Val Tyr Met His Ser Asp Tyr Asn Val Tyr Arg Val Arg Ser Arg Tyr Asn Ser Asp Trp Gly Glu Thr Gly Thr Glu Gln Asp Glu Glu Glu Asp Ser Asp Glu Asn Ser Tyr Tyr Gln Pro Asp Met Glu Tyr Ser Glu Ile Val Gly Leu Pro Glu Glu Glu Glu Ile Pro Ala Asn Arg Lys Ile Lys Phe Ser Ser Ala Pro Ile Lys Val Phe Asn Thr Tyr Ser Asn Glu Asp Tyr Asp Arg Arg Asn Asp Glu Val Asp Pro Val Ala Ala Ser Ala Glu Tyr Glu Leu Glu Lys Arg Val Glu Lys Leu Glu Leu Phe Pro Val Glu Leu Glu Lys Asp Glu Asp Gly Leu Gly Ile Ser Ile Ile Gly Met Gly Val Gly Ala Asp Ala Gly Leu Glu Lys Leu Gly Ile Phe Val Lys Thr Val Thr Glu Gly Gly Ala Ala Gln Arg Asp Gly Arg Ile Gln Val Asn Asp Gln Ile Val Glu Val Asp Gly Ile Ser Leu Val Gly Val Thr Gln Asn Phe Ala Ala Thr Val Leu Arg Asn Thr Lys Gly Asn Val Arg Phe Val Ile Gly Arg Glu Lys Pro Gly Gln Val Ser Glu Val Ala Gln Leu Ile Ser Gln Thr Leu Glu Gln Glu Arg Arg Gln Arg Glu Leu Leu Glu Gln His Tyr Ala Gln Tyr Asp Ala Asp Asp Asp Glu Thr Gly Glu Tyr Ala Thr Asp Glu Glu Glu Asp Glu Val Gly Pro Val Leu Pro Gly Ser Asp Met Ala Ile Glu Val Phe Glu Leu Pro Glu Asn Glu Asp Met Phe Ser Pro Ser Glu Leu Asp Thr Ser Lys Leu Ser His Lys Phe Lys Glu Leu Gln Ile Lys His Ala Val Thr Glu Ala Glu Ile Gln Lys Leu Lys Thr Lys Leu Gln Ala Ala Glu Asn Glu Lys Val Arg Trp Glu Leu Glu Lys Thr Gln Leu Gln Gln Asn Ile Glu Glu Asn Lys Glu Arg Met Leu Lys Leu Glu Ser Tyr Trp Ile Glu Ala Gln Thr Leu Cys His Thr Val Asn Glu His Leu Lys Glu Thr Gln Ser Gln Tyr Gln Ala Leu Glu Lys Lys Tyr Asn Lys Ala Lys Lys Leu Ile Lys Asp Phe Gln Gln Lys Glu Leu Asp Phe Ile Lys Arg Gln Glu Ala Glu Arg Lys Lys Ile Glu Asp Leu Glu Lys Ala His Leu Val Glu Val Gln Gly Leu Gln Val Arg Ile Arg Asp Leu Glu Ala Glu Val Phe Arg Leu Leu Lys Gln Asn Gly Thr Gln Val Asn Asn Asn Asn Asn Ile Phe Glu Arg Arg Thr Ser Leu Gly Glu Val Ser Lys Gly Asp Thr Met Glu Asn Leu Asp Gly Lys Gln Thr Ser Cys Gln Asp Gly Leu Ser Gln Asp Leu Asn Glu Ala Val Pro Glu Thr Glu Arg Leu Asp Ser Lys Ala Leu Lys Thr Arg Ala Gln Leu Ser Val Lys Asn Arg Arg Gln Arg Pro Ser Arg Thr Arg Leu Tyr Asp Ser Val Ser Ser Thr Asp Gly Glu Asp Ser Leu Glu Arg Lys Asn Phe Thr Phe Asn Asp Asp Phe Ser Pro Ser Ser Thr Ser Ser Ala Asp Leu Ser Gly Leu Gly Ala Glu Pro Lys Thr Pro Gly Leu Ser Gln Ser Leu Ala Leu Ser Ser Asp Glu Ile Leu Asp Asp Gly Gln Ser Pro Lys His Ser Gln Cys Gln Asn Arg Ala Val Gln Glu Trp Ser Val Gln Gln Val Ser His Trp Leu Met Ser Leu Asn Leu Glu Gln Tyr Val Ser Glu Phe Ser Ala Gln Asn Ile Thr Gly Glu Gln Leu Leu Gln Leu Asp Gly Asn Lys Leu Lys Ala Leu Gly Met Thr Ala Ser Gln Asp Arg Ala Val Val Lys Lys Lys Leu Lys Glu Met Lys Met Ser Leu Glu Lys Ala Arg Lys Ala Gln Glu Lys Met Glu Lys Gln Arg Glu Lys Leu Arg Arg Lys Glu Gln Glu Gln Met Gln Arg Lys Ser Lys Lys Thr Glu Lys Met Thr Ser Thr Thr Ala Glu Gly Ala Gly Glu Gln <210> 32 <211> 334 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 71963188CD1 <400> 32 Met Leu Glu Thr Leu Arg Glu Arg Leu Leu Ser Val Gln Gln Asp Phe Thr Ser Gly Leu Lys Thr Leu Ser Asp Lys Ser Arg Glu Ala Lys Val Lys Ser Lys Pro Arg Tyr Glu Asp Thr Trp Ala Ala Leu His Arg Arg Ala Lys Asp Cys Ala Ser Ala Gly Glu Leu Val Asp Ser Glu Val Val Met Leu Ser Ala His Trp Glu Lys Lys Lys Thr Ser Leu Val Glu Leu Gln Glu Gln Leu Gln Gln Leu Pro Ala Leu Ile Ala Asp Leu Glu Ser Met Thr Ala Asn Leu Thr His Leu Glu Ala Ser Phe Glu Glu Val Glu Asn Asn Leu Leu His Leu Glu Asp Leu Cys Gly Gln Cys Glu Leu Glu Arg Cys Lys His Met Gln Ser Gln Gln Leu Glu Asn Tyr Lys Lys Asn Lys Arg Lys Glu Leu Glu Thr Phe Lys Ala Glu Leu Asp Ala Glu His Ala Gln Lys Val Leu Glu Met Glu His Thr Gln Gln Met Lys Leu Lys Glu Arg Gln Lys Phe Phe Glu Glu Ala Phe Gln Gln Asp Met Glu Gln Tyr Leu Ser Thr Gly Tyr Leu Gln Ile Ala Glu Arg Arg Glu Pro Ile Gly Ser Met Ser Ser Met Glu Val Asn Val Asp Met Leu Glu Gln Met Asp Leu Met Asp Ile Ser Asp Gln Glu Ala Leu Asp Val Phe Leu Asn Ser Gly Gly Glu Glu Asn Thr Val Leu Ser Pro Ala Leu Gly Pro Glu Ser Ser Thr Cys Gln Asn Glu Ile Thr Leu Gln Val Pro Asn Pro Ser Glu Leu Arg Ala Lys Pro Pro .Ser Ser Ser Ser Thr Cys Thr Asp Ser Ala Thr Arg Asp Ile Ser Glu Gly Gly Glu Ser Pro Val Val Gln Ser Asp Glu Glu Glu Val Gln Val Asp Thr Ala Leu Ala Thr Ser His Thr Asp Arg Glu Ala Thr Pro Asp Gly Gly Glu Asp Ser Asp Ser <210> 33 <211> 661 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 7329220CD1 <400> 33 Met Asn Asp Ile Ser Gln Lys Ala Glu Ile Leu Leu Ser Ser Ser Lys Pro Val Pro Lys Thr Tyr Val Pro Lys Leu Gly Lys Gly Asp Val Lys Asp Lys Phe Glu Ala Met Gln Arg Ala Arg Glu Glu Arg Asn Gln Arg Arg Ser Arg Asp Glu Lys Gln Arg Arg Lys Glu Gln Tyr Ile Arg Glu Arg Glu Trp Asn Arg Arg Lys Gln Glu Ile Lys Glu Met Leu Ala Ser Asp Asp Glu Glu Asp Val Ser Ser Lys Val Glu Lys Ala Tyr Val Pro Lys Leu Thr Gly Thr Val Lys G1y Arg Phe Ala Glu Met Glu Lys Gln Arg Gln Glu Glu Gln Arg Lys Arg Thr Glu Glu Glu Arg Lys Arg Arg Ile Glu Gln Asp Met Leu Glu Lys Arg Lys Ile Gln Arg Glu Leu Ala Lys Arg Ala Glu Gln Glu Gly Asp Asp Ser Leu Leu Ile Thr Val Val Pro Val Lys Ser Tyr Lys Thr Ser Gly Lys Met Lys Lys Asn Phe Glu Asp Leu Glu Lys Glu Arg Glu Glu Lys Glu Arg Ile Lys Tyr Glu Glu Asp Lys Arg Ile Arg Tyr Glu Glu Gln Arg Pro Ser Leu Lys Glu Ala Lys Cys Leu Ser Leu Val Met Asp Asp Glu Ile Glu Ser Glu Ala Lys Lys Glu Ser Leu Ser Pro Arg Lys Leu Lys Leu Thr Phe Glu Glu Leu Glu Arg Gln Arg Gln Glu Asn Arg Lys Lys Gln Ala Glu Glu Glu Ala Arg Lys Arg Leu Glu Glu Glu Lys Arg Ala Phe Glu Glu Ala Arg Arg Gln Met Val Asn Glu Asp Glu Glu Asn Gln Asp Thr Ala Lys Ile Phe Lys Gly Tyr Arg Pro Gly Lys Leu Lys Leu Ser Phe Glu Glu Met Glu Arg Gln Arg Arg Glu Asp Glu Lys Arg Lys Ala Glu Glu Glu Ala Arg Arg Arg Ile Glu Glu Glu Lys Lys Ala Phe Ala Glu Ala Arg Arg Asn Met Val Val Asp Asp Asp Ser Pro Glu Met Tyr Lys Thr Ile Ser Gln Glu Phe Leu Thr Pro Gly Lys Leu Glu Ile Asn Phe Glu Glu Leu Leu Lys Gln Lys Met Glu Glu Glu Lys Arg Arg Thr Glu Glu Glu Arg Lys His Lys Leu Glu Met Glu Lys Gln Glu Phe Glu Gln Leu Arg Gln Glu Met Gly Glu Glu Glu Glu Glu Asn Glu Thr Phe Gly Leu Ser Arg Glu Tyr Glu Glu Leu Ile Lys Leu Lys Arg Ser Gly Ser Ile Gln Ala Lys Asn Leu Lys Ser Lys Phe Glu Lys Ile Gly Gln Leu Ser Glu Lys Glu Ile Gln Lys Lys Ile Glu Glu Glu Arg Ala Arg Arg Arg Ala Ile Asp Leu Glu Ile Lys Glu Arg Glu Ala Glu Asn Phe His Glu Glu Asp Asp Val Asp Val Arg Pro Ala Arg Lys Ser Glu Ala Pro Phe Thr His Lys Val Asn Met Lys Ala Arg Phe Glu Gln Met Ala Lys Ala Arg Glu Glu Glu Glu Gln Arg Arg Ile Glu Glu Gln Lys Leu Leu Arg Met Gln Phe Glu Gln Arg Glu Ile Asp Ala Ala Leu Gln Lys Lys Arg Glu Glu Glu Glu Glu Glu Glu Gly Ser Ile Met Asn Gly Ser Thr Ala Glu Asp Glu Glu Gln Thr Arg Ser Gly Ala Pro Trp Phe Lys Lys Pro Leu Lys Asn Thr Ser Val Val Asp Ser Glu Pro Val Arg Phe Thr Val Lys Val Thr Gly Glu Pro Lys Pro Glu Ile Thr Trp Trp Phe Glu Gly Glu Ile Leu Gln Asp Gly Glu Asp Tyr Gln Tyr Ile Glu Arg Gly Glu Thr Tyr Cys Leu Tyr Leu Pro Glu Thr Phe Pro Glu Asp Gly Gly Glu Tyr Met Cys Lys Ala Val Asn Asn Lys Gly Ser Ala Ala Ser Thr Cys Ile Leu Thr Ile Glu Ser Lys Asn <210> 34 <211> 402 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 8037383CD1 <400> 34 Met Pro Asp Lys Thr Ala Thr Pro Glu Arg Pro Pro Ala Pro Glu Asn Ala Pro Ser Ser Lys Lys Ile Pro Ala Pro Asp Lys Val Pro Ser Pro Glu Lys Thr Leu Thr Leu Gly Asp Lys Ala Ser Ile Pro Gly Asn Ser Thr Ser Gly Lys Ile Pro Ala Pro Asp Lys Val Pro Thr Pro Glu Lys Met Val Thr Pro Glu Asp Lys Ala Ser Ile Pro Glu Asn Ser Ile Ile Pro Glu Glu Thr Leu Thr Val Asp Lys Pro Ser Thr Pro Glu Arg Val Phe Ser Val Glu Glu Ser Pro Ala Leu Glu Ala Pro Pro Met Asp Lys Val Pro Asn Pro Lys Met Ala Pro Leu Gly Asp Glu Ala Pro Thr Leu Glu Lys Val Leu Thr Pro Glu Leu Ser Glu Glu Glu Val Ser Thr Arg Asp Asp Ile Gln Phe His His Phe Ser Ser Glu Glu Ala Leu Gln Lys Val Lys Tyr Phe Val Ala Lys Glu Asp Pro Ser Ser Gln Glu Glu Ala His Thr Pro Glu Ala Pro Pro Pro Gln Pro Pro Ser Ser Glu Arg Cys Leu Gly Glu Met Lys Cys Thr Leu Val Arg Gly Asp Ser Ser Pro Arg Gln Ala Glu Leu Lys Ser Gly Pro Ala Ser Arg Pro Ala Leu Glu Lys Pro His Pro His Glu Glu Ala Thr Thr Leu Pro Glu Glu Ala Pro Ser Asn Asp Glu Arg Thr Pro Glu Glu Glu Ala Pro Pro Asn Glu Gln Arg Pro Leu Arg Glu Glu Val Leu Pro Lys Glu Gly Val Ala Ser Lys Glu Glu Val Thr Leu Lys Glu Glu Leu Pro Pro Lys Glu Glu Val Ala Pro Lys Glu Glu Val Pro Pro Ile Glu Arg Ala Phe Ala Gln Lys Thr Arg Pro Ile Lys Pro Pro Pro Asp Ser Gln Glu Thr Leu Ala Leu Pro Ser Leu Val Pro Gln Asn Tyr Thr Glu Asn Lys Asn Glu Gly Val Asp Val Thr Ser Leu Arg Gly Glu Val Glu Ser Lys Lys Pro Leu Lys Asn Thr Ser Val Val Asp Ser Glu Leu Arg Arg Ala Leu Glu Leu Met Glu Val Gln Leu Glu Arg Lys Leu Thr Asp Ile Trp Glu Glu Leu Lys Ser Glu Lys Glu Gln Arg Arg Arg Leu Glu Val Gln Val Met Gln Gly Thr Gln Lys Ser Gln Thr Pro Arg Val Ile His Thr Gln Thr Gln Thr Tyr <210> 35 <211> 1498 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 5968254CD1 <400> 35 Met Glu Asn Arg Pro Gly Ser Phe Gln Tyr Val Pro Val Gln Leu Gln Gly Gly Ala Pro Trp Gly Phe Thr Leu Lys Gly Gly Leu Glu His Cys Glu Pro Leu Thr Val Ser Lys Ile Glu Asp Gly Gly Lys Ala Ala Leu Ser Gln Lys Met Arg Thr Gly Asp Glu Leu Val Asn Ile Asn Gly Thr Pro Leu Tyr Gly Ser Arg Gln Glu Ala Leu Ile Leu Ile Lys Gly Ser Phe Arg Ile Leu Lys Leu Ile Val Arg Arg Arg Asn Ala Pro Val Ser Arg Pro His Ser Trp His Val Ala Lys Leu Leu Glu Gly Cys Pro Glu Ala Ala Thr Thr Met His Phe Pro Ser Glu Ala Phe Ser Leu Ser Trp His Ser Gly Cys Asn Thr Ser Asp Val Phe Val Gln Trp Cys Pro Leu Ser Arg His Cys Ser Thr Glu Lys Ser Ser Ser Ile Gly Ser Met Glu Ser Leu Glu Gln Pro Gly Gln Ala Thr Tyr Glu Ser His Leu Leu Pro Ile Asp Gln Asn Met Tyr Pro Asn Gln Arg Asp Ser Ala Tyr Ser Ser Phe Ser Ala Ser Ser Asn Ala Ser Asp Cys Ala Leu Ser Leu Arg Pro Glu Glu Pro Ala Ser Thr Asp Cys Ile Met Gln Gly Pro Gly Pro Thr Lys Ala Pro Ser Gly Arg Pro Asn Val Ala Glu Thr Ser Gly Gly Ser Arg Arg Thr Asn Gly Gly His Leu Thr Pro Ser Ser Gln Met Ser Ser Arg Pro Gln Glu Gly Tyr Gln Ser Gly Pro Ala Lys Ala Val Arg Gly Pro Pro Gln Pro Pro Val Arg Arg Asp Ser Leu Gln Ala Ser Arg Ala Gln Leu Leu Asn Gly Glu Gln Arg Arg Ala Ser Glu Pro Val Val Pro Leu Pro Gln Lys Glu Lys Leu Ser Leu Glu Pro Val Leu Pro Ala Arg Asn Pro Asn Arg Phe Cys Cys Leu Ser Gly His Asp Gln Val Thr Ser Glu Gly His Gln Asn Cys Glu Phe Ser Gln Pro Pro Glu Ser Ser Gln Gln Gly Ser Glu His Leu Leu Met Gln Ala Ser Thr Lys Ala Val Gly Ser Pro Lys Ala Cys Asp Arg Ala Ser Ser Val Asp Ser Asn Pro Leu Asn Glu Ala Ser Ala Glu Leu Ala Lys Ala Ser Phe Gly Arg Pro Pro His Leu Ile Gly Pro Thr Gly His Arg His Ser Ala Pro Glu Gln Leu Leu Ala Ser His Leu Gln His Val His Leu Asp Thr Arg Gly Ser Lys Gly Met Glu Leu Pro Pro Val Gln Asp Gly His Gln Trp Thr Leu Ser Pro Leu His Ser Ser His Lys Gly Lys Lys Ser Pro Cys Pro Pro Thr Ala Gly Thr His Asp Gln Ser Ser Lys Glu Arg Lys Thr Arg Gln Val Asp Asp Arg Ser Leu Val Leu Gly His Gln Ser Gln Ser Ser Pro Pro His Gly Glu Ala Asp Gly His Pro Ser Glu Lys Gly Phe Leu Asp Pro Asn Arg Thr Ser Arg Ala Ala Ser Glu Leu Ala Asn Gln Arg Pro Ser Ala Ser Gly Ser Leu Val Gln Gln Ala Thr Asp Cys Ser Ser Thr Thr Lys Ala Ala Ser Gly Thr Glu Ala Gly Glu Glu 545 550 ' 555 Gly Asp Ser Glu Pro Lys Glu Cys Ser Arg Met Gly Gly Arg Arg Ser Gly Gly Thr Arg Gly Arg Ser Ile Gln Asn Arg Arg Lys Ser Glu Arg Phe Ala Thr Asn Leu Arg Asn Glu Ile Gln Arg Arg Lys Ala Gln Leu Gln Lys Ser Lys Gly Pro Leu Ser Gln Leu Cys Asp Thr Lys Glu Pro Val Glu Glu Thr Gln Glu Pro Pro Glu Ser Pro Pro Leu Thr Ala Ser Asn Thr Ser Leu Leu Ser Ser Cys Lys Lys Pro Pro Ser Pro Arg Asp Lys Leu Phe Asn Lys Ser Met Met Leu Arg Ala Arg Ser Ser Glu Cys Leu Ser Gln Ala Pro Glu Ser His Glu Ser Arg Thr Gly Leu Glu Gly Arg Ile Ser Pro Gly Gln Arg Pro Gly Gln Ser Ser Leu Gly Leu Asn Thr Trp Trp Lys Ala Pro Asp Pro Ser Ser Ser Asp Pro Glu Lys Ala His Ala His Cys Gly Val Arg Gly Gly His Trp Arg Trp Ser Pro Glu His Asn Ser Gln Pro Leu Val Ala Ala Ala Met Glu Gly Pro Ser Asn Pro Gly Asp Asn Lys Glu Leu Lys Ala Ser Thr Ala Gln Ala Gly Glu Asp Ala Ile Leu Leu Pro Phe Ala Asp Arg Arg Lys Phe Phe Glu Glu Ser Ser Lys Ser Leu Ser Thr Ser His Leu Pro Gly Leu Thr Thr His Ser Asn Lys Thr Phe Thr Gln Arg Pro Lys Pro Ile Asp Gln Asn Phe Gln Pro Met Ser Ser Ser Cys Arg Glu Leu Arg Arg His Pro Met Asp Gln Ser Tyr His Ser Ala Asp Gln Pro Tyr His Ala Thr Asp Gln Ser Tyr His Ser Met Ser Pro Leu Gln Ser Glu Thr Pro Thr Tyr Ser Glu Cys Phe Ala Ser Lys Gly Leu Glu Asn Ser Met Cys Cys Lys Pro Leu His Cys Gly Asp Phe Asp Tyr His Arg Thr Cys Ser Tyr Ser Cys Ser Val Gln Gly Ala Leu Val His Asp Pro Cys Ile Tyr Cys Ser Gly Glu Ile Cys Pro Ala Leu Leu Lys Arg Asn Met Met Pro Asn Cys Tyr Asn Cys Arg Cys His His His Gln Cys Ile Arg Cys Ser Val Cys Tyr His Asn Pro Gln His Ser Ala Leu Glu Asp Ser Ser Leu Ala Pro Gly Asn Thr Trp Lys Pro Arg Lys Leu Thr Val Gln Glu Phe Pro Gly Asp Lys Trp Asn Pro Ile Thr Gly Asn Arg Lys Thr Ser Gln Ser Gly Arg Glu Met Ala His Ser Lys Thr Ser Phe Ser Trp Ala Thr Pro Phe His Pro Cys Leu Glu Asn Pro Ala Leu Asp Leu Ser Ser Tyr Arg Ala Ile Ser Ser Leu Asp Leu Leu Gly Asp Phe Lys His Ala Leu Lys Lys Ser Glu Glu Thr Ser Val Tyr Glu Glu Gly Ser Ser Leu Ala Ser Met Pro His Pro Leu Arg Ser Arg Ala Phe Ser Glu Ser His Ile Ser Leu Ala Pro Gln Ser'Thr Arg Ala Trp Gly Gln His Arg Arg Glu Leu Phe Ser Lys Gly Asp Glu Thr Gln Ser Asp Leu Leu Gly Ala Arg Lys Lys Ala Phe Pro Pro Pro Arg Pro Pro Pro Pro Asn Trp Glu Lys Tyr Arg Leu Phe Arg Ala Ala Gln Gln Gln Lys Gln Gln Gln Gln Gln Gln Gln Gln Gln Gln Lys Gln Gln Glu Glu Glu Glu Glu Glu Glu Glu Glu Glu Glu Glu Glu Glu Glu Glu Glu Glu Glu Glu Glu Ala Glu Glu Glu Glu Glu Glu Leu Pro Pro Gln Tyr Phe Ser Ser Glu Thr Ser Gly Ser Cys Ala Leu Asn Pro Glu Glu Val Leu Glu Gln Pro Gln Pro Leu Ser Phe Gly His Leu Glu Gly Ser Arg Gln Gly Ser Gln Ser Val Pro Ala Glu Gln Glu Ser Phe Ala Leu His Ser Ser Asp Phe Leu Pro Pro Ile Arg Gly His Leu Gly Ser Gln Pro Glu Gln Ala Gln Pro Pro Cys Tyr Tyr Gly Ile Gly Gly Leu Trp Arg Thr Ser Gly Gln Glu Ala Thr Glu Ser Ala Lys Gln Glu Phe Gln His Phe Ser Pro Pro Ser Gly Ala Pro Gly Ile Pro Thr Ser Tyr Ser Ala Tyr Tyr Asn Ile Ser Val Ala Lys Ala Glu Leu Leu Asn Lys Leu Lys Asp Gln Pro Glu Met Ala Glu Ile Gly Leu Gly Glu Glu Glu Val Asp His Glu Leu Ala Gln Lys Lys Ile Gln Leu Ile Glu Ser Ile Ser Arg Lys Leu Ser Val Leu Arg Glu Ala Gln Arg Gly Leu Leu Glu Asp Ile Asn Ala Asn Ser Ala Leu Gly Glu Glu Val Glu Ala Asn Leu Lys Ala Val Cys Lys Ser Asn Glu Phe Glu Lys Tyr His Leu Phe Val Gly Asp Leu Asp Lys Val Val Asn Leu Leu Leu Ser Leu Ser Gly Arg Leu Ala Arg Val Glu Asn Ala Leu Asn Ser Ile Asp Ser Glu Ala Asn Gln Glu Lys Trp Val Leu Ile Glu Lys Lys Gln Gln Leu Thr Gly Gln Leu Ala Asp Ala Lys Glu Leu Lys Glu His Val Asp Arg Arg Glu Lys Trp Gly Ser Gly Met Val Ser Arg Tyr Leu Pro Gln Asp Gln Leu Gln Asp Tyr Gln His Phe Val Lys Met Lys Ser Ala Leu Ile Ile Glu Gln Arg Glu Leu Glu Glu Lys Ile Lys Leu Gly Glu Glu Gln Leu Lys Cys Leu Arg Glu Ser Leu Leu Leu Gly Pro Ser Asn Phe <210> 36 <211> 757 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1817376CD1 <400> 36 Met Ser Arg Lys Ile Ser Lys Glu Ser Lys Lys Val Asn Ile Ser Ser Ser Leu Glu Ser Glu Asp Ile Ser Leu Glu Thr Thr Val Pro Thr Asp Asp Ile Ser Ser Ser Glu Glu Arg Glu Gly Lys Val Arg Ile Thr Arg Gln Leu Ile Glu Arg Lys Glu Leu Leu His Asn Ile Gln Leu Leu Lys Ile Glu Leu Ser Gln Lys Thr Met Met Ile Asp Asn Leu Lys Val Asp Tyr Leu Thr Lys Ile Glu Glu Leu Glu Glu Lys Leu Asn Asp Ala Leu His Gln Lys Gln Leu Leu Thr Leu Arg Leu Asp Asn Gln Leu Ala Phe Gln Gln Lys Asp Ala Ser Lys Tyr Gln Glu Leu Met Lys Gln Glu Met Glu Thr Ile Leu Leu Arg Gln Lys Gln Leu Glu Glu Thr Asn Leu Gln Leu Arg Glu Lys Ala Gly Asp Val Arg Arg Asn Leu Arg Asp Phe Glu Leu Thr Glu Glu Gln Tyr Ile Lys Leu Lys Ala Phe Pro Glu Asp Gln Leu Ser Ile Pro Glu Tyr Val Ser Val Arg Phe Tyr Glu Leu Val Asn Pro Leu Arg Lys Glu Ile Cys Glu Leu Gln Val Lys Lys Asn Ile Leu Ala Glu Glu Leu Ser Thr Asn Lys Asn Gln Leu Lys Gln Leu Thr Glu Thr Tyr Glu Glu Asp Arg Lys Asn Tyr Ser Glu Val Gln Ile Arg Cys Gln Arg Leu Ala Leu Glu Leu Ala Asp Thr Lys Gln Leu Ile Gln Gln Gly Asp Tyr Arg Gln Glu Asn Tyr Asp Lys Val Lys Ser Glu Arg Asp Ala Leu Glu Gln Glu Val Ile Glu Leu Arg Arg Lys His Glu Ile Leu Glu Ala Ser His Met Ile Gln Thr Lys Glu Arg Ser Glu Leu Ser Lys Glu Val Val Thr Leu Glu Gln Thr Val Thr Leu Leu Gln Lys Asp Lys Glu Tyr Leu Asn Arg Gln Asn Met Glu Leu Ser Val Arg Cys Ala His Glu Glu Asp Arg Leu Glu Arg Leu Gln Ala Gln Leu Glu Glu Ser Lys Lys Ala Arg Glu Glu Met Tyr Glu Lys Tyr Val Ala Ser Arg Asp His Tyr Lys Thr Glu Tyr Glu Asn Lys Leu His Asp Glu Leu Glu Gln Ile Arg Leu Lys Thr Asn Gln Glu Ile Asp Gln Leu Arg Asn Ala Ser Arg Glu Met Tyr Glu Arg Glu Asn Arg Asn Leu Arg Glu Ala Arg Asp Asn Ala Val Ala Glu Lys Glu Arg Ala Val Met Ala Glu Lys Asp Ala Leu Glu Lys His Asp Gln Leu Leu Asp Arg Tyr Arg Glu Leu Gln Leu Ser Thr Glu Ser Lys Val Thr Glu Phe Leu His Gln Ser Lys Leu Lys Ser Phe Glu Ser Glu Arg Val Gln Leu Leu Gln Glu Glu Thr Ala Arg Asn Leu Thr Gln Cys Gln Leu Glu Cys Glu Lys Tyr Gln Lys Lys Leu Glu Val Leu Thr Lys Glu Phe Tyr Ser Leu Gln Ala Ser Ser Glu Lys Arg Ile Thr Glu Leu Gln Ala Gln Asn Ser Glu His Gln Ala Arg Leu Asp Ile Tyr Glu Lys Leu Glu Lys Glu Leu Asp Glu Ile Ile Met Gln Thr Ala Glu Ile Glu Asn Glu Asp Glu Ala Glu Arg Val Leu Phe Ser Tyr Gly Tyr Gly Ala Asn Val Pro Thr Thr Ala Lys Arg Arg Leu Lys Gln Ser Val His Leu Ala Arg Arg Val Leu Gln Leu Glu Lys Gln Asn Ser Leu Ile Leu Lys Asp Leu Glu His Arg Lys Asp Gln Val Thr Gln Leu Ser Gln Glu Leu Asp Arg Ala Asn Ser Leu Leu Asn Gln Thr Gln Gln Pro Tyr Arg Tyr Leu Ile Glu Ser Val Arg Gln Arg Asp Ser Lys Ile Asp Ser Leu Thr Glu Ser Ile Ala Gln Leu Glu Lys Asp Val Ser Asn Leu Asn Lys Glu Lys Ser Ala Leu Leu Gln Thr Lys Asn Gln Met Ala Leu Asp Leu Glu Gln Leu Leu Asn His Arg Glu Glu Leu Ala Ala Met Lys Gln Ile Leu Val Lys Met His Ser Lys His Ser Glu Asn Ser Leu Leu Leu Thr Lys Thr Glu Pro Lys His Val Thr Glu Asn Gln Lys Ser Lys Thr Leu Asn Val Pro Lys Glu His Glu Asp Asn Ile Phe Thr Pro Lys Pro Thr Leu Phe Thr Lys Lys Glu Ala Pro Glu Trp Ser Lys Lys Gln Lys Met Lys Thr <210> 37 <211> 933 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 7503880CD1 <400> 37 Met Arg Val Pro Val Phe Glu Asp Ile Lys Asp Glu Thr Glu Glu Glu Lys Ile Gly Glu Glu Glu Asn Glu Glu Asp Gln Val Phe Tyr Lys Pro Val Ile Glu Asp Leu Ser Met Glu Leu Ala Arg Lys Cys Thr Glu Leu Ile Ser Asp Ile Arg Tyr Lys Glu Glu Phe Lys Lys Ser Lys Asp Lys Cys Thr Phe Val Thr Asp Ser Pro Met Leu Asn His Val Lys Asn Ile Gly Ala Phe Ile Ser Glu Ala Lys Tyr Lys Gly Thr Ile Lys Ala Asp Leu Ser Asn Ser Leu Tyr Lys Arg Met Pro Ala Thr Ile Asp Ser Val Phe Ala Gly Glu Val Thr Gln Leu Gln Ser Glu Val Ala Tyr Lys Gln Lys His Asp Ala Ala Lys Gly Phe Ser Asp Tyr Ala His Met Lys Glu Pro Pro Glu Val Lys His Ala Met Glu Val Asn Lys His Gln Ser Asn Ile Ser Tyr Arg Lys Asp Val Gln Asp Thr His Thr Tyr Ser Ala Glu Leu Asp Arg Pro Asp Ile Lys Met Ala Thr Gln Ile Ser Lys Ile Ile Ser Asn Ala Glu Tyr Lys Lys Gly Gln Gly Ile Met Asn Lys Glu Pro Ala Val Ile Gly Arg Pro Asp Phe Glu His Ala Val Glu Ala Ser Lys Leu Ser Ser Gln Ile Lys Tyr Lys Glu Lys Phe Asp Asn Glu Met Lys Asp Lys Lys His His Tyr Asn Pro Leu Glu Ser Ala Ser Phe Arg Gln Asn Gln Leu Ala Ala Thr Leu Ala Ser Asn Val Lys Tyr Lys Lys Asp Ile Gln Asn Met His Asp Pro Val Ser Asp Leu Pro Asn Leu Leu Phe Leu Asp His Val Leu Lys Ala Ser Lys Met Leu Ser Gly Arg Glu Tyr Lys Lys Leu Phe Glu Glu Asn Lys Gly Met Tyr His Phe Asp Ala Asp Ala Val Glu His Leu His His Lys Gly Asn Ala Val Leu Gln Ser Gln Val Lys Tyr Lys Glu Glu Tyr Glu Lys Asn Lys Gly Lys Pro Met Leu Glu Phe Val Glu Thr Pro Ser Tyr Gln Ala Ser Lys Glu Ala Gln Lys Met Gln Ser Glu Lys Val Tyr Lys Glu Asp Phe Glu Lys Glu Ile Lys Gly Arg Ser Ser Leu Asp Leu Asp Lys Thr Pro Glu Phe Leu His Val Lys Tyr Ile Thr Asn Leu Leu Arg Glu Lys Glu Tyr Lys Lys Asp Leu Glu Asn Glu Ile Lys Gly Lys Gly Met Glu Leu Asn Ser Glu Val Leu Asp Ile Gln Arg Ala Lys Arg Ala Ser Glu Met Ala Ser Glu Lys Glu Tyr Lys Lys Asp Leu Glu Ser Ile Ile Lys Gly Lys Gly Met Gln Ala Gly Thr Asp Thr Leu Glu Met Gln His Ala Lys Lys Ala Ala Glu Ile Ala Ser Glu Lys Asp Tyr Lys Arg Asp Leu Glu Thr Glu Ile Lys Gly Lys Gly Met Gln Val Ser Thr Asp Thr Leu Asp Val Gln Arg Ala Lys Lys Ala Ser Glu Met Ala Ser Gln Lys Gln Tyr Lys Lys Asp Leu Glu Asn Glu Ile Lys Gly Lys Gly Met Gln Val Ser Met Asp Ile Pro Asp Ile Leu Arg Ala Lys Arg Thr Ser Glu Ile Tyr Ser Gln Arg Lys Tyr Lys Asp Glu Ala Glu Lys Met Leu Ser Asn Tyr Ser Thr Ile Ala Asp Thr Pro Glu Ile Gln Arg Ile Lys Thr Thr Gln Gln Asn Ile Ser Ala Val Phe Tyr Lys Lys Glu Val Gly Ala Gly Thr Ala Val Lys Asp Ser Pro Glu Ile Glu Arg Val Lys Lys Asn Gln Gln Asn Ile Ser Ser Val Lys Tyr Lys Glu Glu Ile Lys His Ala Thr Ala Ile Ser Asp Pro Pro Glu Leu Lys Arg Val Lys Glu Asn Gln Lys Asn Ile Ser Asn Leu Gln Tyr Lys Glu Gln Asn Tyr Lys Ala Thr Pro Val Ser Met Thr Pro Glu Ile Glu Arg Val Arg Arg Asn Gln Glu Gln Leu Ser Ala Val Lys Tyr Lys Gly Glu Leu Gln Arg Gly Thr Ala Ile Ser Asp Pro Pro Glu Leu Lys Arg Ala Lys Glu Asn Gln Lys Asn Ile Ser Asn Val Tyr Tyr Arg Gly Gln Leu Gly Arg Ala Thr Thr Leu Ser Val Thr Pro Glu Met Glu Arg Val Lys Lys Asn Gln Glu Asn Ile Ser Ser Val Lys Tyr Thr Gln Asp His Lys Gln Met Lys Gly Arg Pro Ser Leu Ile Leu Asp Thr Pro Ala Met Arg His Val Lys Glu Ala Gln Asn His Ile Ser Met Val Lys Tyr His Glu Asp Phe Glu Lys Thr Lys Gly Arg Gly Phe Thr Pro Val Val Asp Asp Pro Val Thr Glu Arg Val Arg Lys Asn Thr Gln Val Val Ser Asp Ala Ala Tyr Lys Gly Val His Pro His Ile Val Glu Met Asp Arg Arg Pro Gly Ile Ile Val Ala Pro Val Leu Pro Gly Ala Tyr Gln Gln Ser His Ser Gln Gly Tyr Gly Tyr Met His Gln Thr Ser Val Ser Ser Met Arg Ser Met Gln His Ser Pro Asn Leu Arg Thr Tyr Arg Ala Met Tyr Asp Tyr Ser Ala Gln Asp Glu Asp Glu Val Ser Phe Arg Asp Gly Asp Tyr Ile Val Asn Val Gln Pro Ile Asp Asp Gly Trp Met Tyr Gly Thr Val Gln Arg Thr Gly Arg Thr Gly Met Leu Pro Ala Asn Tyr Ile Glu Phe Val Asn <210> 38 <211> 231 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 7504093CD1 <400> 38 Met Pro Leu Val Thr Arg Asn Ile Glu Pro Arg His Leu Cys Arg Gln Thr Leu Pro Ser Val Arg Ser Glu Leu Glu Cys Val Thr Asn Ile Thr Leu Ala Asn Val Ile Arg Gln Leu Gly Ser Leu Ser Lys Tyr Ala Glu Asp Ile Phe Gly Glu Leu Phe Thr Gln Ala Asn Thr Phe Ala Ser Arg Val Ser Ser Leu Ala Glu Arg Val Asp Arg Leu Gln Val Lys Val Thr Gln Leu Asp Pro Lys Glu Glu Glu Val Ser Leu Gln Gly Ile Asn Thr Arg Lys Ala Phe Arg Ser Ser Thr Ile Gln Asp Gln Lys Leu Phe Asp Arg Asn Ser Leu Pro Val Pro Val Leu Glu Thr Tyr Asn Thr Cys Asp Thr Pro Pro Pro Pro Gly Pro Pro Pro Pro Pro Phe Thr Gly Ala Asp Gly Gln Pro Ala Ile Pro Pro Pro Leu Ser Asp Thr Thr Lys Pro Lys Ser Ser Leu Pro Ala Val Ser Asp Ala Arg Ser Asp Leu Leu Ser Ala Ile Arg Gln Gly Phe Gln Leu Arg Arg Val Glu Glu Gln Arg Glu Gln Glu Lys Arg Asp Val Val Gly Asn Asp Val Ala Thr Ile Leu Ser Arg Arg Ile Ala Val Glu Tyr Ser Asp Ser Glu Asp Asp Ser Ser Glu Phe Asp Glu Asp Asp Trp Ser Asp <210> 39 <211> 1011 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 7717791CD1 <400> 39 Met Ala Asp Leu Ser Leu Ala Asp Ala Leu Thr Glu Pro Ser Pro Asp Ile Glu Gly Glu Ile Lys Arg Asp Phe Ile Ala Thr Leu Glu Ala Glu Ala Phe Asp Asp Val Val Gly Glu Thr Val Gly Lys Thr Asp Tyr Ile Pro Leu Leu Asp Val Asp Glu Lys Thr Gly Asn Ser Glu Ser Lys Lys Lys Pro Cys Ser Glu Thr Ser Gln Ile Glu Asp Thr Pro Ser Ser Lys Pro Thr Leu Leu Ala Asn Gly Gly His Gly Val Glu Gly Ser Asp Thr Thr Gly Ser Pro Thr Glu Phe Leu Glu Glu Lys Met Ala Tyr Gln Glu Tyr Pro Asn Ser Gln Asn Trp Pro Glu Asp Thr Asn Phe Cys Phe Gln Pro Glu Gln Val Val Asp Pro Ile Gln Thr Asp Pro Phe Lys Met Tyr His Asp Asp Asp Leu Ala Asp Leu Val Phe Pro Ser Ser Ala Thr Ala Asp Thr Ser Ile Phe Ala Gly Gln Asn Asp Pro Leu Lys Asp Ser Tyr Gly Met Ser Pro Cys Asn Thr Ala Val Val Pro Gln Gly Trp Ser Val Glu Ala Leu Asn Ser Pro His Ser Glu Ser Phe Val Ser Pro Glu Ala Val Ala Glu Pro Pro Gln Pro Thr Ala Val Pro Leu Glu Leu Ala Lys Glu Ile Glu Met Ala Ser Glu Glu Arg Pro Pro Ala Gln Ala Leu Glu Ile Met Met Gly Leu Lys Thr Thr Asp Met Ala Pro Ser Lys Glu Thr Glu Met Ala Leu Ala Lys Asp Met Ala Leu Ala Thr Lys Thr Glu Val Ala Leu Ala Lys Asp Met Glu Ser Pro Thr Lys Leu Asp Val Thr Leu Ala Lys Asp Met Gln Pro Ser Met Glu Ser Asp Met Ala Leu Val Lys Asp Met Glu Leu Pro Thr Glu Lys Glu Val Ala Leu Val Lys Asp Val Arg Trp Pro Thr Glu Thr Asp Val Ser Ser Ala Lys Asn Val Val Leu Pro Thr Glu Thr Glu Val Ala Pro Ala Lys Asp Val Thr Leu Leu Lys Glu Thr Glu Arg Ala Ser Pro Ile Lys Met Asp Leu Ala Pro Ser Lys Asp Met Gly Pro Pro Lys Glu Asn Lys Lys Glu Thr Glu Arg Ala Ser Pro Ile Lys Met Asp Leu Ala Pro Ser Lys Asp Met Gly Pro Pro Lys Glu Asn Lys Ile Val Pro Ala Lys Asp Leu Val Leu Leu Ser Glu Ile Glu Val Ala Gln Ala Asn Asp Ile Ile Ser Ser Thr Glu Ile Ser Ser Ala Glu Lys Val Ala Leu Ser Ser Glu Thr Glu Val Ala Leu Ala Arg Asp Met Thr Leu Pro Pro Glu Thr Asn Val Ile Leu Thr Lys Asp Lys Ala Leu Pro Leu Glu Ala Glu Val Ala Pro Val Lys Asp Met Ala Gln Leu Pro Glu Thr Glu Ile Ala Pro Ala Lys Asp Val Ala Pro Ser Thr Val Lys Glu Val Gly Leu Leu Lys Asp Met Ser Pro Leu Ser Glu Thr Glu Met Ala Leu Gly Lys Asp Val Thr Pro Pro Pro Glu 515 . 520 525 Thr Glu Val Val Leu Ile Lys Asn Val Cys Leu Pro Pro Glu Met Glu Val Ala Leu Thr Glu Asp Gln Val Pro Ala Leu Lys Thr Glu Ala Pro Leu Ala Lys Asp Gly Val Leu Thr Leu Ala Asn Asn Val Thr Pro Ala Lys Asp Val Pro Pro Leu Ser Glu Thr Glu Ala Thr Pro Val Pro Ile Lys Asp Met Glu Ile Ala Gln Thr Gln Lys Gly Ile Ser Glu Asp Ser His Leu Glu Ser Leu Gln Asp Val Gly Gln Ser Ala Ala Pro Thr Phe Met Ile Ser Pro Glu Thr Ile Thr Gly Thr Gly Lys Lys Cys Ser Leu Pro Ala Glu Glu Asp Ser Val Leu Glu Lys Leu Gly Glu Arg Lys Pro Cys Asn Ser Gln Pro Ser Glu Leu Ser Ser Glu Thr Ser Gly Ile Ala Arg Pro Glu Glu Gly Arg Pro Val Val Ser Gly Thr Gly Asn Asp Ile Thr Thr Pro Pro Asn Lys Glu Leu Pro Pro Ser Pro Glu Lys Lys Thr Lys Pro Ile Ala Asp Ala Lys Ala Pro Glu Lys Arg Ala Ser Pro Ser Lys Pro Ala Ser Ala Pro Ala Ser Arg Ser Gly Ser Lys Ser Thr Gln Thr Val Ala Lys Thr Thr Thr Ala Ala Ala Val Ala Ser Thr Gly Pro Ser Ser Arg Ser Pro Ser Thr Leu Leu Pro Lys Lys Pro Thr Ala Ile Lys Thr Glu Gly Lys Pro Ala Glu Val Lys Lys Met Thr Ala Lys Ser Val Pro Ala Asp Leu Ser Arg Pro Lys Ser Thr Ser Thr Ser Ser Met Lys Lys Thr Thr Thr Leu Ser Gly Thr Ala Pro Ala Ala Gly Val Val Pro Ser Arg Val Lys Ala Thr Pro Met Pro Ser Arg Pro Ser Thr Thr Pro Phe Ile Asp Lys Lys Pro Thr Ser Ala Lys Pro Ser Ser Thr Thr Pro Arg Leu Ser Arg Leu Ala Thr Asn Thr 845 ' 850 855 Ser Ala Pro Asp Leu Lys Asn Val Arg Ser Lys Val Gly Ser Thr Glu Asn Ile Lys His Gln Pro Gly Gly Gly Arg Val Gln Ile Gln Asn Lys Lys Val Asp Ile Ser Lys Val Ser Ser Lys Cys Gly Ser Lys Ala Asn Ile Lys His Lys Pro Gly Gly Gly Asp Val Lys Ile Glu Ser Gln Lys Leu Asn Phe Lys Glu Lys Ala Gln Ala Lys Val Gly Ser Leu Asp Asn Val Gly His Leu Pro Ala Gly Gly Ala Val Lys Thr Glu Gly Gly Gly Ser Glu Ala Pro Leu Cys Pro Gly Pro Pro Ala Gly Glu Glu Pro Ala Ile Ser Glu Ala Ala Pro Glu Ala Gly Ala Pro Thr Ser Ala Ser Gly Leu Asn Gly His Pro Thr Leu Ser Gly Gly Gly Asp Gln Arg Glu Ala Gln Thr Leu Asp Ser Gln Ile Gln Glu Thr Ser Ile <210> 40 <211> 601 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 7503472CD1 <400> 40 Met His Cys Lys Val Ser Leu Leu Asp Asp Thr Val Tyr Glu Cys Val Val Glu Lys His Ala Lys Gly Gln Asp Leu Leu Lys Arg Val Cys Glu His Leu Asn Leu Leu Glu Glu Asp Tyr Phe Gly Leu Ala Ile Trp Asp Asn Ala Thr Ser Lys Thr Trp Leu Asp Ser Ala Lys Glu Ile Lys Lys Gln Val Arg Gly Val Pro Trp Asn Phe Thr Phe Asn Val Lys Phe Tyr Pro Pro Asp Pro Ala Gln Leu Thr Glu Asp Ile Thr Arg Tyr Tyr Leu Cys Leu Gln Leu Arg Gln Asp Ile Val Ala Gly Arg Leu Pro Cys Ser Phe Ala Thr Leu Ala Leu Leu Gly Ser Tyr Thr Ile Gln Ser Glu Leu Gly Asp Tyr Asp Pro Glu Leu His Gly Val Asp Tyr Val Ser Asp Phe Lys Leu Ala Pro Asn Gln Thr Lys Glu Leu Glu Glu Lys Val Met Glu Leu His Lys Ser Tyr Arg Ser Met Thr Pro Ala Gln Ala Asp Leu Glu Phe Leu Glu Asn Ala Lys Lys Leu Ser Met Tyr Gly Val Asp Leu His Lys Ala Lys Asp Leu Glu Gly Val Asp Ile Ile Leu Gly Val Cys Ser Ser Gly Leu Leu Val Tyr Lys Asp Lys Leu Arg Ile Asn Arg Phe Pro Trp Pro Lys Val Leu Lys Ile Ser Tyr Lys Arg Ser Ser Phe Phe Ile Lys Ile Arg Pro Gly Glu Gln Glu Gln Tyr Glu Ser Thr Ile Gly Phe Lys Leu Pro Ser Tyr Arg Ala Ala Lys Lys Leu Trp Lys Val Cys Val Glu His His Thr Phe Phe Arg Leu Thr Ser Thr Asp Thr Ile Pro Lys Ser Lys Phe Leu Ala Leu Gly Ser Lys Phe Arg Tyr Ser Gly Arg Thr Gln Ala Gln Thr Arg Gln Ala Ser Ala Leu Ile Asp Arg Pro Ala Pro His Phe Glu Arg Thr Ala Ser Lys Arg Ala Ser Arg Ser Leu Asp Gly Ala Ala Ala Val Asp Ser Ala Asp Arg Ser Pro Arg Pro Thr Ser Ala Pro Ala Ile Thr Gln Gly Gln Val Ala Glu Gly Gly Val Leu Asp Ala Ser Ala Lys Lys Thr Val Val Pro Lys Ala Gln Lys Glu Thr Val Lys Ala Glu Val Lys Lys Glu Asp Glu Pro Pro Glu Gln Ala Glu Pro Glu Pro Thr Glu Ala Trp Lys Asp Leu Asp Lys Ser Gln Glu Glu Ile Lys Lys His His Ala Ser Ile Ser Glu Leu Lys Lys Asn Phe Met Glu Ser Val Pro Glu Pro Arg Pro Ser Glu Trp Asp Lys Arg Leu Ser Thr His Ser Pro Phe Arg Thr Leu Asn Ile Asn Gly Gln Ile Pro Thr Gly Glu Gly Pro Pro Leu Val Lys Thr Gln Thr Val Thr Ile Ser Asp Asn Ala Asn Ala Val Lys Ser Glu Ile Pro Thr Lys Asp Val Pro Ile Val His Thr Glu Thr Lys Thr Ile Thr Tyr Glu Ala Ala Gln Thr Asp Asp Asn Ser Gly Asp Leu Asp Pro Gly Val Leu Leu Thr Ala Gln Thr Ile Thr Ser Glu Thr Pro Ser Ser Thr Thr Thr Thr Gln Ile Thr Lys Thr Val Lys Gly Gly Ile Ser Glu Thr Arg Ile Glu Lys Arg Ile Val Ile Thr Gly Asp Ala Asp Ile Asp His Asp Gln Val Leu Val Gln Ala Ile Lys Glu Ala Lys Glu Gln His Pro Asp Met Ser Val Thr Lys Val Val Val His Gln Glu Thr Glu Ile Ala Asp Glu <210> 41 <211> 377 <212> PRT

<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 7505833CD1 <400> 41 Met Ala Ala Asn Leu Ser Arg Asn Gly Pro Ala Leu Gln Glu Ala Tyr Val Arg Val Val Thr Glu Lys Ser Pro Thr Asp Trp Ala Leu Phe Thr Tyr Glu Gly Asn Ser His Val Ser Thr Met Ala Ser Phe Leu Lys Gly Ala His Val Thr Ile Asn Ala Arg Ala Glu Glu Asp Val Glu Pro Glu Cys Ile Met Glu Lys Val Ala Lys Ala Ser Gly Ala Asn Tyr Ser Phe His Lys Glu Ser Gly Arg Phe Gln Asp Val Gly Pro Gln Ala Pro Val Gly Ser Val Tyr Gln Lys Thr Asn Ala Val Ser Glu Ile Lys Arg Val Gly Lys Asp Ser Phe Trp Ala Lys Ala Glu Lys Glu Glu Glu Asn Arg Arg Leu Glu Glu Lys Arg Arg Ala Glu Glu Ala Gln Pro Gln Leu Glu Gln Glu Arg Arg Glu Arg Glu Leu Arg Glu Ala Ala Arg Arg Glu Gln Arg Tyr Gln Glu Gln Gly Gly Glu Ala Ser Pro Gln Ser Arg Thr Trp Glu Gln Gln Gln Glu Val Val Ser Arg Asn Arg Asn Glu Gln Gly Ser Thr Cys Ala Ser Leu Gln Glu Ser Ala Val His Pro Arg Glu Ile Phe Lys Gln Lys Glu Arg Ala Met Ser Thr Thr Ser Ile Ser Ser Pro Gln Pro Gly Lys Leu Arg Ser Pro Phe Leu Gln Lys Gln Leu Thr Gln Pro Glu Thr His Phe Gly Arg Glu Pro Ala Ala Ala Ile Ser Arg Pro Arg Ala Asp Leu Pro Ala Glu Glu Pro Ala Pro Ser Thr Pro Pro Cys Leu Val Gln Ala Glu Glu Glu Ala Val Tyr Glu Glu Pro Pro Glu Gln Glu Thr Phe Tyr Glu Gln Pro Pro Leu Val Gln Gln Gln Gly Ala Gly Ser Glu His Ile Asp His His Ile Gln Gly Gln Gly Leu Ser Gly Gln Gly Leu Cys Ala Arg Ala Leu Tyr Asp Tyr Gln Ala Ala Asp Asp Thr Glu Ile Ser Phe Asp Pro Glu Asn Leu Ile Thr Gly Ile Glu Val Ile Asp Glu Gly Trp Trp Arg Gly Tyr Gly Pro Asp Gly His Phe Gly Met Phe Pro Ala Asn Tyr Val Glu Leu Ile Glu <210> 42 <211> 378 <212> PRT

<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7505844CD1 <400> 42 Met Ala Asp Pro Lys Tyr Ala Asp Leu Pro Gly Ile Glu Glu Leu Thr Ser Thr Ser Val Glu His Ile Ile Val Asn Pro Asn Ala Ala Tyr Asp Lys Phe Lys Asp Lys Arg Val Gly Thr Lys Gly Leu Asp Phe Ser Asp Arg Ile Gly Lys Thr Lys Arg Thr Gly Tyr Glu Ser Gly Glu Tyr Glu Met Leu Gly Glu Gly Leu Gly Val Lys Glu Thr Pro Gln Gln Lys Tyr Gln Arg Leu Leu His Glu Val Gln Glu Leu Thr Thr Glu Val Glu Lys Ile Lys Thr Thr Val Lys Glu Ser Ala Thr Glu Glu Lys Leu Thr Pro Val Leu Leu Ala Lys Gln Leu Ala Ala Leu Lys Gln Gln Leu Val Ala Ser His Leu Glu Lys Leu Leu Gly Pro Asp Ala Ala Ile Asn Leu Thr Asp Pro Asp Gly Ala Leu Ala Lys Arg Leu Leu Leu Gln Leu Glu Ala Thr Lys Asn Ser Lys Gly Gly Ser Gly Gly Lys Thr Thr Gly Thr Pro Pro Asp Ser Ser Leu Val Thr Tyr Glu Leu His Ser Arg Pro Glu Gln Asp Lys Phe Ser Gln Ala Ala Lys Val Ala Glu Leu Glu Lys Arg Leu Thr Glu Leu Glu Thr Ala Val Arg Cys Asp Gln Asp Ala Gln Asn Pro Leu Ser Ala Gly Leu Gln Gly Ala Cys Leu Met Glu Thr Val Glu Leu Leu Gln Ala Lys Val Ser Ala Leu Asp Leu Ala Val Leu Asp Gln Val Glu Ala Arg Leu Gln Ser Val Leu Gly Lys Val Asn Glu Ile Ala Lys His Lys Ala Ser Val Glu Asp Ala Asp Thr Gln Ser Lys Val His Gln Leu Tyr Glu Thr Ile Gln Arg Trp Ser Pro Ile Ala Ser Thr Leu Pro Glu Leu Val Gln Arg Leu Val Thr Ile Lys Gln Leu His Glu Gln Ala Met Gln Phe Gly Gln Leu Leu Thr His Leu Asp Thr Thr Gln Gln Met Ile Ala Asn Ser Leu Lys Asp Asn Thr Thr Leu Leu Thr Gln Val Gln Thr Thr Met Arg Glu Asn Leu Ala Thr Val Glu Gly Asn Phe Ala Ser Ile Asp Glu Arg Met Lys Lys Leu Gly Lys <210> 43 <211> 142 <212> PRT

DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.

NOTE : Pour les tomes additionels, veuillez contacter 1e Bureau canadien des brevets JUMBO APPLICATIONS/PATENTS
THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE THAN ONE
VOLUME

NOTE: For additional volumes, please contact the Canadian Patent Office NOM DU FICHIER / FILE NAME
NOTE POUR LE TOME / VOLUME NOTE:
Thr Glu Glu

Claims (157)

What is claimed is:

1. An isolated polypeptide selected from the group consisting of:
a) ~a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-51, b) ~a polypeptide comprising a naturally occurring amino acid sequence at least 90%
identical to an amino acid sequence selected from the group consisting of SEQ
ID
NO:1, SEQ ID NO:3-4, SEQ ID NO:7-9, SEQ ID NO:14-16, SEQ ID NO:21, SEQ ID
NO:23, SEQ ID NO:26, SEQ ID NO:28-31, SEQ ID NO:33-34, and SEQ ID NO:39 c) ~a polypeptide consisting essentially of a naturally occurring amino acid sequence at least 99% identical to the amino acid sequence of SEQ ID NO:27, d) ~a polypeptide comprising a naturally occurring amino acid sequence at least 98%
identical to an amino acid sequence selected from the group consisting of SEQ
ID
NO:2, SEQ ID NO:22, SEQ ID NO:36, and SEQ ID NO:48, e) ~a polypeptide comprising a naturally occurring amino acid sequence at least 97%
identical to an amino acid sequence selected from the group consisting of SEQ
ID
NO:13 and SEQ ID NO:24, f) ~a polypeptide comprising a naturally occurring amino acid sequence at least 96%
identical to the amino acid sequence of SEQ ID NO:10, g) ~a polypeptide comprising a naturally occurring amino acid sequence at least 95%
identical to the amino acid sequence of SEQ ID NO:40, h) ~a polypeptide comprising a naturally occurring amino acid sequence at least 94%
identical to the amino acid sequence of SEQ ID NO:45, i) ~a polypeptide comprising a naturally occurring amino acid sequence at least 92%
identical to the amino acid sequence of SEQ ID NO:47, j) ~a polypeptide comprising a naturally occurring amino acid sequence at least 91 %
identical to the amino acid sequence of SEQ ID NO:17, k) ~a polypeptide consisting essentially of a naturally occurring amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:18-20, SEQ ID NO:32, SEQ ID NO:37-38, SEQ ID NO:41-44, SEQ ID
NO:49-51 l)~a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-51, and m) ~an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-51.

2. An isolated polypeptide of claim 1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-51.

3. An isolated polynucleotide encoding a polypeptide of claim 1.

4. An isolated polynucleotide encoding a polypeptide of claim 2.

5. An isolated polynucleotide of claim 4 comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO:52-102.

6. A recombinant polynucleotide comprising a promoter sequence operably linked to a polynucleotide of claim 3.

7. A cell transformed with a recombinant polynucleotide of claim 6.

8. A transgenic organism comprising a recombinant polynucleotide of claim 6.

9. A method of producing a polypeptide of claim 1, the method comprising:
a) culturing a cell under conditions suitable for expression of the polypeptide, wherein said cell is transformed with a recombinant polynucleotide, and said recombinant polynucleotide comprises a promoter sequence operably linked to a polynucleotide encoding the polypeptide of claim 1, and b) recovering the polypeptide so expressed.~

10. A method of claim 9, wherein the polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO:1-51.

11. An isolated antibody which specifically binds to a polypeptide of claim 1.

12. An isolated polynucleotide selected from the group consisting of:
a) ~a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO:52-102, b) ~a polynucleotide comprising a naturally occurring polynucleotide sequence at least 90% identical to a polynucleotide sequence selected from the group consisting of SEQ ID NO:52-67, SEQ ID NO:69-75, SEQ ID NO:77-85, SEQ ID NO:88-97, and SEQ ID NO:99-101, c) ~a polynucleotide comprising a naturally occurring polynucleotide sequence at least 98% identical to a polynucleotide sequence selected from the group consisting of SEQ ID NO:87 and SEQ ID NO:102, d) ~a polynucleotide comprising a naturally occurring polynucleotide sequence at least 97% identical to the polynucleotide sequence of SEQ ID NO:68, e) ~a polynucleotide comprising a naturally occurring polynucleotide sequence at least 93% identical to the polynucleotide sequence of SEQ ID NO:76, f) ~a polynucleotide comprising a naturally occurring polynucleotide sequence at least 92% identical to a polynucleotide sequence selected from the group consisting of SEQ ID NO:86 and SEQ ID NO:98, g) ~a polynucleotide complementary to a polynucleotide of a), h) ~a polynucleotide complementary to a polynucleotide of b), i) ~a polynucleotide complementary to a polynucleotide of c), j) ~a polynucleotide complementary to a polynucleotide of d), k) ~a polynucleotide complementary to a polynucleotide of e), l) ~a polynucleotide complementary to a polynucleotide of f), and m)~an RNA equivalent of a)-1).

13. ~An isolated polynucleotide comprising at least 60 contiguous nucleotides of a polynucleotide of claim 12.

14. A method of detecting a target polynucleotide in a sample, said target polynucleotide having a sequence of a polynucleotide of claim 12, the method comprising:
a) hybridizing the sample with a probe comprising at least 20 contiguous nucleotides comprising a sequence complementary to said target polynucleotide in the sample, and which probe specifically hybridizes to said target polynucleotide, under conditions whereby a hybridization complex is formed between said probe and said target polynucleotide or fragments thereof, and b) detecting the presence or absence of said hybridization complex, and, optionally, if present, the amount thereof.

15. A method of claim 14, wherein the probe comprises at least 60 contiguous nucleotides.

16. A method of detecting a target polynucleotide in a sample, said target polynucleotide having a sequence of a polynucleotide of claim 12, the method comprising:
a) amplifying said target polynucleotide or fragment thereof using polymerase chain reaction amplification, and b) detecting the presence or absence of said amplified target polynucleotide or fragment thereof, and, optionally, if present, the amount thereof.

17. A composition comprising a polypeptide of claim 1 and a pharmaceutically acceptable excipient.

18. A composition of claim 17, wherein the polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO:1-51.

19. A method for treating a disease or condition associated with decreased expression of functional SCAP, comprising administering to a patient in need of such treatment the composition of claim 17.

20. A method of screening a compound for effectiveness as an agonist of a polypeptide of claim 1, the method comprising:
a) exposing a sample comprising a polypeptide of claim 1 to a compound, and b) detecting agonist activity in the sample.

21. A composition comprising an agonist compound identified by a method of claim 20 and a pharmaceutically acceptable excipient.

22. A method for treating a disease or condition associated with decreased expression of functional SCAP, comprising administering to a patient in need of such treatment a composition of claim 21.

23. A method of screening a compound for effectiveness as an antagonist of a polypeptide of claim 1, the method comprising:
a) exposing a sample comprising a polypeptide of claim 1 to a compound, and b) detecting antagonist activity in the sample.

24. A composition comprising an antagonist compound identified by a method of claim 23 and a pharmaceutically acceptable excipient.

25. A method for treating a disease or condition associated with overexpression of functional SCAP, comprising administering to a patient in need of such treatment a composition of claim 24.

26. A method of screening for a compound that specifically binds to the polypeptide of claim 1, the method comprising:
a) combining the polypeptide of claim 1 with at least one test compound under suitable conditions, and b) detecting binding of the polypeptide of claim 1 to the test compound, thereby identifying a compound that specifically binds to the polypeptide of claim 1.

27. A method of screening for a compound that modulates the activity of the polypeptide of claim 1, the method comprising:
a) combining the polypeptide of claim 1 with at least one test compound under conditions permissive for the activity of the polypeptide of claim 1, b) assessing the activity of the polypeptide of claim 1 in the presence of the test compound, and c) comparing tile activity of the polypeptide of claim 1 in the presence of the test compound with the activity of the polypeptide of claim 1 in the absence of the test compound, wherein a change in the activity of the polypeptide of claim 1 in the presence of the test compound is indicative of a compound that modulates the activity of the polypeptide of claim 1.

28. A method of screening a compound for effectiveness in altering expression of a target polynucleotide, wherein said target polynucleotide comprises a sequence of claim 5, the method comprising:
a) exposing a sample comprising the target polynucleotide to a compound, under conditions suitable for the expression of the target polynucleotide, b) detecting altered expression of the target polynucleotide, and c) comparing the expression of the target polynucleotide in the presence of varying amounts of the compound and in the absence of the compound.

29. A method of assessing toxicity of a test compound, the method comprising:
a) treating a biological sample containing nucleic acids with the test compound, b) ~hybridizing the nucleic acids of the treated biological sample with a probe comprising at least 20 contiguous nucleotides of a polynucleotide of claim 12 under conditions whereby a specific hybridization complex is formed between said probe and a target polynucleotide in the biological sample, said target polynucleotide comprising a polynucleotide sequence of a polynucleotide of claim 12 or fragment thereof, c) ~quantifying the amount of hybridization complex, and d) ~comparing the amount of hybridization complex in the treated biological sample with the amount of hybridization complex in an untreated biological sample, wherein a difference in the amount of hybridization complex in the treated biological sample is indicative of toxicity of the test compound.

30. A method for a diagnostic test for a condition or disease associated with the expression of SCAP in a biological sample, the method comprising:
a) combining the biological sample with an antibody of claim 11, under conditions suitable for the antibody to bind the polypeptide and form an antibody:polypeptide complex, and b) detecting the complex, wherein the presence of the complex correlates with the presence of the polypeptide in the biological sample.

31. The antibody of claim 11, wherein the antibody is:
a) a chimeric antibody, b) a single chain antibody, c) a Fab fragment, d) a F(ab')2 fragment, or e) a humanized antibody.

32. A composition comprising an antibody of claim 11 and an acceptable excipient.

33. A method of diagnosing a condition or disease associated with the expression of SCAP in a subject, comprising administering to said subject an effective amount of the composition of claim 32.

34. A composition of claim 32, wherein the antibody is labeled.

35. A method of diagnosing a condition or disease associated with the expression of SCAP in a subject, comprising administering to said subject an effective amount of the composition of claim 34.

36. A method of preparing a polyclonal antibody with the specificity of the antibody of claim 11, the method comprising:
a) immunizing an animal with a polypeptide consisting of an amino acid sequence selected from the group consisting of SEQ ID NO:1-51, or an immunogenic fragment thereof, under conditions to elicit an antibody response, b) isolating antibodies from the animal, and c) screening the isolated antibodies with the polypeptide, thereby identifying a polyclonal antibody which specifically binds to a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-51.

37. A polyclonal antibody produced by a method of claim 36.

38. A composition comprising the polyclonal antibody of claim 37 and a suitable carrier.

39. A method of making a monoclonal antibody with the specificity of the antibody of claim 11, the method comprising:
a) immunizing an animal with a polypeptide consisting of an amino acid sequence selected from the group consisting of SEQ ID NO:1-51, or an immunogenic fragment thereof, under conditions to elicit an antibody response, b) isolating antibody producing cells from the animal, c) fusing the antibody producing cells with immortalized cells to form monoclonal antibody-producing hybridoma cells, d) culturing the hybridoma cells, and e) isolating from the culture monoclonal antibody which specifically binds to a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-51.

40. A monoclonal antibody produced by a method of claim 39.

41. A composition comprising the monoclonal antibody of claim 40 and a suitable carrier.

42. The antibody of claim 11, wherein the antibody is produced by screening a Fab expression library.

43. The antibody of claim 11, wherein the antibody is produced by screening a recombinant immunoglobulin library.

44. A method of detecting a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-51 in a sample, the method comprising:
a) incubating the antibody of claim 11 with the sample under conditions to allow specific binding of the antibody and the polypeptide, and b) detecting specific binding, wherein specific binding indicates the presence of a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-51 in the sample.

45. A method of purifying a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-51 from a sample, the method comprising:
a) incubating the antibody of claim 11 with the sample under conditions to allow specific binding of the antibody and the polypeptide, and~
b) separating the antibody from the sample and obtaining the purified polypeptide comprising an amino acid sequence selected from the group consisting of SEQ >D
NO:1-51.

46. A microarray wherein at least one element of the microarray is a polynucleotide of claim 13.

47. A method of generating an expression profile of a sample which contains polynucleotides, the method comprising:
a) labeling the polynucleotides of the sample, b) contacting the elements of the microarray of claim 46 with the labeled polynucleotides of the sample under conditions suitable for the formation of a hybridization complex, and c) quantifying the expression of the polynucleotides in the sample.

48. An array comprising different nucleotide molecules affixed in distinct physical locations on a solid substrate, wherein at least one of said nucleotide molecules comprises a first oligonucleotide or polynucleotide sequence specifically hybridizable with at least 30 contiguous nucleotides of a target polynucleotide, and wherein said target polynucleotide is a polynucleotide of claim 12.

49. An array of claim 48, wherein said first oligonucleotide or polynucleotide sequence is completely complementary to at least 30 contiguous nucleotides of said target polynucleotide.

50. An array of claim 48, wherein said first oligonucleotide or polynucleotide sequence is completely complementary to at least 60 contiguous nucleotides of said target polynucleotide.

51. An array of claim 48, wherein said first oligonucleotide or polynucleotide sequence is completely complementary to said target polynucleotide.

52. An array of claim 48, which is a microarray.

53. An array of claim 48, further comprising said target polynucleotide hybridized to a nucleotide molecule comprising said first oligonucleotide or polynucleotide sequence.

54. An array of claim 48, wherein a linker joins at least one of said nucleotide molecules to said solid substrate.

55. An array of claim 48, wherein each distinct physical location on the substrate contains multiple nucleotide molecules, and the multiple nucleotide molecules at any single distinct physical location have the same sequence, and each distinct physical location on the substrate contains nucleotide molecules having a sequence which differs from the sequence of nucleotide molecules at another distinct physical location on the substrate.

56. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:1.

57. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:2.

58. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:3.

59. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:4.

60. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:5.

61. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:6.

62. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:7.

63. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:8.

64. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:9.

65. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:10.

66. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:11.

67. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:12.

68. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:13.

69. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:14.

70. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:15.

71. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:16.

72. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:17.

73. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:18.

74. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:19.

75. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:20.

76. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:21.

77. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:22.

78. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:23.

79. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:24.

80. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:25.

81. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:26.

82. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:27.

83. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:28.

84. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:29.

85. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:30.

86. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:31.

87. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:32.

88. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:33.

89. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:34.

90. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:35.

91. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:36.

92. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:37.

93. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:38.

94. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:39.

95. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:40.

96. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:41.

97. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:42.

98. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:43.

99. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:44.

100. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:45.

101. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:46.

102. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:47.

103. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:48.

104. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:49.

105. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:50.

106. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:51.

107. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:52.

108. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:53.

109. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:54.

110. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:55.

111. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:56.

112. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:57.

113. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:58.

114. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:59.

115. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:60.

116. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:61.

117. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:62.

118. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:63.

119. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:64.

120. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:65.

121. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:66.

122. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:67.

123. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:68.

124. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:69.

125. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:70.

126. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:71.

127. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:72.

128. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:73.

129. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:74.

130. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:75.

131. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:76.

132. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:77.

133. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:78.

134. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:79.

135. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:80.

136. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:81.

137. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:82.

138. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:83.

139. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:84.

140. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:85.

141. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:86.

142. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:87.

143. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:88.

144. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:89.

145. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:90.

146. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:91.

147. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:92.

148. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:93.

149. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:94.

150. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:95.

151. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:96.

152. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:97.

153. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:98.

154. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:99.

155. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:100.

156. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:101.

157. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:102.