CA2335644A1 - Phosphorylation effectors - Google Patents

Abstract

The invention provides human phosphorylation effectors (PHSP) and polynucleotides which identify and encode PHSP. The invention also provides expression vectors, host cells, antibodies, agonists, and antagonists. The invention also provides methods for diagnosing, treating, or preventing disorders associated with expression of PHSP.

Description

PHOSPHORYLATION EFFECTORS
TECHNICAL FIELD
This invention relates to nucleic acid and amino acid sequences of phosphorylation effectors and to the use of these sequences in the diagnosis, treatment, and prevention of cell proliferative, immune, and neuronal disorders.
Kinases and phosphatases are critical components of intracellular signal transduction mechanisms. Kinases catalyze the transfer of high energy phosphate groups from adenosine triphosphate (ATP) to various target proteins. Phosphatases, in contrast, remove phosphate groups from proteins. Reversible protein phosphorylation is the main strategy 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.
Protein dephosphorylation occurs when down-regulation of a signaling pathway is required. The coordinate activities of kinases and phosphatases regulate key cellular processes such as proliferation, differentiation, and cell cycle progression. Kinases comprise the largest known enzyme superfamily and are widely varied in their substrate specificities.
Kinases may be categorized based on the specific amino acid residues that are phosphorylated in their substrates:
protein tyrosine kinases (PTK) phosphorylate tyrosine residues, and protein serine/threonine kinases (STK) phosphorylate serine and/or threonine residues. Almost all kinases contain a conserved 250-300 amino acid catalytic domain. This 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 VIA-XI
bind the protein substrate and transfer the gamma phosphate from ATP to the hydroxyl group of a serine, threonine, or tyrosine 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 and IX comprise the highly conserved catalytic core. Kinases may also be categorized 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 Hanks, S. ( 1995) The Protein Kinase Facts Books. Vol I:7-20 Academic Press, San Diego, CA.) STKs include both protein kinase A (PKA) and calcium-dependent protein kinase C

(PKC), both of which transduce signals from plasma membrane receptors. .The activities of PKA
and PKC are directly regulated by second messenger signaling molecules such as cyclic AMP and diacyIglycerol, respectively. A novel kinase identified by genetic analysis in the fission yeast Schizosaccharomvces pombe is encoded by the cekl' gene and is related to both PKA and PKC
(Samejima, I. and Yanagida, M. (1994) MoI. CeII. Biol. 14:6361-6371). cekl+
encodes an unusually large kinase of 1309 amino acids. The kinase domain spans residues 585 to 987, and 112 additional amino acids are present in this domain between subdomains VII
and VIII.
Overexpression of cekl + suppresses mutations in cut8+, a gene required for chromosome segregation during mitosis. Therefore, cekl + may encode a unique member of the PKA/PKC
protein family with a role in mitotic signaling and cell cycle progression.
PTKs may be classified as either transmembrane or nontransmembrane proteins.
Transmembrane tyrosine kinases function as receptors for most growth factors.
Binding of growth factor to the receptor activates the transfer of a phosphate group from ATP to selected tyrosine side chains of the receptor itself and other specific 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 PTKs form signaling complexes with the cytosolic domains of plasma membrane receptors. Receptors that signal through nontransmembrane PTKs include cytokine, hormone, and antigen-specific lymphocytic receptors. 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 Tonks, N. K. ( 1992) Annu. Rev.
Cell Biol.
8:463-93). Regulation of PTK activity may therefore be an important strategy in controlling some types of cancer.
Some kinases utilize carbohydrates as their substrates and are important for glucose metabolism. For example, glycolysis employs four distinct kinases to effect the conversion of glucose to pymvate, a key metabolite in the production of ATP. One of these enzymes is phosphofructokinase (PFK) which catalyzes the transfer of phosphate from ATP
to fructose 6-phosphate. PFK is an allosteric enzyme and a key regulator of glycolysis. In certain genetic muscle disorders, such as muscle phosphofructokinase deficiency type VII, phosphofructokinase activity is absent in muscle and deficient in red blood cells. As a result, afflicted individuals suffer from mild hemolytic anemia and muscle pain (Isselbacher, K.J. et al. ( 1994) Harrison's Principles of Internal Medicine, McGraw-Hill, New York, NY, p. 2102).
Kinase-mediated phosphorylation is antagonized by the activity of phosphatases, which WO 00!06728 PCT/US99/17132 remove phosphate groups by hydrolysis. Phosphatases are classified into one of three evolutionarily distinct families: the protein serine/threonine phosphatases (PPs), the protein tyrosine phosphatases, and the acid/alkaline phosphatases. PPs may be further categorized into four distinct groups: PP-I, PP-IIA, PP-IIB, and PP-IIC. (Cohen, P. (1989) Annu. Rev. Biochem.
58:453-508). PP-I, in particular, dephosphorylates many of the proteins phosphorylated by PKA
and is therefore an important regulator of signal transduction pathways.
Kinase-activated proteins which bind to and inhibit PP-I have been identified. These inhibitors potentiate the activity of kinases such as PKA by allowing protein substrates to remain in their phosphorylated, activated state. A novel inhibitor of PP-I has been purified from porcine aorta (Eto, M.
et al. (1995) J.
Biochem. 118:1104-1107; Eto, M. et al. (1997) FEBS Lett. 410:356-360). This inhibitor, called CPI17, is 147 amino acids in length and is activated by PKC. CPI17 expression is restricted to smooth muscle tissues such as aorta and bladder, suggesting that CPI17 functions in PKC-mediated signal transduction pathways in these tissues, possibly through a calcium-dependent mechanism.
The discovery of new phosphorylation effectors 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 cell proliferative, immune, and neuronal disorders.
SUMMARY OF THE INVENTION
The invention features substantially purified polypeptides, phosphorylation effectors, referred to collectively as "PHSP" and individually as "PHSP-1 to PHSP-31",.
In one aspect, the invention provides a substantially purified polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:I-31, and fragments thereof.
The invention further provides a substantially purified variant having at least 90% amino acid identity to at least one of the amino acid sequences selected from the group consisting of SEQ
ID NO:I-31, and fragments thereof. The invention also provides an isolated and purified polynucleotide encoding the polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-31, and fragments thereof. The invention also includes an isolated and purified polynucleotide variant having at least 80%
polynucleotide sequence identity to the polynucieotide encoding the polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-31, and fragments thereof.
Additionally, the invention provides an isolated and purified polynucleotide which hybridizes under stringent conditions to the polynucleotide encoding the polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-31, and fragments thereof. The invention also provides an isolated and purified polynucleotide having a sequence which is complementary to the polynucleotide encoding the polypeptide comprising the amino acid sequence selected from the group consisting of SEQ 117 NO:1-31, and fragments thereof.
The invention also provides a method for detecting a polynucleotide in a sample containing nucleic acids, the method comprising the steps of (a) hybridizing the complement of the polynucleotide sequence to at least one of the polynucleotides of the sample, thereby forming a hybridization complex; and (b) detecting the hybridization complex, wherein the presence of the hybridization complex correlates with the presence of a polynucleotide in the sampler In one aspect, the method further comprises amplifying the polynucleotide prior to hybridization.
The invention also provides an isolated and purified polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ 1D N0:32-62, and fiagments thereof. The invention further provides an isolated and purified polynucleotide variant having at least 80% polynucleotide sequence identity to the polynucleotide sequence selected from the group consisting of SEQ ID N0:32-62, and fragments thereof. The invention also provides an isolated and purified polynucleotide having a sequence which is complementary to the polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ
ID N0:32-62, and fragments thereof.
The invention further provides an expression vector containing at least a fragment of the polynucleotide encoding the polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-31, and fragments thereof. In another aspect, the expression vector is contained within a host cell.
The invention also provides a method for producing a polypeptide, the method comprising the steps of (a) culturing the host cell containing an expression vector containing at least a fragment of a polynucleotide under conditions suitable for the expression of the polypeptide; and (b) recovering the polypeptide from the host cell culture.
The invention also provides a pharmaceutical composition comprising a substantially purified polypeptide having the amino acid sequence selected from the group consisting of SEQ
ID NO:1-31, and fragments thereof, in conjunction with a suitable pharmaceutical carrier.
The invention further includes a purified antibody which binds to a polypeptide selected from the group consisting of SEQ ID NO:1-31, and fragments thereof. The invention also provides a purified agonist and a purified antagonist to the polypeptide.
The invention also provides a method for treating or preventing a disorder associated with decreased expression or activity of PHSP, the method comprising administering to a subject in need of such treatment an effective amount of a pharmaceutical composition comprising a substantially purified polypeptide having the amino acid sequence selected from the group _q_ WO 00/0672$ PCT/US99/17132 consisting of SEQ 117 NO:1-31, and fragments thereof, in conjunction with a suitable pharmaceutical Garner.
The invention also provides a method for treating or preventing a disorder associated with increased expression or activity of PHSP, the method comprising administering to a subject in need of such treatment an effective amount of an antagonist of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO: l-31, and fragments thereof.
BRIEF DESCRIPTION OF THE TABLES
Table 1 shows nucleotide and polypeptide sequence identification numbers (SEQ
ID NO), clone identification numbers (clone ID), cDNA libraries, and cDNA fragments used to assemble full-length sequences encoding PHSP.
Table 2 shows features of each polypeptide sequence, including potential motifs, homologous sequences, and methods and algorithms used for identification of PHSP.
Table 3 shows the tissue-specific expression patterns of each nucleic acid sequence as I S determined by northern analysis, diseases, disorders, or conditions associated with these tissues, and the vector into which each cDNA was cloned.
Table 4 describes the tissues used to construct the cDNA libraries from which cDNA
clones encoding PHSP were isolated.
Table 5 shows the tools, programs, and algorithms used to analyze PHSP, 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. Ali 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.
DEFINTTIONS
"PHSP" refers to the amino acid sequences of substantially purified PHSP
obtained from any species, particularly a mammalian species, including bovine, ovine, porcine, murine, equine, and preferably the human species, from any source, whether natural, synthetic, semi-synthetic, or recombinant.
The term "agonist" refers to a molecule which, when bound to PHSP, increases or prolongs the duration of the effect of PHSP. Agonists may include proteins, nucleic acids, carbohydrates, or any other molecules which bind to and modulate the effect of PHSP.
An "allelic variant" is an alternative form of the gene encoding PHSP. Allelic variants may result from at least one mutation in the nucleic acid sequence and may result in altered mRNAs or in polypeptides whose structure or function may or may not be altered. Any given natural or recombinant gene may have none, one, or many allelic forms. 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 PHSP include those sequences with deletions, insertions, or substitutions of different nucleotides, resulting in a polynucleotide the same as PHSP
or a polypeptide with at least one functional characteristic of PHSP. Included within this definition are polymorphisms which may or may not be readily detectable using a particular oligonucleotide probe of the polynucleotide encoding PHSP, and improper or unexpected hybridization to allelic variants, with a locus other than the normal chromosomal locus for the polynucleotide sequence encoding PHSP. 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 PHSP. 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 PHSP is retained. For example, negatively charged amino acids may include aspartic acid and glutamic acid, positively charged amino acids may include lysine and arginine, and amino acids with uncharged polar head groups having similar hydrophilicity values may include leucine, isoleucine, and valine; glycine and alanine; asparagine and glutamine; serine and threonine; and phenylalanine and tyrosine.
The terms "amino acid" or "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. In this context, "fragments," "immunogenic fragments," or "antigenic fragments" refer to fragments of PHSP which are preferably at least 5 to about 15 amino acids in length, most preferably at least 14 amino acids, and which retain some biological activity or immunological activity of PHSP. Where "amino acid sequence" is recited to refer to an amino acid 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 carned out using polymerase chain reaction (PCR) technologies well known in the art.
The term "antagonist" refers to a molecule which, when bound to PHSP, decreases the amount or the duration of the effect of the biological or immunological activity of PHSP.
Antagonists may include proteins, nucleic acids, carbohydrates, antibodies, or any other molecules which decrease the effect of PHSP.
The term "antibody" refers to intact molecules as well as to fragments thereof, such as Fab, F(ab')Z, and Fv fi~agments, which are capable of binding the epitopic determinant. Antibodies that bind PHSP polypeptides can be prepared using intact polypeptides or using fragments containing small peptides of interest as the immunizing antigen. The polypeptide or oligopeptide used to immunize an animal (e.g., a mouse, a rat, or a rabbit) can be derived from the translation of RNA, or synthesized chemically, and can be conjugated to a carrier protein if desired. Commonly used carriers that are chemically coupled to peptides include bovine serum albumin, thyroglobulin, and keyhole limpet hemocyanin (KLH). The coupled peptide is then used to immunize the animal.
The term "antigenic determinant" refers to that fragment 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 (given 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 containing a nucleic acid sequence which is complementary to the "sense" strand of a specific nucleic acid sequence.
Antisense molecules may be produced by any method including synthesis or transcription. Once introduced into a cell, the complementary nucleotides combine with natural sequences produced by the cell to form duplexes and to block either transcription or translation. The designation "negative" can refer to the antisense strand, and the designation "positive" can refer to the sense strand.
The term "biologically active," refers to a protein having structural, regulatory, or biochemical functions of a naturally occurnng molecule. Likewise, "immunologicaUy active"
refers to the capability of the natural, recombinant, or synthetic PHSP, or of any oligopeptide thereof, to induce a specific immune response in appropriate animals or cells and to bind with specific antibodies.
The terms "complementary" or "complementarity" refer to the natural binding of polynucleotides by base pairing. For example, the sequence "5' A-G-T 3"' bonds to the complementary sequence "3' T-C-A 5'." Complementarity between two single-stranded molecules may be "partial," such that only some of the nucleic acids bind, or it may be "complete," such that total complementarity exists between the single stranded molecules. The degree of complementarity between nucleic acid strands has significant effects on the efficiency and strength 1 S of the hybridization between the nucleic acid strands. This is of particular importance in amplification reactions, which depend upon binding between nucleic acids strands, and in the design and use of peptide nucleic acid (PNA) moiecules.
A "composition comprising a given polynucleotide sequence" or 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 PHSP or fragments of PHSP may be employed as hybridization probes. The probes may be stored in freeze-dried form and may be associated with a stabilizing agent such as a carbohydrate. In hybridizations, the probe may be deployed in an aqueous solution containing salts (e.g., NaCI), detergents {e.g., sodium dodecyl sulfate; SDS), and other components (e.g., Denhardt's solution, dry milk, salmon sperm DNA, etc.).
"Consensus sequence"refers to a nucleic acid sequence which has been resequenced to resolve uncalled bases, extended using the XL-PCR kit (Perkin-Elmer, Norwalk CT) in the 5' and/or the 3' direction, and resequenced, or which has been assembled from the overlapping sequences of more than one Incyte Clone using a computer program for fragment assembly, such as the GELVIEW fragment assembly system (GCG, Madison WI). Some sequences have been both extended and assembled to produce the consensus sequence.
The term "correlates with expression of a polynucleotide" indicates that the detection of the presence of nucleic acids, the same or related to a nucleic acid sequence encoding PHSP, by northern analysis is indicative of the presence of nucleic acids encoding PHSP
in a sample, and _g_ thereby correlates with expression of the transcript from the polynucleotide encoding PHSP.
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 the chemical modification of a polypeptide sequence, or a polynucleotide sequence. Chemical modifications of a polynucleotide sequence can include, for example, replacement of hydrogen by an alkyl, acyl, 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.
The term "similarity" refers to a degree of complementarity. There may be partial similarity or complete similarity. The word "identity" may substitute for the word "similarity." A
partially complementary sequence that at least partially inhibits an identical sequence from hybridizing to a target nucleic acid is referred to as "substantially similar." The inhibition of hybridization of the completely complementary sequence to the target sequence may be examined using a hybridization assay (Southern or northern blot, solution hybridization, and the like) under conditions of reduced stringency. A substantially similar sequence or hybridization probe will compete for and inhibit the binding of a completely similar (identical) sequence to the target sequence under conditions of reduced stringency. This is not to say that conditions of reduced stringency are such that non-specific binding is permitted, as reduced stringency conditions require that the binding of two sequences to one another be a specific (i.e., a selective) interaction.
The absence of non-specific binding may be tested by the use of a second target sequence which lacks even a partial degree of complementarity (e.g., less than about 30%
similarity or identity).
In the absence of non-specific binding, the substantially similar sequence or probe will not hybridize to the second non-complementary target sequence.
The phrases "percent identity" and "% identity" refer to the percentage of sequence similarity found in a comparison of two or more amino acid or nucleic acid sequences. Percent identity can be determined electronically, e.g., by using the MEGALIGN program (DNASTAR, Madison WI) which creates alignments between two or more sequences according to methods selected by the user, e.g., the clustal method. (See, e.g., Higgins, D.G. and P.M. Sharp ( 1988) Gene 73:237-244.) The clustal algorithm groups sequences into clusters by examining the distances between all pairs. The clusters are aligned pairwise and then in groups. The percentage similarity between two amino acid sequences, e.g., sequence A and sequence B, is calculated by dividing the length of sequence A, minus the number of gap residues in sequence A, minus the number of gap residues in sequence B, into the sum of the residue matches between sequence A
_g_ and sequence B, times one hundred. Gaps of low or of no similarity between the two amino acid sequences are not included in determining percentage similarity. Percent identity between nucleic acid sequences can also be counted or calcuiated by other methods known in the art, e.g., the Jotun Hein method. (See, e.g., Hero, J. (1990) Methods Enzymol. 183:626-645.) Identity between sequences can also be determined by other methods known in the art, e.g., by varying hybridization conditions.
"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 stable mitotic chromosome segregation and maintenance.
The term "humanized antibody" refers to antibody molecules 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 any process by which a strand of nucleic acid binds with a complementary strand through base pairing.
The teen "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 Rat 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" or "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, to the sequence found in the naturally occurring molecule.
"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.
The term "microarray" refers to an arrangement of distinct polynucleotides on a substrate.
The terms "element" or "array element" in a microarray context, refer to hybridizable polynucleotides arranged on the surface of a substrate.
The term "modulate" refers to a change in the activity of PHSP. For example, modulation may cause an increase or a decrease in protein activity, binding characteristics, or any other biological, functional, or immunological properties of PHSP.
The phrases "nucleic acid" or "nucleic acid sequence," as used herein, 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-Iike material. In this context, "fragments" refers to those nucleic acid sequences which, comprise a region of unique polynucleotide sequence that specifically identifies SEQ ID N0:32-62, for example, as distinct from any other sequence in the same genome. For example, a fragment of SEQ ID N0:32-62 is useful in hybridization and amplification technologies and in analogous methods that distinguish SEQ ID N0:32-62 from related polynucleotide sequences. A fragment of SEQ ID N0:32-62 is at least about 1 S-20 nucleotides in length. The precise length of the fragment of SEQ ID N0:32-62 and the region of SEQ ID
N0:32-62 to which the fragment corresponds are routinely determinable by one of ordinary skill in the art based on the intended purpose for the fragment. In some cases, a fragment, when translated, would produce polypeptides retaining some functional characteristic, e.g., antigenicity, or structural domain characteristic, e.g., ATP-binding site, of the full-length polypeptide The terms "operably associated" or "operably linked" refer to functionally related nucleic acid sequences. A promoter is operably associated or operably linked with a coding sequence if the promoter controls the translation of the encoded polypeptide. While operably associated or operably linked nucleic acid sequences can be contiguous and in the same reading frame, certain genetic elements, e.g., repressor genes, are not contiguously linked to the sequence encoding the polypeptide but still bind to operator sequences that control expression of the polypeptide.
The term "oligonucleotide" refers to a nucleic acid sequence of at least about nucleotides to 60 nucleotides, preferably about 15 to 30 nucleotides, and most preferably about 20 to 25 nucleotides, which can be used in PCR amplification or in a hybridization assay or microarray. "Oligonucleotide" is substantially equivalent to the terms "amplimer," "primer,"
"oligomer," and "probe," as these terms are commonly defined in the art.
"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.
The term "sample" is used in its broadest sense. A sample suspected of containing nucleic acids encoding PHSP, or fragments thereof, or PHSP itself, 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" or "specifically binding" refer to that interaction between a protein or peptide and an agonist, an antibody, or an antagonist. 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 containing 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 "stringent conditions" refers to conditions which permit hybridization between polynucleotides and the claimed polynucleotides. Stringent conditions can be defined by salt concentration, the concentration of organic solvent, e.g., formamide, temperature, and other conditions well known in the art. In particular, stringency can be increased by reducing the concentration of salt, increasing the concentration of formamide, or raising the hybridization temperature.
The term "substantially purified" refers to nucleic acid or amino acid sequences that are removed from their natural environment and are isolated or separated, and are at least about 60%
free, preferably about 75% free, and most preferably about 90% free from other components with which they are naturally associated.
A "substitution" refers to the replacement of one or more amino acids or nucleotides by different amino acids 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.
"Transformation" describes a process by which exogenous DNA enters and changes 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, 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 "variant" of PHSP polypeptides refers to an amino acid sequence that is altered by one or more amino acid residues. The variant may have "conservative" changes, wherein a substituted amino acid has similar structural or chemical properties (e.g., replacement of leucine with isoleucine). More rarely, a variant may have "nonconservative" changes (e.g., replacement of glycine with tryptophan). Analogous minor variations may also include amino acid deletions or insertions, or both. Guidance in determining which amino acid residues may be substituted, inserted, or deleted without abolishing biological or immunological activity may be found using computer programs well known in the art, for example, LASERGENE software (DNASTAR).
The term "variant," when used in the context of a polynucleotide sequence, may encompass a polynucleotide sequence related to PHSP. This definition may also include, for example, "allelic" (as defined above), "splice," "species," or "polymorphic"
variants. A splice variant may have significant identity to a reference molecule, but will generally have a greater or lesser number of polynucleotides due to alternate splicing of exons during mRNA processing. The corresponding polypeptide may possess additional functional domains or an absence of domains.
Species variants are polynucleotide sequences that vary from one species to another. 'The resulting polypeptides generally will have significant amino acid identity relative to each other. A
polymorphic variant is a variation in the poiynucleotide 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 base.
The presence of SNPs may be indicative of, for example, a certain population, a disease state, or a propensity for a disease state.
THE INVENTION
The invention is based on the discovery of new human phosphorylation effectors (PHSP), the polynucleotides encoding PHSP, and the use of these compositions for the diagnosis, treatment, or prevention of cell proliferative, immune, and neuronal disorders.
Table 1 lists the Incyte clones used to assemble full length nucleotide sequences encoding PHSP. Columns 1 and 2 show the sequence identification numbers (SEQ )D NOs) of the polypeptide and nucleotide sequences, respectively. Column 3 shows the clone )Ds of the Incyte clones in which nucleic acids encoding each PHSP were identified, and column 4 shows the cDNA libraries from which these clones were isolated. Column 5 shows Incyte clones and their corresponding cDNA libraries. Clones for which cDNA libraries are not indicated were derived from pooled cDNA libraries. The clones in column 5 were used to assemble the consensus nucleotide sequence of each PHSP and are useful as fragments in hybridization technologies.
The columns of Table 2 show various properties of each of the polypeptides of the invention: column 1 references the SEQ ID NO and column 2 shows the number of amino acid residues in each polypeptide. Columns 3 and 4 show potential phosphorylation sites and potential glycosylation sites, respectively. Column 5 shows the amino acid residues comprising signature sequences and motifs. Column 6 shows homologous sequences as identified by BLAST analysis, while column 7 shows analytical methods used to identify each polypeptide through sequence homology and protein motifs.
The columns of Table 3 show the tissue-specificity and diseases, disorders, or conditions associated with nucleotide sequences encoding PHSP. The first column of Table 3 lists the SEQ
ID NOs. Column 2 lists tissue categories which express PHSP as a fraction of total tissue categories expressing PHSP. Column 3 lists diseases, disorders, or conditions associated with those tissues expressing PHSP. Column 4 lists the vectors used to subcIone the cDNA library.
The columns of Table 4 show descriptions of the tissues used to construct the cDNA
libraries from which cDNA clones encoding PHSP were isolated. Column 1 references the SEQ
ID NO, column 2 shows the cDNA libraries from which these clones were isolated, and column 3 shows the tissue origins and other descriptive information relevant to the cDNA libraries in column 2.
The following fragments of the nucleotide sequences encoding PHSP are useful, for example, in hybridization or amplification technologies to identify SEQ ID
N0:32-62 and to distinguish between SEQ ID N0:32-62 and related polynucleotide sequences. The useful fragments include, the fragment of SEQ ID N0:32 from about nucleotide 81 to about nucleotide 110; the fragment of SEQ >D N0:33 from about nucleotide 323 to about nucleotide 352; the fragment of SEQ ID N0:34 from about nucleotide 83 to about nucleotide 112; the fragment of SEQ ID N0:35 from about nucleotide 524 to about nucleotide 553; the fragment of SEQ ID
N0:36 from about nucleotide 275 to about nucleotide 346; the fragment of SEQ
1D N0:37 from about nucleotide 1328 to about nucleotide 139d; the fragment of SEQ ID N0:38 from about nucleotide 245 to about nucleotide 304; the fragment of SEQ ID N0:39 from about nucleotide 1253 to about nucleotide 1312; the fragment of SEQ ID N0:41 from about nucleotide 117 to about nucleotide 170; the fragments of SEQ 117 N0:42 from about nucleotide 109 to about nucleotide 153, and from about nucleotide 325 to about nucleotide 369; the fragments of SEQ ID N0:43 from about nucleotide 380 to about nucleotide 424, and from about nucleotide 1190 to about nucleotide 1234; the fragment of SEQ ID N0:44 from about nucleotide 1 to about nucleotide 46; the fragment of SEQ ID N0:45 from about nucleotide 533 to about nucleotide 577;
the fragments of SEQ ID N0:46 from about nucleotide 109 to about nucleotide 153, and from about nucleotide 379 to about nucleotide 423; the fragment of SEQ ID N0:47 from about nucleotide 1730 to about nucleotide 1774; the fragment of SEQ ID N0:48 from about nucleotide 433 to about nucleotide 477; the fragment of SEQ ID N0:49 from about nucleotide 1117 to about nucleotide 1155; the fragment of SEQ ID NO:50 from about nucleotide 166 to about nucleotide 213;
the fragment of SEQ ID NO:51 from about nucleotide 60 to about nucleotide 95; the fragment of SEQ ID N0:52 from about nucleotide 326 to about nucleotide 370; the fragment of SEQ ID
N0:53 from about nucleotide 25 to about nucleotide 66; the fragment of SEQ ID N0:54 from about nucleotide 55 to about nucleotide 102; the fragment of SEQ ID NO:55 from about nucleotide 138 to about nucleotide 167; the fragment of SEQ ID N0:56 from about nucleotide 29 to about nucleotide 58;
the fragment of SEQ ID N0:57 from about nucleotide 455 to about nucleotide 484; the fragment of SEQ ID N0:58 from about nucleotide 226 to about nucleotide 255; the fragment of SEQ ID
N0:59 from about nucleotide 557 to about nucleotide 598; the fragment of SEQ
ID N0:60 from about nucleotide 284 to about nucleotide 325; the fragment of SEQ ID N0:61 from about nucleotide 1043 to about nucleotide 1090; and the fragment of SEQ )D N0:62 from about nucleotide 84 to about nucleotide 132. The polypeptides encoded by the fragments of SEQ ID
N0:32-62 are useful, for example, as immunogenic peptides. .
The invention also encompasses PHSP variants. A preferred PHSP variant is one which has at least about 80%, more preferably at least about 90%, and most preferably at least about 95%
amino acid sequence identity to the PHSP amino acid sequence, and which contains at least one functional or structural characteristic of PHSP.
The invention also encompasses polynucleotides which encode PHSP. In a particular embodiment, the invention encompasses a.polynucleotide sequence comprising a sequence selected from the group consisting of SEQ ID N0:32-62, which encodes PHSP.
The invention also encompasses a variant of a polynucleotide sequence encoding PHSP. In particular, such a variant polynucleotide sequence will have at least about 80%, more preferably at least about 85%, and most preferably at least about 95% polynucleotide sequence identity to the polynucleotide sequence encoding PHSP. A particular aspect of the invention encompasses a variant of a polynucleotide sequence comprising a sequence selected from the group consisting of SEQ ID
N0:32-62 which has at least about 80%, more preferably at least about 85%, and most preferably at least about 95% polynucleotide sequence identity to a nucleic acid sequence selected from the group consisting of SEQ ID N0:32-62. Any one of the polynucleotide variants described above can encode an amino acid sequence which contains at least one functional or structural characteristic of PHSP.
It will be appreciated by those skilled in the art that as a result of the degeneracy ofthe genetic code, a multitude of polynucleotide sequences encoding PHSP, 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 PHSP, and all such variations are to be considered as being specifically disclosed.
Although nucleotide sequences which encode PHSP and its variants are preferably capable of hybridizing to the nucleotide sequence of the naturally occurring PHSP
under appropriately selected conditions of stringency, it may be advantageous to produce nucleotide sequences encoding PHSP 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 PHSP and its derivatives without altering the encoded amino acid sequences include the production ofRNA 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 PHSP
and PHSP 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 PHSP 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
t 5 N0:32-62 and fragments thereof under various conditions of stringency.
(See, e.g., Wahl, G.M. and S.L. Berger ( 1987) Methods Enzymol. 152:399-407; Kimmel, A.R. ( 1987) Methods Enzymol.
152:507-511.) For example, stringent salt concentration will ordinarily be less than about 750 mM
NaCI and 75 mM trisodium citrate, preferably less than about 500 mM NaCI and 50 mM trisodium citrate, and most preferably less than about 250 mM NaCI and 25 mM trisodium citrate. Low stringency hybridization can be obtained in the absence of organic solvent, e.g., formamide, while high stringency hybridization can be obtained in the presence of at least about 35% formamide, and most preferably at least about 50% formamide. Stringent temperature conditions will ordinarily include temperatures of at least about 30°C, more preferably of at least about 37°C, and most preferably of at least about 42°C. Varying additional parameters, such as hybridization time, the concentration of detergent, e.g.,. sodium dodecyl sulfate (SDS), and the inclusion or exclusion of carrier DNA, are well known to those skilled in the art. Various levels of stringency are accomplished by combining these various conditions as needed. In a preferred embodiment, hybridization will occur at 30°C in 750 mM NaCI, 75 mM trisodium citrate, and 1% SDS. In a more preferred embodiment, hybridization will occur at 37°C in 500 mM NaCI, 50 mM trisodium citrate, 1% SDS, 35%
formamide, and 100 ~g/ml denatured salmon sperm DNA (ssDNA). In a most preferred embodiment, hybridization will occur at 42°C in 250 mM NaCI, 25 mM trisodium citrate, 1% SDS, 50 formamide, and 200 ~.g/ml ssDNA. Useful variations on these conditions will be readily apparent to those skilled in the art.
The washing steps which follow hybridization can also vary in stringency. Wash stringency conditions can be defined by salt concentration and by temperature. As above, wash stringency can be increased by decreasing salt concentration or by increasing temperature.
For example, stringent salt concentration for the wash steps will preferably be less than about 30 mM
NaCI and 3 mM
trisodium citrate, and most preferably less than about 1 S mM NaCI and 1.S mM
trisodium citrate.
Stringent temperature conditions for the wash steps will ordinarily include temperature of at least S about 2S°C, more preferably of at least about 42°C, and most preferably of at least about 68°C. In a preferred embodiment, wash steps will occur at 2S°C in 30 mM NaCI, 3 mM trisodium citrate, and 0.1 % SDS. In a more preferred embodiment, wash steps will occur at 42°C in 1 S mM NaCI, 1.S mM
trisodium citrate, and 0.1 % SDS. In a most preferred embodiment, wash steps will occur at 68°C in 1 S mM NaCI, l .S mM trisodium citrate, and 0.1 % SDS. Additional variations on these conditions will be readily apparent to those skilled in the art.
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 frag~~t of DNA polymerase I, SEQUENASE (US Biochemical, Cleveland OH), Taq polymerase (Perkin-Elmer), thermostable T7 polymerise (Amersham Pharmacia Biotech, Piscataway NJ), or combinations 1 S of polymerises 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 (Hamilton, Reno NV), pettier thermal cycler 200 (PTC200;
MJ Research, Watertown MA) and the ABI CATALYST 800 (Perkin-Elmer). Sequencing is then carried out using the ABI 373 or 377 DNA sequencing systems (Perkin-Ehner), or 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. ( I 997) Short Protocols in Molecular BioloQV, John Wiley & Sons, New York NY, unit 7.7; Meyers, R.A. (1995) Molecular Bioloe~~ and Biotechnoloev, Wiley VCH, New York NY, pp. 8Sb-853.) 2S The nucleic acid sequences encoding PHSP 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.16:8 I 86.) A third method, capture PCR, involves PCR amplification ofDNA
fragments adjacent to known sequences in human and yeast artificial chromosome DNA. (See, e.g., Lagerstrom, M. et 3S al. (199I) PCR Methods Applic. 1:1 I 1-119.) 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. 19:3055-306).
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 IS into 5' non-transcribed regulatory regions.
Capillary electrophoresis systems which are commercially available may be used to analyze the size or confine 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 enutted wavelengths. Output/light intensity may be converted to electrical signal using appropriate software (e.g., GENOTYPER and SEQUENCE NAVIGATOR, Perkin-Elmer), and the entire process from loading of samples to computer analysis and electronic data display may be computercontrolled.
Capillary electrophoresis is especially preferable for sequencing small DNA
fragments which may be present in limited amounts in a particular sample.
In anotherembodiment ofthe invention, polynucleotide sequences or fragments thereofwhich encode PHSP may be cloned in recombinant DNA molecules that direct expression of PHSP, 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 PHSP.
The nucleotide sequences ofthe present invention can be engineered using methods generally known in the art in order to alter PHSP-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 _~8_ sites, alter glycosylation patterns, change codon preference, produce splice variants, and so forth.
In another embodiment, sequences encoding PHSP 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) Nucl. Acids Res. Symp. Ser. 215-223, and Horn, T. et al. (1980) Nucl. Acids Res. Symp.
Ser. 225-232.) Alternatively, PHSP itself or a fragment thereof may be synthesized using chemical methods. For example, peptide synthesis can be performed using various solid-phase techniques. {See, e.g., Roberge, J.Y. et al. ( 1995) Science 269:202-204.) Automated synthesis may be achieved using the ABI 431A Peptide Synthesizer (Perkin-Elmer). Additionally, the amino acid sequence of PHSP, 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.
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, T. (1984) Proteins. Structures and Molecular Properties. WH Freeman, New IS York NY.) In order to express a biologically active PHSP, the nucleotide sequences encoding PHSP 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 PHSP. Such elements may vary in their strength and specificity.
Specific initiation signals may also be used to achieve more efficient translation of sequences encoding PHSP. Such signals include the ATG initiation codon and adjacent sequences, e.g. the Kozak sequence. In cases where sequences encoding PHSP 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 PHSP 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 Clonin,Q. 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 Bioloev, 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 PHSP. 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 vines, CaMV, or tobacco mosaic virus,TMV) or with bacterial expression vectors (e.g., Ti or pBR322 plasmids); or animal cell systems. 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 PHSP. For example, routine cloning, subcloning, and propagation of polynucleotide sequences encoding PHSP can be achieved using a multifunctional E. coli vector such as PBLIJESCRIPT (Stratagene, La Jolla CA) or pSPORT 1 plasmid (Life Technologies). Legation of sequences encoding PHSP into the vector's multiple cloning site disrupts the IacZ 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 PHSP are needed, e.g. for the production of antibodies, vectors which direct high level expression of PHSP may be used. For example, vectors containing the strong, inducible TS or T7 bacteriophage promoter may be used.
Yeast expression systems may be used for production of PHSP. A number of vectors containing constitutive or inducible promoters, such as alpha factor, alcohol oxidase, and PGH, may be used in the yeast Saccharomvces cerevisiae or Pichia pastoris. 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; Grant et al.
( 1987) Methods Enzymol. 153:516-54; and Scorer, C. A. et al. ( 1994) Bio/Technology 12:181-184.) Plant systems may also be used for expression ofPHSP. Transcription of sequences encoding PHSP may be driven viral promoters, e.g., the 35 S 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; Broglie, R. et al. (1984) Science 224:838-843; and Winter, J. et al. ( 1991) Results Probl. Cell Differ.17:85-105.) These constn~cts 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;ev ( 1992) McGraw Hill, New York NY, WO 00/0672$ PCT/US99/17132 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 PHSP
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 PHSP in host cells. (See, e.g., Logan, J. and T. Shenk (1984) Proc.
Natl. Acad. Sci. 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 PHSP in cell Lines is preferred. For example, sequences encoding PHSP 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 tlr or 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; neo confers resistance to the aminoglycosides, neomycin and G-418; and als or pat confer resistance to chlorsulfuron and phosphinotricin acetyltransferase, respectively. (See, e.g., Wigler, M. et al. ( 1980) Proc. Natl. Acad. Sci. 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 formetabolites. (See, e.g., Hartman, S.C. and R.C.
Mulligan ( 1988) Proc. Natl.
Acad. Sci. 85:8047-8051.) Visible markers, e.g., anthocyanins, green fluorescent proteins (GFP;
Clontech), !3 glucuronidase and its substrate >3-glucuronide, or luciferase and its substrate luciferin may be used. These markers can be used not only to identify transformants, ,but also to quantify the amount of transient or stable protein expression attributable to a specific vector system. (See, e.g., Rhodes, C.A. (1995) Methods Mol. Biol. 55:121-131.) Although the presence/absence of marker gene expression suggests that the gene of interest is also present, the presence and expression of the gene may need to be confirmed. For example, if the sequence encoding PHSP is inserted within a marker gene sequence, transformed cells containing sequences encoding PHSP can be identified by the absence of marker gene function. Alternatively, a marker gene can be placed in tandem with a sequence encoding PHSP 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 PHSP
and that express PHSP 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 forthe detection and/or quantification of nucleic acid or protein sequences.
Immunological methods for detecting and measuring the expression of PHSP 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 PHSP 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 Immunology Greene Pub. Associates and Wiley-Interscience, New York NY; and Pound, J.D. ( 1998) ~mmunochemical 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 PHSP
include oligolabeling, nick translation, end-labeling, or PCR amplification using a labeled nucleotide.
Alternatively, the sequences encoding PHSP, 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 polymerise 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 WO 00/06728 PCT/US99/17i32 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 PHSP 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 PHSP may be designed to contain signal sequences which direct secretion of PHSP 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 not limited to, acetylation, carboxylation, glycosylation, phosphorylation, lipidation, and acylation. Post-translationai processing which cleaves a "prepro"
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 forpost-translational activities (e.g., CHO, HeLa, MDCK, HEK293, and WI38), are available from the American Type Culture Collection (ATCC, Bethesda MD) and may be chosen to ensure the correct modification and processing ofthe foreign protein.
In another embodiment of the invention, natural, modified, or recombinant nucleic acid sequences encoding PHSP 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 PHSP protein containing a heterologous moiety that can be recognized by a commercially available antibody may facilitate the screening of peptide libraries for inhibitors of PHSP activity.
Heterologous protein and peptide moieties may also facilitate purification of fusion proteins using commercially available affinity matrices. Such moieties include, but are not limited to, glutathione S-transferase (GST), maltose binding protein (MBP), thioredoxin (Trx), calmodulin binding peptide (CBP), 6-His, FLAG, c-myc, and hemagglutinin (HA). GST, MBP, Trx, CBP, and 6-His enable purification oftheir 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 PHSP encoding sequence and the heterologous protein sequence, so that PHSP 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 PHSP may be achieved in vitro using the TNT rabbit reticulocyte lysate or wheat germ extract systems (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, preferably '3S-methionine.
Fragments of PHSP may be produced not only by recombinant production, but also by direct peptide synthesis using solid-phase techniques. (See, e.g., Creighton, supra.
pp. SS-60.) Protein synthesis may be performed by manual techniques or by automation. Automated synthesis may be achieved, for example, using the ABI 431 A Peptide Synthesizer (Perkin-Elmer).
Various fragments of PHSP may be synthesized separately and then combined to produce the full length molecule.
THERAPEUTICS
Chemical and structural similarity, e.g., in the context of sequences and motifs, exists between regions of PHSP and protein phosphatases. In addition, the expression of PHSP
is closely associated with reproductive tissue, nervous tissue, gastrointestinal tissue, cell proliferation, cancer, inflammation, and immune response. Therefore, PHSP appears to play a role in cell proliferative, immune, and neuronal disorders. In the treatment of disorders associated with increased PHSP
expression or activity, it is desirable to decrease the expression or activity of PHSP. In the treatment of disorders associated with decreased PHSP expression or activity, it is desirable to increase the expression or activity of PHSP.
Therefore, in one embodiment, PHSP or a fragment or derivative thereofmay be administered to a subject to treat or prevent a disorder associated with decreased expression or activity of PHSP.
Examples of such disorders include, but are not limited to, a cell proliferative disorder, such as actinic keratosis, arteriosclerosis, atherosclerosis, bursitis, cirrhosis, hepatitis, mixed connective tissue disease (MCTD), myelofibrosis, paroxysmal nocturnal hemoglobinuria, polycythemia vera, psoriasis, primary thrombocythemia, and 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; an immune disorder, such as acquired imraunodeficiency syndrome (AIDS), Addison's disease, adult respiratory distress syndrome, allergies, ankyIosing spondylitis, amyloidosis, anemia, asthma, atherosclerosis, autoimmune hemolytic anemia, autoimmune thyroiditis, autoimmune polyenodocrinopathy-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 givis, 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; and a neuronal disorder, such as akathesia, Alzheimer's disease, amnesia, amyotcophic lateral sclerosis, bipolar disorder, catatonia, dementia, depression, diabetic neuropathy, Down's syndrome, tardive dyskinesia, dystonias, epilepsy, Huntington's disease, peripheral neuropathy, multiple sclerosis, neurofibromatosis, Parkinson's disease, paranoid psychoses, postherpetic neuralgia, schizophrenia, and Tourette's disorder.
In another embodiment, a vector capable of expressing PHSP or a figment or derivative thereof may be administered to a subject to treat or prevent a disorder associated with decreased expression or activity of PHSP including, but not limited to, those described above.
In a further embodiment, a pharmaceutical composition comprising a substantially purified PHSP 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 PHSP
including, but not limited to, those provided above.
In still another embodiment, an agonist which modulates the activity of PHSP
may be administered to a subject to treat orprevent a disorder associated with decreased expression or activity of PHSP including, but not limited to, those listed above.
In a further embodiment, an antagonist of PHSP may be administered to a subject to treat or prevent a disorder associated with increased expression or activity of PHSP.
Examples of such disorders include, but are not limited to, those described above. In one aspect, an antibody which specifically binds PHSP may be used directly as an antagonist or indirectly as a targeting or delivery mechanism for bringing a pharmaceutical agent to cells or tissue which express PHSP.
In an additional embodiment, a vector expressing the complement of the polynucleotide encoding PHSP may be administered to a subject to treat or prevent a disorder associated with increased expression or activity of PHSP 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 theipy 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 theipeutic efficacy with lower dosages of each agent, thus reducing the potential for adverse side effects.

An antagonist ofPHSP may be produced using methods which are generally known in the art.
In particular, purified PHSP may be used to produce antibodies or to screen libraries of pharmaceutical agents to identify those which specifically bind PHSP.
Antibodies to PHSP 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 especially 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 PHSP 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, platonic polyols, polyanions, peptides, oil emulsions, KLH, and dinitrophenol. Among adjuvants used in humans, BCG
(bacilli Calmette-Guerin) and Corvnebacterium narwm are especially preferable.
It is preferred that the oligopeptides, peptides, or fragments used to induce antibodies to PHSP
have an amino acid sequence consisting of at least about 5 amino acids, and, more preferably, 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 and contain the entire amino acid sequence of a small, naturally occurring molecule. Short stretches of PHSP amino acids may be fused with those of another protein, such as KLH, and antibodies to the chimeric molecule may be produced.
Monoclonal antibodies to PHSP 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 EB V-hybridoma 23 technique. (See, e.g., Kohler, G. et al. ( 1975) Nature 256:495-497;
Kozbor, D. et al. ( 1985) J.
Immunol. Methods 81:31-42; Cote, R.J. et al. (1983) Proc. Natl. Acad. Sci.
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. 81:6851-6855; Neuberger, M.S. et a1. ( 1984) Nature 312:604-608; and Takeda, S. et al. ( 1985) Nature 314:452-454. ) Alternatively, techniques described forthe production of single chain antibodies may be adapted, using methods known in the art, to produce PHSP-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 WO 00/0672$ PCT/US99/17132 D.R. (1991) Proc. Natl. Acad. Sci. 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., Orlandi, R. et al. (1989) Proc. Natl.
Acad. Sci. 86: 3833-3837;
Winter, G. et al. (1991) Nature 349:293-299.) Antibody fragments which contain specific binding sites for PHSP 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 PHSP and its specific antibody. A two-site, monoclonal-based immunoassay utilizing monoclonal antibodies reactive to two non-interfering PHSP epitopes is preferred, but a competitive binding assay may also be employed (Pound, supra).
Various methods such as Scatchard analysis in conjunction with radioimmunoassay techniques may be used to assess the affinity of antibodies for PHSP. Affinity is expressed as an association constant, Ka, which is defined as the molar concentration of PHSP-antibody complex divided by the molar concentrations of free antigen and free antibody under equilibrium conditions.
The ICa determined for a preparation of poIyclonal antibodies, which are heterogeneous in their affinities for multiple PHSP epitopes, represents the average affinity, or avidity, of the antibodies for PHSP. The ICe determined for a preparation of monoclonal antibodies, which are monospecific for a particular PHSP epitope, represents a true measure of affinity. High-affinity antibody preparations with K, ranging from about 109 to 10'2 L/mole are preferred for use in immunoassays in which the PHSP-antibody complex must withstand rigorous manipulations. Low-affinity antibody preparations with K, ranging from about 106 to 10' L/mole are preferred for use in immunopurification and similar procedures which ultimately require dissociation of PHSP, preferably in active form, from the antibody (Catty, D. ( 1988) Antibodies, Volume I: A Practical Approach IRL
Press, Washington, DC;
Liddell, J. E. and Cryer, A. ( 1991 ) A Practical Guide to Monoclonal Antibodies, John Wiley & Sons, New York NY).
The titer and avidity of polyclonal antibody preparations may be further evaluated to determine the quality and suitability of such preparations for certain downstream applications. For example, a polyclonal antibody preparation containing at least 1-2 mg specific antibody/ml, preferably 5-10 mg specific antibody/ml, is preferred for use in procedures requiring precipitation of PHSP-antibody complexes. Procedures for evaluating antibody specificity, titer, and avidity, and guidelines forantibody quality and usage in various applications, are generally available. (See, e.g., Catty, supra.
and Coligan et al. su ra.) In another embodiment of the invention, the polynucleotides encoding PHSP, or any fragment or complement thereof, may be used for therapeutic purposes. In one aspect, the complement of the polynucleotide encoding PHSP may be used in situations in which it would be desirable to block the transcription of the mRNA. In particular, cells may be transformed with sequences complementary to polynucleotides encoding PHSP. Thus, complementary molecules or fragments may be used to modulate PHSP activity, or to achieve regulation of gene function. Such technology is now well known in the art, and sense or antisense oligonucleotides or larger fragments can be designed from various locations along the coding or control regions of sequences encoding PHSP.
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. Methods which are well known to those skilled in the art can be used to construct vectors to express nucleic acid sequences complementary to the polynucleotides encoding PHSP. (See, e.g., Sambrook, supra; Ausubel, 1995, supra.) Genes encoding PHSP can be turned off by transforming a cell or tissue with expression vectors which express high levels of a polynucleotide, or fragment thereof, encoding PHSP. Such constructs may be used to introduce untranslatable sense or antisense sequences into a cell. Even in the absence of integration into the DNA, such vectors may continue to transcribe RNA molecules until they are disabled by endogenous nucleases. Transient expression may last for a month or more with a non-replicating vector, and may last even longer if appropriate replication elements are part of the vector system. _, As mentioned above, modifications of gene expression can be obtained by designing complementary sequences or antisense molecules (DNA, RNA, or PNA) to the control, 5', or regulatory regions of the gene encoding PHSP. Oligonucleotides derived fiom the transcription initiation site, e.g., between about positions -10 and+10 from the start site, are preferred. 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 polymerases, transcription factors, orregulatory molecules. Recent therapeutic advances using triplex DNA have been described in the literature. (See, e.g., Gee, J.E. et al. ( 1994) in Huber, B.E. and B.I.
Carr, Molecular and Immunoloeic Approaches Futura Publishing, Mt. Kisco NY, pp. 163-177.) A
complementary sequence or antisense molecule may also be designed to block tsansiation 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 motifribozyme molecules may specifically and efficiently catalyze endonucleolytic cleavage of sequences encoding PHSP.
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 PHSP. 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.
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) Nature Biotechnology 15:462-466.) Any ofthe therapeutic methods described above may be applied to any subject in need of such therapy, including, for example, mammals such as dogs, cats, cows, horses, rabbits, monkeys, and most preferably, humans.
An additional embodiment of the invention relates to the administration of a pharmaceutical or sterile composition, in conjunction with a pharmaceutically acceptable carrier, for any of the therapeutic effects discussed above. Such pharmaceutical compositions may consist of PHSP, antibodies to PHSP, and mimetics, agonists, antagonists, or inhibitors of PHSP. The compositions may be administered alone or in combination with at least one other agent, such as a stabilizing compound, which may be administered in any sterile, biocompatible pharmaceutical carrier including, but not limited to, saline, buffered saline, dextrose, and water. The compositions may be administered to a patient alone, or in combination with other agents, drugs, or hormones.
The pharmaceutical 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, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, or rectal means.
I S In addition to the active ingredients, these pharmaceutical compositions may contain suitable pharmaceutically-acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
Further details on techniques for formulation and administration may be found in the latest edition of ReminQton's Pharmaceutical Sciences (Maack Publishing, Easton PA).
Pharmaceutical compositions for oral administration can be formulated using pharmaceutically acceptable carriers well known in the art in dosages suitable for oral administration.
Such carriers enable the pharmaceutical compositions to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for ingestion by the patient.
Pharmaceutical preparations for oral use can be obtained through combining active . . 25 . compounds with solid excipient and processing the resultant mixture of granules (optionally, after grinding) to obtain tablets or dragee cores. Suitable auxiliaries can be added, if desired. Suitable excipients include carbohydrate or protein fillers, such as sugars, including lactose, sucrose, mannitol, and sorbitol; starch from corn, wheat, rice, potato, or other plants;
cellulose, such as methyl cellulose, hydroxypropylinethyl-cellulose, or sodium carboxymethylcellulose; gums, including arabic and tragacanth; and proteins, such as gelatin and collagen. If desired, disintegrating or solubilizing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, and alginic acid or a salt thereof, such as sodium alginate.
Dragee cores may be used in conjunction with suitable coatings, such as concentrated sugar solutions, which may also contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.

Dyestuffs or pigments may be added to the tablets or dragee coatings for product identification or to characterize the quantity of active compound, i.e., dosage.
Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating, such as glycerol or sorbitol.
Push-fit capsules can contain active ingredients mixed with fillers or binders, such as lactose or starches, lubricants, such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid, or liquid polyethylene glycol with or without stabilizers.
Pharmaceutical formulations suitable for parenteral administration may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiologically buffered saline. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate, triglycerides, or liposomes. Non-lipid polycationic amino polymers may also be used for delivery. Optionally, the suspension may also contain suitable stabilizers or agents to increase the solubility ofthe compounds and allow forthe preparation of highly concentrated solutions.
For topical or nasal administration, penetrants appropriate to the particular barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
The pharmaceutical compositions of the present invention may be manufactured in a manner that is known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes.
The pharmaceutical composition may be provided as a salt and can be formed with many acids, including but not limited to, hydrochloric, sulfuric, acetic, lactic, tartaric, malic, and succinic acid. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free base forms. In other cases, the preferred preparation may be a lyophilized powder which may contain any or all of the following: 1 mM to 50 mM histidine, 0.1% to 2%
sucrose, and 2% to 7%
mannitol, at a pH range of 4.5 to 5.5, that is combined with buffer prior to use.
After pharmaceutical compositions have been prepared, they can be placed in an appropriate container and labeled for treatment of an indicated condition. For administration of PHSP, such labeling would include amount, frequency, and method of administration.
Pharmaceutical 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.

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, 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 PHSP
or fragments thereof, antibodies of PHSP, and agonists, antagonists or inhibitors of PHSP, 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 EDs° (the dose therapeutically effective in 50% of the population) or LDs° (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 LD~/ED~ ratio. Pharmaceutical 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 EDs° 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 pharmaceutical 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 PHSP may be used for the diagnosis of disorders characterized by expression of PHSP, or in assays to monitor patients being treated with PHSP or agonists, antagonists, or inhibitors of PHSP. Antibodies useful for diagnostic purposes may be prepared in the same manner as described above for therapeutics. Diagnostic assays for PHSP include methods which utilize the antibody and a label to detect PHSP
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 PHSP, including ELISAs, RIAs, and FACS, are known in the art and provide a basis for diagnosing altered or abnormal levels of PHSP expression. Normal or standard values for PHSP expression are established by combining body fluids or cell extracts taken from normal mammalian subjects, preferably human, with antibody to PHSP
underconditions suitable for complex formation. The amount of standard complex formation may be quantitated by various methods, preferably by photometric means. Quantities of PHSP 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 PHSP 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 quantitate gene expression in biopsied tissues in which expression of PHSP may be correlated with disease. The diagnostic assay may be used to determine absence, presence, and excess expression of PHSP, and to monitor regulation of PHSP levels during therapeutic intervention.
In one aspect, hybridization with PCR probes which are capable of detecting polynucleotide sequences, including genomic sequences, encoding PHSP or closely related molecules may be used to identify nucleic acid sequences which encode PHSP. 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 (maximal, high, intermediate, or low), will determine whether the probe identifies only naturally occurring sequences encoding PHSP, allelic variants, or related sequences.
Probes may also be used for the detection of related sequences, and should preferably have at least 50% sequence identity to any of the PHSP encoding sequences. The hybridization probes of the subject invention may be DNA or RNA and may be derived from the sequence of SEQ ID N0:32-62 or from genomic sequences including promoters, enhancers, and introns of the PHSP gene.
Means for producing specific hybridization probes for DNAs encoding PHSP
include the cloning of polynucleotide sequences encoding PHSP or PHSP derivatives into vectors for the production of mRNA probes. Such vectors are known in the art, are commercially available, and may be used to synthesize RNA probes in vitro by means of the addition of the appropriate RNA
polymerises and the appropriate labeled nucleotides. Hybridization probes may be labeled by a variety of reporter groups, for example, by radionucIides such as 'ZP or'sS, or by enzymatic labels, such as alkaline phosphatase coupled to the probe via avidin/biotin coupling systems, and the like.
Polynucleotide sequences encoding PHSP may be used for the diagnosis of disorders associated with expression of PHSP. Examples of such disorders include, but are not limited to, a cell proliferative disorder, such as actinic keratosis, arteriosclerosis, atherosclerosis, bursitis, cirrhosis, hepatitis, mixed connective tissue disease (MCTD), myelofibrosis, paroxysmal nocturnal hemoglobinuria, polycythemia vera, psoriasis, primary thrombocythemia, and 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; an immune disorder, such as acquired immunodeficiency syndrome (A)DS), Addison's disease, adult respiratory distress syndrome, allergies, ankylosing spondylitis, amyloidosis, anemia, asthma, atherosclerosis, autoimmune hemolytic anemia, autoimmune thyroiditis, autoimmune polyenodocrinopathy-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; and a neuronal disorder, such as akathesia, Alzheimer's disease, amnesia, amyotrophic lateral sclerosis, bipolar disorder, catatonia, dementia, depression, diabetic neuropathy, Down's syndrome, tardive dyskinesia, dystonias, epilepsy, Huntington's disease, peripheral neuropathy, multiple sclerosis, neurofibromatosis, Parkinson's disease, paranoid psychoses, postherpetic neuralgia, schizophrenia, and Tourette's disorder. The polynucleotide sequences encoding PHSP 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 PHSP
expression. Such qualitative or quantitative methods are well known in the art.
In a particular aspect, the nucleotide sequences encoding PHSP may be useful in assays that detect the presence of associated disorders, particularly those mentioned above. The nucleotide sequences encoding PHSP may be labeled by standard methods and added to a fluid or tissue sample from a patient under conditions suitable for the formation of hybridization complexes. Aftera suitable incubation period, the sample is washed and the signal is quantitated 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 PHSP 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 PHSP, 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 PHSP, 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 PHSP
may involve the use of PCR. These oligomers may be chemically synthesized, generated enzymatically, orproduced in vitro. Oligomers will preferably contain a fragment of a polynucleotide encoding PHSP, or a fragment of a polynucleotide complementary to the polynucleotide encoding PHSP, 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 quantitation of closely related DNA or RNA sequences.
Methods which may also be used to quantify the expression of PHSP 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 an ELISA format where the oligomer 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 targets in a microarray. The microariay can be used to monitor the expression level of large numbers of genes simultaneously and 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, and to develop and monitor the activities of therapeutic agents.
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.
93:10614-10619; Baldeschweiler et al. (1995) PCT application W095/251116;
Shalon, D. et al.
( 1995) PCT application W095/35505; Heller, R.A. et al. ( 1997) Proc. Natl.
Acad. Sci. 94:2150-2155;
and Heller, M.J. et al. (1997) U.S. Patent No. 5,605,662.) In another embodiment of the invention, nucleic acid sequences encoding PHSP
may be used to generate hybridization probes useful in mapping the naturally occurring genomic sequence. 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, orsingle 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.) Fluorescent in situ hybridization (FISH) may be correlated with other physical chromosome mapping techniques and genetic map data. (See, e.g., Heinz-Ulrich, et al.
(1995) in Meyers, sera.
pp. 965-968.) Examples of genetic map data can be found in various scientific journals or at the Online Mendelian Inheritance in Man (OMIM) site. Correlation between the location of the gene encoding PHSP on a physical chromosomal map and a specific disorder, or a predisposition to a specific disorder, may help define the region of DNA associated with that disorder. The nucleotide sequences of the invention may be used to detect differences in gene sequences among normal, carrier, and affected individuals.
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 number or arm of a particular human chromosome is not known.

WO 00/0672$ PCTNS99117132 New sequences can be assigned to chromosomal arms by physical mapping. This provides valuable information to investigators searching for disease genes using positional cloning or other gene discovery techniques. Once the disease or syndrome has been crudely localized by genetic linkage to a particular genomic region, e.g., ataxia-telangiectasia to 11 q22-23, 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 subject 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, PHSP, 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 PHSP 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 PHSP, or fragments thereof, and washed. Bound PHSP is then detected by methods well known in the art.
Purified PHSP 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 PHSP specifically compete with a test compound for binding PHSP.
In this manner, antibodies can be used to detect the presence of any peptide which shares one or more antigenic determinants with PHSP.
In additional embodiments, the nucleotide sequences which encode PHSP 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 preferred specific 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, in particular U.S. Ser. No. 09/173,482, 09/123,494, 09/152,814, 09/229,005, 60/106,889, 60/109,093, and 60/113,796, are hereby expressly incorporated by reference.

EXAMPLES
I. Construction of cDNA Libraries RNA was purchased from Clontech or isolated from tissues described in Table 4.
Some tissues were homogenized and lysed in guanidinium isothiocyanate, while others were homogenized and Iysed in phenol or in a suitable mixture of denaturants, such as TRIZOL
(Life Technologies), a monophasic solution ofphenol and guanidine isothiocyanate. The resulting lysates were centrifuged over CsCI cushions or extracted with chloroform. RNA was precipitated from the lysates with either isopropanol or sodium acetate and ethanol, or by other routine methods.
Phenol extraction and precipitation of RNA were repeated as necessary to increase RNA
purity. In some cases, RNA was treated with DNase. For most libraries, poly(A+) RNA "vas 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 constricted 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, supra. 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 wereligated into compatible restriction enzyme sites of the polylinker of a suitable plasmid, e.g., PBLUESCRIPT plasmid (Stratagene), pSPORTI plasmid (Life Technologies), or pINCY (Incyte Pharmaceuticals, Palo Alto CA). Recombinant plasmids were transformed into competent E.E. coii cells including XLl-BLUE, XL1-BLUEMRF, or SOLR from Stratagene or DHSa, DH10B, or ELECTROMAX DH 1 OB from Life Technologies.
II. Isolation of cDNA Clones Plasmids were recovered from host cells by in vivo excision, using the UNIZAP
vector system (Stratagene) or 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 kit from QIAGEN.

WO 00/0672$ PCT/US99/17132 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 cDNA sequencing reactions were processed using standard methods or high-throughput instrumentation such as the ABI CATALYST 800 (Perkin-Elmer) thermal cycler or the PTC-200 thermal cycler (MJ Research) in conjunction with the HYDRA microdispenser (Robbins Scientific) or the MICROLAH 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 (Perkin-Elmer).
Electrophoretic separation of cDNA sequencing reactions and detection of labeled polynucleotides were carned out using the MEGABACE 1000 DNA sequencing system (Molecular Dynamics); the ABI PRISM 373 or 377 sequencing systems (Perkin-Elmer) 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, supra. unit 7.7). Some of the cDNA sequences were selected for extension using the techniques disclosed in Example V.
The polynucleotide sequences derived from cDNA sequencing were assembled and analyzed using a combination of software programs which utilize algorithms well known to those skilled in the art. Table 5 summarizes the tools, programs, and algorithms used and provides applicable descriptions, references, and threshold parameters. The first column of Table 5 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, the greater the homology between two sequences). Sequences were analyzed using MACDNASIS PRO
software (Hitachi Software Engineering, South San Francisco CA) and LASERGENE
software (DNASTAR).
The polynucleotide sequences were validated by removing vector, linker, and polyA
sequences and by masking ambiguous bases, using algorithms and programs based on BLAST, dynamic programing, and dinucleotide nearest neighbor analysis. The sequences were then queried against a selection ofpublic databases, such as the GenBank primate, rodent, mammalian, vertebrate, and eukaryote databases, and BLOCKS to acquire annotation using programs based on BLAST, FASTA, and BLIMPS. The sequences were assembled into full length polynucleotide sequences using programs based on Phred, Phrap, and Consed, and 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 amino acid sequences, and these full length sequences were subsequently analyzed by querying against databases such as the GenBank databases (described above), SwissProt, BLOCKS, PRINTS, Prosite, 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, e.g., Eddy, S.R. (1996) Curr. Opin.
Str. Biol. 6:361-365.) The programs described above forthe assembly and analysis offull length polynucleotide and amino acid sequences were also used to identify polynucleotide sequence fragments from SEQ ID
N0:32-62. Fragments from about 20 to about 4000 nucleotides which are useful in hybridization and amplification technologies were described in The Invention section above.
IV. Northern Analysis 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, supra. ch. 4 and 16.) Analogous computer techniques applying BLAST were used to search for identical or related molecules in nucleotide databases such as GenBank or LIFESEQ database (Incyte Pharmaceuticals).
This analysis is much fasterthan 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:
seauence identity x % maximum BLAST score The product score takes into account both the degree of similarity between two sequences and the length of the sequence match. For example, with a product score of 40, the match will be exact within a 1% to 2% error, and, with a product score of 70, the match will be exact.
Similar molecules are usually identified by selecting those which show product scores between 15 and 40, although lower scares may identify related molecules.
The results of northern analyses are reported as a percentage distribution of libraries in which the transcript encoding PHSP occurred. Analysis involved the categorization of cDNA libraries by organ/tissue and disease. The organ/tissue categories included cardiovascular, dermatologic, developmental, endocrine, gastrointestinal, hematopoietic/immune, musculoskeletal, nervous, reproductive, and urologic. The disease/condition categories included cancer, inflammation/trauma, cell proliferation, neurological, and pooled. For each category, the number of libraries expressing the sequence of interest was counted and divided by the total number of libraries across all categories.
Percentage values of tissue-specific and disease- or condition-specific expression are reported in Table 3.
V. Extension of PIiSP Encoding Polynucleotides The full length nucleic acid sequences of SEQ ID N0:32-62 were produced by extension of an appropriate fragment ofthe 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, to initiate 3' extension of the known fragment. The initial primers were designed using OLIGO 4.06 software (National Biosciences), or another appropriate program, to be about 22 to 30 nucleotides in length, to have a GC content of about 50% or more, and to anneal to the target sequence at temperatures of about 68°C to about 72°C. Any stretch of nucleotides which would result in hairpin structures and primer-primer dimerizations was avoided.
Selected human cDNA libraries were used to extend the sequence. Ifmore than one extension was necessary or desired, additional or nested sets of primers were designed.
High fidelity amplification was obtained by PCR using methods well known in the art, pCR
was performed in 96-well plates using the PTC-200 thermal cycler (MJ Research, Inc.). The reaction mix contained DNA template, 200 nmol of each primer, reaction buffer containing Mgz+, (Nga)zS0<, and ~i-mercaptoethanol, Taq DNA polymerase (Amersham Phanmacia Biotech), ELONGASE enzyme (Life Technologies), and Pfu DNA polymerase (Stratagene), with the following parameters for primer pair PCI A and PCI B: Step 1: 94°C, 3 min; Step 2: 94°C, 15 sec;
Step 3: 60°C, 1 min; Step 4: 68 °C, 2 min; Step 5: Steps 2, 3, and 4 repeated 20 times; Step 6: 68 °C, 5 min; Step 7: storage at 4 °C. In the alternative, the parameters for primer pair T7 and SK+ were as follows: Step 1: 94 °C, 3 min; Step 2:
94°C, IS 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 pl PICOGREEN
quantitation reagent (0.25% (v/v) PICOGREEN; Molecular Probes, Eugene OR) dissolved in 1 X TE
and 0.5 ~.1 of undiluted PCR product into each well of an opaque fluorimeter plate (Corning Costar, Acton MA), allowing the DNA to bind to the reagent. The plate was scanned in a Fluoroskan II
(Labsystems Oy, Helsinki, Finland) to measure the fluorescence of the sample and to quantify the concentration of DNA. A 5 ,ul to 10 /cl aliquot of the reaction mixture was analyzed by electrophoresis on a 1 % agarose mini-gel to determine which reactions were successful in extending the sequence.

PCT/iJS99/17132 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 religation into pUC 18 vector (Amersham Pharmacia Biotech). For shotgun sequencing, the digested nucleotides were separated on low concentration (0.6 to 0.8%) agarose gels, fragments were excised, and agar digested with Agar ACE
(Promega). Extended clones were religated using T4 ligase (New England Biolabs, Beverly MA) into pUC I 8 vector (Amersham Pharmacia Biotech), treated with Pfu DNA polymerise (Stratagene) to fill-in restriction site overhangs, and transfected into competent E. cola cells. Transformed cells were selected on antibiotic containing media, 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 polymerise (Amersham Pharmacia Biotech) and Pfu DNA polymerise (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% dimethysulphoxide ( 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 (Perkin-Elmer).
In like manner, the nucleotide sequences of SEQ ID N0:32-62 are used to obtain 5' regulatory sequences using the procedure above, oligonucleotides designed for such extension, and an appropriate genomic library.
VI. Labeling snd Use of Individual Hybridization Probes Hybridization probes derived from SEQ ID N0:32-62 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 oIigomer, 250 /cCi of ('y 'ZP] 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 dextrin 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, Xbal, 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 I6 hours at 40°C. To remove nonspecific signals, blots are sequentially washed at room temperature under increasingly stringent conditions up to 0.1 x saline sodium citrate and 0.5% sodium dodecyl sulfate. Hybridization patterns are compared.
VII. Microarrays A chemical coupling procedure and an ink jet device can be used to synthesize array elements on the surface of a substrate. (See, e.g., Baldeschweiler, supra.) An array 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 by hand or using available methods and machines and contain any appropriate number of elements. After hybridization, nonhybridized probes are removed and a scanner used to determine the levels and patterns of fluorescence. The degree of complementarity and the relative abundance of each probe which hybridizes to an element on the microarray may be assessed through analysis of the scanned images.
Full-length cDNAs, Expressed Sequence Tags (ESTs), or fragments thereof may comprise the elements of the microarray. Fragments suitable for hybridization can be selected using software well known in the art such as LASERGENE software (DNASTAR). Full-length cDNAs, ESTs, or fragments thereof corresponding to one of the nucleotide sequences of the present invention, or selected at random from a cDNA library relevant to the present invention, are arranged on an appropriate substrate, e.g., a glass slide. The cDNA is fixed to the slide using, e.g., W cross-linking followed by thermal and chemical treatments and subsequent drying. (See, e.g., Schena, M. et al.
( 1995) Science 270:467-470; Shalon, D. et al. ( 1996) Genome Res. 6:639-645.) Fluorescent probes are prepared and used for hybridization to the elements on the substrate. The substrate is analyzed by procedures described above.
VIII. Complementary Polynucleotides Sequences complementary to the PHSP-encoding sequences, or any parts thereof, are used to detect, decrease, or inhibit expression of naturally occurring PHSP.
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 PHSP. To inhibit transcription, a complementary oligonucleotide is designed from the most unique S' 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 PHSP-encoding transcript.
IX. Expression of PIiSP
Expression and purification of PHSP is achieved using bacterial or virus-based expression systems. For expression of PHSP in bacteria, cDNA is subcloned into an appropriate vector containing an antibiotic resistance gene and an inducible promoter that directs high levels of cDNA
transcription. Examples of such promoters include, but are not limited to, the trp-lac (tac) hybrid promoter and the TS or T7 bacteriophage promoter in conjunction with the lac operator regulatory element. Recombinant vectors are transformed into suitable bacterial hosts, e.g., BL21(DE3).
Antibiotic resistant bacteria express PHSP upon induction with isopropyl beta-D-thiogalactopyranoside (IPTG). Expression of PHSP in eukaryotic cells is achieved by infecting insect or mammalian cell lines with recombinant AutoQraphica californica nuclear polyhedrosis virus (AcMNPV), commonly known as baculovirus. The nonessential polyhedrin gene of baculovirus is replaced with cDNA encoding PHSP 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 Suodontera frueinerda (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, PHSP 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 ianonicum, 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 PHSP at specifically engineered sites. FLAG, an 8-amino acid peptide, enables immunoaffmity 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 PHSP obtained by these methods can be used directly in the following activity assay.
X. Demonstration of PHSP Activity PHSP protein kinase is measured by the phosphorylation of a substrate in the presence of gamma-labeled'ZP-ATP. PHSP is incubated with an appropriate substrate and'ZP-ATP in a buffered solution. 'zP-labeled product is separated from free 'ZP-ATP by gel electrophoresis or chromatographic procedures, and the incorporated '2P is quantified by phosphorimage analysis or using a scintillation counter. The amount of'~P detected is proportional to the activity of PHSP in this assay. The specific amino acid residue phosphorylated by PHSP may be determined by _99_ phosphoamino acid analysis of the labeled, hydrolyzed protein.
PHSP phosphatase activity is measured by the removal of phosphate from a ['ZP]-labelled substrate. PHSP is incubated with an appropriate ['zP]-labelled substrate in a buffered solution.
Reaction products are separated by gel electrophoresis or chromatographic procedures, and the level of'zP associated with the substrate molecule is quantified by phospho-image analysis or scintillation counting. The difference in'ZP associated with untreated substrate versus PHSP-treated substrate is a measure of phosphatase activity and is proportional to PHSP activity.
XI. Functional Assays PHSP function is assessed by expressing the sequences encoding PHSP 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 ug of recombinant vector are transiently transfected into a human cell line, preferably of endothelial or hematopoietic origin, using either liposome l5 formulations or electroporation. 1-2 ~g of an additional plasmid containing sequences encoding a marker protein are co-transfected. Expression of a marker protein provides a means to distinguish transfected cells from nontransfected cells and is a reliable predictor of cDNA expression from the recombinant vector. Marker proteins of choice include, e.g., Green Fluorescent Protein (GFP;
Clontech), CD64, or a CD64-GFP fusion protein. Flow cytometry (FCM), an automated, laser optics-based technique, is used to identify transfected cells expressing GFP or CD64-GFP and to evaluate properties, for example, their apoptotic state. 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 Cytometrv, Oxford, New York NY.
The influence of PHSP on gene expression can be assessed using highly purified populations of cells transfected with sequences encoding PHSP 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 ofmRNA encoding PHSP and other genes of interest can be analyzed by northern analysis or microarray techniques.
XII. Production of PFISP Specific Antibodies PHSP 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 PHSP 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 15 residues in length are synthesized using an ABI
431A peptide synthesizer (Perkin-Elmer) 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 activity by, for example, binding the peptide to plastic, blocking with 1% BSA, reacting with rabbit antisera, washing, and reacting with radio-iodinated goat anti-rabbit IgG.
XIli. Purification of Naturally Occurring PHSP Using Specific Antibodies Naturally occurnng or recombinant PHSP is substantially purified by immunoaffmity chromatography using antibodies specific for PHSP. An immunoaffinity column is constructed by covalently coupling anti-PHSP 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 PHSP are passed over the immunoaffinity column, and the column is washed under conditions that allow the preferential absorbance of PHSP (e.g., high ionic strength buffers in the presence of detergent). The column is eluted under conditions that disrupt antibody/PHSP 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 PHSP is collected.
XIV. Identification of Molecules Which Interact with PIiSP
PHSP, or biologically active fragments thereof, are labeled with 'ZSI Bolton-Hunter reagent.
(See, e.g., Bolton et al. ( 1973) Biochem. J. 133:529.) Candidate molecules previously arrayed in the wells of a multi-well plate are incubated with the labeled PHSP, washed, and any wells with labeled PHSP complex are assayed. Data obtained using different concentrations of PHSP
are used to calculate values for the number, affinity, and association of PHSP with the candidate molecules.

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 ofthe invention.
Although the invention has been described in connection with specific preferred 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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SEQUENCE LISTING
<110> INYCTE PHARMACEUTICALS, INC.
HILLMAN, Jennifer L.
T-nr~, Preeti TANG, Y. Tom CORLEY, Neil C.
GUEGLER, Karl J.
BAUGHN, Mariah R.
PATTERSON, Chandra BANDMAN, Olga AU-YOUNG, Janice GORGONE, Gina A.
YUE, Henry AZIMZAI, Yalda REDDY, Roopa LU, Dyung Aina M.
SHIH, Leo L.
<120> PHOSPHORYLATION EFFECTORS
<130> PF-0565 PCT
<140> To Be Assigned <141> Herewith <150> 09/123,494; unassigned; 09/152,814; unassigned; 09/173,482;
unassigned;60/106,889; 60/109,093; 60/113,796;
<151> 1998-07-28; 1998-07-28; 1998-09-14; 1998-09-14; 1998-10-14;
1998-10-14;1998-11-03; 1998-ll-19; 1998-12-22 <160> 61 <170> PERL Program <210> 1 <211> 300 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 132240 <400> 1 Met Glu Ser Pro Leu Glu Ser Gln Pro Leu Asp Ser Asp Arg Ser Ile Lys Glu Ser Ser Phe Glu Glu Ser Asn Ile Glu Asp Pro Leu Ile Val Thr Pro Asp Cys Gln Glu Lys Thr Ser Pro Lys Gly Val Glu Asn Pro Ala Val Gln Glu Ser Asn Gln Lys Met Leu Gly Pro Pro Leu Glu Val Leu Lys Thr Leu Ala Ser Lys Arg Asn Ala Val 1/f~

Ala Phe Arg Ser Phe Asn Ser His Ile Asn Ala Ser Asn Asn Ser Glu Pro Ser Arg Met Asn Met Thr Ser Leu Asp Ala Met Asp Ile Ser Cys Ala Tyr Ser Gly Ser Tyr Pro Met Ala Ile Thr Pro Thr Gln Lys Arg Arg Ser Cys Met Pro His Gln Thr Pro Asn Gln Ile Lys Ser Gly Thr Pro Tyr Arg Thr Pro Lys Ser Val Arg Arg Gly Val Ala Pro Val Asp Asp Gly Arg Ile Leu Gly Thr Pro Asp Tyr Leu Ala Pro Glu Leu Leu Leu Gly Arg Ala His Gly Pro Ala Val Asp Txp Trp Ala Leu Gly Val Cys Leu Phe Glu Phe Leu Thr Gly Ile Pro Pro Phe Asn Asp Glu Thr Pro Gln Gln Val Phe Gln Asn Ile Leu Lys Arg Asp Ile Pro Tzp Pro Glu Gly Glu Glu Lys Leu Ser Asp Asn Ala Gln Ser Ala Val Glu Ile Leu Leu Thr Ile Asp Asp Thr Lys Arg. Ala Gly Met Lys Glu Leu Lys Arg His Pro Leu Phe Ser Asp Val Asp Trp Glu Asn Leu Gln His Gln Thr Met Pro Phe Ile Pro Gln Pro Asp Asp Glu Thr Asp Thr Ser Tyr Phe Glu Ala Arg Asn Thr Ala Gln His Leu Thr Val Ser Gly Phe Ser Leu <210> 2 <211> 147 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 2180116 <400> 2 Met Ala Ala Gln Arg Leu Gly Lys Arg Val Leu Ser Lys Leu Gln Ser Pro Ser Arg Ala Arg Gly Pro Gly Gly Ser Pro Gly Gly Met Gln Lys Arg His Ala Arg Val Thr Val Lys Tyr Asp Arg Arg Glu Leu Gln Arg Arg Leu Asp Val Glu Lys Trp Ile Asp Gly Arg Leu Glu Glu Leu Tyr Arg Gly Met Glu AIa Asp Met Pro Asp Glu Ile Asn Ile Asp Glu Leu Leu Glu Leu Glu Ser Glu Glu Glu Arg Ser Arg Lys Ile Gln Gly Leu Leu Lys Ser Cys Gly Lys Pro Val Glu Asp Phe Ile Gln Glu Leu Leu Ala Lys Leu Gln Gly Leu His Arg Gln Pro Gly Leu Arg Gln Pro Ser Pro Ser His Asp Gly Ser Leu Ser Pro Leu Gln Asp Arg Ala Arg Thr Ala His Pro <2I0> 3 <211> 431 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 2197671 <400> 3 Met Ala His Ser Pro Val Gln Ser Gly Leu Pro Gly Met Gln Asn Leu Lys Ala Asp Pro Glu Glu Leu Phe Thr Lys Leu Glu Lys Ile Gly Lys Gly Ser Phe Gly Glu Val Phe Lys Gly Ile Asp Asn Arg Thr Gln Lys Val Val Ala Ile Lys Ile Ile Asp Leu Glu Glu Ala Glu Asp Glu Ile Glu Asp Ile Gln Gln Glu Ile Thr Val Leu Ser 65 7p Gln Cys Asp Ser Pro Tyr Val Thr Lys Tyr Tyr Gly Ser Tyr Leu Lys Asp Thr Lys Leu Trp Ile Ile Met Glu Tyr Leu Gly Gly Gly Ser Ala Leu Asp Leu Leu Glu Pro Gly Arg Leu Asp Glu Thr Gln Ile Ala Thr Ile Leu Arg Glu Ile Leu Lys Gly Leu Asp Tyr Leu His Ser Glu Lys Lys Ile His Arg Asp Ile Lys Ala Ala Asn Val Leu Leu Ser Glu His Gly Glu Val Lys Leu Ala Asp Phe Gly Val Ala Gly Gln Leu Thr Asp Thr Gln Ile Lys Arg Asn Thr Phe Val Gly Thr Pro Phe Trp Met Ala Pro Glu Val Ile Lys Gln Ser Ala Tyr Asp Ser Lys Ala Asp Ile Trp Ser Leu Gly Ile Thr Ala Ile Glu Leu Ala Arg Gly Glu Pro Pro His Ser Glu Leu His Pro Met Lys Val Leu Phe Leu Ile Pro Lys Asn Asn Pro Pro Thr Leu Glu Gly Asn Tyr Ser Lys Pro Leu Lys Glu Phe Val Glu Ala Cys Leu Asn Lys Glu Pro Ser Phe Arg Pro Thr Ala Lys Glu Leu Leu Lys His Lys Phe Ile Leu Arg Asn Ala Lys Lys Thr Ser Tyr Leu Thr Glu Leu Ile Asp Arg Tyr Lys Arg Trp Lys Ala Glu Gln Ser His Asp Asp Ser Ser Ser Glu Asp Ser Asp Ala Glu Thr Asp Gly Gln Ala Ser Gly Gly Ser Asp Ser Gly Asp Trp Ile Phe Thr Ile Arg Glu Lys Asp Pro Lys Asn Leu Glu Asn Gly Ala Leu Gln Pro Ser Asp Leu Asp Arg Asn Lys Met Lys Asp Ile Pro Lys Arg Pro Phe Ser Gln Cys Leu Ser Thr Ile Ile Ser Pro Leu Phe Ala Glu Leu Lys Glu Lys Ser Gln Ala Cys Gly Gly Asn Leu Gly Ser Ile Glu Glu Leu Arg Gly Ala Ile Tyr Leu Ala Glu Glu Ala 390 395 ~'Ys Pro Gly IIe Ser Asp Thr Met Val Ala Gln Leu VaI Gln Arg Leu Gln Arg Tyr Ser Leu Sex Gly Gly Gly Thr Ser Ser His <210> 4 <211> 218 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 2594943 <400> 4 Met Asn Cys Arg Ser Glu Val Leu Glu Val Ser Val Glu Gly Arg Gln Val Glu Glu Ala Met Leu Ala Val Leu His Thr Val Leu Leu His Arg Ser Thr Gly Lys Phe His Tyr Lys Lys Glu Gly Thr Tyr Ser Ile Gly Thr Val Gly Thr Gln Asp Val Asp Cys Asp Phe Ile Asp Phe Thr Tyr Val Arg Val Ser Ser Glu Glu Leu Asp Arg Ala Leu Arg Lys Val Val Gly Glu Phe Lys Asp Ala Leu Arg Asn Ser Gly Gly Asp Gly Leu Gly Gln Met Ser Leu Glu Phe Tyr Gln Lys Lys Lys Ser Arg Trp Pro Phe Ser Asp Glu Cys Ile Pro Trp Glu Val Trp Thr Val Lys Val His Val Val Ala Leu Ala Thr G1u Gln Glu Arg Gln Ile Cys Arg Glu Lys Val Gly Glu Lys Leu Cys Glu Lys Ile Ile Asn Ile Val Glu Val Met Asn Arg His Glu Tyr Leu Pro Lys Met Pro Thr Gln Ser Glu Val Asp Asn Val Phe Asp Thr Gly Leu Arg Asp Val Gln Pro Tyr Leu Tyr Lys Ile Ser Phe- Gln Ile Thr Asp Ala Leu Gly Thr Ser Val Thr Thr Thr Met Arg Arg Leu Ile Lys Asp Thr Leu Ala Leu <210> S
<211> 474 <212> pKT
<213> Homo sapiens <220>
<221> misc feature <223> Incyte Clone Number: 1513871 <400> 5 Met Ile Met Asn Lys Met Lys Asn Phe Lys Arg Arg Phe Ser Leu Ser Val Pro Arg Thr Glu Thr Ile Glu Glu Ser Leu Ala Glu Phe Thr Glu Gln Phe Asn Gln Leu His Asn Arg Arg Asn Glu Asn Leu Gln Leu Gly Pro Leu Gly Arg Asp pro Pro Gln Glu Cys Ser Thr Phe Ser Pro Thr Asp Ser Gly Glu Glu Pro Gly Gln Leu Ser Pro Gly Val Gln Phe Gln Arg Arg Gln Asn Gln Arg Arg Phe Ser Met Glu Asp Val Ser Lys Arg Leu Ser Leu Pro Met Asp Ile Arg Leu Pro Gln Glu Phe Leu Gln Lys Leu Gln Met Glu Ser Pro Asp Leu Pro Lys Pro Leu Ser Arg Met Ser Arg Arg Ala Ser Leu Ser Asp IIe Gly Phe Gly Lys Leu Glu Thr Tyr Val Lys Leu Asp Lys Leu Gly Glu Gly Thr Tyr Ala Thr Val Phe Lys Gly Arg Ser Lys Leu Thr Glu Asn Leu Val Ala Leu Lys Glu Ile Arg Leu Glu His Glu Glu Gly Ala Pro Cys Thr Ala Ile Arg Glu Val Ser Leu Leu Lys Asn Leu Lys His Ala Asn Ile Val Thr Leu His Asp Leu Ile His Thr Asp Arg Ser Leu Thr Leu Val Phe Glu Tyr Leu Asp Ser Asp Leu Lys Gln Tyr Leu Asp His Cys Gly Asn Leu Met Ser Met His Asn Val Lys Ile Phe Met Phe Gln Leu Leu Arg Gly Leu Ala Tyr Cys His His Arg Lys Ile Leu His Arg Asp Leu Lys Pro Gln Asn Leu Leu Ile Asn Glu Arg Gly Glu Leu Lys Leu Ala Asp Phe Gly Leu Ala Arg Ala Lys Ser Val Pro Thr Lys Thr Tyr Ser Asn Glu Val Val Thr Leu Trp Tyr Arg Pro Pro Asp Val Leu Leu Gly Ser Thr Glu Tyr Ser Thr Pro Ile Asp Met Trp Gly Val Gly Cys Ile His Tyr Glu Met Ala Thr Gly Arg Pro Leu Phe Pro Gly Ser Thr Val Lys Glu Glu Leu His Leu Ile Phe Arg Leu Leu Gly Thr Pro Thr Glu Glu Thr Trp Pro Gly Val Thr Ala Phe Ser Glu Phe Arg Thr Tyr Ser Phe Pro Cys Tyr Leu Pro Gln Pro Leu Ile Asn His Ala Pro Arg Leu Asp Thr Asp Gly Ile His Leu Leu Ser Ser Leu Leu Leu Tyr Glu Ser Lys Ser Arg Met Ser Ala Glu Ala Ala Leu Ser His Ser Tyr Phe Arg Ser Leu Gly Glu Arg Val His Gln Leu Glu Asp Thr Ala Ser Ile Phe Ser Leu Lys Glu Ile Gln Leu Gln Lys Asp Pro Gly Tyr Arg Gly Leu Ala Phe Gln Gln Pro Gly Arg Gly Lys Asn Arg Arg Gln Ser Ile Phe <210> 6 <211> 540 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 156108 <400> 6 Met Asn Gly Glu Ala Ile Cys Ser Ala Leu Pro Thr Ile Pro Tyr His Lys Leu Ala Asp Leu Arg Tyr Leu Ser Arg Gly Ala Ser Gly Thr Val Ser Ser Ala Arg His Ala Asp Txp Arg Val Gln Val Ala Val Lys His Leu His Ile His Thr Pro Leu Leu Asp Ser Glu Arg Lys Asp Val Leu Arg Glu Ala Glu Ile Leu His Lys Ala Arg Phe Ser Tyr Ile Leu Pro Ile Leu Gly Ile Cys Asn Glu Pro Glu Phe Leu Gly Ile Val Thr Glu Tyr Met Pro Asn Gly Ser Leu Asn Glu Leu Leu His Arg Lys Thr Glu Tyr Pro Asp Val Ala Trp Pro Leu Arg Phe Arg Ile Leu His Glu Ile Ala Leu Gly Val Asn Tyr Leu His Asn Met Thr Pro Pro Leu Leu His His Asp Leu Lys Thr Gln Asn Ile Leu Leu Asp Asn Glu Phe His Val Lys Ile Ala Asp Phe Gly Leu Ser Lys Trp Arg Met Met Ser Leu Ser Gln Ser Arg Ser Ser Lys Ser Ala Pro Glu Gly Gly Thr Ile Ile Tyr Met Pro Pro Glu Asn Tyr Glu Pro Gly Gln Lys Ser Arg Ala Ser Ile Lys His Asp Ile Tyr Ser Tyr Ala Val Ile Thr Trp Glu Val Leu Ser Arg Lys Gln Pro Phe Glu Asp Val Thr Asn Pro Leu Gln Ile Met Tyr Ser Val Ser Gln Gly His Arg Pro Val Ile Asn Glu Glu Ser Leu Pro Tyr Asp Ile Pro His Arg Ala Arg Met Ile Ser Leu Ile Glu Ser Gly Trp Ala Gln Asn Pro Asp Glu Arg Pro Ser Phe Leu Lys Cys Leu Ile Glu Leu Glu Pro Val Leu Arg Thr Phe Glu Glu Ile Thr Phe Leu Glu Ala Val Ile Gln Leu Lys Lys Thr Lys Leu Gln Ser Val Ser Ser Ala Ile His Leu Cys Asp Lys Lys Lys Met Glu Leu Ser Leu Asn Ile Pro Val Asn His Gly Pro Gln Glu Glu Ser Cys Gly Ser Ser Gln Leu His Glu Asn Ser Gly Ser Pro Glu Thr Ser Arg Ser Leu Pro Ala Pro Gln Asp Asn Asp Phe Leu Ser Arg Lys Ala Gln Asp Cys Tyr Phe Met Lys Leu His His Cys Pro Gly Asn His Ser Trp Asp Ser Thr Ile Ser Gly Ser Gln Arg Ala Ala Phe Cys Asp His Lys Thr Thr Pro Cys Ser Ser Ala Ile Ile Asn Pro Leu Ser Thr Ala Gly Asn Ser G1u Arg Leu Gln Pro Gly Ile Ala Gln Gln Trp Ile Gln Ser Lys Arg Glu Asp Ile Val Asn Gln Met Thr Glu Ala Cys Leu Asn Gln Ser Leu Asp Ala Leu Leu Ser Arg Asp Leu Ile Met Lys Glu Asp Tyr Glu Leu Val Ser Thr Lys Pro Thr Arg Thr Ser Lys Val Arg Gln Leu Leu Asp Thr Thr Asp Ile Gln Gly Glu Glu Phe Ala Lys Val Ile Val Gln Lye Leu Lys Asp Asn Lys Gln Met GIy Leu Gln Pro Tyr Pro Glu Ile Leu Val Val Ser Arg Ser Pro Ser Leu Asn Leu Leu Gln Asn Lys Ser Met <210> 7 <211> 454 <212> PRT
<213> Homo sapiens <220>
<221> misc_~feature <223> Incyte Clone Number: 2883243 <400> 7 Met Tyr Asn Thr Val Trp Asn Met Glu Asp Leu Asp Leu Glu Tyr Ala Lys Thr Asp Ile Asn Cya Gly Thr Asp Leu Met Phe Tyr Ile Glu Met Asp Pro Pro Ala Leu Pro Pro Lys Pro Pro Lys Pro Thr Thr Val Ala Asn Asn Gly Met Aan Asn Asn Met Ser Leu Gln Asp Ala Glu Trp Tyr Trp Gly Asp Ile Ser Arg Glu Glu Val Asn Glu Lys Leu Arg Asp Thr Ala Asp Gly Thr Phe Leu Val Arg Asp Ala Ser Thr Lys Met His Gly Asp Tyr Thr Leu Thr Leu Arg Lys Gly Gly Asn Asn Lys Leu Ile Lys Ile Phe His Arg Asp Gly Lys Tyr Gly Phe Ser Asp Pro Leu Thr Phe Ser Ser Val Val Glu Leu Ile Asn His Tyr Arg Asn Glu Ser Leu Ala Gln Tyr Asn Pro Lys Leu Asp Val Lys Leu Leu Tyr Pro Val Ser Lys Tyr Gln Gln Asp Gln Val Val Lys Glu Asp Asn Ile Glu Ala Val Gly Lys Lys Leu His Glu Tyr Asn Thr Gln Phe Gln Glu Lys Ser Arg Glu Tyr Asp Arg Leu Tyr Glu Glu Tyr Thr Arg Thr Ser Gln Glu Ile Gln Met Lys Arg Thr Ala Ile Glu Ala Phe Aan Glu Thr Ile Lys Ile Phe Glu _ 215 220 225 Glu Gln Cys Gln Thr Gln Glu Arg Tyr Ser Lys Glu Tyr Ile Glu Lys Phe Lys Arg Glu Gly Asn Glu Lys Glu Ile Gln Arg Ile Met His Asn Tyr Asp Lys Leu Lys Ser Arg Ile Ser Glu Ile Ile Asp Ser Arg Arg Arg Leu Glu Glu Asp Leu Lys Lys Gln Ala Ala Glu Tyr Arg Glu Ile Asp Lys Arg Met Asn Ser Ile Lys Pro Asp Leu Ile Gln Leu Arg Lys Thr Arg Asp Gln Tyr Leu Met Trp Leu Thr Gln Lys Gly Val Arg Gln Lys Lys Leu Asn Glu Trp Leu Gly Asn Glu Asn Thr Glu Asp Gln Tyr Ser Leu Val Glu Asp Asp Glu Asp Leu Pro His His Asp Glu Lys Thr Trp Asn Val Gly Ser Ser Asn Arg Asn Lys Ala Glu Asn Leu Leu Arg Gly Lys Arg Asp Gly Thr Phe Leu Val Arg Glu Ser Ser Lys Gln Gly Cys Tyr Ala Cys Ser Val Val Val Asp Gly Glu Val Lys His Cys Val Ile Asn Lys Thr Ala Thr Gly Tyr Gly Phe Ala Glu Pro Tyr Asn Leu Tyr Ser Ser Leu Lys Glu Leu Val Leu His Tyr Gln His Thr Ser Leu Val Gln His Asn Asp Ser Leu Asn Val Thr Leu Ala Tyr Pro Val Tyr Ala Gln Gln Arg Arg <210> 8 <211> 502 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 3173355 <400> 8 Met Phe Gly Thr Leu Leu Leu Tyr Cys Phe Phe Leu Ala Thr Val Pro Ala Leu Ala Glu Thr Gly Gly Glu Arg Gln Leu Ser Pro Glu Lys Ser Glu Ile Trp Gly Pro Gly Leu Lys Ala Asp Val Val Leu Pro Ala Arg Tyr Phe Tyr Ile Gln Ala Val Asp Thr Ser Gly Asn Lys Phe Thr Ser Ser Pro Gly Glu Lys Val Phe Gln Val Lys Val Ser Ala Pro Glu Glu Gln Phe Thr Arg Val Gly Val Gln Val Leu Asp Arg Lys Asp Gly Ser Phe Ile Val Arg Tyr Arg Met Tyr Ala Ser Tyr Lys Asn Leu Lys Val Glu Ile Lys Phe Gln Gly Gln His Val Ala Lys Ser Pro Tyr Ile Leu Lys Gly Pro Val Tyr His Glu Aen Cys Asp Cys Pro Leu Gln Asp Ser Ala Ala Trp Leu Arg Glu Met Asn Cys Pro Glu Thr Ile Ala Gln Ile Gln Arg Asp Leu Ala His Phe Pro Ala Val Asp Pro Glu Lys Ile Ala Val Glu Ile Pro Lys Arg Phe Gly Gln Arg Gln Ser Leu Cys His Tyr Thr Leu Lys Asp Asn Lys Val Tyr Ile Lys Thr His Gly Glu His Val Gly Phe Arg Ile Phe Met Asp Ala Ile Leu Leu Ser Leu Thr Arg Lys Val I

Lys Met Pro Asp Val Glu Leu Phe Val Asn Leu Gly Asp Trp Pro Leu Glu Lys Lys Lys Ser Asn Ser Asn Ile His Pro Ile Phe Ser Trp Cys Gly Ser Thr Asp Ser Lys Asp Ile Val Met Pro Thr Tyr Asp Leu Thr Asp Ser Val Leu Glu Thr Met Gly Arg Val Ser Leu Asp Met Met Ser Val Gln Ala Asn Thr Gly Pro Pro Trp Glu Ser Lys Asn Ser Thr Ala Val Trp Arg Gly Arg Asp Ser Arg Lys Glu Arg Leu Glu Leu Val Lys Leu Ser Arg Lys His Pro Glu Leu Ile Asp Ala Ala Phe Thr Asn Phe Phe Phe Phe Lys His Asp Glu.Asn Leu Tyr Gly Pro Ile Val Lys His Ile Ser Phe Phe Asp Phe Phe Lys His Lys Tyr Gln Ile Asn Ile Asp Gly Thr Val Ala Ala Tyr Arg Leu Pro Tyr Leu Leu Val Gly Asp Ser Val Val Leu Lye Gln Asp Ser Ile Tyr Tyr Glu His Phe Tyr Asn Glu Leu Gln Pro Trp Lys His Tyr Ile Pro Val Lys Ser Asn Leu Ser Asp Leu Leu Glu Lys Leu Lys Trp Ala Lys Asp His Asp Glu Glu Ala Lys Lys Ile Ala Lys Ala Gly Gln Glu Phe Ala Arg Asn Asn Leu Met Gly Asp Asp Ile Phe Cys Tyr Tyr Phe Lys Leu Phe Gln Glu Tyr Ala Asn Leu Gln Val Ser Glu Pro Gln Ile Arg Glu Gly Met Lys Arg Val Glu Pro Gln Thr Glu Asp Asp Leu Phe Pro Cys Thr Cys His Arg Lys Lys Thr Lys Asp Glu Leu <210> 9 <211> 282 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 5116906 <400> 9 Met Trp Ala Cys Gly Val Ile Leu Tyr Ile Leu Leu Val Gly Tyr Pro Pro Phe Trp Asp Glu Asp Gln His Arg 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 Asp Leu Ile Asn Lys Met Leu Thr Ile Asn Pro Ala Lys Arg Ile Thr Ala Ser Glu Ala Leu Lys His Pro Trp Ile Cys Gln Arg Ser Thr Val Ala Ser Met Met His Arg Gln Glu Thr Val Asp Cys Leu Lys Lys Phe Asn Ala Arg Arg Lys Leu Lys Gly Ala Ile Leu Thr Thr Met Leu Ala Thr Arg Asn Phe Ser Ala Ala Lys Ser Leu Leu Lys Lys Pro Asp Gly Val Lys Glu Ser Thr Glu Ser Ser Asn Thr Thr Ile Glu Asp Glu Asp Val Lys Ala Arg Lys Gln Glu Ile Ile Lys Val Thr Glu Gln Leu Ile Glu Ala Ile Asn Asn Gly Asp Phe Glu Ala Tyr Thr Lys Ile Cys Asp Pro Gly Leu Thr Ala Phe Glu Pro Glu Ala Leu Gly Asn Leu Val Glu Gly Met Asp Phe His Arg Phe Tyr Phe Glu Asn Ala Leu Ser Lys Ser Asn Lys Pro Ile His Thr Ile Ile Leu Asn Pro His Val His Leu Val Gly Asp Asp Ala Ala Cys Ile Ala Tyr Ile Arg Leu Thr Gln Tyr Met Asp Gly Ser Gly Met Pro Lys Thr Met Gln 5er Glu Glu Thr Arg Val Trp His Arg Arg Asp Gly Lys Trp Gln Asn Val His Phe His Arg Ser Gly Ser Pro Thr Val Pro Ile Asn <210> 10 <211> 510 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 940589 <400> 10 Met Lys Ala Asp Ile Lys Ile Trp Ile Leu Thr Gly Asp Lys Gln Glu Thr Ala Ile Asn Ile Gly His Ser Cys Lys Leu Leu Lys Lys Asn Met Gly Met Ile Val Ile Asn Glu Gly Ser Leu Asp Ser Phe Ser Asn Thr Gln Asn Ser Arg Lys Glu Ala Val Leu Leu Ala Lys Met Lys His Pro Asn Ile Val Ala Phe Lys Glu Ser Phe Glu Ala Glu Gly His Leu Tyr Ile Val Met Glu Tyr Cys Asp Gly Gly Asp Leu Met Gln Lys Ile Lys Gln Gln Lys Gly Lys Leu Phe Pro Glu Asp Met Ile Leu Asn Trp Phe Thr Gln Met Cys Leu Gly Val Asn His Ile His Lys Lys Arg Val Leu His Arg Asp Ile Lys Ser Lys Asn Ile Phe Leu Thr Gln Asn Gly Lys Val Lys Leu Gly Asp Phe Gly Ser Ala Arg Leu Leu Ser Asn Pro Met Ala Phe Ala Cys Thr Tyr Val Gly Thr Pro Tyr Tyr Val Pro Pro Glu Ile Trp Glu Asn Leu Pro Tyr Asn Asn Lys Ser Asp Ile Trp Ser Leu Gly Cys Ile Leu Tyr Glu Leu Cys Thr Leu Lys His Pro Phe Gln Ala Asn Ser Trp Lys Asn Leu Ile Leu Lys Val Cys Gln Gly Cys Ile Ser Pro Leu Pro Ser His Tyr Ser Tyr Glu Leu Gln Phe Leu Val Lys Gln Met Phe Lys Arg Asn Pro Ser His Arg Pro Ser Ala Thr Thr Leu Leu Ser Arg Gly Ile Val Ala Arg Leu Val Gln Lys Cys Leu Pro Pro Glu Ile Ile Met Glu Tyr Gly Glu Glu Val Leu Glu Glu Ile Lys Asn Ser Lys His Asn Thr Pro Arg Lys Lys Thr Asn Pro Ser Arg Ile Arg Ile Ala Leu Gly Asn Glu Ala Ser Thr Val Gln Glu Glu Glu Gln Asp Arg Lys Gly Ser His Thr Asp Leu Glu Ser Ile Asn Glu Asn Leu Val Glu Ser Ala Leu Arg Arg Val Asn Arg Glu Glu Lys Gly Asn Lys Ser Val Hia Leu Arg Lys Ala Ser Ser Pro Asn Leu His Arg Arg Gln Trp Glu Lys Asn Val Pro Asn Thr Ala Leu Thr Ala Leu Glu Asn Ala Ser Ile Leu Thr Ser Ser Leu Thr Ala Glu Asp Asp Arg Gly Gly Ser Val Ile Lys Tyr Ser Lys Asn Thr Thr Arg Lys Gln Trp Leu Lys Glu Thr Pro Asp Thr Leu Leu Asn Ile Leu Lys Asn Ala Asp Leu Ser Leu Ala Phe Gln Thr Tyr Thr Ile Tyr Arg Pro Gly Ser Glu Gly Phe Leu Lys Gly Pro Leu Ser Glu Glu Thr Glu Ala Ser Asp Ser Val Asp Gly Gly His Asp Ser Val Ile Leu Asp Pro Glu Arg Leu Glu Pro Gly Leu Asp Glu Glu Asp Thr Asp Phe Glu Glu Glu Asp Asp Asn Pro Asp Trp Val Ser Glu Leu Lys Lys Arg Ala Gly Trp Gln Gly Leu Cys Asp Arg <210> 11 <211> 248 <212> PRT
<2I3> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 304421 <400> 11 Met Ala Glu Thr Ser Leu Pro Glu Leu Gly Gly Glu Asp Lys Ala Thr Pro Cys Pro Ser Ile Leu Glu Leu Glu Glu Leu Leu Arg Ala Gly Lys Ser Ser Cys Ser Arg Val Asp Glu Val Trp Pro Asn Leu Phe Ile Gly Asp Ala Met Asp Ser Leu Gln Lys Gln Asp Leu Arg Arg Pro Lys Ile His Gly Ala Val Gln Ala Ser Pro Tyr Gln Pro Pro Thr Leu Ala Ser Leu Gln Arg Leu Leu Trp Val Arg Gln Ala Ala Thr Leu Asn His Ile Asp Glu Val Trp Pro Ser Leu Phe Leu Gly Asp Ala Tyr Ala Ala Arg Asp Lys Ser Lys Leu Ile Gln Leu Gly Ile Thr His Val Val Asn Ala Ala Ala Gly Lys Phe Gln Val Asp Thr Gly Ala Lys Phe Tyr Arg Gly Met Ser Leu Glu Tyr Tyr Gly Ile Glu Ala Asp Asp Asn Pro Phe Phe Asp Leu Ser Val Tyr Phe Leu Pro Val Ala Arg Tyr Ile Arg Ala Ala Leu Ser Val Pro Gln Gly Arg Val Leu Val His Cys Ala Met Gly Val Ser Arg Ser Ala Thr Leu Val Leu Ala Phe Leu Met Ile Tyr Glu Asn Met Thr Leu Val Glu Ala Ile Gln Thr Val Gln Ala His Arg Asn Ile Cys Pro Asn Ser Gly Phe Leu Arg Gln Leu Gln Val Leu Asp Asn Arg Leu Gly Arg Glu Thr Gly Arg Phe <210> 12 <211> 810 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 1213802 i <400> 12 Met Pro Asn Gln Gly Glu Asp Cys Tyr Phe Phe Phe Tyr Ser Thr Cys Thr Lys Gly Asp Ser Cys Pro Phe Arg His Cys Glu Ala Ala Ile Gly Asn Glu Thr Val Cys Thr Leu Trp Gln Glu Gly Arg Cys Phe Arg Gln Val Cys Arg Phe Arg His Met Glu Ile Asp Lye Lys Arg Ser Glu Ile Pro Cys Tyr Trp Glu Asn Gln Pro Thr Gly Cys Gln Lys Leu Asn Cys Ala Phe His His Asn Arg Gly Arg Tyr Val Asp Gly Leu Phe Leu Pro Pro Ser Lys Thr Val Leu Pro Thr Val Pro Glu Ser Pro Glu Glu Glu Val Lys Ala Ser Gln Leu Ser Val Gln Gln Asn Lys Leu Ser Val Gln Ser Asn Pro Ser Pro Gln Leu Arg Ser Val Met Lys Val Glu Ser Ser Glu Asn Val Pro Ser Pro Thr His Pro Pro Val Val Ile Asn Ala Ala Asp Asp Asp Glu Asp Asp Asp Asp Gln Phe Ser Glu Glu Gly Asp Glu Thr Lys Thr Pro Thr Leu Gln Pro Thr Pro Glu Val His Asn Gly Leu Arg Val Thr Ser Val Arg Lys Pro Ala Val Asn Ile Lys Gln Gly Glu Cys Leu Asn Phe Gly Ile Lys Thr Leu Glu Glu Ile Lys Ser Lys Lys Met Lys Glu Lys Ser Lys Lys Gln Gly Glu Gly Ser Ser Gly Val Ser 8er Leu Leu Leu His Pro Glu Pro Val Pro Gly Pro Glu Lys Glu Asn Val Arg Thr Val Val Arg Thr Val Thr Leu Ser Thr Lys Gln Gly Glu Glu Pro Leu Val Arg Leu Ser Leu Thr Glu Arg Leu Gly Lys Arg Lys Phe Ser Ala Gly Gly Asp Ser Asp Pro Pro Leu Lys Arg Ser Leu Ala Gln Arg Leu Gly Lys Lys Val.Glu Ala Pro Glu Thr Asn Ile Asp Lys Thr Pro Lys Lys Ala Gln Val Ser Lys Ser Leu Lys Glu Arg Leu Gly Met Ser Ala Asp Pro Asp Asn Glu Asp Ala Thr Asp Lys Val Asn Lys Val Gly Glu Ile His Val Lys Thr Leu Glu Glu Ile Leu Leu Glu Arg Ala Ser Gln Lys Arg Gly Glu Leu Gln Thr Lys Leu Lys Thr Glu Gly Pro Ser Lys Thr Asp Asp Ser Thr Ser Gly Ala Arg Ser Ser Ser Thr Ile Arg Ile Lys Thr Phe Ser Glu Val Leu Ala Glu Lys Lys His Arg Gln Gln Glu Ala Glu Arg GIn Lys Ser Lys Lys Asp Thr Thr Cys Ile Lys Leu Lys Ile Asp Ser Glu Ile Lys Lys Thr Val Val Leu Pro Pro Ile Val Ala Ser Arg Gly Gln Ser Glu Glu Pro Ala Gly Lys Thr Lys Ser Met Gln Glu Val His Ile Lys Thr Leu Glu Glu Ile Lys Leu Glu Lys Ala Leu Arg Val Gln Gln Ser Ser Glu Ser Ser Thr Ser Ser Pro Ser Gln His Glu Ala Thr Pro Gly Ala Arg Arg Leu Leu Arg Ile Thr Lys Arg Thr Gly Met Lys Glu Glu Lys Asn Leu Gln Glu Gly Asn Glu Val Asp Ser Gln Ser Ser Ile Arg Thr Glu Ala Lys Glu Ala Ser Gly Glu Thr Thr Gly Val Asp Ile Thr Lys Ile Gln Val Lys Arg Cys Glu Thr Met Arg Glu Lys His Met Gln Lys Gln Gln Glu Arg Glu Lys Ser Val Leu Thr Pro Leu Arg Gly Asp Val Ala Ser Cys Asn Thr Gln Val Ala Glu Lys Pro Val Leu Thr Ala Val Pro Gly Ile Thr Arg His Leu Thr Lys Arg Leu Pro Thr Lys Ser Ser Gln Lys Val Glu Val Glu Thr Ser Gly Ile Gly Asp Ser Leu Leu Asn Val Lys Cys Ala Ala Gln Thr Leu Glu Lys Arg Gly Lys Ala Lys Pro Lys Val Asn Val Lys Pro Ser Val Val Lys Val Val Ser Ser Pro Lys Leu Ala Pro Lys Arg Lys Ala Val Glu Met His Ala Ala Val Ile Ala Ala Val Lys Pro Leu Ser Ser Ser Ser Val Leu Gln Glu Pro Pro Ala Lys Lys Ala Ala Val Ala Val Val Pro Leu Val Ser Glu Asp Lys Ser Val Thr Val Pro Glu Ala Glu Asn Pro Arg Asp Ser Leu Val Leu Pro Pro Thr Gln Ser Ser Ser Asp Ser Ser Pro Pro Glu Val Ser Gly Pro Ser Ser Ser Gln Met Ser Met Lys Thr Arg Arg Leu Ser Ser Ala Ser Thr Gly Lys Pro Pro Leu Ser Val Glu Asp Asp Phe Glu Lys Leu Ile Trp Glu Ile Ser Gly Gly Lys Leu Glu Ala Glu Ile Asp Leu Asp Pro Gly Lys Asp Glu Asp Asp Leu Leu Leu Glu Leu Ser Glu Met Ile Asp Ser <210> 13 <211> 549 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 1378134 <400> 13 Met Arg Arg Arg Ala Ser Asn Ala Ala Ala Ala Ala His Thr Ile Gly Gly Ser Lys His Thr Met Asn Asp His Leu His Val Gly Ser His Ala His Gly Gln Ile Gln Val Arg Gln Leu Phe Glu Asp Asn Ser Asn Lys Arg Thr Val Leu Thr Thr Gln Pro Asn Gly Leu Thr Thr Val Gly Lys Thr Gly Leu Pro Val Val Pro Glu Arg Gln Leu Asp Ser Ile His Arg Arg Gln Gly Ser Ser Thr Ser Leu Lys Ser Met Glu Gly Met Gly Lys Val Lys Ala Thr Pro Met Thr Pro Glu Gln Ala Met Lys Gln Tyr Met Gln Lys Leu Thr Ala Phe Glu His His Glu Ile Phe Ser Tyr Pro Glu Ile Tyr Phe Leu Gly Leu Asn Ala Lys Lys Arg Gln Gly Met Thr Gly Gly Pro Asn Asn Gly Gly Tyr Asp Asp Asp Gln Gly Ser Tyr Val Gln Val Pro His Asp His Val Ala Tyr Arg Tyr Glu Val Leu Lys Val Ile Gly Lys Gly Ser Phe Gly Gln Val Val Lys Ala Tyr Asp His Lys Val His Gln His Val Ala Leu Lys Met Val Arg Asn Glu Lys Arg Phe His Arg Gln Ala Ala Glu Glu Ile Arg Ile Leu Glu His Leu Arg Lys Gln Asp Lys Asp Asn Thr Met Asn Val Ile His Met Leu Glu Asn Phe Thr Phe Arg Asn His Ile Cys Met Thr Phe Glu Leu Leu Ser Met Asn Leu Tyr Glu Leu Ile Lys Lys Asn Lys Phe Gln Gly Phe Ser Leu Pro Leu Val Arg Lys Phe Ala His Ser Ile Leu Gln Cys Leu Asp Ala Leu His Lys Asn Arg Ile Ile His Cys Asp Leu Lys Pro Glu Asn Ile Leu Leu Lys Gln Gln Gly Arg Ser Gly Ile Lys Val Ile Asp Phe Gly Ser Ser Cys Tyr Glu His Gln Arg Val Tyr Thr Tyr Ile Gln Ser Arg Phe Tyr Arg Ala Pro Glu Val Ile Leu Gly Ala Arg Tyr Gly Met Pro Ile Asp Met Trp Ser Leu Gly Cys Ile Leu Ala Glu Leu Leu Thr Gly Tyr Pro Leu Leu Pro Gly Glu Asp Glu Gly Asp Gln Leu Ala Cys Met Ile Glu Leu Leu Gly Met Pro Ser Gln Lys Leu Leu Asp Ala Ser Lys Arg Ala Lys Asn Phe Val Ser Ser Lys Gly Tyr pro Arg Tyr Cys Thr Val Thr Thr Leu Ser Asp Gly Ser Val Val Leu Asn Gly Gly Arg Ser Arg Arg Gly Lys Leu Arg Gly Pro Pro Glu Ser Arg Glu Trp Gly Asn Ala Leu Lys Gly Cys Asp Asp Pro Leu Phe Leu Asp Phe Leu Lys Gln Cys Leu Glu Trp Asp Pro Ala Val Arg Met Thr Pro Gly Gln Ala Leu Arg His pro Trp Leu Arg Arg Arg Leu Pro Lys Pro Pro Thr Gly Glu Lys Thr Ser Val Lys Arg Ile Thr Glu Ser Thr Gly Ala Ile Thr Ser Ile Ser Lys Leu Pro Pro Pro Ser Ser Ser Ala Ser Lys Leu Arg Thr Asn Leu Ala Gln Met Thr Asp Ala Asn Gly Asn Ile Gln Gln Arg Thr Val Leu Pro Lys Leu Val Ser <210> 14 <211> 416 <212> PRT
<213> Homo sapiens <220>
<221> misc-feature <223> Incyte Clone Number: 1490070 <400> 14 Met Met Pro Gln Leu Gln Phe Lys Asp Ala Phe Trp Cys Arg Asp Phe Thr Ala His Thr Gly Tyr Glu Val Leu Leu Gln Arg Leu Leu Asp Gly Arg Lys Met Cys Lys Asp Met Val Glu Leu Leu Trp Gln Arg Ala Gln Ala Glu Glu Arg Tyr Gly Lys Glu Leu Val Gln Ile Ala Arg Lys Ala Gly Gly Gln Thr Glu Ile Asn Ser Leu Arg Ala Ser Phe Asp Ser Leu Lys Gln Gln Met Glu Asn Val Gly Ser Ser His Ile Gln Leu Ala Leu Thr Leu Arg Glu Glu Leu Arg Ser Leu Glu Glu Phe Arg Glu Arg GIn Lys Glu Gln Arg Lys Lys Tyr Glu Ala Val Met Asp Arg Val Gln Lys Ser Lys Leu Ser Leu Tyr Lys Lys Ala Met Glu Ser Lys Lys Thr Tyr Glu Gln Lys Cys Arg Asp Ala Asp Asp Ala Glu Gln Ala Phe Glu Arg Ile Ser Ala Asn Gly His Gln Lys Gln Val Glu Lys Ser Gln Asn Lys Ala Arg Gln Cys Lys Asp Ser Ala Thr Glu Ala Glu Arg Val Tyr Arg Gln Ser Ile Ala Gln Leu Glu Lys Val Arg Ala Glu Trp Glu Gln Glu His Arg Thr Thr Cys Glu Ala Phe Gln Leu Gln Glu Phe Asp Arg Leu Thr Ile Leu Arg Asn Ala Leu Trp Val His Ser Asn Gln Leu Ser Met Gln Cys Val Lys Asp Asp Glu Leu Tyr Glu Glu Val Arg Leu Thr Leu Glu Gly Cys Ser Ile Asp Ala Asp Ile Asp Ser Phe Ile Gln Ala Lys Ser Thr Gly Thr Glu Pro Pro Ala Pro Val Pro Tyr Gln Asn Tyr Tyr Asp Arg Glu Val Thr Pro Leu Thr Ser Ser Pro Gly Ile Gln Pro Ser Cys Gly Met Ile Lys Arg Phe Ser Gly Leu Leu His Gly Ser Pro Lys Thr Thr Ser Leu AIa Ala Ser Ala Ala Ser Thr Glu Thr Leu Thr Pro Thr Pro Glu Arg Asn Glu Gly Val Tyr Thr Ala Ile Ala Val Gln Glu Ile Gln Gly Asn Pro Ala Ser Pro Ala Gln Glu Tyr Arg Ala Leu Tyr Asp Tyr Thr Ala Gln Asn Pro Asp Glu Leu Asp Leu Ser Ala Gly Asp Ile Leu Glu Val Ile Leu Glu Gly Glu Asp Gly Trp Trp Thr Val Glu Arg Asn Gly Gln Arg Gly Phe Val Pro Gly Ser Tyr Leu Glu Lys Leu <210> 15 <211> 425 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 1997814 <400> 15 Met Glu Gln Gly Leu Glu Glu Glu Glu Glu Val Asp Pro Arg Ile Gln Gly Glu Leu Glu Lys Leu Asn Gln Ser Thr Asp Asp Ile Asn Arg Arg Glu Thr Glu Leu Glu Asp Ala Arg Gln Lys Phe Arg Ser Val Leu Val Glu Ala Thr Val Lys Leu Asp Glu Leu Val Lys Lys Ile Gly Lys Ala Val Glu Asp Ser Lys Pro Tyr Trp Glu Ala Arg Arg Val Ala Arg Gln Ala Gln Leu Glu Ala Gln Lys Ala Thr Gln Asp Phe Gln Arg Ala Thr Glu Val Leu Arg Ala Ala Lys Glu Thr Ile Ser Leu Ala Glu Gln Arg Leu Leu Glu Asp Asp Lys Arg Gln Phe Asp Ser Ala Trp Gln Glu Met Leu Asn His Ala Thr Gln Arg Val Met Glu Ala Glu Gln Thr Lys Thr Arg Ser Glu Leu Val His Lys Glu Thr Ala Ala Arg Tyr Asn Ala Ala Met Gly Arg Met Arg Gln Leu Glu Lys Lys Leu Lys Arg Ala Ile Asn Lys Ser Lys Pro Tyr Phe Glu Leu Lys Ala Lys Tyr Tyr Val Gln Leu Glu Gln Leu Lys Lys Thr Val Asp Asp Leu Gln Ala Lys Leu Thr Leu Ala Lys Gly Glu Tyr Lys Met Ala Leu Lys Asn Leu Glu Met Ile Ser Asp Glu Ile His Glu Arg Arg Arg Ser Ser Ala Met Gly Pro Arg Gly Cys Gly Val Gly Ala Glu Gly Ser Ser Thr Ser Val Glu Asp Leu Pro Gly Ser Lys Pro Glu Pro Asp Ala Ile Ser Val Ala Ser Glu Ala Phe Glu Asp Asp Ser Cys Ser Asn Phe Val Ser Glu Asp Asp Ser Glu Thr Gln Ser Val Ser Ser Phe Ser Ser Gly Pro Thr Ser Pro Ser Glu Met Pro Asp Gln Phe Pro Ala Val Val Arg Pro Gly Ser Leu Asp Leu Pro Ser Pro Val Ser Leu Ser Glu Phe Gly Met Met Phe Pro Val Leu Gly Pro Arg Ser Glu Cys Ser Gly Ala Ser Ser Pro Glu Cys Glu Val Glu Arg Gly Asp Arg Ala Glu Gly Ala Glu Asn Lys Thr Ser Asp Lys Ala Asn Asn Asn Arg Gly Leu Ser Ser Sex Ser Gly Ser Gly Gly Ser Ser Lys Ser Gln Ser Ser Thr Ser Pro Glu Gly Gln Ala Leu Glu Asn Arg Met Lys Gln Leu Ser Leu Gln Cys Ser Lys Gly Arg Asp Gly Ile Ile Ala Asp Ile Lys Met Val Gln Ile Gly <210> 16 <211> 1135 i <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 2299715 <400> 16 Met Ala Asn Asp Ser Pro Ala Lys Ser Leu Val Asp Ile Asp Leu Ser Ser Leu Arg Asp Pro Ala Gly Ile Phe Glu Leu Val Glu Val Val Gly Asn Gly Thr Tyr Gly Gln Val Tyr Lys Gly Arg His Val Lys Thr Gly Gln Leu Ala Ala Ile Lys Val Met Asp Val Thr Glu Asp Glu Glu Glu Glu Ile Lys Leu Glu Ile Asn Met Leu Lys Lys Tyr Ser His His Arg Asn Ile Ala Thr Tyr Tyr Gly Ala Phe Ile Lys Lys Ser Pro Pro Gly His Asp Asp Gln Leu Trp Leu Val Met g5 100 105 Glu Phe Cys Gly Ala Gly Ser Ile Thr Asp Leu Val Lys Asn Thr Lys Gly Asn Thr Leu Lys Glu Asp Trp Ile Ala Tyr Ile Ser Arg Glu Ile Leu Arg Gly Leu Ala His Leu His Ile His His Val Ile His Arg Asp Ile Lys Gly Gln Asn Val Leu Leu Thr Glu Asn Ala Gly Val Lys Leu Val Asp Phe Gly Val Ser Ala Gln Leu Asp Arg Thr Val Gly Arg Arg Asn Thr Phe Ile Gly Thr Pro Tyr Trp Met Ala Pro Glu Val Ile Ala Cys Asp Glu Asn Pro Asp Ala Thr Tyr Asp Tyr Arg Ser Asp Leu Trp Ser Cys Gly Ile Thr Ala Ile Glu Met Ala Glu Gly Ala Pro Pro Leu Cys Asp Met His Pro Met Arg Ala Leu Phe Leu Ile Pro Arg Asn Pro Pro Pro Arg Leu Lys Ser Lys Lys Trp Ser Lys Lys Phe Phe Ser Phe Ile Glu Gly Cys Leu Val Lys Asn Tyr Met Gln Arg Pro Ser Thr Glu Gln Leu Leu Lys His Pro Phe Ile Arg Asp Gln Pro Asn Glu Arg Gln Val Arg Ile Gln Leu Lys Asp His Ile Asp Arg Thr Arg Lys Lys Arg Gly Glu Lys Asp Glu Thr Glu Tyr Glu Tyr Ser Gly Ser Glu Glu Glu Glu Glu Glu Val Pro Glu Gln Glu Gly Glu Pro Ser Ser Ile Val Asn Val Pro Gly Glu Ser Thr Leu Arg Arg Asp Phe Leu Arg Leu Gln WO 00/0672$ PCT/US99/17132 Gln Glu Asn Lys Glu Arg Ser Glu Ala Leu Arg Arg Gln Gln Leu Leu Gln Glu Gln Gln Leu Arg Glu Gln Glu Glu Tyr Lys Arg Gln Leu Leu Ala Glu Arg Gln Lys Arg Ile Glu Gln Gln Lys Glu Gln Arg Arg Arg Leu Glu Glu Gln Gln Arg Arg Glu Arg Glu Ala Arg Arg Gln Gln Glu Arg Glu Gln Arg Arg Arg Glu Gln Glu Glu Lys Arg Arg Leu Glu Glu Leu Glu Arg Arg Arg Lys Glu Glu Glu Glu Arg Arg Arg Ala Glu Glu Glu Lys Arg Arg Val Glu Arg Glu Gln Glu Tyr Ile Arg Arg Gln Leu Glu Glu Glu Gln Arg His Leu Glu Val Leu Gln Gln Gln Leu Leu Gln Glu Gln Ala Met Leu Leu His Asp His Arg Arg Pro His Pro Gln His Ser Gln Gln Pro Pro Pro Pro Gln Gln Glu Arg Ser Lys Pro Ser Phe His Ala Pro Glu Pro Lys Ala His Tyr Glu Pro Ala Asp Arg Ala Arg Glu Val Pro Val Arg Thr Thr Ser Arg Ser Pro Val Leu Ser Arg Arg Asp Ser Pro Leu Gln Gly Ser Gly Gln Gln Asn Ser Gln Ala Gly Gln Arg Asn Ser Thr Ser Ile Glu Pro Arg Leu Leu Trp Glu Arg Val Glu Lys Leu Val Pro Arg Pro Gly Ser Gly Ser Ser Ser Gly Ser Ser Asn Ser Gly Ser Gln Pro Gly Ser His Pro Gly Ser Gln Ser Gly Ser Gly Glu Arg Phe Arg Val Arg Ser Ser Ser Lys Ser Glu Gly Ser Pro Ser Gln Arg Leu Glu Asn Ala Val Lys Lys Pro Glu Asp Lys Lys Glu Val Phe Arg Pro Leu Lys Pro Ala Asp Leu Thr Ala Leu Ala Lys Glu Leu Arg Ala Val Glu Asp Val Arg Pro Pro His Lys Val Thr Asp Tyr Ser Ser Sex Ser Glu Glu Ser Gly Thr Thr Asp Glu Glu Asp Asp Asp Val Glu Gln Glu Gly Ala Asp Glu Ser Thr Ser Gly Pro Glu Asp Thr Arg Ala Ala Ser Ser Leu Asn Leu Ser Asn Gly Glu Thr Glu Ser Val Lys Thr Met Ile Val His Asp Asp Val Glu Ser Glu Pro Ala Met Thr Pro Ser Lys Glu Gly Thr Leu Ile Val Arg Gln Thr Gln Ser Ala Ser Ser Thr Leu Gln Lys His Lys Ser Ser Ser Ser Phe Thr Pro Phe Ile Asp Pro Arg Leu Leu Gln Ile Ser Pro Ser Ser Gly Thr Thr Val Thr Ser Val Val Gly Phe Ser Cys Asp Gly Met Arg Pro Glu Ala Ile Arg Gln Asp Pro Thr Arg Lys Gly Ser Val Val Asn Val Asn Pro Thr Asn Thr Arg Pro Gln Ser Asp Thr Pro Glu Ile Arg Lys Tyr Lys Lys Arg Phe Asn Ser Glu Ile Leu Cys Ala Ala Leu Trp Gly Val Asn Leu Leu Val Gly Thr Glu Ser Gly Leu Met Leu Leu Asp Arg Ser Gly Gln Gly Lys Val Tyr Pro Leu Ile Asn Arg Arg Arg Phe Gln Gln Met Asp Val Leu Glu Gly Leu Asn Val Leu Val Thr Ile Ser Gly Lys Lys Asp Lys Leu Arg Val Tyr Tyr Leu Ser Trp Leu Arg Asn Lys Ile Leu His Asn Asp Pro Glu Val Glu Lys Lys Gln Gly Trp Thr Thr Val Gly Asp Leu Glu Gly Cys Val His Tyr Lys Val Val Lys Tyr Glu Arg Ile Lys Phe Leu Val Ile Ala Leu Lys Ser Ser Val Glu Val Tyr Ala Trp Ala Pro Lys Pro Tyr His Lys Phe Met Ala Phe Lys Ser Phe Gly Glu Leu Val His Gly Ser Cys Ala Gly Phe His Ala Val Asp Val Asp Ser Gly Ser Val Tyr Asp Ile Tyr Leu Pro Thr His Ile Gln Cys Ser Ile Lys Pro His Ala Ile Ile Ile Leu Pro Asn Thr Asp Gly Met Glu Leu Leu Val Cys Tyr Glu Asp Glu Gly Val Tyr Val Asn Thr Tyr Gly Arg Ile Thr Lys Asp Val Val Leu Gln Trp Gly Glu Met Pro Thr Ser Val Ala Tyr Ile Arg Ser Asn Gln Thr Met Gly Trp Gly Glu Lys Ala Ile Glu Ile Arg Ser Val Glu Thr Gly His Leu Asp Gly Val Phe Met His Lys Arg Ala Gln Arg Leu Lys Phe Leu Cys Glu Arg Asn Asp Lys Val Phe Phe Ala Ser Val Arg Ser Gly Gly Ser Ser Gln Val Tyr Phe Met Thr Leu Gly Arg Thr Sex Leu Leu Ser Trp <210> 17 <211> 228 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 209854 <400> 17 Met Pro Thr Asn Cys Ala Ala Ala Gly Cys Ala Thr Thr Tyr Asn Lys His Ile Asn Ile Ser Phe His Arg Phe Pro Leu Asp Pro Lys Arg Arg Lys Glu Trp Val Arg Leu Val Arg Arg Lys Asn Phe Val Pro Gly Lys His Thr Phe Leu Cys Ser Lys His Phe Glu Ala Ser Cys Phe Asp Leu Thr Gly Gln Thr Arg Arg Leu Lys Met Asp Ala Val Pro Thr Ile Phe Asp Phe Cys Thr His Ile Lys Ser Met Lys Leu Lys Ser Arg Asn Leu Leu Lys Lys Asn Asn Ser Cys Ser Pro Ala Gly Pro Ser Asn Leu Lys Ser Asn Ile Ser Ser Gln Gln Val Leu Leu Glu His Ser Tyr Ala Phe Arg Asn Pro Met Glu Ala Lys Lys Arg Ile Ile Lys Leu Glu Lys Glu Ile Ala Ser Leu Arg Arg Lys Met Lys Thr Cys Leu Gln Lys Glu Arg Arg Ala Thr Arg Arg Trp Ile Lys Ala Thr Cys Leu Val Lys Asn Leu Glu Ala Asn Ser Val Leu Pro Lys Gly Thr Ser Glu His Met Leu Pro Thr Ala Leu Ser Ser Leu Pro Leu Glu Asp Phe Lys Ile Leu Glu Gln Asp Gln Gln Asp Lys Thr Leu Leu Ser Leu Asn Leu Lys Gln Thr Lys Ser Thr Phe Ile <210> 18 <211> 503 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 1384286 <400> 18 Met Ala Thr Thr Val Thr Cys Thr Arg Phe Thr Asp Glu Tyr Gln Leu Tyr Glu Asp Ile Gly Lys Gly Ala Phe Ser Val VaI Arg Arg Cys Val Lys Leu Cys Thr Gly His Glu Tyr Ala Ala Lys Ile Ile 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 Ser 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 Glu Tyr Tyr Ser Glu Ala Asp Ala Ser His Cys Ile Gln Gln Ile Leu Glu Ala Val Leu His Cys His Gln Met Gly Val 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 Asp Gln Gln Ala Trp Phe Gly Phe Ala Gly Thr Pro Gly Tyr Leu Ser Pro Glu Val Leu Arg Lys Glu Ala Tyr Gly Lys Pro Val Asp Ile Trp Ala Cys Gly Val Ile Leu Tyr Ile Leu Leu Val Gly Tyr Pro Pro Phe Trp Asp Glu 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 His Glu Ala Leu Lys His Pro Trp Val Cys Gln Arg Ser Thr Val Ala Ser Met Met His Arg Gln Glu Thr Val Glu Cys Leu Lys Lys Phe Asn Ala Arg Arg Lys Leu Lys Gly Ala Ile Leu Thr Thr Met Leu Ala Thr Arg Asn Phe Ser Ala Ala Lys Ser Leu Leu Asn Lys Lys Ala Asp Gly Val Lys Pro His Thr Asn Ser Thr Lys Asn Ser Ala Ala Ala Thr Ser Pro Lys Gly Thr Leu Pro Pro Ala Ala Leu Glu Ser Ser Asp Ser Ala Asn Thr Thr Ile Glu Asp Glu Asp Ala Lys Ala Arg Lys Gln Glu Ile Ile Lys Thr Thr Glu Gln Leu Ile Glu Ala Val Asn Asn Gly Asp Phe Glu Ala Tyr Ala Lys Ile Cys Asp Pro Gly Leu Thr Ser Phe Glu Pro Glu Ala Leu Gly Asn Leu Val Glu Gly Met Asp Phe His Arg Phe Tyr Phe Glu Asn Leu Leu Ala 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 Gln Asn Val His Phe His Cys Ser Gly Ala Pro Val Ala Pro Leu Gln <210> 19 <211> 433 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 1512656 <400> 19 Met Thr Gly Glu Gln Ala Gly Arg Lys Arg Ser Arg Ala Ala Arg Pro Glu Gly Thr Pro Val Arg Arg Glu Arg Thr Gln Glu Pro Gly Leu Gly Pro Gly Ala Arg Ala Met Ala Ala Glu Ala Arg Thr Ala Val Ala Gly Ser Ala Val Gly Gly Cys Leu Ala Lys Gly Asp Gly Leu Gln Gln Ser Cys Pro Asp Thr Thr Pro Lys Arg Lys Arg Arg Ala Ser Ser Leu Arg Asp Ala Glu Arg Arg Ala Tyr Ser Gln Tr p Cys Arg Glu Tyr Gly Gly Ala Trp Arg Arg Val Gln Leu Pro Glu Glu Leu Arg Val Pro Val Ser Gly Gly Leu Ser Asn Tyr Leu Leu lI0 115 120 Phe Arg Cys Ser Pro Asp His Leu Pro Ser Val Gly Leu Glu Glu Pro Arg Glu Val Leu Arg Leu Tyr Gly Ala Ile Leu Leu Gln Gly Val Asp Ser Leu Leu Glu Ser Val Met Phe Ala Ile..Leu Val Ala Glu Arg Ser Leu Pro Gln Leu Tyr Gly Val Phe Pro Gly Glu Gly Arg Leu Glu Gln Ile Pro Ser Arg Pro Leu Lys Thr Tyr Gln Glu Leu Arg Glu Pro Leu Ser Ala Ala Ile Ala Thr Lys Val Met Ala Gln Phe His Gly Glu Met Pro Phe Thr Lys Glu Pro Met His Trp Leu Phe Gly Thr Glu Arg Tyr Leu Lys Gln Ile Gln Met Asp Leu Pro Pro Thr Gly Pro Glu Met Asn Leu Leu Glu Met Leu Tyr Ser Leu Lys Asp Glu Gly Asn Leu Arg Lys Leu Leu Glu Met Ser Thr Pro Ser Pro Val Phe Cys His Asn Asp Ile Gln Glu Val Gly Asn WO 00/0672$ PCT/US99/17132 Ile Leu Leu Leu Ser Glu Pro Glu Asn Ala Asp Ser Leu Met Leu Val Asp Phe Glu Tyr Ser Ser Tyr Asn Tyr Arg Gly Phe Asp Ile Gly Asn His Phe Cys Glu Trp Val Tyr Asp Tyr Thr His Glu Glu Trp Pro Phe Tyr Lys Ala Arg Pro Thr Asp Tyr Pro Thr Gln Glu Gln Gln Leu Hie Phe Ile Arg His Tyr Leu Ala Glu Ala Lys Lys Gly Glu Thr Leu Ser Gln Glu Glu Gln Arg Lys Leu Glu Glu Asp Leu Leu Val Glu Val Ser Arg Tyr Ala Leu Ala Ser His Phe Phe Trp Gly Leu Trp Ser Ile Leu Gln Ala Ser Met Ser Thr Ile Glu Phe Gly Tyr Leu Asp Tyr Ala Gln Ser Arg Phe Gln Phe Tyr Phe Gln Gln Lys Gly Gln Leu Thr Ser Val His Ser Ser Ser <210> 20 <211> 527 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 2098635 <400> 20 Met Ser Leu Cys Gly Ala Arg Ala Asn Ala Lys Met Met Ala Ala Tyr Asn Gly Gly Thr Ser Ala Ala Ala Ala Gly His His His His His His His His Leu Pro His Leu Pro Pro Pro His Leu Leu His His His His Pro Gln His His Leu His Pro Gly Ser Ala Ala Ala Val His Pro Val Gln Gln His Thr Ser Ser Ala Ala AIa Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Met Leu Asn Pro Gly Gln Gln Gln Pro Tyr Phe Pro Ser Pro Ala Pro Gly Gln Ala Pro Gly Pro Ala Ala Ala Ala Pro Ala Gln Val Gln Ala Ala Ala Ala Ala Thr Val Lys Ala His His His Gln His Ser His His Pro Gln Gln Gln Leu Asp Ile Glu Pro Asp Arg Pro Ile Gly Tyr Gly Ala Phe Gly Val Val Trp Ser Val Thr Asp Pro Arg Asp Gly Lys Arg Val Ala Leu Lys Lys Met Pro Asn Val Phe Gln Asn Leu Val Ser Cys Lys Arg Val Phe Arg Glu Leu Lys Met Leu Cys Phe Phe Lys His Asp Asn Val Leu Ser Ala Leu Asp Ile Leu Gln Pro Pro His Ile Asp Tyr Phe Glu Glu Ile Tyr Val Val Thr Glu Leu Met Gln Ser Asp Leu His Lys Ile Ile Val Ser Pro Gln Pro Leu Ser Ser Asp His Val Lys Val Phe Leu Tyr Gln Ile Leu Arg Gly Leu Lys Tyr Leu His ser Ala Gly Ile Leu His Arg Asp Ile Lys Pro Gly Asn Leu Leu Val Asn Ser Asn Cys Val Leu Lys Ile Cys Asp Phe Gly Leu Ala Arg Val Glu Glu Leu Asp Glu Ser Arg His Met Thr Gln Glu Val Val Thr Gln Tyr Tyr Arg Ala Pro Glu Ile Leu Met Gly Ser Arg His Tyr Ser Asn Ala Ile Asp Ile Trp Ser Val Gly Cys Ile Phe Ala Glu Leu Leu Gly Arg Arg Ile Leu Phe Gln Ala Gln Ser Pro Ile Gln Gln Leu Asp Leu Ile Thr Asp Leu Leu Gly Thr Pro Ser Leu Glu Ala Met Arg Thr Ala Cys Glu Gly Ala Lys Ala His Ile Leu Arg Gly Pro His Lys Gln Pro Ser Leu Pro Val Leu Tyr Thr Leu Ser Ser Gln Ala Thr His Glu Ala Val His Leu Leu Cys Arg Met Leu Val Phe Asp Pro Ser Lys Arg Ile Ser Ala Lys Asp Ala Leu Ala His Pro Tyr Leu Asp Glu Gly Arg Leu Arg Tyr His Thr Cys Met Cys Lys Cys Cys Phe Ser Thr Ser Thr Gly Arg Val Tyr Thr Ser Asp Phe Glu Pro Val Thr Asn Pro Lys Phe Asp Asp Thr Phe Glu Lys Asn Leu Ser Ser Val Arg Gln Val Lys Glu Ile Ile His Gln Phe Ile Leu Glu Gln Gln Lys Gly Asn Arg Val Pro Leu Cys Ile Asn Pro Gln Ser Ala Ala Phe Lys Ser Phe Ile Ser Ser Thr Val Ala Gln Pro Ser Glu Met Pro Pro Ser Pro Leu Val Trp Glu <210> 21 <211> 322 <212> PRT
<213> Homo sapiens <220>

i <221> misc_feature <223> Incyte Clone Number: 2446646 <400> 21 Met Glu Gly Ile Ser Asn Phe Lys Thr Pro Ser Lys Leu Ser Glu Lys Lys Lys Ser Val Leu Cys Ser Thr Pro Thr Ile Asn Ile Pro Ala Ser Pro Phe Met Gln Lys Leu Gly Phe Gly Thr Gly Val Asn Val Tyr Leu Met Lys Arg Ser Pro Arg Gly Leu Ser His Ser Pro Trp Ala Val Lys Lys Ile Asn Pro Ile Cys Asn Asp His Tyr Arg ser Val Tyr Gln Lys Arg Leu Met Asp Glu Ala Lys Ile Leu Lys Ser Leu His His Pro Asn Ile Val Gly Tyr Arg Ala Phe Thr Glu g5 100 105 Ala Asn Asp Gly Ser Leu Cys Leu Ala Met Glu Tyr Gly Gly Glu Lys Ser Leu Asn Asp Leu Ile Glu Glu Arg Tyr Lys Ala Ser Gln Asp Pro Phe Pro Ala Ala Ile Ile Leu Lys Val Ala Leu Asn Met Ala Arg Gly Leu Lys Tyr Leu His Gln Glu Lys Lys Leu Leu His Gly Asp Ile Lys Ser Ser Asn Val Val Ile Lys Gly Asp Phe Glu Thr Ile Lys Ile Cys Asp Val Gly Val Ser Leu Pro Leu Asp Glu Asn Met Thr Val Thr Asp Pro Glu Ala Cys Tyr Ile Gly Thr Glu Pro Trp Lys Pro Lys Glu Ala Val Glu Glu Asn Gly Val Ile Thr Asp Lys Ala Asp Ile Phe Ala Phe Gly Leu Thr Leu Trp Glu Met Met Thr Leu Ser Ile Pro His Ile Asn Leu Ser Asn Asp Asp Asp Asp Glu Asp Lys Thr Phe Asp Glu Ser Asp Phe Asp Asp Glu Ala Tyr Tyr Ala Ala Leu Gly Thr Arg Pro Pro Ile Asn Met Glu Glu Leu Asp Glu Ser Tyr Gln Lys Val Ile Glu Leu Phe Ser Val Cys Thr Asn Glu Asp Pro Lys Asp Arg Pro Ser Ala Ala His Ile Val Glu Ala Leu Glu Thr Asp Val <210> 22 <211> 802 <212> PRT
<213> Homo sapiens <220>
<221> mist feature <223> Incyte Clone Number: 2764911 <400> 22 Met Glu Glu Glu Gly Gly Ser Ser Gly Gly Ala Ala Gly Thr Ser Ala Asp Gly Gly Asp Gly Gly Glu Gln Leu Leu Thr Val Lys His Glu Leu Arg Thr Ala Asn Leu Thr Gly His Ala Glu Lys Val Gly Ile Glu Asn Phe Glu Leu Leu Lys Val Leu Gly Thr Gly Ala Tyr Gly Lys Val Phe Leu val Arg Lys Ile Ser Gly His Asp Thr Gly Lys Leu Tyr Ala Met Lys Val Leu Lys Lys Ala Thr Ile Val Gln Lys Ala Lys Thr Thr Glu His Thr Arg Thr Glu Arg Gln Val Leu Glu His Ile Arg Gln Ser Pro Phe Leu Val Thr Leu His Tyr Ala Phe Gln Thr Glu Thr Lys Leu His Leu Ile Leu Asp Tyr Ile Asn Gly Gly Glu Leu Phe Thr His Leu Ser Gln Arg Glu Arg Phe Thr Glu His Glu Val Gln Ile Tyr Val Gly Glu Ile Val Leu Ala Leu Glu His Leu His Lys Leu Gly Ile Ile Tyr Arg Asp Ile Lys Leu Glu Asn Ile Leu Leu Asp Ser Asn Gly His Val Val Leu Thr Asp Phe Gly Leu Ser Lys Glu Phe Val Ala Asp Glu Thr Glu Arg Ala Tyr Ser Phe Cys Gly Thr Ile Glu Tyr Met Ala Pro Asp Ile Val Arg Gly Gly Asp Ser Gly His Asp Lys Ala Val Asp Trp Trp Ser Leu Gly Val Leu Met Tyr Glu Leu Leu Thr Gly Ala Ser Pro Phe Thr Val Asp Gly Glu Lys Asn Ser Gln Ala Glu Ile Ser Arg Arg Ile Leu Lys Ser Glu Pro Pro Tyr Pro Gln Glu Met Ser Ala Leu Ala Lys Asp Leu Ile Gln Arg Leu Leu Met Lys Asp Pro Lys Lys Arg Leu Gly Cys Gly Pro Arg Asp Ala Asp Glu Ile Lys Glu His Leu Phe Phe Gln Lys Ile Asn Trp Asp Asp Leu Ala Ala Lys Lys Val Pro Ala Pro Phe Lys Pro Val Ile Arg Asp Glu Leu Asp Val Ser Asn Phe Ala Glu Glu Phe Thr Glu Met Asp Pro Thr Tyr Ser Pro Ala Ala Leu Pro Gln Ser Sex Glu Lys Leu Phe Gln Gly Tyr Ser Phe Val Ala Pro Ser Ile Leu Phe Lys Arg Asn Ala Ala Val Ile Asp Pro Leu Gln Phe His Met Gly Val Glu Arg Pro Gly Val Thr Asn Val Ala Arg Ser Ala Met Met Lys Asp Ser Pro Phe Tyr Gln His Tyr Asp Leu Asp Leu Lys Asp Lys Pro Leu Gly Glu Gly Ser Phe Ser Ile Cys Arg Lys Cys Val His Lys Lys Ser Asn Gln Ala Phe Ala Val Lys Ile Ile Ser Lys Arg Met Glu Ala Asn Thr Gln Lys Glu Ile Thr Ala Leu Glu Leu Cys Glu Gly His Pro Asn Ile Val Lys Leu His Glu Val Phe His Asp Gln Leu His Thr Phe Leu Val Met Glu Leu Leu Asn Gly Gly Glu Leu Phe Glu Arg Ile Lys Lys Lys Lys His Phe Ser Glu Thr Glu Ala Ser Tyr Ile Met Arg Lys Leu Val Ser Ala Val Ser His Met His Asp Val Gly Val Val His Arg Asp Leu Lys Pro Glu Asn Leu Leu Phe Thr Asp Glu Asn Asp Asn Leu Glu Ile Lys Ile Ile Asp Phe Gly Phe Ala Arg Leu Lys Pro Pro Asp Asn Gln Pro Leu Lys Thr Pro Cys Phe Thr Leu His Tyr Ala Ala Pro Glu Leu Leu Asn Gln Asn Gly Tyr Asp Glu Ser Cys Asp Leu Trp Ser Leu Gly Val Ile Leu Tyr Thr Met Leu Ser Gly Gln Val Pro Phe Gln Ser His Asp Arg Ser Leu Thr Cys Thr Ser Ala Val Glu Ile Met Lys Lys Ile Lys Lys Gly Asp Phe Ser Phe Glu Gly Glu Ala Trp Lys Asn Val Ser Gln Glu Ala Lys Asp Leu Ile Gln Gly Leu Leu Thr Val Asp Pro Asn Lys Arg Leu Lys Met Ser Gly Leu Arg Tyr Asn Glu Trp Leu Gln Asp Gly Ser Gln Leu Ser Ser Asn Pro Leu Met Thr Pro Asp Ile Leu Gly Ser Ser Gly Ala Ala Val His Thr Cys Val Lys Ala Thr Phe His Ala Phe Asn Lys Tyr Lys Arg Glu Gly Phe Cys Leu Gln Asn Val Asp Lys Ala Pro Leu Ala Lys Arg Arg Lys Met Lys Lys Thr Ser Thr Ser Thr Glu Thr Ar9 Ser Ser Ser Ser Glu Ser Ser His Ser Ser Ser Ser His Ser His Gly Lys Thr Thr Pro Thr Lys Thr Leu Gln Pro Ser Asn Pro Ala Asp Ser Asn Asn Pro Glu Thr Leu Phe Gln Phe Ser Asp Ser Val Ala <210> 23 <211> 641 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 3013946 <400> 23 Met Ala Thr Thr Val Thr Cys Thr Arg Phe Thr Asp Glu Tyr Gln Leu Tyr Glu Asp Ile Gly Lys Gly Ala Phe Ser Val Val Arg Arg Cys Val Lys Leu Cys Thr Gly His Glu Tyr Ala Ala Lys Ile Ile 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 Ser 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 Glu Tyr Tyr Ser Glu Ala Asp Ala Ser His Cys Ile Gln Gln Ile Leu Glu Ala Val Leu His Cys His Gin Met Gly Val 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 Asp Gln Gln Ala Trp Phe Gly Phe Ala Gly Thr Pro Gly Tyr Leu Ser Pro Glu Val Leu Arg Lys Glu Ala Tyr Gly Lys Pro Val Asp Ile Trp Ala Cys Gly Val Ile Leu Tyr Ile Leu Leu Val Gly Tyr Pro Pro Phe Trp Asp Glu 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 His Glu Ala Leu Lys His Pro Trp Val Cys Gln Arg Ser Thr Val Ala Ser Met Met His Arg Gln Glu Thr Val Glu Cys Leu Lys Lys Phe Asn Ala Arg Arg Lys Leu Lys Gly Ala Ile Leu Thr Thr Met Leu Ala Thr Arg Asn Phe Ser Ala Lys Ser Leu Leu Asn Lys Lys Ala Asp Gly Val Lys Pro Gln Thr Asn Ser Thr Lys Asn Ser Ala Ala Ala Thr Ser Pro Lys Gly Thr Leu Pro Pro Ala Ala Leu Glu Pro Gln Thr Thr Val Ile His Asn Pro Val Asp Gly Ile Lys Glu Ser Ser Asp Ser Ala Asn Thr Thr Ile Glu Asp Glu Asp Ala Lys Ala Pro Arg Val Pro Asp Ile Leu Ser Ser Val Arg Arg Gly Ser Gly Ala Pro Glu Ala Glu Gly Pro Leu Pro Cys Pro Ser Pro Ala Pro Phe Gly Pro Leu Pro Ala Pro Ser Pro Arg Ile Ser Asp Ile Leu Asn Ser Val Arg Arg Gly Ser Gly Thr Pro Glu Ala Glu Gly Pro Leu Ser Ala Gly Pro Pro Pro Cys Leu Ser Pro Ala Leu Leu Gly Pro Leu Ser Ser Pro Ser Pro Arg Ile Ser Asp Ile Leu Asn Ser Val Arg Arg Gly Ser Gly Thr Pro Glu Ala Lys Gly Pro Ser Pro Val Gly Pro Pro Pro Cys Pro Ser Pro Thr Ile Pro Gly Pro Leu Pro Thr Pro Ser Arg Lys Gln Glu Ile Ile Lys Thr Thr Glu Gln Leu Ile Glu Ala Val Asn Asn Gly Asp Phe Glu Ala Tyr Ala Lys Ile Cys Asp Pro Gly Leu Thr Ser Phe Glu Pro Glu Ala Leu Gly Asn Leu Val Glu Gly Met Asp Phe His Arg Phe Tyr Phe Glu Asn Leu Leu Ala 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 Gln Asn Val His Phe His Cys Ser Gly Ala Pro Val Ala Pro Leu Gln <210> 24 <211> 588 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 067967 <400> 24 Met Gly Gly Thr Ala Arg Gly Pro Gly Arg Lys Asp Ala Gly Pro Pro Gly Ala Gly Leu Pro Pro Gln Gln Arg Arg Leu Gly Asp Gly Val Tyr Asp Thr Phe Met Met Ile Asp Glu Thr Lys Cys Pro Pro WO 00/06728 PC'T/US99/17132 Cys Ser Asn Val Leu Cys Asn Pro Ser Glu Pro Pro Ser Pro Arg Arg Leu Asn Met Thr Thr Glu Gln Phe Thr Gly Asp His Thr Gln His Phe Leu Asp Gly Gly Glu Met Lys Val Glu Gln Leu Phe Gln Glu Phe Gly Asn Arg Lys Ser Asn Thr Ile Gln Ser Asp Gly Ile Ser Asp Ser Glu Lys Cys Ser Pro Thr Val Ser Gln Gly Lys Ser Ser Asp Cys Leu Asn Thr Val Lys Ser Asn Ser Ser Ser Lys Ala Pro Lys Val Val Pro Leu Thr Pro Glu Gln Ala Leu Lys Gln Tyr Lys His His Leu Thr Ala Tyr Glu Lys Leu Glu Ile Ile Asn Tyr Pro Glu Ile Tyr Phe Val Gly Pro Asn Ala Lys Lys Arg His Gly Val Ile Gly Gly Pro Asn Asn Gly Gly Tyr Asp Asp Ala Asp Gly Ala Tyr Ile His Val Pro Arg Asp His Leu Ala Tyr Arg Tyr Glu Val Leu Lys Ile Ile Gly Lys Gly Ser Phe Gly Gln Val Ala Arg Val Tyr Asp His Lys Leu Arg Gln Tyr Val Ala Leu Lys Met Val Arg Asn Glu Lys Arg Phe His Arg Gln Ala Ala Glu Glu Ile Arg Ile Leu Glu His Leu Lys Lys Gln Asp Lys Thr Gly Ser Met Asn Val Ile His Met Leu Glu Ser Phe Thr Phe Arg Asn His Val Cys Met Ala Phe Glu Leu Leu Ser Ile Asp Leu Tyr Glu Leu Ile Lys Lys Asn Lys Phe Gln Gly Phe Ser Val Gln Leu Val Arg Lys Phe Ala Gln Ser Ile Leu Gln Ser Leu Asp Ala Leu His Lys Asn Lys Ile Ile His Cys Asp Leu Lys Pro Glu Asn Ile Leu Leu Lys His His Gly Arg Ser Ser Thr Lys Val Ile Asp Phe Gly Ser ser Cys Phe Glu Tyr Gln Lys Leu Tyr Thr Tyr Ile Gln Ser Arg Phe Tyr Arg Ala Pro Glu Ile Ile Leu Gly Ser Arg Tyr Ser Thr Pro Ile Asp Ile Trp Ser Phe Gly Cys Ile Leu Ala Glu Leu Leu Thr Gly Gln Pro Leu Phe Pro Gly Glu Asp Glu Gly Asp Gln Leu Ala Cys Met Met Glu Leu Leu Gly Met Pro Pro Pro Lys Leu Leu Glu Gln Ser Lys Arg Ala Lys Tyr Phe Ile Asn Ser Lys Gly Ile Pro Arg Tyr Cys Ser Val Thr Thr Gln Ala Asp Gly Arg Val Val Leu Val Gly Gly Arg Ser Arg Arg Gly Lys Lys Arg Gly Pro Pro Gly Ser Lys Asp Trp Gly Thr Ala Leu Lys Gly Cys Asp Asp Tyr Leu Phe Ile Glu Phe Leu Lys Arg Cys Leu His Trp Asp Pro Ser Ala Arg Leu Thr Pro Ala Gln Ala Leu Arg His Pro Trp Ile Ser Lys Ser Val Pro Arg Pro Leu Thr Thr Ile Asp Lys Val Ser Gly Lys Arg Val Val Asn Pro Ala Ser Ala Phe Gln Gly Leu Gly Ser Lys Leu Pro Pro Val Val Gly Ile Ala Asn Lys Leu Lys Ala Asn Leu Met Ser Glu Thr Asn Gly Ser Ile Pro Leu Cys Ser Val Leu Pro Lys Leu Ile Ser <210> 25 <211> 389 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 346275 <400> 25 Met Ser Asp Val Cys Ser Ser Gln Arg Ala Glu His Glu His Leu Pro Gly Leu Val Pro Pro Pro Ser Gly Met Gly Val Arg Lys Gly Ser Ser Pro Leu Lys Ser His Pro Cys Arg Glu Lys Ser Val Ser Asn Arg Arg Ser Gly Lys Thr Ile Val Arg Ser Ala Val Glu Glu Val Arg Thr Ala Gly Leu Phe Arg Ser Gly Phe Ser Glu Glu Lys Ala Thr Gly Lys Leu Phe Ala Val Lys Cys Ile Pro Lys Lys Ala Leu Lys Gly Lys Glu Ser Ser Ile Glu Asn Glu Ile Ala Val Leu Arg Lys Ile Lys His Glu Asn Ile Val Ala Leu Glu Asp Ile Tyr Glu ser Pro Asn His Leu Tyr Leu Val Met Gln Leu Val Ser Gly Gly Glu Leu Phe Asp Arg Ile Val Glu Lys Gly Phe Tyr Thr Glu Lys Asp Ala Ser Thr Leu Ile Arg Gln Val Leu Asp Ala Val Tyr Tyr Leu His Arg Met Gly Ile Val His Arg Asp Leu Lys Pro Glu Asn Leu Leu Tyr Tyr Ser Gln Asp Glu Glu Ser Lys Ile Met Ile Ser Asp Phe Gly Leu Ser Lys Met Glu Gly Lys Gly Asp Val Met Ser Thr Ala Cys Gly Thr Pro Gly Tyr Val Ala Pro Glu Val Leu Ala Gln Lys Pro Tyr Ser Lys Ala Val Asp Cys Trp Ser Ile Gly Val Ile Ala Tyr Ile Leu Leu Cys Gly Tyr Pro Pro Phe Tyr Asp Glu Asn Asp Ser Lys Leu Phe Glu Gln Ile Leu Lys Ala Glu Tyr Glu Phe Asp Ser Pro Tyr Trp Asp Asp Ile Ser Asp Ser Ala Lys Asp Phe Ile Arg Asn Leu Met Glu Lys Asp Pro Asn Lys Arg Tyr Thr Cys Glu Gln Ala Ala Arg His Pro Trp Ile Ala Gly Asp Thr Ala Leu Asn Lys Asn Ile His Glu Ser Val Ser Ala Gln Ile Arg Lys Asn Phe Ala Lys Ser Lys Trp Arg Gln Ala Phe Asn Ala Thr Ala Val Val Arg His Met Arg Lys Leu His Leu Gly Ser Ser Leu Asp Ser Ser Asn Ala Ser Val Ser Ser Ser Leu Ser Leu Ala Ser Gln Lys Asp Cys Ala Tyr Val Ala Lys Pro Glu Ser Leu Ser <210> 26 <211> 343 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 283746 <400> 26 Met Ile Gly Glu Glu Ala Met Ile Asn Tyr Glu Asn Phe Leu Lys Val Gly Glu Lys Ala Gly Ala Lys Cys Lys Gln Phe Phe Thr Ala Lys Val Phe Ala Lys Leu Leu His Thr Asp Ser Tyr Gly Arg Ile Ser Ile Met Gln Phe Phe Asn Tyr Val Met Arg Lys Val Trp Leu His Gln Thr Arg Ile Gly Leu Ser Leu Tyr Asp Val Ala Gly Gln Gly Tyr Leu Arg Glu Ser Asp Leu Glu Asn Tyr Ile Leu Glu Leu Ile Pro Thr Leu Pro Gln Leu Asp Gly Leu Glu Lys Ser Phe Tyr g5 100 105 Ser Phe Tyr Val Cys Thr Ala Val Arg Lys Phe Phe Phe Phe Leu Asp Pro Leu Arg Thr Gly Lys Ile Lys Ile Gln Asp Ile Leu Ala Cys Ser Phe Leu Asp Asp Leu Leu Glu Leu Arg Asp Glu Glu Leu Ser Lys Glu Ser Gln Glu Thr Asn Trp Phe Ser Ala Pro Ser Ala Leu Arg Val Tyr Gly Gln Tyr Leu Asn Leu Asp Lys Asp His Asn Gly Met Leu Ser Lys Glu Glu Leu Ser Arg Tyr Gly Thr Ala Thr Met Thr Asn Val Phe Leu Asp Arg Val Phe Gln Glu Cys Leu Thr Tyr Asp Gly Glu Met Asp Tyr Lys Thr Tyr Leu Asp Phe Val Leu Ala Leu Glu Asn Arg Lys Glu Pro Ala Ala Leu Gln Tyr Ile Phe Lys Leu Leu Asp Ile Glu Asn Lys Gly Tyr Leu Asn Val Phe Ser Leu Asn Tyr Phe Phe Arg Ala Ile Gln Glu Leu Met Lys Ile His Gly Gln Asp Pro Val Ser Phe Gln Asp Val Lys Asp Glu Ile Phe Asp Met Val Lys Pro Lys Asp Pro Leu Lys Ile Ser Leu Gln Asp Leu Ile Asn Ser Asn Gln Gly Asp Thr Val Thr Thr Ile Leu Ile Asp Leu Asn Gly Phe Trp Thr Tyr Glu Asn Arg Glu Ala Leu Val Ala Asn Asp Ser Glu Asn Ser Ala Asp Leu Asp Asp Thr <210> 27 <211> 184 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 2696537 <400> 27 Met Gly Asn Gly Met Asn Lys Ile Leu Pro Gly Leu Tyr Ile Gly Asn Phe Lys Asp Ala Arg Asp Ala Glu Gln Leu Ser Lys Asn Lys Val Thr His Ile Leu Ser Val His Asp Ser Ala Arg Pro Met Leu Glu Gly Val Lys Tyr Leu Cys Ile Pro Ala Ala Asp Ser Pro Ser Gln Asn Leu Thr Arg His Phe Lys Glu Ser Ile Lys Phe Ile His Glu Cys Arg Leu Arg Gly Glu Ser Cys Leu Val His Cys Leu Ala Gly Val Ser Arg Ser Val Thr Leu Val Ile Ala Tyr Ile Met Thr Val Thr Asp Phe Gly Trp Glu Asp Ala Leu His Thr Val Arg Ala Gly Arg Ser Cys Ala Asn Pro Asn Val Gly Phe Gln Arg Gln Leu Gln Glu Phe Glu Lys His Glu Val Hie Gln Tyr Arg Gln Trp Leu Lys Glu Glu Tyr Gly Glu Ser Pro Leu Gln Asp Ala Glu Glu Ala Lys Asn Ile Leu Ala Ala Pro Gly Ile Leu Lys Phe Trp Ala Phe Leu Arg Arg Leu <210> 29 <211> 118 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 619292 <400> 29 Met Gly Leu Ile Asp Gly Met His Thr His Leu Gly Ala Pro Gly Leu Tyr Ile Gln Thr Leu Leu Pro Gly Ser Pro Ala Ala Ala Asp Gly Arg Leu Ser Leu Gly Asp Arg Ile Leu Glu Val Asn Gly Ser Ser Leu Leu Gly Leu Gly Tyr Leu Arg Ala Val Asp Leu Ile Arg His Gly Gly Lys Lys Met Arg Phe Leu Val Ala Lys Ser Asp Val Gly Lys Gln Pro Arg Arg Ser Ile her Ala Arg Pro Leu Ser Arg Gly Ala Ala Arg Thr Pro Pro Gln Ala Arg His Pro Val Pro Pro Gly Asp Thr Gly Leu Pro Pro Ala Phe Val Pro Val Leu <210> 30 <211> 356 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 2054049 <400> 30 Met Val Gly Val Ser Gly Lys Arg Ser Lys Glu Asp Glu Lys Tyr Leu Gln Ala Ile Met Asp Ser Asn Ala Gln Sex His Lys Ile Phe Ile Phe Asp Ala Arg Pro Ser Val Asn Ala Val Ala Asn Lys Ala Lys Gly Gly Gly Tyr Glu Ser Glu Asp Ala Tyr Gln Asn Ala Glu Leu Val Phe Leu Aep Ile His Asn Ile His Val Met Arg Glu Ser Leu Arg Lys Leu Lys Glu Ile Val Tyr Pro Asn Ile Glu Glu Thr His Trp Leu Ser Asn Leu Glu Ser Thr His Trp Leu Glu His Ile Lys Leu Ile Leu Ala Gly Ala Leu Arg Ile Ala Asp Lys Val Glu Ser Gly Lys Thr Ser Val Val Val His Cys Ser Asp Gly Trp Asp Arg Thr Ala Gln Leu Thr Ser Leu Ala Met Leu Met Leu Asp Gly Tyr Tyr Arg Thr Ile Arg Gly Phe Glu Val Leu Val Glu Lys Glu Trp Leu Ser Phe Gly His Arg Phe Gln Leu Arg Val Gly His Gly Asp Lys Asn His Ala Asp Ala Asp Arg Ser Pro Val Phe Leu Gln Phe Ile Asp Cys Val Trp Gln Met Thr Arg Gln Phe Pro Thr Ala Phe Glu Phe Asn Glu Tyr Phe Leu Ile Thr Ile Leu Asp His Leu Tyr Ser Cys Leu Phe Gly Thr Phe Leu Cys Asn Ser Glu Gln Gln Arg Gly Lys Glu Asn Leu Pro Lys Arg Thr Val Ser Leu Trp Ser Tyr Ile Asn Ser Gln Leu Glu Asp Phe Thr Asn Pro Leu Tyr Gly Ser Tyr Ser Asn His Val Leu Tyr Pro Val Ala Ser Met Arg His Leu Glu Leu Trp Val Gly Tyr Tyr Ile Arg Trp Asn Pro Arg Met Lys Pro Gln Glu Pro Ile His Asn Arg Tyr Lys Glu Leu Leu Ala Lys Arg Ala Glu Leu Gln Lys Lys Val Glu Glu Leu Gln Arg Glu Ile Ser Asn Arg Ser Thr Ser Ser Ser Glu Arg Ala Ser Ser Pro Ala Gln Cys Val Thr Pro Val Gln Thr Val Val <210> 31 <211> 453 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 2843910 <400> 31 Met Ala Gly Ala Gly Gly Phe Gly Cys Pro Ala Gly Gly Asn Asp Phe Gln Trp Cys Phe Ser Gln Val Lys Gly Ala Ile Asp Glu Asp Val Ala Glu Ala Asp Ile Ile Ser Thr Val Glu Phe Asn Tyr Ser Gly Asp Leu Leu Ala Thr Gly Asp Lys Gly Gly Arg Val Val Ile Phe Gln Arg Glu Gln Glu Asn Lys Ser Arg Pro His Ser Arg Gly Glu Tyr Asn Val Tyr Ser Thr Phe Gln Ser His Glu Pro Glu Phe Asp Tyr Leu Lys Ser Leu Glu Ile Glu Glu Lys Ile Asn Lys Ile Arg Trp Leu Pro Gln Gln Asn Ala Ala His Phe Leu Leu Ser Thr Asn Asp Lys Thr Ile Lys Leu Trp Lys Ile Ser Glu Arg Asp Lys Arg Ala Glu Gly Tyr Asn Leu Lys Asp Glu Asp Gly Arg Leu Arg Asp Pro Phe Arg Ile Thr Ala Leu Arg Val Pro Ile Leu Lys Pro Met Asp Leu Met Val Glu Ala Ser Pro Arg Arg Ile Phe Ala Asn Ala His Thr Tyr His Ile Asn Ser Ile Ser Val Asn Ser Asp His Glu Thr Tyr Leu Ser Ala Asp Asp Leu Arg Ile Asn Leu Trp His Leu Glu Ile Thr Asp Arg Ser Phe Asn Ile Val Asp Ile Lys Pro Ala Asn Met Glu Glu Leu Thr Glu Val Ile Thr Ala Ala Glu Phe His Pro His Gln Cys Asn Val Phe Val Tyr Ser Ser Ser Lys Gly Thr Ile Arg Leu Gars Asp Met Arg Ser Ser Ala Leu Cys Asp Arg His Ser Lys Phe Phe Glu Glu Pro Glu Asp Pro Ser Ser Arg Ser Phe Phe Ser Glu Ile Ile Ser Ser Ile Ser Asp Val Lys Phe Ser His Ser Gly Arg Tyr Met Met Thr Arg Asp Tyr Leu Ser Val Lys Val Trp Asp Leu Asn Met Glu Ser Arg Pro Val Glu Thr His Gln Val His Glu Tyr Leu Arg Ser Lys Leu Cys Ser Leu Tyr Glu Asn Asp Cys Ile Phe Asp Lys Phe Glu Cys Cys Trp Asn Gly Ser Asp Ser Ala Ile Met Thr Gly Ser Tyr Asn Aen Phe Phe Arg Met Phe Asp Arg Asp Thr Arg Arg Asp Val Thr Leu Glu Ala Ser Arg Glu Ser Ser Lys Pro Arg Ala Ser Leu Lys Pro Arg Lys Val Cys Thr Gly Gly Lys Arg Arg Lys Asp Glu Ile Ser Val Asp Ser Leu Asp Phe Asn Lys Lys Ile Leu His Thr Ala Trp His Pro Val Asp Asn Val Ile Ala Val Ala Ala Thr Asn Asn Leu Tyr Ile Phe Gln Asp Lys Ile Asn 450 <210> 32 <211> 1221 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 132240 <400> 32 cttttcctgg aatttctata atggaaagtc cattagaaag tcagccctta gattcagata 60 gaagcatcaa agaatcctct tttgaagaat caaatattga agatccactt attgtaacac 120 cagattgcca agaaaagacc tcaccaaaag gtgtcgagaa ccctgctgta caagagagta 180 accaaaaaat gttaggtcct cctttggagg tgctgaaaac gttagcctct aaaagaaatg 240 ctgttgcttt tcgaagtttt aacagtcata ttaatgcatc caataactca gaaccatcca 300 gaatgaacat gacttcttta gatgcaatgg atatttcgtg tgcctacagt ggttcatatc 360 ccatggctat aacccctact caaaaaagaa gatcctgtat gccacatcag accccaaatc 420 agatcaagtc gggaactcca taccgaactc cgaagagtgt gagaagaggg gtggcccccg 480 ttgatgatgg gcgaattcta ggaaccccag actaccttgc acctgagctg ttactaggca 540 gggcccatgg tcctgcggta gactggtggg cacttggagt ttgcttgttt gaatttctaa 600 caggaattcc ccctttcaat gatgaaacac cacaacaagt attccagaat attctgaaaa 660 gagatatccc ttggccagaa ggtgaagaaa agttatctga taatgctcaa agtgcagtag 720 aaatactttt aaccattgat gatacaaaga gagctggaat gaaagagcta aaacgtcatc 780 ctctcttcag tgatgtggac tgggaaaatc tgcagcatca gactatgcct ttcatccccc 840 agccagatga tgaaacagat acctcctatt ttgaagccag gaatactgct cagcacctga 900 ctgtatctgg atttagtctg tagcacaaaa attttccttt tagtctagcc ttgtgttata 960 gaatgaactt gcataattat atactcctta atactagatt gatctaaggg ggaaagatca 1020 ttatttaacc tagttcaatg tgcttttaat gtacgttaca gctttcacag agttaaaagg 1080 ctgaaaggaa tatagtcagt aatttatctt aacctcaaaa ctgtatataa atcttcaaag 1140 cttttttcat ttatttattt tgtttattgc actttatgaa aactgaagca tcaataaaat 1200 tagaggacac taaaaaaaaa a 1221 <210> 33 <211> 542 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 2180116 <400> 33 tggccaggct gggtccagca gcgcgatggc agctcagcgg ctgggcaagc gcgtgctgag 60 caagctgcag tctccatcgc gggcccgcgg gccagggggc agtcccgggg ggatgcagaa 120 gcggcacgcg cgcgtcaccg tcaagtatga ccggcgggag ctgcagcggc ggctggacgt 180 ggagaagtgg atcgacgggc gcctggagga gctgtaccgc ggcatggagg cagacatgcc 240 cgatgagatc aacattgatg aattgttgga gttagagagt gaagaggaga gaagecggaa 300 aatccaggga ctcctgaagt catgtgggaa acctgtcgag gacttcatcc aggagctgct 360 ggcaaagctt caaggcctcc acaggcagcc cggcctccgc cagccaagcc cctcccacga 420 cggcagcctc agccccctcc aggaccgggc ccggactgct cacccctgac cctcttgcac 480 tctccctgcc ccccggacgc cgcccagctt gcttgtgtat aagttgtatt taatggattc 540 WO 00/06728 PCT/US99/1?132 tt 542 <210> 34 <211> 2778 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <222> 2548, 2557, 2645, 2722, 2557, 2762, 2765 <223> Incyte Clone Number: 2197671 <400> 34 cgcggatcgt cgcggcccgg ccgtcccgtc ccaggaagtg gccgtcctga gcgccatggc 60 tcactccccg gtgcagtcgg gcctgcccgg catgcagaac ctaaaggcag acccagaaga 120 gctttttaca aaactagaga aaattgggaa gggctccttt ggagaggtgt tcaaaggcat -180 tgacaatcgg actcagaaag tggttgccat aaagatcatt gatctggaag aagctgaaga 240 tgagatagag gacattcaac aagaaatcac agtgctgagt cagtgtgaca gtccatatgt 300 aaccaaatat tatggatcct atctgaagga tacaaaatta tggataataa tggaatatct 360 tggtggaggc tccgcactag atctattaga acctggccga ttagatgaaa cccagatcgc 420 tactatatta agagaaatac tgaaaggact cgattatctc cattcggaga agaaaatcca 480 cagagacatt aaagcggcca acgtcctgct gtctgagcat ggcgaggtga agctggcgga 540 ctttggcgtg gctggccagc tgacagacac ccagatcaaa aggaacacct tcgtgggcac 600 cccattctgg atggcacccg aggtcatcaa acagtcggcc tatgactcga aggcagacat 660 ctggtccctg ggcataacag ctattgaact tgcaagaggg gaaccacctc attccgagct 720 gcaccccatg aaagttttat tcctcattcc aaagaacaac ccaccgacgt tggaaggaaa 780 ctacagtaaa cccctcaagg agtttgtgga ggcctgtttg aataaggagc cgagctttag 840 acccactgct aaggagttat tgaagcacaa gtttatacta cgcaatgcaa agaaaacttc 900 ctacttgacc gagctcatcg acaggtacaa gagatggaag gccgagcaga gccatgacga 960 ctcgagctcc gaggattccg acgcggaaac agatggccaa gcctcggggg gcagtgattc 1020 tggggactgg atcttcacaa tccgagaaaa agatcccaag aatctcgaga atggagctct 1080 tcagccatcg gacttggaca gaaataagat gaaagacatc ccaaagaggc ctttctctca 1140 gtgtttatct acaattattt ctcctctgtt tgcagagttg aaggagaaga gccaggcgtg 1200 cggagggaac ttggggtcca ttgaagagct gcgaggggcc atctacctag cggaggaggc 1260 gtgccctggc atctccgaca ccatggtggc ccagctcgtg cagcggctcc agagatactc 1320 tctaagtggt ggaggaactt catcccactg aaattccttt ggcatttggg gttttgtttt 1380 tctttttttc cttcttcatc ctcctccttt tttaaaagtc aacgagagcc ttcgctgact 1440 ccaccgaaga ggtgcgccac tgggagccac cccagtgcca ggcgcccgtc cagggacaca 1500 cacagtcttc actgtgctgc agccagatga agtctctcag atgggtgggg agggtcagct 1560 ccttccagcg atcattttat tttattttat tacttttgtt tttaatttta accatagtgc 1620 acatattcca ggaaagtgtc tttaaaaaca aaaacaaacc ctgaaatgta tatttgggat 1680 tatgataagg caactaaaga catgaaacct caggtatcct gctttaagtt gataactccc 1740 tctgggagct ggagaatcgc tctggtggat gggtgtacag atttgtatat aatgtcattt 1800 ttacggaaac cctttcggcg tgcataagga atcactgtgt acaaactggc caagtgcttc 1860 tgtagataac gtcagtggag taaatattcg acaggccata acttgagtct attgccttgc 1920 ctttattaca tgtacatttt gaattctgtg accagtgatt tgggttttat tttgtatttg 1980 cagggtttgt cattaataat taatgcccct ctcttacaga acactcctat ttgtacctca 2040 acaaatgcaa attttccccg tttgccctac gccccttttg gtacacctag aggttgattt 2100 cctttttcat cgatggtact atttcttagt gttttaaatt ggaacatatc ttgcctcatg 2160 aagctttaaa ttataatttt cagtttctcc ccatgaagcg ctctcgtctg acatttgttt 2220 ggaatcgtgc cactgctggt ctgcgccaga tgtaccgtcc tttccaatac gattttctgt 2280 tgcaccttgt agtggattct gcatatcatc tttcccacct aaaaatgtct gaatgcttac 2340 acaaataaat tttataacac gcttattttg catactcctt gaaatgtgac tettcagagg 2400 acagggtacc tgctgtgtat gtgtggccgt gcgtgtgtac tcgtggctgt gtgtgtgtga 2460 tgagacactt tggaagactc cagggagaag ttcccagggc tggagctgcc gagtgcccag 2520 gtcagcgccc tgggctgctt gcgcaatngc tcaccgngat gatgcattgg aggttgctga 2580 cctgtgcgat tgctgtagcg gttgccaggg accttaaggg gttattttgc ttccctggga 2640 ggggncctat gtttctaggc aagcagccat gtgtctaatt ttctgggttt gctgtgggga 2700 cctgattggg ggagggggaa anctttgggg ttcttggagt gggagggttc gtgccancaa 2760 tnttncctgg taaaaaag 2778 <210> 35 <211> 1424 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 2594943 <400> 35 ggctcagcct ccgacccagg tggtctggag cctgccggga gagtggtggc atctgagagg 60 ctggtcgtgg actgtggttg ggggaggtgg gagctgtttt aaccgtgtgc cccctctcct 120 gtgccggcgt gggcatcccc cggggcagtg gaacgcgggc gctcctccag cttccgagtc 180 cagccagcct gggcgcgggg cgccgccccc gagacacccg aggagtccgt tcctccctgg 240 ttacgtggac tgtggagctg gtctcttgtg gctcagcgcc gtgcggaggt tgaagcgtac 300 ctgcggaggt cgcaccaggg cgtgaggagg aggaggaagg gcatgagccg agcttgagga 360 atccgtgctc caaactctac actcaagggt ggcccttggg tagggtgaag atcccctgtc 420 tttatcctag ttccacacct tggtgtgggt tactgggtgc aggatgaact gtcgctcgga 480 ggtgctggag gtgtcggtgg aggggcggca ggtggaggag gccatgctgg ctgtgctgca 540 cacggtgctt ctgcaccgca gcacaggcaa gttccactac aagaaggagg gcacctactc 600 cattggcacc gtgggcaccc aggatgttga ctgtgacttc atcgacttca cttatgtgcg 660 tgtctcttct gaggaactgg atcgtgccct gcgcaaggtt gttggggagt tcaaggatgc 720 actgcgcaac tctggtggcg atgggctggg gcagatgtcc ttggagttct accagaagaa 780 gaagtctcgc tggccattct cagacgagtg catcccatgg gaagtgtgga cggtcaaggt 840 gcatgtggta gccctggcca cggagcagga gcggcagatc tgccgggaga aggtgggtga 900 gaaactctgc gagaagatca tcaacatcgt ggaggtgatg aatcggcatg agtacttgcc 960 caagatgccc acacagtcgg aggtggataa cgtgtttgac acaggcttgc gggacgtgca 1020 gccctacctg tacaagatct ccttccagat cactgatgcc ctgggcacct cagtcaccac 1080 caccatgcgc aggctcatca aagacaccct tgccctctga gcgtcgctgg atctctggga 1140 gctccttgat ggctcccaga ccttggcttt tgggaattgc acttttgggc ctttgggctc 1200 tggaacctgc tctgggtcat tggtgagact tggaaggggc agcccccgct ggcttcttgg 1260 ttttgtggtt gccagcctca ggtcatcctt ttaatctttg ctgatggttc agtcctgcct 1320 ctactgtctc tccatagccc tggtggggtc ccccttcttt ctccactgta cagaagagcc 1380 accactggga tggggaataa agttgagaac atgaaaaaaa aaaa 1424 <210> 36 <211> 1839 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 1513871 <400> 36 cctcctcctc ggccagctca ggttgcagct tctctgggga actgctcacc tttccggagc 60 aggggaagct gccccgtgcc cgggagggag cgggcgcacc gcggccccca ggacacgcgc 120 tgacccggct gcccagtccc tcatgatcat gaacaagatg aagaacttta agcgccgttt 180 ctccctgtca gtgccccgca ctgagaccat tgaagaatcc ttggctgaat tcacggagca 240 attcaaccag ctccacaacc ggcggaatga gaacttgcag ctcggtcctc ttggcagaga 300 ccccccgcag gagtgcagca ccttctcccc aacagacagc ggggaggagc cggggcagct 360 ctcccctggc gtgcagttcc agcggcggca gaaccagcgc cgcttctcca tggaggacgt 420 cagcaagagg ctctctctgc ccatggatat ccgcctgccc caggaattcc tacagaagct 480 acagatggag agcccagatc tgcccaagcc gctcagccgc atgtcccgcc gggcctccct 540 gtcagacatt ggctttggga aactggaaac atacgtgaaa ctggacaaac tgggagaggg 600 cacctatgcc acagtcttca aagggcgcag caaactgacg gagaaccttg tggccctgaa 660 agagatccgg ctggagcacg aggagggagc gccctgcact gccatccgag aggtgtctct 720 gctgaagaac ctgaagcacg ccaatattgt gaccctgcat gacctcatcc acacagatcg 780 gtccctcacc ctggtgtttg agtacctgga cagtgacctg aagcagtatc tggaccactg 840 tgggaacctc atgagcatgc acaacgtcaa gattttcatg ttccagctgc tccggggcct 900 cgcctactgt caccaccgca agatcctgca ccgggacctg aagccccaga acctgctcat 960 caacgagagg ggggagctga agctggccga ctttggactg gccagggcca agtcagtgcc 1020 cacaaagact tactccaatg aggtggtgac cctgtggtac aggccccccg atgtgctgct 1080 gggatccaca gagtactcca cccccattga tatgtggggc gtgggctgca tccactacga 1140 gatggccaca gggaggcccc tcttcccggg ctccacagtc aaggaggagc tgcacctcat 1200 ctttcgcctc ctcgggaccc ccacagaaga gacgtggccc ggcgtgaccg ccttctctga 1260 gttccgcacc tacagcttcc cctgctacct cccgcagccg ctcatcaacc acgcgcccag 1320 gttggatacg gatggcatcc acctcctgag cagcctgctc ctgtatgaat ccaagagtcg 1380 catgtcagca gaggctgccc tgagtcactc ctacttccgg tctctgggag agcgtgtgca 1440 ccagcttgaa gacactgcct ccatcttctc cctgaaggag atccagctcc agaaggaccc 1500 aggctaccga ggcttggcct tccagcagcc aggacgaggg aagaacaggc ggcagagcat 1560 cttctgagcc acgcccacct tgctgtggcc aagggacaag agatcacatg gagcacaaat 1620 tcgggtagga tggagcctgt gtggccctcg gaggactgaa gaacgagggc tgacagcagc 1680 ctggaagacc gcttggcagg cttttggcca agtgtttttc tttgtggttt cgatctgctg 1740 ccagtagttt cagtggatac aacgtgcttt aggagttggg tgggaaagtc ttgctagagg 1800 gtttaggggg aggtttctac cgttgactcg gtttagggc 1839 <210> 37 <211> 2024 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 156108 <400> 37 gtcagctctg gttcggagaa gcagcggctg gcgtgggcca tccggggaat gggcgccctc 60 gtgacctagt gttgcggggc aaaaagggtc ttgccggcct cgctcgtgca ggggcgtatc 120 tgggcgcctg agcgcggcgt gggagccttg ggagccgccg cagcaggggg cacacccgga.180 accggcctga gcgcccggga ccatgaacgg ggaggccatc tgcagcgccc tgcccaccat 240 tccctaccac aaactcgccg acctgcgcta cctgagccgc ggcgcctctg gcactgtgtc 300 gtccgcccgc cacgcagact ggcgcgtcca ggtggccgtg aagcacctgc acatccacac 360 tccgctgctc gacagtgaaa gaaaggatgt cttaagagaa gctgaaattt tacacaaagc 420 tagatttagt tacattcttc caattttggg aatttgcaat gagcctgaat ttttgggaat 480 agttactgaa tacatgccaa atggatcatt aaatgaactc ctacatagga aaactgaata 540 tcctgatgtt gcttggccat tgagatttcg catcctgcat gaaattgccc ttggtgtaaa 600 ttacctgcac aatatgactc ctcctttact tcatcatgac ttgaagactc agaatatctt 660 attggacaat gaatttcatg ttaagattgc agattttggt ttatcaaagt ggcgcatgat 720 gtccctctca cagtcacgaa gtagcaaatc tgcaccagaa ggagggacaa ttatctatat 780 gccacctgaa aactatgaac ctggacaaaa atcaagggcc agtatcaagc acgatatata 840 tagctatgca gttatcacat gggaagtgtt atccagaaaa cagccttttg aagatgtcac 900 caatcctttg cagataatgt atagtgtgtc acaaggacat cgacctgtta ttaatgaaga 960 aagtttgcca tatgatatac ctcaccgagc acgtatgatc tctctaatag aaagtggatg 1020 ggcacaaaat ccagatgaaa gaccatcttt cttaaaatgt ttaatagaac ttgaaccagt 1080 tttgagaaca tttgaagaga taacttttct tgaagctgtt attcagctaa agaaaacaaa 1140 gttacagagt gtttcaagtg ccattcacct atgtgacaag aagaaaatgg aattatctct 1200 gaacatacct gtaaatcatg gtccacaaga ggaatcatgt ggatcctctc agctccatga 1260 aaatagtggt tctcctgaaa cttcaaggtc cctgccagct cctcaagaca atgatttttt 1320 atctagaaaa gctcaagact gttattttat gaagctgcat cactgtcctg gaaatcacag 1380 ttgggatagc accatttctg gatctcaaag ggctgcattc tgtgatcaca agaccactcc 1440 atgctcttca gcaataataa atccactctc aactgcagga aactcagaac gtctgcagcc 1500 tggtatagcc cagcagtgga tccagagcaa aagggaagac attgtgaacc aaatgacaga 1560 agcctgcctt aaccagtcgc tagatgccct tctgtccagg gacttgatca tgaaagagga 1620 ctatgaactt gttagtacca agcctacaag gacctcaaaa gtcagacaat tactagacac 1680 tactgacatc caaggagaag aatttgccaa agttatagta caaaaattga aagataacaa 1740 acaaatgggt cttcagcctt acccggaaat acttgtggtt tctagatcac catctttaaa 1800 tttacttcaa aataaaagca tgtaagtgac tgtttttcaa gaagaaatgt gtttcataaa 1860 aggatattta tatctctgtt gctttgactt tttttatata aaatccgtga gtattaaagc 1920 tttattgaag gttctttggg taaatattag tctccctcca tgacactgca gtattttttt 1980 taattaatac aagtaaaaag tttgaatttt gctacataaa aaaa 2024 <210> 38 <211> 1861 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 2883243 <400> 38 gcttcttagt gaggttggca ttatgttaag gctggtatgg aagacaactg atgaagcagg 60 agtggtctgg tgacattttt ctgacttgat tggctggggc gtgtgatgta ataggtttca 120 gtgcagcccc ttataggttt taaaatgaat tccaagacac cattacaaag aaagccggac 180 tcttttctta taactgagct cagccaagga aactcttgca caaatgtaca atactgtttg 240 gaatatggaa gacctggatt tagaatatgc caagacagat ataaattgtg gcacagactt 300 gatgttttat atagaaatgg acccaccagc actgcctcct aaaccaccaa aacctactac 360 tgtagccaac aacggtatga ataacaatat gtccttacaa gatgctgaat ggtactgggg 420 agatatctcg agggaagaag tgaatgaaaa acttcgagat acagcagacg ggaccttttt 480 ggtacgagat gcgtctacta aaatgcatgg tgattatact cttacactaa ggaaaggggg 540 aaataacaaa ttaatcaaaa tatttcatcg agatgggaaa tatggcttct ctgacccatt 600 aaccttcagt tctgtggttg aattaataaa ccactaccgg aatgaatctc tagctcagta 660 taatcccaaa ttggatgtga aattacttta tccagtatcc aaataccaac aggatcaagt 720 tgtcaaagaa gataatattg aagctgtagg gaaaaaatta catgaatata acactcagtt 780 tcaagaaaaa agtcgagaat atgatagatt atatgaagaa tatacccgca catcccagga 840 aatccaaatg aaaaggacag ctattgaagc atttaatgaa accataaaaa tatttgaaga 900 acagtgccag acccaagagc ggtacagcaa agaatacata gaaaagttta aacgtgaagg 960 caatgagaaa gaaatacaaa ggattatgca taattatgat aagttgaagt ctcgaatcag 1020 tgaaattatt gacagtagaa gaagattgga agaagacttg aagaagcagg cagctgagta 1080 tcgagaaatt gacaaacgta tgaacagcat taaaccagac cttatccagc tgagaaagac 1140 gagagaccaa tacttgatgt ggttgactca aaaaggtgtt cggcaaaaga agttgaacga 1200 gtggttgggc aatgaaaaca ctgaagacca atattcactg gtggaagatg atgaagattt 1260 gccccatcat gatgagaaga catggaatgt tggaagcagc aaccgaaaca aagctgaaaa 1320 cctgttgcga gggaagcgag atggcacttt tcttgtccgg gagagcagta aacagggctg 1380 ctatgcctgc tctgtagtgg tggacggcga agtaaagcat tgtgtcataa acaaaacagc 1440 aactggctat ggctttgccg agccctataa cttgtacagc tctctgaaag aactggtgct 1500 acattaccaa cacacctccc ttgtgcagca caacgactcc ctcaatgtca cactagccta 1560 cccagtatat gcacagcaga ggcgatgaag cgcttactct ttgatccttc tcctgaagtt 1620 cagccaccct gaggcctctg gaaagcaaag ggctcctctc cagtctgatc tgtgaattga 1680 gctgcagaaa cgaagccaac tttttttgga tgggactagt gctttctttc acaaaaaaga 1740 agtaggggaa gacatgcagc ctaaggctgt atgatgacca cacgttccta agctggagtg 1800 cttatccctt ctttttcttt ttttctttgg tttaatttaa agccacaacc acatacaaca 1860 c <210> 39 <211> 2045 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 3173355 <400> 39 cttggctgga acctgagacg gattcgctcc caaatgatgc tccagtggca ggagcaactc 60 aagttcatca ttgtcctgag agagaggagc agcgcggttc tcggccggga cagcagaacg 120 ccaggggacc ctcacctggg cgcgccgggg cacgggcttt gattgtcctg gggtcgcgga 180 gacccgcgcg cctgccctgc acgccgggcg gcaacctttg cagtcgcgtt ggctgctgcg 240 atcggccggc gggtccctgc cgaaggctcg gctgcttctg tccacctctt acacttcttc 300 atttatcggt ggatcatttc gagagtccgt cttgtaaatg tttggcactt tgctacttta 360 ttgcttcttt ctggcgacag ttccagcact cgccgagacc ggcggagaaa ggcagctgag 420 cccggagaag agcgaaatat ggggacccgg gctaaaagca gacgtcgtcc ttcccgcccg 480 ctatttctat attcaggcag tggatacatc agggaataaa ttcacatctt ctccaggcga 540 aaaggtcttc caggtgaaag tctcagcacc agaggagcaa ttcactagag ttggagtcca 600 ggttttagac cgaaaagatg ggtccttcat agtaagatac agaatgtatg caagctacaa 660 aaatctgaag gtggaaatta aattccaagg gcaacatgtg gccaaatccc catatatttt 720 aaaagggccg gtttaccatg agaactgtga ctgtcctctg caagatagtg cagcctggct 780 acgggagatg aactgccctg aaaccattgc tcagattcag agagatctgg cacatttccc 840 tgctgtggat ccagaaaaga ttgcagtaga aatcccaaaa agatttggac agaggcagag 900 cctatgtcac tacaccttaa aggataacaa ggtttatatc aagactcatg gtgaacatgt 960 ' aggttttaga attttcatgg atgccatact actttctttg actagaaagg tgaagatgcc 1020 agatgtggag ctctttgtta atttgggaga ctggcctttg gaaaaaaaga aatccaattc 1080 aaacatccat ccgatctttt cctggtgtgg ctccacagat tccaaggata tcgtgatgcc 1140 tacgtacgat ttgactgatt ctgttctgga aaccatgggc cgggtaagtc tggatatgat 1200 gtccgtgcaa gctaacacgg gtcctccctg ggaaagcaaa aattccactg ccgtctggag 1260 agggcgagac agccgcaaag agagactcga gctggttaaa ctcagtagaa aacacccaga 1320 actcatagac gctgctttca ccaacttttt cttctttaaa cacgatgaaa acctgtatgg 1380 tcccattgtg aaacatattt cattttttga tttcttcaag cataagtatc aaataaatat 1440 cgatggcact gtagcagctt atcgcctgcc atatttgcta gttggtgaca gtgttgtgct 1500 gaagcaggat tccatctact atgaacattt ttacaatgag ctgcagccct ggaaacacta 1560 cattccagtt aagagcaacc tgagcgatct gctagaaaaa cttaaatggg cgaaagatca 1620 cgatgaagag gccaaaaaga tagcaaaagc aggacaagaa tttgcaagaa ataatctcat 1680 gggcgatgac atattctgtt attatttcaa acttttccag gaatatgcca atttacaagt 1740 gagtgagccc caaatccgag agggcatgaa aagggtagaa ccacagactg aggacgacct 1800 cttcccttgt acttgccata ggaaaaagac caaagatgaa ctctgatatg caaaataact 1860 tctattagaa taatggtgct ctgaagactc ttcttaacta aaaagaagaa tttttttaag 1920 tattaattcc atggacaata taaaatctgt gtgattgttt gcagtatgaa gacacatttc 1980 tacttatgca gtattctcat gactgtactt taaagtacat ttttagaatt ttataataaa 2040 accac <210> 40 <211> 1260 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 5116906 <400> 40 cgatattttt ctttcttagt ttcccatttc atattgtttt gtcaaatcaa ctgtgactca 60 ttaacatctc ttttccctag gttttgctgg cacacctgga tatctttctc cagaagtttt 120 acgtaaagat ccttatggaa agccagtgga tatgtgggca tgtggtgtca ttctctatat 180 tctacttgtg gggtatccac ccttctggga tgaagaccaa cacagactct atcagcagat 240 caaggctgga gcttatgatt ttccatcacc agaatgggac acggtgactc ctgaagccaa 300 agacctcatc aataaaatgc ttactatcaa ccctgccaaa cgcatcacag cctcagaggc 360 actgaagcac ccatggatct gtcaacgttc tactgttgct tccatgatgc acagacagga 420 gactgtagac tgcttgaaga aatttaatgc tagaagaaaa ctaaagggtg ccatcttgac 480 aactatgctg gctacaagga atttctcagc agccaagagt ttgttgaaga aaccagatgg 540 agtaaaggag tcaactgaga gttcaaatac aacaattgag gatgaagatg tgaaagcacg 600 aaagcaagag attatcaaag tcactgaaca actgatcgaa gctatcaaca atggggactt'660 tgaagcctac acaaaaatct gtgacccagg ccttactgct tttgaacctg aagctttggg 720 taatttagtg gaagggatgg attttcaccg attctacttt gaaaatgctt tgtccaaaag 780 caataaacca atccacacta ttattctaaa ccctcatgta catctggtag gggatgatgc 840 cgcctgcata gcatatatta ggctcacaca gtacatggat ggcagtggaa tgccaaagac 900 aatgcagtca gaagagactc gtgtgtggca ccgccgggat ggaaagtggc agaatgttca 960 ttttcatcgc tcggggtcac caacagtacc catcaactaa atttcaacag tgccacttct 1020 gcattctctg ttctcaaggc acctggatgg tgaccctggg ccgtcctctc ctcctcttca 1080 tgcatgtttc tgagtgcatg aagttgtgaa ggtcctacat gtaatgcata tgtgatgcat 1140 catcttatca tatattcctt cctatacatt gtttacactt caactacggg gatgttccac 1200 acaaacttaa attactgttg gcaaaacaat agggggagat tagacaaaaa aaaaaaaaaa 1260 <210> 41 <211> 2059 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 940589 <400> 41 aaaccataga aacgctaatg aaagcagaca tcaaaatctg gatccttaca ggggacaagc 60 aagaaactgc cattaacatc ggacactcct gcaaactgtt gaagaagaac atgggaatga 120 ttgttataaa tgaaggctct cttgattctt tctctaatac acagaattct aggaaggagg 180 ctgttctttt agccaaaatg aaacacccta atattgttgc cttcaaagaa tcatttgaag 240 ctgaaggaca cttgtatatt gtgatggaat actgtgatgg aggggatcta atgcaaaaga 300 ttaaacagca gaaaggaaag ttatttcctg aagacatgat acttaattgg tttacccaaa 360 tgtgccttgg agtaaatcac attcacaaga aacgtgtgct acacagagat atcaagtcca 420 agaatatctt cctcactcag aatggaaaag tgaaattggg agactttgga tctgcccgtc 480 ttctctccaa tccgatggca tttgcttgta cctatgtggg aactccttat tatgtgcctc 540 cagaaatttg ggaaaacctg ccttataaca ataaaagtga catctggtcc ttgggttgca 600 tcctgtatga actctgtacc cttaagcatc catttcaggc aaatagttgg aaaaatctta 660 tcctcaaagt atgtcaaggg tgcatcagtc cactgccgtc tcattactcc tatgaacttc 720 agttcctagt caagcagatg tttaaaagga atccctcaca tcgcccctcg gctacaacgc 780 ttctctctcg aggcatcgta gctcggcttg tccagaagtg cttacccccc gagatcatca 840 tggaatatgg tgaggaagta ttagaagaaa taaaaaattc gaagcataac acaccaagaa 900 aaaaaacaaa ccccagcaga atcaggatag ctttgggaaa tgaagcaagc acagtgcaag 960 aggaagaaca agatagaaag ggtagccata ctgatttgga aagcattaat gaaaatttag 1020 ttgaaagtgc attgagaaga gtaaacagag aagaaaaagg taataagtca gtccatctga 1080 ggaaagccag ttcaccaaat cttcatagac gacagtggga gaaaaatgta cccaatacag 1140 ctcttacagc tttggaaaat gcatccatac tcacctccag tttaacagca gaggacgata 1200 gaggtggttc tgtaataaag tacagcaaaa atactactcg taagcagtgg ctcaaagaga 1260 ccccggacac tttgttgaac atccttaaga atgctgatct cagcttggct tttcaaacat 1320 acacaatata tagaccaggt tcagaagggt tcttgaaagg ccccctgtct gaagaaacag 1380 aagcatcgga cagtgttgat ggaggtcacg attctgtcat tttggatcca gagcgacttg 1440 agcctgggct agatgaggag gacacggact ttgaggagga agatgacaac cccgactggg 1500 tgtcagagct gaagaagcga gctggatggc aaggcctgtg cgacagataa tgcctgagga 1560 aatgttcctg agtcacgctg aggagagcct tcactcagga gttcatgctg agatgatcat 1620 gagttcatgc gacgtatatt ttcctttgga aacagaatga agcagaggaa actcttaata 1680 cttaaaatcg ttcttgatta gtatcgtgag tttgaaaagt ctagaactcc tgtaagtttt 1740 tgaactcaag ggagaaggta tagtggaatg agtgtgagca tcgggctttg cagtcccata 1800 gaacagaaat gggatgctag cgtgccacta cctacttgtg tgattgtggg aaattactta 1860 acctcttcaa gccccaattt cctcaaccat aaaatgaaga taataatgcc tacctcagag 1920 ggatgctgac cacagacctt tatagcagcc cgtatgatat tattcacatt atgatatgtg 1980 tttattatta tgtgactctt tttacatttc ctaaaggttt gagaattaaa tatatttaat 2040 tatgaaaaaa aaaaaaaaa 2059 <210> 42 <211> 1023 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 304421 <400> 42 gaggcagagg ggtgggcggg ctggcccatg gctgagacct ctctcccaga gctgggggga 60 gaggacaaag ccacgccttg ccccagcatc ctggagctgg aggagctcct gcgggcaggg 120 aagtcttctt gcagccgtgt ggacgaagtt tggcccaacc ttttcatagg agatgcgatg 180 gactcactgc agaagcagga cctccggagg cccaagatcc atggggcagt ccaggcatct 240 ccctaccagc cgcccacatt ggcttcgctg cagcgcttgc tgtgggtccg tcaggctgcc 300 acactgaacc atatcgatga ggtctggccc agcctcttcc tgggagatgc gtacgcagcc 360 cgggacaaga gcaagctgat ccagctggga atcacccacg ttgtgaatgc cgctgcaggc 420 aagttccagg tggacacagg tgccaaattc taccgtggaa tgtccctgga gtactatggc 480 atcgaggcgg atgacaaccc cttcttcgac ctcagtgtct actttctgcc tgttgctcga 540 tacatccgag ctgccctcag tgttccccaa ggccgcgtgc tggtacactg tgccatgggg 600 gtaagccgct ctgccacact tgtcctggcc ttcctcatga tctatgagaa catgacgctg 660 gtagaggcca tccagacggt gcaggcccac cgcaatatct gccctaactc aggcttcctc 720 cggcagctcc aggttctgga caaccgactg gggcgggaga cggggcggtt ctgatctggc 780 aggcagccag gatccctgac ccttggccca accccaccag cctggccctg ggaacagcag 840 gctctgctgt ttctagtgac cctgagatgt aaacagcaag tgggggctga ggcagaggca 900 gggatagctg ggtggtgacc tcttagcggg tggatttccc tgacccaatt cagagattct 960 ttatgcaaaa gtgagttcag tccatctcta taataaaata ttcatcgtca taaaaaaaaa 1020 aaa <210> 43 <211> 4416 <212> DNA

WO 00/0672$
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 1213802 <400> 43 gaaatttttt tctgcctcat tattattaat tcatggattg agtgttggtt cgacctacag 60 gcgtaataga ttggaactca gtgaagacac agatgttcct gttcagagca accagctaat 120 gattacagtt taaagacaat ttctgtgatc aagttgtcat ttggaagatt aaacccattt 180 cacgaggact tggagcctgg tccttgcttt gaggaagcag tggcttgttt caagaagcca 240 cttctgatct aagaatctac ccagcatgcc taatcaagga gaagactgct attttttttt 300 ctattccaca tgtaccaaag gcgacagctg cccattccgt cactgtgaag ctgcaatagg 360 aaatgaaact gtttgcacat tatggcaaga agggcgctgt tttcgacagg tgtgcaggtt 420 tcggcacatg gagattgata aaaaacgcag tgaaattcct tgttattggg aaaatcagcc 480 aacaggatgt caaaaattaa actgcgcttt ccatcacaat agaggacgat atgttgatgg 540 ccttttecta cctccgagca aaactgtgtt gcccactgtg cctgagtcac cagaagagga 600 agtgaaggct agccaacttt cagttcagca gaacaaattg tctgtccagt ccaatccttc 660 ccctcagctg cggagcgtta tgaaagtaga aagttccgaa aatgttccta gccccacgca 720 tccaccagtt gtaattaatg ctgcagatga tgatgaagat gatgatgatc agttttctga 78p ggaaggtgat gaaaccaaaa cacctaccct gcaaccaact cctgaagttc acaatggatt 840 acgagtgact tctgtccgga aacctgcagt caatataaag caaggtgaat gtttgaattt 900 tggaataaaa actcttgagg aaattaagtc aaagaaaatg aaggaaaaat ctaagaagca 960 aggt9agggt tettcaggag tttccagtct tttactccac cctgagcccg ttccaggtcc 1020 tgaaaaagaa aatgtcagga ctgtggtgag gacagtaact ctctccacca aacaaggaga 1080 agaacccttg gttagattga gtcttactga gagactgggg aaacgaaaat tttcagcagg 1140 cggtgacagt gatcctccat taaagcgtag cctggcacag aggcta ggga agaaagttga 1200 agctccagaa actaacattg acaaaacacc aaagaaagct caagtttcca agtctcttaa 1260 ggagcgatta ggcatgtcag ctgatccaga taatgaggat gcaacagata aagttaataa 1320 agttggtgag atccatgtga agacattaga agaaattctt cttgaaagag ccagtcagaa 1380 acgtggagaa ttgcaaacta aactcaagac agaaggacct tcaaaaactg atgattctac 1440 ttcaggagca agaagctcct ccactatccg tatcaaaacc ttctctgagg tcctggctga 1500 aaaaaaacat cggcagcagg aagcagagag acaaaaaagc aaaaaggata caacttgcat 1560 caagctaaag attgatagtg aaattaaaaa aacagtagtt ttgccaccca ttgttgccag 1620 cagaggacaa tcagaggagc ctgcaggtaa aacaaagtct atgcaggagg tgcacatcaa 1680 gacgctggaa gaaattaaac tggagaaggc actgagggtg cagcagagct ctgagagcag 1740 caccagctcc ccgtctcaac acgaggccac tccaggggca aggcggctgc tgcgaatcac 1800 caaaagaaca gggatgaaag aagagaagaa ccttcaggaa ggaaatgaag ttgattctca 1860 gagcagtatt agaacagaag ctaaagaggc ttcaggtgag accacaggag ttgacatcac 1920 taaaattcaa gtcaagagat gtgagaccat gagagagaag cacatgcaga aacagcagga 1980 gagggaaaaa tcagtcttga cacctcttcg gggagatgta gcctcttgca atacccaagt 2040 ggcagagaaa ccagtgctca ctgctgtgcc aggaatcaca cggcacctga ccaagcggct 2100 tcccacaaag tcatcccaga aggtggaggt agaaacctca gggattggag actcattatt 2160 gaatgtgaaa tgtgcagcac agaccttgga aaaaaggggt aaagctaaac ccaaagtgaa 2220 cgtgaagcca tctgtggtta aagttgtgtc atcccccaaa ttggccccaa aacgtaaggc 2280 agtggagatg cacgctgctg tcattgccgc tgtgaagcca ctcagctcca gcagtgtcct 2340 acaggaaccc ccagccaaaa aggcagctgt ggctgttgtc ccgcttgtct ctgaggacaa 2400 atcagtcact gtgcctgaag cagaaaatcc tagagacagt cttgtgctgc ctccaaccca 2460 gtcctcttca gattcctcac ccccggaggt gtctggccct tcctcatccc aaatgagcat 2520 gaaaactcgc cgactcagct ctgcctcaac aggaaagccc ccactctctg tggaggatga 2580 ttttgagaaa ctaatatggg agatttcagg aggcaaattg gaagctgaga ttgacctgga 2640 tcctgggaaa gatgaagatg accttctgct tgagctatca gaaatgattg atagctgaag 2700 gtggtagtga ggacacttta aaaaaaaaat cgccaaaaaa ctggacttag tttcatctat 2760 tgtaacattt acctgagatg atcatttctt tagtctagaa tttgccccaa atcagaagta 2820 tacctctgaa ttatctgtat gtgtcctgga ttccttgggg tcagattttt aaagttactt 2880 tataaccatt ttgtccattt gatgccattg tttatcatct tttgagaaaa aagttctgtc 2940 atacccttct ctccacaaaa aagagactga gagggagatc aagtgaaagg gtgcaagcga 3000 acttagtgac tccttgaggt gtttgtcagt tttggttttt ttcttctttg ttgtattctt 3060 tatgtattgt cttgatgtac ttaatattac ctgagtttga aatggatgaa gacagctgct 3120 accattaagg accaaatttt atgctaccac taaacaaaaa tacccactca gtctgtgtta 3180 aattgtatgt ctttttaaag gtatttaaag attcaactaa gctttaaaga gggctgagca 3240 gctcaggaag cctgtaatgt gggcataact ctttggacct gatcttgatg cttctgctgc 3300 tctgttagcc tctgaagagc aatatctaat ttattattac tgtaattttt taaaaggctt 3360 taaagtgcct caggggtccc ctgaaactaa ttttctattt ctgggattcc ctggattcat 3420 tatatgagat ggtgacatga ttagaggaat tcttttttag tatgaaaatt gtcccttttc 3480 ttcttcagta cttgcctcct tgctggcatt gaattaacac agggacaaaa tttggttaat 3540 tttttatttc taactctccc aacaaacccc tgttgcccag tatttgtttg gtggccttta 3600 accacctgag ggaaaaaatg agcttattca agctgccaat atttatctat gggctgtagc 3660 agtacactga attgtactgt gccagggata ttgagatgct ctgggggtgt attgtatacc 3720 tgccagtttt cttcatttct gaattgagtt ttcttttctt gatgttggtt tccttcatat 3780 cacctcaagg tttagatttg tgaaggaata agcatgatgg aaataatagt cttgaaagga 3840 gatatgttgt atataatcag gaggaagagg aaggaaggac ttacccattt tgatattttg 3900 ctgtaggtgg ccagttttgt ttctcatagg gaaatctgac ccacctgtca tgttggctcc 3960 taaggaactg ctgttgtaag cggctcatca agagttgaac ttcacgtagc cttgttggga 4020 atatggaaaa ggaagaaagc cacaggactg cccattcagt cttgggaaga ttgggatgat 4080 tctgcacaag caaaaatgac tgaagtttat gtatagacac acctetacca atccatcttc 4140 agctgactga atgttgtatg atagcccttc tccaaagcag aggtagaatg ttcaggtttc 4200 accatggatt ttctacttat ttcgtttttg gaatcagctt acagattcca ggtccctttt 4260 gtatatattc tttattcttt tgctttttta aaaaataatt ttgtttcata tttaaagcac 4320 ttgtattagt caatgtttcg tgttccgcat tatttgaacc atttgccctt acagaaagag 4380 aaatacttgt ttgtgtttta aataaaactg atgtag 4416 <210> 44 <211> 2068 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 1378134 <400> 44 gcagtccatc agtccgctga tgcgtcgccg ggccagcaac gctgccgccg cagcccacac 60 ga,ttggcggc agtaagcaca caatgaatga tcacctgcat gtcggcagcc acgctcacgg 120 acagatccag gttcgacagt tgtttgagga taacagtaac aagcggacag tgctcacgac 180 acaaccaaat gggcttacaa cagtgggcaa aacgggcttg ccagtggtgc cagagcggca 240 gctggacagc attcatagac ggcaggggag ctccacctct ctaaagtcca tggaaggcat 300 ggggaaggtg aaagccaccc ccatgacacc tgaacaagca atgaagcaat acatgcaaaa 360 actcacagcc ttcgaacacc atgagatttt cagctaccct gaaatatatt tcttgggtct 420 aaatgctaag aagcgccagg gcatgacagg tgggcccaac aatggtggct atgatgatga 480 ccagggatca tatgtgcagg tgccccacga tcacgtggct tacaggtatg aggtcctcaa 540 ggtcattggg aaggggagct ttgggcaggt ggtcaaggcc tacgatcaca aagtccacca 600 gcacgtggcc ctaaagatgg tgcggaatga gaagcgcttc caccggcaag cagcggagga 660 gatccgaatc ctggaacacc tgcggaagca ggacaaggat aacacaatga atgtcatcca 720 tatgctggag aatttcacct tccgcaacca catctgcatg acgtttgagc tgctgagcat 780 gaacctctat gagctcatca agaagaataa attccagggc ttcagtctgc ctttggttcg 840 caagtttgcc cactcgattc tgcagtgctt ggatgctttg cacaaaaaca gaataattca 900 ctgtgacctt aagcccgaga acattttgtt aaagcagcag ggtagaagcg gtattaaagt 960 aattgatttt ggctccagtt gttacgagca tcagcgtgtc tacacgtaca tccagtcgcg 1020 tttttaccgg gctccagaag tgatccttgg ggccaggtat ggcatgccca ttgatatgtg 1080 gagcctgggc tgcattttag cagagctcct gacgggttac cccctcttgc ctggggaaga 1140 tgaaggggac cagctggcct gtatgattga actgttgggc atgccctcac agaaactgct 1200 ggatgcatcc aaacgagcca aaaattttgt gagctccaag ggttatcccc gttactgcac 1260 tgtcacgact ctctcagatg gctctgtggt cctaaacgga ggccgttccc ggagggggaa 1320 actgaggggc ccaccggaga gcagagagtg ggggaacgcg ctgaaggggt gtgatgatcc 1380 ccttttcctt gacttcttaa aacagtgttt agagtgggat cctgcagtgc gcatgacccc 1440 aggccaggct ttgcggcacc cctggctgag gaggcggttg ccaaagcctc ccaccgggga 1500 gaaaacgtca gtgaaaagga taactgagag caccggtgct atcacatcta tatccaagtt 1560 acctccacct tctagctcag cttccaaact gaggactaat ttggcgcaga tgacagatgc 1620 caatgggaat attcagcaga ggacagtgtt gccaaaactt gttagctgag ctcacgtccc 1680 ctgatgctgg taacctgaaa gatacgacat tgctgagcct tactgggttg aaaaggagta 1740 gctcagacct gtttttattt gctcaataac tctactcatt tgtatctttt cagcacttaa 1800 ttttaatgta agaaagttgt tcattttgtt tttataaaat acatgaggac aatgctttaa 1860 gtttttatac tttcagaaac tttttgtgtt ctaaaagtac aatgagcctt actgtattta 1920 gtgtggcaga ataataacat cagtggcagg ccactgatta cttcatgact gccacgcatt 1980 tacagattgg tgtcaaagac attcactatg tttttatggt tcatgttata tcctccccag 2040 ggtgacagcc ccttaaggcc ctcctttt 2068 <210> 45 <211> 1850 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 1490070 <400> 45 gggctgcctg cctgcctgcc tgcctgcctg gcccggcccg agctccagcc tgcctcttcc 60 actggccact gcctcccacc cagggctggc atccctgctc cctgccctgg gtcccagact 120 gtgtcctcca tcaccgcagg tcggtgaggg gctgggctgg acaccagggc ccgccctccc 180 atcactgagc tccactcctt cctcattttg ctgctgattc tagccccaaa caaaacaggt 240 tgagcttttt cctcccctca gaagctcctc tctggctcgt ggctgccttc tgagtgttgc 300 agacggcgcc ggccgggaag gggggcctgg gccagccctg ccaggactgg gacgctgctg 360 ctggcgcctg gccctccatc aggccagcct gtggcaggag agtgagcttt gccgcggcag 420 acgcctgagg atgatgcccc agctgcagtt caaagatgcc ttttggtgca gggacttcac 480 agcccacacg ggctacgagg tgctgctgca gcggcttctg gatggcagga agatgtgcaa 540 agacatggtg gagctactgt ggcagagggc ccaggcggag gagcggtacg ggaaggagct 600 ggtgcagatc gcacggaagg caggtggcca gacggagatc aactccctga gggcctcctt 660 tgactccttg aagcagcaaa tggagaatgt gggcagctca cacatccagc tggccctgac 720 cctgcgtgag gagctgcgga gtctcgagga gtttcgtgag aggcagaagg agcagaggaa 780 gaagtatgag gccgtcatgg accgggtcca gaagagcaag ctgtcgctct acaagaaggc 840 catggagtcc aagaagacat acgagcagaa gtgccgggac gcggacgacg cggagcaggc 900 cttcgagcgc attagcgcca acggccacca gaagcaggtg gagaagagtc agaacaaagc 960 caggcagtgc aaggactcgg ccaccgaggc agagcgggta tacaggcaga gcattgcgca 1020 gctggagaag gtccgggctg agtgggagca ggagcaccgg accacctgtg aggcctttca 1080 gctgcaagag tttgaccggc tgaccattct ccgcaacgcc ctgtgggtgc acagcaacca 1140 gctctccatg cagtgtgtca aggatgatga gctctacgag gaagtgcggc tgacgctgga 1200 aggctgcagc atagacgccg acatcgacag tttcatccag gccaagagca cgggcacaga 1260 gccccccgct ccggtgccct accagaacta ttacgatcgg gaggtcaccc cgctgaccag 1320 cagccctggc atacagccgt cctgcggcat gataaagagg ttctctggac tgctgcacgg 1380 aagtcccaag accacttcgt tggcagcttc tgctgcgtcc acagagaccc tgacccccac 1440 ccccgagcgg aatgagggtg tctacacagc catcgcagtg caggagatac agggaaaccc 1500 ggcctcacca gcccaggagt accgggcgct ctacgattat acagcgcaga acccagatga 1560 gctggacctg tccgcgggag acatcctgga ggtgatcctg gaaggggagg atggctggtg 1620 gactgtggag aggaacgggc agcgtggctt cgtccctggt tcctacctgg agaagctttg 1680 aggaagggcc aggagcccct tcggacctgc cctgccagtg gagccagcag tgcccccagc 1740 actgtcccca ccttgctagg gcccagaacc aagcgtcccc cagccccgag agggagcctg 1800 tcgtctccca gggaataaag gagtgcgttc tgttctcaaa aaaaaaaaaa 1850 <210> 46 <211> 2534 <212> DNA
<2I3> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 1997814 <400> 46 gaagagggga tggagcaggg gctggaggag gaagaagagg tggatccccg gatccaggga 60 gaactggaga agttaaatca gtccacggat gatatcaaca gacgggagac tgaacttgag 120 gatgctcgtc agaagttccg ctctgttctg gttgaagcaa cggtgaaact ggatgaactg 180 gtgaagaaaa ttggcaaagc tgtggaagac tccaagccct actgggaggc acggagggtg 240 gcgaggcagg ctcagctgga agctcagaaa gccacgcagg acttccagag ggccacagag 300 gtgctccgtg ccgccaagga gaccatctcc ctggccgagc agcggctgct ggaggatgac 360 aagcggcagt tcgactccgc ctggcaggag atgctgaatc acgccactca gagggtcatg 420 gaggcggagc agaccaagac caggagcgag ctggtgcata aggagacggc agccaggtac 480 aatgccgcca tgggccgcat gcgacagctg gagaagaaac tcaagagagc catcaacaag 540 tccaagcctt attttgaact caaggcaaag tactatgtgc agctcgagca actgaaaaag 600 actgtggatg acctgcaggc caaactgacc ctggcaaaag gcgagtacaa gatggccctg 660 aagaacctgg agatgatctc agatgagatc cacgagcggc ggcgctccag tgccatgggg 720 cctcggggat gcggtgttgg tgctgagggc agcagcacat ctgtggagga tctgccaggg 780 agcaaacctg agcctgatgc catttctgtg gcctcggagg cctttgaaga tgacagctgt 840 agcaactttg tgtctgaaga tgactcggaa acccagtccg tgtccagctt tagttcagga 900 ccaacaagcc cgtctgagat gcctgaccag ttccctgcgg ttgtgaggcc tggcagcctg 960 gatctgccca gccctgtgtc cctgtcagag tttgggatga tgttcccagt gttgggccct 1020 cgaagtgaat gcagcggggc ctcctcccct gaatgtgaag tagaacgagg agacagggca 1080 gaaggggcag agaataaaac aagtgacaaa gccaacaaca accggggcct cagcagtagc 1140 agtggcagtg gtggcagcag taagagccaa agcagcacct cccctgaggg ccaggccttg 1200 gagaaccgga tgaagcagct ctccctacag tgctcaaagg gaagagatgg aattattgct 1260 gacataaaaa tggtgcagat tggctgattc atcctgggcc ctggccgatg tgcatatcaa 1320 catttataca tggaactgga gaacattgtg ccaataatca tttaatatat gccaaatctt 1380 acacgtctac tctaaactgc tctaatgaag tttcagtgac cttgagggct aaagattgtt 1440 cttctgggta agagctcttg ggctggtttt tcagagcaga gttcttgttg tgggtagact 1500 gtgactaggt tcacagcctt tgtggaacat tccgtataac ggcattgtgg aagcaataac 1560 tagttcctat gaaagaacca gagctgggaa gatggctggg aagccaggcc aaagtggggg 1620 caacagcttg cttctctttc tcttctcacc ctcagtttgt atgggaaaat ggagatgtcc 1680 tctccacttt atcccacgat atctaaatga aaaagaaaga aaacccacac acaaagcaaa 1740 aactcaagta ttaagagcac atatttttga cccagtggag gcttaaaaaa aaaaaaatcc 1800 aagaacacaa ttcattttca ccacctctgg tgttcagagg gggcttttaa aaaagcgtgt 1860 atgctgggat acccattaaa accattttct agaaggctac catgagctgc actttttggg 1920 gtgggaaagg tgaatgccag tggggatgcg gggggatgag ggtaggaggg acttatagaa 1980 ggggatttgt ggctgtgggg gagaaggttc tacagcataa gccttatcct gccagccaag 2040 gggatttatt ctaagagaag tgcatgtgaa gaatggttgc cactgttatt agattgacaa 2100 gatgttaatt tctctgtagg ttgtaacttt aaaaataaat gaaattattt aagggttatg 2160 ctgcactagt attccttaga ggaaacagtt ctttaaagtt aggaaaggga gtaggcaggc 2220 atgtgttggc aaaggctgtt aatagtagtt aagtgttaag actgcttttc tttaacgttt 2280 tcatggtaat gcatatttag agcactgtat ttttgtcttg ttaagaaaat ttagcatttc 2340 taaaagaaaa aagcaaccct ctttcaaact gttaattctg tcacagcctg tatattttag 2400 WO 00/0672$ PCT/US99/17132 tcatttgtaa atctcttcat acaatagtga cttctttttt gactgataca gtatcttaat 2460 tacaaggtta ttttgtactt gtcttaatac actaagtgta ataaaaacgg cttgagaaaa 2520 gttaaaaaaa aaaa 2534 <210> 47 <211> 3786 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 2299715 <400> 47 ccgtcctcga ggcgaggaga gtaccgggcc ggcccggctg ccgcgcgagg agcgcggtcg 60 gcggcctggt ctgcggctga gatacacaga gcgacagaga catttattgt tatttgtttt 120 ttggtggcaa aaagggaaaa tggcgaacga ctcccctgca aaaagtctgg tggacatcga 180 cctctcctcc ctgcgggatc ctgctgggat ttttgagctg gtggaagtgg ttggaaatgg 240 cacctatgga caagtctata agggtcgaca tgttaaaacg ggtcagttgg cagccatcaa 300 agttatggat gtcactgagg atgaagagga agaaatcaaa ctggagataa atatgctaaa 360 gaaatactct catcacagaa acattgcaac atattatggt gctttcatca aaaagagccc 420 tccaggacat gatgaccaac tctggcttgt tatggagttc tgtggggctg ggtccattac 480 agaccttgtg aagaacacca aagggaacac actcaaagaa gactggatcg cttacatctc 540 cagagaaatc ctgaggggac tggcacatct tcacattcat catgtgattc accgggatat 600 caagggccag aatgtgttgc tgactgagaa tgcaggggtg aaacttgttg actttggtgt 660 gagtgctcag ctggacagga ctgtggggcg gagaaatacg ttcataggca ctccctactg 720 gatggctcct gaggtcatcg cctgtgatga gaacccagat gccacctatg attacagaag 780 tgatctttgg tcttgtggca ttacagccat tgagatggca gaaggtgctc cccctctctg 840 tgacatgcat ccaatgagag cactgtttct cattcccaga aaccctcctc cccggctgaa 900 gtcaaaaaaa tggtcgaaga agttttttag ttttatagaa gggtgcctgg tgaagaatta 960 catgcagcgg ccctctacag agcagctttt gaaacatcct tttataaggg atcagccaaa 1020 tgaaaggcaa gttagaatcc agcttaagga tcatatagat cgtaccagga agaagagagg 1080 cgagaaagat gaaactgagt atgagtacag tgggagtgag gaagaagagg aggaagtgcc 1140 tgaacaggaa ggagagccaa gttccattgt gaacgtgcct ggtgagtcta ctcttcgccg 1200 agatttcctg agactgcagc aggagaacaa ggaacgttcc gaggctcttc ggagacaaca 1260 gttactacag gagcaacagc tccgggagca ggaagaatat aaaaggcaac tgctggcaga 1320 gagacagaag cggattgagc agcagaaaga acagaggcga cggctagaag agcaacaaag 1380 gagagagcgg gaagctagaa ggcagcagga acgtgaacag cgaaggagag aacaagaaga 1440 aaagaggcgt ctagaggagt tggagagaag gcgcaaagaa gaagaggaga ggagacgggc 1500 agaagaagaa aagaggagag ttgaaagaga acaggagtat atcaggcgac agctagaaga 1560 ggagcagcgg cacttggaag tccttcagca gcagctgctc caggagcagg ccatgttact 1620 gcatgaccat aggaggccgc acccgcagca ctcgcagcag ccgccaccac cgcagcagga 1680 aaggagcaag ccaagcttcc atgctcccga gcccaaagcc cactacgagc ctgctgaccg 1740 agcgcgagag gttcctgtga gaacaacatc tcgctcccct gttctgtccc gtcgagattc 1800 cccactgcag ggcagtgggc agcagaatag ccaggcagga cagagaaact ccaccagtat 1860 tgagcccagg cttctgtggg agagagtgga gaagctggtg cccagacctg gcagtggcag 1920 ctcctcaggg tccagcaact caggatccca gcccgggtct caccctgggt ctcagagtgg 1980 ctccggggaa cgcttcagag tgagatcatc atccaagtct gaaggctctc catctcagcg 2040 cctggaaaat gcagtgaaaa aacctgaaga taaaaaggaa gttttcagac ccctcaagcc 2100 tgctgatctg accgcactgg ccaaagagct tcgagcagtg gaagatgtac ggccacctca 2160 caaagtaacg gactactcct catccagtga ggagtcgggg acgacggatg aggaggacga 2220 cgatgtggag caggaagggg ctgacgagtc cacctcagga ccagaggaca ccagagcagc 2280 gtcatctctg aatttgagca atggtgaaac ggaatctgtg aaaaccatga ttgtccatga 2340 tgatgtagaa agtgagccgg ccatgacccc atccaaggag ggcactctaa tcgtccgcca 2400 gactcagtcc gctagtagca cactccagaa acacaaatct tcctcctcct ttacaccttt 2460 tatagacccc agattactac agatttctcc atctagcgga acaacagtga catctgtggt 2520 gggattttcc tgtgatggga tgagaccaga agccataagg caagatccta cccggaaagg 2580 ctcagtggtc aatgtgaatc ctaccaacac taggccacag agtgacaccc cggagattcg 2640 taaatacaag aagaggttta actctgagat tctgtgtgct gccttatggg gagtgaattt 2700 gctagtgggt acagagagtg gcctgatgct gctggacaga agtggccaag ggaaggtcta 2760 tcctcttatc aaccgaagac gatttcaaca aatggacgta cttgagggct tgaatgtctt 2820 ggtgacaata tctggcaaaa aggataagtt acgtgtctac tatttgtcct ggttaagaaa 2880 taaaatactt cacaatgatc cagaagttga gaagaagcag ggatggacaa ccgtagggga 2940 tttggaagga tgtgtacatt ataaagttgt aaaatatgaa agaatcaaat ttctggtgat 3000 tgctttgaag agttctgtgg aagtctatgc gtgggcacca aagccatatc acaaatttat 3060 ggcctttaag tcatttggag aattggtaca tggatcctgt gctggattcc atgctgttga 3120 tgtggattca ggatcagtct atgacattta tctaccaaca catatccagt gtagcatcaa 3180 accccatgca atcatcatcc tccccaatac agatggaatg gagcttctgg tgtgctatga 3240 agatgagggg gtttatgtaa acacatatgg aaggatcacc aaggatgtag ttctacagtg 3300 gggagagatg cctacatcag tagcatatat tcgatccaat cagacaatgg gctggggaga 3360 gaaggccata gagatccgat ctgtggaaac tggtcacttg gatggtgtgt tcatgcacaa 3420 aagggctcaa agactaaaat tcttgtgtga acgcaatgac aaggtgttct ttgcctctgt 3480 tcggtctggt ggcagcagtc aggtttattt catgacctta ggcaggactt ctcttctgag 3540 ctggtagaag cagtgtgatc cagggattac tggcctccag agtcttcaag atcctgagaa 3600 cttggaattc cttgtaactg gagctcggag ctgcaccgag ggcaaccagg acagctgtgt 3660 gtgcagacct catgtgttgg gttctctccc ctccttcctg ttcctcttat ataccagttt 3720 atccccattc tttttttttt tcttactcca aaataaatca aggctgcaat gcagctggtg 3780 ctgtta 3786 <210> 48 <211> 1182 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 209854 <400> 48 gttggtgaag tcaagcgaag gcgactagag ctccaggagg gccagttctg tgggctctag 60 tcggccatat taataaagag aaagggaagg ctgaccgtcc ttcgcctccg cccccacata 120 cacacccctt cttcccactc cgctctcacg actaagctct cacgattaag gcacgcctgc 180 ctcgattgtc cagcctctgc cagaagaaag cttagcagcc agcgcctcag tagagaccta 240 agggcgctga atgagtggga aagggaaatg ccgaccaatt gcgctgcggc gggctgtgcc 300 actacctaca acaagcacat taacatcagc ttccacaggt ttcctttgga tcctaaaaga 360 agaaaagaat gggttcgcct ggttaggcgc aaaaattttg tgccaggaaa acacactttt 420 ctttgttcaa agcactttga agcctcctgt tttgacctaa caggacaaac tcgacgactt 480 aaaatggatg ctgttccaac catttttgat ttttgtaccc atataaagtc tatgaaactc 540 aagtcaagga atcttttgaa gaaaaacaac agttgttctc cagctggacc atctaattta 600 aaatcaaaca ttagtagtca gcaagtacta cttgaacaca gctatgcctt taggaatcct 660 atggaggcaa aaaagaggat cattasactg gaaaaagaaa tagcaagctt aagaagaaaa 720 atgaaaactt gcctacaaaa ggaacgcaga gcaactcgaa gatggatcaa agccacgtgt 780 ttggtaaaga atttagaagc aaatagtgta ttacctaaag gtacatcaga acacatgtta 840 ccaactgcct taagcagtct tcctttggaa gattttaaga tccttgaaca agatcaacaa 900 gataaaacac tgctaagtct aaatctaaaa cagaccaaga gtaccttcat ttaaatttag 960 cttgcacaga gcttgatgcc tatccttcat tcttttcaga agtaaagata attatggcac 1020 ttatgccaaa attcattatt taataaagtt ttacttgaag taacattact gaatttgtga 1080 agacttgatt acaaaagaat aaaaaacttc atatggaaat tttatttgaa aatgagtgga 1140 agtgccttac attagaatta cggactttca aaactatgat as 1182 <210> 49 <211> 1676 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 1384286 <400> 49 tcgccgagcc cgtccgccgc cgccatggcc accacggtga cctgcacccg cttcaccgac 60 gagtaccagc tctacgagga tattggcaag ggggctttct ctgtggtccg acgctgtgtc 120 aagctctgca ccggccatga gtatgcagcc aagatcatca acaccaagaa gctgtcagcc 180 agagatcacc agaagctgga gagagaggct cggatctgcc gccttctgaa gcattccaac 240 atcgtgcgtc tccacgacag catctccgag gagggcttcc actacctggt cttcgatctg 300 gtcactggtg gggagctctt tgaagacatt gtggcgagag agtactacag cgaggctgat 360 gccagtcact gtatccagca gatcctggag gccgttctcc attgtcacca aatgggggtc 420 gtccacagag acctcaagcc ggagaacctg cttctggcca gcaagtgcaa aggggctgca 480 gtgaagctgg cagacttcgg cctagctatc gaggtgcagg gggaccagca ggcatggttt 540 ggtttcgctg gcacaccagg ctacctgtcc cctgaggtcc ttcgcaaaga ggcgtacggc 600 aagcccgtgg acatctgggc atgtggggtg atcctgtaca tcctgctcgt gggctaccca 660 cccttctggg acgaggacca gcacaagctg taccagcaga tcaaggctgg tgcctatgac 720 ttcccgtccc ctgagtggga caccgtcact cctgaagcca aaaacctcat caaccagatg 780 ctgaccatca accctgccaa gcgcatcaca gcccatgagg ccctgaagca cccgtgggtc 840 tgccaacgct ccacggtagc atccatgatg cacagacagg agactgtgga gtgtctgaaa 900 aagttcaatg ccaggagaaa gctcaaggga gccatcctca ccaccatgct ggccacacgg 960 aatttctcag cagccaagag tttactcaac aagaaagcag atggagtcaa gccccatacg 1020 aatagcacca aaaacagtgc agccgccacc agccccaaag ggacgcttcc tcctgccgcc 1080 ctggagtctt ctgacagtgc caataccacc atagaggatg aagacgctaa agcccggaag 1140 caggagatca ttaagaccac ggagcagctc atcgaggccg tcaacaacgg tgactttgag 1200 gcctacgcga aaatctgtga cccagggctg acctcgtttg agcctgaagc actgggcaac 1260 ctggttgaag ggatggactt ccacagattc tacttcgaga acctgctggc caagaacagc 1320 aagccgatcc acacgaccat cctgaaccca cacgtgcacg tcattggaga ggatgccgcc 1380 tgcatcgctt acatccggct cacgcagtac attgacgggc agggccggcc ccgcaccagc 1440 cagtctgagg agacccgcgt gtggcaccgc cgcgacggca agtggcagaa cgtgcacttc 1500 cactgctcgg gcgcgcctgt ggccccgctg cagtgaagag ctgcgccctg gtttcgccgg 1560 acagagttgg tgtttggagc ccgactgccc tcgggcacac ggcctgcctg tcgcatgttt 1620 gtgtctgcct cgttccctcc cctggtgcct gtgtctgcag aaaaacaagc ccgact 1676 <210> 50 <211> 1597 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 1512656 <400> 50 tcggccttcg gaaagacccc cgggccgggg cacggagaga gccgagcgcc gcagccgtga 60 gccgaataga gccggagaga cccgagtatg accggagaag cccaggccgg ccggaagagg 120 agccgagcgc ggccggaagg aaccgagccc gtccgaaggg agcggacgca gcctggcctg 180 gggcccggtc gagcccgcgc catggcggcc gaggcgacag ctgtggccgg aagcggggct 240 gttggcggct gcctggccaa agacggcttg cagcagtcta agtgcccgga cactacccca 300 aaacggcggc gcgcctcgtc gctgtcgcgt gacgccgagc gccgagccta ccaatggtgc 360 cgggagtact tgggcggggc ctggcgccga gtgcagcccg aggagctgag ggtttacccc 420 gtgagcggag gcctcagcaa cctgctcttc cgctgctcgc tcccggacca cctgcccagc 480 gttggcgagg agccccggga ggtgcttctg cggctgtacg gagccatctt gcagggcgtg 540 gactccctgg tgctagaaag cgtgatgttc gccatacttg cggagcggtc gctggggccc 600 cagctgtacg gagtcttccc agagggccgg ctggaacagt acatcccaag tcggccattg 660 aaaactcaag agcttcgaga gccagtgttg tcagcagcca ttgccacgaa gatggcgcaa 720 tttcatggca tggagatgcc tttcaccaag gagccccact ggctgtttgg gaccatggag 780 cggtacctaa aacagatcca ggacctgccc ccaactggcc tccctgagat gaacctgctg 840 gagatgtaca gcctgaagga tgagatgggc aacctcagga agttactaga gtctacccca 900 tcgccagtcg tcttctgcca caatgacatc caggaaggga acatcttgct gctctcagag 960 ccagaaaatg ctgacagcct catgctggtg gacttcgagt acagcagtta taactatagg 1020 ggctttgaca ttgggaacca tttttgtgag tgggtttatg attatactca cgaggaatgg 1080 cctttctaca aagcaaggcc cacagactac cccactcaag aacagcagtt gcattttatt 1140 cgtcattacc tggcagaggc aaagaaaggt gagaccctct cccaagagga gcagagaaaa 1200 ctggaagaag atttgctggt agaagtcagt cggtatgctc tggcatccca tttcttctgg 1260 ggtctgtggt ccatcctcca ggcatccatg tccaccatag aatttggtta cttggactat 1320 gcccagtctc ggttccagtt ctacttccag cagaaggggc agctgaccag tgtccactcc 1380 tcatcctgac tccaccctcc cactccttgg atttctcctg gagcctccag ggcaggacct 1440 tggagggagg aacaacgagc agaaggccct ggcgactggg ctgagccccc aagtgaaact 1500 gaggttcagg agaccggcct gttcctgagt ttgagtaggt ccccatggct ggcaggccag 1560 agccccgtgc tgtgtatgta acacaataaa caagctg 1597 <210> 51 <211> 2145 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 2098635 <400> 51 cccacgcgtc cggacagctt gacccagttt gctttccaat caaagggcat ttattttgaa 60 tgtctctttg tggcgcaaga gccaacgcaa aaatgatggc ggcttacaat ggcggtacat 120 ctgcagcagc agcaggtcac caccaccacc atcaccacca ccttccacac ctccctcetc 180 ctcacctgct tcaccaccac caccctcaac accatcttca tecggggtcg gctgecgctg 240 tacaccctgt acagcagcac acctcttcgg cagctgcggc agccgcagca gcggctgcag 300 ctgcagccat gttaaaccct gggcaacaac agccatattt cccatcaccg gcaccggggc 360 aggctcctgg accagctgca gcagccccag ctcaggtaca ggctgccgca gctgctacag 420 ttaaggcgca ccatcatcag cactcgcatc atccacagca gcagctggat attgagccgg 480 atagacctat tggatatgga gcctttggtg ttgtctggtc agtaacagat ccaagagatg 540 gaaagagagt agcgctcaaa aagatgccca acgtcttcca gaatctggtc tcttgcaaaa 600 gggtcttccg ggaattgaag atgttgtgtt tttttaagca tgataatgta ctctctgccc 660 ttgacatact ccaacctcca cacattgact attttgaaga aatatatgtt gtcacagaat 720 tgatgcagag tgacctacat aaaattatcg tctctcctca accactcagc tcagatcatg 780 tcaaagtttt tctttatcag attttgcgag gtttgaaata tctecattca gctggcattt 840 tacatcgaga cattaagcca gggaatctcc ttgtgaacag caactgtgtt ctaaagattt 900 gtgattttgg attggccaga gtggaagagt tagatgaatc ccgtcatatg actcaggaag 960 ttgttactca gtattatcgg gctccagaaa tcctgatggg cagccgtcat tacagcaatg 1020 ctattgacat ctggtctgtg ggatgtatct ttgcagaact actaggacga agaatattgt 1080 ttcaggcaca gagtcccatt cagcagttgg atttgatcac ggatctgttg ggcacaccat 1140 cactggaagc aatgaggaca gcttgtgaag gcgctaaggc acatatactc aggggtcctc 1200 ataaacagcc atctcttcct gtactctata ccctgtctag ccaggctaca catgaagctg 1260 ttcatctcct ttgcaggatg ttggtctttg atccatccaa aagaatatcc gctaaggatg 1320 ccttagccca cccctaccta gatgaagggc gactacgata tcacacatgt atgtgtaaat 1380 gttgcttttc cacctccact ggaagagttt ataccagtga ctttgagcct gtcaccaatc 1440 ccaaatttga tgacactttc gagaagaacc tcagttctgt ccgacaggtt aaagaaatta 1500 ttcatcagtt cattttggaa cagcagaaag gaaacagagt gcctctctgc atcaaccctc 1560 agtctgctgc ttttaagagc tttattagtt ccactgttgc tcagccatct gagatgcccc 1620 catctcctct ggtgtgggag tgatggtgga agataatgta ctactgaaga tgtaatgtag 1680 ctttccactg gagtctggga tttgcaattc tggaggttaa tcatgcttgt actgtaattt 1740 tactaatgaa gttttaaatt aacaaccact acttgtatga tatgaataat atttagaaat 1800 gttactagac ttttaatctt gtaaagtggt tgtgctttta gaagaaaaat attttaccca 1860 gagttgcaca tgttttatga atttagtgca gctgttatgg ctcacctcag aacaaaagag 1920 aattgaacca aatttgggag tttggggttt tatgttttgt ttttettttc taaaatgaag 1980 tgagattgtt cacacacaca cacacacaca cacacacaca cacaaacaca aaggacagtc 2040 atacattttg atatttgagc cattcctaaa gatttggggt tttctaaaac taaagaatct 2100 aggaaccttg cctgcgacca atcatggagc cacgtgagct gatcg 2145 <210> 52 <211> 1454 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 2446646 <400> 52 gggttcgaat tgcaacggca gctgccgggc gtatgtgttg gtgctagagg cagctgcagg 60 gtctcgctgg gggccgctcg ggaccaattt tgaagaggta cttggccacg acttattttc 120 acctccgacc tttccttcca ggcggtgaga ctctggactg agagtggett tcacaatgga 180 agggatcagt aatttcaaga caccaagcaa attatcagaa aaaaagaaat ctgtattatg 240 ttcaactcca actataaata tcccggcctc tccgtttatg cagaagcttg gctttggtac 300 tggggtaaat gtgtacctaa tgaaaagatc tccaagaggt ttgtctcatt ctccttgggc 360 tgtaaaaaag attaatccta tatgtaatga tcattatcga agtgtgtatc aaaagagact 420 aatggatgaa gctaagattt tgaaaagcct tcatcatcca aacattgttg gttatcgtgc 480 ttttactgaa gccaatgatg gcagtctgtg tcttgctatg gaatatggag gtgaaaagtc 540 tctaaatgac ttaatagaag aacgatataa agccagccaa gatccttttc cagcagccat 600 aattttaaaa gttgctttga atatggcaag agggttaaag tatctgcacc aagaaaagaa 660 actgcttcat ggagacataa agtcttcaaa tgttgtaatt aaaggcgatt ttgaaacaat 720 taaaatctgt gatgtaggag tctctctacc actggatgaa aatatgactg tgactgaccc 780 tgaggcttgt tacattggca cagagccatg gaaacccaaa gaagctgtgg aggagaatgg 840 tgttattact gacaaggcag acatatttgc ctttggcctt actttgtggg aaatgatgac 900 tttatcgatt ccacacatta atctttcaaa tgatgatgat gatgaagata aaacttttga 960 tgaaagtgat tttgatgatg aagcatacta tgcagcgttg ggaactaggc cacctattaa 1020 tatggaagaa ctggatgaat cataccagaa agtaattgaa ctcttctctg tatgcactaa 1080 tgaagaccct aaagatcgtc cttctgctgc acacattgtt gaagctctgg aaacagatgt 1140 ctagtgatca tctcagctga agtgtggctt gcgtaaataa ctgtttattc caaaatattt 1200 acatagttac tatcagtagt tattagactc taaaattggc atatttgagg accatagttt 1260 cttgttaaca tatggataac tatttctaat atgaaatatg cttatattgg ctataagcac 1320 ttggaattgt actgggtttt ctgtaaagtt ttagaaacta gctacataag tactttgata 1380 ctgctcatgc tgacttaaaa cactagcagt aaaacgctgt aaactgtaac attaaattga 1440 atgaccatta cttt <210> 53 <211> 3225 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 2764911 <400> 53 tggagcaggg ggcggtttgg ttgcgcggta ctagcggtgc ccgccgaatg gggaggaggc 60 gaggagcgag ccgtgcggcc agagcgggaa agagactcgt ctttgcgtcc gagttctgga 120 gccgccgcac cccgactcct ggggccgcgg cagcggctgc gaggggacgg gcgtccgctg 180 tctcctgggt tcccctcgta gcgacccgcg ggatcggaaa aaaaggagaa gatggaggag 240 gagggtggca gcagcggcgg cgccgcgggg accagcgcgg acggcggcga cggaggagag 300 cagctcctca ctgtcaagca cgagctgcgg actgctaatt tgacaggaca tgctgagaag 360 gtgggaatag aaaattttga gctcctgaag gtcctaggaa ctggagctta tggaaaagta 420 tttctagttc gtaaaataag tggccatgat actggaaagc tgtatgccat gaaagttttg 480 aaaaaggcaa caatcgttca aaaggccaaa accacagagc atacaaggac agaacgacaa 540 gtcctggaac acattaggca gtcgccattt ttggtaacat tacattatgc tttccagaca 600 gaaaccaaac ttcatctcat tttagattat ataaatggtg gtgaactttt tacccatctt 660 tctcaaagag agcgtttcac agagcatgag gtgcagattt atgttggaga gattgtgctt 720 gccctcgaac atctccacaa gttggggatt atatatcgtg atattaagct tgagaatatt 780 ctacttgatt ctaatggcca tgtggtgctg acagattttg gtctgagtaa ggagtttgtg 840 gctgatgaaa ctgaaagagc atattccttt tgtggaacta ttgaatacat ggcaccagat 900 attgtcagag ggggagattc aggacatgac aaggcagttg actggtggag tttgggtgtt 960 ctaatgtatg aattactaac tggagcatct cctttcactg ttgatggaga aaaaaattcc 1020 caagctgaga tatctaggag aatattaaaa agtgagcctc catatcccca agaaatgagt 1080 gctttagcga aagacctaat tcagcgtctt ttgatgaaag atcccaagaa gagattggga 1140 tgtggtccac gtgatgcaga tgaaatcaaa gaacatctct tctttcagaa aataaattgg 1200 gatgatttag ccgccaaaaa agtgcctgca ccatttaagc cagtcattcg agatgaatta 1260 gatgtgagta actttgcaga agagttcaca gaaatggatc ccacttattc tcccgcagcc 1320 ctgccccaga gttctgagaa gctgtttcag ggctattcct ttgttgctcc ttccatccta 1380 ttcaagcgta atgcagctgt catagaccct cttcagtttc acatgggagt tgaacgtcct 1440 ggagtgacaa atgttgccag gagtgcaatg atgaaggact ctccattcta tcaacactat 1500 gacctagatt tgaaggacaa acccctggga gaaggtagtt tttcaatttg tcgaaagtgt 1560 gtgcataaaa aaagtaacca agcttttgca gtcaaaataa tcagcaaaag gatggaagcc 1620 aatactcaaa aggaaataac agctctggaa ctctgtgaag gacaccccaa tattgtgaag 1680 ttgcatgaag tttttcatga tcagcttcac acgtttctag tgatggaact tctgaatgga 1740 ggagaactgt ttgagcgcat taagaaaaag aagcacttca gtgagacgga agccagctac 1800 atcatgagga agcttgtttc agctgtaagc cacatgcatg atgttggagt ggtgcacagg 1860 gatctgaaac ctgagaattt attgttcacc gatgaaaatg acaatttgga aattaaaata 1920 attgattttg gatttgcacg gctaaagcca ccggataatc agcccctgaa gactccatgc 1980 ttcacccttc attatgccgc cccagagctc ttgaatcaga acggctacga tgagtcctgt 2040 gacctgtgga gcttgggcgt cattttgtac acaatgttgt cagg~caggt tcccttccaa 2100 tctcatgacc gaagtttgac gtgtaccagc gcggtggaaa tcatgaagaa aattaaaaag 2160 ggagatttct cctttgaagg agaagcctgg aagaatgtat cccaagaggc taaagatttg 2220 atccaaggac ttctcacagt agatccaaac aaaaggctta aaatgtctgg cttgaggtac 2280 aatgaatggc tacaagatgg aagtcagctg tcctccaatc ctctgatgac tccggatatt 2340 ctaggatctt ccggagctgc cgtgcatacc tgtgtgaaag caaccttcca cgcctttaac 2400 aaatacaaga gagaggggtt ttgccttcag aatgttgata aggccccttt ggctaagaga 2460 agaaaaatga aaaagactag caccagtacc gagacacgca gcagttccag tgagagttcc 2520 cattcttctt cctctcattc tcacggtaaa actacaccca ccaagacact gcagcccagc 2580 aatcctgccg acagcaataa cccggagacc ctcttccagt tctcggactc agtagcttag 2640 gcatggtagg agtgtatcag tgatccattg cacctttatt ccctcagcat atgcctgagg 2700 cgatctttta tgcttttaaa aatgtttccc gttggtctca ttggaatctg cctcctaatg 2760 atttttttca ggaaaacctg tttggttatc ctcattcaaa agcactggac agagaatgtt 2820 actgtgaata gagcacatat tactcttttt agcaacctag catgatgcca acaagactat 2880 tcttgaaaga gcaaaggttc ctgtaaattt aattagggct agatttgagc tgcttgtaag 2940 tcacaggttt tccagatgtc tgccaacaag aaatgactca tactgtgatg ataccttttg 3000 ctttgccttg tggacaatgt gggtttttga aatttgcacc cttcaaacaa tgatttatca 3060 WO 00/Ob72$ PCT/US99/17132 gagaaagggg tctgttttca aaaaagattc tgtaatgaat tttatgtgtg gcatatactt 3120 atttcttgag agaagatttt aacttattgt ttttatttta tggttacata tgatgataac 3180 ctgctattat taaacttttt ctaaaaagtg aaaaaaaaaa aaaaa 3225 <210> 54 <211> 2110 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 3013946 <400> 54 tcgccgagcc cgtccgccgc cgccatggcc accacggtga cctgcacccg cttcaccgac 60 gagtaccagc tctacgagga tattggcaag ggggctttct ctgtggtccg acgctgtgtc 120 aagctctgca ccggccatga gtatgcagcc aagatcatca acaccaagaa gctgtcagcc 180 agagatcacc agaagctgga gagagaggct cggatctgcc gccttctgaa gcattccaac 240 atcgtgcgtc tccacgacag catctccgag gagggcttcc actacctggt cttcgatctg 300 gtcactggtg gggagctctt tgaagacatt gtggcgagag agtactacag cgaggctgat 360 gccagtcact gtatccagca gatcctggag gccgttctcc attgtcacca aatgggggtc 420 gtccacagag acctcaagcc ggagaacctg cttctggcca gcaagtgcaa aggggctgca 480 gtgaagctgg cagacttcgg cctagctatc gaggtgcagg gggaccagca ggcatggttt 540 ggtttcgctg gcacaccagg ctacctgtcc cctgaggtcc ttcgcaaaga ggcgtat ggc 600 aagcctgtgg acatctgggc atgtggggtg atcctgtaca tcctgctcgt gggctaccca 660 cccttctggg acgaggacca gcacaagctg taccagcaga tcaaggctgg tgcctatgac 720 ttcccgtccc ctgagtggga caccgtcact cctgaagcca aaaacctcat caaccagatg 780 ctgaccatca accctgccaa gcgcatcaca gcccatgagg ccctgaagca cccgtgggtc 840 tgccaacgct ccacggtagc atccatgatg cacagacagg agactgtgga gtgtctgaaa 900 aagttcaatg ccaggagaaa gctcaaggga gccatcctca ccaccatgct ggccacacgg 960 aatttctcag ccaagagttt actcaacaag aaagcagatg gagtcaagcc ccagacgaat 1020 agcaccaaaa acagtgcagc cgccaccagc cccaaaggga cgcttcctcc tgccgccctg 1080 gagcctcaaa ccaccgtcat ccataaccca gtggacggga ttaaggagtc ttctgacagt 1140 gccaatacca ccatagagga tgaagacgct aaagccccca gggtccccga catcctgagc 1200 tcagtgagga ggggctcggg agccccagaa gccgaggggc ccctgccctg cccatctccg 1260 gctccctttg gccccctgcc agctccatcc cccaggatct ctgacatcct gaactctgtg 1320 agaaggggtt caggaacccc agaagccgag gggcccctct cagcggggcc cccgccctgc 1380 ctgtctccgg ctctcctagg ccccctgtcc tccccgtccc ccaggatctc tgacatcctg 1440 aactctgtga ggaggggctc agggacccca gaagccaagg gcccctcgcc agtggggccc 1500 ccgccctgcc catctccgac tatccctggc cccctgccca ccccatcccg gaagcaggag 1560 atcattaaga ccacggagca gctcatcgag gccgtcaaca acggtgactt tgaggcctac 1620 gcgaaaatct gtgacccagg gctgacctcg tttgagcctg aagcactggg caacctggtt 1680 gaagggatgg acttccacag attctacttc gagaacctgc tggccaagaa cagcaagcca 1740 atccacacga ccatcctgaa cccacacgtg cacgtcattg gagaggatgc cgcctgcatc 1800 gcttacatcc ggctcacgca gtacattgac gggcagggcc ggccccgcac cagccagtct 1860 gaggagaccc gcgtgtggca ccgccgcgac ggcaagtggc agaatgtgca cttccactgc 1920 tcgggcgcgc ctgtggcccc gctgcagtga agagctgcgc cctggtttcg ccggacagag 1980 ttggtgtttg gagcccgact gccctcgggc acacggcctg cctgtcgcat gtttgtgtct 2040 gcctcgttcc ctcccctggt gcctgtgtct gcagaaaaac aagaccagat gtgatttgtt 2100 aaaaaaaaaa <210> 55 <211> 2140 <212> DNA

<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 067967 <400> 55 gtgcgctgag ctgcagtgtc tggtcgagag tacccgtggg agcgtcgcgc cgcggaggca 60 gccgtcccgg cgtaggtggc gtggccgacc ggacccccaa ctggcgcctc tccccgcgcg 120 gggtcccgag ctaggagatg ggaggcacag ctcgtgggcc tgggcggaag gatgcggggc 180 cgcctggggc cgggctcccg ccccagcagc ggaggttggg ggatggtgtc tatgacacct 240 tcatgatgat agatgaaacc aaatgtcccc cctgttcaaa tgtactctgc aatccttctg 300 aaccaccttc acccagaaga ctaaatatga ccactgagca gtttacagga gatcatactc 360 agcacttttt ggatggaggt gagatgaagg tagaacagct gtttcaagaa tttggcaaca 420 gaaaatccaa tactattcag tcagatggca tcagtgactc tgaaaaatgc tctcctactg 480 tttctcaggg taaaagttca gattgcttga atacagtaaa atccaacagt tcatccaagg 540 cacccaaagt ggtgcctctg actccagaac aagccctgaa gcaatataaa caccacctca 600 ctgcctatga gaaactggaa ataattaatt atccagasat ttactttgta ggtccaaatg 660 ccaagaaaag acatggagtt attggtggtc ccaataatgg agggtatgat gatgcagatg 720 gggcctatat tcatgtacct cgagaccatc tagcttatcg atatgaggtg ctgaaaatta 780 ttggcaaggg gagttttggg caggtggcca gggtctatga tcacaaactt cgacagtacg 840 tggccctaaa aatggtgcgc aatgagaagc gctttcatcg tcaagcagct gaggagatcc 900 ggattttgga gcatcttaag aaacaggata aaactggtag tatgaacgtt atccacatgc 960 tggaaagttt cacattccgg aaccatgttt gcatggcctt tgaattgctg agcatagacc 1020 tttatgagct gattaaaaaa aataagtttc agggttttag cgtccagttg gtacgcaagt 1080 ttgcccagtc catcttgcaa tctttggatg ccctccacaa aaataagatt attcactgcg 1140 atctgaagcc agaaaacatt ctcctgaaac accacgggcg cagttcaacc aaggtcattg 1200 actttgggtc cagctgtttc gagtaccaga agctctacac atatatccag tctcggttct 1260 acagagctcc agaaatcatc ttaggaagcc gctacagcac accaattgac atatggagtt 1320 ttggctgcat ccttgcagaa cttttaacag gacagcctct cttccctgga gaggatgaag 1380 gagaccagtt ggcctgcatg atggagcttc tagggatgcc accaccaaaa cttctggagc 1440 aatccaaacg tgccaagtac tttattaatt ccaagggcat accccgctac tgctctgtga 1500 ctacccaggc agatgggagg gttgtgcttg tggggggtcg ctcacgtagg ggtaaaaagc 1560 ggggtccccc aggcagcaaa gactggggga cagcactgaa agggtgtgat gactacttgt 1620 ttatagagtt cttgaaaagg tgtcttcact gggacccctc tgcccgcttg accccagctc 1680 aagcattaag acacccttgg attagcaagt ctgtccccag acctctcacc accatagaca 1740 aggtgtcagg gaaacgggta gttaatcctg caagtgcttt ccagggattg ggttccaagc 1800 tgcctccagt tgttggaata gccaataagc ttaaagctaa cttaatgtca gaaaccaatg 1860 gtagtatacc cctatgcagt gtattgccaa aactgattag ctagtggaca gagatatgcc 1920 cagagatgca tatgtgtata tttttatgat cttacaaacc tgcaaatgga aaaaatgcaa 1980 gcccattggt ggatgttttt gttagagtag acttttttta aacaagacaa aacattttta 2040 tatgattata aaagaattct tcaagggcta attacctaac cagcttgtat tggccatctg 2100 gaatatgcat taaatgactt tttataggtc aaaaaaaaaa 2140 <210> 56 <211> 1728 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 346275 <400> 56 gacagacaaa gcgccgccac gcgtccgcat gtcggatgtt tgtagcagtc agagagcaga 60 acatgagcat ctgccaggtc tggttccccc accatcaggg atgggagtga gaaaggggag 120 ttcccctctg aagagccacc cctgcaggga gaaatctgtc tccaacagga gatctgggaa 180 gaccatagtg agaagtgctg tcgaagaggt ccgcacagcg ggccttttcc gaagtggttt 240 tagcgaagag aaggcaactg gcaagctctt tgctgtgaag tgtatcccta agaaggcgct 300 gaagggcaag gaaagcagca tagagaatga gatagccgtc ctgagaaaga ttaagcatga 360 aaatattgtt gccctggaag acatttatga aagcccaaat cacctgtact tggtcatgca 420 gctggtgtcc ggtggagagc tgtttgaccg gatagtggag aaggggtttt atacagagaa 480 ggatgccagc actctgatcc gccaagtctt ggacgccgtg tactatctcc acagaatggg 540 catcgtccac agagacctca agcccgaaaa tctcttgtac tacagtcaag atgaggagtc 600 caaaataatg atcagtgact ttggattgtc aaaaatggag ggcaaaggag atgtgatgtc 660 cactgcctgt ggaactccag gctatgtcgc tcctgaagtc ctcgcccaga aaccttacag 720 caaagccgtt gactgctggt ccatcggagt gattgcctac atcttgctct gcggctaccc 780 tcctttttat gatgaaaatg actccaagct ctttgagcag atcctcaagg cggaatatga 840 gtttgactct ccctactggg atgacatctc cgactctgca aaagacttca ttcggaacct 900 gatggagaag gacccgaata aaagatacac gtgtgagcag gcagctcggc acccatggat 960 cgctggtgac acagccctca acaaaaacat ccacgagtcc gtcagcgccc agatccggaa 1020 aaactttgcc aagagcaaat ggagacaagc atttaatgcc acggccgtcg tgagacatat 1080 gagaaaacta cacctcggca gcagcctgga cagttcaaat gcaagtgttt cgagcagcct 1140 cagtttggcc agccaaaaag actgtgcgta tgtagcaaaa ccagaatccc tcagctgaca 1200 ctgaagacga gcctggggtg gagaggaggg agccggcatc tgccgagcac ctcctgtttg 1260 ccaggcgctt tctatactta atcccatgtc atgcgaccct aggacttttt ttaacatgta 1320 atcactgggc cgggtgcagt ggctcacgcc tgtaatccca acactttggg aggctgaggc 1380 aggaggactg tttgagttca ggagttttaa gaccagcctg accaacatgg tgaaacccca 1440 tctctactaa aatataaaaa ttagccgggt gtggtggcga gcacctgtaa tgtcagctac 1500 ttgggaggct gaggcaggag aatcacttga acccaggaag cggaggttgc aatgagctga 1560 gatcacacca ctgcactcca gcctgggtga cagattgaga ctccctctca aaaaaaaaag 1620 ggaaatcatt gaacactcgt ggaaccctag gtattgcata ttccatttac ggtttgggaa 1680 tccagggctc aagtcctcgc aggggtaccg agctcgagat cgtaatca 1728 <210> 57 <211> 1610 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 283746 <400> 57 gtcgcctctg aaggagaacc attttccatc tctttcatag ttttttcccc cagtcagcgt 60 ggtagcggta ttctccgcgg cagtgacagt aattgttttt gcctctttag ccaagacttc 120 cgccctcgat caagatggtg gttggacggc cttcctaacc tttacggggc ctggcggtgc 180 tgacgcctga gctggtaggg gtggagcagg taggaaacag caaatgcaga agctgctgcg 240 cggaagtcgg ccatggactg gaaagaagtt cttcgtcggc gcctagcgac gcccaacacc 300 tgtccaaaca ctgcctgctg aagatgaagt cttactacag aaattaagag aggaatcaag 360 agctgtcttt ctacaaagaa aaagcagaga actgttagat aatgaagaat tacagaactt 420 atggtttttg ctggacaaac accagacacc acctatgatt ggagaggaag cgatgatcaa 480 ttacgaaaac tttttgaagg ttggtgaaaa ggctggagca aagtgcaagc aatttttcac 540 agcaaaagtc tttgctaaac tccttcatac agattcatat ggaagaattt ccatcatgca 600 gttctttaat tatgtcatga gaaaagtttg gcttcatcaa acaagaatag gactcagttt 660 atatgatgtc gctgggcagg ggtaccttcg ggaatctgat ttagaaaact acatattgga 720 acttatccct acgttgccac aattagatgg tctggaaaaa tctttctact ccttttatgt 780 ttgtacagca gttaggaagt tcttcttctt tttagatcct ttaagaacag gaaagataaa 840 aattcaagat attttagcat gcagcttcct agatgattta ttggagctaa gggatgagga 900 actgtccaag gagagtcaag aaacaaattg gttttctgct ccttctgccc taagagttta 960 tggccagtac ttgaatcttg ataaagatca caatggcatg ctcagtaaag aagaactctc 1020 acgctatgga acagctacca tgaccaatgt cttcttagac cgtgttttcc aggagtgtct 1080 cacttatgat ggagaaatgg actataagac ctacttggac tttgtccttg cattagaaaa 1140 cagaaaggaa cctgcagctc tacaatatat tttcaaactg cttgatattg agaacaaagg 1200 atacctgaat gtcttttcac ttaattattt ctttagggcc atacaggaac taatgaaaat 1260 ccatggacaa gatcctgttt catttcaaga tgtcaaggat gaaatctttg acatggtaaa 1320 accaaaggat cctttgaaaa tctctcttca ggatttaatc aacagtaatc aaggagacac 1380 agtaaccacc attctaatcg atttgaatgg cttctggact tacgagaaca gagaggctct 1440 tgttgcaaat gacagtgaaa actctgcaga ccttgatgat acatgatctc tgaaagacta 1500 gactgtctta tattatgaga tacttgaatg ctgcatgtaa agcctttaaa gcaaaatcct 1560 cagaaatggt ctaaataaaa cacttgatat gcctagagaa aaaaaaaaaa 1610 <210> 58 <211> 1290 <212> DNA
<213> Homo sapiens , <220>
<221> misc_feature <223> Incyte Clone Number: 2696537 <400> 58 ccggctcccg ccgggaagtt ctaggccgcc gcacagaaag ccctgccctc cacgccgggt 60 ctctggagcg ccctgggttg cccggccggt ccctgccgct gacttgttga cactgcgagc 120 actcagtccc tcccgcgcgc ctcctccccg cccgccccgc cgctcctcct ccctgtaaca 180 tgccatagtg cgcctgcgac cacacggccg gggcgctagc gttcgccttc agccaccatg 240 gggaatggga tgaacaagat cctgcccggc ctgtacatcg gcaacttcaa agatgccaga 300 gacgcggaac aattgagcaa gaacaaggtg acacatattc tgtctgtcca tgatagtgcc 360 aggcctatgt tggagggagt taaatacctg tgcatcccag cagcggattc accatctcaa 420 aacctgacaa gacatttcaa agaaagtatt aaattcattc acgagtgccg gctccgcggt 480 gagagctgcc ttgtacactg cctggccggg gtctccagga gcgtgacact ggtgatcgca 540 tacatcatga ccgtcactga ctttggctgg gaggatgccc tgcacaccgt gcgtgctggg 600 agatcctgtg ccaaccccaa cgtgggcttc cagagacagc tccaggagtt tgagaagcat 660 gaggtccatc agtatcggca gtggctgaag gaagaatatg gagagagccc tttgcaggat 720 gcagaagaag ccaaaaacat tctggccgct ccgggaattc tgaagttctg ggcctttctc 780 agaagactgt aatgtacctg aagtttctga aatattgcaa acccacagag tttaggctgg 840 tgctgccaaa aagaaaagca acatagagtt taagtatcca gtagtgattt gtaaacttgt 900 ttttcatttg aagctgaata tatacgtagt catgtttatg ttgagaacta aggatattct 960 ttagcaagag aaaatatttt ccccttatcc ccactgctgt ggaggtttct gtacctcgct 1020 tggatgcctg taaggatccc gggagccttg ccgcactgcc ttgtgggtgg cttggcgctc 1080 gtgattgctt cctgtgaacg cctcccaagg acgagcccag tgtagttgtg tggcgtgaac 1140 tctgcccgtg tgttctcaaa ttccccagct tgggaaatag cccttggtgt gggttttatc 1200 tctggtttgt gttctccgtg gtggaattga ccgaaagctc tatgttttcg ttaataaagg 1260 gcaacttagc caagtttaaa aaaaaaaaaa 1290 <210> 59 <211> 2281 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 551178 <400> 59 tgatgatcca gatgttaaag cacaagtgga agtgctgtcc gctgcactac gtgcttccag 60 cctggatgca catgaagaga ccatcagtat agaaaagaga agtgatttgc aagatgaact 120 ggatataaat gagctaccaa attgtaaaat aaatcaagaa gattctgtgc ctttaatcag 180 cgatgctgtt gagaatatgg actccactct tcactatatt cacagcgatt cagacttgag 240 caacaatagc agttttagcc ctgatgagga aaggagaact aaagtacaag atgttgtacc 300 tcaggcgttg ttagatcagt atttatctat gactgaccct tctcgtgcac agacggttga 360 cactgaaatt gctaagcact gtgcatatag cctccctggt gtggccttga cactcggaag 420 acagaattgg cactgcctga gagagacgta tgagactctg gcctcagaca tgcagtggaa 480 agttcgacga actctagcat tctccatcca cgagcttgca gttattcttg gagatcaatt 540 gacagctgca gatctggttc caatttttaa tggattttta aaagacctcg atgaagtcag 600 gataggtgtt cttaaacact tgcatgattt tctgaagctt cttcatattg acaaaagaag 660 agaatatctt tatcaacttc aggagttttt ggtgacagat aatagtagaa attggcggtt 720 tcgagctgaa ctggctgaac agctgatttt acttctagag ttatatagtc ccagagatgt 780 ttatgactat ttacgtccca ttgctctgaa tctgtgtgca gacaaagttt cttctgttcg 840 ttggatttcc tacaagttgg tcagcgagat ggtgaagaag ctgcacgcgg caacaccacc 900 aacgttcgga gtggacctca tcaatgagct tgtggagaac tttggcagat gtcccaagtg 960 gtctggtcgg caagcctttg tctttgtctg ccagactgtc attgaggatg actgccttcc 1020 catggaccag tttgctgtgc atctcatgcc gcatctgcta accttagcaa atgacagggt 1080 tcctaacgtg cgagtgctgc ttgcaaagac attaagacaa actctactag aaaaagacta 1140 tttcttggcc tctgccagct gccaccagga ggctgtggag cagaccatca tggctcttca 1200 gatggaccgt gacagcgatg tcaagtattt tgcaagcatc caccctgcca gtaccaaaat 1260 ctccgaagat gccatgagca cagcgtcctc aacctactag aaggcttgaa tctcggtgtc 1320 tttcctgctt ccatgagagc cgaggttcag tgggcattcg ccacgcatgt gacctgggat 1380 agctttcggg ggaggagaga ccttcctctc ctgcggactt cattgcaggt gcaagttgcc 1440 tacacccaat accagggatt tcaagagtca agagaaagta cagtaaacac tattatctta 1500 tcttgacttt aaggggaaat aatttctcag aggattataa ttgtcacega agccttaaat 1560 ccttctgtct tcctgactga atgaaacttg aattggcaga gcattttcct tatggaaggg 1620 atgagattcc cagagacctg cattgetttc tcctggtttt atttaacaat cgacaaatga 1680 aattcttaca gcctgaaggc agacgtgtgc ccagatgtga aagagacctt cagtatcagc 1740 cctaactctt ctctcccagg aaggacttgc tgggctctgt ggccagctgt ccagcccagc 1800 cctgtgtgtg aatcgtttgt gacgtgtgca aatgggaaag gaggggtttt tacatctcct 1860 aaaggacctg atgccaacac aagtaggatt gacttaaact cttaagcgca gcatattgct 1920 gtacacattt acagaatggt tgctgagtgt ctgtgtctga ttttttcatg ctggtcatga 1980 cctgaaggaa atttattaga cgtataatgt atgtctggtg tttttaactt gatcatgatc 2040 agctctgagg tgcaacttct tcacatactg tacatacctg tgaccactct tgggagtgct 2100 gcagtcttta atcatgctgt ttaaactgtt gtggcacaag ttctcttgtc caaataaaat 2160 ttattaataa gatctataga gagagatata tacacttttg attgttttct agatgtctac 2220 caataaatgc aatttgtgac ctgtattaat gatttaaagt gggaaactag attaaaatat 2280 a 22$1 <210> 60 <211> 632 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 619292 <400> 60 cggacgcgtg gggtecagcc gcagctccag caccgaggac ttctgctacg tcttcacggt 60 ggagctggaa cgaggcccct ccgggctggg gatgggcctg atcgacggga tgcacacgca 120 cctgggcgcc cccgggctct acatccagac cctgctcccg ggcagccccg cagcggccga 180 cgggcgcctg tcgctggggg accgtatcct ggaggtgaat ggcagcagcc tcctgggcct 240 PC'f/US99/17132 tggctacctg agagctgtgg acctgatccg tcatggcggg aagaagatgc ggttcetggt 300 cgcgaagtcc gacgttggga aacagccaag aagatccatt tccgcacgcc ccctctctag 360 gggggctgcg aggacacccc cacaggcccg gcacccggtc ccacctggtg acactgggct 420 tcctcccgcc ttcgtccctg ttttgtaact gaccaagttg ggtcccgggt ggggagcctc 480 accctgggga catgcctgtt gataacatgc atctcagtgt aggttctatt tatatggcag 540 atgacgtgaa attgtgatgt ttgttacaga gcttttatgt ttaaagactt caatggagaa 600 gtacggttca ataaactatt tttcccgttc tt 632 <210> 61 <211> 2347 <212> DNA
<213> Homo sapiens <220>
<221> miec'feature <223> Incyte Clone Number: 2054049 <400> 61 cccagtttta tcatggattc atcctgaaag tcaagccaca atcactcggt gtagccagcc 60 catggttgga gtgagtggaa agcgaagcaa agaagatgaa aaataccttc aagctatcat 120 ggattccaat gcccagtctc acaaaatctt tatatttgat gcccggccaa gtgttaatgc 180 tgttgccaac aaggcaaagg gtggaggtta tgaaagtgaa gatgcctatc aaaatgctga 240 actagttttc ctggatatcc acaatattca tgttatgaga gaatcattac gaaaacttaa 300 ggagattgtg taccccaaca ttgaggaaac ccactggttg tctaacttgg aatctactca 360 ttggctagaa catattaagc ttattcttgc aggggctctt aggattgctg acaaggtaga 420 gtcagggaag acgtctgtgg tagtgcattg cagtgatggt tgggatcgca cagctcagct 480 cacttccctt gccatgctca tgttggatgg atactatcga accatccgag gatttgaagt 540 ccttgtggag aaagaatggc taagttttgg acatcgattt caactaagag ttggccatgg 600 agataagaac catgcagatg cagacagatc gcctgttttt cttcaattta ttgactgtgt 660 etggcagatg acaagacagt ttcctaccgc atttgaattc aatgagtatt ttctcattac 720 cattttggac cacctataca gctgcttatt cggaacattc ctctgtaata gtgaacaaca 780 gagaggaaaa gagaatcttc ctaaaaggac tgtgtcactg tggtcttaca taaacagcca 840 gctggaagac ttcactaatc ctctctatgg gagctattcc aatcatgtcc tttatccagt 900 agccagcatg cgccacctag agctctgggt gggatattac ataaggtgga atccacggat 960 gaaaccacag gaacctattc acaacagata caaagaactt cttgctaaac gagcagagct 1020 tcagaaaaaa gtagaggaac tacagagaga gatttctaac cgatcaacct catcctcaga 1080 gagagccagc tctcctgcac agtgtgtcac tcctgtccaa actgttgtat aaaggactgt 1140 aagatcaggg gcatcattgc tatacactct tgattacact ggcagctcta tgagtagaaa 1200 gtcttcggaa tttagaaccc atctatgaga gaaagttcag tcactttatt tattttaaat 1260 ctctctagga tgagtttaga actgtagcag tgcaggtggc ttaagtgaag taactccata 1320 tgtaattaca tgattatgat actaatcttt taagtatcca aagaatatta aaatacttca 1380 atcctggatt cacagtggga acaagtttct attaaaaggc aaatgctgtt acaaattttt 1440 ggcatctggt aatattaaaa ccattttaga aatacactct gtgctcactg tgcagaggaa 1500 catcagtttt caaaccaaca ctgaaattct gtggcatcac atatattggg ccttgatgtc 1560 atgacagatc aaaatcattt gatatccctt tctccattct aggtttttct ttttttcagt 1620 aactgattta ccttgatcac ttttcaactt ccatattctt catatagtaa aaggcaaagt 1680 gttgaagata ctacggtgtg gtagtagttg aaaattattg ccgtcattat ttacatactt 1740 aagacatatt agcaagttga tccaaaatgg gaggccttat agatgtgctt gggggaaaat 1800 gaaggggaga aagtagccat acaggagttc aaagaattcc atgcccttca gattagccca 1860 attaccagaa acatcatgaa agatatttta aaaactaatt atttactaca gtgtatttca 1920 cttgtcttgt gtgtctgaac acacagaagc taattagcaa gtttttaaga agtatttaaa 1980 aatcttacta ggattgacat tttttctgaa ttctgtataa atagcttata gtgagaagta 2040 ctgtgctcaa attttacatt tttttccttt gcaaattctg taatttcact caacgattaa 2100 gtctaccaaa gaacacactg catgtaaaag atgtattaca atctcaaagc cagtaaaaga 2160 aatcttgctt cactgttcac ctgctacaag taagagtttg gtgctggtag aaacatttga 2220 ctctgatgtc tattttattc tacataagag ccatatgtaa tgtactgtaa caaaggagct 2280 tcttgtcccc ttggtctttt aattaaaaga aattccaact gacttttaaa ctttaaaaaa 2340 aaaaaaa <210> 62 <211> 1737 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte Clone Number: 2843910 <400> 62 ccggggctga gcgctcggct gcagcggcgc ggaggccgtc tccctggtct gccgcggtcc 60 ccgcccgtcc cgccgccggc tgccatggca ggagccggag ggttcggctg ccccgcgggc 120 ggcaacgact tccagtggtg cttctcgcag gtcaaggggg ccatcgacga ggacgtggcc 180 gaagcggaca tcatttccac cgttgagttt aattactctg gagatcttct tgcaacagga 240 gacaagggcg gcagagttgt tatttttcag cgtgaacaag agaataaaag ccgccctcat 300 tctaggggag aatataatgt ttacagcacc tttcaaagtc atgaaccgga gtttgactat 360 ttgaaaagtc tagaaattga ggaaaaaatt aataaaatta ggtggttacc acaacagaat 420 gctgctcatt ttctactgtc tacaaatgat aaaactataa aattatggaa aataagtgaa 480 cgggataaaa gagcagaagg ttataacctg aaagacgaag atggaagact tcgagaccca 540 tttaggatca cggcgctacg ggtcccaata ttgaagccca tggatcttat ggtagaagcg 600 agtccacggc gaatttttgc aaatgctcac acatatcata taaattccat ttcagtaaat 660 agtgatcatg aaacatatct ttctgcagat gacctgagaa ttaatttatg gcacttagaa 720 atcacagata gaagctttaa catcgtggac atcaagcctg ctaacatgga ggagctgacc 780 gaagtcatca ctgcagccga gttccacccg caccagtgca acgtgttcgt ctacagcagt 840 agcaaaggga ccatccgcct gtgtgacatg cgctcctcgg ccctgtgcga cagacactcc 900 aagttttttg aagagcctga agatcccagc agtaggtcct tcttctcaga aataatttca 960 tccatatccg atgtaaaatt cagtcatagt gggcggtaca tgatgaccag agactacctg 1020 tcggtgaagg tgtgggacct caacatggag agcaggccgg tggagaccca ccaggtccac 1080 gagtacctgc gcagcaagct ctgctctctc tatgagaacg actgcatctt tgacaagttt 1140 gagtgttgct ggaacggttc ggatagcgcc atcatgaccg ggtcctataa caacttcttc 1200 aggatgtttg atagagacac gcggagggat gtgaccctgg aggcetcgag agagagcagc 1260 aaaccgcgcg ccagcctcaa accccggaag gtgtgtacgg ggggtaagcg gaggaaagac 1320 gagatcagtg tggacagtct ggacttcaac aagaagatcc tgcacacagc ctggcacccc 1380 gtggacaatg tcattgccgt ggctgccacc aataacttgt acatattcca ggacaaaatc 1440 aactagagac gcgaacgtga ggaccaagtc ttgtcttgca tagttaagcc ggacattttt 1500 etgtcagaga aaaggcatca ttgtccgctc cattaagaac agtgacgcac ctgctacttc 1560 ccttcacaga cacaggagaa agccgcctcc gctggaggcc cggtgtggtt ccgcctcggc 1620 gaggcgcgag acaggcgctg ctgctcacgt ggagacgctc tcgaagcaga gttgacggac 1680 actgctccca aaaggtcatt actcagaata aatgtattta tttcaaaaaa aaaaaaa 1737

Claims (20)

What is claimed is:

1. A substantially purified polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-31, and fragments thereof.

2. A substantially purified variant having at least 90% amino acid sequence identity to the amino acid sequence of claim 1.

3. An isolated and purified polynucleotide encoding the polypeptide of claim 1.

4. An isolated and purified polynucleotide variant having at least 80%
polynucleotide sequence identity to the polynucleotide of claim 3.

5. An isolated and purified polynucleotide which hybridizes under stringent conditions to the polynucleotide of claim 3.

6. An isolated and purified polynucleotide having a sequence which is complementary to the polynucleotide of claim 3.

7. A method for detecting a polynucleotide, the method comprising the steps of (a) hybridizing the polynucleotide of claim 6 to at least one nucleic acid in a sample, thereby forming a hybridization complex; and (b) detecting the hybridization complex, wherein the presence of the hybridization complex correlates with the presence of the polynucleotide in the sample.

8. The method of claim 7 further comprising amplifying the polynucleotide prior to hybridization.

9. An isolated and purified polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID N0:32-62 and fragments thereof.

10. An isolated and purified polynucleotide variant having at least 80%
polynucleotide sequence identity to the polynucleotide of claim 9.

11. An isolated and purified polynucleotide having a sequence which is complementary to the polynucleotide of claim 9.

12. An expression vector comprising at least a fragment of the polynucleotide of claim 3.

13. A host cell comprising the expression vector of claim 12.

14. A method for producing a polypeptide, the method comprising the steps of a) culturing the host cell of claim 13 under conditions suitable for the expression of the polypeptide; and b) recovering the polypeptide from the host cell culture.

15. A pharmaceutical composition comprising the polypeptide of claim 1 in conjunction with a suitable pharmaceutical carrier.

16. A purified antibody which specifically binds to the polypeptide of claim 1.

17. A purified agonist of the polypeptide of claim 1.

18. A purified antagonist of the polypeptide of claim 1.

19. A method for treating or preventing a disorder associated with decreased expression or activity of PHSP, the method comprising administering to a subject in need of such treatment an effective amount of the pharmaceutical composition of claim 15.

20. A method for treating or preventing a disorder associated with increased expression or activity of PHSP, the method comprising administering to a subject in need of such treatment an effective amount of the antagonist of claim 18.