CA2410610A1 - Human kinases - Google Patents

Abstract

The invention provides human kinases (PKIN) and polynucleotides which identify and encode PKIN. The invention also provides expression vectors, host cells, antibodies, agonists, and antagonists. The invention also provides methods for diagnosing, treating or prevention disorders associated with aberrant expression of PKIN.

Description

HUMAN KINASES
TECHNICAL FIELD
This invention relates to nucleic acid and amino acid sequences of human kinases and to the use of these sequences in the diagnosis, treatment, and prevention of cancer, immune disorders, disorders affecting growth and development, cardiovascular diseases, and lipid disorders, and in the assessment of the effects of exogenous compounds on the expressio~l of nucleic acid and amino acid sequences of human kinases.
BACKGROUND OF THE INVENTION
Kinases comprise the largest known enzyme superfamily and vary widely in their target molecules. Kinases catalyze the transfer of high energy phosphate groups from a phosphate donor to a phosphate acceptor. Nucleotides usually serve as the phosphate donor in these reactions, with most kinases utilizing adenosine triphosphate (ATP). The phosphate acceptor can be any of a variety of molecules, including nucleosides, nucleotides, lipids, carbohydrates, and proteins. Proteins are phosphorylated on hydroxyamino acids. Addition of a phosphate group alters the local charge on the acceptor molecule, causing internal conformational changes and potentially influencing intermolecular contacts. Reversible protein phosphorylation is the primary method for regulating protein activity in eukaryotic cells. In general, proteins are activated by phosphorylation in response to extracellular signals such as hormones, neurotransmitters, and growth and differentiation factors. The activated proteins initiate the cell's intracellular response by way of intracellular signaling pathways and second messenger molecules such as cyclic nucleotides, calcium-calmodulin, inositol, and various mitogens, that regulate protein phosphorylation.
Kinases are involved in all aspects of a cell's function, from basic metabolic processes, such as glycolysis, to cell-cycle regulation, differentiation, and communication with the extracellular environment through signal transduction cascades. Inappropriate phosphorylation of proteins in cells has been linked to changes in cell cycle progression and cell differentiation.
Changes in the cell cycle have been linked to induction of apoptosis or cancer. Changes in cell differentiation have been linked to diseases and disorders of the reproductive system, immune system, and skeletal muscle.
There are two classes of protein kinases. One class, protein tyrosine kinases (PTKs), phosphorylates tyrosine residues, and the other class, protein serineJthreonine kinases (STKs), phosphorylates serine and threonine residues. Some PTKs and STI~s possess structural characteristics of both families and have dual specificity for both tyrosine and serine/threonine residues. Almost all kinases contain a conserved 250-300 amino acid catalytic domain containing specific residues and sequence motifs characteristic of the kinase family. The protein kinase catalytic domain can be further divided into 11 subdomains. N-terminal subdomains I-IV fold into a two-lobed structure which binds and orients the ATP donor molecule, and subdomain V spans the two lobes. C-terminal subdomains VI-XI bind the protein substrate and transfer the gamma phosphate from ATP to the hydroxyl group of a tyrosine, serine, or threonine residue. Each of the 11 subdomains contains specific catalytic residues or amino acid motifs characteristic of that subdomain. For example, subdomain I contains an 8-amino acid glycine-rich ATP binding consensus motif, subdomain II contains a critical lysine residue required for maximal catalytic activity, and subdomains VI through IX comprise the highly conserved catalytic core. PTKs and STKs also contain distinct sequence motifs in subdomains VI and VIII which may confer hydroxyamino acid specificity.
In addition, kinases may also be classified by additional amino acid sequences, generally between 5 and 100 residues, which either flank or occur within the kinase domain. These additional amino acid sequences regulate kinase activity and determine substrate specificity. (Reviewed in Hardie, G. and S. Hanks (1995) The Protein Kinase Facts Book, Vol I, pp. 17-20 Academic Press, San Diego CA.). In particular, two protein kinase signature sequences have been identified in the kinase domain, the first containing an active site lysine residue involved in ATP binding, and the second containing an aspartate residue important for catalytic activity. If a protein analyzed includes the two protein kinase signatures, the probability of that protein being a protein kinase is close to 100% (PROSITE:
PDOC00100, November 1995).
Protein Tyrosine Kinases Protein tyrosine kinases (PTKs) may be classified as either transmembrane, receptor PTKs or nontransmembrane, nonreceptor.PTK proteins. Transmembrane tyrosine kinases function as receptors for most growth factors. Growth factors bind to the receptor tyrosine kinase (RTK), which causes the receptor to phosphorylate itself (autophosphorylation) and specific intracellular second messenger proteins. Growth factors (GF) that associate with receptor PTKs include epidermal GF, platelet-derived GF, fibroblast GF, hepatocyte GF, insulin and insulin-like GFs, nerve GF, vascular endothelial GF, and macrophage colony stimulating factor.
Nontransmembrane, nonreceptor PTKs lack transmembrane regions and, instead, form signaling complexes with the cytosolic domains of plasma membrane receptors.
Receptors that function through non-receptor PTKs include those for cytokines and hormones (growth hormone and prolactin), and antigen-specific receptors on T and B lymphocytes.
Many PTKs were first identified as oncogene products in cancer cells in which PTK activation was no longer subject to normal cellular controls. In fact, about one third of the known oncogenes encode PTKs, Furthermore, cellular transformation (oncogenesis) is often accompanied by increased tyrosine phosphorylation activity (Charbonneau, H. and N.K. Tonks (1992) Annu.
Rev. Cell Biol.
8:463-493). Regulation of PTK activity may therefore be an important strategy in controlling some types of cancer.
Protein Serine/Threonine Kinases Protein serinelthreonine kinases (STKs) are nontransmembrane proteins. A
subclass of STKs are known as ERKs (extracellular signal regulated kinases) or MAPs (mitogen-activated protein kinases) and are activated after cell stimulation by a variety of hormones and growth factors. Cell stimulation induces a signaling cascade leading to phosphorylation of MEK
(MAP/ERK kinase) which, in turn, activates ERK via serine and threonine phosphorylation. A varied number of proteins represent the downstream effectors for the active ERK and implicate it in the control of cell proliferation and differentiation, as well as regulation of the cytoskeleton. Activation of ERK
is normally transient, and cells possess dual specificity phosphatases that are responsible for its down-regulation. Also, numerous studies have shown that elevated ERK activity is associated with some cancers.
Other STKs include the second messenger dependent protein kinases such as the cyclic-AMP
dependent protein kinases (PKA), calcium-calmodulin (CaM) dependent protein kinases, and the mitogen-activated protein kinases (MAP); the cyclin-dependent protein kinases; checkpoint and cell cycle kinases; Numb-associated kinase (Nak); human Fused (hFu); proliferation-related kinases; 5'-AMP-activated protein kinases; and kinases involved in apoptosis.
The second messenger dependent protein kinases primarily mediate the effects of second messengers such as cyclic AMP (cAMP), cyclic GMP, inositol triphosphate, phosphatidylinositol, 3,4,5-triphosphate, cyclic ADP ribose, arachidonic acid, diacylglycerol and calcium-calmodulin. The PKAs are involved in mediating hormone-induced cellular responses and are activated by cAMP
produced within the cell in response to hormone stimulation. cAMP is an intracellular mediator of hormone action in all animal cells that have been studied. Hormone-induced cellular responses include thyroid hormone secretion, cortisol secretion, progesterone secretion, glycogen breakdown, bone resorption, and regulation of heart rate and force of heart muscle contraction. PKA is found in all animal cells and is thought to account for the effects of cAMP in most of these cells. Altered PKA
expression is implicated in a variety of disorders and diseases including cancer, thyroid disorders, diabetes, atherosclerosis, and cardiovascular disease (Isselbacher, K.J. et al. (1994) Harrison's Principles of Internal Medicine, McGraw-Hill, New York NY, pp. 416-431, 1887).
The casein kinase I (CKI) gene family is another subfamily of serine/threonine protein kinases.
This continuously expanding group of kinases have been implicated in the regulation of numerous cytoplasmic and nuclear processes, including cell metabolism, and DNA
replication and repair. CKI
enzymes are present in the membranes, nucleus, cytoplasm and cytoskeleton of eukaryotic cells, and on the mitotic spindles of mammalian cells (Fish, K.J. et al. (1995) J. Biol.
Chem. 270:14875-14883).
The CKI family members all have a short amino-terminal domain of 9-76 amino acids, a highly conserved kinase domain of 284 amino acids, and a variable carboxyl-terminal domain that ranges from 24 to over 200 amino acids in length (Cegielska, A. et al. (1998) J. Biol.
Chem. 273:1357-1364). The CKI family is comprised of highly related proteins, as seen by the identification of isoforms of casein kinase I from a variety of sources. There are at least five mammalian isoforms, a, (3, y, 8, and s. Fish et al., identified CKI-epsilon from a human placenta cDNA library. It is a basic protein of 416 amino acids and is closest to CKI-delta. Through recombinant expression, it was determined to phosphorylate known CKI substrates and was inhibited by the CKI-specific inhibitor CKI-7.
The human gene for CKI-epsilon was able to rescue yeast with a slow-growth phenotype caused by deletion of the yeast CKI locus, HRR250 (Fish et al., su ra).
The mammalian circadian mutation tau was found to be a semidominant autosomal allele of CKI-epsilon that markedly shortens period length of circadian rhythms in Syrian hamsters. The tau locus is encoded by casein kinase I-epsilon, which is also a homolog of the Drosophila circadian gene double-time. Studies of both the wildtype and tau mutant CKI-epsilon enzyme indicated that the mutant enzyme has a noticeable reduction in the maximum velocity and autophosphorylation state. Further, in vitro, CKI-epsilon is able to interact with mammalian PERIOD proteins, while the mutant enzyme is deficient in its ability to phosphorylate PERIOD. Lowrey et al., have proposed that CKI-epsilon plays a major role in delaying the negative feedback signal within the transcription-translation-based autoregulatory loop that composes the core of the circadian mechanism.
Therefore the CKI-epsilon enzyme is an ideal target for pharmaceutical compounds influencing circadian rhythms, jet-lag and sleep, in addition to other physiologic and metabolic processes under circadian regulation (Lowrey, P.L.
et al. (2000) Science 288:483-491).
Homeodomain-interacting protein kinases (HIPKs) are serine/threonine kinases and novel members of the DYRK kinase subfamily (Hofmann, T.G. et al. (2000) Biochimie 82:1123-1127).
HIPKs contain a conserved protein kinase domain separated from a domain that interacts with homeoproteins. HIPKs are nuclear kinases, and HIPK2 is highly expressed in neuronal tissue (Kim, Y.H. et al. (1998) J. Biol. Chem. 273:25875-25879; Wang, Y. et al. (2001) Biochim. Biophys. Acta 1518:168-172). HIPKs act as corepressors for homeodomian transcription factors. This corepressor activity is seen in posttranslational modifications such as ubiquitination and phosphorylation, each of which are important in the regulation of cellular protein function (Kim, Y.H.
et al, (1999) Proc. Natl.
Acad. Sci. USA 96:12350-12355).
Calcium-Calmodulin Dependent Protein Kinases Calcium-calmodulin dependent (CaM) kinases are involved in regulation of smooth muscle contraction, glycogen breakdown (phosphorylase kinase), and neurotransmission (CaM kinase I and CaM kinase II). CaM dependent protein kinases are activated by calmodulin, an intracellular calcium receptor, in response to the concentration of free calcium in the cell. Many CaM kinases are also activated by phosphorylation. Some CaM kinases are also activated by autophosphorylation or by other regulatory kinases. CaM kinase I phosphorylates a variety of substrates including the neurotransmitter-related proteins synapsin I and II, the gene transcription regulator, CREB, and the cystic fibrosis conductance regulator protein, CFTR (Haribabu, B. et al.
(1995) EMBO J. 14:3679-3686). CaM kinase II also phosphorylates synapsin at different sites and controls the synthesis of catecholamines in the brain through phosphorylation and activation of tyrosine hydroxylase. CaM
kinase II controls the synthesis of catecholamines and seratonin, through phosphorylation/activation of tyrosine hydroxylase and tryptophan hydroxylase, respectively (Fujisawa, H.
(1990) BioEssays 12:27-29). The mRNA encoding a calmodulin-binding protein kinase-like protein was found to be enriched in mammalian forebrain. This protein is associated with vesicles in both axons and dendrites and accumulates largely postnatally. The amino acid sequence of this protein is similar to CaM-dependent STKs, and the protein binds calmodulin in the presence of calcium (Godbout, M.
et al. (1994) J.
Neurosci. 14:1-13).
Mito~en-Activated Protein Kinases The mitogen-activated protein kinases (MAP) which mediate signal transduction from the cell surface to the nucleus via phosphorylation cascades are another STK family that regulates intracellular signaling pathways. Several subgroups have been identified, and each manifests different substrate specificities and responds to distinct extracellular stimuli (Egan, S.E. and R.A. Weinberg (1993) Nature 365:781-783). MAP kinase signaling pathways are present in mammalian cells as well as in yeast. The extracellular stimuli which activate MAP kinase pathways include epidermal growth factor (EGF), ultraviolet light, hyperosmolar medium, heat shock, endotoxic lipopolysaccharide (LPS), and pro-inflammatory cytokines such as tumor necrosis factor (TNF) and interleukin-1 (IL-1). Altered MAP
kinase expression is implicated in a variety of disease conditions including cancer, inflammation, immune disorders, and disorders affecting growth and development.
Cyclin-Dependent Protein Kinases The cyclin-dependent protein kinases (CDKs) are STKs that control the progression of cells through the cell cycle. The entry and exit of a cell from mitosis are regulated by the synthesis and destruction of a family of activating proteins called cyclins. Cyclins are small regulatory proteins that bind to and activate CDKs, which then phosphorylate and activate selected proteins involved in the mitotic process. CDKs are unique in that they require multiple inputs to become activated. In addition to cyclin binding, CDK activation requires the phosphorylation of a specific threonine residue and the dephosphorylation of a specific tyrosine residue on the CDK.
Another family of STKs associated with the cell cycle are the NIMA (never in mitosis)-related kinases (Neks). Both CDKs and Neks are involved in duplication, maturation, and separation of the microtubule organizing center, the centrosome, in animal cells (Fry, A.M. et al. (1998) EMBO J.
17:470-481).
Checkpoint and Cell Cycle Kinases In the process of cell division, the order and timing of cell cycle transitions are under contxol of cell cycle checkpoints, which ensure that critical events such as DNA
replication and chromosome segregation are carried out with precision. If DNA is damaged, e.g. by radiation, a checkpoint pathway is activated that arrests the cell cycle to provide time for repair. If the damage is extensive, apoptosis is induced. In the absence of such checkpoints, the damaged DNA is inherited by aberrant cells which may cause proliferative disorders such as cancer. Protein kinases play an important role in this process.
For example, a specific kinase, checkpoint kinase 1 (Chk1), has been identified in yeast and mammals, and is activated by DNA damage in yeast. Activation of Chkl leads to the arrest of the cell at the G2/M transition (Sanchez, Y. et al. (1997) Science 277:1497-1501).
Specifically, Chk1 phosphorylates the cell division cycle phosphatase CDC25, inhibiting its normal function which is to dephosphorylate and activate the cyclin-dependent kinase Cdc2. Cdc2 activation controls the entry of cells into mitosis (Peng, C.-Y. et al. (1997) Science 277:1501-1505). Thus, activation of Chkl prevents the damaged cell from entering mitosis. A similar deficiency in a checkpoint kinase, such as Chkl, may also contribute to cancer by failure to arrest cells with damaged DNA at other checkpoints such as G2/M.
Proliferation-Related Kinases Proliferation-related kinase is a serum/cytokine inducible STK that is involved in regulation of the cell cycle and cell proliferation in human megakarocytic cells (Li, B. et al. (1996) J. Biol. Chem.
271:19402-19408). Proliferation-related kinase is related to the polo (derived from Drosophila polo gene) family of STKs implicated in cell division. Proliferation-related kinase is downregulated in lung tumor tissue and may be a proto-oncogene whose deregulated expression in normal tissue leads to oncogenic transformation.

5'-AMP-activated protein kinase A ligand-activated STK protein kinase is 5'-AMP-activated protein kinase (AMPK) (Gao, G. et al. (1996) J. Biol Chem. 271:8675-8681). Mammalian AMPK is a regulator of fatty acid and sterol synthesis through phosphorylation of the enzymes acetyl-CoA carboxylase and hydroxymethylglutaxyl-CoA reductase and mediates responses of these pathways to cellular stresses such as heat shock and depletion of glucose and ATP. AMPK is a heterotrimeric complex comprised of a catalytic alpha subunit and two non-catalytic beta and gamma subunits that are believed to regulate the activity of the alpha subunit. Subunits of AMPK have a much wider distribution in non-lipogenic tissues such as brain, heart, spleen, and lung than expected. This distribution suggests that its role may extend beyond regulation of lipid metabolism alone.
Kinases in Apoptosis Apoptosis is a highly regulated signaling pathway leading to cell death that plays a crucial role in tissue development and homeostasis. Deregulation of this process is associated with the pathogenesis of a number of diseases including autoimmune disease, neurodegenerative disorders, and cancer.
Various STKs play key roles in this process. ZIP kinase is an STK containing a C-terminal leucine zipper domain in addition to its N-terminal protein kinase domain. This C-terminal domain appears to mediate homodimerization and activation of the kinase as well as interactions with transcription factors such as activating transcription factor, ATF4, a member of the cyclic-AMP
responsive element binding protein (ATFICREB) family of transcriptional factors (Sanjo, H. et al. (1998) J. Biol. Chem.
273:29066-29071). DRAK1 and DRAK2 are STKs that share homology with the death-associated protein kinases (DAP kinases), known to function in interferon-'y induced apoptosis (Sanjo et al., supra). Like ZIP kinase, DAP kinases contain a C-terminal protein-protein interaction domain, in the form of ankyrin repeats, in addition to the N-terminal kinase domain. ZIP, DAP, and DRAK kinases induce morphological changes associated with apoptosis when transfected into NIH3T3 cells (Sanjo et al., supra). However, deletion of either the N-terminal kinase catalytic domain or the C-terminal domain of these proteins abolishes apoptosis activity, indicating that in addition to the kinase activity, activity in the C-terminal domain is also necessary for apoptosis, possibly as an interacting domain with a regulator or a specific substrate.
RICK is another STK recently identified as mediating a specific apoptotic pathway involving the death receptor, CD95 (Inohara, N. et al. (1998) J. Biol. Chem. 273:12296-12300). CD95 is a member of the tumor necrosis factor receptor superfamily and plays a critical role in the regulation and homeostasis of the immune system (Nagata, S. (1997) Cell 88:355-365). The CD95 receptor signaling pathway involves recruitment of various intracellular molecules to a receptor complex following ligand binding. This process includes recruitment of the cysteine protease caspase-8 which, in turn, activates a caspase cascade leading to cell death. RICK is composed of an N-terminal kinase catalytic domain and a C-terminal "caspase-recruitment" domain that interacts with caspase-like domains, indicating that RICK plays a role in the recruitment of caspase-8. This interpretation is supported by the fact that the expression of RICK in human 293T cells promotes activation of caspase-8 and potentiates the induction of apoptosis by various proteins involved in the CD95 apoptosis pathway (Inohara et al., supra).
Mitochondrial Protein Kinases A novel class of eukaryotic kinases, related by sequence to prokaryotic histidine protein kinases, are the mitochondrial protein kinases (MPKs) which seem to have no sequence similarity with other eukaryotic protein kinases. These protein kinases are located exclusively in the mitochondrial matrix space and may have evolved from genes originally present in respiration-dependent bacteria which were endocytosed by primitive eukaryotic cells. MPI~s are responsible for phosphorylation and inactivation of the branched-chain alpha-ketoacid dehydrogenase and pyruvate dehydrogenase complexes (Harris, R.A. et al. (1995) Adv. Enzyme Regul. 34:147-162). Five MPKs have been identified. Four members correspond to pyruvate dehydrogenase kinase isozymes, regulating the activity of the pyruvate dehydrogenase complex, which is an important regulatory enzyme at the interface between glycolysis and the citric acid cycle. The fifth member corresponds to a branched-chain alpha-ketoacid dehydrogenase kinase, important in the regulation of the pathway for the disposal of branched-chain amino acids. (Harris, R.A. et al. (1997) Adv. Enzyme Regul.
37:271-293). Both starvation and the diabetic state are known to result in a great increase in the activity of the pyruvate dehydrogenase kinase in the liver, heart and muscle of the rat. This increase contributes in both disease states to the phosphorylation and inactivation of the pyruvate dehydrogenase complex and conservation of pyruvate and lactate for gluconeogenesis (Harris (1995) supra).
KINASES WITH NON-PROTEIN SUBSTRATES
Lipid and Inositol kinases Lipid kinases phosphorylate hydroxyl residues on lipid head groups. A family of kinases involved in phosphorylation of phosphatidylinositol (PI) has been described, each member phosphorylating a specific carbon on the inositol ring (Leevers, S.J. et al.
(1999) Curr. Opin. Cell. Biol.
11:219-225). The phosphorylation of phosphatidylinositol is involved in activation of the protein kinase C signaling pathway. The inositol phospholipids (phosphoinositides) intracellular signaling pathway begins with binding of a signaling molecule to a G-protein linked receptor in the plasma membrane.
This leads to the phosphorylation of phosphatidylinositol (PI) residues on the inner side of the plasma membrane by inositol kinases, thus converting PI residues to the biphosphate state (PIP2). PIPZ is then cleaved into inositol triphosphate (IP3) and diacylglycerol. These two products act as mediators for separate signaling pathways. Cellular responses that are mediated by these pathways are glycogen breakdown in the liver in response to vasopressin, smooth muscle contraction in response to acetylcholine, and thrombin-induced platelet aggregation.
PI 3-kinase (PI3K), which phosphorylates the D3 position of PI and its derivatives, has a central role in growth factor signal cascades involved in cell growth, differentiation, and metabolism.

PI3K is a heterodimer consisting of an adapter subunit and a catalytic subunit. The adapter subunit acts as a scaffolding protein, interacting with specific tyrosine-phosphorylated proteins, lipid moieties, and other cytosolic. factors. When the adapter subunit binds tyrosine phosphorylated targets, such as the insulin responsive substrate (IRS)-1, the catalytic subunit is activated and converts PI (4,5) ~bisphosphate (P1P2) to PI (3,4,5) P3 (PIPS). PIPS then activates a number of other proteins, including PKA, protein kinase B (PKB), protein kinase C (PKC), glycogen synthase kinase (GSK)-3, and p70 ribosomal s6 kinase. PI3K also interacts directly with the cytoskeletal organizing proteins, Rac, rho, and cdc42 (Shepherd, P.R. et al. (1998) Biochem. J. 333:471-490). Animal models for diabetes, such as obese and fat mice, have altered PI3K adapter subunit levels. Specific mutations in the adapter subunit have also been found in an insulin-resistant Danish population, suggesting a role for PI3K in type-2 diabetes (Shepard, supra).
An example of lipid kinase phosphorylation activity is the phosphorylation of D-erythro-sphingosine to the sphingolipid metabolite, sphingosine-1-phosphate (SPP). SPP has emerged as a novel lipid second-messenger with both extracellular and intracellular actions (Kohama, T. et al. (1998) J. Biol. Chem. 273:23722-23728). Extracellularly, SPP is a ligand for the G-protein coupled receptor EDG-1 (endothelial-derived, G-protein coupled receptor).
Intracellularly, SPP
regulates cell growth, survival, motility, and cytoskeletal changes. SPP
levels are regulated by sphingosine kinases that specifically phosphorylate D-erythro-sphingosine to SPP. The importance of sphingosine kinase in cell signaling is indicated by the fact that various stimuli, including platelet-derived growth factor (PDGF), nerve growth factor, and activation of protein kinase C, increase cellular levels of SPP by activation of sphingosine kinase, and the fact that competitive inhibitors of the enzyme selectively inhibit cell proliferation induced by PDGF (Kohama et al., supra).
Purine Nucleotide Kinases The purine nucleotide kinases, adenylate kinase (ATP:AMP phosphotransferase, or AdK) and guanylate kinase (ATP:GMP phosphotransferase, or GuK) play a key role in nucleotide metabolism and are crucial to the synthesis and regulation of cellular levels of ATP and GTP, respectively. These two molecules are precursors in DNA and RNA synthesis in growing cells and provide the primary source of biochemical energy in cells (ATP), and signal transduction pathways (GTP).
Inhibition of various steps in the synthesis of these two molecules has been the basis of many antiproliferative drugs for cancer and antiviral therapy (Pillwein, K. et al. (1990) Cancer Res. 50:1576-1579).
AdK is found in almost all cell types and is especially abundant in cells having high rates of ATP synthesis and utilization such as skeletal muscle. In these cells AdK is physically associated with mitochondria and myofibrils, the subcellular structures that are involved in energy production and utilization, respectively. Recent studies have demonstrated a major function for AdK in transferring high energy phosphoryls from metabolic processes generating ATP to cellular components consuming ATP (Zeleznikar, R.J. et al. (1995) J. Biol. Chem. 270:7311-7319). Thus AdK
may have a pivotal role in maintaining energy production in cells, particularly those having a high rate of growth or metabolism such as cancer cells, and may provide a target for suppression of its activity to treat certain cancers.
Alternatively, reduced AdK activity may be a source of various metabolic, muscle-energy disorders that can result in cardiac or respiratory failure and may be treatable by increasing AdK activity.
GuK, in addition to providing a key step in the synthesis of GTP for RNA and DNA synthesis, also fulfills an essential function in signal transduction pathways of cells through the regulation of GDP
and GTP. Specifically, GTP binding to membrane associated G proteins mediates the activation of cell receptors, subsequent intracellular activation of adenyl cyclase, and production of the second messenger, cyclic AMP. GDP binding to G proteins inhibits these processes. GDP
and GTP levels also control the activity of certain oncogenic proteins such as p21~ known to be involved in control of cell proliferation and oncogenesis (Bos, J.L. (1989) Cancer Res. 49:4682-4689). High ratios of GTP:GDP caused by suppression of GuK cause activation of p2lras and promote oncogenesis.
Increasing GuK activity to increase levels of GDP and reduce the GTP:GDP ratio may provide a therapeutic strategy to reverse oncogenesis.
GuK is an important enzyme in the phosphorylation and activation of certain antiviral drugs useful in the treatment of herpes virus infections. These drugs include the guanine homologs acyclovir and buciclovir (Miller, W.H. and R.L. Miller (1980) J. Biol. Chem. 255:7204-7207; Stenberg, K. et al.
(1986) J. Biol. Chem. 261:2134-2139). Increasing GuK activity in infected cells may provide a therapeutic strategy for augmenting the effectiveness of these drugs and possibly for reducing the necessary dosages of the drugs.
Pvrimidine Kinases The pyrimidine kinases are deoxycytidine kinase and thymidine kinase 1 and 2.
Deoxycytidine kinase is located in the nucleus, and thymidine kinase 1 and 2 are found in the cytosol (Johansson, M. et al. (1997) Proc. Natl. Acad. Sci. USA 94:11941-11945). Phosphorylation of deoxyribonucleosides by pyrimidine kinases provides an alternative pathway for de novo synthesis of DNA precursors. The role of pyrimidine kinases, like purine kinases, in phosphorylation is critical to the activation of several chemotherapeutically important nucleoside analogues (Arner E.S. and S.
Eriksson (1995) Pharmacol.
Ther.67:155-186).
The discovery of new human kinases and the polynucleotides encoding them satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention, and treatment of cancer, immune disorders, disorders affecting growth and development, cardiovascular diseases, and lipid disorders, and in the assessment of the effects of exogenous compounds on the expression of nucleic acid and amino acid sequences of human kinases.
SUMMARY OF THE INVENTION
The invention features purified polypeptides, human kinases, referred to collectively as "PKIN"
and individually as "PKIN-1," "PKIN-2," "PKIN-3," "PKIN-4," "PKIN-5," "PHIN-6," "PKIN-7,"
"PI~IN-8," "PKIN-9," "PKIN-10," "PHIN-11," "PKIN-12," "PI~IN-13," "PKIN-14,"
"PHIN-15,"
"PHIN-16," "PKIN-17," "PKIN-18," "PHIN-19," "PKIN-20," "PKIN-21," "PKIN-22,"
"PKIN-23,"
"PKIN-24," "PHIN-25," and "PKIN-26." In one aspect, the invention 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 N0:1-26, 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:1-26, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-26, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID
NO:1-26. In one alternative, the invention provides an isolated polypeptide comprising the amino acid sequence of SEQ
ID NO:1-26.
The invention further 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 ID N0:1-26, 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 N0:1-26, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID N0:1-26, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID N0:1-26. In one alternative, the polynucleotide encodes a polypeptide selected from the group consisting of SEQ
ID N0:1-26. In another alternative, the polynucleotide is selected from the group consisting of SEQ ID N0:27-52.
Additionally, the invention 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 ID
N0:1-26, 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 N0:1-26, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID N0:1-26, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-26. In one alternative, the invention provides a cell transformed with the recombinant polynucleotide. In another alternative, the invention provides a transgenic organism comprising the recombinant polynucleotide.
The invention also 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:1-26, 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:1-26, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID N0:1-26, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-26. 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.
Additionally, the invention 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:1-26, 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 N0:1-26, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID N0:1-26, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-26.
The invention further 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
N0:27-52, 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 N0:27-52, 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 one alternative, the polynucleotide comprises at least 60 contiguous nucleotides.
Additionally, the invention provides a method for detecting a target polynucleotide in a sample, said target polynucleotide having a sequence of a polynucleotide selected from the group consisting of a) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID
N0:27-52, 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 N0:27-52, 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, and optionally, if present, the amount thereof. In one alternative, the probe comprises at least 60 contiguous nucleotides.
The invention further provides a method for detecting a target polynucleotide in a sample, said target polynucleotide having a sequence of a polynucleotide selected from the group consisting of a) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID
N0:27-52, 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 N0:27-52, 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, and, optionally, if present, the amount thereof.
The invention further 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:l-26, 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 N0:1-26, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID N0:1-26, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID
NO:1-26, and a pharmaceutically acceptable excipient In one embodiment, the composition comprises an amino acid sequence selected from the group consisting of SEQ ID NO:1-26. The invention additionally provides a method of treating a disease or condition associated with decreased expression of functional PKIN, comprising administering to a patient in need of such treatment the composition.
The invention also 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 N0:1-26, 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 N0:1-26, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-26, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID
NO:1-26. The method comprises a) exposing a sample comprising the polypeptide to a compound, and b) detecting agonist activity in the sample. In one alternative, the invention provides a composition comprising an agonist compound identified by the method and a pharmaceutically acceptable excipient. In another alternative, the invention provides a method of treating a disease or condition associated with decreased expression of functional PKIN, comprising administering to a patient in need of such treatment the composition.
Additionally, the invention 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 ID N0:1-26, 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 N0:1-26, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID N0:1-26, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID N0:1-26. The method comprises a) exposing a sample comprising the polypeptide to a compound, and b) detecting antagonist activity in the sample.
In one alternative, the invention provides a composition comprising an antagonist compound identified by the method and a pharmaceutically acceptable excipient. In another alternative, the invention provides a method of treating a disease or condition associated with overexpression of functional PI~IN, comprising administering to a patient in need of such treatment the composition.
The invention further 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 ID N0:1-26, 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:1-26, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-26, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID
NO:I-26. 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.
The invention further 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 ID N0:1-26, 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 N0:1-26, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-26, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID

N0:1-26. 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.
The invention further provides a method for screening a compound for effectiveness in altering expression of a target polynucleotide, wherein said target polynucleotide comprises a sequence selected from the group consisting of SEQ ID N0:27-52, the method comprising a) exposing a sample comprising the target polynucleotide to a compound, and b) detecting altered expression of the target polynucleotide.
The invention further 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 N0:27-52, ii) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 90% identical to a polynucleotide sequence selected from the group consisting of SEQ ID N0:27-52, 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
N0:27-52, ii) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 90%
identical to a polynucleotide sequence selected from the group consisting of SEQ ID N0:27-52, 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 comprises a fragment of a polynucleotide sequence 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 the full length polynucleotide and polypeptide sequences of the present invention.
Table 2 shows the GenBank identification number and annotation of the nearest GenBank homolog for polypeptides of the invention. The probability score for the match between each polypeptide and its GenBank homolog is also shown.
Table 3 shows structural features of polypeptide sequences of the invention, 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 sequences of the invention, along with selected fragments of the polynucleotide sequences.
Table 5 shows the representative cDNA library for polynucleotides of the invention.
Table 6 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 the polynucleotides and polypeptides of the invention, along with applicable descriptions, references, and threshold parameters.
DESCRIPTION OF THE INVENTION
Before the present proteins, nucleotide sequences, and methods are described, it is understood that this invention is not limited to the particular machines, 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 present invention which will be limited only by the appended claims.
It must be noted that 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 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
"PKIN" refers to the amino acid sequences of substantially purified PKIN
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 PKIN. Agonists may include proteins, nucleic acids, carbohydrates, small molecules, or any other compound or composition which modulates the activity of PKIN either by directly interacting with PKIN or by acting on components of the biological pathway in which PKIN
participates.
An "allelic variant" is an alternative form of the gene encoding PKIN. Allelic variants may result from at least one mutation in the nucleic acid sequence and may result i~ 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 PKIN include those sequences with deletions, insertions, or substitutions of different nucleotides, resulting in a polypeptide the same as PI~IN or a polypeptide with at least one functional characteristic of PKIN. Included within this definition are polymorphisms which may or may not be readily detectable using a particular oligonucleotide probe of the polynucleotide encoding PKIN, and improper or unexpected hybridization to allelic variants, with a locus other than the normal chromosomal locus for the polynucleotide sequence encoding PKIN. 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 PKIN. Deliberate amino acid substitutions may be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity, and/or the amphipathic nature of the residues, as long as the biological or immunological activity of PKIN 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" refer to an oligopeptide, peptide, polypeptide, or 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 sequence.
Amplification is generally carried out using polymerise chain reaction (PCR) technologies well known in the art.
The term "antagonist" refers to a molecule which inhibits or attenuates the biological activity of PHIN. Antagonists may include proteins such as antibodies, nucleic acids, carbohydrates, small molecules, or any other compound or composition which modulates the activity of PKIN either by directly interacting with PKIN ox by acting on components of the biological pathway in which PKIN
participates.
The term "antibody" refers to intact immunoglobulin molecules as well as to fragments thereof, such as Fab, F(ab')2, and Fv fragments, which are capable of binding an epitopic determinant.
Antibodies that bind PKIN 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 (I~L,H). 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 "antisense" refers to any composition capable of base-pairing with the "sense"
(coding) strand of 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 PKIN, 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 sequence" and a "composition comprising a given amino acid sequence" refer broadly to any composition containing the given polynucleotide or amino acid sequence. The composition may comprise a dry formulation or an aqueous solution.
Compositions comprising polynucleotide sequences encoding PKIN or fragments of PKIN may be employed as hybridization probes. The pxobes 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., NaCl), 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 S' 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 (GCG, Madison WI) 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 hydrogenby 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.
A "fragment" is a unique portion of PKIN or the polynucleotide encoding PKIN
which is 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 5 to 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 500 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 N0:27-52 comprises a region of unique polynucleotide sequence that specifically identifies SEQ ID N0:27-52, for example, as distinct from any other sequence in the genome from which the fragment was obtained. A fragment of SEQ ID N0:27-52 is useful, for example, in hybridization and amplification technologies and in analogous methods that distinguish SEQ ID N0:27-52 from related polynucleotide sequences. The precise length of a fragment of SEQ
ID N0:27-52 and the region of SEQ ID N0:27-52 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 ID NO:1-26 is encoded by a fragment of SEQ ID NO:27-52. A
fragment of SEQ ID N0:1-26 comprises a region of unique amino acid sequence that specifically identifies SEQ ID NO:1-26. For example, a fragment of SEQ ID NO:l-26 is useful as an immunogenic peptide for the development of antibodies that specifically recognize SEQ ID NO:l-26.
The precise length of a fragment of SEQ ID N0:1-26 and the region of SEQ ID N0:1-26 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 "full length" polynucleotide sequence 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" polypeptide sequence.
"Homology" refers to sequence similarity or, interchangeably, 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 residue matches between at least two polynucleotide sequences aligned using a standardized algorithm. Such an algoritlun 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 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. Percent identity is reported by CLUSTAL V as the "percent similarity" between aligned polynucleotide sequences.
Alternatively, a suite of commonly used and freely available sequence comparison algorithms 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 NCB, Bethesda, MD, and on the Internet at http://www.ncbi.nlm.nih.gov/BLAST/. 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 Opefa Gap: 5 and Extension Gap: 2 penalties Gap x drop-off. 50 Expect: 10 Word Size: 11 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 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.
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. As with polynucleotide alignments, the percent identity is reported by CLUSTAL V as the "percent similarity"
between aligned polypeptide sequence pairs.
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:
Matrix: BLOSUM62 Opefa Gap: 11 and Exter2sion Gap: 1 penalties Gap x drop-off.' S0 Expect: 10 Word Size: 3 Filter: ort 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 50, 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/mI 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 Tm 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 'Tin and conditions for nucleic acid hybridization are well known and can be found in Sambrook, J.
et al. (1989) Molecular Cloning: A Laboratory Manual, 2"d ed., vol. 1-3, Cold Spring Harbor Press, Plainview NY; specifically see volume 2, chapter 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 ~ g/ml. Organic solvent, such as formamide at a concentration of about 35-50% vlv, 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 acid sequences 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 sequence present in solution and another nucleic acid sequence 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 nucleotide 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 PKIN
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 PI~IN which is useful in any of the antibody production methods disclosed herein or known in the art.
The term "microaxray" refers to an arrangement of a plurality of polynucleotides, polypeptides, or other chemical compounds on a substrate.
The terms "element" and "array element" refer to a polynucleotide, polypeptide, or other chemical compound having a unique and defined position on a microarray.
The term "modulate" refers to a change in the activity of PHIN. For example, modulation may cause an increase or a decrease in protein activity, binding characteristics, or any other biological, functional, or immunological properties of PI~IN.
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 PHIN 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 PHIN.
"Probe" refers to nucleic acid sequences encoding PHIN, their complements, or fragments thereof, which are used to detect identical, allelic or related nucleic acid sequences. 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
polymerase enzyme. Primer pairs can be used for amplification (and identification) of a nucleic acid sequence, e.g., by the polymerase 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 the references, for example Sambrook, J. et al. (1989) Molecular Cloning: A Laboratorv Manual, 2nd ed., vol. 1-3, Cold Spring Harbor Press, Plainview NY; Ausubel, F.M. et al. (1987) Current Protocols in Molecular Biolo~y, Greene Publ. Assoc. & Wiley-Intersciences, New York NY; 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/MIT 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 sequence 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, 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 sequence, is composed of the same linear sequence of nucleotides as the reference DNA sequence 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 PKIN, nucleic acids encoding PI~IN, 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 antagonists 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 60% free, preferably at least 75% free and most preferably at least 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" 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. 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 et al. (1989), 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 alternative 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 polynucleotide sequences 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 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 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 of one of the polypeptides.
THE INVENTION
The invention is based on the discovery of new human human kinases (PHIN), the polynucleotides encoding PKIN, and the use of these compositions for the diagnosis, treatment, or prevention of cancer, immune disorders, disorders affecting growth and development, cardiovascular diseases, and lipid disorders.
Table 1 summarizes the nomenclature for the full length polynucleotide and polypeptide sequences 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.
Table 2 shows sequences with homology to the polypeptides of the invention as identified by BLAST analysis against the GenBank protein (genpept) database. Columns 1 and 2 show the polypeptide sequence identification number (Polypeptide SEQ ID 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.
Column 4 shows the probability score for the match between each polypeptide and its GenBank homolog. Column 5 shows the annotation of the GenBank homolog 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 ID 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 column 5 shows potential glycosylation sites, as determined by the MOTIFS
program of the GCG sequence analysis software package (Genetics Computer Group, Madison WI).

Column 6 shows amino acid residues comprising signature sequences, domains, and motifs. Column 7 shows analytical methods for protein structure/funct~on 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 human kinases. For example, SEQ ID N0:4 is 94% identical to rat serinelthreonine kinase (GenBank ID 82052189) 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 N0:4 also contains a protein kinase domain as determined by searching for statistically significant matches in 20 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 ID N0:4 is a protein kinase. In an alternate example, SEQ ID
NO: 23 is 88%
identical to murine protein kinase (GenBank ID 8406058) 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 N0:23 also contains an eukaryotic protein kinase 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 ID N0:23 is a protein kinase. In an alternate example, SEQ ID N0:6 is 85% identical to rabbit myosin light chain kinase (GenBank ID 8165506) as determined by the Basic Local Alignment Search Tool (BLAST). (See Table 2.) The BLAST probability score is 1.5e-272, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance.
SEQ ID N0:6 also contains a eukaryotic protein kinase 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 MOTIFS
analyses provide further corroborative evidence that SEQ ID N0:6 is a myosin light chain kinase. In an alternate example, SEQ ID N0:1 is 64% identical to murine serine/threonine kinase (GenBank ID 8404634) as determined by the Basic Local Alignment Search Tool (BLAST). (See Table 2.) The BLAST
probability score is 4.5e-60, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance. SEQ ID N0:1 also contains a protein kinase 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 MOTIFS, BLIMPS and PROFILESCAN analyses provide further corroborative evidence that SEQ ID NO:l is a protein kinase, notably a serine/threonine kinase. In an alternate example, SEQ ID
N0:19 is 49% identical to human G-protein-coupled receptor kinase GRK4-beta (GenBank ID 8992672) as determined by the Basic Local Alignment Search Tool (BLAST). (See Table 2.) The BLAST
probability score is 4.3e-129, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance. SEQ ID N0:19 also contains a regulator of G-protein signaling 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 ID N0:19 is a G-protein-coupled receptor kinase. SEQ ID N0:2-3, SEQ ID NO:S, SEQ ID N0:7-18, SEQ ID
N0:20-22 and SEQ ID N0:24-26 were analyzed and annotated in a similar manner. The algorithms and parameters for the analysis of SEQ ID NO:l-26 are described in Table 7.
As shown in Table 4, the full length polynucleotide sequences of the present invention were assembled using cDNA sequences or coding (exon) sequences derived from genomic DNA, or any combination of these two types of sequences. Columns l and 2 list the polynucleotide sequence identification number (Polynucleotide SEQ ID NO:) and the corresponding Incyte polynucleotide consensus sequence number (Incyte Polynucleotide ID) for each polynucleotide of the invention..
Column 3 shows the length of each polynucleotide sequence in basepairs. Column 4 lists fragments of the polynucleotide sequences which are useful, for example, in hybridization or amplification technologies that identify SEQ ID N0:27-52 or that distinguish between SEQ ID
N0:27-52 and related polynucleotide sequences. Column 5 shotws identification numbers corresponding to cDNA
sequences, coding sequences (exons) predicted from genomic DNA, and/or sequence assemblages comprised of both cDNA and genomic DNA. These sequences were used to assemble the full length polynucleotide sequences of the invention. Columns 6 and 7 of Table 4 show the nucleotide start (5') and stop (3') positions of the cDNA andlor genomic sequences in column 5 relative to their respective full length sequences.
The identification numbers in Column 5 of Table 4 may refer specifically, for example, to Incyte cDNAs along with their corresponding cDNA libraries. For example, 6829315H1 is the identification number of an Incyte cDNA sequence, and SINTNOR01 is the cDNA
library from which it is derived. Incyte cDNAs for which cDNA libraries are not indicated were derived from pooled cDNA libraries (e.8., 55057226H1). Alternatively, the identification numbers in column 5 may refer to GenBank cDNAs or ESTs (e.8., 82954208) which contributed to the assembly of the full length polynucleotide sequences. In addition, the identification numbers in column 5 may identify sequences derived from the ENSEMBL (The Sanger Centre, Cambridge, UK) database (i.e., those sequences including the designation "ENST"). Alternatively, the identification numbers in column 5 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 identification numbers in column 5 may refer to assemblages of both cDNA and Genscan-predicted exons brought together by an "exon stitching"
algorithm. For example, FL XXh:XXX NI N~ YYYYY N3 Nø represents a "stitched"
sequence in which XXXXXX is the identification number of the cluster of sequences to which the algorithm was applied, and YYYYI' is the number of the prediction generated by the algorithm, and N1,2.3...> if present, represent specific exons that may have been manually edited during analysis (See Example V).
Alternatively, the identification numbers in column 5 may refer to assemblages of exons brought together by an "exon-stretching" algorithm. For example, FLXXXXXX
gAAAAA_gBBBBB_1 N is the identification number of 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, ENST for example, 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).

In some cases, Incyte cDNA coverage redundant with the sequence coverage shown in column 5 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 polynucleotide sequences 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 polynucleotide sequences. The tissues and vectors which were used to construct the cDNA libraries shown in Table 5 are described in Table 6.
The invention also encompasses PKIN variants. A preferred PKIN variant is one which has at least about 80%, or alternatively at least about 90%, or even at least about 95% amino acid sequence identity to the PKIN amino acid sequence, and which contains at least one functional or structural characteristic of PKIN.
The invention also encompasses polynucleotides which encode PKIN. In a particular embodiment, the invention encompasses a polynucleotide sequence comprising a sequence selected from the group consisting of SEQ ID N0:27-52, which encodes PKIN. The polynucleotide sequences of SEQ ID NO:27-52, 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 a variant of a polynucleotide sequence encoding PKIN. In particular, such a variant polynucleotide sequence will have at least about 70%, or alternatively at least about 85%, or even at least about 95% polynucleotide sequence identity to the polynucleotide sequence encoding PKIN. A particular aspect of the invention encompasses a variant of a polynucleotide sequence compxising a sequence selected from the group consisting of SEQ ID
N0:27-52 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 N0:27-52.
Any one of the polynucleotide variants described above can encode an amino acid sequence which contains at least one functional or structural characteristic of PKIN.
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 PKIN, 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 PI~iN, and all such variations are to be considered as being specifically disclosed.
Although nucleotide sequences which encode PKIN and its variants are generally capable of hybridizing to the nucleotide sequence of the naturally occurring PHIN under appropriately selected conditions of stringency, it may be advantageous to produce nucleotide sequences encoding PHIN 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 PKIN
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 DNA sequences which encode PKIN
and PKIN
derivatives, or fragments thereof, entirely by synthetic chemistry. After production, the synthetic sequence 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 sequence encoding PKIN or any fragment thereof.
Also encompassed by the invention are polynucleotide sequences that are capable of hybridizing to the claimed polynucleotide sequences, and, in particular, to those shown in SEQ ID
N0:27-52 and fragments thereof under various conditions of stringency. (See, e.g., Wahl, G.M. and S.L. Berger (1987) Methods Enzymol. 152:399-407; I~immel, 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 Pharmacia Biotech, Piscataway NJ), or combinations of polymerases and proofreading exonucleases such as those found in the ELONGASE
amplification system (Life Technologies, Gaithersburg MD). 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 CATALYST 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 (Molecular Dynamics, Sunnyvale CA), or other systems known in the art. The resulting sequences are analyzed using a variety of algorithms which are well known in the art. (See, e.g., Ausubel, F.M. (1997) Short Protocols in Molecular Biolo~y, John Wiley & Sons, New York NY, unit 7.7; Meyers, R.A.
(1995) Molecular Biology and Biotechnolo~y, Wiley VCH, New York NY, pp. 856-853.) The nucleic acid sequences encoding PKIN 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. (See, e.g., 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. (See, e.g., 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. (See, e.g., 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. (See, e.g., 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, polynucleotide sequences or fragments thereof which encode PKIN may be cloned in recombinant DNA molecules that direct expression of PHIN, or fragments or functional equivalents thereof, in appropriate host cells. Due to the inherent degeneracy of the genetic code, other DNA sequences which encode substantially the same or a functionally equivalent amino acid sequence may be produced and used to express PKIN.
The nucleotide sequences of the present invention can be engineered using methods generally known in the art in order to alter PHIN-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 Number 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 PKIN, 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 selectionlscreening. 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, sequences encoding PKIN may be synthesized, in whole or in part, using chemical methods well known in the art. (See, e.g., Caruthers, M.H. et al. (1980) Nucleic Acids Symp. Ser. 7:215-223; and Horn, T. et al. (1980) Nucleic Acids Symp. Ser.
7:225-232.) Alternatively, PKIN itself or a fragment thereof may be synthesized using chemical methods.
For example, peptide synthesis can be performed using various solution-phase or solid-phase techniques. (See, e.g., Creighton, T. (1984) Proteins, Structures and Molecular Properties, WH
Freeman, New York NY, pp.
55-60; and 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 PKIN, 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. (See, e.g., 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.
(See, e.g., Creighton, sera, pp. 28-53.) In order to express a biologically active PKIN, the nucleotide sequences encoding PKIN 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 polynucleotide sequences encoding PKIN. Such elements may vary in their strength and specificity.
Specific initiation signals may also be used to achieve more efficient translation of sequences encoding PKIN. Such signals include the ATG initiation codon and adjacent sequences, e.g. the Kozak sequence. In cases where sequences encoding PKIN 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. (See, e.g., 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 sequences encoding PHIN and appropriate transcriptional and translational control elements. These methods include in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic recombination. (See, e.g., Sambrook, J. et al. (1989) Molecular Cloning, A Laboratory Manual, Cold Spring Harbor Press, Plainview NY, ch. 4, 8, and 16-17; Ausubel, F.M. et al. (1995) Current Protocols in Molecular Biolo~y, John Wiley & Sons, New York NY, ch. 9, 13, and 16.) A variety of expression vector/host systems may be utilized to contain and express sequences encoding PI~IN. 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. (See, e.g., Sambrook, su ra; Ausubel, 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. 6:307-311; 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; and 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 nucleotide sequences to the targeted organ, tissue, or cell population. (See, e.g., Di Nicola, M. et al. (1998) Cancer Gen. Ther. 5(6):350-356; Yu, M. et al. (1993) Proc. Natl. Acad. Sci.
USA 90(13):6340-6344; Buller, R.M. et al. (1985) Nature 317(6040):813-815;
McGregor, D.P. et al.
(1994) Mol. Immunol. 31(3):219-226; and 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 polynucleotide sequences encoding PKIN. For example, routine cloning, subcloning, and propagation of polynucleotide sequences encoding PKIN can be achieved using a multifunctional E. coli vector such as PBLUESCRIPT (Stratagene, La Jolla CA) or PSPORT1 plasmid (Life Technologies). Ligation of sequences encoding PKIN 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. (See, e.g., Van Heeke, G. and S.M. Schuster (1989) J. Biol. Chem.
264:5503-5509.) When large quantities of PKIN are needed, e.g. for the production of antibodies, vectors which direct high level expression of PKIN 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 PKIN. 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 ~astoris. In addition, such vectors direct either the secretion or intracellular retention of expressed proteins and enable integration of foreign sequences into the host genome for stable propagation. (See, e.g., Ausubel, 1995, supra;
Bitter, G.A. et al. (1987) Methods Enzymol. 153:516-544; and Scorer, C.A. et al. (1994) Bio/Technology 12:181-184.) Plant systems may also be used for expression of PKIN. Transcription of sequences encoding PKIN 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. (See, e.g., Coruzzi, G. et al. (1984) EMBO J. 3:1671-1680; Brogue, R. et al. (1984) Science 224:838-843; and 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. (See, e.g., 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, sequences encoding PHIN
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 PHIN in host cells. (See, e.g., 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. (See, e.g., Harrington, J.J. et al.
(1997) Nat. Genet. 15:345-355.) For long term production of recombinant proteins in mammalian systems, stable expression of PKIN in cell lines is preferred. For example, sequences encoding PKIN can be transformed into cell lines using expression vectors which may contain viral origins of replication and/or 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 apr= cells, respectively. (See, e.g., 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; Tzeo confers resistance to the aminoglycosides neomycin and G-418; and als and pat confer resistance to chlorsulfuron and phosphinotricin acetyltransferase, respectively. (See, e.g., 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. (See, e.g., 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),13 glucuronidase and its substrate 13-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. (See, e.g., Rhodes, C.A.
(1995) Methods Mol. Biol. 55:121-131.) Although the presencelabsence 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 PKIN is inserted within a marker gene sequence, transformed cells containing sequences encoding PKIN can be identified by the absence of marker gene function. Alternatively, a marker gene can be placed in tandem with a sequence encoding PKIN 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 nucleic acid sequence encoding PKIN
and that express.
PKIN 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 PI~IN
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 PKIN is preferred, but a competitive binding assay may be employed. These and other assays are well known in the art. (See, e.g., 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; and 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 PKIN
include oligolabeling, nick translation, end-labeling, or PCR amplification using a labeled nucleotide. Alternatively, the sequences encoding PKIN, 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 Pharmacia Biotech, 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 nucleotide sequences encoding PKIN 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 PKIN may be designed to contain signal sequences which direct secretion of PKIN 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 sequences. or to process the expressed protein in the desired fashion. Such modifications of the polypeptide include, but are riot 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 nucleic acid sequences encoding PKIN 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 PKIN protein containing a heterologous moiety that can be recognized by a commercially available antibody may facilitate the screening of peptide libraries for inhibitors of PKIN activity. Heterologous protein and peptide moieties may also facilitate purification of fusion proteins using commercially available afFnity 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 PKIN encoding sequence and the heterologous protein sequence, so that PKIN may be cleaved away from the heterologous moiety following purification. Methods for fusion protein expression and purification are discussed in Ausubel (1995, supra, ch. 10). A
variety of commercially available kits may also be used to facilitate expression and purification of fusion proteins.
In a further embodiment of the invention, synthesis of radiolabeled PKIN 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.
PI~IN of the present invention or fragments thereof may be used to screen for compounds that specifically bind to PKIN. At least one and up to a plurality of test compounds may be screened for specific binding to PHIN. Examples of test compounds include antibodies, oligonucleotides, proteins (e.g., receptors), or small molecules.
In one embodiment, the compound thus identified is closely related to the natural ligand of PKIN, e.g., a ligand or fragment thereof, a natural substrate, a structural or functional mimetic, or a natural binding partner. (See, e.g., Coligan, J.E. et al. (1991) Current Protocols in Immunolo~y 1(2):
Chapter S.) Similarly, the compound can be closely related to the natural receptor to which PKIN
binds, or to at least a fragment of the receptor, e.g., the ligand binding site. In either case, the compound can be rationally designed using known techniques. In one embodiment, screening for these compounds involves producing appropriate cells which express PKIN, either as a secreted protein or on the cell membrane. Preferred cells include cells from mammals, yeast, Drosophila, or E.
coli. Cells expressing PKIN or cell membrane fractions which contain PKIN are then contacted with a test compound and binding, stimulation, or inhibition of activity of either PKIN 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 PHIN, either in solution or affixed to a solid support, and detecting the binding of PHIN 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.
PKIN of the present invention or fragments thereof may be used to screen for compounds that modulate the activity of PKIN. Such compounds may include agonists, antagonists, or partial or inverse agonists. In one embodiment, an assay is performed under conditions permissive for PKIN
activity, wherein PKIN is combined with at least one test compound, and the activity of PKIN in the presence of a test compound is compared with the activity of PKIN in the absence of the test compound.
A change in the activity of PKIN in the presence of the test compound is indicative of a compound that modulates the activity of PKIN. Alternatively, a test compound is combined with an in vitro or cell-free system comprising PKIN under conditions suitable for PKiN activity, and the assay is performed. In either of these assays, a test compound which modulates the activity of PKIN 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 PKIN 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 Number 5,175,383 and U.S. Patent Number 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-loxP
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 PKIN 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 PKIN 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 PKIN 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 PKIN, e.g., by secreting PKIN 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 PHIN and human kinases. In addition, the expression of PHIN
is closely associated with lipid disorders, pancreatic islet cells, liver disease, leukocytes, umbilical endothelial cells, cancer, as well as, normal and diseased brain, renal, reproductive, bladder tumor, posterior hippocampus, kidney, small intestine, colon, and digestive tissues. Therefore, PKIN appears to play a role in cancer, immune disorders, disorders affecting growth and development, cardiovascular diseases, and lipid disorders. In the treatment of disorders associated with increased PKIN expression or activity, it is desirable to decrease the expression or activity of PI~IN. In the treatment of disorders associated with decreased PKIN expression or activity, it is desirable to increase the expression or activity of PI~iN.
IS Therefore, in one embodiment, PKIN 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 PKIN.
Examples of such disorders include, but are not linuted to, a cancer, such as adenocarcinoma, leukemia, lymphoma, melanoma, myeloma, sarcoma, teratocarcinoma, and, in particular,, cancers 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, leukemias such as multiple myeloma and lymphomas such as Hodgkin's disease; an immune disorder, such as acquired immunodeficiency syndrome (AIDS), Addison's disease, adult respiratory distress syndrome, allergies, ankylosing spondylitis, amyloidosis, anemia, asthma, atherosclerosis, autoimmune hemolytic anemia, autoimmune thyroiditis, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), bronchitis, cholecystitis, contact dermatitis, Crohn's disease, atopic dermatitis, dermatomyositis, diabetes mellitus, emphysema, episodic lymphopenia with lymphocytotoxins, erythroblastosis fetalis, erythema nodosum, atrophic gastritis, glomerulonephritis, Goodpasture's syndrome, gout, Graves' disease, Hashimoto's thyroiditis, hypereosinophilia, irritable bowel syndrome, multiple sclerosis, myasthenia gravis, myocardial or pericardial inflammation, osteoarthritis, osteoporosis, pancreatitis, polymyositis, psoriasis, Reiter's syndrome, rheumatoid arthritis, scleroderma, Sjogren's syndrome, systemic anaphylaxis, systemic lupus erythematosus, systemic sclerosis, thrombocytopenic purpura, ulcerative colitis, uveitis, Werner syndrome, complications of cancer, hemodialysis, and extracorporeal circulation, viral, bacterial, fungal, parasitic, protozoal, and helminthic infections, and trauma; a growth and developmental 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 cancers including adenocarcinoma, leukemia, lymphoma, melanoma, myeloma, sarcoma, teratocarcinoma, and, in particular, cancers 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, renal tubular acidosis, anemia, Cushing's syndrome, achondroplastic dwarfism, Duchenne and Becker muscular dystrophy, epilepsy, gonadal dysgenesis, WAGR syndrome (Wilms' tumor, aniridia, genitourinary abnormalities, and mental retardation), Smith-Magenis syndrome, myelodysplastic syndrome, hereditary mucoepithelial dysplasia, hereditary keratodermas, hereditary neuropathies such as Charcot-Marie-Tooth disease and neurofibromatosis, hypothyroidism, hydrocephalus, seizure disorders such as Syndenham's chorea and cerebral palsy, spina bifida, anencephaly, craniorachischisis, congenital glaucoma, cataract, and sensorineural hearing loss; a cardiovascular disease, such as arteriovenous fistula, atherosclerosis, hypertension, vasculitis, Raynaud's disease, aneurysms, arterial dissections, varicose veins, thrombophlebitis and phlebothrombosis, vascular tumors, and complications of thrombolysis, balloon angioplasty, vascular replacement, and coronary artery bypass graft surgery, congestive heart failure, ischemic heart disease, angina pectoris, myocardial infarction, hypertensive heart disease, degenerative valvular heart disease, calcific aortic valve stenosis, congenitally bicuspid aortic valve, mitral annular calcification, mitral valve prola~se, rheumatic fever and rheumatic heart disease, infective endocarditis, nonbacterial thrombotic endocarditis, endocarditis of systemic lupus erythematosus, carcinoid heart disease, cardiomyopathy, myocarditis, pericarditis, neoplastic heart disease, congenital heart disease, and complications of cardiac transplantation, congenital lung anomalies, atelectasis, pulmonary congestion and edema, pulmonary embolism, pulmonary hemorrhage, pulmonary infarction, pulmonary hypertension, vascular sclerosis, obstructive pulmonary disease, restrictive pulmonary disease, chronic obstructive pulmonary disease, emphysema, chronic bronchitis, bronchial asthma, bronchiectasis, bacterial pneumonia, viral and mycoplasmal pneumonia, lung abscess, pulmonary tuberculosis, diffuse interstitial diseases, pneumoconioses, sarcoidosis, idiopathic pulmonary fibrosis, desquamative interstitial pneumonitis, hypersensitivity pneumonitis, pulmonary eosinophilia bronchiolitis obliterans-organizing pneumonia, diffuse pulmonary hemorrhage syndromes, Goodpasture's syndromes, idiopathic pulmonary hemosiderosis, pulmonary involvement in collagen-vascular disorders, pulmonary alveolar proteinosis, lung tumors, inflammatory and noninflammatory pleural effusions, pneumothorax, pleural tumors, drug-induced lung disease, radiation-induced lung disease, and complications of lung transplantation; and a lipid disorder, such as fatty liver, cholestasis, primary biliary cirrhosis, carnitine deficiency, carnitine palmitoyltransferase deficiency, myoadenylate deaminase deficiency, hypertriglyceridemia, lipid storage disorders such Fabry's disease, Gaucher's disease, Niemann-Pick's disease, metachromatic leukodystrophy, adrenoleukodystrophy, GMZ
gangliosidosis, and ceroid lipofuscinosis, abetalipoproteinemia, Tangier disease, hyperlipoproteinemia, diabetes mellitus, lipodystrophy, lipomatoses, acute panniculitis, disseminated fat necrosis, adiposis dolorosa, lipoid adrenal hyperplasia, minimal change disease, lipomas, atherosclerosis, hypercholesterolemia, hypercholesterolemia with hypertriglyceridemia, primary hypoalphalipoproteinemia, hypothyroidism, renal disease, liver disease, lecithin:cholesterol acyltransferase deficiency, cerebrotendinous xanthomatosis, sitosterolemia, hypocholesterolemia, Tay-Sachs disease, Sandhoff's disease, hyperlipidemia, hyperlipemia, lipid myopathies, and obesity.
In another embodiment, a vector capable of expressing PKIN 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 PKIN including, but not limited to, those described above.
In a further embodiment, a composition comprising a substantially purified PKIN 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 PKIN including, but not limited to, those provided above.
In still another embodiment, an agonist which modulates the activity of PKIN
may be administered to a subject to treat or prevent a disorder associated with decreased expression or activity of PKIN including, but not limited to, those listed above.
In a further embodiment, an antagonist of PKIN may be administered to a subject to treat or prevent a disorder associated with increased expression or activity of PKIN.
Examples of such disorders include, but are not limited to, those cancer, immune disorders, disorders affecting growth and development, cardiovascular diseases, and lipid disorders described above. In one aspect, an antibody which specifically binds PKIN 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 PKIN.
In an additional embodiment, a vector expressing the complement of the polynucleotide encoding PKIN may be administered to a subject to treat or prevent a disorder associated with increased expression or activity of PKIN including, but not limited to, those described above.
In other embodiments, any of the proteins, antagonists, antibodies, agonists, complementary sequences, or vectors of the invention 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 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 PI~IN may be produced using methods which are generally known in the art.
In particular, purified PKIN may be used to produce antibodies or to screen libraries of pharmaceutical agents to identify those which specifically bind PKIN. Antibodies to PI~IN 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. Neutralizing antibodies (i.e., those which inhibit dimer formation) are generally preferred for therapeutic use.
For the production of antibodies, various hosts including goats, rabbits, rats, mice, humans, and others may be immunized by injection with PKIN 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 PKIN
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 identical to a portion of the amino acid sequence of the natural protein.
Short stretches of PI~IN amino acids may be fused with those of another protein, such as KhH, and antibodies to the chimeric molecule may be produced.
Monoclonal antibodies to PI~IN 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. (See, e.g., Kohler, G. et al. (1975) Nature 256:495-497; I~ozbor, D. et al. (1985) J.
Immunol. Methods 81:31-42; Cote, R.J. et al. (1983) Proc. Natl. Acad. Sci. USA
80:2026-2030; and 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. (See, e.g., Morrison, S.L. et al. (1984) Proc.
Natl. Acad. Sci. USA 81:6851-6855; Neuberger, M.S. et al. (1984) Nature 312:604-608; and 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 PKIN-specific single chain antibodies. Antibodies with related specificity, but of distinct idiotypic composition, may be generated by chain shuffling from random combinatorial immunoglobulin libraries. (See, e.g., 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. (See, e.g., Clrlandi, 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 PKIN 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. (See, e.g., 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 PKIN and its specific antibody. A two-site, monoclonal-based immunoassay utilizing monoclonal antibodies reactive to two non-interfering PKIN epitopes is generally used, but a competitive binding assay may also be employed (Pound, su ra).
Various methods such as Scatchard analysis in conjunction with radioimmunoassay techniques may be used to assess the affinity of antibodies for PHIN. Affinity is expressed as an association constant, I~, which is defined as the molar concentration of PHIN-antibody complex divided by the molar concentrations of free antigen and free antibody under equilibrium conditions. The I~ determined for a preparation of polyclonal antibodies, which are heterogeneous in their affinities for multiple PKJN
epitopes, represents the average afFnity, or avidity, of the antibodies for PI~IN. The I~ determined for a preparation of monoclonal antibodies, which are monospecific for a particular PKIN epitope, represents a true measure of affinity. High-affinity antibody preparations with I~ ranging from about 109 to 1012 L/mole are preferred for use in immunoassays in which the PHIN-antibody complex must withstand rigorous manipulations. Low-affinity antibody preparations with Ka ranging from about 106 to 10' L/mole are preferred for use in immunopurification and similar procedures which ultimately require dissociation of PKIN, 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/m1, is generally employed in procedures requiring precipitation of PKIN-antibody complexes. Procedures for evaluating antibody specificity, titer, and avidity, and guidelines for antibody quality and usage in various applications, are generally available.
(See, e.g., Catty, su ra, and Coligan et al. supra.) In another embodiment of the invention, the polynucleotides encoding PKIN, or any fragment or complement thereof, may be used for therapeutic purposes. In one aspect, modifications of gene 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 PKIN.
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 PKIN. (See, e.g., Agrawal, S., ed. (1996) Antisense TheraQeutics, Humana Press Inc., 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. (See, e.g., Slater, J.E. et al. (1998) J. Allergy Cli. Immunol. 102(3):469-475; and Scanlon, K.J. et al. (1995) 9(13):1288-1296.) Antisense sequences can also be introduced intracellularly through the use of viral vectors, such as retrovirus and adeno-associated virus vectors. (See, e.g., Miller, A.D. (I990) Blood 76:271; Ausubel, supra; Uckert, W. and W. Walther (1994) Pharmacol. Ther.
63(3):323-347.) Other gene delivery mechanisms include liposome-derived systems, artificial viral envelopes, and other systems known in the art. (See, e.g., Rossi, J.J. (1995) Br. Med. Bull.
51(1):217-225; Boado, R.J. et al. (1998) J. Pharm. Sci. 87(11):1308-1315; and Morris, M.C. et al. (1997) Nucleic Acids Res.
25(14):2730-2736.) In another embodiment of the invention, polynucleotides encoding PKIN 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 (SCID)-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 falcinarum and Trypanosoma cruzi). In the case where a genetic deficiency in PKIN expression or regulation causes disease, the expression of PKIN 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 PKIN
are treated by constructing mammalian expression vectors encoding PKIN and introducing these vectors by mechanical means into PKIN-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 PKIN include, but are not limited to, the PCDNA 3.1, EPITAG, PRCCMV2, PREP, PVAX vectors (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). PKIN 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 FI~506/rapamycin inducible promoter; or the RU486/mifepristone inducible promoter (Rossi, F.M.V.
and Blau, H.M. supra)), or (iii) a tissue-specific promoter or the native promoter of the endogenous gene encoding PKIN 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 PI~IN expression are treated by constructing a retrovirus vector consisting of (i) the polynucleotide encoding PKIN 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 Number 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 the alternative, an adenovirus-based gene therapy delivery system is used to deliver polynucleotides encoding PKIN to cells which have one or more genetic abnormalities with respect to the expression of PHIN. 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 Number 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, both incorporated by reference herein.

In another alternative, a herpes-based, gene therapy delivery system is used to deliver polynucleotides encoding PKIN to target cells which have one or more genetic abnormalities with respect to the expression of PKIN. The use of herpes simplex virus (HSV)-based vectors may be especially valuable for introducing PKIN 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 Number 5,804,413 to DeLuca ("Herpes simplex virus strains for gene transfer"), which is hereby incorporated by reference. U.S. Patent Number 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, hereby incorporated by reference. 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 alternative, an alphavirus (positive, single-stranded RNA virus) vector is used to deliver polynucleotides encoding PKIN 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 PKIN
into the alphavirus genome in place of the capsid-coding region results in the production of a large number of PKIN-coding RNAs and the synthesis of high levels of PKIN 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 PKIN 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. (See, e.g., Gee, J.E. et a1. (1994) in Huber, B.E. and B.I. Carr, Molecular and Immunolo~ic 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 sequences encoding PI~IN.
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 of the invention 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 of DNA sequences encoding PKIN. 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.
An additional embodiment of the invention encompasses a method for screening for a compound which is effective in altering expression of a polynucleotide encoding PKIN. 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 PKIN
expression or activity, a compound which specifically inhibits expression of the polynucleotide encoding PKIN may be therapeutically useful, and in the treatment of disorders associated with decreased PKIN expression or activity, a compound which specifically promotes expression of the polynucleotide encoding PKIN may be therapeutically useful.
At least one, and up to a plurality, of 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 PKIN 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 PKIN 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 PKIN. 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:E1S) 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. (See, e.g., 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 Remin~ton's Pharmaceutical Sciences (Maack Publishing, Easton PA). Such compositions may consist of PKIN, antibodies to PKIN, and mimetics, agonists, antagonists, or inhibitors of PKIN.
The compositions utilized in this invention may be administered by any number of routes including, but not limited to, oral, intravenous, intramuscular, infra-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 has the advantage of 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 PKIN or fragments thereof. For example, liposome preparations containing a cell-impermeable macromolecule may promote cell fusion and intracellular delivery of the macromolecule. Alternatively, PHIN 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 PHIN or fragments thereof, antibodies of PKIN, and agonists, antagonists or inhibitors of PI~IN, 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 ~cg to 100,000 ~cg, 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 PKIN may be used for the diagnosis of disorders characterized by expression of PKIN, or in assays to monitor patients being treated with PHIN or agonists, antagonists, or inhibitors of PKIN. Antibodies useful for diagnostic purposes may be prepared in the same manner as described above for therapeutics. Diagnostic assays for PI~IN
include methods which utilize the antibody and a label to detect PI~IN 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 PI~IN, including ELISAs, RIAs, and FACS, are known in the art and provide a basis for diagnosing altered or abnormal levels of PKIN
expression. Normal or standard values for PKIN expression are established by combining body fluids or cell extracts taken from normal mammalian subjects, for example, human subjects, with antibodies to PKIN under conditions suitable for complex formation. The amount of standard complex formation may be quantitated by various methods, such as photometric means. Quantities of PKIN
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, the polynucleotides encoding PI~IN may be used for diagnostic purposes. The polynucleotides which may be used include oligonucleotide sequences, 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 PI~IN may be correlated with disease. The diagnostic assay may be used to determine absence, presence, and excess expression of PHIN, and to monitor regulation of PKIN levels during therapeutic intervention.
In one aspect, hybridization with PCR probes which are capable of detecting polynucleotide sequences, including genomic sequences, encoding PI~IN or closely related molecules may be used to identify nucleic acid sequences which encode PHIN. 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 PI~IN, 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 PHIN encoding sequences. The hybridization probes of the subject invention may be DNA or RNA and may be derived from the sequence of SEQ ID
N0:27-52 or from genomic sequences including promoters, enhancers, and introns of the PKIN
gene.
Means for producing specific hybridization probes for DNAs encoding PKIN
include the cloning of polynucleotide sequences encoding PKIN or PKTN 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 vitxo 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 355, or by enzymatic labels, such as alkaline phosphatase coupled to the probe via avidin/biotin coupling systems, and the like.
Polynucleotide sequences encoding PKIN may be used for the diagnosis of disorders associated with expression of PKIN. Examples of such disorders include, but are not limited to, a cancer, such as adenocarcinoma, leukemia, lymphoma, melanoma, myeloma, sarcoma, teratocarcinoma, and, in particular, cancers 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, leukemias such as multiple myeloma and lymphomas such as Hodgkin's disease; an immune disorder, such as acquired immunodeficiency syndrome (AIDS), Addison's disease, adult respiratory distress syndrome, allergies, ankylosing spondylitis, amyloidosis, anemia, asthma, atherosclerosis, autoimmune hemolytic anemia, autoimmune thyroiditis, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), bronchitis, cholecystitis, contact dermatitis, Crohn's disease, atopic dermatitis, dermatomyositis, diabetes mellitus, emphysema, episodic lymphopenia with lymphocytotoxins, erythroblastosis fetalis, erythema nodosum, atrophic gastritis, glomerulonephritis, Goodpasture's syndrome, gout, Graves' disease, Hashimoto's thyroiditis, hypereosinophilia, irritable bowel syndrome, multiple sclerosis, myasthenia gravis, myocardial or pericardial inflammation, osteoarthritis, osteoporosis, pancreatitis, polymyositis, psoriasis, Reiter's syndrome, rheumatoid arthritis, scleroderma, Sjogren's syndrome, systemic anaphylaxis, systemic lupus erythematosus, systemic sclerosis, thrombocytopenic purpura, ulcerative colitis, uveitis, Werner syndrome, complications of cancer, hemodialysis, and extracorporeal circulation, viral, bacterial, fungal, parasitic, protozoal, and helminthic infections, and trauma; a growth and developmental 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 cancers including adenocarcinoma, leukemia, lymphoma, melanoma, myeloma, sarcoma, teratocarcinoma, and, in particular, cancers of the adrenal gland, bladder, bone, bone marrow, brain, breast, cervix, gall bladder, ganglia, gastrointestinal tract, heart, kidney, liver, S lung, muscle, ovary, pancreas, parathyroid, penis, prostate, salivary glands, skin, spleen, testis, thymus, thyroid, and uterus, renal tubular acidosis, anemia, Cushing's syndrome, achondroplastic dwarfism, Duchenne and Becker muscular dystrophy, epilepsy, gonadal dysgenesis, WAGR
syndrome (Wilms' tumor, aniridia, genitourinary abnormalities, and mental retardation), Smith-Magenis syndrome, myelodysplastic syndrome, hereditary mucoepithelial dysplasia, hereditary keratodermas, hereditary neuropathies such as Charcot-Marie-Tooth disease and neurofibromatosis, hypothyroidism, hydrocephalus, seizure disorders such as Syndenham's chorea and cerebral palsy, spina bifida, anencephaly, craniorachischisis, congenital glaucoma, cataract, and sensorineural hearing loss; a cardiovascular disease, such as arteriovenous fistula, atherosclerosis, hypertension, vasculitis, Raynaud's disease, aneurysms, arterial dissections, varicose veins, thrombophlebitis and phlebothrombosis, vascular tumors, and complications of thrombolysis, balloon angioplasty, vascular replacement, and coronary artery bypass graft surgery, congestive heart failure, ischemic heart disease, angina pectoris, myocardial infarction, hypertensive heart disease, degenerative valvular heart disease, calcific aortic valve stenosis, congenitally bicuspid aortic valve, mural annular calcification, mural valve prolapse, rheumatic fever and rheumatic heart disease, infective endocarditis, nonbacterial thrombotic endocarditis, endocarditis of systemic lupus erythematosus, caxcinoid heart disease, cardiomyopathy, myocarditis, pericarditis, neoplastic heart disease, congenital heart disease, and complications of cardiac transplantation, congenital lung anomalies, atelectasis, pulmonary congestion and edema, pulmonary embolism, pulmonary hemorrhage, pulmonary infarction, pulmonary hypertension, vascular sclerosis, obstructive pulmonary disease, restrictive pulmonary disease, chronic obstructive pulmonary disease, emphysema, chronic bronchitis, bronchial asthma, bronchiectasis, bacterial pneumonia, viral and mycoplasmal pneumonia, lung abscess, pulmonary tuberculosis, diffuse interstitial diseases, pneumoconioses, sarcoidosis, idiopathic pulmonary fibrosis, desquamative interstitial pneumonitis, hypersensitivity pneumonitis, pulmonary eosinophilia bronchiolitis obliterans-organizing pneumonia, diffuse pulmonary hemorrhage syndromes, Goodpasture's syndromes, idiopathic pulmonary hemosiderosis, pulmonary involvement in collagen-vascular disorders, pulmonary alveolar proteinosis, lung tumors, inflammatory and noninflammatory pleural effusions, pneumothorax, pleural tumors, drug-induced lung disease, radiation-induced lung disease, and complications of lung transplantation; and a lipid disorder, such as fatty liver, cholestasis, primary biliary cirrhosis, caxnitine deficiency, carnitine palmitoyltransferase deficiency, myoadenylate deaminase deficiency, hypertriglyceridemia, lipid storage disorders such Fabry's disease, Gaucher's disease, Niemann-Pick's disease, metachromatic leukodystrophy, adrenoleukodystrophy, GM2 gangliosidosis, and ceroid lipofuscinosis, abetalipoproteinemia, Tangier disease, hyperlipoproteinemia, diabetes mellitus, lipodystrophy, lipomatoses, acute panniculitis, disseminated fat necrosis, adiposis dolorosa, lipoid adrenal hyperplasia, minimal change disease, lipomas, atherosclerosis, hypercholesterolemia, hypercholesterolenua with hypertnglyceridemia, primary hypoalphalipoproteinemia, hypothyroidism, renal disease, liver disease, lecithin:cholesterol acyltransferase deficiency, cerebrotendinous xanthomatosis, sitosterolemia, hypocholesterolemia, Tay-Sachs disease, Sandhoffs disease, hyperlipidemia, hyperlipemia, lipid myopathies, and obesity. The polynucleotide sequences encoding PI~iN 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 PKIN expression. Such qualitative or quantitative methods are well known in the art.
In a particular aspect, the nucleotide sequences encoding PI~IN may be useful in assays that detect the presence of associated disorders, particularly those mentioned above. The nucleotide sequences encoding PI~iN may be labeled by standard methods axed 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 in comparison to a control sample then the presence of altered levels of nucleotide sequences encoding PKIN 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 PHIN, 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 PKIN, 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 PKIN
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 PHIN, or a fragment of a polynucleotide complementary to the polynucleotide encoding PI~IN, 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 the polynucleotide sequences encoding PKIN 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 the polynucleotide sequences encoding PKIN 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 fiuorescently 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).

Methods which may also be used to quantify the expression of PKIN include radiolabeling or biotinylating nucleotides, coamplification of a control nucleic acid, and interpolating results from standard curves. (See, e.g., 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 -polynucleotide sequences 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, PKIN, fragments of PHIN, or antibodies specific for PI~IN 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. (See Seilhamer et al., "Comparative Gene Transcript Analysis,"
U.S. Patent Number 5,840,484, 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, expressly incorporated by reference herein).
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 one embodiment, the toxicity of a test compound is 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 particular embodiment relates to the use of the polypeptide sequences of the present invention 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 the present invention. In some cases, further sequence data may be obtained for definitive protein identification.
A proteomic profile may also be generated using antibodies specific for PKIN
to quantify the levels of PKIN 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. (See, e.g., 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; and Heller, M.J. et al. (1997) U.S. Patent No. 5,605,662.) Various types of microaxrays are well known and thoroughly described in DNA Microarrays: A Practical Approach, M.
Schena, ed. (1999) Oxford University Press, London, hereby expressly incorporated by reference.
In another embodiment of the invention, nucleic acid sequences encoding PKIN
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 multi-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. (See, e.g., Harrington, J.J. et al. (1997) Nat.
Genet. 15:345-355; Price, C.M. (1993) Blood Rev. 7:127-134; and Trask, B.J.
(1991) Trends Genet.
7:149-154.) Once mapped, the nucleic acid sequences of the invention 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). (See, for example, Larder, 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. (See, e.g., 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 it Man (OMIM) World Wide Web site. Correlation between the location of the gene encoding PHIN 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 11q22-23, any sequences mapping to that area may represent associated or regulatory genes for further investigation. (See, e.g., 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, PHIN, 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 PHIN 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. (See, e.g., 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 PI~IN, or fragments thereof, and washed. Bound PKIN is then detected by methods well known in the art. Purified PKIN 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 PKIN specifically compete with a test compound for binding PKIN. In this manner, antibodies can be used to detect the presence of any peptide which shares one or more antigenic determinants with PKIN.
In additional embodiments, the nucleotide sequences which encode PKIN 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 !imitative 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. 60/212,073, U.S. Ser. No. 60/213,467, U.S. Ser. No.
60/215,651, U.S. Ser.
No. 60/216,605, U.S. Ser. No. 60/218,372, and U.S. Ser. No. 60/228,056 are expressly incorporated by reference herein.
EXAMPLES
I. Construction of cDNA Libraries Incyte cDNAs were derived from cDNA libraries described in the LIFESEQ GOLD
database (Incyte Genomics, Palo Alto CA) and shown in Table 4, column 5. 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 (Life Technologies), a monophasic solution of phenol and guanidine isothiocyanate. The resulting lysates were centrifuged over CsCl 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 (Life Technologies), using the recommended procedures or similar methods known in the art. (See, e.g., Ausubel, 1997, su ra, units 5.1-6.6.) 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 S 1000, SEPHAROSE CL2B, or SEPHAROSE CL4B column chromatography (Amersham Pharmacia Biotech) 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 (Life Technologies), PCDNA2.1 plasmid (Invitrogen, Carlsbad CA), PBI~-CMV plasmid (Stratagene), or pINCY (Incyte Genomics, Palo Alto CA), or derivatives thereof. Recombinant plasmids were transformed into competent E. coli cells including XL1-Blue, XL1-BlueMRF, or SOLR from Stratagene or DHSa, DH10B, or ElectroMAX
DH10B from Life Technologies.
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 Pharmacia Biotech 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 (Molecular Dynamics); 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 (reviewed in Ausubel, 1997, s-upra, unit 7.7). 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, and hidden Markov model (HMM)-based protein family databases such as PFAM.
(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 of the invention 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, BLOCKS, PRINTS, DOMO, PRODOM, Prosite, and hidden Markov model (HMM)-based protein family databases such as PFAM. Full length polynucleotide sequences are also analyzed using MACDNASIS PRO software (Hitachi Software Engineering, South San Francisco 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
N0:27-52. Fragments from about 20 to about 4000 nucleotides which are useful in hybridization and amplification technologies are described in Table 4, column 4.
IV. Identification and Editing of Coding Sequences from Genomic DNA
Putative human kinases 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 (See Burge, C. and S. Karfin (1997) J. Mol. Biol. 268:78-94, and 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 human kinases, the encoded polypeptides were analyzed by querying against PFAM
25 models for human kinases. Potential human kinases were also identified by homology to Incyte cDNA
sequences that had been annotated as human kinases. 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 andlor 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" Sequences 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 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" Seguences 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 IV. A
2U 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 GenB ank protein homolog. The GenB ank 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 PI~IN Encoding Polynucleotides The sequences which were used to assemble SEQ ID N0:27-52 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 N0:27-52 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, 1 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.
In this manner, SEQ ID N0:27 was mapped to chromosome 19 and SEQ ID N0:35 was mapped to chromosome 15 within the interval from 72.30 to 77.30 centiMorgans.
SEQ ID N0:48 was mapped to chromosome 10 within the interval from 93.80 to 96.90 centiMorgans. SEQ ID
N0:49 was mapped to chromosome 13 within the interval from 11.60 to 22.80 centiMorgans, to chromosome 17 within the interval from 0.60 to 14.80 centiMorgans, and to chromosome 20 within the interval from 57.70 to 64.10 centiMorgans. More than one map location is reported for SEQ ID
N0:49, indicating that sequences having different map locations were assembled into a single cluster.
This situation occurs, for example, when sequences having strong similarity, but not complete identity, are assembled into a single cluster.
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. (See, e.g., Sambrook, supra, ch. 7; Ausubel (1995) s_u~ra, ch. 4 and 16.) Analogous computer techniques applying BLAST were used to search for identical.or related molecules in cDNA 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 Identi~
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 5 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, polynucleotide sequences encoding PHIN 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;
heroic 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 diseaselcondition 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 PKIN. cDNA sequences and cDNA library/tissue information are found in the LIFESEQ
GOLD database (Incyte Genomics, Palo Alto CA).
VIII. Extension of PKIN Encoding Polynucleotides Full length polynucleotide sequences were also 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 SO% 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 Mg2+, (NH4)2S04, and 2-mercaptoethanol, Taq DNA polymerise (Amersham Pharmacia Biotech), ELONGASE enzyme (Life Technologies), and Pfu DNA polymerise (Stratagene), with the following parameters for primer pair PCI A and PCI B: Step l: 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 ~l 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 ,u1 to 10 ~cl 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 Pharmacia Biotech). Fox 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 Pharmacia Biotech), treated with Pfu DNA polymerise (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 Pharmacia Biotech) 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 Pharmacia Biotech) or the ABI PRISM BIGDYE Terminator cycle sequencing ready reaction kit (Applied Biosystems).
In like manner, full length polynucleotide sequences 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. Labeling and Use of Individual Hybridization Probes Hybridization probes derived from SEQ ID N0:27-52 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-32P] adenosine triphosphate (Amersham Pharmacia Biotech), and T4 polynucleotide kinase (DuPont NEN, Boston MA). The labeled oligonucleotides are substantially purified using a SEPHADEX
G-25 superfine size exclusion dextran bead column (Amersham Pharmacia Biotech). 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.
X. 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, su ra.), 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 (1999), su ra). Suggested substrates include silicon, silica, glass slides, glass chips, and silicon wafers. Alternatively, a 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, W, 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. (See, e.g., Schena, M. et al.
(1995) Science 270:467-470;
Shalom D. et al. (1996) Genome Res. 6:639-645; Marshall, A. and J. Hodgson (1998) Nat. Biotechnol.
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 microaxray 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/pl oligo-(dT) primer (2lmer), 1X first strand buffer, 0.03 units/~il RNase inhibitor, S00 ~M dATP, 500 ~M dGTP, 500 ~M dTTP, 40 ~M
dCTP, 40 EtM dCTP-Cy3 (BDS) or dCTP-Cy5 (Amersham Pharmacia Biotech). The reverse transcription reaction is performed in a 25 ml volume containing 200 ng poly(A)~ RNA with GEMBRIGHT kits (Incyte). 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
Laboratories, Inc.
(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 N~ and resuspended in 14 iil SX SSC/0.2% SDS.
Microarray Pr~aration 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 Pharmacia Biotech).
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 US
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 STRATALINI~ER UV-crosslinker (Stratagene).
MicroaiTays 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 ~.Q of sample mixture consisting of 0.2 ~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 cm2 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 ~1 of SX SSC in a corner of the chamber. The chamber containing the arrays is incubated for about 6.5 hours at 60° C. The arxays are washed fox 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 N~ 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 fiuorophore 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 (Iow 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).

XI. Complementary Polynucleotides Sequences complementary to the PKIN-encoding sequences, or any parts thereof, are used to detect, decrease, or inhibit expression of naturally occurring PKIN. 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 PKIN. 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 PKIN-encoding transcript.
XII. Expression of PKIN
Expression and purification of PKIN is achieved using bacterial or virus-based expression systems. For expression of PKIN 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 T5 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 PKIN upon induction with isopropyl beta-D-thiogalactopyranoside (IPTG).
Expression of PKIN 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 PKIN
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 S~odoptera fru~iperda (Sf9) insect cells in most cases, or human hepatocytes, in some cases. Infection of the latter requires additional genetic modifications to baculovirus. (See 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, PKIN 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 Pharmacia Biotech). Following purification, the GST moiety can be proteolytically cleaved from PKIN 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 (1995, supra, ch. 10 and 16). Purified PKIN obtained by these methods can be used directly in the assays shown in Examples XVI, XVII, and XVIII where applicable.
XIII. Functional Assays PKIN function is assessed by expressing the sequences encoding PKIN 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 (Life Technologies) and PCR3.1 (Invitrogen, Carlsbad CA), both of which contain the cytomegalovirus promoter. 5-10 ~g 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 ug 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 fluorescein-conjugated Annexin V protein to the cell surface. Methods in flow cytometry are discussed in Ormerod, M. G.
(1994) Flow Cytometry, Oxford, New York NY.
The influence of PHIN on gene expression can be assessed using highly purified populations of cells transfected with sequences encoding PKIN 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 CD64 (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 PI~IN and other genes of interest can be analyzed by northern analysis or microarray techniques.

XIV. Production of PKIN Specific Antibodies PKIN 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 rabbits and to produce antibodies using standard protocols.
Alternatively, the PKIN 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. (See, e.g., Ausubel, 1995, supra, ch. 11.) Typically, oligopeptides of about 15 residues in length are synthesized using an ABI 431 A
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. (See, e.g., Ausubel, 1995, supra.) Rabbits are immunized with the oligopeptide-KLH complex in complete Freund's adjuvant. Resulting antisera are tested for antipeptide and anti-PKIN activity by, for example, binding the peptide or PI~iN to a substrate, blocking with 1 %
BSA, reacting with rabbit antisera, washing, and reacting with radio-iodinated goat anti-rabbit IgG.
XV. Purification of Naturally Occurring PKIN Using Specific Antibodies Naturally occurring or recombinant PI~LN is substantially purified by immunoaffinity chromatography using antibodies specific for PKIN. An immunoaffinity column is constructed by covalently coupling anti-PKIN antibody to an activated chromatographic resin, such as CNBr-activated SEPHAROSE (Amersham Pharmacia Biotech). After the coupling, the resin is blocked and washed according to the manufacturer's instructions.
Media containing PKIN are passed over the immunoaffinity column, and the column is washed under conditions that allow the preferential absorbance of PKIN (e.g., high ionic strength buffers in the presence of detergent). The column is eluted under conditions that disrupt antibody/PKIN 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 PHIN is collected.
XVI. Identification of Molecules Which Interact with PKIN
PHIN, or biologically active fragments thereof, are labeled with lasl Bolton-Hunter reagent.
(See, e.g., 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 PI~IN, washed, and any wells with labeled PHIN complex are assayed. Data obtained using different concentrations of PKIN are used to calculate values for the number, affinity, and association of PKIN with the candidate molecules.

Alternatively, molecules interacting with PKIN 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).
PKIN 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).
XVII. Demonstration of PKIN Activity Generally, protein kinase activity is measured by quantifying the phosphorylation of a protein substrate by PKIN in the presence of gamma-labeled 32P-ATP. PKIN is incubated with the protein substrate, 32P-ATP, and an appropriate kinase buffer. The 32P incorporated into the substrate is separated from free 32P-ATP by electrophoresis and the incorporated 32P is counted using a radioisotope counter. The amount of incorporated 32P is proportional to the activity of PKIN. A determination of the specific amino acid residue phosphorylated is made by phosphoamino acid analysis of the hydrolyzed protein.
In one alternative, protein kinase activity is measured by quantifying the transfer of gamma phosphate from adenosine triphosphate (ATP) to a serine, threonine or tyrosine residue in a protein substrate. The reaction occurs between a protein kinase sample with a biotinylated peptide substrate and gamma 32P-ATP. Following the reaction, free avidin in solution is added for binding to the biotinylated 32P-peptide product. The binding sample then undergoes a centrifugal ultrafiltration process with a membrane which will retain the product-auidin complex and allow passage of free gamma 32P-ATP. The reservoir of the centrifuged unit containing the 32P-peptide product as retentate is then counted in a scintillation counter. This procedure allows assay of any type of protein kinase sample, depending on the peptide substrate and kinase reaction buffer selected. This assay is provided in kit form (ASUA, Affinity Ultrafiltration Separation Assay, Transbio Corporation, Baltimore MD, U.S. Patent No. 5,869,275). Suggested substrates and their respective enzymes are as follows: Histone H1 (Sigma) and p34°a°Zkinase, Annexin I, Angiotensin (Sigma) and EGF receptor kinase, Annexin II
and src kinase, ERKl & ERK2 substrates and MEK, and myelin basic protein and ERK (Pearson, J.D.
et al. (1991) Methods Enzymol. 200:62-81).
In another alternative, protein kinase activity of PKIN is demonstrated in vitro in an assay containing PKIN, 50.1 of kinase buffer, 1 ~.g substrate, such as myelin basic protein (MBP) or synthetic peptide substrates, I mM DTT, 10 ~.g ATP, and O.S~.Ci ['y-33P]ATP. The reaction is incubated at 30°C for 30 minutes and stopped by pipetting onto P81 paper. The unincorporated ['y-33P]ATP is removed by washing and the incorporated radioactivity is measured using a radioactivity scintillation counter. Alternatively, the reaction is stopped by heating to 100 ° C
in the presence of SDS loading buffer and visualized on a 12% SDS polyacrylamide gel by autoradiography.
Incorporated radioactivity is corrected for reactions carried out in the absence of PKIN or in the presence of the inactive kinase, K38A.
In yet another alternative, adenylate kinase or guanylate kinase activity may be measured by the incorporation of 32P from gamma-labeled 32P -ATP into ADP or GDP using a gamma radioisotope counter. The enzyme, in a kinase buffer, is incubated together with the appropriate nucleotide mono-phosphate substrate (AMP or GMP) and 32P-labeled ATP as the phosphate donor. The reaction is incubated at 37°C and terminated by addition of trichloroacetic acid. The acid extract is neutralized and subjected to gel electrophoresis to separate the mono-, di-, and triphosphonucleotide fractions.
The diphosphonucleotide fraction is cut out and counted. The radioactivity recovered is proportional to the enzyme activity.
In yet another alternative, other assays for PKIN include scintillation proximity assays (SPA), scintillation plate technology and filter binding assays. Useful substrates include recombinant proteins tagged with glutathione transferase, or synthetic peptide substrates tagged with biotin. Inhibitors of PKIN activity, such as small organic molecules, proteins or peptides, may be identified by such assays.
XVIII. Enhancement/Inhibition of Protein I~inase Activity Agonists or antagonists of PKIN activation or inhibition may be tested using assays described in section XVII. Agonists cause an increase in PKIN activity and antagonists cause a decrease in PKIN
activity.
Various modifications and variations of the described 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.
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.
Indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in molecular biology or related fields are intended to be within the scope of the following claims.

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<110> INCYTE GENOMICS, INC.
YUE, Henry LAL, Preeti BANDMAN, Olga BOROWSKY, Mark L.
AU-YOUNG, Janice LU, Yan GANDHI, Ameena R.
TRIBOULEY, Catherine M.
WALIA, Narinder K.
YAO, Monique G.
LU, Dyung Aina M.
GREENWALD, Sara R.
RAMKUMAR, Jayalaxini GRIFFIN, Jennifer A.
KEARNEY, Liam BURFORD, Neil NGUYEN, Danniel B.
TANG, Y. Tom BAUGHN, Mariah R.
HE, Ann THORNTON, Michael HAFALIA, April PATTERSON, Chandra GURURAJAN, Rajagopal LO, Terence P.
KHAH, Farrah A.
RECIPON, Shirley A.
AZIMZAI, Yalda POLICKY, Jennifer L.
DING, Li GRETHER, Megan ELLIOTT, Vicki S.
THANGAVELU, Kavitha BATRA, Sajeev ISON, Craig H.
<120> HUMAN KINASES
<130> PI-0125 PCT
<140> To Be Assigned <141> Herewith <150> 60/212,073; 60/213,467; 60/215,651; 60/216,605; 60/218,372;
60/228,056 <151> 2000-06-15; 2000-06-23; 2000-06-30; 2000-07-07; 2000-07-13; 2000-08-<160> 52 <170> PERL Program <210> 1 <211> 273 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 2011384CD1 <400> 1 Met Ser G1y Asp Lys Leu Leu Ser Glu Leu Gly Tyr Lys Leu Gly Arg Thr Ile Gly Glu Gly Ser Tyr Ser Lys Val Lys Val Ala Thr Ser Lys Lys Tyr Lys Gly Thr Va1 Ala Ile Lys Val Val Asp Arg Arg Arg Ala Pro Pro Asp Phe Val Asn Lys Phe Leu Pro Arg Glu Leu Ser Ile Leu Arg Gly Val Arg His Pro His Ile Val His Val Phe Glu Phe Ile Glu Val Cys Asn Gly Lys Leu Tyr Ile Va1 Met Glu Ala Ala Ala Thr Asp Leu Leu Gln A1a Va1 Gln Arg Asn Gly Arg Ile Pro Gly Val Gln Ala Arg Asp Leu Phe Ala Gln I1e Ala Gly Ala Val Arg Tyr Leu His Asp His His Leu Val His Arg Asp Leu Lys Cys Glu Asn Val Leu Leu Ser Pro Asp Glu Arg Arg Val Lys Leu Thr Asp Phe Gly Phe Gly Arg Gln Ala His Gly Tyr Pro 155 l60 165 Asp Leu Ser Thr Thr Tyr Cys Gly Ser Ala Ala Tyr Ala Ser Pro 170 l75 180 Glu Val Leu Leu G1y I1e Pro Tyr Asp Pro Lys Lys Tyr Asp Val Trp Ser Met Gly Val Va1 Leu Tyr Val Met Val Thr Gly Cys Met Pro Phe Asp Asp Ser Asp Ile Ala Gly Leu Pro Arg Arg Gln Lys Arg Gly Val Leu Tyr Pro Glu Gly Leu Glu Leu Ser Glu Arg Cys Lys Ala Leu Ile Ala Glu Leu Leu Gln Phe Ser Pro Ser Ala Arg Pro Ser Ala Gly Gln Val Ala Arg Asn Cys Trp Leu Arg Ala G1y Asp Ser G1y <210> 2 <211> 329 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 2004888CD1 <400> 2 Met Leu Thr Ser Leu Ala Gln Lys Trp Phe Pro Glu Leu Pro Leu Leu His Pro G1u Ile Gly Leu Leu Lys Tyr Met Asn Ser Gly Gly Leu Leu Thr Met Ser Leu Glu Arg Asp Leu Leu Asp Ala Glu Pro Met Lys Glu Leu Ser Ser Lys Arg Pro Leu Val Arg Ser Glu Val Asn Gly G1n Ile Ile Leu Leu Lys Gly Tyr Ser Val Asp Val Asp Thr Glu Ala Lys Val Ile Glu Arg Ala A1a Thr Tyr His Arg Ala Trp Arg Glu A1a G1u Gly Asp Ser Gly Leu Leu Pro Leu Ile Phe Leu Phe Leu Cys Lys Ser Asp Pro Met Ala Tyr Leu Met Val Pro Tyr Tyr Pro Arg Ala Asn Leu Asn Ala Val Gln A1a Asn Met Pro Leu Asn Ser Glu Glu Thr Leu Lys Val Met Lys Gly Val Ala Gln Gly Leu His Thr Leu His Lys Ala Asp Ile Tle His Gly Ser Leu His Gln Asn Asn Val Phe Ala Leu Asn Arg Glu Gln Gly Ile Val Gly Asp Phe Asp Phe Thr Lys Ser Val Ser Gln Arg Ala Ser Val Asn Met Met Val Gly Asp Leu Ser Leu Met Ser Pro Glu Leu Lys Met Gly Lys Pro Ala Ser Pro Gly Ser Asp Leu Tyr Ala Tyr Gly Cys Leu Leu Leu Trp Leu Ser Val Gln Asn Gln Glu Phe Glu Ile Asn Lys Asp Gly Ile Pro Lys Val Asp Gln Phe His Leu Asp Asp Lys Val Lys Ser Leu Leu Cys Ser Leu Ile Cys Tyr Arg Ser Ser Met Thr Ala Glu Gln Val Leu Asn Ala Glu Cys Phe Leu Met Pro Lys Glu Gln Ser Val Pro Asn Pro Glu Lys Asp Thr Glu Tyr Thr Leu Tyr Lys Lys Glu Glu Glu Ile Lys Thr Glu Asn Leu Asp Lys Cys Met Glu Lys Thr Arg Asn Gly Glu Ala Asn Phe Asp Cys <210> 3 <211> 938 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 2258952CD1 <400> 3 Met Met Ser Asp Thr Ser Thr Phe Pro Asn His Pro Ser Ser Pro Ala Ala Ser Pro Ser Gly Gly Arg Gly Val Met Ala Ser Pro Ala Trp Asp Arg Ser Lys Gly Trp Ser Gln Thr Pro Gln Arg A1a Asp Phe Val Ser Thr Pro Leu Gln Val His Thr Leu Arg Pro Glu Asn Leu Leu Leu Val Ser Thr Leu Asp Gly Ser Leu His Ala Leu Ser Lys G1n Thr Gly Asp Leu Lys Trp Thr Leu Arg Asp Asp Pro Va1 80 ~ 85 90 Ile G1u Gly Pro Met Tyr Val Thr Glu Met Ala Phe Leu Ser Asp Pro Ala Asp Gly Ser Leu Tyr Ile Leu Gly Thr Gln Lys G1n Gln Gly Leu Met Lys Leu Pro Phe Thr Ile Pro Glu Leu Val His Ala Ser Pro Cys Arg Ser Ser Asp Gly Val Phe Tyr Thr Gly Arg Lys Gln Asp A1a Trp Phe Val Val Asp Pro Glu Ser Gly Glu Thr Gln Met Thr Leu Thr Thr Glu Gly Pro Ser Thr Pro Arg Leu Tyr Ile Gly Arg Thr Gln Tyr Thr Val Thr Met His Asp Pro Arg A1a Pro Ala Leu Arg Trp Asn Thr Thr Tyr Arg Arg Tyr Ser Ala Pro Pro Met Asp Gly Ser Pro G1y Lys Tyr Met Ser His Leu Ala Ser Cys Gly Met Gly Leu Leu Leu Thr Val Asp Pro Gly Ser Gly Thr Val Leu Trp Thr Gln Asp Leu Gly Val Pro Val Met Gly Val Tyr Thr Trp His Gln Asp Gly Leu Arg Gln Leu Pro His Leu Thr Leu Ala 260 . 265 270 Arg Asp Thr Leu His Phe Leu Ala Leu Arg Trp Gly His Ile Arg Leu Pro Ala Ser Gly Pro Arg Asp Thr Ala Thr Leu Phe Ser Thr Leu Asp Thr Gln Leu Leu Met Thr Leu Tyr Val Gly Lys Asp Glu Thr Gly Phe Tyr Val Ser Lys Ala Leu Val His Thr Gly Va1 A1a Leu Val Pro Arg Gly Leu Thr Leu Ala Pro Ala Asp Gly Pro Thr Thr Asp Glu Va1 Thr Leu Gln Val Ser Gly Glu Arg Glu Gly Ser 350 355 ~ 360 Pro Ser Thr Ala Val Arg Tyr Pro Ser Gly Ser Val Ala Leu Pro Ser Gln Trp Leu Leu Ile Gly His His Glu Leu Pro Pro Val Leu His Thr Thr Met Leu Arg Va1 His Pro Thr Leu Gly Ser Gly Thr Ala G1u Thr Arg Pro Pro Glu Asn Thr Gln Ala Pro Ala Phe Phe Leu Glu Leu Leu Ser Leu Ser Arg Glu Lys Leu Trp Asp Ser Glu Leu His Pro Glu Glu Lys Thr Pro Asp Ser Tyr Leu Gly Leu Gly Pro Gln Asp Leu Leu Ala Ala Ser Leu Thr Ala Val Leu Leu Gly Gly Trp Ile Leu Phe Val Met Arg Gln Gln Gln Glu Thr Pro Leu Ala Pro Ala Asp Phe Ala His Ile Ser Gln Asp Ala Gln Ser Leu His Ser Gly Ala Ser Arg Arg Ser Gln Lys Arg Leu Gln Ser Pro Ser Pro G1u Ser Pro Pro Ser Ser Pro Pro Ala Glu Gln Leu Thr Val Val Gly Lys Ile Ser Phe Asn Pro Lys Asp Val Leu Gly Arg Gly Ala Gly Gly Thr Phe Val Phe Arg Gly Gln Phe G1u Gly Arg Ala Va1 Ala Val Lys Arg Leu Leu Arg Glu Cys Phe G1y Leu Val Arg Arg G1u Val Gln Leu Leu Gln Glu Ser Asp Arg His Pro Asn Val Leu Arg Tyr Phe Cys Thr Glu Arg Gly Pro Gln Phe His Tyr Ile Ala Leu Glu Leu Cys Arg Ala Ser Leu Gln Glu Tyr Val Glu Asn Pro Asp Leu Asp Arg Gly Gly Leu Glu Pro Glu Val Val Leu Gln Gln Leu Met Ser G1y Leu Ala His Leu His Ser Leu His Ile Val His Arg Asp Leu Lys Pro Gly Asn Ile Leu Ile Thr Gly Pro Asp Ser Gln Gly Leu Gly Arg Val Va1 Leu Ser Asp Phe Gly Leu Cys Lys Lys Leu Pro Ala Gly Arg Cys Ser Phe Ser Leu His Ser Gly Ile Pro Gly Thr Glu Gly Trp Met Ala Pro G1u Leu Leu G1n Leu Leu Pro Pro Asp Ser Pro Thr Ser Ala Val Asp Ile Phe Ser Ala Gly Cys Val Phe Tyr Tyr Va1 Leu Ser Gly Gly Ser His Pro Phe Gly Asp Ser Leu Tyr Arg Gln A1a Asn Ile Leu Thr Gly Ala Pro Cys Leu Ala His Leu Glu Glu G1u Val His Asp Lys Val Val Ala Arg Asp Leu Val Gly Ala Met Leu Ser Pro Leu Pro Gln Pro Arg Pro Ser Ala Pro Gln Val Leu Ala His Pro Phe Phe Trp Ser Arg Ala Lys Gln Leu Gln Phe Phe Gln Asp Val Ser Asp Trp Leu Glu Lys Glu Ser Glu Gln Glu Pro Leu Val Arg Ala Leu Glu Ala Gly Gly Cys Ala Val Val Arg Asp Asn Trp His Glu His Ile Ser Met Pro Leu Gln Thr Asp Leu Arg Lys Phe Arg Ser Tyr Lys Gly Thr Ser Val Arg Asp Leu Leu Arg Ala Val Arg Asn Lys Lys His His Tyr Arg Glu Leu Pro Val Glu Val Arg Gln Ala Leu Gly Gln Val Pro Asp Gly Phe Val Gln Tyr Phe Thr Asn Arg Phe Pro Arg Leu Leu Leu His Thr His Arg Ala Met Arg Ser Cys Ala Ser Glu Ser Leu Phe Leu Pro Tyr Tyr Pro Pro Asp Ser Glu Ala Arg Arg Pro Cys Pro Gly Ala Thr Gly Arg <210> 4 <211> 795 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7473244CD1 <400> 4 Met Ser Ala Arg Thr Pro Leu Pro Thr Val Asn Glu Arg Asp Thr Glu Asn His Thr Ser Val Asp Gly Tyr Thr Glu Pro His Ile Gln Pro Thr Lys Ser Ser Ser Arg Gln Asn I1e Pro Arg Cys Arg Asn Ser Ile Thr Ser Ala Thr Asp Glu Gln Pro His Ile Gly Asn Tyr Arg Leu Gln Lys Thr Ile Gly Lys Gly Asn Phe Ala Lys Val Lys Leu Ala Arg His Val Leu Thr Gly Arg Glu Val A1a Val Lys Ile Ile Asp Lys Thr Gln Leu Asn Pro Thr Ser Leu Gln Lys Leu Phe Arg Glu Val Arg Ile Met Lys Ile Leu Asn His Pro Asn Ile Val Lys Leu Phe Glu Val Ile G1u Thr Glu Lys Thr Leu Tyr Leu Val Met Glu Tyr Ala Ser Gly Gly Glu Val Phe Asp Tyr Leu Val A1a His Gly Arg Met Lys Glu Lys Glu Ala Arg A1a Lys Phe Arg Gln Ile Val Ser AIa Val Gln Tyr Cys His Gln Lys Tyr Ile Val His Arg Asp Leu Lys Ala Glu Asn Leu Leu Leu Asp Gly Asp Met Asn 185 l90 195 Ile Lys Ile Ala Asp Phe Gly Phe Ser Asn Glu Phe Thr Val Gly Asn Lys Leu Asp Thr Phe Cys Gly Ser Pro Pro Tyr Ala Ala Pro Glu Leu Phe Gln Gly Lys Lys Tyr Asp Gly Pro Glu Val Asp Val Trp Ser Leu Gly Val Ile Leu Tyr Thr Leu Val Ser Gly Ser Leu Pro Phe Asp Gly Gln Asn Leu Lys Glu Leu Arg Glu Arg Val Leu Arg Gly Lys Tyr Arg Ile Pro Phe Tyr Met Ser Thr Asp Cys Glu Asn Leu Leu Lys Lys Leu Leu Val Leu Asn Pro Ile Lys Arg Gly Ser Leu Glu Gln Ile Met Lys Asp Arg Trp Met Asn Val Gly His Glu Glu Glu Glu Leu Lys Pro Tyr Thr Glu Pro Asp Pro Asp Phe Asn Asp Thr Lys Arg Ile Asp Ile Met Val Thr Met Gly Phe Ala Arg Asp Glu Ile Asn Asp A1a Leu Ile Asn Gln Lys Tyr Asp Glu Val Met Ala Thr Tyr Ile Leu Leu Gly Arg Lys Pro Pro Glu Phe Glu G1y Gly G1u Ser Leu Ser Ser Gly Asn Leu Cys G1n Arg Ser Arg Pro Ser Ser Asp Leu Asn Asn Ser Thr Leu Gln Ser Pro Ala His Leu Lys Va1 Gln Arg Ser Ile Ser Ala Asn Gln Lys Gln Arg Arg Phe Ser Asp His Ala Gly Pro Ser Ile Pro Pro Ala Val Ser Tyr Thr Lys Arg Pro Gln Ala Asn Ser Val Glu Ser Glu Gln Lys Glu Glu Trp Asp Lys Asp Val Ala Arg Lys Leu Gly Ser Thr Thr Val Gly Ser Lys Ser G1u Met Thr A1a Ser Pro Leu Val Gly Pro Glu Arg Lys Lys Ser Ser Thr Ile Pro Ser Asn Asn Va1 Tyr Ser Gly Gly Ser Met Ala Arg Arg Asn Thr Tyr Val Cys Glu Arg Thr Thr Asp Arg Tyr Val Ala Leu G1n Asn Gly Lys Asp Ser Ser Leu Thr Glu Met Ser Val Ser Ser Ile Ser Ser Ala Gly Ser Ser Val Ala Ser Ala Val Pro Ser Ala Arg Pro Arg His Gln Lys Ser Met Ser Thr Ser Gly His Pro I1e Lys Val Thr Leu Pro Thr Ile Lys Asp Gly Ser Glu Ala Tyr Arg Pro G1y Thr Thr G1n Arg Val Pro Ala Ala Ser Pro Ser Ala His Ser Ile Ser Thr Ala Thr Pro Asp Arg Thr Arg Phe Pro Arg Gly Ser Ser Ser Arg Ser Thr Phe His Gly Glu Gln Leu Arg Glu Arg Arg Ser Val Ala Tyr Asn Gly Pro Pro Ala Ser Pro Ser His Glu Thr Gly Ala Phe Ala His Ala Arg Arg Gly Thr Ser Thr Gly Ile Ile Ser Lys Ile Thr Ser Lys Phe Val Arg Arg Asp Pro Ser Glu Gly Glu Ala Ser Gly Arg Thr Asp Thr Ser Arg Ser Thr Ser Gly Glu Pro Lys Glu Arg Asp Lys Glu Glu Gly Lys Asp Ser Lys Pro Arg Ser Leu Arg Phe Thr Trp Ser Met Lys Thr Thr Ser Ser Met Asp Pro Asn Asp Met Met Arg Glu Ile Arg Lys Val Leu Asp Ala Asn Asn Cys Asp Tyr Glu Gln Lys Glu Arg Phe Leu Leu Phe Cys Val His Gly Asp Ala Arg Gln Asp Ser Leu Val Gln Trp Glu Met Glu Val Cys Lys Leu Pro Arg Leu Ser Leu Asn Gly Val Arg Phe Lys Arg Ile Ser Gly Thr Ser Ile Ala Phe Lys Asn Ile A1a Ser Lys Ile Ala Asn Glu Leu Lys Leu <210> 5 <211> 656 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 1242491CD1 <400> 5 Met Met Ser Trp Asn Leu Asn Lys Leu Gln Ser Phe Leu Leu Gly Asp Gly Ser Phe Gly Ser Val Tyr Arg A1a Ala Tyr Glu Gly Glu Glu Val Ala Val Lys Ile Phe Asn Lys His Thr Ser Leu Arg Leu Leu Arg G1n Glu Leu Val Va1 Leu Cys His Leu His His Pro Ser Leu Ile Ser Leu Leu Ala Ala Gly Ile Arg Pro Arg Met Leu Val Met Glu Leu Ala Ser Lys Gly Ser Leu Asp Arg. Leu Leu Gln Gln Asp Lys Ala Ser Leu Thr Arg Thr Leu Gln His Arg Ile Ala Leu His Val A1a Asp Gly Leu Arg Tyr Leu His Ser A1a Met Ile Ile Tyr Arg Asp Leu Lys Pro His Asn Val Leu Leu Phe Thr Leu Tyr Pro,Asn Ala Ala Ile I1e Ala Lys Ile Ala Asp Tyr Gly Ile Ala Gln Tyr Cys Cys Arg Met Gly Ile Lys Thr Ser Glu Gly Thr Pro Gly Phe Arg Ala Pro Glu Val Ala Arg G1y Asn Val Ile Tyr Asn 170 175 ~ 180 Gln Gln Ala Asp Val Tyr Ser Phe Gly Leu Leu Leu Tyr Asp Ile Leu Thr Thr Gly Gly Arg I1e Val Glu Gly Leu Lys Phe Pro Asn Glu Phe Asp Glu Leu Glu Ile Gln Gly Lys Leu Pro Asp Pro Val Lys Glu Tyr Gly Cys Ala Pro Trp Pro Met Val Glu Lys Leu I1e Lys Gln Cys Leu Lys Glu Asn Pro Gln Glu Arg Pro Thr Ser Ala Gln Val Phe Asp Ile Leu Asn Ser Ala Glu Leu Val Cys Leu Thr Arg Arg Ile Leu Leu Pro Lys Asn Val Ile Val Glu Cys Met Val Ala Thr His His Asn Ser Arg Asn Ala Ser Ile Trp Leu Gly Cys Gly His Thr Asp Arg Gly Gln Leu Ser Phe Leu Asp Leu Asn Thr Glu Gly Tyr Thr Ser Glu Glu Val Ala Asp Ser Arg Ile Leu Cys Leu A1a Leu Val His Leu Pro Val Glu Lys Glu Ser Trp Ile Val Ser Gly Thr Gln Ser Gly Thr Leu Leu Val Ile Asn Thr Glu Asp Gly Lys Lys Arg His Thr Leu Glu Lys Met Thr Asp Ser Val Thr Cys Leu Tyr Cys Asn Ser Phe Ser Lys Gln Ser Lys Gln Lys Asn Phe Leu Leu Val Gly Thr Ala Asp Gly Lys Leu Ala Ile Phe Glu Asp Lys Thr Val Lys Leu Lys Gly Ala Ala Pro Leu Lys Ile Leu Asn Ile Gly Asn Val Ser Thr Pro Leu Met Cys Leu Ser G1u Ser Thr Asn Ser Thr Glu Arg Asn Val Met Trp Gly Gly Cys Gly Thr Lys Ile Phe Ser Phe Ser Asn Asp Phe Thr Ile Gln Lys Leu I1e Glu Thr Arg Thr Ser Gln Leu Phe Ser Tyr Ala Ala Phe Ser Asp Ser Asn Ile Ile Thr Val Val Val Asp Thr Ala Leu Tyr Ile Ala Lys Gln Asn Ser Pro Val Val Glu Val Trp Asp Lys Lys Thr Glu Lys Leu Cys Gly Leu Ile Asp Cys Val His Phe Leu Arg Glu Val Thr Val Lys Glu Asn Lys Glu Ser Lys His Lys Met Ser Tyr Ser Gly Arg Val Lys Thr Leu Cys Leu Gln Lys Asn Thr Ala,Leu Trp Ile Gly Thr Gly Gly Gly His Ile Leu Leu Leu Asp Leu Ser Thr Arg Arg Leu Ile Arg Val Ile Tyr Asn Phe Cys Asn Ser Val Arg Val Met Met Thr Ala Gln Leu Gly Ser Leu Lys Asn Val Met Leu Val Leu Gly Tyr Asn Arg Lys Asn Thr Glu Gly Thr Gln Lys Gln Lys Glu I1e Gln Ser Cys Leu Thr Va1 Trp Asp Ile Asn Leu Pro His Glu Val Gln Asn Leu Glu Lys His Ile Glu Val Arg Lys Glu Leu Ala Glu Lys Met Arg Arg Thr Ser Val Glu <210> 6 <211> 596 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 2634875CD1 <400> 6 Met Ala Thr Glu Asn Gly Ala Val Glu Leu Gly Ile Gln Asn Pro 1 5 l0 15 Ser Thr Asp Lys Ala Pro Lys Gly Pro Thr Gly Glu Arg Pro Leu Ala Ala Gly Lys Asp Pro Gly Pro Pro Asp Pro Lys Lys Ala Pro Asp Pro Pro Thr Leu Lys Lys Asp Ala Lys Ala Pro Ala Ser Glu Lys Gly Asp Gly Thr Leu Ala Gln Pro Ser Thr Ser Ser Gln Gly Pro Lys Gly Glu Gly Asp Arg Gly Gly Gly Pro Ala Glu Gly Ser Ala Gly Pro Pro Ala Ala Leu Pro Gln Gln Thr Ala Thr Pro Glu Thr Ser Val Lys Lys Pro Lys Ala Glu Gln Gly Ala Ser Gly Ser Gln Asp Pro Gly Lys Pro Arg Val Gly Lys Lys Ala Ala Glu Gly Gln Ala Ala Ala Arg Arg Gly Ser Pro Ala Phe Leu His Ser Pro Ser Cys Pro Ala Ile T1e Ser Ser Ser Glu Lys Leu Leu Ala Lys Lys Pro Pro Ser Glu Ala Ser Glu Leu Thr Phe Glu Gly Val Pro Met Thr His Ser Pro Thr Asp Pro Arg Pro Ala Lys Ala Glu Glu Gly Lys Asn Ile Leu Ala Glu Ser Gln Lys Glu Val Gly Glu Lys Thr Pro Gly Gln Ala Gly Gln Ala Lys Met Gln Gly Asp Thr Ser Arg Gly Ile Glu Phe Gln Ala Val Pro Ser Glu Lys Ser Glu Val Gly Gln A1a Leu Cys Leu Thr Ala Arg G1u Glu Asp Cys Phe Gln Ile Leu Asp Asp Cys Pro Pro Pro Pro Ala Pro Phe Pro His Arg Met Val Glu Leu Arg Thr Gly Asn Val Ser Ser Glu Phe Ser Met Asn Ser Lys Glu Ala Leu Gly Gly Gly Lys Phe Gly Ala Val Cys Thr Cys Met Glu Lys Ala Thr Gly Leu Lys Leu Ala Ala Lys Val Ile Lys Lys Gln Thr Pro Lys Asp Lys Glu Met Val Leu Leu Glu Ile Glu Val Met Asn Gln Leu Asn His Arg Asn Leu Ile Gln Leu Tyr Ala Ala Ile Glu Thr Pro His Glu Ile Val Leu Phe Met Glu Tyr Ile G1u Gly Gly Glu Leu Phe Glu Arg Ile Val Asp G1u Asp Tyr His Leu Thr Glu Val Asp Thr Met Val Phe Val~Arg Gln Ile Cys Asp Gly Ile Leu Phe Ser Val Leu Glu Arg Val Leu His Leu Asp Leu Lys Pro Glu Asn Ile Leu Cys Va1 Asn Thr Thr Gly His Leu Val Lys Ile Ile Asp Phe Gly Leu Ala Arg Arg Tyr Asn Pro Asn Glu Lys Leu Lys Val Asn Phe Gly Thr Pro Glu Phe Leu Ser Pro Glu Val Val Lys Gly Asp Gln Ile Ser Asp Lys Thr Asp Met Trp Ser Met Gly Val Ile Thr Tyr Met Leu Leu Ser Gly Leu Ser Pro Phe Leu Gly Asp Asp Asp Thr Glu Thr Leu Asn Asn Val Leu Ser Gly Asn Trp Tyr Phe Asp Glu Glu Thr Phe Glu Ala Val Ser Asp Glu Ala Lys Asp Phe Val Ser Asn Leu Ile Val Lys Asp Gln Arg Ala Arg Met Asn Ala Ala Gln Cys Leu Ala His Pro Trp Leu Asn Asn Leu A1a Glu Lys Ala Lys Arg Cys Asn Arg Arg Leu Lys Ser Gln Ile Leu Leu Lys Lys Tyr Leu Met Lys Arg Arg Trp Lys Lys Asn Phe Ile Ala Val Ser Ala Ala Asn Arg Phe Lys Lys Ile Ser Ser Ser Gly Ala Leu Met Ala Leu Gly Val <210> 7 <211> 497 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 3951059CD1 <400> 7 Met Leu Lys Phe Lys Tyr Gly Ala Arg Asn Pro Leu Asp Ala Gly Ala Ala Glu Pro Ile Ala Ser Arg A1a Ser Arg Leu Asn Leu Phe Phe Gln Gly Lys Pro Pro Phe Met Thr Gln Gln Gln Met Ser Pro Leu Ser Arg Glu Gly Ile Leu Asp Ala Leu Phe Val Leu Phe Glu G1u Cys Ser Gln Pro Ala Leu Met Lys Ile Lys His Val Ser Asn Phe Val Arg Lys Tyr Ser Asp Thr Ile Ala Glu Leu G1n G1u Leu Gln Pro Ser A1a Lys Asp Phe Glu Va1 Arg Ser Leu Va1 Gly Cys Gly His Phe Ala Glu Val Gln Val Val Arg Glu Lys Ala Thr Gly Asp Ile Tyr Ala Met Lys Val Met Lys Lys Lys Ala Leu Leu Ala Gln Glu Gln Val Ser Phe Phe Glu Glu Glu Arg Asn Ile Leu Ser Arg Ser Thr Ser Pro Trp Ile Pro Gln Leu Gln Tyr Ala Phe Gln Asp Lys Asn His Leu Tyr Leu Val Met Glu Tyr G1n Pro Gly Gly Asp Leu Leu Ser Leu Leu Asn Arg Tyr Glu Asp Gln Leu Asp G1u Asn Leu Ile Gln Phe Tyr Leu Ala Glu Leu Ile Leu Ala Val His Ser Val His Leu Met Gly Tyr Val His Arg Asp I1e Lys Pro Glu Asn Tle Leu Va1 Asp Arg Thr Gly His Ile Lys Leu Va1 Asp Phe G1y Ser Ala Ala Lys Met Asn Ser Asn Lys Met Val Asn Ala Lys Leu Pro Ile Gly Thr Pro Asp Tyr Met Ala Pro Glu Val Leu Thr Val Met Asn Gly Asp Gly Lys Gly Thr Tyr Arg Leu Asp Cys Asp Trp Trp Ser Val Gly Val Ile Ala Tyr Glu Met Ile Tyr Gly Arg Ser Pro Phe Ala Glu Gly Thr Ser Ala Arg Thr Phe Asn Asn Ile Met Asn Phe G1n Arg Phe Leu Lys Phe Pro Asp Asp Pro Lys Val Ser Ser Asp Phe Leu Asp Leu Ile Gln Ser Leu Leu Cys Gly Gln Lys Glu Arg Leu Lys Phe Glu Gly Leu Cys Cys His Pro Phe Phe Ser Lys Ile Asp Trp Asn Asn Ile Arg Asn Ser Pro Pro Pro Phe Val Pro Thr Leu Lys Ser Asp Asp Asp Thr Ser Asn Phe Asp Glu 380 385 . 390 Pro Glu Lys Asn Ser Trp Val Ser Ser Ser Pro Cys Gln Leu Ser Pro Ser Gly Phe Ser Gly Glu Glu Leu Pro Phe Val Gly Phe Ser Tyr Ser Lys Ala Leu Gly I1e Leu Gly Arg Ser G1u Ser Val Val 425 ' 430 435 Ser Gly Leu Asp Ser Pro Ala Lys Thr Ser Ser Met G1u Lys Lys Leu Leu Ile Lys Ser Lys Glu Leu Gln Asp Ser Gln Asp Lys Cys His Lys Val Phe Ile Ser Ala Ala Gly Leu Leu Pro Cys Ser Arg Ile Leu Pro Ser Val Tyr Ala Lys Gly Ser Ala Arg Gly Arg Cys Trp Leu <210> 8 <211> 1171 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 7395890CD1 <400> 8 Met Ala Pro Val Tyr Glu Gly Met Ala Ser His Val Gln Val Phe 1 5 l0 15 Ser Pro His Thr Leu Gln Ser Ser Ala Phe Cys Ser Val Lys Lys Leu Lys Ile Glu Pro Ser Ser Asn Trp Asp Met Thr Gly Tyr Gly Ser His Ser Lys Val Tyr Ser Gln Ser Lys Asn Ile Pro Leu Ser Gln Pro Ala Thr Thr Thr Val Ser Thr Ser Leu Pro Val Pro Asn Pro Ser Leu Pro Tyr Glu Gln Thr Ile Val Phe Pro Gly Ser Thr Gly His Ile Val Val Thr Ser Ala Ser Ser Thr Ser Val Thr Gly Gln Val Leu Gly Gly Pro His Asn Leu Met Arg Arg Ser Thr Va1 Ser Leu Leu Asp Thr Tyr Gln Lys Cys Gly Leu Lys Arg Lys Ser Glu Glu Ile Glu Asn Thr Ser Ser Val Gln Ile Ile Glu Glu His Pro Pro Met Ile Gln Asn Asn A1a Ser Gly Ala Thr Val Ala Thr Ala Thr Thr Ser Thr Ala Thr Ser Lys Asn Ser Gly Ser Asn Ser Glu Gly Asp Tyr Gln Leu Val Gln His Glu Val Leu Cys Ser Met Thr Asn Thr Tyr G1u Val Leu Glu Phe Leu Gly Arg Gly Thr Phe Gly Gln Val Val Lys Cys Trp Lys Arg G1y Thr Asn Glu Ile Val Ala Ile Lys Ile Leu Lys Asn His Pro Ser Tyr Ala Arg Gln Gly Gln Tle G1u Val Ser Ile Leu Ala Arg Leu Ser Thr Glu Ser Ala Asp Asp Tyr Asn Phe Val Arg Ala Tyr Glu Cys Phe Gln His Lys Asn His Thr Cys Leu Val Phe G1u Met Leu Glu Gln Asn Leu Tyr Asp Phe Leu Lys Gln Asn Lys Phe Ser Pro Leu Pro Leu Lys Tyr Ile Arg Pro Val Leu Gln Gln Val Ala Thr Ala Leu Met Lys Leu Lys Ser Leu Gly Leu Ile His Ala Asp Leu Lys Pro Glu Asn Ile Met Leu Val Asp Pro Ser Arg Gln Pro Tyr Arg Val Lys Val Ile Asp Phe Gly Ser Ala Ser His Val Ser Lys Ala Val Cys Ser Thr Tyr Leu Gln Ser Arg Tyr Tyr Arg Ala Pro Glu I1e Ile Leu Gly Leu Pro Phe Cys Glu Ala Ile Asp Met Trp Ser Leu Gly Cys Val I1e Ala Glu Leu Phe Leu Gly Trp Pro Leu Tyr Pro Gly Ala Ser Glu Tyr Asp Gln I1e Arg Tyr Ile Ser Gln Thr Gln Gly Leu Pro A1a Glu Tyr Leu Leu Ser Ala Gly Thr Lys Thr Thr Arg Phe Phe Asn Arg Asp Thr Asp Ser Pro Tyr Pro Leu Trp Arg Leu Lys Thr Pro Asp Asp His Glu Ala G1u Thr Gly Ile Lys Ser Lys Glu Ala Arg Lys Tyr Ile Phe Asn Cys Leu Asp Asp Met Ala Gln Val Asn Met Thr Thr Asp Leu Glu Gly Ser Asp Met Leu Val Glu Lys Ala Asp Arg Arg Glu Phe Ile Asp Leu Leu Lys Lys Met Leu Thr Ile Asp Ala Asp Lys Arg Ile Thr Pro Ile Glu Thr Leu Asn His Pro Phe Val Thr Met Thr His Leu Leu Asp Phe Pro His Ser Thr His Val Lys Ser Cys Phe Gln Asn Met Glu Ile Cys Lys Arg Arg Val Asn Met Tyr Asp Thr Val Asn Gln Ser Lys Thr Pro Phe Ile Thr His Val Ala Pro Ser Thr Ser Thr Asn Leu Thr Met Thr Phe Asn Asn Gln Leu Thr Thr Val His Asn Gln Pro Ser Ala Ala Ser Met Ala Ala Val Ala Gln Arg Ser Met Pro Leu Gln Thr Gly Thr Ala Gln Ile Cys Ala Arg Pro Asp Pro Phe G1n Gln Ala Leu Ile Val Cys Pro Pro Gly Phe Gln Gly Leu G1n Ala Ser Pro Ser Lys His Ala Gly Tyr Ser Val Arg Met Glu Asn Ala Val Pro Ile Val Thr Gln Ala Pro Gly Ala Gln Pro Leu Gln Ile Gln Pro Gly Leu Leu Ala Gln Gln Ala Trp Pro Ser Gly Thr Gln Gln Ile Leu Leu Pro Pro Ala Trp Gln Gln Leu Thr Gly Val Ala Thr His Thr Ser Val Gln His Ala Thr Val Ile Pro Glu Thr Met Ala Gly Thr Gln Gln Leu Ala Asp Trp Arg Asn Thr His A1a His Gly Ser His Tyr Asn Pro Ile Met Gln Gln Pro Ala Leu Leu Thr Gly His Val Thr Leu Pro Ala Ala Gln Pro Leu Asn Val Gly Val A1a His Val Met Arg Gln Gln Pro Thr Ser Thr Thr Ser Ser Arg Lys Ser Lys Gln His Gln Ser Ser Val Arg Asn Val Ser Thr Cys Glu Val Ser Ser Ser Gln Ala Ile Ser Ser Pro Gln Arg Ser Lys Arg Val Lys Glu Asn Thr Pro Pro Arg Cys Ala Met Val His Ser Ser Pro Ala Cys Ser Thr Ser Val Thr Cys Gly Trp Gly Asp Val Ala Ser Ser Thr Thr Arg Glu Arg Gln Arg Gln Thr Ile Va1 Ile Pro Asp Thr Pro Ser Pro Thr Val Ser Val I1e Thr Ile Ser Ser Asp Thr Asp Glu Glu Glu Glu Gln Lys His Ala Pro Thr Ser Thr Val Ser Lys Gln Arg Lys Asn Val Ile Ser Cys Val Thr Val His Asp Ser Pro Tyr Ser Asp Ser Ser Ser Asn Thr Ser Pro Tyr Ser Val Gln Gln Arg Ala Gly His Asn Asn Ala Asn Ala Phe Asp Thr Lys G1y Ser Leu Glu Asn His Cys Thr Gly Asn Pro Arg Thr Ile Ile Val Pro Pro Leu Lys Thr Gln Ala Ser G1u Va1 Leu Val Glu Cys Asp Ser Leu Val Pro Val Asn Thr Ser His His Ser Ser Ser Tyr Lys Ser Lys Ser Ser Ser Asn Val Thr Ser Thr Ser G1y His Ser Ser Gly Ser Ser Ser Gly Ala Ile Thr Tyr Arg Gln Gln Arg Pro Gly Pro His Phe Gln Gln Gln Gln Pro Leu Asn Leu Ser Gln Ala Gln Gln His Ile Thr Thr Asp Arg Thr Gly Ser His Arg Arg Gln Gln Ala Tyr Ile Thr Pro Thr Met Ala Gln Ala Pro Tyr Ser Phe Pro His Asn Ser Pro Ser His Gly Thr Val His Pro His Leu Ala Ala A1a Ala Ala A1a Ala His Leu Pro Thr G1n Pro His Leu Tyr Thr Tyr Thr Ala Pro A1a A1a Leu Gly Ser Thr Gly Thr Va1 A1a His Leu Val Ala Ser Gln Gly Ser Ala Arg His Thr Val Gln His Thr Ala Tyr Pro Ala Ser Ile Val His Gln Val Pro Val Ser Met Gly Pro Arg Val Leu Pro Ser Pro Thr Ile His Pro Ser Gln Tyr Pro Ala Gln Phe Ala His Gln Thr Tyr Ile Ser Ala Ser Pro Ala Ser Thr Val Tyr Thr Gly Tyr Pro Leu Ser Pro Ala Lys Val Asn Gln Tyr Pro Tyr Ile <210> 9 <211> 470 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7475546CD1 <400> 9 Met A1a Gly Pro Gly Trp Gly Pro Pro Arg Leu Asp Gly Phe Ile Leu Thr Glu Arg Leu Gly Ser Gly Thr Tyr Ala Thr Val Tyr Lys Ala Tyr Ala Lys Lys Asp Thr Arg Glu Val Val Ala Ile Lys Cys 35 40 45' Va1 Ala Lys Lys Ser Leu Asn Lys Ala Ser Val G1u Asn Leu Leu Thr Glu I1e Glu Ile Leu Lys Gly Ile Arg His Pro His Ile Val G1n Leu Lys Asp Phe Gln Trp Asp Ser Asp Asn Ile Tyr Leu Ile Met Glu Phe Cys Ala G1y Gly Asp Leu Ser Arg Phe Ile His Thr Arg Arg Ile Leu Pro Glu Lys Val Ala Arg Val Phe Met Gln Gln Leu Ala Ser Ala Leu Gln Phe Leu His Glu Arg Asn Ile Ser His Leu Asp Leu Lys Pro Gln Asn Ile Leu Leu Ser Ser Leu Glu Lys Pro His Leu Lys Leu Ala Asp Phe Gly Phe Ala Gln His Met Ser Pro Trp Asp Glu Lys His Val Leu Arg Gly Ser Pro Leu Tyr Met Ala Pro Glu Met Val Cys Gln Arg Gln Tyr Asp Ala Arg Val Asp Leu Trp Ser Met Gly Val Ile Leu Tyr Glu Ala Leu Phe Gly Gln Pro Pro Phe Ala Ser Arg Ser Phe Ser Glu Leu Glu Glu Lys Ile Arg Ser Asn Arg Val Ile Glu Leu Pro Leu Arg Pro Leu Leu Ser Arg Asp Cys Arg Asp Leu Leu Gln Arg Leu Leu Glu Arg Asp Pro Ser Arg Arg Ile Ser Phe Gln Asp Phe Phe Ala His Pro Trp Val Asp Leu Glu His Met Pro Ser Gly Glu Ser Leu Gly Arg Ala Thr Ala Leu Val Val Gln Ala Va1 Lys Lys Asp Gln Glu Gly Asp Ser Ala Ala Ala Leu Ser Leu Tyr Cys Lys Ala Leu Asp Phe Phe Val Pro Ala Leu His Tyr Glu Val Asp A1a Gln Arg Lys Glu Ala Ile Lys Ala Lys Va1 Gly Gln Tyr Val Ser Arg Ala Glu Glu Leu Lys Ala Tle Val Ser Ser Ser Asn Gln Ala Leu Leu Arg Gln Gly Thr Ser Ala Arg Asp Leu Leu Arg Glu Met Ala Arg Asp Lys Pro Arg Leu Leu Ala A1a Leu Glu Val Ala Ser Ala Ala Met Ala Lys Glu Glu Ala Ala Gly Gly Glu Gln Asp Ala Leu Asp Leu Tyr Gln His Ser Leu G1y Glu Leu Leu Leu Leu Leu Ala Ala Glu Pro Pro Gly Arg Arg Arg G1u Leu Leu His Thr Glu Val Gln Asn Leu Met Ala Arg Ala Glu Tyr Leu Lys Glu Gln Met Arg Glu Ser Arg Trp Glu Ala Asp Thr Leu Asp Lys Glu Gly Leu Ser Glu Ser Va1 Arg Ser Ser Cys Thr Leu Gln <210> 10 <211> 422 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 7477076CD1 <400> 10 Met Asp His Pro Ser Arg Glu Lys Asp Glu Arg Gln Arg Thr Thr Lys Pro Met Ala Gln Arg Ser Ala His Cys Ser Arg Pro Ser G1y Ser Ser Ser Ser Ser Gly Val Leu Met Val Gly Pro Asn Phe Arg Val Gly Lys Lys Ile Gly Cys Gly Asn Phe Gly Glu Leu Arg Leu Gly Lys Asn Leu Tyr Thr Asn Glu Tyr Val Ala Ile Lys Leu Glu Pro Ile Lys Ser Arg Ala Pro Gln Leu His Leu Glu Tyr Arg Phe Tyr Lys Gln Leu Gly Ser Ala Gly Glu Gly Leu Pro Gln Val Tyr Tyr Phe G1y Pro Cys Gly Lys Tyr Asn Ala Met Val Leu Glu Leu Leu Gly Pro Ser Leu Glu Asp Leu Phe Asp Leu Cys Asp Arg Thr Phe Thr Leu Lys Thr Val Leu Met Tle Ala Ile Gln Leu Leu Ser Arg Met Glu Tyr Val His Ser Lys Asn Leu I1e Tyr Arg Asp Val Lys Pro Glu Asn Phe Leu Ile Gly Arg Gln Gly Asn Lys Lys Glu l70 175 180 His Val Ile His I1e Ile Asp Phe Gly Leu Ala Lys Glu Tyr Ile Asp Pro Glu Thr Lys Lys His Ile Pro Tyr Arg Glu His Lys Ser Leu Thr Gly Thr Ala Arg Tyr Met Ser Ile Asn Thr His Leu Gly Lys Glu Gln Ser Arg Arg Asp Asp Leu Glu Ala Leu Gly His Met Phe Met Tyr Phe Leu Arg Gly Ser Leu Pro Trp Gln Gly Leu Lys Ala Asp Thr Leu Lys G1u Arg Tyr Gln Lys Ile G1y Asp Thr Lys Arg Asn Thr Pro 21e Glu Ala Leu Cys Glu Asn Phe Pro Glu Glu Met A1a Thr Tyr Leu Arg Tyr Val Arg Arg Leu Asp Phe Phe Glu Lys Pro Asp Tyr Glu Tyr Leu Arg Thr Leu Phe Thr Asp Leu Phe Glu Lys Lys Gly Tyr Thr Phe Asp Tyr Ala Tyr Asp Trp Val Gly Arg Pro Ile Pro Thr Pro Val G1y Ser Val His Val Asp Ser Gly Ala Ser Ala Ile Thr Arg Glu Ser His Thr His Arg Asp Arg Pro Ser Gln Gln Gln Pro Leu Arg Asn Gln Val Val Ser Ser Thr Asn Gly Glu Leu Asn Val Asp Asp Pro Thr Gly Ala His Ser Asn Ala Pro Ile Thr Ala His Ala Glu Val G1u Val Val Glu Glu Ala Lys Cys Cys Cys Phe Phe Lys Arg Lys Arg Lys Lys Thr Ala Gln Arg His Lys <210> 11 <211> 240 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: .1874092CD1 <400> l1 Met Pro Val Ser Lys Cys Pro Lys Lys Ser Glu Ser Leu Trp Lys Gly Trp Asp Arg Lys Ala Gln Arg Asn Gly Leu Arg Ser Gln Val Tyr Ala Val Asn Gly Asp Tyr Tyr Val Gly Glu Trp Lys Asp Asn Val Lys His Gly Lys Gly Thr Gln Val Trp Lys Lys Lys Gly Ala Ile Tyr Glu Gly Asp Trp Lys Phe Gly Lys Arg Asp Gly Tyr Gly Thr Leu Ser Leu Pro Asp Gln Gln Thr Gly Lys Cys Arg Arg Val Tyr Ser Gly Trp Trp Lys Gly Asp Lys Lys Ser Gly Tyr Gly Ile Gln Phe Phe Gly Pro Lys Glu Tyr Tyr Glu Gly Asp Trp Cys Gly Ser Gln Arg Ser Gly Trp G1y Arg Met Tyr Tyr Ser Asn Gly Asp Ile Tyr Glu Gly Gln Trp Glu Asn Asp Lys Pro Asn Gly Glu Gly Met Leu Arg Leu Lys Asn Gly Asn Arg Tyr Glu Gly Cys Trp Glu Arg Gly Met Lys Asn Gly Ala Gly Arg Phe Phe His Leu Asp His Gly Gln Leu Phe Glu Gly Phe Trp Val Asp Asn Met Ala Lys Cys Gly Thr Met Ile Asp Phe Gly Arg Asp Glu Ala Pro Glu Pro Thr 200 ~ 205 210 Gln Phe Pro Ile Pro Glu Val Lys I1e Leu Asp Pro Asp Gly Val Leu Ala Glu Ala Leu Ala Met Phe Arg Lys Thr Glu Glu G1y Asp <210> 12 <211> 594 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 4841542CD1 <400> 12 Met Lys Lys Gln Ala Val Lys Arg His His His Lys His Asn Leu Arg His Arg Tyr Glu Phe Leu Glu Thr Leu Gly Lys Gly Thr Tyr G1y Lys Val Lys Lys Ala Arg Glu Ser Ser Gly Arg Leu Val Ala Ile Lys Ser Ile Arg Lys Asp Lys Ile Lys Asp Glu Gln Asp Leu Met His Ile Arg Arg Glu Ile Glu Ile Met Ser Ser Leu Asn His Pro His I1e Ile Ala Ile His G1u Val Phe Glu Asn Ser Ser Lys Ile Val Ile Val Met Glu Tyr Ala Ser Arg Gly Asp Leu Tyr Asp Tyr Ile Ser G1u Arg Gln Gln Leu Ser Glu Arg G1u Ala Arg His Phe Phe Arg Gln Ile Val Ser Ala Val His Tyr Cys His Gln Asn Arg Val Val His Arg Asp Leu Lys Leu G1u Asn I1e Leu Leu Gly Ala Asn Gly Asn I1e Lys Ile Ala Asp Phe G1y Leu Ser Asn Leu Tyr His Gln Gly Lys Phe Leu Gln Thr Phe Cys Gly Ser Pro Leu Tyr Ala Ser Pro Glu Ile Val Asn Gly Lys Pro Tyr Thr Gly Pro Glu Val Asp Ser Trp Ser Leu Gly Val Leu Leu Tyr Ile Leu Val His Gly Thr Met Pro Phe Asp G1y His Asp His Lys Ile Leu Val Lys Gln Ile Ser Asn Gly Ala Tyr Arg Glu Pro Pro Lys Pro Ser Asp Ala Cys Gly Leu Ile Arg Trp Leu Leu Met Val Asn Pro Thr Arg Arg Ala Thr Leu Glu Asp Val Ala Ser His Trp Trp Val Asn Trp Gly Tyr Ala Thr Arg Val G1y Glu Gln Glu Ala Pro His Glu Gly Gly His Pro Gly Ser Asp Ser Ala Arg Ala Ser Met Ala Asp Trp Leu Arg Arg Ser Ser Arg Pro Leu Leu Glu Asn Gly Ala Lys Val Cys Ser Phe Phe Lys Gln His Ala Pro Gly Gly Gly Ser Thr Thr Pro Gly Leu Glu Arg Gln His Ser Leu Lys Lys Ser Arg Lys G1u Asn Asp Met A1a G1n Ser Leu His Ser Asp Thr Ala Asp Asp Thr Ala His Arg Pro Gly Lys Ser Asn Leu Lys Leu Pro Lys Gly Ile Leu Lys Lys Lys Val Ser Ala Ser Ala Glu Gly Va1 G1n Glu Asp Pro Pro Glu Leu Ser Pro Ile Pro Ala Ser Pro Gly Gln Ala Ala Pro Leu Leu Pro Lys Lys Gly Ile Leu Lys Lys Pro Arg Gln Arg Glu Ser Gly Tyr Tyr Ser Ser Pro Glu Pro Ser Glu Ser Gly 425 430 43.5 Glu Leu Leu Asp Ala Gly Asp Val Phe Val Ser Gly Asp Pro Lys Glu Gln Lys Pro Pro Gln Ala Ser Gly Leu Leu Leu His Arg Lys Gly Ile Leu Lys Leu Asn Gly Lys Phe Ser Gln Thr Ala Leu Glu Leu Ala Ala Pro Thr Thr Phe Gly Ser Leu Asp Glu Leu Ala Pro Pro Arg Pro Leu Ala Arg Ala Ser Arg Pro Ser Gly Ala Val Ser Glu Asp Ser Ile Leu Ser Ser Glu Ser Phe Asp Gln Leu Asp Leu Pro Glu Arg Leu Pro Glu Pro Pro Leu Arg Gly Cys Val Ser Val Asp Asn Leu Thr Gly Leu Glu Glu Pro Pro Ser Glu Gly Pro Gly Sex Cys Leu Arg Arg Trp Arg Gln Asp Pro Leu Gly Asp Ser Cys Phe Ser Leu Thr Asp Cys Gln Glu Val Thr Ala Thr Tyr Arg Gln Ala Leu Arg Val Cys Ser Lys Leu Thr <210> 13 <211> 473 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7472695CD1 17!61 <400> 13 Met Ser Gln Thr Ser Ser Ile Gly Ser Ala Glu Ser Leu Ile Ser Leu Glu Arg Lys Lys Glu Lys Asn Ile Asn Arg Asp Ile Thr Ser Arg Lys Asp Leu Pro Ser Arg Thr Ser Asn Val Glu Arg Lys Ala Ser Gln Gln Gln Trp Gly Arg Gly Asn Phe Thr Glu Gly Lys Val Pro His I1e Arg Ile Glu Asn Gly Ala Ala Ile Glu Glu I1e Tyr Thr Phe Gly Arg Ile Leu Gly Lys Gly Ser Phe Gly Ile Val Ile Glu Ala Thr Asp Lys Glu Thr Glu Thr Lys Trp Ala Ile Lys Lys Val Asn Lys Glu Lys Ala Gly Ser Ser A1a Val Lys Leu Leu Glu Arg Glu Val Asn Ile Leu Lys Ser Val Lys His Glu His Ile Ile His Leu Glu Gln Val Phe Glu Thr Pro Lys Lys Met Tyr Leu Val Met Glu Leu Cys Glu Asp Gly Glu Leu Lys Glu Ile Leu Asp Arg Lys Gly His Phe Ser Glu Asn Glu Thr Arg Trp Ile Ile Gln Ser Leu Ala Ser Ala I1e Ala Tyr Leu His Asn Asn Asp Ile Val His Arg Asp Leu Lys Leu Glu Asn Ile Met Val Lys Ser Ser Leu Ile Asp Asp Asn Asn Glu Ile Asn Leu Asn Ile Lys Val Thr Asp Phe Gly Leu A1a Val Lys Lys G1n Ser Arg Ser Glu A1a Met Leu Gln Ala Thr Cys Gly Thr Pro Ile Tyr Met Ala Pro Glu Val Ile Ser Ala His Asp Tyr Ser Gln Gln Cys Asp Ile Trp Ser I1e Gly Val Val Met Tyr Met Leu Leu Arg Gly Glu Pro Pro Phe Leu Ala Ser Ser Glu Glu Lys Leu Phe Glu Leu Ile Arg Lys Gly Glu Leu His Phe Glu Asn Ala Val Trp Asn Ser Ile Ser Asp Cys Ala Lys Ser 305 ~ 310 ~ 315 Val Leu Lys Gln Leu Met Lys Val Asp Pro Ala His Arg Ile Thr Ala Lys Glu Leu Leu Asp Asn G1n Trp Leu Thr Gly Asn Lys Leu Ser Ser Val Arg Pro Thr Asn Va1 Leu Glu Met Met Lys Glu Trp Lys Asn Asn Pro Glu Ser Val Glu Glu Asn Thr Thr Glu Glu Lys Asn Lys Pro Ser Thr G1u Glu Lys Leu Lys Ser Tyr Gln Pro Trp Gly Asn Val Pro Asp Ala Asn Tyr Thr Ser Asp Glu Glu Glu G1u Lys Gln Ser Thr A1a Tyr Glu Lys Gln Phe Pro Ala Thr Ser Lys Asp Asn Phe Asp Met Cys Ser Ser Ser Phe Thr Ser Ser Lys Leu Leu Pro Ala Glu Ile Lys Gly Glu Met Glu Lys Thr Pro Val Thr Pro Ser Gln Gly Thr Ala Thr Lys Tyr Pro Ala Lys Ser Gly Ala Leu Ser Arg Thr Lys Lys Lys Leu <210> 14 <211> 947 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7477966CD1 <400> 14 Met Met Ser Asp Thr Ser Thr Phe Pro Asn His Pro Ser Ser Pro Ala Ala Ser Pro Ser Gly Gly Arg Gly Val Met Ala Ser Pro Ala Trp Asp Arg Ser Lys Gly Trp Ser Gln Thr Pro Gln Arg Ala Asp Phe Val Ser Thr Pro Leu Gln Val His Thr Leu Arg Pro Glu Asn Leu Leu Leu Val Ser Thr Leu Asp Gly Ser Leu His Ala Leu Ser Lys Gln Thr Gly Asp Leu Lys Trp Thr Leu Arg Asp Asp Pro Val Ile Glu Gly Pro Met Tyr Val Thr Glu Met Ala Phe Leu Ser Asp Pro Ala Asp G1y Ser Leu Tyr Ile Leu Gly Thr Gln Lys Gln Gln Gly Leu Met Lys Leu Pro Phe Thr I1e Pro Glu Leu Val His A1a Ser Pro Cys Arg Ser Ser Asp Gly Val Phe Tyr Thr Gly Arg Lys Gln Asp Ala Trp Phe Val Val Asp Pro Glu Ser Gly Glu Thr Gln Met Thr Leu Thr Thr Glu Gly Pro Ser Thr Pro Arg Leu Tyr Ile Gly Arg Thr Gln Tyr Thr Val Thr Met His Asp Pro Arg Ala Pro Ala Leu Arg Trp Asn Thr Thr Tyr Arg Arg Tyr Ser Ala Pro Pro Met Asp Gly Ser Pro Gly Lys Tyr Met Ser His Leu Ala Ser Cys Gly Met Gly Leu Leu Leu Thr Val Asp Pro Gly Ser Gly Thr Val Leu Trp Thr Gln Asp Leu Gly Val Pro Val Met Gly Val Tyr Thr Trp His Gln Asp Gly Leu Arg Gln Leu Pro His Leu Thr Leu Ala Arg Asp Thr Leu His Phe Leu Ala Leu Arg Trp Gly His Ile Arg Leu Pro Ala Ser Gly Pro Arg Asp Thr Ala Thr Leu Phe Ser Thr Leu Asp Thr Gln Leu Leu Met Thr Leu Tyr Val Gly Lys Asp Glu Thr Gly Phe Tyr Val Ser Lys Ala Leu Val His Thr Gly Val Ala Leu Val Pro Arg Gly Leu Thr Leu Ala Pro Ala Asp Gly Pro Thr Thr Asp Glu Val Thr Leu Gln Val Ser Gly Glu Arg Glu Gly Ser Pro Ser Thr Ala Val Arg Tyr Pro Ser Gly Ser Val Ala Leu Pro Ser Gln Trp Leu Leu Ile Gly His His Glu Leu Pro Pro Val Leu His Thr Thr Met Leu Arg Val His Pro Thr Leu Gly Ser Gly Thr Ala Glu Thr Arg Pro Pro Glu Asn Thr Gln Ala Pro Ala Phe Phe Leu Glu Leu Leu Ser Leu Ser Arg Glu Lys Leu Trp Asp Ser Glu Leu His Pro Glu Glu Lys Thr Pro Asp Ser Tyr Leu Gly Leu Gly Pro Gln Asp Leu Leu Ala Ala Ser Leu Thr Ala Val Leu Leu Gly Gly Trp Tle Leu Phe Val Met Arg Gln Gln Gln Pro Gln Val Val Glu Lys Gln Gln Glu Thr Pro Leu Ala Pro Ala Asp Phe A1a His Ile Ser Gln Asp Ala Gln Ser Leu His Ser Gly Ala Ser Arg Arg Ser Gln Lys Arg Leu Gln Ser Pro Ser Lys Gln Ala Gln Pro Leu Asp Asp Pro Glu Ala Glu Gln Leu Thr Val Val Gly Lys Ile Ser Phe Asn Pro Lys Asp Val Leu Gly Arg Gly Ala Gly Gly Thr Phe Val Phe Arg Gly Gln Phe Glu Gly Arg Ala Val Ala Val Lys Arg Leu Leu Arg Glu Cys Phe Gly Leu Val Arg Arg Glu Val Gln Leu Leu Gln Glu Ser Asp Arg His Pro Asn Val Leu Arg Tyr Phe Cys Thr Glu Arg Gly Pro Gln Phe His Tyr Ile Ala Leu Glu Leu Cys Arg Ala Ser Leu Gln Glu Tyr Val Glu Asn Pro Asp Leu Asp Arg Gly Gly Leu Glu Pro G1u Val Val Leu Gln G1n Leu Met Ser G1y Leu Ala His Leu His Ser Leu His Ile Val His Arg Asp Leu Lys Pro Gly Asn Ile Leu Ile Thr Gly Pro Asp Ser Gln Gly Leu Gly Arg Val Val Leu Ser Asp Phe Gly Leu Cys Lys Lys Leu Pro Ala 680 . 685 690 Gly Arg Cys Ser Phe Ser Leu His Ser Gly I1e Pro Gly Thr Glu Gly Trp Met A1a Pro Glu Leu Leu Gln Leu Leu Pro Pro Asp Ser Pro Thr Ser Ala Val Asp Ile Phe Ser Ala Gly Cys Val Phe Tyr Tyr Val Leu Ser Gly Gly Ser His Pro Phe Gly Asp Ser Leu Tyr Arg Gln Ala As~n Ile Leu Thr Gly Ala Pro Cys Leu Ala His Leu Glu Glu Glu Val His Asp Lys Vah Val Ala Arg Asp Leu Val Gly Ala Met Leu Ser Pro Leu Pro Gln Pro Arg Pro Ser Ala Pro Gln Val Leu Ala His Pro Phe Phe Trp Ser Arg Ala Lys Gln Leu Gln Phe Phe Gln Asp Val Ser Asp Trp Leu Glu Lys Glu Ser Glu Gln Glu Pro Leu Val Arg Ala Leu Glu Ala Gly Gly Cys Ala Val Val Arg Asp Asn Trp His Glu His Ile Ser Met Pro Leu Gln Thr Asp Leu Arg Lys Phe Arg Ser Tyr Lys Gly Thr Ser Val Arg Asp Leu Leu Arg Ala Val Arg Asn Lys Lys His His Tyr Arg Glu Leu Pro Val G1u Val Arg Gln Ala Leu Gly Gln Val Pro Asp Gly Phe Val Gln Tyr Phe Thr Asn Arg Phe Pro Arg Leu Leu Leu His Thr His Arg Ala Met Arg Ser Cys Ala Ser Glu Ser Leu Phe Leu Pro Tyr Tyr Pro Pro Asp Ser Glu Ala Arg Arg Pro Cys Pro Gly Ala Thr Gly Arg <210> 15 <211> 641 <222> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7163416CD1 <400> 15 Met Phe Arg Lys Lys Lys Lys Lys Arg Pro Glu Ile Ser Ala Pro Gln Asn Phe Gln His Arg Val His Thr Ser Phe Asp Pro Lys Glu Gly Lys Phe Val Gly Leu Pro Pro Gln Trp Gln Asn Ile Leu Asp Thr Leu Arg Arg Pro Lys Pro Val Val Asp Pro Ser Arg Ile Thr Arg Val Gln Leu Gln Pro~Met Lys Thr Val Val Arg Gly Ser Ala Met Pro Val Asp Gly Tyr Ile Ser Gly Leu Leu Asn Asp Ile Gln Lys Leu Ser Val Ile Ser Ser Asn Thr Leu Arg Gly Arg Ser Pro 95' 100 105 Thr Ser Arg Arg Arg Ala Gln Ser Leu Gly Leu Leu Gly Asp Glu His Trp Ala Thr Asp Pro Asp Met Tyr Leu Gln Ser Pro Gln Ser Glu Arg Thr Asp Pro His Gly Leu Tyr Leu Ser Cys Asn Gly Gly Thr Pro Ala Gly His Lys Gln Met Pro Trp Pro Glu Pro Gln Ser Pro Arg Val Leu Pro Asn Gly Leu Ala Ala Lys Ala Gln Ser Leu Gly Pro A1a G1u Phe Gln Gly A1a Ser Gln Arg Cys Leu Gln Leu 185 190 ' 195 Gly Ala Cys Leu Gln Ser Ser Pro Pro Gly Ala Ser Pro Pro Thr Gly Thr Asn Arg His Gly Met Lys Ala Ala Lys His Gly Ser Glu Glu Ala Arg Pro Gln Ser Cys Leu Val Gly Ser Ala Thr Gly Arg Pro Gly Gly Glu Gly Ser Pro Ser Pro Lys Thr Arg Glu Ser Ser Leu Lys Arg Arg Leu Phe Arg Ser Met Phe Leu Ser Thr Ala Ala Thr Ala Pro Pro Ser Ser Ser Lys Pro G1y Pro Pro Pro Gln Ser Lys Pro Asn Ser Ser Phe Arg Pro Pro Gln Lys Asp Asn Pro Pro Ser Leu Val Ala Lys Ala Gln Ser Leu Pro Ser Asp Gln Pro Val Gly Thr Phe Ser Pro Leu Thr Thr Ser Asp Thr Ser Ser Pro Gln Lys Ser Leu Arg Thr Ala Pro Ala Thr Gly Gln Leu Pro Gly Arg Ser Ser Pro A1a Gly Ser Pro Arg Thr Trp His Ala Gln Ile Ser Thr Ser Asn Leu Tyr Leu Pro Gln Asp Pro Thr Val Ala Lys Gly Ala Leu Ala Gly Glu Asp Thr Gly Val Val Thr His Glu Gln Phe Lys Ala Ala Leu Arg Met Val Val Asp Gln Gly Asp Pro Arg Leu Leu Leu Asp Ser Tyr Val Lys Tle Gly Glu G1y Ser Thr Gly Ile Val Cys Leu Ala Arg Glu Lys His Ser Gly Arg G1n Val Ala Val Lys Met Met Asp Leu Arg Lys Gln Gln Arg Arg Glu Leu Leu Phe Asn Glu Val Val I1e Met Arg Asp Tyr Gln His Phe Asn Val Val Glu Met Tyr Lys Ser Tyr Leu Val Gly Glu Glu Leu Trp Val Leu Met Glu Phe Leu Gln Gly Gly Ala Leu Thr Asp Ile Va1 Ser Gln Val Arg Leu Asn Glu Glu G1n Ile Ala Thr Val Cys Glu Ala Val Leu Gln Ala Leu AIa Tyr Leu His A1a Gln Gly Val Ile His Arg Asp Ile Lys Ser Asp Ser Ile Leu Leu Thr Leu Asp Gly Arg Val Lys Leu Ser Asp Phe Gly Phe Cys Ala Gln Ile Ser Lys Asp Val Pro Lys Arg Lys Ser Leu Val Gly Thr Pro Tyr Trp Met Ala Pro Glu Val Ile Ser Arg Ser Leu Tyr Ala Thr Glu Val Asp Ile Trp Ser Leu Gly Ile Met Val Ile Glu Met Val Asp Gly Glu Pro Pro Tyr Phe Ser Asp Ser Pro Val Gln Ala Met Lys Arg Leu Arg Asp Ser Pro Pro Pro Lys Leu Lys Asn Ser His Lys Val Ser Trp His Thr Arg Val Arg Pro Arg Arg Pro His Ser Ser <210> 16 <211> 576 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 7472822CD1 <400> 16 Met Pro A1a Leu Ser Thr Gly Ser Gly Ser Asp Thr Gly Leu Tyr Glu Leu Leu Ala Ala Leu Pro Ala Gln Leu Gln Pro His Val Asp Ser Gln Glu Asp Leu Thr Phe Leu Trp Asp Met Phe G1y Glu Lys Ser Leu His Ser Leu Val Lys Ile His G1u Lys Leu His Tyr Tyr Glu Lys Gln Ser Pro Val Pro~Ile Leu His Gly Ala Ala Ala Leu Ala Asp Asp Leu Ala Glu Glu Leu Gln Asn Lys Pro Leu Asn Ser Glu Ile Arg Glu Leu Leu Lys Leu Leu Ser Lys Pro Asn Val Lys Ala Leu Leu Ser Val His Asp Thr Va1 Ala Gln Lys Asn Tyr Asp Pro Val Leu Pro Pro Met Pro Glu Asp Ile Asp Asp Glu Glu Asp Ser Val Lys Ile Ile Arg Leu Val Lys Asn Arg Glu Pro Leu Gly Ala Thr Ile Lys Lys Asp Glu Gln Thr Gly Ala Ile Ile Val Ala Arg Ile Met Arg Gly Gly Ala A1a Asp Arg Ser Gly Leu Ile His 22!61 Val Gly Asp Glu Leu Arg Glu Val Asn Gly Ile Pro Val Glu Asp Lys Arg Pro Glu Glu Ile Ile Gln Ile Leu Ala Gln Ser Gln Gly Ala Ile Thr Phe Lys Ile Ile Pro Gly Ser Lys Glu Glu Thr Pro Ser Lys Glu Gly Lys Met Phe Ile Lys Ala Leu Phe Asp Tyr Asn Pro Asn Glu Asp Lys Ala Ile Pro Cys Lys Glu Ala Gly Leu Ser Phe Lys Lys GIy Asp Ile Leu Gln Ile Met Ser Gln Asp Asp Ala Thr Trp Trp Gln Ala Lys His Glu Ala Asp Ala Asn Pro Arg Ala Gly Leu T1e Pro Ser Lys His Phe Gln G1u Arg Arg Leu Ala Leu Arg Arg Pro Glu Ile Leu Val Gln Pro Leu Lys Val Ser Asn Arg Lys Ser Ser Gly Phe Arg Lys Ser Phe Arg Leu Ser Arg Lys Asp Lys Lys Thr Asn Lys Ser Met Tyr Glu Cys Lys Lys Ser Asp Gln Tyr Asp Thr Ala Asp Val'Pro Thr Tyr Glu Glu Val Thr Pro Tyr Arg Arg Gln Thr Asn Glu Lys Tyr Arg Leu Val Val Leu Val Gly Pro Val Gly Val Gly Leu Asn Glu Leu Lys Arg Lys Leu Leu Ile Ser Asp Thr Gln His Tyr G1y Val Thr Val Pro His Thr Thr Arg Ala Arg Arg Ser Gln Glu Ser Asp Gly Val Glu Tyr Ile Phe Ile Ser Lys His Leu Phe Glu Thr Asp Val Gln Asn Asn Lys Phe Ile Glu Tyr Gly Glu Tyr Lys Asn Asn Tyr Tyr Gly Thr Ser Ile Asp Ser Val Arg Ser Val Leu Ala Lys Asn Lys Val Cys Leu Leu Asp Val Gln Pro His Thr Val Lys His Leu Arg Thr Leu Glu Phe Lys Pro Tyr Val Ile Phe Ile Lys Pro Pro Ser Ile Glu Arg Leu Arg Glu Thr Arg Lys Asn Ala Lys Ile Ile Ser Ser Arg Asp Asp Gln Gly Ala Ala Lys Pro Phe Thr Glu Glu Asp Phe Gln Glu Met Ile Lys Ser Ala Gln Ile Met Glu Ser Gln Tyr Gly His Leu Phe Asp Lys Ile Ile Ile Asn Asp Asp Leu Thr Val Ala Phe Asn Glu Leu Lys Thr Thr Phe Asp Lys Leu Glu Thr Glu Thr His Trp Val Pro Val Ser Trp Leu His Ser <210> 17 <211> 794 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7477486CD1 <400> 17 Met Val Ala Gly Leu Thr Leu Gly Lys Gly Pro Glu Ser Pro Asp G1y Asp Val Ser Val Pro Glu Arg Lys Asp Glu Val Ala Gly Gly Gly Gly Glu Glu Glu Glu Ala Glu Glu Arg Gly Arg His Ala Gln Tyr Val Gly Pro Tyr Arg Leu Glu Lys Thr Leu G1y Lys Gly GIn Thr G1y Leu Val Lys Leu Gly Val His Cys Ile Thr Gly Gln Lys Va1 Ala I1e Lys Ile Val Asn Arg Glu Lys Leu Ser Glu Ser Val Leu Met Lys Val Glu Arg Glu Ile AIa Tle Leu Lys Leu Ile GIu His Pro His Val Leu Lys Leu His Asp Val Tyr Glu Asn Lys Lys Tyr Leu Tyr Leu VaI Leu Glu His Val Ser Gly Gly Glu Leu Phe Asp Tyr Leu Val Lys Lys Gly Arg Leu Thr Pro Lys G1u Ala Arg Lys Phe Phe Arg Gln I1e Val Ser Ala Leu Asp Phe Cys His Ser Tyr Ser IIe Cys His Arg Asp Leu Lys Pro GIu Asn Leu Leu Leu Asp Glu Lys Asn Asn Ile Arg Ile A1a Asp Phe Gly Met Ala Ser Leu Gln Val Gly Asp Ser Leu Leu Glu Thr Ser Cys Gly Ser Pro His Tyr Ala Cys Pro Glu Val Ile Lys Gly Glu Lys Tyr Asp Gly Arg Arg Ala Asp Met Trp Ser Cys Gly Val Ile Leu Phe Ala Leu Leu Val Gly Ala Leu Pro Phe Asp Asp Asp Asn Leu Arg Gln Leu Leu Glu Lys Val Lys Arg Gly Val Phe His Met Pro His Phe Ile Pro Pro Asp Cys Gln Ser Leu Leu Arg Gly Met Ile GIu Val Glu Pro Glu Lys Arg Leu Ser Leu Glu Gln Ile Gln Lys His Pro Trp Tyr Leu Gly Gly Lys His Glu Pro Asp Pro Cys Leu Glu Pro Ala 305 310 . 315 Pro Gly Arg Arg Va1 Ala Met Arg Ser Leu Pro Ser Asn Gly Glu Leu Asp Pro Asp Val Leu Glu Ser Met Ala Ser Leu GIy Cys Phe Arg Asp Arg Glu Arg Leu His Arg Glu Leu Arg Ser Glu Glu Glu Asn Gln Glu Lys Met I1e Tyr Tyr Leu Leu Leu Asp Arg Lys Glu Arg Tyr Pro Ser Cys G1u Asp Gln Asp Leu Pro Pro Arg Asn Asp Val Asp Pro Pro Arg Lys Arg Val Asp Ser Pro Met Leu Ser Arg His G1y Lys Arg Arg Pro Glu Arg Lys Ser Met Glu Val Leu Ser Ile Thr Asp Ala Gly Gly Gly Gly Ser Pro Val Pro Thr Arg Arg Ala Leu Glu Met Ala Gln His Ser Gln Arg Ser Arg Ser Val Ser Gly Ala Ser Thr Gly Leu Ser Ser Ser Pro Leu Ser Ser Pro Arg Ser Pro Val Phe Ser Phe Ser Pro Glu Pro Gly Ala Gly Asp Glu Ala Arg Gly Gly Gly Ser Pro Thr Ser Lys Thr Gln Thr Leu Pro Ser Arg Gly Pro Arg Gly Gly Gly Ala Gly Glu G1n Pro Pro Pro Pro Ser Ala Arg Ser Thr Pro Leu Pro Gly Pro Pro Gly Ser Pro Arg Ser Ser Gly Gly Thr Pro Leu His Ser Pro Leu His Thr Pro Arg Ala Ser Pro Thr Gly Thr Pro Gly Thr Thr Pro Pro Pro Ser Pro Gly Gly Gly Val Gly Gly Ala Ala Trp Arg Ser Arg Leu Asn Ser Ile Arg Asn Ser Phe Leu Gly Ser Pro Arg Phe His Arg Arg Lys Met Gln Val Pro Thr A1a Glu Glu Met Ser Ser Leu Thr Pro Glu Ser Ser Pro Glu Leu Ala Lys Arg Ser Trp Phe G1y Asn Phe Ile Ser Leu Asp Lys Glu Glu Gln Tle Phe Leu Val Leu Lys Asp Lys Pro Leu Ser Ser Tle Lys Ala Asp Ile Val His Ala Phe Leu Ser Ile Pro Ser Leu Ser His Ser Val Leu Ser Gln Thr Ser Phe Arg Ala Glu Tyr Lys A1a Ser Gly Gly Pro Ser Val Phe Gln Lys Pro Val Arg Phe Glri Val Asp Ile Ser Ser Ser Glu Gly Pro Glu Pro Ser Pro Arg Arg Asp Gly Ser Gly Gly Gly Gly Ile Tyr Ser Va1 Thr Phe Thr Leu Ile Ser Gly Pro Ser Arg Arg Phe Lys Arg Val Val Glu Thr Ile Gln Ala Gln Leu Leu Ser Thr His Asp Gln Pro Ser Val Gln Ala Leu A1a Asp Glu Lys Asn Gly Ala Gln Thr Arg Pro Ala Gly Ala Pro Pro Arg Ser Leu Gln Pro Pro Pro Gly Arg Pro Asp Pro Glu Leu Ser Ser Ser Pro Arg Arg Gly Pro Pro Lys Asp Lys Lys Leu Leu Ala Thr Asn Gly Thr Pro Leu Pro <210> 18 <211> 504 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 3773709CD1 <400> 18 Met Ser G1y Leu Leu Thr Asp Pro Glu Gln Arg Ala Gln Glu Pro Arg Tyr Pro Gly Phe Val Leu Gly Leu Asp Val Gly Ser Ser Val Ile Arg Cys His Val Tyr Asp Arg Ala Ala Arg Val Cys Gly Ser Ser Val Gln Lys Val Glu Asn Leu Tyr Pro Gln Ile Gly Trp Val Glu Ile Asp Pro Asp Val Leu Trp I1e Gln Phe Val Ala Val Ile Lys Glu Ala Val Lys Ala Ala Gly Ile Gln Met Asn Gln I1e Val Gly Leu Gly Ile Ser Thr Gln Arg Ala Thr Phe Ile Thr Trp Asn Lys Lys Thr Gly Asn His Phe His Asn Phe Ile Ser Trp Gln Asp Leu Arg Ala Val Glu Leu Val Lys Ser Trp Asn Asn Ser Leu Leu Met Lys Ile Phe His Ser Ser Cys Arg Val Leu His Phe Phe Thr Arg Ser Lys Arg Leu Phe Thr ATa Ser Leu Phe Thr Phe Thr Thr Gln Gln Thr Ser Leu Arg Leu Val Trp Ile Leu G1n Asn Leu Thr Glu Val Gln Lys Ala Val Glu Glu Glu Asn Cys Cys Phe Gly Thr Ile Asp Thr Trp Trp Leu Tyr Lys Leu Thr Lys Gly Ser Val Tyr Ala Thr Asp Phe Ser Asn Ala Ser Thr Thr Gly Leu Phe Asp Pro Tyr Ser His Asn Phe Gly Ser Val Asp Glu Glu Ile Phe Gly Val Pro Ile Pro Ile Val Ala Leu Val Ala Asp Gln Gln Ser Ala Met Phe Gly Glu Cys Cys Phe Gln Thr Gly Asp Val Lys Leu Thr Met Gly Thr Gly Thr Phe Leu Asp Ile Asn Thr Gly Asn Ser Leu Gln Gln Thr Thr Gly Gly Phe Tyr Pro Leu Ile Gly Trp Lys Ile Gly Gln Glu Val Val Cys Leu Ala Glu Ser Asn Ala Gly Asp Thr Gly Thr Ala Ile Lys Trp Ala Gln Gln Leu Asp Leu Phe Thr Asp A1a Ala Glu Thr Glu Lys Met Ala Lys Ser Leu Glu Asp Ser Glu Gly Val Cys Phe Val Pro Ser Phe Ser Gly Leu Gln A1a Pro Leu Asn Asp Pro Trp Ala Cys Ala Ser Phe Met Gly Leu Lys Pro Ser Thr 3f5 370 375 Ser Lys Tyr His Leu Val Arg Ala Ile Leu Glu Ser Ile Ala Phe Arg Asn Lys Gln Leu Tyr Glu Met Met Lys Lys Glu Ile His Ile Pro Val Arg Lys Ile Arg Ala Asp Gly Gly Val Cys Lys Asn Gly Phe Val Met Gln Met Thr Ser Asp Leu Ile Asn Glu Asn I1e Asp Arg Pro Ala Asp Ile Asp Met Ser Cys Leu Gly Ala Ala Ser Leu Ala Gly Leu Ala Val Gly Phe Trp Thr Asp Lys Glu Glu Leu Lys Lys Leu Arg Gln Ser Glu Val Val Phe Lys Pro Gln Lys Lys Cys Gln Glu Tyr Glu Met Ser Leu Glu Asn Trp Ala Lys A1a Val Lys Arg Ser Met Asn Trp Tyr Asn Lys Thr <210> 19 <211> 553 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7477204CD1 <400> 19 Met Val Asp Met Gly Ala Leu Asp Asn Leu Ile Ala Asn Thr Ala '1 5 10 15 Tyr Leu Gln Ala Arg Lys Pro Ser Asp Cys Asp Ser Lys Glu Leu Gln Arg Arg Arg Arg Ser Leu Ala Leu Pro Gly Leu Gln Gly Cys 26!61 Ala Glu Leu Arg Gln Lys Leu Ser Leu Asn Phe His Ser Leu Cys Glu Gln Gln Pro Ile Gly Arg Arg Leu Phe Arg Asp Phe Leu Ala Thr Val Pro Thr Phe Arg Lys Ala Ala Thr Phe Leu Glu Asp Val Gln Asn Trp Glu Leu Ala Glu Glu Gly Pro Thr Lys Asp Ser Ala Leu Gln Gly Leu Val Ala Thr Cys Ala Ser Ala Pro Ala Pro Gly Asn Pro Gln Pro Phe Leu Ser Gln Ala Val Ala Thr Lys Cys Gln Ala Ala Thr Thr Glu Glu Glu Arg Val Ala Ala Val Thr Leu Ala Lys Ala Glu Ala Met Ala Phe Leu Gln Glu Gln Pro Phe Lys Asp Phe Val Thr Ser Ala Phe Tyr Asp Lys Phe Leu Gln Trp Lys Leu Phe Glu Met Gln Pro Val Ser Asp Lys Tyr Phe Thr Glu Phe Arg Val Leu Gly Lys Gly Gly Phe Gly Glu Val Cys Ala Val Gln Val Lys Asn Thr Gly Lys Met Tyr Ala Cys Lys Lys Leu Asp Lys Lys Arg Leu Lys Lys Lys Gly Gly Glu Lys Met Ala Leu Leu Glu Lys Glu Ile Leu Glu Lys Val Ser Ser Pro Phe Ile Val Ser Leu Ala Tyr Ala Phe Glu Ser Lys Thr His Leu Cys Leu Val Met Ser Leu Met Asn Gly Gly Asp Leu Lys Phe His Ile Tyr Asn Val Gly Thr Arg Gly Leu Asp Met Ser Arg Val Ile Phe Tyr Ser Ala G1n Ile Ala Cys Gly Met Leu His Leu His Glu Leu Gly Ile Va1 Tyr Arg 305 ~ 310 315 Asp Met Lys Pro Glu Asn Val Leu Leu Asp Asp Leu Gly Asn Cys Arg Leu Ser Asp Leu Gly Leu Ala Val Glu Met Lys Gly Gly Lys Pro Ile Thr G1n Arg Ala G1y Thr Asn Gly Tyr Met Ala Pro Glu Ile Leu Met Glu Lys Val Ser Tyr Ser Tyr Pro Val Asp Trp Phe Ala Met Gly Cys Ser Ile Tyr Glu Met Val Ala Gly Arg Thr Pro Phe Lys Asp Tyr Lys Glu Lys Val Ser Lys Glu Asp Leu Lys Gln Arg Thr Leu G1n Asp Glu Val Lys Phe G1n His Asp Asn Phe Thr Glu Glu Ala Lys Asp Ile Cys Arg Leu Phe Leu Ala Lys Lys Pro Glu Gln Arg Leu G1y Ser Arg Glu Lys Ser Asp Asp Pro Arg Lys His His Phe Phe Lys Thr Ile Asn Phe Pro Arg Leu Glu Ala Gly Leu Ile Glu Pro Pro Phe Val Pro Asp Pro Ser Val Val Tyr Ala Lys Asp Ile Ala Glu Ile Asp Asp Phe Ser Glu Val Arg Gly Val Glu Phe Asp Asp Lys Asp Lys Gln Phe Phe Lys Asn Phe Ala Thr Gly Ala Val Pro Ile Ala Trp Gln Glu Glu Ile Ile Glu Thr Gly Leu Phe Glu Glu Leu Asn Asp Pro Asn Arg Pro Thr Gly Cys Glu Glu G1y Asn Ser Ser Lys Ser Gly Val Cys Leu Leu Leu <210> 20 <211> 871 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 3016969CD1 <400> 20 Met Gly Pro Gly Asp Ile Ser Leu Pro Gly Arg Pro Lys Pro Gly Pro Cys Ser Ser Pro Gly Ser Ala Ser Gln Ala Ser Ser Ser Gln Val Ser Ser Leu Arg Val Gly Ser Ser Gln Val Gly Thr Glu Pro Gly Pro Ser Leu Asp Ala Glu Gly Trp Thr Gln Glu Ala Glu Asp Leu Ser Asp Ser Thr Pro Thr Leu Gln Arg Pro Gln Glu Gln Val Thr Met Arg Lys Phe Ser Leu Gly Gly Arg Gly Gly Tyr Ala Gly Val Ala Gly Tyr Gly Thr Phe Ala Phe Gly Gly Asp Ala Gly Gly Met Leu Gly Gln Gly Pro Met Trp Ala Arg Ile Ala Trp Ala Val Ser Gln Ser Glu Glu G1u Glu Gln Glu Glu Ala Arg Ala Glu Ser G1n Ser Glu Glu Gln Gln Glu A1a Arg Ala Glu Ser Pro Leu Pro G1n Val Ser Ala Arg Pro Val Pro Glu Val GIy Arg Ala Pro Thr Arg Ser Ser Pro Glu Pro Thr Pro Trp Glu Asp Ile Gly Gln Val Ser Leu Val Gln Tle Arg Asp Leu Ser G1y Asp Ala G1u Ala Ala Asp Thr Ile Ser Leu Asp Ile Ser Glu Val Asp Pro Ala Tyr Leu Asn Leu Ser Asp Leu Tyr Asp Ile Lys Tyr Leu Pro Phe Glu Phe Met Ile Phe Arg Lys Val Pro Lys Ser Ala Gln Pro Glu Pro Pro Ser Pro Met Ala Glu Glu Glu Leu Ala Glu Phe Pro Glu Pro Thr Trp Pro Trp Pro Gly Glu Leu Gly Pro His Ala Gly Leu G1u Ile Thr Glu Glu Ser Glu Asp Val Asp Ala Leu Leu Ala Glu Ala Ala Val Gly Arg Lys Arg Lys Trp Ser Ser Pro Ser Arg Ser Leu Phe His Phe Pro Gly Arg His Leu Pro Leu Asp Glu Pro Ala Glu Leu Gly Leu Arg Glu Arg Val Lys Ala Ser Val Glu His Ile Ser Arg Ile Leu Lys Gly Arg Pro Glu Gly Leu Glu Lys Glu Gly Pro Pro Arg Lys Lys Pro Gly Leu Ala Ser Phe Arg Leu Ser Gly Leu Lys Ser Trp Asp Arg Ala Pro Thr Phe Leu Arg Glu Leu Ser Asp Glu Thr Va1 Val Leu Gly Gln Ser Val Thr Leu Ala Cys Gln Val Ser Ala Gln Pro A1a Ala Gln Ala Thr Trp Ser Lys Asp Gly Ala Pro Leu Glu Ser Ser Ser Arg Val Leu Ile Ser Ala Thr Leu Lys Asn Phe Gln Leu Leu Thr Ile Leu Val Va1 Val Ala Glu Asp Leu Gly Va1 Tyr Thr Cys Ser Val Ser Asn Ala Leu GIy Thr VaI Thr Thr Thr Gly Val Leu Arg Lys Ala Glu Arg Pro Ser Ser Ser Pro Cys Pro Asp Ile GIy Glu Val Tyr Ala Asp GIy Val Leu Leu Val Trp Lys Pro Val Glu Ser Tyr Gly Pro Val Thr Tyr Ile Val Gln Cys Ser Leu Glu GIy Gly Ser Trp Thr Thr Leu Ala Ser Asp Ile Phe Asp Cys Cys Tyr Leu Thr Ser Lys Leu Ser Arg Gly Gly Thr Tyr Thr Phe Arg Thr Ala Cys Val Ser Lys Ala Gly Met Gly Pro Tyr Ser Ser Pro Ser Glu Gln Val Leu Leu Gly Gly Pro Ser His Leu Ala Ser Glu Glu Glu Ser Gln Gly Arg Ser Ala Gln Pro Leu Pro Ser Thr Lys Thr Phe Ala Phe Gln Thr Gln I1e Gln Arg Gly Arg Phe Ser Val Val Arg Gln Cys Trp Glu Lys Ala Ser Gly Arg Ala Leu Ala Ala Lys Ile Ile Pro Tyr His Pro Lys Asp Lys Thr Ala Val Leu Arg Glu Tyr Glu Ala Leu Lys Gly Leu Arg His Pro His Leu Ala Gln Leu His Ala Ala Tyr Leu Ser Pro Arg His Leu Val Leu Ile Leu Glu Leu Cys Ser Gly Pro Glu Leu Leu Pro Cys Leu A1a Glu Arg Ala Ser Tyr Ser Glu Ser Glu Val Lys Asp Tyr Leu Trp Gln Met Leu Ser Ala Thr Gln Tyr Leu His Asn Gln His Ile 68.0 685 690 Leu His Leu Asp Leu Arg Ser Glu Asn Met Ile Ile Thr G1u Tyr Asn Leu Leu Lys Val Val Asp Leu Gly Asn A1a Gln Ser Leu Ser Gln Glu Lys Va1 Leu Pro Ser Asp Lys Phe Lys Asp Tyr Leu Glu Thr Met Ala Pro Glu Leu Leu Glu Gly Gln Gly Ala Val Pro G1n Thr Asp Ile Trp Ala Ile Gly Val Thr Ala Phe Ile Met Leu Ser A1a Glu Tyr Pro Val Ser Ser Glu Gly Ala Arg Asp Leu Gln Arg Gly Leu Arg Lys Gly Leu Val Arg Leu Ser Arg Cys Tyr Ala Gly Leu Ser Gly Gly Ala Val Ala Phe Leu Arg Ser Thr Leu Cys Ala Gln Pro Trp Gly Arg Pro Cys Ala Ser Ser Cys Leu Gln Cys Pro Trp Leu Thr Glu Glu Gly Pro Ala Cys Ser Arg Pro A1a Pro Val Thr Phe Pro Thr Ala Arg Leu Arg Val Phe Val Arg Asn Arg Glu Lys Arg Arg Ala Leu Leu Tyr Lys Arg His Asn Leu Ala Gln Val Arg <210> 21 <211> 765 <212> PRT

<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 063497CD2 <400> 21 Met Ala G1y Phe Lys Arg Gly Tyr Asp Gly Lys Ile Ala Gly Leu Tyr Asp Leu Asp Lys Thr Leu Gly Arg Gly His Phe Ala Val Val Lys Leu Ala Arg His Val Phe Thr Gly G1u Lys Val Ala Val Lys Val Ile Asp Lys Thr Lys Leu Asp Thr Leu Ala Thr Gly His Leu Phe Gln Glu Val Arg Cys Met Lys Leu Val Gln His Pro Asn Ile Val Arg Leu Tyr Glu Val Ile Asp Thr Gln Thr Lys Leu Tyr Leu I1e Leu Glu Leu Gly Asp Gly Gly Asp Met Phe Asp Tyr Ile Met Lys His Glu Glu Gly Leu Asn Glu Asp Leu Ala Lys Lys Tyr Phe Ala Gln Ile Val His Ala.Ile Ser Tyr Cys His Lys Leu His Val Val His Arg Asp Leu Lys Pro Glu Asn Val Val Phe Phe Glu Lys 140. 145 150 Gln Gly Leu Val Lys Leu Thr Asp Phe Gly Phe Ser Asn Lys Phe Gln Pro Gly Lys Lys Leu Thr Thr Ser Cys Gly Ser Leu Ala Tyr Ser Ala Pro Glu Ile Leu Leu Gly Asp Glu Tyr Asp Ala Pro Ala Val Asp Ile Trp Ser Leu Gly Val Ile Leu Phe Met Leu VaI Cys Gly Gln Pro Pro Phe Gln Glu Ala Asn Asp Ser Glu Thr Leu Thr Met Ile Met Asp Cys Lys Tyr Thr Val Pro Ser His Val Ser Lys Glu Cys Lys Asp Leu Ile Thr Arg Met Leu Gln Arg Asp Pro Lys Arg Arg Ala Ser Leu Glu Glu Ile Glu Asn His Pro Trp Leu Gln Gly Val Asp Pro Ser Pro Ala Thr Lys Tyr Asn Ile Pro Leu Val Ser Tyr Lys Asn Leu Ser Glu Glu Glu His Asn Ser Ile IIe Gln Arg Met Val Leu Gly Asp Ile Ala Asp Arg Asp Ala Ile Val Glu A1a Leu Glu Thr Asn Arg Tyr Asn His Ile Thr Ala Thr Tyr Phe Leu Leu Ala Glu Arg Ile Leu Arg Glu Lys Gln Glu Lys Glu'Ile Gln Thr Arg Ser Ala Ser Pro Ser Asn Ile Lys Ala Gln Phe Arg Gln Ser Trp Pro Thr Lys Ile Asp Val Pro Gln Asp Leu Glu Asp Asp Leu Thr Ala Thr Pro Leu Ser His Ala Thr Val Pro Gln Ser Pro Ala Arg Ala A1a Asp Ser Val Leu Asn Gly His Arg Ser Lys Gly Leu Cys Asp Ser Ala Lys Lys Asp Asp Leu Pro Glu Leu Ala Gly Pro Ala Leu Ser Thr Val Pro Pro Ala Ser Leu Lys Pro Thr Ala Ser Gly Arg Lys Cys Leu Phe Arg Val Glu Glu Asp Glu Glu Glu Asp Glu Glu Asp Lys Lys Pro Met Ser Leu Ser Thr Gln Val Val Leu Arg Arg Lys Pro Ser Val Thr Asn Arg Leu Thr Ser Arg Lys Ser Ala Pro Va1 Leu Asn Gln Ile Phe G1u Glu Gly Glu Ser Asp Asp Glu Phe Asp Met Asp Glu Asn Leu Pro Pro Lys Leu Ser Arg Leu Lys Met Asn Ile Ala Ser Pro Gly Thr Val His Lys Arg Tyr His Arg Arg Lys Ser Gln Gly Arg Gly Ser Ser Cys Ser Ser Ser Glu Thr Ser Asp Asp Asp Ser Glu Ser Arg Arg Arg Leu Asp Lys Asp Ser Gly Phe Thr Tyr Ser Trp His Arg Arg Asp Ser Ser GIu Gly Pro Pro GIy Ser Glu Gly Asp Gly GIy Gly G1n Ser Lys Pro Ser Asn Ala Ser Gly Gly Val Asp Lys Ala Ser Pro Ser Glu Asn Asn Ala G1y Gly Gly Ser Pro Ser Ser Gly Ser Gly Gly Asn Pro Thr Asn Thr Ser G1y Thr Thr Arg Arg Cys Ala Gly Pro Ser Asn Ser Met Gln Leu Ala Ser Arg Ser Ala G1y Glu Leu Val Glu Ser Leu Lys Leu Met Ser Leu Cys Leu Gly Ser Gln Leu His Gly Ser Thr Lys Tyr Ile Ile Asp Pro Gln Asn Gly Leu Ser Phe Ser Ser Val Lys Val Gln Glu Lys Ser Thr Trp Lys Met Cys Ile Ser Ser Thr Gly Asn Ala Gly Gln Val Pro AIa Val GIy Gly 21e Lys Phe Phe Ser Asp His Met Ala Asp Thr Thr Thr Glu Leu Glu Arg I1e Lys Ser Lys Asn Leu Lys Asn Asn Val Leu Gln Leu Pro Leu Cys Glu Lys Thr Ile Ser Val Asn Ile G1n Arg Asn Pro Lys Glu Gly Leu Leu Cys Ala Ser Ser Pro Ala Ser Cys Cys His Val Ile <210> 22 <211> 588 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1625436CD1 <400> 22 Met Ala Thr Thr Ala Thr Cys Thr Arg Phe Thr Asp Asp Tyr Gln Leu Phe Glu Glu Leu Gly Lys Gly Ala Phe Ser Val Val Arg Arg Cys Val Lys Lys Thr Ser Thr G1n Glu Tyr Ala Ala Lys Tle Tle Asn Thr Lys Lys Leu Ser Ala Arg Asp His Gln Lys Leu Glu Arg Glu Ala Arg Ile Cys Arg Leu Leu Lys His Pro Asn Ile Val Arg Leu His Asp Ser Ile Ser Glu Glu Gly Phe His Tyr Leu Val Phe Asp Leu Val Thr Gly Gly Glu Leu Phe Glu Asp Ile Val Ala Arg G1u Tyr Tyr Ser Glu Ala Asp Ala Ser His Cys Ile His G1n Ile Leu Glu Ser Val Asn His I1e His Gln His Asp Ile Val His Arg Asp Leu Lys Pro Glu Asn Leu Leu Leu Ala Ser Lys Cys Lys Gly Ala Ala Val Lys Leu Ala Asp Phe Gly Leu Ala Ile Glu Val Gln Gly Glu Gln Gln Ala Trp Phe Gly Phe Ala G1y Thr Pro Gly Tyr Leu Ser Pro Glu Val Leu Arg Lys Asp Pro Tyr G1y Lys Pro Va1 Asp Ile Trp Ala Cys Gly Val Ile Leu Tyr Ile Leu Leu Val Gly Tyr Pro Pro Phe Trp Asp GIu Asp Gln His Lys Leu Tyr Gln Gln Ile Lys Ala Gly Ala Tyr Asp Phe Pro Ser Pro Glu Trp Asp Thr Val Thr Pro Glu Ala Lys Asn Leu Ile Asn Gln Met Leu Thr Ile Asn Pro Ala Lys Arg Ile Thr Ala Asp Gln Ala Leu Lys Tyr Pro Trp Val Cys Gln Arg Ser Thr Va1 Ala Ser Met Met His Arg Gln GIu Thr Val Glu Cys Leu Arg Lys Phe Asn Ala Arg Arg Lys Leu Lys G1y Ala Ile Leu Thr Thr Met Leu Val Ser Arg Asn Phe Ser Val Gly Arg Gln Ser Ser Ala Pro Ala Ser Pro Ala Ala Ser Ala Ala Gly Leu Ala Gly Gln Ala Ala Lys Ser Leu Leu Asn Lys Lys Ser Asp Gly Gly Val Lys Lys Arg Lys Ser Ser Ser Ser Val His Leu Met Pro G1n Ser Asn Asn Lys Asn Ser Leu Val Ser Pro Ala Gln Glu Pro Ala Pro Leu Gln Thr Ala Met Glu Pro Gln Thr Thr Val Val His Asn Ala Thr Asp Gly Ile Lys G1y Ser Thr Glu Ser Cys Asn Thr Thr Thr Glu Asp Glu Asp Leu Lys Ala Ala Pro Leu Arg Thr Gly Asn Gly Ser Ser Val Pro Glu Gly Arg Ser Ser Arg Asp Arg Thr A1a Pro Ser Ala Gly Met Gln Pro Gln Pro Ser Leu Cys Ser Ser Ala Met Arg Lys Gln Glu Ile Ile Lys Ile Thr Glu Gln Leu Ile Glu Ala Ile Asn Asn Gly Asp Phe Glu Ala Tyr 2hr Lys Ile Cys Asp Pro Gly Leu Thr Ser Phe Glu Pro Glu A1a Leu Gly Asn Leu Val Glu Gly Met Asp Phe His Lys Phe Tyr Phe Glu Asn Leu Leu Ser Lys Asn Ser Lys Pro Ile His Thr Thr Ile Leu Asn Pro His Val His Val Ile Gly Glu Asp Ala Ala Cys Ile Ala Tyr Ile Arg Leu Thr Gln Tyr Ile Asp Gly Gln Gly Arg Pro Arg Thr Ser Gln Ser Glu Glu Thr Arg Val Trp His Arg Arg Asp Gly Lys Trp Leu Asn Val His Tyr His Cys Ser Gly Ala Pro Ala Ala Pro Leu Gln <210> 23 <211> 1798 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 3330646CD1 <400> 23 Met Lys Arg Ser Arg Cys Arg Asp Arg Pro Gln Pro Pro Pro Pro Asp Arg Arg Glu Asp Gly Val Gln Arg Ala Ala Glu Leu Ser Gln Ser Leu Pro Pro Arg Arg Arg A1a Pro Pro Gly Arg Gln Arg Leu Glu Glu Arg Thr Gly Pro Ala Gly Pro Glu Gly Lys Glu Gln Asp Val Ala Thr Gly Val Ser Pro Leu Leu Phe Arg Lys Leu Ser Asn Pro Asp Ile Phe Ser Ser Thr Gly Lys Val Lys Leu Gln Arg Gln Leu Ser Gln Asp Asp Cys Lys Leu Trp Arg Gly Asn Leu Ala Ser Ser Leu Ser Gly Lys Gln Leu Leu Pro Leu Ser Ser Ser Val His Ser Ser Val Gly Gln Val Thr Trp Gln Ser Ser Gly Glu Ala Ser Asn Leu Val Arg Met Arg Asn G1n Ser Leu Gly~Gln Ser Ala Pro Ser Leu Thr Ala Gly Leu Lys Glu Leu Ser Leu Pro Arg Arg Gly Ser Phe Cys Arg Thr Ser Asn Arg Lys Ser Leu Ile Val Thr Ser Ser Thr Ser Pro Thr Leu Pro Arg Pro His Ser Pro Leu His Gly His Thr Gly Asn Ser Pro Leu Asp Ser Pro Arg Asn Phe Ser Pro Asn Ala Pro A1a His Phe Ser Phe Val Pro Ala Arg Arg Thr Asp Gly Arg Arg Trp Ser Leu Ala Ser Leu Pro Ser Ser Gly Tyr Gly Thr Asn Thr Pro Ser Ser Thr Val Ser Ser Ser Cys Ser Ser Gln Glu Lys Leu His Gln Leu Pro Phe Gln Pro Thr Ala Asp Glu Leu His Phe Leu Thr Lys His Phe Ser Thr Glu Ser Val Pro Asp Glu Glu Gly Arg Gln Ser Pro Ala Met Arg Pro Arg Ser Arg Ser Leu Ser Pro G1y Arg Ser Pro Va1 Ser Phe Asp Ser Glu Ile Ile Met Met Asn His Val Tyr Lys Glu Arg Phe Pro Lys Ala Thr Ala Gln Met Glu Glu Arg Leu Ala Glu Phe Ile Ser Ser Asn Thr Pro Asp Ser Val Leu Pro Leu Ala Asp Gly Ala Leu Ser Phe I1e His His Gln Val Ile Glu Met Ala Arg Asp Cys Leu Asp Lys Ser Arg Ser GIy Leu I1e Thr Ser Gln Tyr Phe Tyr Glu Leu Gln Glu Asn Leu Glu Lys Leu Leu G1n Asp Ala His Glu Arg Ser Glu Ser Ser Glu Val Ala Phe Val Met Gln Leu Val Lys Lys Leu Met Ile Ile Ile Ala Arg Pro Ala Arg Leu Leu Glu Cys Leu Glu Phe Asp Pro Glu Glu Phe Tyr His Leu Leu Glu Ala Ala Glu Gly His Ala Lys Glu Gly Gln Gly hle Lys Cys Asp Ile Pro Arg Tyr Ile Val Ser Gln Leu Gly Leu Thr Arg Asp Pro Leu Glu Glu Met Ala Gln Leu Ser Ser Cys Asp Ser Pro Asp Thr Pro Glu Thr Asp Asp Ser Tle Glu G1y His Gly Ala Ser Leu Pro Ser Lys Lys Thr Pro Ser Glu Glu Asp Phe Glu Thr Ile Lys Leu Ile Ser Asn Gly Ala Tyr Gly Ala Val Phe Leu Val Arg His Lys Ser Thr Arg Gln Arg Phe Ala Met Lys Lys Ile Asn Lys Gln Asn Leu Ile Leu Arg Asn Gln Ile Gln Gln Ala Phe Val Glu Arg Asp Ile Leu Thr Phe Ala Glu Asn Pro Phe Val Val Ser Met Phe Cys Ser Phe Asp Thr Lys Arg His Leu Cys Met Val Met Glu Tyr Va1 Glu Gly Gly Asp Cys Ala Thr Leu Leu Lys Asn Ile Gly Ala Leu Pro Val Asp Met Val Arg Leu Tyr Phe Ala Glu Thr Val Leu Ala Leu Glu Tyr Leu His Asn Tyr Gly Ile Val His Arg Asp Leu Lys Pro Asp Asn Leu Leu Ile Thr Ser Met Gly His Ile Lys Leu Thr Asp Phe Gly Leu Ser Lys Met Gly Leu Met Ser Leu Thr Thr Asn Leu Tyr Glu Gly His Ile Glu Lys Asp Ala Arg Glu Phe Leu Asp Lys Gln Val Cys Gly Thr Pro Glu Tyr Ile Ala Pro G1u Val Ile Leu Arg Gln Gly Tyr G1y Lys Pro Val Asp Trp Trp Ala Met Gly Ile Ile Leu Tyr Glu Phe Leu Val Gly Cys Val Pro Phe Phe Gly Asp Thr Pro Glu Glu Leu Phe Gly Gln Val Ile Ser Asp Glu Tle Val Trp Pro Glu G1y Asp Glu A1a Leu Pro Pro Asp Ala Gln Asp Leu Thr Ser Lys Leu Leu His Gln Asn Pro Leu Glu Arg Leu Gly Thr Gly Ser Ala Tyr Glu Val Lys Gln His Pro Phe Phe Thr Gly Leu Asp Trp Thr Gly Leu Leu Arg Gln Lys Ala Glu Phe Ile Pro Gln Leu Glu Ser Glu Asp Asp Thr Ser Tyr Phe Asp Thr Arg Ser Glu Arg Tyr His His Met Asp Ser Glu Asp Glu Glu Glu Va1 Ser Glu Asp Gly Cys Leu Glu Ile Arg Gln Phe Ser Ser Cys Ser Pro Arg Phe Asn Lys Val Tyr Ser Ser Met Glu Arg Leu Ser Leu Leu Glu Glu Arg Arg Thr Pro Pro Pro Thr Lys Arg Ser Leu Ser Glu Glu Lys Glu Asp His Ser Asp Gly Leu Ala Gly Leu Lys Gly Arg Asp Arg Ser Trp Val Ile Gly Ser Pro Glu Ile Leu Arg Lys Arg Leu Ser Val Ser Glu Ser Ser His Thr Glu Ser Asp Ser Ser Pro Pro Met Thr Val Arg Arg Arg Cys 34!61 Ser G1y Leu Leu Asp Ala Pro Arg Phe Pro Glu Gly Pro Glu Glu A1a Ser Ser Thr Leu Arg Arg Gln Pro Gln Glu Gly Ile Trp Val Leu Thr Pro Pro Ser Gly Glu Gly Val Ser Gly Pro Val Thr Glu His Ser Gly Glu Gln Arg Pro Lys Leu Asp Glu Glu Ala Val Gly Arg Ser Ser G1y Ser Ser Pro Ala Met Glu Thr Arg Gly Arg Gly Thr Ser Gln Leu Ala Glu Gly Ala Thr Ala Lys Ala Ile Ser Asp Leu Ala Val Arg Arg Ala Arg His Arg Leu Leu Ser Gly Asp Ser Thr Glu Lys Arg Thr Ala Arg Pro Val Asn Lys Val Ile Lys Ser Ala Ser Ala Thr Ala Leu Ser Leu Leu Ile Pro Ser Glu His His Thr Cys Ser Pro Leu Ala Ser Pro Met Ser Pro His Ser Gln Ser Ser Asn Pro Ser Ser Arg Asp Ser Ser Pro Ser Arg Asp Phe Leu Pro Ala Leu Gly Ser Met Arg Pro Pro Tle Ile Ile His Arg Ala Gly Lys Lys Tyr Gly Phe Thr Leu Arg Ala Ile Arg Val Tyr Met Gly Asp Ser Asp Val Tyr Thr Val His His Met Val Trp His Val G1u Asp Gly Gly Pro Ala Ser Glu Ala G1y Leu Arg Gln Gly Asp Leu Ile Thr His Val Asn Gly Glu Pro Val His Gly Leu Val His Thr Glu Val Val Glu Leu Ile Leu Lys Ser Gly Asn Lys Va1 Ala Ile Ser Thr Thr Pro Leu Glu Asn Thr Ser Ile Lys Val Gly Pro Ala Arg Lys Gly Ser Tyr Lys Ala Lys Met Ala Arg Arg Ser Lys Arg Ser Arg Gly Lys Asp Gly Gln Glu Ser Arg Lys Arg Ser Ser Leu Phe Arg Lys Ile Thr Lys Gln A1a Ser Leu Leu His Thr Ser Arg Ser Leu Ser Ser Leu Asn Arg Ser Leu Ser Ser Gly Glu Ser Gly Pro G1y Ser Pro Thr His Ser His Ser Leu Ser Pro Arg Ser Pro Thr Gln Gly Tyr Arg Val Thr Pro Asp Ala Val His Ser Val Gly Gly Asn Ser Ser Gln Ser Ser Ser Pro Ser Ser Ser Val Pro Ser Ser Pro Ala Gly Ser Gly His Thr Arg Pro Ser Ser Leu His Gly Leu Ala Pro Lys Leu Gln Arg Gln Tyr Arg Ser Pro Arg Arg Lys Ser Ala Gly Ser Ile Pro Leu Ser Pro Leu Ala His Thr Pro Ser Pro Pro Pro Pro Thr Ala Ser Pro Gln Arg Ser Pro Ser Pro Leu Ser Gly His Val Ala Gln Ala Phe Pro Thr Lys Leu His Leu Ser Pro Pro Leu Gly Arg G1n Leu Ser Arg Pro Lys Ser Ala Glu Pro Pro Arg Ser Pro Leu Leu Lys Arg Va1 Gln Ser Ala Glu Lys Leu A1a Ala Ala Leu Ala Ala Ser Glu Lys Lys Leu Ala Thr Ser Arg Lys His Ser Leu Asp Leu Pro His Ser Glu Leu Lys Lys Glu Leu Pro Pro Arg Glu Val Ser Pro Leu Glu Val Val Gly Ala Arg Ser Val Leu Ser Gly Lys Gly Ala Leu Pro Gly Lys Gly Val Leu Gln Pro Ala Pro Ser Arg Ala Leu Gly Thr Leu Arg Gln Asp Arg Ala Glu Arg Arg Glu Ser Leu Gln Lys Gln Glu Ala Ile Arg Glu Val Asp Ser Ser Glu Asp Asp Thr G1u Glu Gly Pro Glu Asn Ser Gln Gly Ala Gln Glu Leu Ser Leu Ala Pro His Pro Glu Val Ser Gln Ser Val Ala Pro Lys Gly Ala Gly Glu Ser Gly Glu Glu Asp 1535 7.540 1545 Pro Phe Pro Ser Arg Asp Pro Arg Ser Leu Gly Pro Met Val Pro Ser Leu Leu Thr Gly Ile Thr Leu Gly Pro Pro Arg Met Glu Ser Pro Ser Gly Pro His Arg Arg Leu Gly Ser Pro Gln Ala Ile Glu Glu Ala Ala Ser Ser Ser Ser Ala Gly Pro Asn Leu Gly Gln Ser Gly Ala Thr Asp Pro Ile Pro Pro Glu Gly Cys Trp Lys Ala Gln His Leu His Thr Gln Ala Leu Thr Ala Leu Ser Pro Ser Thr Ser Gly Leu Thr Pro Thr Ser Ser Cys Ser Pro Pro Ser Ser Thr Ser Gly Lys Leu Ser Met Trp Ser Trp Lys Ser Leu Ile Glu Gly Pro Asp Arg Ala Ser Pro Ser Arg Lys Ala Thr Met Ala Gly Gly Leu A1a Asn Leu Gln Asp Leu Glu Asn Thr Thr Pro Ala Gln Pro Lys Asn Leu Ser Pro Arg Glu Gln Gly Lys Thr Gln Pro Pro Ser Ala Pro Arg Leu Ala His Pro Ser Tyr Glu Asp Pro Ser Gln Gly Trp Leu Trp Glu Ser Glu Cys Ala Gln Ala Val Lys G1u Asp Pro Ala Leu Ser Ile Thr Gln Val Pro Asp Ala Ser Gly Asp Arg Arg Gln Asp Val Pro Cys Arg Gly Cys Pro Leu Thr Gln Lys Ser Glu Pro Ser Leu Arg Arg Gly Gln Glu Pro Gly Gly His Gln Lys His Arg Asp Leu Ala Leu Val Pro Asp Glu Leu Leu Lys Gln Thr <210> 24 <211> 362 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 3562763CD1 <400> 24 Met Asp Pro Val Ala Ala Glu Ala Pro Gly Glu Ala Phe Leu Ala Arg Arg Arg Pro Glu Gly Gly Gly Gly Ser Ala Arg Pro Arg Tyr Ser Leu Leu Ala Glu Ile Gly Arg Gly Ser Tyr Gly Val Val Tyr Glu Ala Val Ala Gly Arg Ser Gly Ala Arg Val Ala Val Lys Lys Ile Arg Cys Asp Ala Pro Glu Asn Val Glu Leu Ala Leu A1a Glu Phe Trp Ala Leu Thr Ser Leu Lys Arg Arg His Gln Asn Val Val Gln Phe Glu Glu Cys Val Leu Gln Arg Asn Gly Leu Ala Gln Arg Met Ser His Gly Asn Lys Ser Ser Gln Leu Tyr Leu Arg Leu Val Glu Thr Ser Leu Lys Gly Glu Arg Ile Leu Gly Tyr Ala Glu Glu Pro Cys Tyr Leu Trp Phe Val Met Glu Phe Cys Glu Gly Gly Asp Leu Asn Gln Tyr Val Leu Ser Arg Arg Pro Asp Pro Ala Thr Asn Lys Ser Phe Met Leu Gln Leu Thr Ser Ala Tle Ala Phe Leu His Lys Asn His Ile Val His Arg Asp Leu Lys Pro Asp Asn Tle Leu Ile Thr Glu Arg Ser Gly Thr Pro Ile Leu Lys Va1 Ala Asp Phe Gly Leu Ser Lys Val Cys Ala Gly Leu Ala Pro Arg Gly Lys Glu Gly Asn Gln Asp Asn Lys Asn Val Asn Val Asn Lys Tyr Trp Leu Ser Ser Ala Cys G1y Ser Asp Phe Tyr Met Ala Pro Glu Val Trp Glu Gly His Tyr Thr Ala Lys Ala Asp Ile Phe Ala Leu Gly Ile I1e Ile Trp Ala Met Ile Glu Arg Ile Thr Phe Tle Asp Ser Glu Thr Lys Lys Glu Leu Leu Gly Thr Tyr Ile Lys Gln Gly Thr Glu Ile Val Pro Val G1y Glu Ala Leu Leu Glu Asn Pro Lys Met Glu Leu His Ile Pro Gln Lys Arg Arg Thr Ser Met Ser G1u Gly Ile Lys Gln Leu Leu Lys Asp Met Leu Ala Ala Asn Pro Gln Asp Arg Pro Asp Ala Phe G1u Leu Glu Thr Arg Met Asp Gln Val Thr Cys Ala Ala <210> 25 <211> 275 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> IiZCyte ID No: 621293CD1 <400> 25 Met Val Pro Glu Asp Ile Ser Glu Leu Glu Thr Ala Gln Lys Leu Leu Glu Tyr His Arg Asn Ile Val Arg Val Ile Pro Ser Tyr Pro Lys Ile Leu Lys Val Ile Ser Ala Asp Gln Pro Cys Val Asp Val Phe Tyr Gln Ala Leu Thr Tyr Val Gln Ser Asn His Arg Thr Asn Ala Pro Phe Thr Pro Arg Val Leu Leu Leu Gly Pro Va1 Gly Ser Gly Lys Ser Leu Gln Ala Ala Leu Leu A1a Gln Lys Tyr Arg Leu Val Asn Val Cys Cys Gly G1n Leu Leu Lys Glu Ala Val Ala Asp Arg Thr Thr Phe Gly Glu Leu Tle Gln Pro Phe Phe Glu Lys Glu Met Ala Val Pro Asp Ser Leu Leu Met Lys Va1 Leu Ser Gln Arg Leu Asp Gln Gln Asp Cys Ile Glri Lys Gly Trp Va1 Leu His Gly Val Pro Arg Asp Leu Asp Gln Ala His Leu Leu Asn Arg Leu Gly Tyr Asn Pro Asn Arg Val Phe Phe Leu Asn Val Pro Phe Asp Ser Ile Met Glu Arg Leu Thr Leu Arg Arg Ile Asp Pro Val Thr Gly Glu Arg Tyr His Leu Met Tyr Lys Pro Pro Pro Thr Met Glu Ile Gln Ala Arg Leu Leu Gln Asn Pro Lys Asp Ala Glu Glu Gln Va1 Lys Leu Lys Met Asp Leu Phe Tyr Arg Asn Ser Ala Asp Leu Glu Gln Leu Tyr Gly Ser Ala Ile Thr Leu Asn Gly Asp Gln Asp Pro Tyr Thr Val Phe Glu Tyr Ile Glu Ser Gly Ile Ile Asn Pro Leu Pro Lys Lys Ile Pro <210> 26 <211> 660 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7480774CD1 <400> 26 Met Arg Leu Glu A1a Pro Arg Gly Gly Arg Arg Arg Gln Pro Gly Gln G1n Arg Pro Gly Pro Gly Ala Gly Ala Pro Ala Gly Arg Pro Glu Gly Gly Gly Pro Trp Ala Arg Thr Glu Glu Ser Ser Leu His Ser Glu Pro Glu Arg Ala G1y Leu Gly Pro Ala Pro Gly Thr Glu Ser Pro-Gln Ala Glu Phe Trp Thr Asp Gly Gln Thr Glu Pro Ala Ala Ala Gly Leu Gly Val Glu Thr Glu Arg Pro Lys Gln Lys Thr Glu Pro Asp Arg Ser Ser Leu Arg Thr His Leu Glu Trp Ser Trp Ser Glu Leu G1u Thr Thr Cys Leu Trp Thr Glu Thr Gly Thr Asp Gly Leu Trp Thr Asp Pro His Arg Ser Asp Leu G1n Phe Gln Pro Glu Glu A1a Ser Pro Trp Thr Gln Pro Gly Val His Gly Pro Trp Thr Glu Leu Glu Thr His Gly Ser Gln Thr Gln Pro Glu Arg Val Lys Ser Trp Ala Asp Asn Leu Trp Thr His Gln Asn Ser Ser Ser Leu Gln Thr His Pro Glu Gly Ala Cys Pro Ser Lys Glu Pro Ser Ala Asp Gly Ser Trp Lys Glu Leu Tyr Thr Asp Gly Ser Arg Thr Gln Gln Asp Ile Glu G1y Pro Trp Thr Glu Pro Tyr Thr Asp Gly Ser Gln Lys Lys Gln Asp Thr Glu Ala Ala Arg Lys Gln Pro Gly Thr Gly G1y Phe Gln Ile Gln Gln Asp Thr Asp G1y Ser Trp Thr Gln Pro Ser Thr Asp Gly Ser Gln Thr Ala Pro Gly Thr Asp Cys Leu Leu Gly Glu Pro Glu Asp Gly Pro Leu Glu Glu Pro Glu Pro Gly Glu Leu Leu Thr His Leu Tyr Ser His Leu Lys Cys Ser Pro Leu Cys Pro Val Pro Arg Leu Ile Ile Thr Pro Glu Thr Pro G1u Pro Glu Ala Gln Pro VaI Gly Pro Pro Ser Arg Val Glu Gly Gly Ser Gly Gly Phe Ser Ser Ala Ser Ser Phe Asp Glu Ser Glu Asp Asp Va1 Val Ala Gly Gly Gly G1y Ala Ser Asp Pro Glu Asp Arg Ser Gly Ser Lys Pro Trp Lys Lys Leu Lys Thr Val Leu Lys Tyr Ser Pro Phe Val Val Ser Phe Arg Lys His Tyr Pro Trp Val G1n Leu Ser Gly His Ala Gly Asn Phe Gln Ala Gly Glu Asp Gly Arg Ile Leu Lys Arg Phe Cys Gln Cys Glu Gln Arg Ser Leu Glu Gln Leu Met Lys Asp Pro Leu Arg Pro Phe Val Pro Ala Tyr Tyr Gly Met Val Leu Gln Asp Gly G1n Thr Phe Asn Gln Met Glu Asp Leu Leu Ala Asp Phe Glu Gly Pro Ser Ile Met Asp Cys Lys Met Gly Ser Arg Thr Tyr Leu G1u Glu Glu Leu Val Lys Ala Arg Glu Arg Pro Arg Pro Arg Lys Asp Met Tyr Glu Lys Met Val Ala Val Asp Pro Gly Ala Pro Thr Pro G1u Glu His Ala Gln Gly Ala Val Thr Lys Pro Arg Tyr Met Gln Trp Arg Glu Thr Met Ser Ser Thr Ser Thr Leu Gly Phe Arg Ile Glu Gly Ile Lys Lys Ala Asp Gly Thr Cys Asn Thr Asn Phe Lys Lys Thr Gln A1a Leu Glu Gln Val Thr Lys Val Leu Glu Asp Phe Val Asp Gly Asp His Val Ile Leu Gln Lys Tyr Val Ala Cys Leu Glu Glu Leu Arg Glu Ala Leu Glu Ile Ser Pro Phe Phe Lys Thr His Glu Val Val Gly Ser Ser Leu Leu Phe Val His Asp His Thr Gly Leu Ala Lys Val Trp Met Ile Asp Phe Gly Lys Thr Val Ala Leu Pro Asp His Gln Thr Leu Ser His Arg Leu Pro Trp Ala Glu Gly Asn Arg Glu Asp Gly Tyr Leu Trp Gly Leu Asp Asn Met Ile Cys Leu Leu Gln Gly Leu Ala Gln Ser <210> 27 <211> 822 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 2011384CB1 <400> 27 atgtcgggag acaaacttct gagcgaactc ggttataagc tgggccgcac aattggagag 60 ggcagctact ccaaggtgaa ggtggccaca tccaagaagt acaagggtac cgtggccatc 120 aaggtggtgg accggcggcg agcgcccccg gacttcgtca acaagttcct gccgcgagag 180 ctgtccatcc tgcggggcgt gcgacacccg cacatcgtgc acgtcttcga gttcatcgag 240 gtgtgcaacg ggaaactgta catcgtgatg gaagcggccg ccaccgacct gctgcaagcc 300 gtgcagcgca acgggcgcat ccccggagtt caggcgcgcg acctctttgc gcagatcgcc 360 ggcgccgtgc gctacctgca cgatcatcac ctggtgcacc gcgacctcaa gtgcgaaaac 420 gtgctgctga gcccggacga gcgccgcgtc aagctcaccg acttcggctt cggccgccag 480 gcccatggct acccagacct gagcaccacc tactgcggct cagccgccta cgcgtcaccc 540 gaggtgctcc tgggcatccc ctacgacccc aagaagtacg atgtgtggag catgggcgtc 600 gtgctctacg tcatggtcac cgggtgcatg cccttcgacg actcggacat cgccggcctg 660 ccccggcgcc agaaacgcgg cgtgctctat cccgaaggcc tcgagctgtc cgagcgctgc 720 aaggccctga tcgccgagct gctgcagttc agcccgtccg ccaggccctc cgcgggccag 780 gtagcgcgca actgctggct gcgcgccggg gactccggct ag 822 <210> 28 <211> 1376 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte TD No: 2004888CB1 <220>
<221> unsure <222> 1369 <223> a, t, c, g, or other <400> 28 gcttattgaa tatttaaata agagtcccag tgtggatcac ttgctatcca ttaagaagac 60 attgaaaagc ttaaaagctc tactcagatg gaaattggtt gaaaagagta atttggaaga 120 gtcagatgat cctgatggct ctcaaattga gaaaataaaa gaagaaataa ctcagctgcg 180 caataatgtc tttcaggaaa tttatcatga gagagaggaa tatgagatgc taactagttt 240 ggcacagaaa tggttccctg agctgcctct gcttcatcct gaaataggat tactcaaata 300 catgaactct ggtggtctcc ttacaatgag cttggaacga gatcttcttg atgctgagcc 360 catgaaggaa cttagcagca agcgtccttt ggtacgttct gaggttaatg ggcagataat 420 tctgttaaag ggctattctg tggatgttga cacagaagcc aaggtgattg agagagcagc 480 cacctaccat agagcttgga gagaagctga aggagactca gggttactgc cattgatatt 540 cctgttttta tgtaagtctg atcctatggc ttatctgatg gtcccatact accctagggc 600 aaacctgaat gctgttcaag ccaacatgcc tttaaattca gaagaaactt taaaggtcat 660 gaaaggtgtt gcccagggtc tgcatacatt gcataaggct gacataattc atggatcact 720 tcatcagaac aatgtatttg ctttaaaccg tgaacaagga attgttggag attttgactt 780 caccaaatct gtgagtcagc gagcctcggt gaacatgatg gttggtgact tgagtttgat 840 gtcacctgag ttgaaaatgg gaaaacctgc ttctccaggt tcagacttat atgcttatgg 900 ctgcctctta ttatggcttt ctgttcaaaa tcaggagttt gagataaata aagatggaat 960 ccccaaagtg gatcagtttc atctggatga taaagtcaaa tccctcctct gtagcttgat 1020 atgttataga agttcaatga ctgctgaaca agttttaaat gctgaatgtt tcttgatgcc 1080 aaaggagcaa tcagttccaa acccagaaaa agatactgaa tacaccctat ataaaaagga 1140 agaagaaata aagacggaga acttggataa atgtatggag aagacaagaa atggtgaagc 1200 caactttgat tgttaaatta ttattgttgt tgttgcagag gttcttttta aaaactttgg 1260 tttggttaat acacagaaat atctagaaat gttctgggac tagttgagtt gtatctttag 1320 tattcaggtt gaagaaaaat aaagatgtgt ggtatactag ttctgatgng ctgtgc 1376 <210> 29 <211> 3468 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 2258952CB1 <400> 29 ttccactata acctttctct agggtcaaag agatgatgag tgacaccagc acgttcccca 60 atcacccttc ctcccctgct gcatccccat ctgggggaag gggagtcatg gccagccctg 120 cttgggacag gagcaaaggg tggtcccaga cccctcagag agctgacttt gtctctaccc 180 ccttgcaggt tcatactctc aggccagaga acctcctgct ggtgtccacc ttggatggaa 240 gtctccacgc actaagcaag cagacagggg acctgaagtg gactctgagg gatgatcccg 300 tcatcgaagg accaatgtac gtcacagaaa tggcctttct ctctgaccca gcagatggca 360 gcctgtacat cttggggacc caaaaacaac agggattaat gaaactgcca ttcaccatcc 420 ctgagctggt tcatgcctct ccctgccgca gctctgatgg ggtcttctac acaggccgga 480 agcaggatgc ctggtttgtg gtggaccctg agtcagggga gacccagatg acactgacca 540 cagagggtcc ctccaccccc cgcctctaca ttggccgaac acagtatacg gtcaccatgc 600 atgacccaag agccccagcc ctgcgctgga acaccaccta ccgccgctac tcagcgcccc 660 ccatggatgg ctcacctggg aaatacatga gccacctggc gtcctgcggg atgggcctgc 720 tgctcactgt ggacccagga agcgggacgg tgctgtggac acaggacctg ggcgtgcctg 780 tgatgggcgt ctacacctgg caccaggacg gcctgcgcca gctgccgcat ctcacgctgg 840 ctcgagacac tctgcatttc ctcgccctcc gctggggcca catccgactg cctgcctcag 900 gcccccggga cacagccacc ctcttctcta ccttggacac ccagctgcta atgacgctgt 960 atgtggggaa ggatgaaact ggcttctatg tctctaaagc actggtccac acaggagtgg 1020 ccctggtgcc tcgtggactg accctggccc ccgcagatgg ccccaccaca gatgaggtga 1080 cactccaagt ctcaggagag cgagagggct cacccagcac tgctgttaga tacccctcag 1140 gcagtgtggc cctcccaagc cagtggctgc tcattggaca ccacgagcta cccccagtcc 1200 tgcacaccac catgctgagg gtccatccca ccctggggag tggaactgca gagacaagac 1260 ctccagagaa tacccaggcc ccagccttct tcttggagct attgagcctg agccgagaga 1320 aactttggga ctccgagctg catccagaag aaaaaactcc agactcttac ttggggctgg 1380 gaccccaaga cctgctggca gctagcctca ctgctgtcct cctgggaggg tggattctct 1440 ttgtgatgag gcagcaacag gagacccccc tggcacctgc agactttgct cacatctccc 1500 aggatgccca gtccctgcac tcgggggcca gccggaggag ccagaagagg cttcagagtc 1560 cctcacctga gtcaccaccc tcctctcccc cagctgagca actcaccgta gtggggaaga 1620 tttccttcaa tcccaaggac gtgctgggcc gcggggcagg cgggactttc gttttcaggg 1680 gacagtttga gggacgggca gtggctgtca agcggctcct ccgcgagtgc tttggcctgg 1740 ttcggcggga agttcaactg ctgcaggagt ctgacaggca ccccaacgtg ctccgctact 1800 tctgcaccga gcggggaccc cagttccact acattgccct ggagctctgc cgggcctcct 1860 tgcaggagta cgtagaaaac_ccggacctgg atcgcggggg tctggagccc gaggtcgtgc 1920 tgcagcagct gatgtctggc ctggcccacc tgcactcttt acacatagtg caccgggacc 1980 tgaagccagg aaatattctc atcaccgggc ctgacagcca gggcctgggc agagtggtgc 2040 tctcagactt cggcctctgc aagaagctgc ctgctggccg ctgtagcttc agcctccact 2100 ccggcatccc cggcacggaa ggctggatgg cgcccgagct tctgcagctc ctgccaccag 2160 acagtcctac cagcgctgtg gacatcttct ctgcaggctg cgtgttctac tacgtgcttt 2220 ctggtggcag ccaccccttt ggagacagtc tttatcgcca ggcaaacatc ctcacagggg 2280 ctccctgt.ct ggctcacctg gaggaagagg tccacgacaa ggtggttgcc cgggacctgg 2340 ttggagccat gttgagccca ctgccgcagc cacgcccctc tgccccccag gtgctggccc 2400 accccttctt ttggagcaga gccaagcaac tccagttctt ccaggacgtc agtgactggc 2460 tggagaagga gtccgagcag gagcccctgg tgagggcact ggaggcggga ggctgcgcag 2520 tggtccggga caactggcac gagcacatct ccatgccgct gcagacagat ctgagaaagt 2580 tccggtccta taaggggaca tcagtgcgag acctgctccg tgctgtgagg aacaagaagc 2640 accactacag ggagctccca gttgaggtgc gacaggcact cggccaagtc cctgatggct 2700 tcgtccagta cttcacaaac cgcttcccac ggctgctcct ccacacgcac cgagccatga 2760 ggagctgcgc ctctgagagc ctcttcctgc cctactaccc gccagactca gaggccagga 2820 ggccatgccc tggggccaca gggaggtgag gtgggctgga tgccacacag atggtctccg 2880 tgctggctca ctgaagagct gagcctgtgg ctggcctcag aatcaggctg ggtgcagtgg 2940 ctcacacctg taatcccagc attttgggag gctgagtgag aggatcactt gagctcagga 3000 gttcgagacc agcctggcca acatggcaac accccatttc tacaaaaaat ttgtaaaatt 3060 agccaggcat ggtggcgcac gcctgtagtc ccagctgctt gggaggctga ggtgggagaa 3120 tcacttgagc ccaggagttc gaggctgcag tgagccagga tcatgccact gcactccagc 3180 ctggtccaca gagagacact gtcaccccct ttcccccaca agactggcag aggctgggca 3240 gcctggggct gatgaagcag agatgttcgc tggatcccag gccctggcac ccctcaggaa 3300 atacaagaaa aagaatattc acatctgttt aatgtgcata aagccaagga aaggacagtt 3360 ccgaattcaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 3420 aaaaaaaaaa aaaaagaaga aaaaaaaaaa aaagaagaag acccagac 3468 <210> 30 <211> 2831 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7473244CB1 <400> 30 cttctcccgc cggggccgct tgttgcaccg ccccgcggcc tgcgggagcc gctcgccccg 60 gccttgtgct cgcgtccgca cccctttcct gtcgcccccc ggggcccgca ccacagcccg 120 gccggcgaga ccccggccag accccgctgc ccgcacaaaa tgtcggcccg gacgccattg 180 ccgacggtga acgagcggga cacggaaaat catacatctg tggatggata tactgaacca 240 cacatccagc ctaccaagtc gagtagcaga cagaacatcc cccggtgtag aaactccatt 300 acgtcagcaa cagatgaaca gcctcacatt ggaaattacc gtttacaaaa aacaataggg 360 aagggaaatt ttgccaaagt caaattggca agacacgttc taactggtag agaggttgct 420 gtgaaaataa tagacaaaac tcagctaaat cctaccagtc tacaaaagtt atttcgagaa 480 gtacgaataa tgaagatact gaatcatcct aatatagtaa aattgtttga agttattgaa 540 acagagaaga ctctctattt agtcatggaa tacgcgagtg ggggtgaagt atttgattac 600 ttagttgccc atggaagaat gaaagagaaa gaggcccgtg caaaatttag gcagattgta 660 tctgctgtac agtattgtca tcaaaagtac attgttcacc gtgatcttaa ggctgaaaac 720 cttctccttg atggtgatat gaatattaaa attgctgact ttggttttag taatgaattt 780 acagttggga acaaattgga cacattttgt ggaagcccac cctatgctgc tcccgagctt 840 ttccaaggaa agaagtatga tgggcctgaa gtggatgtgt ggagtctggg cgtcattctc 900 tatacattag tcagtggctc cttgcctttc gatggccaga atttaaagga actgcgagag 960 cgagttttac gagggaagta ccgtattccc ttctatatgt ccacagactg tgaaaatctt 2020 ctgaagaaat tattagtcct gaatccaata aagagaggca gcttggaaca aataatgaaa 1080 gatcgatgga tgaatgttgg tcatgaagag gaagaactaa agccatatac tgagcctgat 1140 ccggatttca atgacacaaa aagaatagac attatggtca ccatgggctt tgcacgagat 1200 gaaataaatg atgccttaat aaatcagaag tatgatgaag ttatggctac ttatattctt 1260 ctaggtagaa aaccacctga atttgaaggt ggtgaatcgt tatccagtgg aaacttgtgt 1320 cagaggtccc ggcccagtag tgacttaaac aacagcactc ttcagtcccc tgctcacctg 1380 aaggtccaga gaagtatctc agcaaatcag aagcagcggc gtttcagtga tcatgctggt 1440 ccatccattc ctcctgctgt atcatatacc aaaagacctc aggctaacag tgtggaaagt 1500 gaacagaaag aggagtggga caaagatgtg gctcgaaaac ttggcagcac aacagttgga 1560 tcaaaaagcg agatgactgc aagccctctt gtagggccag agaggaaaaa atcttcaact 1620 attccaagta acaatgtgta ttctggaggt agcatggcaa gaaggaatac atatgtctgt 1680 gaaaggacca cagatcgata cgtagcattg cagaatggaa aagacagcag ccttacggag 1740 atgtctgtga gtagcatatc ttctgcaggc tcttctgtgg cctctgctgt cccctcagca 1800 cgaccccgcc accagaagtc catgtccact tctggtcatc ctattaaagt cacactgcca 1860 accattaaag acggctctga agcttaccgg cctggtacaa cccagagagt gcctgctgct 1920 tccccatctg ctcacagtat tagtactgcg actccagacc ggacccgttt tccccgaggg 1980 agctcaagcc gaagcacttt ccatggtgaa cagctccggg agcgacgcag cgttgcttat 2040 aatgggccac ctgcttcacc atcccatgaa acgggtgcat ttgcacatgc cagaagggga 2100 acgtcaactg gtataataag caaaatcaca tccaaatttg ttcgcaggga tccaagtgaa 2160 ggcgaagcca gtggcagaac cgacacctca agaagtacat caggggaacc aaaagaaaga 2220 gacaaggaag agggtaaaga ttctaagccg cgttctttgc ggttcacatg gagtatgaag 2280 accactagtt caatggaccc taatgacatg atgagagaaa tccgaaaagt gttagatgca 2340 aataactgtg attatgagca aaaagagaga tttttgcttt tctgtgtcca tggagacgct 2400 agacaggata gcctcgtgca gtgggagatg gaagtctgca agttgccacg actgtcactt 2460 aatggggttc gcttcaagcg aatatctggg acatctattg cctttaagaa cattgcatca 2520 aaaatagcaa atgagcttaa gctgtaaaga agtccaaatt tacaggttca gggaagatac 2580 atacatatat gaggtacagt ttttgaatgt actggtaatg cctaatgtgg tctgcctgtg 2640 aatctcccca tgtagaattt gcccttaatg caataaggtt atacatagtt atgaactgta 2700 aaattaaagt cagtatgaac tataataaat atctgtagct taaaaagtag gttcacatgt 2760 acaggtaagt atattgtgta tttctgttca ttttctgttc atagagttgt ataataaaac 2820 atgattgctt t 2831 <210> 31 <211> 2693 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1242491CB1 <400> 31 agtgtgctgg aaagattgcc cctgacttga tttggctgac ctgcctagaa atattatgtt 60 gaataatgat gagttggaat ttgaacaagc tccagagttt tctcctaggt gatggcagtt 120 ttggatcagt ttaccgagca gcctatgaag gagaagaagt ggctgtgaag atttttaata 180 aacatacatc actcaggctg ttaagacaag agcttgtggt gctttgccac ctccaccacc 240 ccagtttgat atctttgctg gcagctggga ttcgtccccg gatgttggtg atggagttag 300 cctccaaggg ttccttggat cgcctgcttc agcaggacaa agccagcctc actagaaccc 360 tacagcacag gattgcactc cacgtagctg atggtttgag atacctccac tcagccatga 420 ttatataccg agacctgaaa ccccacaatg tgctgctttt cacactgtat cccaatgctg 480 ccatcattgc aaagattgct gactacggca ttgctcagta ctgctgtaga atggggataa 540 aaacatcaga gggcacacca gggtttcgtg cacctgaagt tgccagagga aatgtcattt 600 ataaccaaca ggctgatgtt tattcatttg gtttactact ctatgacatt ttgacaactg 660 gaggtagaat agtagagggt ttgaagtttc caaatgagtt tgatgaatta gaaatacaag 720 gaaaattacc tgatccagtt aaagaatatg gttgtgcccc atggcctatg gttgagaaat 780 taattaaaca gtgtttgaaa gaaaatcctc aagaaaggcc tacttctgcc caggtctttg 840 acattttgaa ttcagctgaa ttagtctgtc tgacgagacg cattttatta cctaaaaacg 900 taattgttga atgcatggtt gctacacatc acaacagcag gaatgcaagc atttggctgg 960 gctgtgggca caccgacaga ggacagctct catttcttga cttaaatact gaaggataca 1020 cttctgagga agttgctgat agtagaatat tgtgcttagc cttggtgcat cttcctgttg 1080 aaaaggaaag ctggattgtg tctgggacac agtctggtac tctcctggtc atcaataccg 1140 aagatgggaa aaagagacat accctagaaa agatgactga ttctgtcact tgtttgtatt 1200 gcaattcctt ttccaagcaa agcaaacaaa aaaattttct tttggttgga accgctgatg 1260 gcaagttagc aatttttgaa gataagactg ttaagcttaa aggagctgct cctttgaaga 1320 tactaaatat aggaaatgtc agtactccat tgatgtgttt gagtgaatcc acaaattcaa 1380 cggaaagaaa tgtaatgtgg ggaggatgtg gcacaaagat tttctccttt tctaatgatt 1440 tcaccattca gaaactcatt gagacaagaa caagccaact gttttcttat gcagctttca 1500 gtgattccaa catcataaca gtggtggtag acactgctct ctatattgct aagcaaaata 1560 gccctgttgt ggaagtgtgg gataagaaaa ctgaaaaact ctgtggacta atagactgcg 1620 tgcacttttt aagggaggta acggtaaaag aaaacaagga atcaaaacac aaaatgtctt 1680 attctgggag agtgaaaacc ctctgccttc agaagaacac tgctctttgg ataggaactg 1740 gaggaggcca tattttactc ctggatcttt caactcgtcg acttatacgt gtaatttaca 1800 acttttgtaa ttcggtcaga gtcatgatga cagcacagct aggaagcctt aaaaatgtca 1860 tgctggtatt gggctacaac cggaaaaata ctgaaggtac acaaaagcag aaagagatac 1920 aatcttgctt gaccgtttgg gacatcaatc ttccacatga agtgcaaaat ttagaaaaac 1980 acattgaagt gagaaaagaa ttagctgaaa aaatgagacg aacatctgtt gagtaagaga 2040 gaaataggaa ttgtctttgg ataggaaaat tattctctcc tcttgtaaat atttatttta 2100 aaaatgttca catggaaagg gtactcacat tttttgaaat agctcgtgtg tatgaaggaa 2160 tgttattatt tttaatttaa atatatgtaa aaatacttac cagtaaatgt gtattttaaa 2220 gaactattta aaacacaatg ttatatttct tataaatacc agttactttc gttcattaat 2280 taatgaaaat aaatctgtga agtacctaat ttaagtactc atactaaaat ttataaggcc 2340 gataattttt tgttttcttg tctgtaatgg aggtaaactt tattttaaat tctgtgctta 2400 agacaggact attgcttgtc gatttttcta gaaatctgca cggtataatg aaaatattaa 2460 gacagtttcc catgtaatgt attccttctt agattgcatc gaaatgcact atcatatatg 2520 cttgtaaata ttcaaatgaa tttgcactaa taaagtcctt tgttggtatg tgaattctct 2580 ttgttgctgt tgcaaacagt gcatcttaca caacttcact caattcaaaa gaaaactcca 2640 ttaaaagtac taatgaaaaa acatgacata ctgtcaaagt cctcatatct agg 2693 <210> 32 <211> 2973 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 2634875CB1 <400> 32 agtgtgctgg aaagactgcc cacacccctg cctccgcctc tgcccacccg gcccaatccc 60 ttacaactgc ccaggactgc tcctgagcag ccgctgggag acagacggca accaggttgc 120 ccctctttgc tccaggtacc tctctcccct cagttagcag gcctcggctt cctgtctcac 180 tgcagccaga cgagagggga aattggacag cctgacacac tccactcttg tttctgcagc 240 tagaaagact tgagttagac aagcagcagc acacgcctcc ctacctcatg gcgacagaaa 300 atggagcagt tgagctggga attcagaacc catcaacaga caaggcacct aaaggtccca 360 caggtgaaag acccctggct gcagggaaag accctggccc cccagaccca aagaaagctc 420 cggatccacc caccctgaag aaagatgcca aagcccctgc ctcagagaaa ggggatggta 480 ccctggccca accctcaact agcagccaag gccccaaagg agagggtgac aggggcgggg 540 ggcccgcgga gggcagtgct gggcccccgg cagccctgcc ccagcagact gcgacacctg 600 agaccagcgt caagaagccc aaggctgagc agggagcctc aggcagccag gatcctggaa 660 agcccagggt gggcaagaag gcagcagagg gccaagcagc agccaggagg ggctcacctg 720 cctttctgca tagccccagc tgtcctgcca tcatctccag ttctgagaag ctgctggcca 780 agaagccccc aagcgaggca tcagagctca cctttgaagg ggtgcccatg acccacagcc 840 ccacggatcc caggccagcc aaggcagaag aaggaaagaa catcctggca gagagccaga 900 aggaagtggg agagaaaacc ccaggccagg ctggccaggc taagatgcaa ggggacacct 960 cgagggggat tgagttccag gctgttccct cagagaaatc cgaggtgggg caggccctct 1020 gtctcacagc cagggaggag gactgcttcc agattttgga tgattgcccg ccacctccgg 1080 cccccttccc tcaccgcatg gtggagctga ggaccgggaa tgtcagcagt gaattcagta 1140 tgaactccaa ggaggcgctc ggaggtggca agtttggggc agtctgtacc tgcatggaga 1200 aagccacagg cctcaagctg gcagccaagg tcatcaagaa acagactccc aaagacaagg 1260 aaatggtgtt gctggagatt gaggtcatga accagctgaa ccaccgcaat ctgatccagc 1320 tgtatgcagc catcgagact ccgcatgaga tcgtcctgtt catggagtac atcgagggcg 1380 gagagctctt cgagaggatt gtggatgagg actaccatct gaccgaggtg gacaccatgg 1440 tgtttgtcag gcagatctgt gacgggatcc tcttcagtgt gctggaaagg gttttgcacc 1500 tggaoctcaa gccagagaac atcctgtgtg tcaacaccac cgggcatttg gtgaagatca 1560 ttgactttgg cctggcacgg aggtataacc ccaacgagaa gctgaaggtg aactttggga 1620 ccccagagtt cctgtcacct gaggtggtga agggtgacca aatctccgat aagacagaca 1680 tgtggagtat gggggtgatc acctacatgc tgctgagcgg cctctccccc ttcctgggag 1740 atgatgacac agagacccta aacaacgttc tatctggcaa ctggtacttt gatgaagaga 1800 cctttgaggc cgtatcagac gaggccaaag actttgtctc caacctcatc gtcaaggacc 1860 agagggcccg gatgaacgct gcccagtgtc tcgcccatcc ctggctcaac aacctggcgg 1920 agaaagccaa acgctgtaac cgacgcctta agtcccagat cttgcttaag aaatacctca 1980 tgaagaggcg ctggaagaaa aacttcattg ctgtcagcgc tgccaaccgc ttcaagaaga 2040 tcagcagctc gggggcactg atggctctgg gggtctgagc cctgggcgca gctgaagcct 2100 ggacgcagcc acacagtggc cggggctgaa gccacacagc ccagaaggcc agaaaaggca 2160 gccagatccc cagggcagcc tcgttaggac aaggctgtgc caggctggga ggctcggggc 2220 tccccacgcc cccatgcagt gaccgcttcc ccgatgtgag ccgcctcgga gtgtggcctg 2280 gatccatcct gctagcacct ccccagacag ggctccagcc tgtcggccac accccagact 2340 ccaggccccc gttgaagccg ctcccggttc cctccccagc tcctcgtctt tgaactgccg 2400 ccgccgtggt gacccctgct ttgccccact gggagagtcc ttagcctggg cctcctccta 2460 gctggagtgc catggctggg gggtctcagc atgtagggct tctgtggttg tggatgggag 2520 gctcctggtg gggcagaaag gctgcaacgc tgattcctaa ggcccagctg ccagggaaga 2580 cagagcaggc tttgtgagag aggacctcca tgcccccgcc acctccccac tccagcagat 2640 aaggccgagc ccacaccatc tggcccaggc tggcccccac ccaccttcct tgcgaccacc 2700 aacacacagg aactctgtgt gagagagagg gcgcccagcc caggcctggt ggagggggag 2760 gggagaagcc aagggacaca ggagaccacc cccgagcttg cctcagggcc aagccggccc 2820 aacccaacca ctcggggccc ccatcttggg ggtcacecat ggcctcagat gatggggtca 2880 gcaggcccag gagaattagg aaggccatgg ggcagcctcc agtctgctct cagcttgtgc 2940 cttgtaaata aatgtacagg ttggaaaaaa aaa 2973 <210> 33 <211> 2066 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 3951059CB1 <400> 33 cgccagtggg gagatgttga agttcaaata tggagcgcgg aatcctttgg atgctggtgc 60 tgctgaaccc attgccagcc gggcctccag gctgaatctg ttcttccagg ggaaaccacc 120 ctttatgact caacagcaga tgtctcctct ttcccgagaa gggatattag atgccctctt 180 tgttctcttt gaagaatgca gtcagcctgc tctgatgaag attaagcacg tgagcaactt 240 tgtccggaag tattccgaca ccatagctga gttacaggag ctccagcctt cggcaaagga 300 cttcgaagtc agaagtcttg taggttgtgg tcactttgct gaagtgcagg tggtaagaga 360 gaaagcaacc ggggacatct atgctatgaa agtgatgaag aagaaggctt tattggccca 420 ggagcaggtt tcattttttg aggaagagcg gaacatatta tctcgaagca caagcccgtg 480 gatcccccaa ttacagtatg cctttcagga caaaaatcac ctttatctgg tcatggaata 540 tcagcctgga ggggacttgc tgtcactttt gaatagatat gaggaccagt tagatgaaaa 600 cctgatacag ttttacctag ctgagctgat tttggctgtt cacagcgttc atctgatggg 660 atacgtgcat cgagacatca agcctgagaa cattctcgtt gaccgcacag gacacatcaa 720 gctggtggat tttggatctg ccgcgaaaat gaattcaaac aagatggtga atgccaaact 780 cccgattggg accccagatt acatggctcc tgaagtgctg actgtgatga acggggatgg 840 aaaaggcacc taccgcctgg actgtgactg gtggtcagtg ggcgtgattg cctatgagat 900 gatttatggg agatccccct tcgcagaggg aacctctgcc agaaccttca ataacattat 960 gaatttccag cggtttttga aatttccaga tgaccccaaa gtgagcagtg actttcttga 1020 tctgattcaa agcttgttgt gcggccagaa agagagactg aagtttgaag gtctttgctg 1080 ccatcctttc ttctctaaaa ttgactggaa caacattcgt aactctcctc cccccttcgt 1140 tcccaccctc aagtctgacg atgacacctc caattttgat gaaccagaga agaattcgtg 1200 ggtttcatcc tctccgtgcc agctgagccc ctcaggcttc tcgggtgaag aactgccgtt 1260 tgtggggttt tcgtacagca aggcactggg gattcttggt agatctgagt ctgttgtgtc 1320 gggtctggac tcccctgcca agactagctc catggaaaag aaacttctca tcaaaagcaa 1380 agagctacaa gactctcagg acaagtgtca caaggtattt atttccgcag ccggcctcct 1440 tccttgctcc aggatcctcc cgtccgtata tgccaaggga tccgcccggg gccgctgctg 1500 gctctgagcc gcctgatccg tagagagtga ggcgctcctg ccttcgctga agtcgcgcct 1560 ccagcagctc agagggagat gaattcgggc cttgctgttg ctgtaaatcc tttaaatcta 1620 aaccagagga ggccctggat ttaaacagtc cgtttctcag catgacccag ccagatgtct 1680 gcttcttccg gcaggtggcc tgggtcctca cctgtggctg agatacatcc catctgcttt 1740 gagtgatgcg aagtctctct tcctagtctt ttaaaactcc tgcttatgtc actgcggcca 1800 ctgtgttgat tacgctcaac gtctcttaac attcactgtt cctgcccaga ggcaacgctc 1860 tggaaactaa taagtcactg cttgcctggg actcctaaga gtgcagacga ataaatatct 1920 ccttgccctg tcctggattt gtcctctaga tctttgcaag gagatggggg gggatcaaga 1980 tggatttggg ataaaattaa agtgacgtct gcaaaaacaa aacaaaaaca aaagcaaaca 2040 ggtgaaaaat gatgattgtg gcttcc 2066 <210> 34 <211> 3975 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 7395890CB1 <400> 34 agtgtgctgg aaagggcggc ctcggctgcg ccgagagcgg agacacaggc tcaagatggc 60 agattccgac tgaggctggg ggggccgagc tcgcgcgccg ctttcccgtc cccgttgcca 120 tgaaccgcgg acaccccggc cccgatggcc cccgtgtacg aaggtatggc ctcacatgtg 180 caagttttct cccctcacac ccttcaatca agtgccttct gtagtgtgaa gaaactgaaa 240 atagagccga gttccaactg ggacatgact gggtacggct cccacagcaa agtgtatagc 300 cagagcaaga acatccccct gtcgcagcca gccaccacaa ccgtcagcac ctccttgccg 360 gtcccaaacc caagcctacc ttacgagcag accatcgtct tcccaggaag caccgggcac 420 atcgtggtca cctcagcaag cagcacttct gtcaccgggc aagtcctcgg cggaccacac 480 aacctaatgc gtcgaagcac tgtgagcctc cttgatacct accaaaaatg tggactcaag 540 cgtaagagcg aggagatcga gaacacaagc agcgtgcaga tcatcgagga gcatccaccc 600 atgattcaga ataatgcaag cggggccact gtcgccactg ccaccacgtc tactgccacc 660 tccaaaaaca gcggctccaa cagcgagggc gactatcagc tggtgcagca tgaggtgctg 720 tgctccatga ccaacaccta cgaggtctta gagttcttgg gccgagggac gtttgggcaa 780 gtggtcaagt gctggaaacg gggcaccaat gagatcgtag ccatcaagat cctgaagaac 840 cacccatcct atgcccgaca aggtcagatt gaagtgagca tcctggcccg gttgagcacg 900 gagagtgccg atgactataa cttcgtccgg gcctacgaat gcttccagca caagaaccac 960 acgtgcttgg tcttcgagat gttggagcag aacctctatg actttctgaa gcaaaacaag 1020 tttagcccct tgcccctcaa atacattcgc ccagttctcc agcaggtagc cacagccctg 1080 atgaaactca aaagcctagg tcttatccac gctgacctca aaccagaaaa catcatgctg 1140 gtggatccat ctagacaacc atacagagtc aaggtcatcg actttggttc agccagccac 1200 gtctccaagg ctgtgtgctc cacctacttg cagtccagat attacagggc ccctgagatc 1260 atccttggtt taccattttg tgaggcaatt gacatgtggt ccctgggctg tgttattgca 1320 gaattgttcc tgggttggcc gttatatcca ggagcttcgg,agtatgatca gattcggtat 1380 atttcacaaa cacagggttt gcctgctgaa tatttattaa gcgccgggac aaagacaact 1440 aggtttttca accgtgacac ggactcacca tatcctttgt ggagactgaa gacaccagat 1500 gaccatgaag cagagacagg gattaagtca aaagaagcaa gaaagtacat tttcaactgt 1560 ttagatgata tggcccaggt gaacatgacg acagatttgg aagggagcga catgttggta 1620 gaaaaggctg accggcggga gttcattgac ctgttgaaga agatgctgac cattgatgct 1680 gacaagagaa tcactccaat cgaaaccctg aaccatccct ttgtcaccat gacacactta 1740 ctcgattttc cccacagcac acacgtcaaa tcatgtttcc agaacatgga gatctgcaag 1800 cgtcgggtga atatgtatga cacggtgaac cagagcaaaa cccctttc~t cacgcacgtg 1860 gcccccagca cgtccaccaa cctgaccatg acctttaaca accagctgac cactgtccac 1920 aaccagccct cagcggcatc catggctgca gtggcccagc ggagcatgcc cctgcagaca 1980 ggaacagccc agatttgtgc ccggcctgac ccgttccagc aagctctcat cgtgtgtccc 2040 cccggcttcc aaggcttgca ggcctctccc tctaagcacg ctggctactc ggtgcgaatg 2100 gaaaatgcag ttcccatcgt cactcaagcc ccaggagctc agcctcttca gatccaacca 2160 ggtctgcttg cccagcaggc ttggccaagt gggacccagc agatcctgct tcccccagca 2220 tggcagcaac tgactggagt ggccacccac acatcagtgc agcatgccac cgtgattccc 2280 gagaccatgg caggcaccca gcagctggcg gactggagaa atacgcatgc tcacggaagc 2340 cattataatc ccatcatgca gcagcctgca ctattgaccg gtcatgtgac ccttccagca 2400 gcacagccct taaatgtggg tgtggcccac gtgatgcggc agcagccaac cagcaccacc 2460 tcctcccgga agagtaagca gcaccagtca tctgtgagaa atgtctccac ctgtgaggtg 2520 tcctcctctc aggccatcag ctccccacag cgatccaagc gtgtcaagga gaacacacct 2580 ccccgctgtg ccatggtgca cagtagcccg gcctgcagca cctcggtcac ctgtgggtgg 2640 ggcgacgtgg cctccagcac cacccgggaa cggcagcggc agacaattgt cattcccgac 2700 actcccagcc ccacggtcag cgtcatcacc atcagcagtg acacggacga ggaggaggaa 2760 cagaaacacg cccccaccag cactgtctcc aagcaaagaa aaaacgtcat cagctgtgtc 2820 acagtccacg actcccccta ctccgactcc tccagcaaca ccagccccta ctccgtgcag 2880 cagcgtgctg ggcacaacaa tgccaatgcc tttgacacca aggggagcct ggagaatcac 2940 tgcacgggga acccccgaac catcatcgtg ccacccctga aaacccaggc cagcgaagta 3000 ttggtggagt gtgatagcct ggtgccagtc aacaccagtc accactcgtc ctcctacaag 3060 tccaagtcct ccagcaacgt gacctccacc agcggtcact cttcagggag ctcatctgga 3120 gccatcacct accggcagca gcggccgggc ccccacttcc agcagcagca gccactcaat 3180 ctcagccagg ctcagcagca catcaccacg gaccgcactg ggagccaccg aaggcagcag 3240 gcctacatca ctcccaccat ggcccaggct ccgtactcct tcccgcacaa cagccccagc 3300 cacggcactg tgcacccgca tctggctgca gccgctgccg ctgcccacct ccccacccag 3360 ccccacctct acacctacac tgcgccggcg gccctgggct ccaccggcac cgtggcccac 3420 ctggtggcct cgcaaggctc tgcgcgccac accgtgcagc acactgccta cccagccagc 3480 atcgtccacc aggtccccgt gagcatgggc ccccgggtcc tgccctcgcc caccatccac 3540 ccgagtcagt atccagccca atttgcccac cagacctaca tcagcgcctc gccagcctcc 3600 accgtctaca ctggataccc actgagcccc gccaaggtca accagtaccc ttacatataa 3660 acactggagg ggagggaggg agggagggag ggagagaatg gcccgaggga ggagggagag 3720 aaggagggag gcgctcctgg gaccgtgggc gctggccttt tatactgaag atgccgcaca 3780 caaacaatgc aaacggggca ggtgcggggg gggggggggc agagggcagg ggcacggggt 3840 cgggacacca gtgaaacttg aaccgggaag tgggaggacg tagagcagag aagagaacat 3900 ttttaaaagg aagggattaa agagggtggg aaatctatgg tttttatttt aaaaaagaaa 3960 aaggaaaaaa aaaaa 3975 <210> 35 <211> 1918 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7475546CB1 <400> 35 ccgcccgcag cgaggaagcg cccgcgcggg cgcaggcggc cgggatggcg gggcccggct 60 ggggtccccc gcgcctggac ggcttcatcc tcaccgagcg cctgggcagc ggcacgtacg 120 ccacggtgta caaggcctac gccaagaagg acactcgtga agtggtagcc ataaagtgtg 180 tagccaagaa aagtctgaac aaggcatcgg tggagaacct cctcacggag attgagatcc 240 tcaagggcat tcgacatccc cacattgtgc agctgaaaga ctttcagtgg gacagtgaca 300 atatctacct catcatggag ttttgcgcag ggggcgacct gtctcgcttc atccataccc 360 gcaggattct gcctgagaag gtggcgcgtg tcttcatgca gcaattagct agcgccctgc 420 aattcctgca tgaacggaat atctctcacc tggatctgaa gccacagaac attctactga 480 gctccttgga gaagccccac ctaaaactgg cagactttgg tttcgcacaa cacatgtccc 540 cgtgggatga gaagcacgtg ctccgtggct cccccctcta catggccccc gagatggtgt 600 gccagcggca gtatgacgcc cgcgtggacc tctggtccat gggggtcatc ctgtatgaag 660 ccctcttcgg gcagcccccc tttgcctcca ggtcgttctc ggagctggaa gagaagatcc 720 gtagcaaccg ggtcatcgag ctccccttgc ggcccctgct ctcccgagac tgccgggacc 780 tactgcagcg gctcctggag cgggacccca gccgtcgcat ctccttccag gacttctttg 840 cgcacccctg ggtggacctg gagcacatgc ccagtgggga gagtctgggg cgagcaaccg 900 ccctggtggt gcaggctgtg aagaaagacc aggaggggga ttcagcagcc gccttatcac 960 tctactgcaa ggctctggac ttctttgtac ctgccctgca ctatgaagtg gatgcccagc 1020 ggaaggaggc aattaaggca aaggtggggc agtacgtgtc ccgggctgag gagctcaagg 1080 ccatcgtctc ctcttccaat caggccctgc tgaggcaggg gacctctgcc cgagacctgc 1140 tcagagagat ggcccgggac aagccacgcc tcctagctgc cctggaagtg gcttcagctg 1200 ccatggccaa ggaggaggcc gccggcgggg agcaggatgc cctggacctg taccagcaca 1260 gcctggggga gctactgctg ttgctggcag cggagccccc gggccggagg cgggagctgc 1320 ttcacactga ggttcagaac ctcatggccc gagctgaata cttgaaggag cagatgaggg 1380 aatctcgctg ggaagctgac accctggaca aagagggact gtcggaatct gttcgtagct 1440 cttgcaccct tcagtgaccc tagaagaatg attggacaga tgtgagccat ctggagcaga 1500 ggggcactaa cccaggctga cgccaagaat gaagtggccc actgcagccc tggcgagcag 1560 gcttcttgga tggacagtgc tgagaccccc atatcccaga gtccccagcc tccctcaggt 1620 tactctgcac cccacagatg gtttgatggc tgtgctgtat actggagggg~agggcaggac 1680 tctgggagaa cagcacttct ttcatgagac ctttgttact cggtggttac tgggtcctgt 1740 gcctgtccgt tttggggcat gcagccctct atcatttttg gctccgagaa gagggcaagg 1800 ggcccccgca gggtacttct gtgcttgccc tcgccctgcc agcaggcagc tgtgcccctg 1860 gcctggcctt cccgggaccc cttattccaa ctcagctcct ctttgcactg gaatgggg 1918 <210> 36 <211> 1689 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7477076CB1 <400> 36 agtgtgctgg aaagctttcc agacccctcc ctcccgctcc tgggaaagag agaaaccacc 60 gctgcgggtg ggtagagaag cacttggcgc ctcggggagg ggaccgcgcc cgcctcattt 120 gcgccttgca gcactgctgg accaggttac aagatgttca cctaagattg agacctagtg 180 actacatttc ctacgggaac aaataaatgg tttttcatct cccggagata cattacaaac 240 aaatatggtg ctaaaagaac tccttacctt tctctgacta caatttattt ggacatactt 300 ttgtattgaa gagaggtata catactgaag ctacttgctg tactatagga gactctgtcc 360 tgtaggatca tggaccatcc tagtagggaa aaggatgaaa gacaacggac aactaaaccc 420 atggcacaaa ggagtgcaca ctgctctcga ccatctggct cctcatcgtc ctctggggtt 480 cttatggtgg gacccaactt cagggttggc aagaagatag gatgtgggaa cttcggagag 540 ctcagattag gtaaaaatct ctacaccaat gaatatgtag caatcaaact ggaaccaata 600 aaatcacgtg ctccacagct tcatttagag tacagatttt ataaacagct tggcagtgca 660 ggtgaaggtc tcccacaggt gtattacttt ggaccatgtg ggaaatataa tgccatggtg 720 ctggagctcc ttggccctag cttggaggac ttgtttgacc tctgtgaccg aacatttact 780 ttgaagacgg tgttaatgat agccatccag ctgctttctc gaatggaata cgtgcactca 840 aagaacctca tttaccgaga tgtcaagcca gagaacttcc tgattggtcg acaaggcaat 900 aagaaagagc atgttataca cattatagac tttggactgg ccaaggaata cattgacccc 960 gaaaccaaaa aacacatacc ttatagggaa cacaaaagtt taactggaac tgcaagatat 1020 atgtctatca acacgcatct tggcaaagag caaagccgga gagatgattt ggaagcccta 1080 ggccatatgt tcatgtattt ccttcgaggc agcctcccct ggcaaggact caaggctgac 1140 acattaaaag agagatatca aaaaattggt gacaccaaaa ggaatactcc cattgaagct 1200 ctctgtgaga actttccaga ggagatggca acctaccttc gatatgtcag gcgactggac 1260 ttctttgaaa aacctgatta tgagtattta cggaccctct tcacagacct ctttgaaaag 1320 aaaggctaca cctttgacta tgcctatgat tgggttggga gacctattcc tactccagta 1380 gggtcagttc acgtagattc tggtgcatct gcaataactc gagaaagcca cacacatagg 1440 gatcggccat cacaacagca gcctcttcga aatcaggtgg ttagctcaac caatggagag 1500 ctgaatgttg atgatcccac gggagcccac tccaatgcac caatcacagc tcatgccgag 1560 gtggaggtag tggaggaagc taagtgctgc tgtttcttta agaggaaacg gaagaagact 1620 gctcagcgcc acaagtgacc agtgcctccc aggagtcctc agggcctggg ggactctgac 1680 tcaattgta 1689 <210> 37 <211> 1054 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1874092CB1 <400> 37 ggctggatgc tgcgatcccg caggtgagcg cagcaccctc cagccttgca gaagcagcca 60 ccatgccagt ctctaagtgc ccaaaaaagt cggagtccct gtggaagggg tgggaccgga 120 aggcccagag gaacggcctg cggagccagg tatacgctgt gaatggcgac tactatgtgg 180 gcgagtggaa ggacaacgtg aaacacggga aaggaacaca ggtctggaag aagaaaggag 240 ccatctatga gggggactgg aagtttggga agcgagacgg ctacggcacc ctcagccttc 300 ctgaccaaca gacaggaaag tgcaggagag tctactcagg ctggtggaaa ggtgataaga 360 aatcgggtta tgggatccag tttttcggac ccaaggagta ttatgagggt gactggtgtg 420 gcagccagcg cagcgggtgg ggccgcatgt attacagcaa cggcgacatc tacgagggac 480 agtgggagaa cgacaagccc aacggggagg gcatgctgcg cctgaagaac gggaaccgct 540 acgagggctg ctgggagaga ggcatgaaga acggggcggg gcgtttcttc catctggacc 600 acggccagct gtttgaaggc ttctgggtgg acaatatggc caaatgcggg acgatgatcg 660 actttggccg tgacgaggcc cctgagccca ctcagttccc cattcctgag gtcaaaatcc 720 tagaccctga tggtgtgctg gcggaggcct tggccatgtt caggaagaca gaggaaggag 780 attgatgcca gagaacacaa acgcttcagg agaaattcaa gcctgtgtca cccgatcgct 840 cagaccagtg cggctctggc tggaggagtc agcagcagct ccaggcatga ccccggcacc 900 ctcatagggc ccctcactac ccccagcact gggtcatttc ttgccaatag gaaggctggt 960 gcttctctcc caggctgtcc tcgggaccct cttcattctc tgatctcatc ctggaatgca 1020 tgagaataaa gaataaccaa gtggtaaaaa aaaa 1054 <210> 38 <211> 3360 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 4841542CB1 <400> 38 agtgtgctgg aaaagcgctt cagccctccc cgcacagcct actgattccc ctgccgccct 60 tgctcacctc ctgctcgcca tggagtcgct ggttttcgcg cggcgctccg gccccactcc 120 ctcggcgcag agctagcccg gccgctggcg gaagggctga tcaagtcgcc caagccccta 180 atgaagaagc aggcggtgaa gcggcaccac cacaagcaca acctgcggca ccgctacgag 240 ttcctggaga ccctgggcaa aggcacctac gggaaggtga agaaggcgcg ggagagctcg.300 gggcgcctgg tggccatcaa gtcaatccgg aaggacaaaa tcaaagatga gcaagatctg 360 atgcacatac ggagggagat tgagatcatg tcatcgctca accaccctca catcattgcc 420 atccatgaag tgtttgagaa cagcagcaag atcgtgatcg tcatggagta tgccagccgg 480 ggcgaccttt atgactacat cagcgagcgg cagcagctca gtgagcgcga agctaggcat 540 ttcttccggc agatcgtctc tgccgtgcac tattgccatc agaacagagt tgtccaccga 600 gatctcaagc tggagaacat cctcttgggt gccaatggga atatcaagat tgctgacttc 660 ggcctctcca acctctacca tcaaggcaag ttcctgcaga cattctgtgg gagccccctc 720 tatgcctcgc cagagattgt caatgggaag ccctacacag gcccagaggt ggacagctgg 780 tccctgggtg ttctcctcta catcctggtg catggcacca tgccctttga tgggcatgac 840 cataagatcc tagtgaaaca gatcagcaac ggggcctacc gggagccacc taaaccctct 900 gatgcctgtg gcctgatccg gtggctgttg atggtgaacc ccacccgccg ggccaccctg 960 gaggatgtgg ccagtcactg gtgggtcaac tggggctacg ccacccgagt gggagagcag 1020 gaggctccgc atgagggtgg gcaccctggc agtgactctg cccgcgcctc catggctgac 1080 tggctccggc gttcctcccg ccccctcctg gagaatgggg ccaaggtgtg cagcttcttc 1140 aagcagcatg cacctggtgg gggaagcacc acccctggcc tggagcgcca gcattcgctc 1200 aagaagtccc gcaaggagaa tgacatggcc cagtctctcc acagtgacac ggctgatgac 1260 actgcccatc gccctggcaa gagcaacctc aagctgccaa agggcattct caagaagaag 1320 gtgtcagcct ctgcagaagg ggtacaggag gaccctccgg agctcagccc aatccctgcg 1380 agcccagggc aggctgcccc cctgctcccc aagaagggca ttctcaagaa gccccgacag 1440' cgcgagtctg gctactactc ctctcccgag cccagtgaat ctggggagct cttggacgca 1500 ggcgacgtgt ttgtgagtgg ggatcccaag,gagcagaagc ctccgcaagc ttcagggctg~1560 ctcctccatc gcaaaggcat cctcaaactc aatggcaagt tctcccagac agccttggag 1620 ctcgcggccc ccaccacctt cggctccctg gatgaactcg ccccacctcg ccccctggcc.1680 cgggccagcc gaccctcagg ggctgtgagc gaggacagca tcctgtcctc tgagtccttt 174 0 gaccagctgg acttgcctga acggctccca gagcccccac tgcggggctg tgtgtctgtg'1800.
gacaacctca cggggcttga ggagcccccc tcagagggcc ctggaagctg cctgaggcgc 1860 tggcggcagg atcctttggg ggacagctgc ttttccctga cagactgcca ggaggtgaca 1920 gcgacctacc gacaggcact gagggtctgc tcaaagctca cctgagtgga gtaggcattg 1980 ccccagcccg gtcaggctct cagatgcagc tggttgcacc ccgaggggag atgccttctc 2040 ccccacctcc caggacctgc atcccagctc agaaggctga gagggtttgc agtggagccc 2100 tgagcagggc tggatatggg aagtaggcaa atgaaatgcg ccaagggttc agtgtctgtc 2160 ttcagccctg ctgaacgaag aggatactaa agagagggga acgggaatgc ccgcgacaga 2220 gtccacattg cctgtttctt gtgtacatgg gggggccaca gagacctgga aagagaactc 2280 tcccagggcc catctcctgc atcccatgaa tactctgtac acatggtgcc ttctaaggac 2340 agctccttcc ctactcattc cctgcccaag tggggccaga cctctttaca cacacattcc 2400 cgttcctacc aaccaccaga actggatggt ggcaccccta atgtgcatga ggcatcctgg 2460 gaatggtctg gagtaacgct tcgttatttt tatttttatt tttatttatt tatttatttt 2520 tttgagacgg agtttcgctc ttggtgccca ggctagagtg caatggcgcg atctcagctc 2580 acctcaacct ccgcctcccg ggttcaagcg attctcctgc ctcagcctcc ctagtagctg 2640 ggattacagg cgcccgccac catgcccggc taattttgta tttttagtag agacagggtt .2700 tctccatgtt ggtcaggctg gtctcaaact cccgacctca ggtgatccac ccacctcggc 2760 ctcccaaagt gctgggatta caggcgtgag ccaccgcgcc ccacctaacc cttccttatt 2820 tagcctagga gtaagagaac acaatctctg tttcttcaat ggttctcttc ccttttccat 2880 cctccaaacc tggcctgagc ctcctgaagt tgctgctgtg aatctgaaag acttgaaaag 2940 cctccgcctg ctgtgtggac ttcatctcaa ggggcccagc ctcctctgga ctccaccttg 3000 gacctcagtg actcagaact tctgcctcta agctgctcta aagtccagac tatggatgtg 3060 ttctctaggc cttcaggact ctagaatgtc catatttatt tttatgttct tggctttgtg 3120 ttttaggaaa agtgaatctt gctgttttca ataatgtgaa tgctatgttc tgggaaaatc 3180 cactatgaca tctaagtttt gtgtacagag agatattttt gcaactattt ccacctcctc 3240 ccacaacccc ccacactcca ctccacactc ttgagtctct ttacctaatg gtctctacct 3300 aatggacctc cgtggccaaa aagtaccatt aaaaccagaa aggtgattgg aaaaaaaaaa 3360 <210> 39 <21l> 2240 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Tncyte ID No: 7472695CB1 <400> 39 cgggctgaaa agtttctccc ggtgcagaat tccgggctca gcgacagcct gcgccgagtg 60 tgcgcacctg tcggagaccc gccagtccgc cggccccggc ctgaagttaa atcattttgg 120 aaagtgatac agcaaaacaa gggttcctcc agttttggtg gtggaaatgt cacagacatc 180 aagcattggt agtgcagaat ctttaatttc actggagaga aaaaaagaaa aaaatatcaa 240 cagagatata acctccagga aagatttgcc ctcaagaacc tcaaatgtag agagaaaagc 300 atctcagcaa caatggggtc ggggcaactt tacagaagga aaagttcctc acataaggat 360 tgagaatgga gctgctattg aggaaatcta tacctttgga agaatattgg gaaaagggag 420 ctttggaata gtcattgaag cgacagacaa ggaaacagaa acgaagtggg caattaaaaa 480 agtgaacaaa gaaaaggctg gaagctctgc tgtgaagtta cttgaacgag aggtgaacat 540 tctgaaaagt gtaaaacatg aacacatcat acatctggaa caagtatttg aaacgccaaa 600 gaaaatgtac cttgtgatgg agctttgtga ggatggagaa ctcaaagaaa ttctggatag 660 gaaagggcat ttctcagaga atgagacaag gtggatcatt caaagtctcg catcagctat 720 agcatatctt cacaataatg atattgtaca tagagatctg aaactggaaa atataatggt 780 taaaagcagt cttattgatg ataacaatga aataaactta aacataaagg tgactgattt 840 tggcttagcg gtgaagaagc aaagtaggag tgaagccatg ctgcaggcca catgtgggac 900 tcctatctat atggcccctg aagttatcag tgcccacgac tatagccagc agtgtgacat 960 ttggagcata ggcgtcgtaa tgtacatgtt attacgtgga gaaccaccct ttttggcaag 1020 ctcagaagag aagctttttg agttaataag aaaaggagaa ctacattttg aaaatgcagt 1080 ctggaattcc ataagtgact gtgctaaaag tgttttgaaa caacttatga aagtagatcc 1140 tgctcacaga atcacagcta aggaactact agataaccag tggttaacag gcaataaact 1200 ttcttcggtg agaccaacca atgtattaga gatgatgaag gaatggaaaa ataacccaga 1260 aagtgttgag gaaaacacaa cagaagagaa gaataagccg tccactgaag aaaagttgaa 1320 aagttaccaa ccctggggaa atgtccctga tgccaattac acttcagatg aagaggagga 1380 aaaacagtct actgcttatg aaaagcaatt tcctgcaacc agtaaggaca actttgatat 1440 gtgcagttca agtttcacat ctagcaaact ccttccagct gaaatcaagg gagaaatgga 1500 gaaaacccct gtgactccaa gccaaggaac agcaaccaag taccctgcta aatccggcgc 1560.
cctgtccaga accaaaaaga aactctaagg ttccctccag tgttggacag tacaaaaaca 1620 aagctgctct tgttagcact ttgatgaggg ggtaggaggg gaagaagaca gccctatgct 1680 gagcttgtag ccttttagct ccacagagcc ccgccatgtg tttgcaccag cttaaaattg 1740 aagctgctta tctccaaagc agcataagct gcacgtggca ttaaaggaca gccaccagta 1800 ggcttggcag tgggctgcag tggaaatcaa ctcaagatgt acacgaaggt tttttagggg 1860 ggcagatacc ttcaatttaa ggctgtgggc acacttgctc atttttactt caaattctta 1920 tgtttaggca cagctattta taggggaaaa caagaggcca aatatagtaa tggaggtgcc 1980 aaataattat gtgcactttg cactagaaga ctttgttaga aaattactaa taaacttgcc 2040 atacgtatta cagcagaagt gcttcagtca ttcacatgtg ttcgtgagat tttaggttgc 2100 tatagattgt ttaagacagc ttattttaaa tgtagaaaaa taggagattt tgtaactgct 2160 tgccattaac ttgctgctaa attcccaatg tattgattaa atcaataaaa aacagatgtt 2220 actcagcaaa aaaaaaaaaa 2240 <210> 40 <211> 3340 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte TD No: 7477966CB1 <400> 40 cactataacc tttctctagg gtcaaagaga tgatgagtga caccagcacg ttccccaatc 60 acccttcctc ccctgctgca tccccatctg ggggaagggg agtcatggcc agccctgctt 120 gggacaggag caaagggtgg tcccagaccc ctcagagagc tgactttgtc tctaccccct 180 tgcaggttca tactctcagg ccagagaacc tcctgctggt gtccaccttg gatggaagtc 240 tccacgcact aagcaagcag acaggggacc tgaagtggac tctgagggat gatcccgtca 300 tcgaaggacc aatgtacgtc acagaaatgg cctttctctc tgacccagca gatggcagcc 360 tgtacatctt ggggacccaa aaacaacagg gattaatgaa actgccattc accatccctg 420 agctggttca tgcctctccc tgccgcagct ctgatggggt cttctacaca ggccggaagc 480 aggatgcctg gtttgtggtg gaccctgagt caggggagac ccagatgaca ctgaccacag 540 agggtccctc caccccccgc ctctacattg gccgaacaca gtatacggtc accatgcatg 600 acccaagagc cccagccctg cgctggaaca ccacctaccg ccgctactca gcgcccccca 660 tggatggctc acctgggaaa tacatgagcc acctggcgtc ctgcgggatg ggcctgctgc 720 tcactgtgga cccaggaagc gggacggtgc tgtggacaca ggacctgggc gtgcctgtga 780 tgggcgtcta cacctggcac caggacggcc tgcgccagct gccgcatctc acgctggctc 840 gagacactct gcatttcctc gccctccgct ggggccacat ccgactgcct gcctcaggcc 900 cccgggacac agccaccctc ttctctacct tggacaccca gctgctaatg acgctgtatg 960 tggggaagga tgaaactggc ttctatgtct ctaaagcact ggtccacaca ggagtggccc 1020 tggtgcctcg tggactgacc ctggcccccg cagatggccc caccacagat gaggtgacac 1080 tccaagtctc aggagagcga gagggctcac ccagcactgc tgttagatac ccctcaggca 1140 gtgtggccct cccaagccag tggctgctca ttggacacca cgagctaccc ccagtcctgc 1200 acaccaccat gctgagggtc catcccaccc tggggagtgg aactgcagag acaagacctc 1260 cagagaatac ccaggcccca gccttcttct tggagctatt gagcctgagc cgagagaaac 1320 tttgggactc cgagctgcat ccagaagaaa aaactccaga ctcttacttg gggctgggac 1380 cccaagacct gctggcagct agcctcactg ctgtcctcct gggagggtgg attctctttg 1440 tgatgaggca gcaacagccg caggtggtgg agaagcagca ggagaccccc ctggcacctg 1500 cagactttgc tcacatctcc caggatgccc agtccctgca ctcgggggcc agccggagga 1560 gccagaagag gcttcagagt ccctcaaagc aagcccagcc actcgacgac cctgaagctg 1620 agcaactcac cgtagtgggg aagatttcct tcaatcccaa ggacgtgctg ggccgcgggg 1680 caggcgggac tttcgttttc cggggacagt ttgagggacg ggcagtggct gtcaagcggc 1740 tcctccgcga gtgctttggc ctggttcggc gggaagttca actgctgcag gagtctgaca 1800 ggcaccccaa cgtgctccgc tacttctgca ccgagcgggg accccagttc cactacattg 1860 ccctggagct ctgccgggcc tccttgcagg agtacgtaga aaacccggac ctggatcgcg 1920 ggggtctgga gcccgaggtc gtgctgcagc agctgatgtc tggcctggcc cacctgcact 1980 ctttacacat agtgcaccgg gacctgaagc caggaaatat tctcatcacc gggcctgaca 2040 gccagggcct gggcagagtg gtgctctcag acttcggcct ctgcaagaag ctgcctgctg 2100 gccgctgtag cttcagcctc cactccggca tccccggcac ggaaggctgg atggcgcccg 2160 agcttctgca gctcctgcca ccagacagtc ctaccagcgc tgtggacatc ttctctgcag 2220 gctgcgtgtt ctactacgtg ctttctggtg gcagccaccc ctttggagac agtctttatc 2280 gccaggcaaa catcctcaca ggggctccct gtctggctca cctggaggaa gaggtccacg 2340 acaaggtggt tgcccgggac ctggttggag ccatgttgag cccactgccg cagccacgcc 2400 cctctgcccc ccaggtgctg gcccacccct tcttttggag cagagccaag caactccagt 2460 tcttccagga cgtcagtgac tggctggaga aggagtccga gcaggagccc ctggtgaggg 2520 cactggaggc gggaggctgc gcagtggtcc gggacaactg gcacgagcac atctccatgc 2580 cgctgcagac agatctgaga aagttccggt cctataaggg gacatcagtg cgagacctgc 2640 tccgtgctgt~gaggaacaag aagcaccact acagggagct cccagttgag gtgcgacagg 2700 cactcggcca agtccctgat ggcttcgtcc agtacttcac aaaccgcttc ccacggctgc 2760.
tcctccacac gcaccgagcc atgaggagct gcgcctctga gagcctcttc ctgccctact 2820 acccgccaga ctcagaggcc aggaggccat gccctggggc cacagggagg tgaggtgggc 2880 tggatgccac acagatggtc tccgtgctgg ctcactgaag agctgagcct gtggctggcc 2940 tcagaatcag gctgggtgca gtggctcaca cctgtaatcc cagcattttg ggaggctgag 3000 tgagaggatc acttgagctc aggagttcga gaccagcctg gccaacatgg caacacccca 3060 tttctacaaa aaatttgtaa aattagccag gcatggtggc gcacgcctgt agtcccagct 3120 gcttgggagg ctgaggtggg agaatcactt gagcccagga gttcgaggct gcagtgagcc 3180 aggatcatgc cactgcactc cagcctggtc cacagagaga cactgtcacc ccctttcccc 3240 cacaagactg gcagaggctg ggcagcctgg ggctgatgaa gcagagatgt tcgctggatc 3300 ccagctcctg gcacactgta aggaaataca acgaagaggt 3340 <210> 41 <211> 2539 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 7163416CB1 <400> 41 cggaggactg gcccagcaag gtcccaggtc ttccctctcc tcagcgccta agagagaggc 60 ccagtgcggg tgaggagtcg cgaggaagag gcggaaggcg ccggaaggca ccatgttccg 120 caagaaaaag aagaaacgcc ctgagatctc agcgccacag aacttccagc accgtgtcca 180 cacctccttc gaccccaaag aaggcaagtt tgtgggcctc cccccacaat ggcagaacat 240 cctggacaca ctgcggcgcc ccaagcccgt ggtggaccct tcgcgaatca cacgggtgca 300 gctccagccc atgaagacag tggtgcgggg cagcgcgatg cctgtggatg gctacatctc 360 ggggctgctc aacgacatcc agaagttgtc agtcatcagc tccaacaccc tgcgtggccg 420 cagccccacc agccggcggc gggcacagtc cctggggctg ctgggggatg agcactgggc 480 caccgaccca gacatgtacc tccagagccc ccagtctgag cgcactgacc cccacggcct 540 ctacctcagc tgcaacgggg gcacaccagc aggccacaag cagatgccgt ggcccgagcc 600 acagagccca cgggtcctgc ccaatgggct ggctgcaaag gcacagtccc tgggccccgc 660 cgagtttcag ggtgcctcgc agcgctgtct gcagctgggt gcctgcctgc agagctcccc 720 accaggagcc tcgcccccca cgggcaccaa taggcatgga atgaaggctg ccaagcatgg 780 ctctgaggag gcccggccac agtcctgcct ggtgggctca gccacaggca ggccaggtgg 840 ggaaggcagc cctagcccta agacccggga gagcagcctg aagcgcaggc tattccgaag 900 catgttcctg tccactgctg ccacagcccc tccaagcagc agcaagccag gccctccacc 960 acagagcaag cccaactcct ctttccgacc gccgcagaaa gacaaccccc caagcctggt 1020 ggccaaggcc cagtccttgc cctcggacca gccggtgggg accttcagcc ctctgaccac 1080 ttcggatacc agcagccccc agaagtccct ccgcacagcc ccggccacag gccagcttcc 1140 aggccggtct tccccagcgg gatccccccg cacctggcac gcccagatca gcaccagcaa 1200 cctgtacctg ccccaggacc ccacggttgc caagggtgcc ctggctggtg aggacacagg 1260 tgttgtgaca catgagcagt tcaaggctgc gctcaggatg gtggtggacc agggtgaccc 1320 ccggctgctg ctggacagct acgtgaagat tggcgagggc tccaccggca tcgtctgctt 1380 ggcccgggag aagcactcgg gccgccaggt ggccgtcaag atgatggacc tcaggaagca 1440 gcagcgcagg gagctgctct tcaacgaggt ggtgatcatg cgggactacc agcacttcaa 1500 cgtggtggag atgtacaaga gctacctggt gggcgaggag ctgtgggtgc tcatggagtt 1560 cctgcaggga ggagccctca cagacatcgt ctcccaagtc aggctgaatg aggagcagat 1620 tgccactgtg tgtgaggctg tgctgcaggc cctggcctac ctgcatgctc agggtgtcat 1680 ccaccgggac atcaagagtg actccatcct gctgaccctc gatggcaggg tgaagctctc 1740 ggacttcgga ttctgtgctc agatcagcaa agacgtccct aagaggaagt ccctggtggg 1800 aaccccctac tggatggctc ctgaagtgat ctccaggtct ttgtatgcca ctgaggtgga 1860 tatctggtct ctgggcatca tggtgattga gatggtagat ggggagccac cgtacttcag 1920 tgactcccca gtgcaagcca tgaagaggct ccgggacagc cccccaccca agctgaaaaa 1980 ctctcacaag gtcagttggc acacaagggt gcgacctcgc agaccccatt cctcctgagg 2040 caaggggacc agaacctggg ctcccagcat ctcccttcca ctgaagccac agggtctggg 2100 ctcctggaaa aggctcctct ttccccacac aaaacccgca cctgggtgtg gagccgcatc 2260 tacgcacaag ttcgcatgtg cgctccgaca agtcgcctcc cacggctgtg gcaggagagt 2220 tgctgcttgg cagaagggtt gctgcttggc aggcactggt cggaagccca gtggggccca 2280 tgagcaggga aagccaggac accagcaatc cctgctgtcc agggagggat ccggagaagc 2340 ttcactgagc acaaaccctt ctaacccgtg tcgggagatc cataccatga ttcgatgtcc 2400 tgtccatcac ggcgagtcgg ctcatgctcc atcgttgcac accccgacac agctaagcca 2460 cagcgttccc cttaaagcca gtataagtgc atggaagtgt atacatgtaa ccctttttgc 2520 caaatcggcc ccaaccccg 2539 <210> 42 <211> 2377 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7472822CB1 <400> 42 agtgtgctgg aaagttgaat tggaattccc tgtggctgtc cgaaggcagg gtgtccggag 60 agcggtgggc tgacctgttc ctacaccttg catcatgcca gctttgtcaa cgggatctgg 120 gagtgacact ggtctgtatg agctgttggc tgctctgcca gcccagctgc agccacatgt 180 ggatagccag gaagacctga ccttectctg ggatatgttt ggtgaaaaaa gcctgcattc 240 attggtaaag attcatgaaa aactacacta ctatgagaag cagagtccgg tgcccattct 300 ccatggtgcg gcggccttgg ccgatgatct ggccgaagag cttcagaaca agccattaaa 360 cagtgagatc agagagctgt tgaaactact gtcaaaaccc aatgtgaagg ctttgctctc 420 tgtacatgat actgtggctc agaagaatta cgacccagtg ttgcctccta tgcctgaaga 480 tattgacgat gaggaagact cagtaaaaat aatccgtctg gtcaaaaata gagaaccact 540 gggagctacc attaagaagg atgaacagac cggggcgatc attgtggcca gaatcatgag 600 aggaggagct gcagatagaa gtggtcttat tcatgttggt gatgaactta gggaagtcaa 660 cgggatacca gtggaggata aaaggcctga ggaaataata cagattttgg ctcagtctca 720 gggagcaatt acatttaaga ttatacccgg cagcaaagag gagacaccat caaaagaagg 780 caagatgttt atcaaagccc tctttgacta taatcctaat gaggataagg caattccatg 840 taaggaagct gggctttctt tcaaaaaggg agatattctt cagattatga gccaagatga 900 tgcaacttgg tggcaagcga aacacgaagc tgatgccaac cccagggcag gcttgatccc 960 ctcaaagcat ttccaggaaa ggagattggc tttgagacga ccagaaatat tggttcagcc 1020 cctgaaagtt tccaacagga aatcatctgg ttttagaaaa agttttcgtc ttagtagaaa 1080 agataagaaa acaaataaat ccatgtatga atgcaagaag agtgatcagt acgacacagc 1140 tgacgtaccc acatacgaag aagtgacacc gtatcggcga caaactaatg aaaaatacag 1200 actcgttgtc ttggttggtc ccgtgggagt agggctgaat gaactgaaac gaaagctgct 1260 gatcagtgac acccagcact atggcgtgac agtgccccat accaccagag caagaagaag 1320 ccaggagagt gatggtgttg aatacatttt catttccaag catttgtttg agacagatgt 1380 acaaaataac aagtttattg aatatggaga atataaaaac aactactacg gcacaagtat 1440 agactcagtt cggtctgtcc ttgctaaaaa caaagtttgt ttgttggatg ttcagcctca 1500 tacagtgaag catttaagga cactagaatt taagccctat gtgatattta taaagcctcc 1560 atcaatagag cgtttgagag aaacaagaaa aaatgcaaag attatttcaa gcagagatga 1620 ccaaggtgct gcaaaaccct tcacagaaga agattttcaa gaaatgatta aatctgcaca 1680 gataatggaa agtcaatatg gtcatctttt tgacaaaatt ataataaatg atgacctcac 1740 tgtggcattc aatgagctca aaacaacttt tgacaaatta gagacagaga cccattgggt 1800 gccagtgagc tggttacatt cataactaag agaaatttcc ataattgtct ttttctatag 1860 agtgcatgat gaaatcaatt acagttttgg tagtagggtt tttaaatcta tatcactgtc 1920 atagatgtac aatcttggtt caagttgaat gctggttttg tttgtatctt tttacagcct 1980 tatttcaaac gccatgtgtt agtataagat ccgaaatcaa aatatgcaca gtactgtatt 2040 ctaagcaaaa cctcaaacct tctcgttgtc ttcaatatcg ctctatctcc aagatgaggc 2100 tgaaattttc agagagactt agctagaggc ttagtatgta tgggagttca gcgcttctgc 2160 tggtctcagg tgtggctgct gctgtcgagt ttgcatgtta gctgttgaag gtatcaattc 2220 agcagccatg agcagctcca gacagacagc gtgagctctg ctgtttetgg gtggatcatc 2280 acagatttag ccgggcaggc agtaaggtgt cctcttacta ttcaaaagtg tagactttct 2340 gggggatcca ctagttctac acgccgcccc cgtgacc 2377 <210> 43 <211> 2897 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7477486CB1 <400> 43 atggtggcgg ggttaacttt ggggaagggc ccggagtccc cggatggtga tgtcagcgtg 60 ccggagagaa aggacgaggt ggcgggggga ggcggagagg aggaggaggc cgaagagaga 120 gggcgccacg cccaatatgt gggcccctat cggctggaga agacgctggg caaaggacag 180 acagggctgg ttaaactcgg ggtccactgc atcacgggtc agaaggtcgc catcaagatc 240 gtgaaccggg agaagctgtc ggagtcggtg ctgatgaagg tggagcggga gatcgccatc 300 ctgaagctca tcgaacaccc acatgtcctc aagctccacg acgtctacga gaacaagaaa 360 tatttgtacc tggttctgga gcacgtctcg gggggtgagc tattcgacta cctggtaaag 420 aaggggagac tgacgcccaa ggaggcccga aagttcttcc gccagattgt gtctgcgctg 480 gacttctgcc acagctactc catctgccac agagacctaa agcccgagaa cctgcttttg 540 gatgagaaaa acaacatccg cattgcagac ttcggcatgg cgtccctgca ggtgggggac 600 agcctcctgg agaccagctg cgggtccccc cattatgcgt gtccagaggt gattaagggg 660 gaaaaatatg atggccgccg ggcagacatg tggagctgtg gagtcatcct cttcgccctg 720, ctcgtggggg ctctgccctt tgatgacgac aacctccgcc agctgctgga gaaggtgaaa 780 cggggcgtct tccacatgcc ccacttcatt cctccagatt gccagagcct cctgagggga 840 atgatcgaag tggagcccga aaaaaggctc agtctggagc aaattcagaa acatccttgg 900 tacctaggcg ggaaacacga gccagacccg tgcctggagc cagcccctgg ccgccgggta 960 gccatgcgga gcctgccatc caacggagag ctggaccccg acgtcctaga gagcatggca 1020 tcactgggct gcttcaggga ccgcgagagg ctgcatcgcg agctgcgcag tgaggaggag 1080 aaccaagaaa agatgatata ttatctgctt ttggatcgga aggagcggta tcccagctgt 1140 gaggaccagg acctgcctcc ccggaatgat gttgaccccc cccggaagcg tgtggattct 1200 cccatgctga gccgtcacgg gaagcggcga ccagagcgga agtccatgga agtcctgagc 1260 atcaccgatg ccgggggtgg tggctcccct gtacccaccc gacgggcctt ggagatggcc 1320 cagcacagcc agagatcccg tagcgtcagt ggagcctcca cgggtctgtc ctccagccct 1380 ctaagcagcc caaggagtcc ggtcttttcc ttttcaccgg agccgggggc tggagatgag 1440 gctcgaggcg ggggctcccc gacttccaaa acgcagacgc tgccttctcg gggccccagg 1500 ggtgggggcg ccggggagca gcccccgccc cccagtgccc gctccacacc cctgcccggc 1560 cccccaggct ccccgcgctc ctctggcggg acccccttgc actcgcctct gcacacgccc 1620 cgggccagtc ccaccgggac cccggggaca acaccacccc ccagccccgg cggtggcgtc 1680 gggggagccg cctggaggag tcgtctcaac tccatccgca acagcttcct gggctcccct 1740 cgctttcacc ggcgcaagat gcaggtccct accgctgagg agatgtccag cttgacgcca 1800 gagtcctccc cggagctggc aaaacgctcc tggttcggga acttcatctc cttggacaaa 1860 gaagaacaaa tattcctcgt gctaaaggac aaacctctca gcagcatcaa agcagacatc 1920 gtccatgcct ttctgtcgat ccccagcctg agtcacagtg tgctgtcaca gaccagcttc 1980 agggccgagt acaaggccag tggcggcccc tccgtcttcc aaaagcccgt ccgcttccag 2040 gtggacatca gctcctctga gggtccagag ccctccccgc gacgggacgg cagcggaggt 2100 ggtggcatct actccgtcac cttcactctc atctcgggtc ccagccgtcg gttcaagcga 2160 gtggtggaga ccatccaggc acagctcctg agcactcatg accagccctc cgtgcaggcc 2220 ctggcagacg agaagaacgg ggcccagacc cggcctgctg gtgccccacc ccgaagcctg 2280 cagcccccac ccggccgccc agacccagag ctgagcagct ctccccgccg aggccccccc 2340 aaggacaaga agctcctggc caccaacggg acccctctgc cctgacccca cggggccggg 2400 gagggagggg acccccctcc accccccttc cgtgcccccc aactgtgaat ctgtaaataa 2460 ggcccaagga acatgtcggg aggggggtgg acacaaaaac cggccttgcc ctgcagggat 2520 ggggctccac aggccgtgcc caactgcggg tggttctagg ggaacagggg gcgggggagc 2580 tgtttctatt ttatttattg attaatttat tattttattt attgatcaat ctctctgcgg 2640 ggtgcggtgg gggagggacg ggagctggtt ggggtggctt agcagatccg gacagggccc 2700 tctgtccctg tgtcgtcccc aaccccctct tcccgggccc ctcctcccct ggtccttccc 2760 cccacgacct tctgtacgga tttgctctcc ggaaggaatt ctgataacgc gtgatcctgc 2820 ctgcgtccgt gtctctgatt ccgccggcgg caaaaaaaac acaacaccaa caacacaaca 2880 gggcacaaca aaaaaaa 2897 <210> 44 <211> 3361 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 3773709CB1 <220>
<221> unsure <222> 96 <223> a, t, c, g, or other <400> 44 ggctgagccg ggttggggcc cgggttgggc cgcccgggga ctctggagca ttgggatttg 60 tagcgcgccc tctgggtagg cggctgtagc ggagangcgt gcgggatcgg gatgtcgggg 120 ctgctcacgg acccggagca gagagcgcag gagccgcggt accccggctt cgtgctgggg 180 ctggatgtgg gcagttctgt gatccgctgc cacgtctatg.accgggcggc gcgggtctgc 240 ggctccagcg tgcagaaggt agaaaatctt tatcctcaaa ttggctgggt agaaattgat 300 cctgatgttc tttggattca atttgttgcc gtaataaaag aagcagtcaa agctgcagga 360 atacagatga atcaaattgt tggtcttggc atttcaacac agagagcaac ttttattacg 420 tggaacaaga aaacaggaaa tcattttcac aactttataa gttggcaaga cttaagagct 480 gttgaacttg taaaatcttg gaataattct cttcttatga agatatttca cagttcttgc 540 cgagtgcttc actttttcac tagaagtaaa cgacttttta cagccagttt gttcactttc 600 acaacccagc agacttcttt gagattggtc tggattttac agaacttgac tgaggtgcaa 660 aaggcagttg aagaagaaaa ttgctgcttt gggactatcg atacctggtg gttatataag 720 ctcacaaaag gttctgtata tgccacagat ttttcaaatg ctagtacaac tggacttttt 780 gacccatata gccacaattt tggatcagtg gatgaagaga tatttggtgt gcctatacca 840 atagttgcct tggttgctga ccagcaatca gccatgtttg gagagtgctg cttccagaca 900 ggtgatgtga aattaaccat gggaactggg acatttttgg atattaacac tggaaatagc 960 cttcaacaga ctactggagg cttttatcca ttaattgggt ggaagattgg gcaagaagtc 1020 gtatgcttag ctgaaagcaa tgcaggagac actggtactg ccataaaatg ggctcagcag 1080 ttagaccttt tcacagatgc tgctgagact gaaaaaatgg ccaaaagttt ggaggattct 1140 gaaggagttt gttttgttcc atcttttagt ggattacagg ctccattaaa tgacccctgg 1200 gcatgtgcct cttttatggg tttgaagcct tctaccagta aataccatct tgtacgagca 1260 atattggagt caatagcttt cagaaacaaa cagttatatg agatgatgaa gaaagagatt 1320 catattcctg taagaaaaat ccgggcagat ggaggagttt gtaagaatgg ttttgtcatg 1380 cagatgactt cagacctgat taatgagaat atagacagac ctgccgacat tgacatgtca 1440 tgcctgggtg cagcttctct agctggcctt gctgttgggt tttggactga caaggaggaa 1500 ctaaagaaac tgagacaaag tgaagtggtt ttcaagccac agaagaaatg tcaagaatat 1560 gaaatgagtc tggaaaactg ggccaaagca gtgaaacgct ccatgaattg gtataacaag 1620 acataacact aaatgaaatg atcaaaacca taggtagctg gtttatgtga cgtgcagatg 1680 agatgaagct cagggataac ccatatgaca atgactaaga ggagaaaatt ttaaataagc 1740 ttcataactt aagaagcatt gcttttaaaa aaacaaaacg gaacaaaaaa ctcttatttt 1800 tttcccctaa accatggtaa ggcagcaata cctcaaaact ttatatcttc tattttgtag 1860 caaattccaa aggacattag tcatttccaa ccacattttg acagttatgg gtcctcttcc 1920 tttttatact gggtcagtgg tacataggaa cataatgatt taccatccaa gctaatagtt 1980 ctgggtcaag taccatgcac atattgttcc aaaattatgt gaaacgtatt tctttaattc 2040 tttaagtggg ctatttgaag tacatatagc taaaaagaaa gaataactga gaaaatgtgg 2100 aattttgaaa cattaatatt ttatgtttaa agccataatt tcctaatatt atatccaaat 2160 atgagcttaa tatgtccctc tcagataagc ttatgagata gttaatgctt tcctttactg 2220 gtcttaaaga cactgcctta atttttcctt gttcaaccaa aatctgagca ttctttctat 2280 gttgaaaaca ctgaaaaact aattttagtt aatgaactag aaagaatatt gttttttaag 2340 aaacagaaaa atactactta ttttccttct caaataacgt ttctttcaaa aacttctggc 2400 tgaagtataa catgctggta gttaacataa atcttgtctt tctcttgttc tttatctttc 2460 tttgttattt agatgcttgt ataaatgtct tttgttttta ttaagtgcct aattgacaga 2520 gcttaatttg aagaagtgcc ctaatttatt gaccacttaa gaattgcctt tattggggta 2580 ttttatttgt tcctgcgtct ttttgatgtt tgttcagtct actcatccct gtgagtatgt 2640 gtgggggaca gctgatagaa gggaggagag tgtgtctatg ctcaggattg ccctttagcc 2700 actcagccag agatccacag ggagcaacaa ggacagtttc acatgcttag actttcttgg 2760 aagaaacagt gaggaggagt aagtcgtgag tagtgtcaag ctggatgtag aattgtccta 2820 aggcagttga ccccaccttc caacatgttt tcactttatt tgcccctccc tacatttggg 2880 ttaggttcca tttggatttg cagcaataat gactttattt ctctcttggt caggatttgg 2940 cacataaaat ccttttatta tagaactagc tattttagtt acatagtaat gtaactaatg 3000 gagagattta tagagaattt tgtttttgct gtcatatatg tccattttgg agacagatat 3060 gatagaacta gaaattaagt tgcatttctg caagtgccat ttgaatgaac ttcaagtatc 3120 ttcttaatta ttaaattttc tgatgaaggc attgtaacaa atatatagta ttattaaatc 3180 taattaatat ttggaaatat taataaatag gtattttatt tactgtaaaa agtcaaactt 3240 cattatgtag ataaatctta ttcttttcat tctttcccct gtttacatcc tttttacaaa 3300 gcttagtcac caattaaagc tttcctatca aaatcagaaa agaaaaaaag agaagacaca 3360 c 3361 <210> 45 <211> 1662 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7477204CB1 <400> 45 atggtggaca tgggggccct ggacaacctg atcgccaaca ccgcctacct gcaggcccgg 60 aagccctcgg actgcgacag caaagagctg cagcggcggc ggcgtagcct ggccctgccc 120 gggctgcagg gctgcgcgga gctccgccag aagctgtccc tgaacttcca cagcctgtgt 180 gagcagcagc ccatcggtcg ccgcctcttc cgtgacttcc tagccacagt gcccacgttc 240 cgcaaggcgg caaccttcct agaggacgtg cagaactggg agctggccga ggagggaccc 300 accaaagaca gcgcgctgca ggggctggtg gccacttgtg cgagtgcccc tgccccgggg 360 aacccgcaac ccttcctcag ccaggccgtg gccaccaagt gccaagcagc caccactgag 420 gaagagcgag tggctgcagt gacgctggcc aaggctgagg ccatggcttt cttgcaagag 480 cagcccttta aggatttcgt gaccagcgcc ttctacgaca agtttctgca4gtggaaactc 540 ttcgagatgc aaccagtgtc agacaagtac ttcactgagt tcagagtgct ggggaaaggt.600 ggttttgggg aggtatgtgc cgtccaggtg aaaaacactg ggaagatgta tgcctgtaag 660 aaactggaca agaagcggct gaagaagaaa ggtggcgaga agatggctct cttggaaaag 720 gaaatcttgg agaaggtcag cagccctttc attgtctctc tggcctatgc ctttgagagc 780 aagacccatc tctgccttgt catgagcctg atgaatgggg gagacctcaa gttccacatc 840 tacaacgtgg gcacgcgtgg cctggacatg agccgggtga tcttttactc ggcccagata 900 gcctgtggga tgctgcacct ccatgaactc ggcatcgtct atcgggacat gaagcctgag 960 aatgtgcttc tggatgacct cggcaactgc aggttatctg acctggggct ggccgtggag 1020 atgaagggtg gcaagcccat cacccagagg gctggaacca atggttacat ggctcctgag 1080 atcctaatgg aaaaggtaag ttattcctat cctgtggact ggtttgccat gggatgcagc 1140 atttatgaaa tggttgctgg acgaacacca ttcaaagatt acaaggaaaa ggtcagtaaa 1200 gaggatctga agcaaagaac tctgcaagac gaggtcaaat tccagcatga taacttcaca 1260 gaggaagcaa aagatatttg caggctcttc ttggctaaga aaccagagca acgcttagga 1320 agcagagaaa agtctgatga tcccaggaaa catcatttct ttaaaacgat caactttcct 1380 cgcctggaag ctggcctaat tgaaccccca tttgtgccag acccttcagt ggtttatgcc 1440 aaagacatcg ctgaaattga tgatttctct gaggttcggg gggtggaatt tgatgacaaa 1500 gataagcagt tcttcaaaaa ctttgcgaca ggtgctgttc ctatagcatg gcaggaagaa 1560 attatagaaa cgggactgtt tgaggaactg aatgacccca acagacctac gggttgtgag 1620 gagggtaatt catccaagtc tggcgtgtgt ttgttattgt as 1662 <210> 46 <211> 3225 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 3016969CB1 <400> 46 agtgtgctgg aaaggccgcc agggaggagc aggccaccct cctggccaaa gccccctcat 60 tcgagactgc cctccggctg cctgcctctg gcacccactt ggcccctggc cacagccact 120 ccctggaaca tgactctccg agcacccccc gcccctcctc ggaggcctgc ggtgaggcac 180 agcgactgcc ttcagccccc tccggggggg cccctatcag ggacatgggg caccctcagg 240 gctccaagca gcttccatcc actggtggcc acccaggcac tgctcagcca gagaggccat 300 ccccggacag cccttggggg cagccagccc ctttctgcca ccccaagcag ggttctgccc 360 cccaggaggg ctgcagcccc cacccagcag ttgccccatg ccctcctggc tccttccctc 420 caggatcttg caaagaggcc cccttagtac cctcaagccc cttcttgggg acagccccag 480 gcaccccctg cccctgccaa agcaagcccc ccattggact ctaagatggg gcctggagac 540 atctctcttc ctgggaggcc aaaacccggc ccctgcagtt ccccagggtc agcctcccag 600 gcgagctctt cccaagtgag ctccctcagg gtgggctcct cccaggtggg cacagagcct 660 ggcccctccc tggatgcgga gggctggacc caggaggctg aggatctgtc cgactccaca 720 cccaccttgc agcggcctca ggaacaggtg accatgcgca agttctccct gggtggtcgc 780 gggggctacg caggcgtggc tggctatggc acctttgcct ttggtggaga tgcagggggc 840 atgctggggc aggggcccat gtgggccagg atagcctggg ctgtgtccca gtcggaggag 900 gaggagcagg aggaggccag ggctgagtcc cagtcggagg agcagcagga ggccagggct 960 gagagcccac tgccccaggt cagtgcaagg cctgtgcctg aggtcggcag ggctcccacc 1020 aggagctctc cagagcccac cccatgggag gacatcgggc aggtctccct ggtgcagatc 1080 cgggacctgt caggtgatgc ggaggcggcc gacacaatat ccctggacat ttccgaggtg 1140 gaccccgcct acctcaacct ctcagacctg tacgatatca agtacctccc attcgagttt 1200 atgatcttca ggaaagtccc caagtccgct cagccagagc cgccctcccc catggctgag 1260 gaggagctgg ccgagttccc ggagcccacg tggccctggc caggtgaact gggcccccac 1320 gcaggcctgg agatcacaga ggagtcagag gatgtggacg cgctgctggc agaggctgcc 1380 gtgggcagga agcgcaagtg gtcctcgccg tcacgcagcc tcttccactt ccctgggagg 1440 cacctgccgc tggacgagcc tgcagagctg gggctgcgtg agagagtgaa ggcctccgtg 1500 gagcacatct cccggatcct'gaagggcagg ccggaaggtc tggagaagga ggggcccccc 1560 aggaagaagc caggccttgc ttccttccgg,ctctcaggtc tgaagagctg ggaccgagcg 1620 ccgacattcc taagggagct ctcagatgag actgtggtcc tgggccagtc agtgacactg 1680 gcctgccagg tgtcagccca gccagctgcc caggccacct ggagcaaaga cggagccccc 1740 ctggagagca gcagccgtgt cctcatctct gccaccctca agaacttcca gcttctgacc 1800 atcctggtgg tggtggctga ggacctgggt gtgtacacct gcagcgtgag caatgcgctg 1860 gggacagtga ccaccacggg cgtcctccgg aaggcagagc gcccctcatc ttcgccatgc 1920 ccggatatcg gggaggtgta cgcggatggg gtgctgctgg tctggaagcc cgtggaatcc 1980 tacggccctg tgacctacat tgtgcagtgc agcctagaag gcggcagctg gaccacactg 2040 gcctccgaca tctttgactg ctgctacctg accagcaagc tctcccgggg tggcacctac 2100 accttccgca cggcatgtgt cagcaaggca ggaatgggtc cctacagcag cccctcggag 2160 caagtcctcc tgggagggcc cagccacctg gcctctgagg aggagagcca ggggcggtca 2220 gcccaacccc tgcccagcac aaagaccttc gcattccaga cacagatcca gaggggccgc 2280 ttcagcgtgg tgcggcaatg ctgggagaag gccagcgggc gggcgctggc cgccaagatc 2340.
atcccctacc accccaagga caagacagca gtgctgcgcg aatacgaggc cctcaagggc 2400 ctgcgccacc cgcacctggc ccagctgcac gcagcctacc tcagcccccg gcacctggtg 2460' ctcatcttgg agctgtgctc tgggcccgag ctgctcccct gcctggccga gagggcctcc 2520 tactcagaat ccgaggtgaa ggactacctg tggcagatgt tgagtgccac ccagtacctg 2580 cacaaccagc acatcctgca cctggacctg aggtccgaga acatgatcat caccgaatac 2640 aacctgctca aggtcgtgga cctgggcaat gcacagagcc tcagccagga gaaggtgctg 2700 ccctcagaca agttcaagga ctacctagag accatggctc cagagctcct ggagggccag 2760 ggggctgttc cacagacaga catctgggcc atcggtgtga cagccttcat catgctgagc 2820 gccgagtacc cggtgagcag cgagggtgca cgcgacctgc agagaggact gcgcaagggg 2880 ctggtccggc tgagccgctg ctacgcgggg ctgtccgggg gcgccgtggc cttcctgcgc 2940 agcactctgt gcgcccagcc ctggggccgg ccctgcgcgt ccagctgcct gcagtgcccg 3000 tggctaacag aggagggccc ggcctgttcg cggcccgcgc ccgtgacctt ccctaccgcg 3060 cggctgcgcg tcttcgtgcg caatcgcgag aagagacgcg cgctgctgta caagaggcac 3120 aacctggccc aggtgcgctg agggtcgccc cggccacacc cttggtctcc ccgctggggg 3180 tcgctgcaga cgcgccaata aaaacgcaca gccgggcgag aaaaa 3225 <210> 47 <211> 4772 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 063497CB1 <400> 47 gcggacggac gctcgcctgc cggctgagga aaaagaagca actaacaaaa cactgtgata 60 ataaggatta ttcagtatgc agtttgcagg atatccatga cgacattgaa aatgaatttt 120 ttgtattcac cagatattct tatatgagaa gatctatttt aaacagtcta aatatttttt 180 cttctgttgg accagcatgg caggatttaa gcgagggtat gatggaaaga ttgctggatt 240 atatgatctg gataaaacct tgggtcgagg ccattttgcc gtggttaaac ttgccaggca 300 tgtctttacg ggtgaaaagg tggcagtaaa agttattgac aagacaaaac tggacactct 360 agctactggt catcttttcc aggaagtgag atgcatgaaa ctagtgcagc atcctaacat 420 cgtccgcctt tatgaagtta ttgacaccca gaccaaacta tatcttattc tagaacttgg 480 ggatggagga gatatgtttg attatataat gaaacatgag gagggtctta atgaagactt 540 ggccaagaag tattttgctc agatagttca tgctatatct tattgccata aactccatgt 600 ggttcacaga gacttaaaac cagagaatgt agtcttcttt gaaaaacaag gtcttgtaaa 660 gttgacagac tttgggttca gcaacaaatt tcaaccaggg aagaagctca ctacaagctg 720 tggatctctt gcatattccg ctccagaaat tctgcttggt gatgagtatg atgcacctgc 780 agtagatatt tggagtctgg gagtgatcct tttcatgttg gtgtgtgggc agccgccctt 840 tcaagaagcc aatgacagtg aaacactgac aatgatcatg gattgcaaat atacagtacc 900 atcccatgtg tctaaagagt gtaaagacct aatcacacgg atgctacaga gagatcccaa 960 gagaagggct tctttagaag agattgaaaa tcatccttgg cttcagggag tggacccttc 1020 accagctaca aagtataaca ttccccttgt gtcatacaaa aatctctcgg aagaggagca 1080 caacagcatc attcagcgca tggtgcttgg ggacatagcg gatcgagacg ccattgtaga 1140 agccctggaa accaacaggt ataaccatat cacagccaca tacttcctgc tggctgaaag 1200 gatcctgaga gaaaagcaag agaaagaaat acagaccaga tctgcaagcc cgagcaatat 1260 caaggcccag tttaggcagt catggccaac caaaattgat gtaccccagg accttgagga 1320 tgacctcacg gccactcctt tgtcccacgc gactgtccct cagtctcctg ctcgggctgc 1380 tgacagtgtc ctcaatggcc acaggagcaa aggcctgtgt gactcagcta agaaagatga 1440 cctccctgag ttggctggac cagcactctc tacggtgcca cccgcaagct taaaacccac 1500 agccagtggg cggaagtgtc tgttcagggt ggaagaagat gaagaggaag atgaggagga 1560 caagaaaccc atgtccctct caacacaagt ggttttgcgc cggaagccat ctgtaaccaa 1620 ccgcctgaca tccaggaaga gtgcgcccgt cctcaaccag atctttgagg aaggggaatc 1680 tgacgatgag tttgacatgg atgagaatct gcctcccaag ttgagcaggt taaagatgaa 1740 tatagcttct ccaggtacag ttcacaaacg ctaccaccgg aggaaaagtc agggccgggg 1800 ctccagctgc agtagttcgg agaccagtga tgatgattct gaaagccggc ggcggctcga 1860 taaagatagc gggttcacct actcctggca ccgacgggat agcagcgagg ggccccctgg 1920 cagtgagggg gatggcgggg gccagagcaa gccaagcaat gccagtggag gggtggacaa 1980 ggccagcccc agtgagaaca atgctggtgg gggcagtccc tccagcggct cgggtggcaa 2040 ccccaccaat acatcgggta ccacacgccg ctgtgccggc cccagcaact ccatgcagct 2100 ggcctctcgc agtgctgggg agctcgttga gagcctcaaa ctcatgagcc tctgcctcgg 2160 ctcccagctt catgggagca ccaagtacat tattgatcca cagaatggct tgtcattttc 2220 cagtgtgaaa gtccaagaga aatctacgtg gaaaatgtgc attagctcca cagggaatgc 2280 agggcaggtc cctgcagtgg gcggcataaa gtttttctct gaccacatgg cagataccac 2340 cactgaattg gaacggataa agagcaagaa cctgaaaaat aacgtgctgc agctacctct 2400 gtgcgaaaag accatctctg tgaacatcca gcggaaccct aaggaggggc tgctgtgcgc 2460 atccagccca gccagctgtt gccatgtcat ctgactgtgg ccccatctgg ccgctagcac 2520 gcttcctgct cagagcagtg aagaccggct cacttcactg ttccatttgg ttttactatt 2580 ttaaagtggg cgttaggagc aattatttat tacctttcca tttgttcgcc tgatgatgtg 2640 acaatgcatg gtctttgtgc atgctgctag acacttttct ttcccagccg aaaagcctat 2700 tatgtaattt ttacattcat aattttaatg tggatgatca ggattaaatc aagatatata 2760 tctggaacct cttaaaaatg gagcacttag aaatttgttg ttctgcactt aacctagaga 2820 gagaaaaaat gcttttcttt gtgaaaaatc tgaattcctg tcctgacctt ctgtgatgtg 2880 gaaaccctag gctctgagac acactctctg gtgtctgaga cagaaccaaa gcaataacgt 2940 tgtgatgccc acaggcctgg agccagctag cgaccttgtg ccgcccagct gtccatggcc 3000 cgtgcagagc agaggacagt gagtgtctgc actgagaacc ttaaaccaca gttgaacata 3060 cccacacctg tttgtcttaa gctatagtgt aaaaacaaag tttgggctct gaaaatttaa 3120 ctgaaaaaga tttccttgtt tttgtaatag gtgagataaa gtacttagat ttataaggca 3180 gcttcccctg tagtgataaa ttacaagcag acaatcttat tttgtaatgt gatgaagtga 3240 tgatgtctta actctactta gagagtgtat gtctgtctaa cagaacaaaa agatgctctg 3300 tgtaaattcc ttcctgtagg gcacactgca ggatttccat gtagatagaa gaactatagg 3360 gcctagtaca gaaggtgcac acaaatgttg gcaaagtcaa aaccccatga attaaaacct 3420 actggaattt ggtttttagg agtttggtaa ttagattatc tcttttgtta ttttcattca 3480 gttatatcct ttggctcagc tagctttgaa attggctgat gaaaaaatat acataaaagg 3540 gtaaaattca cacatacagc aaacaaaaat gcacaaagcc tgcttcgtaa cttttttttc 3600 tggaattgtt tttcactttg cctttttctg ccaaaacaat aatcaaagaa ctcttgcttt 3660 aacctattcc tgtacaaaga ctgtttttga ccagataatc atctgttgtg gcattctatc 3720 ttgtaggaca ctgtatattg caaattgctg attatggaag gggccagttg ctgttttttc 3780 atgcagtgcc ctgggagtct taaaagcagt gcttagcaac attggtgata gcatgtggct 3840 gggacccagg gcccttcccc actcttcagc cccgagtcat gtgtctgagg tgacggactg 3900 agacgcatct ggtcctgtaa ttcagagagt gggcacatca ccaaagaact gcattgctgt 3960 ggtcactgtt tcttcaagta cacactgact ctgctacttt aggataaata tattttactc 4020 agaactctga atttcacagt atacttacta aactaagtaa aaatgatact taaaatactt 4080 56!61 attttacttt ctagacctag gctagatgtt ttaagctaca gctctagttc attgtgatat 4140 ttataatttg aaagctatga gaatagatgt gtgggtgaag ccatagaaca tatttgcttg 4200 aaattcttga gcagggatct tataaagggc cagaaataag atgtgtggtt cacatagata 4260 gtgagcgtaa catctgtatt aaacatagga gagaagttta taaagggcat tggcaataaa 4320 ctctttgttg cagctgtttt ccaagcagtg taaatacttt ttcctgtgat tatgtatagc 4380 cttggaatgg caccttttaa ctaacccata tgtgtttggt ttcaatggtt ttttatattc 4440 agatgtatat atggtgctca ctttaggatc agcagtgttg accatttatg ctgcatagct 4500 gtattatagc cttattagtt gtgtggttga cccttggggt atacaaaaat ctctcggaag 4560 aggagcacaa cagcatcatt cagcgcatgg tgcttgggga catagcggat cgagacgcca 4620 ttgtagaagc cctggaaacc aacaggtata accatatcac agccacatac ttcctgctgg 4680 ctgcaaagga tcctgagaga aaagcaagag aaagaaatac agaccagatc tgcaagcccg 4740 agcaatatca aggcccagtt taggcagtca tg 4772 <210> 48 <211> 1880 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1625436CB1 <400> 48 ctcttgctcc ctcggccggg cggcggtgac tgtgcaccga cgtcggcgcg ggctgcaccg 60 ccgcgtccgc ccgcccgcca gcatggccac caccgccacc tgcacccgtt tcaccgacga 120 ctaccagctc ttcgaggagc ttggcaaggg tgctttctct gtggtccgca ggtgtgtgaa 180 gaaaacctcc acgcaggagt acgcagcaaa aatcatcaat accaagaaat tgtctgcccg 240 ggatcaccag aaactagaac gtgaggctcg gatatgtcga cttctgaaac atccaaacat 300 cgtgcgcctc catgacagta tttctgaaga agggtttcac tacctcgtgt ttgaccttgt 360 taccggcggg gagctgtttg aagacattgt ggccagagag tactacagtg aagcagatgc 420 cagccactgt atacatcaga ttctggagag tgttaaccac atccaccagc atgacatcgt 480 ccacagggac ctgaagcctg agaacctgct gctggcgagt aaatgcaagg gtgccgccgt 540 caagctggct gattttggcc tagccatcga agtacaggga gagcagcagg cttggtttgg 600 ttttgctggc accccaggtt acttgtcccc tgaggtcttg aggaaagatc cctatggaaa 660 acctgtggat atctgggcct gcggggtcat cctgtatatc ctcctggtgg gctatcctcc 720 cttctgggat gaggatcagc acaagctgta tcagcagatc aaggctggag cctatgattt 780 cccatcacca gaatgggaca cggtaactcc tgaagccaag aacttgatca accagatgct 840 gaccataaac ccagcaaagc gcatcacggc tgaccaggct ctcaagtacc cgtgggtctg 900 tcaacgatcc acggtggcat ccatgatgca tcgtcaggag actgtggagt gtttgcgcaa 960 gttcaatgcc cggagaaaac tgaagggtgc catcctcacg accatgcttg tctccaggaa 1020 cttctcagtt ggcaggcaga gctccgcccc cgcctcgcct gccgcgagcg ccgccggcct 1080 ggccgggcaa gctgccaaaa gcctattgaa caagaagtcg gatggcggtg tcaagaaaag 1140 gaagtcgagt tccagcgtgc acctaatgcc acagagcaac aacaaaaaca gtctcgtaag 1200 cccagcccaa gagcccgcgc ccttgcagac ggccatggag ccacaaacca ctgtggtaca 1260 caacgctaca gatgggatca agggctccac agagagctgc aacaccacca cagaagatga 1320 ggacctcaaa gctgccccgc tccgcactgg gaatggcagc tcggtgcctg aaggacggag 1380 ctcccgggac agaacagccc cctctgcagg catgcagccc cagccttctc tctgctcctc 1440 agccatgcga aaacaggaga tcattaagat tacagaacag ctgattgaag ccatcaacaa 1500 tggggacttt gaggcctaca cgaagatttg tgatccaggc ctcacttcct ttgagcctga 1560 ggcccttggt aacctcgtgg aggggatgga tttccataag ttttactttg agaatctcct 1620 gtccaagaac agcaagccta tccataccac catcctaaac ccacacgtcc acgtgattgg 1680 ggaggacgca gcgtgcatcg cctacatccg cctcacccag tacatcgacg ggcagggtcg 1740 gcctcgcacc agccagtcag aagagacccg ggtctggcac cgtcgggatg gcaagtggct 1800 caatgtccac tatcactgct caggggcccc tgccgcaccg ctgcagtgag ctcagccaca 1860 ggggctttag gagattccag <210> 49 <211> 5747 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 3330646CB1 <400> 49 ggtaggcagg cggctgagcc ggcggcgggt ggcctgccca acgtgtgctg ggtgggagaa 60 ggcgaggcgg cagcgatgct gtctcttccg tgaggagcgc agaggaggtc gcggcgccgg 120 aggccccaga aggctcgaag gcgccgcggg ctggggtcgg tggcttaggg agcccgtccg 180 gccatggtgg ccgcgggtgg tggttggcgc ggctgcgctg cggcccgggg cagtgcggag 240 ccgggacagt cgcggcgctg acgcccgcgg gccccagctg cagatatgaa gcggagccgc 300 tgccgcgacc gaccgcagcc gccgccgccc gaccgccggg aggatggagt tcagcgggca 360 gcggagctgt ctcagtcttt gccgccgcgc cggcgagcgc cgcccgggag gcagcggctg 420 gaggagcgga cgggccccgc ggggcccgag ggcaaggagc aggatgtagc aactggagtt 480 agtcccctgc tcttcaggaa actcagtaat cctgacatat tttcatccac tggaaaagtt 540 aaacttcagc gacaactgag tcaggatgat tgtaagttat ggagaggaaa cctggccagc 600 tctctatcgg gtaagcagct gctccctttg tccagcagtg tacatagcag tgtgggacag 660 gtgacttggc agtcgtcagg agaagcatca aacctggttc gaatgagaaa ccagtccctt 720 ggacagtctg caccttctct tactgctggc ctgaaggagt tgagccttcc aagaagaggc 780 agcttttgtc ggacaagtaa ccgcaagagc ttgattgtga cctctagcac atcacctaca 840 ctaccacggc cacactcacc actccatggc cacacaggta acagtccttt ggacagcccc 900 cggaatttct ctccaaatgc acctgctcac ttttcttttg ttcctgcccg taggactgat 960 gggcggcgct ggtctttggc ctctttgccc tcttcaggat atggaactaa cactcctagc 1020 tccactgtct catcatcatg ctcctcacag gaaaagctgc atcagttgcc tttccagcct 1080 acagctgatg agctgcactt tttgacgaag catttcagca cagagagcgt accagatgag 1140 gaaggacggc agtccccagc catg'cggcct cgctcccgga gcctcagtcc cggacgatcc 1200 ccagtatcct ttgacagtga aataataatg atgaatcatg tttacaaaga aagattccca 1260 aaggccaccg cacaaatgga agagcgacta gcagagttta tttcctccaa cactccagac 1320 agcgtgctgc ccttggcaga tggagccctg agctttattc atcatcaggt gattgagatg 2380 gcccgagact gcctggataa atctcggagt ggcctcatta catcacaata cttctacgaa 1440 cttcaagaga atttggagaa acttttacaa gatgctcatg agcgctcaga gagctcagaa 1500 gtggcttttg tgatgcagct ggtgaaaaag ctgatgatta tcattgcccg cccagcacgt 1560 ctcctggaat gcctggagtt tgaccctgaa gagttctacc accttttaga agcagctgag 1620 ggccacgcca aagagggaca agggattaaa tgtgacattc cccgctacat cgttagccag 1680 ctgggcctca cccgggatcc cctagaagaa atggcccagt tgagcagctg tgacagtcct 1740 gacactccag agacagatga ttctattgag ggccatgggg catctctgcc atctaaaaag 1800 acaccctctg aagaggactt cgagaccatt aagctcatca gcaatggcgc ctatggggct 1860 gtatttctgg tgcggcacaa gtccacccgg cagcgctttg ccatgaagaa gatcaacaag 1920 cagaacctga tcctacggaa ccagatccag caggccttcg tggagcgtga catactgact 1980 ttcgctgaga acccctttgt ggtcagcatg ttctgctcct ttgataccaa gcgccacttg 2040 tgcatggtga tggagtacgt tgaaggggga gactgtgcca ctctgctgaa gaatattggg 2100 gccctgcctg tggacatggt gcgtctatac tttgcggaaa ctgtgctggc cctggagtac 2160 ttacacaact atggcatcgt gcaccgtgac ctcaagcctg acaacctcct aattacatcc 2220 atggggcaca tcaagctcac ggactttgga ctgtccaaaa tgggcctcat gagtctgaca 2280 acgaacttgt atgagggtca tattgaaaag gatgcccggg aattcctgga caagcaggta 2340 tgcgggaccc cagaatacat tgcgcctgag gtgatcctgc gccagggcta tgggaagcca.2400 gtggactggt gggccatggg cattatcctg tatgagttcc tggtgggctg cgtccctttt 246.0 tttggagata ctccggagga gctctttggg caggtgatca gtgatgagat tgtgtggcct 2520 gagggtgatg aggcactgcc cccagacgcc caggacctca cctccaaact gctccaccag 2580 aaccctctgg agagacttgg cacaggcagt gcctatgagg tgaagcagca cccattcttt 2640 actggtctgg actggacagg acttctccgc cagaaggctg aatttattcc tcagttggag 2700 tcagaggatg atactagcta ttttgacacc cgctcagagc gataccacca catggactcg 2760 gaggatgagg aagaagtgag tgaggatggc tgccttgaga tccgccagtt ctcttcctgc 2820 tctccaaggt tcaacaaggt gtacagcagc atggagcggc tctcactgct cgaggagcgc 2880 cggacaccac ccccgaccaa gcgcagcctg agtgaggaga aggaggacca ttcagatggc 2940 ctggcagggc tcaaaggccg agaccggagc tgggtgattg gctcccctga gatattacgg 3000 aagcggctgt cggtgtctga gtcatcccac acagagagtg actcaagccc tccaatgaca 3060 gtgcgacgcc gctgctcagg cctcctggat gcgcctcggt tcccggaggg ccctgaggag 3120 gccagcagca ccctcaggag gcaaccacag gagggtatat gggtcctgac acccccatct 3180 ggagaggggg tatctgggcc tgtcactgaa cactcagggg agcagcggcc aaagctggat 3240 gaggaagctg ttggccggag cagtggttcc agtccagcta tggagacccg aggccgtggg 3300 acctcacagc tggctgaggg agccacagcc aaggccatca gtgacctggc tgtgcgtagg 3360 gcccgccacc ggctgctctc tggggactca acagagaagc gcactgctcg ccctgtcaac 3420 aaagtgatca agtccgcctc agccacagcc ctctcactcc tcattccttc ggaacaccac 3480 acctgctccc cgttggccag ccccatgtcc ccacattctc agtcgtccaa cccatcatcc 3540 cgggactctt ctccaagcag ggacttcttg ccagcccttg gcagcatgag gcctcccatc 3600 atcatccacc gagctggcaa gaagtatggc ttcaccctgc gggccattcg cgtctacatg 3660 ggtgactccg atgtctacac cgtgcaccat atggtgtggc acgtggagga tggaggtccg 3720 gccagtgagg 'cagggcttcg tcaaggtgac ctcatcaccc atgtcaatgg ggaacctgtg 3780 catggcctgg tgcacacgga ggtggtagag ctgatcctga agagtggaaa caaggtggcc 3840 atttcaacaa ctcccctgga gaacacatcc attaaagtgg ggccagctcg gaagggcagc 3900 tacaaggcca agatggcccg aaggagcaag aggagccgcg gcaaggatgg gcaagaaagc 3960 agaaaaagga gctccctgtt ccgcaagatc accaagcaag catccctgct ccacaccagc 4020 cgcagccttt cttcccttaa ccgctccttg tcatcagggg agagtgggcc aggctctccc 4080 acacacagcc acagcctttc cccccgatct cccactcaag gctaccgggt gacccccgat 4140 gctgtgcatt cagtgggagg gaattcatca cagagcagct cccccagctc cagcgtgccc 4200 agttccccag ccggctctgg gcacacacgg cccagctccc tccacggtct ggcacccaag 4260 ctccaacgcc agtaccgctc tccacggcgc aagtcagcag gcagcatccc actgtcacca 4320 ctggcccaca ccccttctcc cccaccccca acagcttcac ctcagcggtc cccatcgccc 4380 ctgtctggcc atgtagccca ggcctttccc acaaagcttc acttgtcacc tcccctgggc 4440 aggcaactct cacggcccaa gagtgcggag ccaccccgtt caccactact caagagggtg 4500 cagtcggctg agaaactggc agcagcactt gccgcctctg agaagaagct agccacttct 4560 cgcaagcaca gccttgacct gccccactct gaactaaaga aggaactgcc gcccagggaa 4620 gtgagccctc tggaggtagt tggagccagg agtgtgctgt ctggcaaggg ggccctgcca 4680 gggaaggggg tgctgcagcc tgctccctca cgggccctag gcaccctccg gcaggaccga 4740 gccgaacgac gggagtcgct gcagaagcaa gaagccattc gtgaggtgga ctcctcagag 4800 gacgacaccg aggaagggcc tgagaacagc cagggtgcac aggagctgag cttggcacct 4860 cacccagaag tgagccagag tgtggcccct aaaggagcag gagagagtgg ggaagaggat 4920 cctttcccgt ccagagaccc taggagcctg ggcccaatgg tcccaagcct attgacaggg 4980 atcacactgg ggcctcccag aatggaaagt cecagtggtc cccacaggag gctcgggagc 5040 ccacaagcca ttgaggaggc tgccagctcc tcctcagcag gccccaacct aggtcagtct 5100 ggagccacag accccatccc tcctgaaggt tgctggaagg cccagcacct ccacacccag 5160 gcactaacag cactttctcc cagcacttcg ggactcaccc ccaccagcag ttgctctcct 5220 cccagctcca cctctgggaa gctgagcatg tggtcctgga aatcccttat tgagggccca 5280 gacagggcat ccccaagcag aaaggcaacc atggcaggtg ggctagccaa cctccaggat 5340 ttggaaaaca caactccagc ccagcctaag aacctgtctc ccagggagca ggggaagaca 5400 cagccaccta gtgcccccag actggcccat ccatcttatg aggatcccag ccagggctgg 5460 ctatgggagt ctgagtgtgc acaagcagtg aaagaggatc cagccctgag catcacccaa 5520 gtgcctgatg cctcaggtga cagaaggcag gacgttccat gccgaggctg ccccctcacc 5580 cagaagtctg agcccagcct caggaggggc caagaaccag ggggccatca aaagcatcgg 5640 gatttggcat tggttccaga tgagctttta aagcaaacat agcagttgtt tgccatttct 5700 tgcactcaga cctgtgtaat atatgctcct ggaaaccaaa aaaaaaa 5747 <210> 50 <211> 3418 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 3562763CB1 <400> 50 gaggtgggac gccccgcggc ctacgctcct ggcctccccg ccttggcctg gccgtttaac 60 cgattctttc gcccgcaggt cacaatccaa ggtccggctc ctccgcgtcc cagggccgga 120 cggagggatg aggcaggggg ggcccgggca gcgccgttgc tgctcccccc gccgcccgca 180 gccatggaaa cggggaagga cggcgcccgc agaggtacac aaagcccgga gcggaaaatg 240 cgaagcccag tgccgcgggc gcccagcacg aagctgagcc ggcggcggcg cccgggccat 300 ggatccggtg gctgccgagg ccccgggcga ggccttcctg gcgcggcgac ggcctgaggg 360 cggtggcggg tccgcgcggc cgcgttacag cctgttggcg gagatcgggc gcggcagcta 420 cggcgtggtt tatgaggcag tggccgggcg cagcggggcc cgggtggcgg tcaagaagat 480 ccgctgcgac gcccccgaga acgtggagct ggcgctggct gaattctggg ccctcaccag 540 cctcaagcgg cgccaccaga acgtcgtgca gtttgaggag tgcgtcctgc agcgcaatgg 600 gttagcccag cgcatgagtc acggcaacaa gagctcgcag ctttacctgc gcctggtgga 660 gacctcgctg aaaggagaaa ggatcctggg ttatgctgag gagccctgct atctctggtt 720 tgtcatggag ttctgtgaag gtggagacct gaatcagtat gtcctgtccc ggaggccaga 780 cccagccacc aacaaaagtt tcatgctaca gctgacgagc gccattgcct tcctgcacaa 840 aaaccatatt gtgcacaggg acctgaagcc agacaacatc ctcatcacag agcggtctgg 900 cacccccatc ctcaaagtgg ccgactttgg actaagcaag gtctgtgctg ggctggcacc 960 ccgaggcaaa gagggcaatc aagacaacaa aaatgtgaat gtgaataagt actggctgtc 1020 ctcagcctgc ggttcggact tctacatggc tcctgaagtc tgggagggac actacacagc 1080 caaggcggac atctttgccc tgggcattat catctgggca atgatagaaa gaatcacttt 1140 tattgactct gagaccaaga aggagctcct ggggacctac attaaacagg ggactgagat 1200 cgtccctgtt ggtgaggcgc tgctagaaaa cccaaagatg gagttgcaca tcccccaaaa 1260 acgcaggact tccatgtctg aggggatcaa gcagctcttg aaagatatgt tagctgctaa 1320 cccacaggac cggcctgatg cctttgaact tgaaaccaga atggaccagg tcacatgtgc 1380 tgcttaaaat tcagggctaa gcattttggg tgattttaaa ctaggtcgat tcctcgggac 1440 ccacagtctc accacgtctc ctccagagga cggcagaggg tacaggtggt ggcctggccg 1500 gttggcgatc tcccgacagc tggatccggc aatgtgaagc ttttgtttgg gtttccccgc 1560 ttctttttag ttttgcttta tttttttcct tttcttttct tttttttttt tcctctttcc 1620 tttttttaaa tttaaaccat tgagacttca gaagagcagg acacaatgct gtggacaggc 1680 accaatttct ttaaagaaat tcaatgtggg caaggcatat gtgtaaattt cacttttact 1740 ttttataagg ggttagggag ctatttttgg ttttgtcctt cactttccct ctgtcttcct 1800 tctttatact tttctcagtt ctacttatga cacctcattt ccctagagaa ggcctgcctc 1860 cccataggga atctgggggt ttcttctgga acggggcgtg aggacacaag gaggcctctg 1920 ggccacgcct ccctaccaga tgcaggaact cctggactcc ttggtgggct ggccctggct 1980 agcccttggg cctcggagat gatcagaggt gaagaaccgc ctggaagagg acaggcccag 2040 ggtttggcca ggagaactaa gaaggtctca actccaggct ttgttgtgtt taagctattg 2100 agagccccag gccacaccag gacttgcagt ggtgggaatc cattcctctt ctgccctgtg 2160 ttgcagggaa ctaggaggta agggtggagg gcgaccatct cgctcttgct ggcggtggag 2220 cagccatccc tgcctttctg ttgggaaaaa ctgttgtgcc aaactcttgt gtggaacaca 2280 gctgggtctt cagcaggcat ctgtcactgc cgtgaggtca gcgcttctca cctaactgcc 2340 tcctggattg tcatcttccc agatgtgtcc catagtgtcc aggtgtcaca gagacggcct 2400 gaggccctaa gatctggttg tgactttgcc atgataacag ggtgtcctga actggctgcc 2460 gttgtcgtgt tctcacagtg aagggcgtgc cctgtgtgcc ggggtccatg gtgtcatatg 2520 cagtgacaca cactgtcaag cgccatttcc ctcacccctg gagacttact gttaggtgcc 2580 tgccctcagt atagacgtat ccaatgggaa aacagcggac ctgcccagag cagggaggtg 2640 tcgtggaact gggtagaccc cctgcagcgt taggggccca tttgtgggct cgccaccttc 2700 aggcttcccc agccatgaca cttcagcccc gccacccatg cctgtctgct gcagccatcc 2760 ttgcactctc cagcgacact ctcgcacctc cctaggggaa gcttccctcc ccctgggctg 2820 ctgctctgag cccgtctgtt ctccccctgc aagaaggggc aatgctcttg tgttgtccct 2880 ctgtctggac gcgcctggcc actccgaagg cttttcaccc cattatggcc aaatagtata 2940 gggccactgg ggagggggaa gggaatcatt ttgtgttcat ttttgttttc tgtttcacct 3000 aaaccagcat aggattgata ggggagacgg ttggcgggca tttccgtttc tatgtgacta 3060 tgtgaccaag gcagcagggg cttttacctg ctaggcggca gtcctttggc cctgagaatt 3120 tgggagagaa cagtgcatca ggccaggctc agcaatatgt ttgctcacat tctttcagcc 3180 ttctctcacc cccctcaaca ccaaactttc ttccttgtga gcagaaggtt ggctgctgtt 3240 agcaggatcc cacagtgata accaggccct tcccttccta agccaaaacc cattgtgact 3300 gcctgtctct cctgtctctg acttctcagg cagcctcctg agtgcactga gttgtatccg 3360 agagggtggg aacagcagca tcccctaatt gcagtacacg gttccttttc cgcccgcc 3418 <210> 51 <211> 995 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 622293CB1 <400> 51 cactttgact ggccacccga atctgaaatc cagaaccgtc tcatggtgcc agaggacatc 60 tcagagctgg agacggctca gaaactgctg gagtatcata ggaacatcgt cagggtcatt 120 ccctcctacc ccaaaatcct caaagtcatc agtgctgacc agccatgtgt ggacgtcttc 180 taccaggctc tgacctatgt ccaaagcaac catcgtacta atgccccgtt caccccgagg 240 gtgctgctgc tcgggcctgt gggcagtggg aaaagtctgc aggccgccct cctggcccag 300 aaatacaggc ttgtcaatgt ctgctgtggg caactgctga aagaggctgt ggcagatagg 360 accacgtttg gcgagctcat ccagcccttc tttgaaaagg agatggcagt tcctgacagc 420 ctcctcatga aggtgctgag ccagcgcctg gaccagcagg actgcatcca gaaaggctgg 480 gtgctacacg gcgtcccgcg ggacctcgac caggcacacc tgctgaaccg cctgggctac 540 aatcccaaca gggtgttttt cctgaatgtg ccatttgatt ccatcatgga gcggctgact 600 ctgagaagaa ttgatccagt cactggggaa aggtaccacc tcatgtacaa gccacctccc 660 accatggaga tccaggctcg cctcctgcag aacccaaagg atgctgaaga gcaggtcaag 720 ctgaaaatgg acctgttcta caggaactca gctgacttgg agcagttgta tgggtcggcc 780 atcaccctca atggggacca ggacccatac acagtcttcg aatacatcga gagtgggatc 840 attaatcccc tgcccaagaa aatcccctga tgggttcaga gccaggagcg ctgccccagg 900 gaaagagtta atcccctgcc cccagccccc cagcctcggc acagctcccc taaaaagcca 960 ataaagcctg ctggatacca aaaaaaaaaa aaagc 995 <210> 52 <211> 2459 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7480774CB1 <400> 52 gcggcgtagt ggttctgaac atggatagga ggggagatga tagctgctgg cgtccggtga 60 gcgtgggcag agcgtagtgc gggcagctgc ccagcggaag gatcggatga gactggaggc 120 gccgcgagga gggcggcggc ggcagccggg acagcagcga cctgggcccg gcgcaggggc 180 cccggcgggg cggccggagg ggggggggcc ctgggcccgg acagaggagt ccagcctcca 240 cagcgagcct gagagggccg gcctcgggcc tgcgccgggg acagagagtc cgcaggcaga 300 attctggaca gacggacaga ctgagcccgc ggcagctggc cttggagtag agaccgagag 360 gcccaagcaa aagacggagc cagacaggtc cagcctccgg acgcatctag aatggagctg 420 gtcagagctg gagacgactt gtctttggac ggagaccggg acagatggcc tttggactga 480 tccgcacagg tccgacctcc agtttcagcc cgaggaggcc agcccctgga cacagccagg 540 ggttcatggg ccctggacag agctggaaac gcatgggtca cagactcagc cagagagggt 600 caagtcctgg gctgataacc tctggaccca ccagaacagt tccagcctcc agactcaccc 660 agaaggagcc tgtccctcaa aagagccaag tgctgatggc tcctggaaag aattgtatac 720 tgatggctcc aggacacaac aggatattga aggtccctgg acagagccat atactgatgg 780 ctcccagaaa aaacaggata ctgaagcagc caggaaacag cctggcactg gtggtttcca 840 aatacaacag gatactgatg gctcctggac acaacctagc actgacggtt cccagacagc 900 acctgggaca gactgcctct tgggagagcc tgaggatggc ccattagagg aaccagagcc 960 tggagaattg ctgactcacc tgtactctca cctgaagtgt agccccctgt gccctgtgcc 1020 ccgcctcatc attacccctg agacccctga gcctgaggcc cagccagtgg gacccccctc 1080 ccgggttgag gggggcagcg gcggcttctc ctctgcctct tctttcgacg agtctgagga 1140 tgacgtggtg gccgggggcg gaggtgccag cgatcccgag gacaggtctg ggagcaaacc 1200 ctggaagaag ctgaagacag ttctgaagta ttcacccttt gtggtctcct tccgaaaaca 1260 ctacccttgg gtccagcttt ctggacatgc tgggaacttc caggcaggag aggatggtcg 1320 gattctgaaa cgtttctgtc agtgtgagca gcgcagcctg gagcagctga tgaaagaccc 1380 gctgcgacct ttcgtgcctg cctactatgg catggtgctg caggatggcc agaccttcaa 1440 ccagatggaa gacctcctgg ctgactttga gggcccctcc attatggact gcaagatggg 1500 cagcaggacc tatctggaag aggagctagt gaaggcacgg gaacgtcccc gtccccggaa 1560 ggacatgtat gagaagatgg tggctgtgga ccctggggcc cctacccctg aggagcatgc 1620 ccagggtgca gtcaccaagc cccgctacat gcagtggagg gaaaccatga gctccacctc 1680 taccctgggc ttccggatcg agggcatcaa gaaggcagat gggacctgta acaccaactt 1740 caagaagacg caggcactgg agcaggtgac aaaagtgctg gaggacttcg tggatggaga 1800 ccacgtcatc ctgcaaaagt acgtggcatg cctagaagaa cttcgtgaag ctctggagat 1860 ctcccccttc ttcaagaccc acgaggtggt aggcagctcc ctcctcttcg tgcacgacca 1920 caccggcctg gccaaggtct ggatgataga cttcggcaag acggtggcct tgcccgacca 1980 ccagacgctc agccacaggc tgccctgggc tgagggcaac cgtgaggacg gctacctctg 2040 gggcctggac aacatgatct gcctcctgca ggggctggca cagagctgag ctgctcagcc 2100 accatcaggt taattggatg gcgccagtct ggctggagga gccctgagat gccatgggag 2160 gcctgaggtt ggccacgggg gagctggcct ccagggacgg gagagattgt gtcatgtgcc 2220 acacgagacc aacgtggaaa agtctgaagg gccttgggag accaggtagc acctggcccc 2280 atcatgatgc aggggttttg gggacctgga aggaaggtga tgaggcagtg agtcagaaaa 2340 accagaacgg ggtccccgga tctgccggga aggcttctga ggggctgccc gtgagagcat 2400 tcagttcaca tgtaacaggg tagggggatc cactagttta taatgccggc cgcgtggta 2459

Claims (96)

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:1-26, 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:1-26, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-26, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-26.

2. An isolated polypeptide of claim 1 selected from the group consisting of SEQ ID NO:1-26.

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 selected from the group consisting of SEQ ID
NO:27-52.

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

11. 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:27-52, 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:27-52, c) a polynucleotide complementary to a polynucleotide of a), d) a polynucleotide complementary to a polynucleotide of b), and e) an RNA equivalent of a)-d).

12. An isolated polynucleotide comprising at least 60 contiguous nucleotides of a polynucleotide of claim 11.

13. A method for detecting a target polynucleotide in a sample, said target polynucleotide having a sequence of a polynucleotide of claim 11, 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.

14. A method of claim 13, wherein the probe comprises at least 60 contiguous nucleotides.

15. A method for detecting a target polynucleotide in a sample, said target polynucleotide having a sequence of a polynucleotide of claim 11, 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.

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

17. A composition of claim 16, wherein the polypeptide has an amino acid sequence selected from the group consisting of SEQ ID NO:1-26.

18. A method for treating a disease or condition associated with decreased expression of functional PKIN, comprising administering to a patient in need of such treatment the composition of claim 16.

19. A method for 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.

20. A composition comprising an agonist compound identified by a method of claim 19 and a pharmaceutically acceptable excipient.

21. A method for treating a disease or condition associated with decreased expression of functional PKIN, comprising administering to a patient in need of such treatment a composition of claim 20.

22. A method for 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.

23. A composition comprising an antagonist compound identified by a method of claim 22 and a pharmaceutically acceptable excipient.

24. A method for treating a disease or condition associated with overexpression of functional PKIN, comprising administering to a patient in need of such treatment a composition of claim 23.

25. A method of screening for a compound that specifically binds to the polypeptide of claim 1, said method comprising the steps of:
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.

26. A method of screening for a compound that modulates the activity of the polypeptide of claim 1, said 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 the 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.

27. A method for 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.

28. 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 of claim 11 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 11 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.

29. A diagnostic test for a condition or disease associated with the expression of PKIN in a biological sample comprising the steps of:
a) combining the biological sample with an antibody of claim 10, 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.

30. The antibody of claim 10, 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.

31. A composition comprising an antibody of claim 10 and an acceptable excipient.

32. A method of diagnosing a condition or disease associated with the expression of PKIN in a subject, comprising administering to said subject an effective amount of the composition of claim 31.

33. A composition of claim 31, wherein the antibody is labeled.

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

35. A method of preparing a polyclonal antibody with the specificity of the antibody of claim comprising:
a) immunizing an animal with a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-26, or an immunogenic fragment thereof, under conditions to elicit an antibody response;
b) isolating antibodies from said animal; and c) screening the isolated antibodies with the polypeptide, thereby identifying a polyclonal antibody which binds specifically to a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-26.

36. An antibody produced by a method of claim 35.

37. A composition comprising the antibody of claim 36 and a suitable carrier.

38. A method of making a monoclonal antibody with the specificity of the antibody of claim comprising:
a) immunizing an animal with a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-26, 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 binds specifically to a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID
NO:1-26.

39. A monoclonal antibody produced by a method of claim 38.

40. A composition comprising the antibody of claim 39 and a suitable carrier.

41. The antibody of claim 10, wherein the antibody is produced by screening a Fab expression library.

42. The antibody of claim 10, wherein the antibody is produced by screening a recombinant immunoglobulin library.

43. A method for detecting a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-26 in a sample, comprising the steps of:
a) incubating the antibody of claim 10 with a 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 having an amino acid sequence selected from the group consisting of SEQ ID NO:1-26 in the sample.

44. A method of purifying a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-26 from a sample, the method comprising:
a) incubating the antibody of claim 10 with a 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 having an amino acid sequence selected from the group consisting of SEQ ID NO:1-26.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

71. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:27.

72. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:28.

73. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:29.

74. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:30.

75. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:31.

76. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:32.

77. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:33.

78. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:34.

79. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:35.

80. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:36.

81. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:37.

82. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:38.

83. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:39.

84. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:40.

85. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:41.

86. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:42.

87. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:43.

88. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:44.

89. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:45.

90. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:46.

91. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:47.

92. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:48.

93. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:49.

94. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:50.

95. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:51.

96. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:52.