KR20230136786A - Composition for diagnosing pancreatic cancer - Google Patents

Abstract

The present invention provides compositions, kits, and information that can diagnose pancreatic cancer more precisely or predict the prognosis of pancreatic cancer by using biomarkers that can be linked to metabolic tumor volume, a quantitative parameter used for metabolic activity. It's about how to do it.

Description

Composition for diagnosing pancreatic cancer}

The present invention relates to a composition for diagnosing pancreatic cancer, a kit, and a method for providing information for diagnosis.

Pancreatic cancer is the seventh leading cause of cancer-related death worldwide, but ranks second to fifth in developed countries. Patients with pancreatic cancer have a low survival rate, with an estimated 5-year survival rate of less than 5% due to early metastasis and recurrence after surgery. Pancreatic cancer generally has problems being diagnosed at an advanced stage due to symptoms that are not noticeable in the early stages, lack of specific tumor markers, and difficulty detecting the cancer in the early stages.

Pancreatic cancer is usually diagnosed clinically with one or two medical imaging and blood tests. Although existing tumor markers are clinically useful, they are known to be ineffective in early detection of pancreatic cancer. Carbohydrate antigen 19-9 (CA19-9), the most widely used pancreatic cancer biomarker, has limitations in the early detection of pancreatic cancer, such as insufficient sensitivity or specificity to help with early diagnosis of pancreatic cancer. In order to facilitate more precise early diagnosis, research is being actively conducted to discover pancreatic cancer-specific biomarkers.

We identified metabolic tumor as a quantitative parameter used for metabolic activity in positron emission tomography (PET) using 2-[18F] Fluoro-2-deoxy-D-glucose (FDG), the most common metabolic imaging technique in standard pancreatic cancer treatment. The present invention was completed by discovering a biomarker that can be linked to metabolic tumor volume.

One object of the present invention is to provide a composition for diagnosing cancer.

Another object of the present invention is to provide a kit for diagnosing cancer.

Another object of the present invention is to provide a method for providing information regarding the diagnosis of cancer.

Another object of the present invention is to provide a composition for predicting the prognosis of cancer.

Another object of the present invention is to provide a kit for predicting the prognosis of cancer.

Another object of the present invention is to provide a method for providing information regarding the prognosis of cancer.

Another object of the present invention is to provide a panel for diagnosing cancer or predicting the prognosis of cancer.

However, the technical problem to be achieved by the present invention is not limited to the problems mentioned above, and other problems not mentioned can be clearly understood by those skilled in the art from the description below.

DETAILED DESCRIPTION OF THE INVENTION Various embodiments described herein are described below with reference to the drawings. In the following description, various specific details, such as specific forms, compositions, and processes, are set forth in order to provide a thorough understanding of the invention. However, certain embodiments may be practiced without one or more of these specific details or in conjunction with other known methods and forms. In other instances, well-known processes and manufacturing techniques are not described in specific detail so as not to unnecessarily obscure the invention. Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, form, composition or characteristic described in connection with the embodiment is included in one or more embodiments of the invention. Accordingly, the phrases “in one embodiment” or “an embodiment” expressed in various places throughout this specification do not necessarily refer to the same embodiment of the invention. Additionally, particular features, shapes, compositions, or properties may be combined in any suitable way in one or more embodiments.

Unless there is a special definition in the specification, all scientific and technical terms used in the specification have the same meaning as commonly understood by a person skilled in the art in the technical field to which the present invention pertains.

According to one embodiment of the present invention, it relates to a composition for diagnosing cancer.

In the present invention, the diagnostic composition includes CNOT1 (CCR4-NOT Transcription Complex Subunit 1), KIF11 (kinesin family member 11), SLC44A1 (Solute Carrier Family 44 Member 1), MSI1 (Musashi RNA Binding Protein 1), and SDK1 (Sidekick Cell Adhesion). At least one protein selected from the group consisting of Molecule 1) and SYNGR1 (Synaptogyrin 1); Alternatively, it may include an agent that measures the expression level of the gene encoding it.

In the present invention, “CNOT1 (CCR4-NOT Transcription Complex Subunit 1)” corresponds to the protein encoded by the CNOT1 gene in humans. This is the part of the CCR4-Not complex that diadenylates mRNA and acts as a scaffold protein to associate with other subunits of the complex. CNOT1-related diseases include Pancreatic Agenesis and Holoprosencephaly with or without Vissers-Bodmer Syndrome. The CNOT1 protein may be composed of the amino acid sequence represented by SEQ ID NO: 1, but is not limited thereto.

In the present invention, "KIF11 (kinesin family member 11)" is known to encode a motor protein belonging to the kinesin-like protein family, and members of this protein family are also known to be involved in various types of spindle dynamics. The functions of the gene product include chromosome positioning, centromere separation, and bipolar spindle production during cell mitosis. The KIF11 protein may consist of the amino acid sequence represented by SEQ ID NO: 2, but is not limited thereto.

In the present invention, the "SLC44A1 (Solute Carrier Family 44 Member 1)", also known as CD92 or CTL1, activates choline transmembrane transporter activity and is involved in choline transport and transmembrane transport, which is also related to glioma. It is known that The SLC44A1 protein may consist of the amino acid sequence represented by SEQ ID NO: 3, but is not limited thereto.

In the present invention, “MSI1 (Musashi RNA Binding Protein 1)” encodes a protein containing two conserved tandem RNA recognition motifs. Expression of the above gene is known to be correlated with malignancy and proliferative activity of glioma and melanoma. The MSI1 protein may consist of the amino acid sequence shown in SEQ ID NO: 4, but is not limited thereto.

In the present invention, “SDK1 (Sidekick Cell Adhesion Molecule 1)” is a member of the immunoglobulin superfamily, and the protein encoded by this gene includes 6 immunoglobulin-like domains and 13 fibronectin type III domains. Fibronectin type III domains are present in both extracellular and intracellular proteins, and tandem repeats are known to contain binding sites for DNA, heparin, and the cell surface. The SDK1 protein may consist of the amino acid sequence shown in SEQ ID NO: 5, but is not limited thereto.

In the present invention, “SYNGR1 (Synaptogyrin 1)” encodes an integral membrane protein associated with presynaptic vesicles in nerve cells. The exact function of this protein is unclear, but studies of similar murine proteins have shown that it functions in synaptic plasticity that is not required for synaptic transmission. The gene product belongs to the synaptogyrin gene family, and three alternatively spliced variants encoding three different isoforms are known. The SYNGR1 protein may be composed of the amino acid sequence represented by SEQ ID NO: 6, but is not limited thereto.

In the present invention, the diagnostic composition includes CELSR1 (Cadherin EGF LAG Seven-Pass G-Type Receptor 1), DCLRE1B (DNA Cross-Link Repair 1B), ITGA3 (Integrin Subunit Alpha 3), KIAA1217 (Sickle Tail Protein Homolog), and MBOAT2 ( Membrane Bound O-Acyltransferase Domain Containing 2), RCC1 (Regulator Of Chromosome Condensation 1), SON (SON DNA And RNA Binding Protein), TLDC1 (MTOR Associated Protein, Eak-7 Homolog), ZFP69 (Zinc Finger Protein 69 Homolog), ADCY1 (Adenylate Cyclase 1), ARL6IP4 (ADP Ribosylation Factor Like GTPase 6 Interacting Protein 4), ATP8A1 (ATPase Phospholipid Transporting 8A1), COX14 (Cytochrome C Oxidase Assembly Factor COX14), EPOR (Erythropoietin Receptor), FAM110D (Family With Sequence Similarity) 110 Member D), GADD45G (Growth Arrest And DNA Damage Inducible Gamma), HHEX (Hematopoietically Expressed Homeobox), INPP5B (Inositol Polyphosphate-5-Phosphatase B), KCNJ8 (Potassium Inwardly Rectifying Channel Subfamily J Member 8), LIN7B (Lin- 7 homolog B), at least one protein selected from the group consisting of PAK3 (P21 Activated Kinase 3), RBP5 (Retinol Binding Protein 5), and SNHG7 (Small Nucleolar RNA Host Gene 7); Alternatively, it may additionally include an agent that measures the expression level of the gene encoding it.

In the present invention, “CELSR1 (Cadherin EGF LAG Seven-Pass G-Type Receptor 1)” is a member of the flamingo subfamily, which is part of the cadherin superfamily. Flamingo cadherin is located in the plasma membrane and has nine cadherin domains, seven epidermal growth factor-like repeats and two laminin A G-type repeats in the ectodomain. Certain members are known to be developmentally regulated neuron-specific genes that play unspecified roles in early embryogenesis. The CELSR1 protein may consist of the amino acid sequence shown in SEQ ID NO: 7, but is not limited thereto.

In the present invention, "DCLRE1B (DNA Cross-Link Repair 1B)" physically blocks transcription, replication, and separation of DNA by preventing strand separation of cross-links between DNA strands. DCLRE1B is known to be one of several evolutionarily conserved genes involved in the repair of interstrand cross-links. The DCLRE1B protein may consist of the amino acid sequence represented by SEQ ID NO: 8, but is not limited thereto.

In the present invention, “ITGA3 (Integrin Subunit Alpha 3)” encodes a member of the integrin alpha chain family. Integrins are heterodimeric integral membrane proteins composed of alpha and beta chains that function as cell surface adhesion molecules. The encoded preprotein is proteolytically processed to generate light and heavy chains that make up the alpha 3 subunit, which in turn is called the beta 1 subunit. The subunits combine to form integrins, which interact with extracellular matrix proteins, including members of the laminin family. It is also known that the expression of this gene is correlated with breast cancer metastasis. The ITGA3 protein may consist of the amino acid sequence represented by SEQ ID NO: 9, but is not limited thereto.

In the present invention, the "KIAA1217 (Sickle Tail Protein Homolog)" is also known as ETL4 or SKT, and is expected to be involved in the development of the embryonic skeletal system and is expected to be activated in the cytoplasm. The KIAA1217 protein may be composed of the amino acid sequence represented by SEQ ID NO: 10, but is not limited thereto.

In the present invention, “MBOAT2 (Membrane Bound O-Acyltransferase Domain Containing 2)” activates 1-acylglycerophosphocholine O-acyltransferase activity. 1-acylglycerophosphoethanolamine O-acyltransferase activity; and 1-acylglycerophosphoserine O-acyltransferase activity. Involved in phosphatidylcholine acyl chain remodeling; Phosphatidylethanolamine acyl chain remodeling; and phosphatidylserine acyl-chain remodeling. The MBOAT2 protein may consist of the amino acid sequence represented by SEQ ID NO: 11, but is not limited thereto.

In the present invention, “RCC1 (Regulator Of Chromosome Condensation 1)” activates several functions including guanyl-nucleotide exchange factor activity. Nucleosomal DNA binding activity; and protein heterodimerization activity. It is also known to be involved in several processes, including the G1/S transition of the mitotic cell cycle. The RCC1 protein may consist of the amino acid sequence represented by SEQ ID NO: 12, but is not limited thereto.

In the present invention, the "SON (SON DNA And RNA Binding Protein)" encodes a protein that binds to RNA and particularly promotes pre-mRNA splicing of transcripts with poor splicing sites. The protein is also known to recognize specific DNA sequences found in human hepatitis B virus (HBV) and inhibit HBV core promoter activity. The SON protein may be composed of the amino acid sequence represented by SEQ ID NO: 13, but is not limited thereto.

In the present invention, “TLDC1 (MTOR Associated Protein, Eak-7 Homolog)” is also known as MEAK7 or EAK7, and is known to be involved in several processes including TOR signaling. The TLDC1 protein may consist of the amino acid sequence represented by SEQ ID NO: 14, but is not limited thereto.

In the present invention, the "ZFP69 (Zinc Finger Protein 69 Homolog)" is predicted to enable DNA binding transcriptional repression activity, RNA polymerase II specific and RNA polymerase II transcription control region sequence specific DNA binding activity, It is known to be involved in the negative regulation of transcription by RNA polymerase II and the regulation of lipid metabolic processes. The ZFP69 protein may consist of the amino acid sequence shown in SEQ ID NO: 15, but is not limited thereto.

In the present invention, “ADCY1 (Adenylate Cyclase 1)” encodes a member of the adenylate cyclase gene family mainly expressed in the brain. It is also known that the above protein is regulated by calcium/calmodulin concentration and may be involved in brain development. The ADCY1 protein may consist of the amino acid sequence represented by SEQ ID NO: 16, but is not limited thereto.

In the present invention, "ARL6IP4 (ADP Ribosylation Factor Like GTPase 6 Interacting Protein 4)" is a gene that enables the same protein binding activity and is known to be involved in RNA splicing and mRNA processing. The ARL6IP4 protein may consist of the amino acid sequence represented by SEQ ID NO: 17, but is not limited thereto.

In the present invention, the "ATP8A1 (ATPase Phospholipid Transporting 8A1)" refers to a P-type adenosine triphosphatase (P-type ATPase), which corresponds to a protein family that induces uphill transport of ions across the membrane using the free energy of ATP hydrolysis. do. Several subfamilies of P-type ATPases have been identified, with one subfamily catalyzing the transport of heavy metal ions. Another subfamily transports non-metallic ions (NMHI). The protein encoded by this gene is a member of the third subfamily of P-type ATPases and is known to play a role in transporting amphipathic substances such as phosphatidylserine. The ATP8A1 protein may consist of the amino acid sequence represented by SEQ ID NO: 18, but is not limited thereto.

In the present invention, “COX14 (Cytochrome C Oxidase Assembly Factor COX14)” encodes a small, single-pass transmembrane protein localized to mitochondria. This protein is known to play a role in coordinating the initial steps of cytochrome c oxidase (COX, also known as complex IV) subunit assembly, particularly the synthesis and assembly of the COX I subunit of the holoenzyme. The COX14 protein may consist of the amino acid sequence represented by SEQ ID NO: 19, but is not limited thereto.

In the present invention, “EPOR (Erythropoietin Receptor)” encodes the erythropoietin receptor, a member of the cytokine receptor family. Upon binding to erythropoietin, this receptor activates the Jak2 tyrosine kinase, which activates various intracellular pathways, including Ras/MAP kinase, phosphatidylinositol 3-kinase, and STAT transcription factors, and stimulated erythropoietin receptors play a role in erythroid cell survival. It is known to do so. The ID3 may be composed of the amino acid sequence represented by SEQ ID NO: 20, but is not limited thereto.

In the present invention, "FAM110D (Family With Sequence Similarity 110 Member D)" is also known as GRRP1, and is known to be widely expressed in fat (RPKM 4.8), lung (RPKM 1.8), and 21 other tissues. The FAM110D protein may be composed of the amino acid sequence represented by SEQ ID NO: 21, but is not limited thereto.

In the present invention, "GADD45G (Growth Arrest And DNA Damage Inducible Gamma)" is a member of a gene group whose transcription level increases during stressful growth arrest conditions and after treatment with DNA damaging agents. The protein encoded by this gene is known to respond to environmental stress by mediating activation of the p38/JNK pathway through MTK1/MEKK4 kinase. The GADD45G protein may consist of the amino acid sequence represented by SEQ ID NO: 22, but is not limited thereto.

In the present invention, the “Hematopoietically Expressed Homeobox (HHEX)” encodes a member of the homeobox family of transcription factors involved in many developmental processes. It is known that this protein may play a role in hematopoietic differentiation due to its expression in specific hematopoietic lineages. The HHEX protein may be composed of the amino acid sequence shown in SEQ ID NO: 23, but is not limited thereto.

In the present invention, “INPP5B (Inositol Polyphosphate-5-Phosphatase B)” encodes a member of the inositol polyphosphate-5-phosphatase family. This enzyme functions to regulate calcium signaling by inactivating inositol phosphate. The encoded protein is localized in the cytoplasm and mitochondria and is also known to associate with membranes through an isoprenyl modification near the C-terminus. The INPP5B protein may consist of the amino acid sequence represented by SEQ ID NO: 24, but is not limited thereto.

In the present invention, "KCNJ8 (Potassium Inwardly Rectifying Channel Subfamily J Member 8)" encodes an integral membrane protein, and the protein encoded by this gene is an inward-rectifier type potassium channel. Potassium channels exist in most mammalian cells and participate in a wide range of physiological responses. It is also known that defects in the above genes can cause J-wave syndrome and sudden infant death syndrome (SIDS). The KCNJ8 protein may consist of the amino acid sequence represented by SEQ ID NO: 25, but is not limited thereto.

In the present invention, “LIN7B (Lin-7 homolog B)” activates protein domain-specific binding activity. It is known to be involved in maintaining epithelial cell apical/basal polarity. The LIN7B protein may consist of the amino acid sequence shown in SEQ ID NO: 26, but is not limited thereto.

In the present invention, the "PAK3 (P21 Activated Kinase 3)" encodes a serine-threonine kinase, and the protein encoded by this gene forms an activated complex with GTP-binding RAS-like (P21), CDC2, and RAC1. . This protein is known to be required for rapid cytoskeletal reorganization of dendritic spines involved in dendritic development and synaptic plasticity. The PAK3 protein may consist of the amino acid sequence shown in SEQ ID NO: 27, but is not limited thereto.

In the present invention, “RBP5 (Retinol Binding Protein 5)” encodes a cellular retinol binding protein that is highly expressed in the kidney and liver. Downregulation of the encoded protein in hepatocellular carcinoma is known to be associated with large tumor size and poor patient survival. The RBP5 protein may consist of the amino acid sequence represented by SEQ ID NO: 28, but is not limited thereto.

In the present invention, “SNHG7 (Small Nucleolar RNA Host Gene 7)” is known to be expressed in the ovary (RPKM 15.1), thyroid (RPKM 12.1), and 25 other tissues. The SNHG7 protein may consist of the amino acid sequence represented by SEQ ID NO: 29, but is not limited thereto.

In the present invention, the composition is intended to be applied to a biological sample isolated from an object of interest, and the biological sample includes, but is not limited to, a solid tissue sample, tissue culture, liquid tissue sample, cell, or cell fragment. Additionally, non-limiting examples of biological samples include whole blood, leukocytes, peripheral blood mononuclear cells, buffy coat, plasma, serum, Sputum, tears, mucus, nasal washes, nasal aspirate, breath, urine, semen, saliva, Peritoneal washings, ascites, cystic fluid, meningeal fluid, amniotic fluid, glandular fluid, pancreatic fluid, lymph fluid, Pleural fluid, nipple aspirate, bronchial aspirate, synovial fluid, joint aspirate, organ secretions, cells, cell extract It may include one or more selected from the group consisting of cell extract and cerebrospinal fluid, but is not limited thereto.

In the present invention, the “object of interest” refers to an individual that has developed cancer or is likely to develop cancer, and may be a mammal, including humans, for example, humans, rats, mice, guinea pigs, hamsters, rabbits, monkeys, and dogs. , may be selected from the group consisting of cats, cows, horses, pigs, sheep and goats, and preferably may be humans, but is not limited thereto.

When measuring the expression level of a marker according to the present invention from a biological sample isolated from an individual of interest in the present invention, the occurrence or likelihood of developing a disease can be confirmed very quickly and easily.

In the present invention, the term “cancer” refers to or refers to a physiological condition typically characterized by uncontrolled cell growth in mammals. In the present invention, the cancer includes pancreatic cancer, thyroid cancer, parathyroid cancer, stomach cancer, ovarian cancer, colon cancer, liver cancer, breast cancer, cervical cancer, lung cancer, non-small cell lung cancer, prostate cancer, gallbladder cancer, biliary tract cancer, non-Hodgkin lymphoma, and Hodgkin lymphoma. , blood cancer, bladder cancer, kidney cancer, melanoma, colon cancer, bone cancer, skin cancer, head cancer, uterine cancer, rectal cancer, brain tumor, perianal cancer, fallopian tube carcinoma, endometrial carcinoma, vaginal cancer, vulvar carcinoma, esophageal cancer, small intestine cancer, and endocrine cancer. , adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, ureteral cancer, renal cell carcinoma, renal pelvic carcinoma, CNS central nervous system tumor, primary CNS lymphoma, spinal cord tumor, brainstem glioma, or pituitary adenoma. , Preferably, it may be pancreatic cancer, but is not limited thereto as long as it is a type of cancer in which cancer progression, such as tumor differentiation and/or proliferation, is dependent on the cancer cells and/or cancer stem cells described in the present invention.

In the present invention, “pancreatic cancer” refers to cancer originating from pancreatic cells. There are several types of pancreatic cancer, and pancreatic adenocarcinoma, which arises from pancreatic duct cells, accounts for about 90%, so pancreatic cancer generally refers to pancreatic ductal adenocarcinoma. In addition, there are cystic cancer (cystadenocarcinoma) and endocrine tumors. Approximately 5 to 10% of pancreatic cancer patients have a genetic predisposition, and approximately 7.8% of pancreatic cancer patients have a family history of pancreatic cancer, which is higher than the 0.6% incidence of pancreatic cancer in the general population. Pancreatic cancer is a cancer with a very poor prognosis, with a 5-year survival rate of less than 5%. The reason is that most cancers are discovered after they have progressed, so surgical resection is possible at the time of discovery in less than 20% of cases. Even if the cancer is completely resected with the naked eye, the survival rate is not improved due to micrometastasis, and there is little response to anticancer drugs and radiation therapy. Because it is low. Therefore, the most important way to improve survival rate is to detect early and perform surgery when there are no symptoms or when symptoms are non-specific.

In the present invention, “diagnosis” means confirming the presence or characteristics of a pathological condition. For the purposes of the present invention, the diagnosis may be to predict the possibility of the onset, growth, progression or metastasis of cancer, or may refer to cancer as another disease, such as a pancreatic disease, especially pancreatitis (both acute and chronic). , it may be to distinguish pancreatic benign tumors (such as lipoma or intrapancreatic papillary mucinous neoplasm (IPMN)), or it may be to distinguish carcinoma, especially pancreatic cancer from other carcinomas.

In the present invention, “pancreatitis” refers to a disease caused by inflammation of the pancreas and includes acute pancreatitis and chronic pancreatitis. Pancreatic juice contains digestive enzymes such as amylase (which hydrolyzes carbohydrates), trypsin (which hydrolyzes proteins), and lipase (which hydrolyzes fats). Pancreatitis not only occurs when the pancreatic juice does not flow smoothly due to alcohol abuse, gallstones, etc., causing the enzymes to cause autolysis of the pancreas, but also due to various causes such as metabolic disorders, drugs, and abdominal injuries. Pancreatitis is an inflammatory disease of the pancreas that causes damage to pancreatic glandular cells, extensive interstitial edema, hemorrhage, and migration of neutrophilic granulocytes to the site of injury. Pancreatitis can be broadly divided into two types: mild type, in which interstitial edema and peripancreatic fat necrosis are found, peripancreatic and intrapancreatic (peripancreatic) pancreatitis. There is severe type of pancreatitis accompanied by extensive intrapancreatic fatty necrosis, pancreatic parenchymal necrosis, and hemorrhage.

In the present invention, the agent for measuring the expression level of the protein includes at least one selected from the group consisting of antibodies, oligopeptides, ligands, PNA (peptide nucleic acids), and aptamers that specifically bind to the protein. It can be done, but is not limited to this.

In the present invention, the “antibody” refers to a substance that specifically binds to an antigen and causes an antigen-antibody reaction. For the purposes of the present invention, antibody refers to an antibody that specifically binds to the protein. Antibodies of the present invention include polyclonal antibodies, monoclonal antibodies, and recombinant antibodies. The antibody can be easily produced using techniques well known in the art. For example, polyclonal antibodies can be produced by methods well known in the art, including the process of injecting the protein antigen into an animal and collecting blood from the animal to obtain serum containing the antibody. These polyclonal antibodies can be produced from any animal, such as goats, rabbits, sheep, monkeys, horses, pigs, cows, dogs, etc. In addition, monoclonal antibodies can be prepared using the hybridoma method (see Kohler and Milstein (1976) European Journal of Immunology 6:511-519), which is well known in the art, or phage antibody library technology (Clackson et al, Nature, 352 :624-628, 1991; Marks et al, J. Mol. Biol., 222:58, 1-597, 1991). Antibodies prepared by the above method can be separated and purified using methods such as gel electrophoresis, dialysis, salt precipitation, ion exchange chromatography, and affinity chromatography. Additionally, antibodies of the invention include intact forms with two full-length light chains and two full-length heavy chains, as well as functional fragments of the antibody molecule. A functional fragment of an antibody molecule refers to a fragment that possesses at least an antigen-binding function, and includes Fab, F(ab'), F(ab')2, and Fv.

In the present invention, the “oligopeptide” is a peptide composed of 2 to 20 amino acids and may include dipeptide, tripeptide, tetrapeptide, and pentapeptide, but is not limited thereto.

In the present invention, "Peptide Nucleic Acid (PNA)" refers to an artificially synthesized polymer similar to DNA or RNA, and was first introduced by Professors Nielsen, Egholm, Berg and Buchardt at the University of Copenhagen, Denmark in 1991. While DNA has a phosphate-ribose sugar backbone, PNA has a repeated N-(2-aminoethyl)-glycine backbone linked by peptide bonds, which greatly increases its binding force and stability to DNA or RNA, making it useful in molecular biology. , is used in diagnostic analysis and antisense therapy. PNA was described in Nielsen PE, Egholm M, Berg RH, Buchardt O (December 1991). "Sequence-selective recognition of DNA by strand displacement with a thymine-substituted polyamide". Science 254 (5037): 1497-1500] is disclosed in detail.

In the present invention, the “aptamer” is an oligonucleic acid or peptide molecule, and general details of aptamers are described in Bock LC et al., Nature 355(6360):5646 (1992); Hoppe-Seyler F, Butz K "Peptide aptamers: powerful new tools for molecular medicine". J Mol Med. 78(8):42630(2000); Cohen BA, Colas P, Brent R. “An artificial cell-cycle inhibitor isolated from a combinatorial library”. Proc Natl Acad Sci USA. 95(24): 142727 (1998)].

In the present invention, the agent for measuring the expression level of the gene encoding the protein may include one or more selected from the group consisting of primers, probes, and antisense nucleotides that specifically bind to the gene encoding the protein. It is not limited.

In the present invention, the “primer” is a fragment that recognizes the target gene sequence and includes forward and reverse primer pairs, but is preferably a primer pair that provides analysis results with specificity and sensitivity. High specificity can be granted when the nucleic acid sequence of the primer is a sequence that is inconsistent with the non-target sequence present in the sample, so that the primer amplifies only the target gene sequence containing the complementary primer binding site and does not cause non-specific amplification. .

In the present invention, the “probe” refers to a substance that can specifically bind to a target substance to be detected in a sample, and refers to a substance that can specifically confirm the presence of the target substance in the sample through the binding. The type of probe is not limited as it is a material commonly used in the art, but is preferably PNA (peptide nucleic acid), LNA (locked nucleic acid), peptide, polypeptide, protein, RNA or DNA, and is most preferred. It is PNA. More specifically, the probe is a biomaterial that is derived from or similar to living organisms or includes those manufactured in vitro, such as enzymes, proteins, antibodies, microorganisms, animal and plant cells and organs, nerve cells, DNA, and It may be RNA, DNA includes cDNA, genomic DNA, and oligonucleotides, RNA includes genomic RNA, mRNA, and oligonucleotides, and examples of proteins may include antibodies, antigens, enzymes, peptides, etc.

In the present invention, “LNA (Locked nucleic acids)” refers to nucleic acid analogs containing 2'-O, 4'-C methylene bridges [J Weiler, J Hunziker and J Hall Gene Therapy (2006) 13, 496.502 ]. LNA nucleosides contain the common nucleic acid bases of DNA and RNA and can form base pairs according to the Watson-Crick base pairing rules. However, due to the 'locking' of the molecule due to the methylene bridge, LNA does not form the ideal shape in Watson-Crick bonding. When LNA is included in a DNA or RNA oligonucleotide, the LNA can pair with the complementary nucleotide chain more quickly and increase the stability of the double helix.

In the present invention, the "antisense" refers to a sequence of nucleotide bases in which an antisense oligomer hybridizes with a target sequence in RNA by Watson-Crick base pairing, allowing the formation of an oligomeric heteroduplex, typically mRNA and RNA, within the target sequence. and an oligomer having an intersubunit backbone. Oligomers may have exact or approximate sequence complementarity to the target sequence.

CNOT1, KIF11, SLC44A1, MSI1, SDK1, SYNGR1, ELSR1, DCLRE1B, ITGA3, KIAA1217, MBOAT2, RCC1, SON, TLDC1, ZFP69, ADCY1, ARL6IP4, ATP8A1, COX14, EPOR, FAM110D, GADD45G, HHEX, according to the present invention. Information on the proteins of INPP5B, KCNJ8, LIN7B, PAK3, RBP5 or SNHG7 or the genes encoding them is known, so those skilled in the art can use this to designate primers, probes or antisense nucleotides that specifically bind to the genes encoding the proteins. You will be able to design it easily.

In the present invention, CNOT1, KIF11, SLC44A1, MSI1, SDK1, SYNGR1, ELSR1, DCLRE1B, ITGA3, KIAA1217, MBOAT2, RCC1, SON, TLDC1, ZFP69, ADCY1, ARL6IP4, ATP8A1, COX14, EPOR, FAM110D, GADD45G, HHEX, INPP5B, KCNJ8, LIN7B, PAK3, RBP5 or SNHG7 proteins or genes encoding them can be measured from biological samples isolated from the subject of interest.

In the present invention, the diagnostic composition can be used to predict the possibility of cancer onset, growth, progression, or metastasis, or can be used to treat cancer as another disease, such as pancreatic disease, especially pancreatitis (both acute and chronic). , It can be used to distinguish pancreatic benign tumors (lipoma or intrapancreatic papillary mucinous neoplasm (IPMN), etc.), or it can be used to differentiate carcinoma, especially pancreatic cancer, from other carcinomas. .

According to another embodiment of the present invention, it relates to a kit for diagnosing cancer comprising the diagnostic composition of the present invention.

In the present invention, the “kit” refers to a tool that can evaluate the expression level of a biomarker by labeling a probe or antibody that specifically binds to a biomarker component with a detectable label. It includes not only direct labeling of a detectable substance related to a probe or antibody by reaction with a substrate, but also indirect labeling in which a label that develops color through reactivity with another directly labeled reagent is conjugated. It may include a chromogenic substrate solution, a washing solution, and other solutions that will undergo a color reaction with the label, and may be prepared including reagent components to be used. In the present invention, the kit may be a kit containing the essential elements required to perform RT-PCR, including a test tube, reaction buffer, deoxynucleotides (dNTPs), and Taq-polymerization, in addition to each primer pair specific for the marker gene. It may contain enzymes, reverse transcriptase, DNase, RNase inhibitor, sterile water, etc. Additionally, the kit may be a kit for detecting genes for cancer diagnosis that includes essential elements needed to perform a DNA chip. The DNA chip kit includes a substrate to which a cDNA corresponding to a gene or a fragment thereof is attached as a probe, and the substrate may include a cDNA corresponding to a quantitative control gene or a fragment thereof. The kit of the present invention is not limited thereto, as long as it is known in the art.

In the present invention, the kit may be an RT-PCR kit, DNA chip kit, ELISA kit, protein chip kit, rapid kit, or MRM (multiple reaction monitoring) kit.

The kit of the present invention may further include one or more other component compositions, solutions, or devices suitable for the analysis method. For example, in the present invention, the kit may further include essential elements required to perform a reverse transcription polymerase reaction. The reverse transcription polymerase reaction kit contains a pair of primers specific for the gene encoding the marker protein. Primers are nucleotides having a sequence specific to the nucleic acid sequence of the gene, and may have a length of about 7 bp to 50 bp, more preferably about 10 bp to 30 bp. It may also include primers specific to the nucleic acid sequence of the control gene. Other reverse transcription polymerase reaction kits include test tubes or other suitable containers, reaction buffer (pH and magnesium concentration vary), deoxynucleotides (dNTPs), enzymes such as Taq-polymerase and reverse transcriptase, DNase, and the RNase inhibitor DEPC. -Can include DEPC-water, sterilized water, etc.

Additionally, the kit for diagnosing cancer of the present invention may include essential elements required to perform DNA chip testing. A DNA chip kit may include a substrate to which a cDNA or oligonucleotide corresponding to a gene or a fragment thereof is attached, and reagents, agents, enzymes, etc. for producing a fluorescent label probe. The substrate may also include cDNA or oligonucleotides corresponding to control genes or fragments thereof.

Additionally, the cancer diagnostic kit of the present invention may include essential elements necessary to perform ELISA. ELISA kits contain antibodies specific for these proteins. Antibodies are antibodies that have high specificity and affinity for a marker protein and almost no cross-reactivity to other proteins, and may be monoclonal antibodies, polyclonal antibodies, or recombinant antibodies. Additionally, ELISA kits may include antibodies specific for control proteins. Other ELISA kits include reagents that can detect bound antibodies, such as labeled secondary antibodies, chromophores, enzymes (e.g., conjugated with antibodies) and their substrates or those that can bind to antibodies. It may contain other substances, etc.

In the present invention, the fixture for the antigen-antibody binding reaction includes a nitrocellulose membrane, a PVDF membrane, a well plate synthesized from polyvinyl resin or polystyrene resin, and a glass slide glass. It may be used, but is not limited thereto.

In addition, in the present invention, the label for the secondary antibody is preferably a conventional coloring agent that produces a color reaction, such as HRP (horseradish peroxidase), alkaline phosphatase, colloid gold, and FITC (poly L Labels such as fluorescein and dye, such as -lysine-fluorecein isothiocyanate) and RITC (rhodamine-B-isothiocyanate), may be used, but are not limited thereto.

In addition, the chromogenic substrate for inducing color development in the present invention is preferably used according to the label that produces a color reaction, such as TMB (3,3',5,5'-tetramethyl bezidine), ABTS [2,2 '-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)], OPD (o-phenylenediamine), etc. can be used. At this time, it is more preferable that the chromogenic substrate is provided dissolved in a buffer solution (0.1 M NaAc, pH 5.5). A chromogenic substrate such as TMB is decomposed by HRP used as a marker for the secondary antibody conjugate to produce a chromogenic deposit, and the presence or absence of the marker proteins is detected by visually checking the degree of deposition of the chromogenic deposit.

In the present invention, the washing solution preferably contains a phosphate buffer solution, NaCl, and Tween 20, and a buffer solution (PBST) consisting of 0.02 M phosphate buffer solution, 0.13 M NaCl, and 0.05% Tween 20 is more preferable. do. After the antigen-antibody binding reaction, the washing solution reacts with the secondary antibody to the antigen-antibody conjugate, then adds an appropriate amount to the fixative and washes 3 to 6 times. The reaction stopping solution may preferably be a sulfuric acid solution (H ₂ SO ₄ ).

According to another embodiment of the present invention, it relates to a method of providing information for diagnosing cancer.

The method of the present invention extracts CNOT1 (CCR4-NOT Transcription Complex Subunit 1), KIF11 (kinesin family member 11), SLC44A1 (Solute Carrier Family 44 Member 1), and MSI1 (Musashi RNA Binding Protein) from biological samples isolated from the target individual. 1), at least one protein selected from the group consisting of SDK1 (Sidekick Cell Adhesion Molecule 1) and SYNGR1 (Synaptogyrin 1); Alternatively, it may include measuring the expression level of the gene encoding the protein.

In the present invention, the object of interest is an individual that has developed or is likely to develop cancer and may be a mammal, including humans, for example, humans, rats, mice, guinea pigs, hamsters, rabbits, monkeys, dogs, and cats. , may be selected from the group consisting of cattle, horses, pigs, sheep, and goats, and preferably may be humans, but is not limited thereto.

In the present invention, the biological sample refers to any material, biological fluid, tissue, or cell obtained from or derived from an individual, such as whole blood, leukocytes, and peripheral blood mononuclear cells. ), white blood cell buffy coat, plasma, serum, sputum, tears, mucus, nasal washes, nasal aspirate, respiration (breath, urine, semen, saliva, peritoneal washings, ascites, cystic fluid, meningeal fluid, amniotic fluid) , glandular fluid, pancreatic fluid, lymph fluid, pleural fluid, nipple aspirate, bronchial aspirate, synovial fluid, joint aspirate. It may be one or more selected from the group consisting of joint aspirate, organ secretions, cells, cell extract, and cerebrospinal fluid, but is not limited thereto.

In the present invention, the method is used to extract CELSR1 (Cadherin EGF LAG Seven-Pass G-Type Receptor 1), DCLRE1B (DNA Cross-Link Repair 1B), ITGA3 (Integrin Subunit Alpha 3), and KIAA1217 from biological samples isolated from the target individual. (Sickle Tail Protein Homolog), MBOAT2 (Membrane Bound O-Acyltransferase Domain Containing 2), RCC1 (Regulator Of Chromosome Condensation 1), SON (SON DNA And RNA Binding Protein), TLDC1 (MTOR Associated Protein, Eak-7 Homolog), ZFP69 (Zinc Finger Protein 69 Homolog), ADCY1 (Adenylate Cyclase 1), ARL6IP4 (ADP Ribosylation Factor Like GTPase 6 Interacting Protein 4), ATP8A1 (ATPase Phospholipid Transporting 8A1), COX14 (Cytochrome C Oxidase Assembly Factor COX14), EPOR (Erythropoietin) Receptor), FAM110D (Family With Sequence Similarity 110 Member D), GADD45G (Growth Arrest And DNA Damage Inducible Gamma), HHEX (Hematopoietically Expressed Homeobox), INPP5B (Inositol Polyphosphate-5-Phosphatase B), KCNJ8 (Potassium Inwardly Rectifying Channel Subfamily) J Member 8), at least one protein selected from the group consisting of Lin-7 homolog B (LIN7B), P21 Activated Kinase 3 (PAK3), Retinol Binding Protein 5 (RBP5), and Small Nucleolar RNA Host Gene 7 (SNHG7); Alternatively, the step of measuring the expression level of the gene encoding this may be further included.

In the present invention, the agent for measuring the expression level of the protein includes at least one selected from the group consisting of antibodies, oligopeptides, ligands, PNA (peptide nucleic acids), and aptamers that specifically bind to the protein. can do.

In the present invention, the expression level of the protein can be measured using protein chip analysis, immunoassay, ligand binding assay, MALDI-TOF (Matrix Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry) analysis, and SELDI-TOF (Sulface Enhanced Laser Desorption/SELDI-TOF). Ionization Time of Flight Mass Spectrometry) analysis, radioimmunoassay, radioimmunodiffusion method, Ouchteroni immunodiffusion method, rocket immunoelectrophoresis, tissue immunostaining, complement fixation assay, two-dimensional electrophoresis analysis, liquid chromatography-mass spectrometry ( It can be performed by liquid chromatography-Mass Spectrometry (LC-MS), LC-MS/MS (liquid chromatography-Mass Spectrometry/Mass Spectrometry), Western blotting, or ELISA (enzyme linked immunosorbent assay).

Additionally, in the present invention, the expression level of the protein can be measured by a multiple reaction monitoring (MRM) method.

In the present invention, in the multiple reaction monitoring method, the internal standard material may be a synthetic peptide or Escherichia coli beta galactosidase in which a specific amino acid constituting the target peptide is isotopically substituted.

In the present invention, the agent for measuring the expression level of the gene encoding the protein may include one or more selected from the group consisting of primers, probes, and antisense nucleotides that specifically bind to the gene encoding the protein.

In the present invention, the expression level of the gene encoding the protein can be measured using reverse transcription polymerase reaction (RT-PCR), competitive reverse transcription polymerase reaction (Competitive RT-PCR), and real-time reverse transcription polymerase reaction (Real-time RT-PCR). , RNase protection assay (RPA), Northern blotting, or DNA chip.

In the method of the present invention, descriptions of 29 biomarkers, cancer, antibodies, oligopeptides, ligands, PNA (peptide nucleic acid), aptamers, etc., and descriptions of primers, probes, etc. are duplicated as previously described and are included in the specification. To avoid excessive complexity, detailed description is omitted below.

In one embodiment of the present invention, the method includes at least one protein selected from the group consisting of CNOT1, KIF11, and SLC44A1 measured on a biological sample of the subject of interest; Alternatively, if the expression level of the gene encoding this is higher than that of the control group, it can be predicted that the subject of interest has developed or is highly likely to develop cancer.

In another embodiment of the present invention, the method of the present invention includes at least one protein selected from the group consisting of MSI1, SDK1, and SYNGR1 measured on a biological sample of the subject of interest; Alternatively, if the expression level of the gene encoding this is lower than that of the control group, it can be predicted that the subject of interest has developed or is highly likely to develop cancer.

In addition, in the present invention, in addition to cases where the expression level of at least one protein selected from the group consisting of CNOT1, KIF11, and SLC44A1 or the gene encoding the same measured in the biological sample of the subject of interest is higher than that of the control group, CELSR1, DCLRE1B When the expression level of at least one protein selected from the group consisting of , ITGA3, KIAA1217, MBOAT2, RCC1, SON, TLDC1 and ZFP69 or the gene encoding it is higher than the control group, cancer has occurred or is likely to occur in the subject of interest. It can be predicted to be high.

In the present invention, at least one protein selected from the group consisting of MSI1, SDK1, and SYNGR1 measured on a biological sample of the subject of interest; Or, in addition to the case where the expression level of the gene encoding this is lower than the control group, additionally at least selected from the group consisting of ADCY1, ARL6IP4, ATP8A1, COX14, EPOR, FAM110D, GADD45G, HHEX, INPP5B, KCNJ8, LIN7B, PAK3, RBP5 and SNHG7 If the expression level of one protein or the gene encoding it is lower than that of the control group, it can be predicted that cancer has occurred or is highly likely to occur in the subject of interest.

In the present invention, “control group” refers to the expression level of the corresponding biomarker protein or the gene encoding the protein in a healthy normal control group, or the average of the expression level of the corresponding marker protein or the gene encoding the corresponding marker protein in biological samples derived from pancreatic disease patients. It may be an intermediate value, or it may be an average or median value of the expression level of the marker protein or the gene encoding the marker protein in a biological sample derived from a cancer patient, preferably a cancer patient other than pancreatic cancer, but is not limited thereto.

In the method of the present invention, predicting that the cancer has developed or is highly likely to develop includes not only predicting the possibility of the onset, growth, progression, or metastasis of the cancer, but also predicting that the cancer has developed or is likely to develop in the subject of interest. Diseases suspected to be cancer are distinguished from other diseases, especially pancreatic diseases (e.g., pancreatitis (both acute or chronic), benign pancreatic tumors (lipoma or intraductal papillary mucinous neoplasm (IPMN), etc.)) and are classified as cancer. It includes predicting, and in addition, it may include predicting that the cancer that has developed or is suspected to have developed in the subject of interest is pancreatic cancer by distinguishing it from other carcinomas.

In the present invention, the cancer includes pancreatic cancer, thyroid cancer, parathyroid cancer, stomach cancer, ovarian cancer, colon cancer, liver cancer, breast cancer, cervical cancer, lung cancer, non-small cell lung cancer, prostate cancer, gallbladder cancer, biliary tract cancer, non-Hodgkin lymphoma, and Hodgkin lymphoma. , blood cancer, bladder cancer, kidney cancer, melanoma, colon cancer, bone cancer, skin cancer, head cancer, uterine cancer, rectal cancer, brain tumor, perianal cancer, fallopian tube carcinoma, endometrial carcinoma, vaginal cancer, vulvar carcinoma, esophageal cancer, small intestine cancer, and endocrine cancer. , adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, ureteral cancer, renal cell carcinoma, renal pelvic carcinoma, CNS central nervous system tumor, primary CNS lymphoma, spinal cord tumor, brainstem glioma, or pituitary adenoma. , Preferably, it may be pancreatic cancer, but is not limited thereto as long as it is a type of cancer in which cancer progression, such as tumor differentiation and/or proliferation, is dependent on the cancer cells and/or cancer stem cells described in the present invention.

According to another embodiment of the present invention, it relates to a composition for predicting the prognosis of cancer.

In the present invention, the composition for predicting prognosis includes CNOT1 (CCR4-NOT Transcription Complex Subunit 1), KIF11 (kinesin family member 11), SLC44A1 (Solute Carrier Family 44 Member 1), MSI1 (Musashi RNA Binding Protein 1), and SDK1 (Sidekick). At least one protein selected from the group consisting of Cell Adhesion Molecule 1) and SYNGR1 (Synaptogyrin 1); Alternatively, it may include an agent that measures the expression level of the gene encoding it.

In the present invention, the composition for predicting prognosis includes CELSR1 (Cadherin EGF LAG Seven-Pass G-Type Receptor 1), DCLRE1B (DNA Cross-Link Repair 1B), ITGA3 (Integrin Subunit Alpha 3), KIAA1217 (Sickle Tail Protein Homolog), MBOAT2 (Membrane Bound O-Acyltransferase Domain Containing 2), RCC1 (Regulator Of Chromosome Condensation 1), SON (SON DNA And RNA Binding Protein), TLDC1 (MTOR Associated Protein, Eak-7 Homolog), ZFP69 (Zinc Finger Protein 69 Homolog) ), ADCY1 (Adenylate Cyclase 1), ARL6IP4 (ADP Ribosylation Factor Like GTPase 6 Interacting Protein 4), ATP8A1 (ATPase Phospholipid Transporting 8A1), COX14 (Cytochrome C Oxidase Assembly Factor COX14), EPOR (Erythropoietin Receptor), FAM110D (Family With Sequence Similarity 110 Member D), GADD45G (Growth Arrest And DNA Damage Inducible Gamma), HHEX (Hematopoietically Expressed Homeobox), INPP5B (Inositol Polyphosphate-5-Phosphatase B), KCNJ8 (Potassium Inwardly Rectifying Channel Subfamily J Member 8), LIN7B ( At least one protein selected from the group consisting of Lin-7 homolog B), P21 Activated Kinase 3 (PAK3), Retinol Binding Protein 5 (RBP5), and Small Nucleolar RNA Host Gene 7 (SNHG7); Alternatively, it may additionally include an agent that measures the expression level of the gene encoding it.

“Prognosis” in the present invention refers to the act of predicting in advance the course of a disease and the outcome of death or survival. The prognosis or prognostic diagnosis may be interpreted as meaning that the course of a disease may vary depending on the patient's physiological or environmental condition, and all actions that predict the course of the disease before and after treatment by comprehensively considering the patient's condition. You can. For the purpose of the present invention, the prognosis can be interpreted as the act of determining whether the survival rate after the onset of cancer is predicted to be low or the response to treatment is expected to be poor.

In the composition for predicting prognosis of the present invention, the description of the agent for measuring the expression level of 29 biomarkers, cancer, protein or gene, etc. overlaps with what was previously described and to avoid excessive complexity of the specification, detailed description thereof will be omitted below.

According to another embodiment of the present invention, it relates to a kit for predicting the prognosis of cancer comprising the composition for predicting the prognosis of the present invention.

In the kit for predicting prognosis of the present invention, descriptions of prognosis, cancer, type of kit, etc. overlap with what was previously described and to avoid excessive complexity of the specification, detailed descriptions thereof are omitted below.

According to another embodiment of the present invention, it relates to a method of providing information for predicting the prognosis of cancer.

The method of the present invention extracts CNOT1 (CCR4-NOT Transcription Complex Subunit 1), KIF11 (kinesin family member 11), SLC44A1 (Solute Carrier Family 44 Member 1), and MSI1 (Musashi RNA Binding Protein) from biological samples isolated from the target individual. 1), at least one protein selected from the group consisting of SDK1 (Sidekick Cell Adhesion Molecule 1) and SYNGR1 (Synaptogyrin 1); Alternatively, it may include measuring the expression level of the gene encoding the protein.

In the present invention, the method is used to extract CELSR1 (Cadherin EGF LAG Seven-Pass G-Type Receptor 1), DCLRE1B (DNA Cross-Link Repair 1B), ITGA3 (Integrin Subunit Alpha 3), and KIAA1217 from biological samples isolated from the target individual. (Sickle Tail Protein Homolog), MBOAT2 (Membrane Bound O-Acyltransferase Domain Containing 2), RCC1 (Regulator Of Chromosome Condensation 1), SON (SON DNA And RNA Binding Protein), TLDC1 (MTOR Associated Protein, Eak-7 Homolog), ZFP69 (Zinc Finger Protein 69 Homolog), ADCY1 (Adenylate Cyclase 1), ARL6IP4 (ADP Ribosylation Factor Like GTPase 6 Interacting Protein 4), ATP8A1 (ATPase Phospholipid Transporting 8A1), COX14 (Cytochrome C Oxidase Assembly Factor COX14), EPOR (Erythropoietin) Receptor), FAM110D (Family With Sequence Similarity 110 Member D), GADD45G (Growth Arrest And DNA Damage Inducible Gamma), HHEX (Hematopoietically Expressed Homeobox), INPP5B (Inositol Polyphosphate-5-Phosphatase B), KCNJ8 (Potassium Inwardly Rectifying Channel Subfamily) J Member 8), at least one protein selected from the group consisting of Lin-7 homolog B (LIN7B), P21 Activated Kinase 3 (PAK3), Retinol Binding Protein 5 (RBP5), and Small Nucleolar RNA Host Gene 7 (SNHG7); Alternatively, the step of measuring the expression level of the gene encoding this may be further included.

In one embodiment of the present invention, the method includes at least one protein selected from the group consisting of CNOT1, KIF11, and SLC44A1 measured on a biological sample of the subject of interest; Alternatively, if the expression level of the gene encoding this is higher than the control group, the prognosis of cancer can be predicted to be poor.

In another embodiment of the present invention, the method of the present invention includes at least one protein selected from the group consisting of MSI1, SDK1, and SYNGR1 measured on a biological sample of the subject of interest; Alternatively, if the expression level of the gene encoding this is lower than the control group, the prognosis of cancer can be predicted to be poor.

In addition, in the present invention, in addition to cases where the expression level of at least one protein selected from the group consisting of CNOT1, KIF11, and SLC44A1 or the gene encoding the same measured in the biological sample of the subject of interest is higher than that of the control group, CELSR1, DCLRE1B When the expression level of at least one protein selected from the group consisting of , ITGA3, KIAA1217, MBOAT2, RCC1, SON, TLDC1 and ZFP69 or the gene encoding it is higher than the control group, the prognosis of cancer can be predicted to be poor.

In the present invention, at least one protein selected from the group consisting of MSI1, SDK1, and SYNGR1 measured on a biological sample of the subject of interest; Or, in addition to the case where the expression level of the gene encoding this is lower than the control group, additionally at least selected from the group consisting of ADCY1, ARL6IP4, ATP8A1, COX14, EPOR, FAM110D, GADD45G, HHEX, INPP5B, KCNJ8, LIN7B, PAK3, RBP5 and SNHG7 If the expression level of one protein or the gene encoding it is lower than that of the control group, the prognosis of cancer can be predicted to be poor.

In the method of the present invention, descriptions of 29 biomarkers, cancer, prognosis, target entity, biological sample, control group, etc. overlap with what was previously described, and detailed descriptions thereof are omitted hereinafter to avoid excessive complexity of the specification.

According to another embodiment of the present invention, it relates to a panel for diagnosing or predicting prognosis of cancer.

The panel of the present invention includes CNOT1 (CCR4-NOT Transcription Complex Subunit 1), KIF11 (kinesin family member 11), SLC44A1 (Solute Carrier Family 44 Member 1), MSI1 (Musashi RNA Binding Protein 1), and SDK1 (Sidekick Cell Adhesion Molecule) 1) and at least one protein selected from the group consisting of SYNGR1 (Synaptogyrin 1); Alternatively, it may include an agent that measures the expression level of the gene encoding it.

The panel of the present invention includes CELSR1 (Cadherin EGF LAG Seven-Pass G-Type Receptor 1), DCLRE1B (DNA Cross-Link Repair 1B), ITGA3 (Integrin Subunit Alpha 3), KIAA1217 (Sickle Tail Protein Homolog), and MBOAT2 (Membrane Bound O-Acyltransferase Domain Containing 2), RCC1 (Regulator Of Chromosome Condensation 1), SON (SON DNA And RNA Binding Protein), TLDC1 (MTOR Associated Protein, Eak-7 Homolog), ZFP69 (Zinc Finger Protein 69 Homolog), ADCY1 (Adenylate Cyclase 1), ARL6IP4 (ADP Ribosylation Factor Like GTPase 6 Interacting Protein 4), ATP8A1 (ATPase Phospholipid Transporting 8A1), COX14 (Cytochrome C Oxidase Assembly Factor COX14), EPOR (Erythropoietin Receptor), FAM110D (Family With Sequence Similarity 110) Member D), GADD45G (Growth Arrest And DNA Damage Inducible Gamma), HHEX (Hematopoietically Expressed Homeobox), INPP5B (Inositol Polyphosphate-5-Phosphatase B), KCNJ8 (Potassium Inwardly Rectifying Channel Subfamily J Member 8), LIN7B (Lin-7) at least one protein selected from the group consisting of homolog B), P21 Activated Kinase 3 (PAK3), Retinol Binding Protein 5 (RBP5), and Small Nucleolar RNA Host Gene 7 (SNHG7); Alternatively, it may further include an agent that measures the expression level of the gene encoding it.

In the method of the present invention, descriptions of 29 biomarkers, cancer, prognosis, agents for measuring expression levels of proteins or genes, etc. overlap with what was previously described, and detailed descriptions thereof are omitted hereinafter to avoid excessive complexity of the specification.

The present invention detects the occurrence or likelihood of developing cancer, especially pancreatic cancer, by measuring the expression level of a biomarker protein or the gene encoding it, which can be linked to metabolic tumor volume, a quantitative parameter used for metabolic activity. It can be accurately predicted or diagnosed.

)를 분류한 결과를 나타낸 도이다.
도 5a 내지 도 5d는 본 발명의 일 실시예에 따른 단일 마커(MUG 또는 MDG) 및 MUG 결합 마커(도 5b; A), MUG-MDG 결합 마커(도 5c; B) 및 MDG 결합 마커(도 5d; C) 간의 생존율을 비교 분석한 결과를 나타낸 도이다.
도 6a 및 도 6b는 본 발명의 일 실시예에 따른 MAG 및 TCGA 마커의 상관 매트릭스(a)와 상부에 위치한 삼각형 부분(b)을 나타낸 도이다.
도 7a는 본 발명의 일 실시예에 따른 MAG 마커와 실제 임상에서 사용되는 혈액 검사 마커인 CA19-9 및 CEACAMB와의 상관 관계를 분석한 결과를 나타낸 도이다.
도 7b 내지 도 7e는 본 발명의 일 실시예에 따른 MAG 마커의 실제 임상에서 사용되는 병기, 치료평가 기준, 무병(disease-free; DF)과 재발성 또는 진행성(Recurrent or progressive; RP) 암에의 적용 가능성을 확인한 도이다.Figure 1a is a diagram showing a PET image of a pancreatic cancer patient according to an embodiment of the present invention.
Figure 1b is a diagram showing the results of heatmap analysis of genes commonly found in tissues of MTV-low and MTV-high pancreatic cancer patients according to an embodiment of the present invention.
Figure 1c is a bar graph showing the fold change distribution of up- or down-regulated genes in the MTV-low group and MTV-high group according to an embodiment of the present invention.
Figures 2a and 2b show highly expressed genes (MTV-upregulated genes; MUG) and underexpressed genes (MTV- This diagram shows the results of comparative analysis of downregulated gene (MDG) expression.
Figures 3A and 3B are diagrams showing the results of survival analysis between low- and high-expression groups of MTV-related genes according to an embodiment of the present invention.
Figures 4a and 4b show genes significantly correlated with MAG (MTV RNA-Seq only, TCGA-PAAD only, or MTV) from classification of MTV RNA-Seq and TCGA-PAAD data sets according to an embodiment of the present invention.

) is a diagram showing the results of classification.
5A to 5D show a single marker (MUG or MDG) and a MUG binding marker (FIG. 5B; A), a MUG-MDG binding marker (FIG. 5C; B), and an MDG binding marker (FIG. 5D) according to an embodiment of the present invention. ; C) This diagram shows the results of comparative analysis of liver survival rates.
Figures 6a and 6b are diagrams showing the correlation matrix (a) of MAG and TCGA markers and the triangular portion (b) located at the top according to an embodiment of the present invention.
Figure 7a is a diagram showing the results of analyzing the correlation between the MAG marker and CA19-9 and CEACAMB, blood test markers used in actual clinical practice, according to an embodiment of the present invention.
Figures 7b to 7e show the stage, treatment evaluation criteria, and disease-free (DF) and recurrent or progressive (RP) cancers used in actual clinical trials of MAG markers according to an embodiment of the present invention. This is a province that confirmed the applicability of .

Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .

Example 1: Transcriptome analysis of MTV (Metabolic Tumor Volume)-related genes expressed in pancreatic cancer

To analyze the total transcriptome of metabolic tumor volume (MTV)-related gene expression, PET images were taken from patients with pancreatic cancer, and the PET images are shown in Figure 1a. In Figure 1a, the image on the left corresponds to a pancreatic cancer patient with low MTV, and the image on the right corresponds to a pancreatic cancer patient with high MTV.

Total RNA was isolated using TRizolTM Reagent (Invitrogen, MA) from tissue samples obtained from a total of 14 individuals in the low-MTV pancreatic cancer patient group (n=7) and the high-MTV pancreatic cancer patient group (n=7), followed by Lexogen RIBO. rRNA was removed using a COP rRNA depletion kit (Lexogen RIBO COP rRNA depletion kit, Vienna, Austria). RNA quality was analyzed on a NanoDrop 2000 (Thermo Fisher Scientific, MA) and Agilent 2100 Bioanalyzer (Agilent Technologies, CA), with 1.8 for OD260/280, 1.6 for OD260/230, and 7.0 for RNA integrity number (RIN). Excess RNA was used to construct an RNA library using the SMARTer® Stranded RNA-Seq Kit (Clontech Laboratories, Inc. CA). Sequencing was performed on a Hiseq 2500 System (Illumina, CA), and base calling was performed with Illumina Casava 1.8 software. Sequenced reads were trimmed for adapter sequences, masked for low complexity or low quality sequences using the FASTX trimmer tool, and then the entire hg19 genome was mapped using TopHat. Read counts were extracted and normalized using edgeR. The expression profile was extracted from the expression level obtained through transcript quantification of each sample using the read count (rear count) and FPKM (Fragments Per Kilobase of transcript per Million mapped reads) value, which is a normalization value that takes into account transcript length and depth of coverage. did. Genes or transcripts differentially expressed were selected through statistical hypothesis testing of the expression values of two or more groups under different conditions, heatmap analysis of gene expression was performed, and the results are shown in Figure 1b. More specifically, in 14 samples obtained from MTV-low or MTV-high pancreatic cancer patient tissue, the MTV RNA-Seq dataset was divided into 1) cancer area, 2 ) normal area, 3) the cancer area compared to normal area, and were divided into three categories, MTV-low expression (MTV-low) and MTV-high expression (MTV- high) performed a t-test to obtain significant differentially expressed genes (DEGs) between the two groups, and selected genes with a p-value less than 0.05 using an Excel-based differentially expressed gene analysis tool (ExDEGA, Ebiogen, Seoul, South Korea). Selected. For 377 genes with FPKM values of 10 or more commonly seen through preliminary screening of RNA-seq data, the cancer-to-normal ratio was converted to log2 and expressed, 2 in the MTV-high expression group compared to the MTV-low expression group. Up-regulated and down-regulated genes that differed more than a fold and showed statistical significance were selected and displayed in a bar graph (see Figures 1b and 1c).

Experimental results show that, as shown in Figure 1a, metabolic tumor volume (MTV) is related to the diagnosis and prognosis of pancreatic cancer, and differentially expressed genes (DEGs) between MTV-low and high groups are sensitive and specific for pancreatic cancer. It was confirmed that it could be an enemy marker. Referring to the results of RNA sequencing (RNA-Seq) performed on normal and cancerous regions of pancreatic cancer tissue to establish biomarkers, the clustered heatmap shows that in the MTV-high expression group compared to the MTV-low expression group, It can be seen that 211 genes were generally up-regulated and 166 genes were generally down-regulated (Figure 1b left). Among the 211 up-regulated genes, 44 genes showed a difference of more than 2-fold and showed statistical significance (Figure 1b, upper right). On the other hand, 56 of the 166 downregulated genes showed a difference of more than 2-fold and showed statistical significance (Figure 1b, bottom right). The fold change was distributed approximately 2-fold for both up- and down-regulated genes, but some down-regulated genes showed more than 10-fold (see Figure 1c).

Functional annotation (GO) analysis identified up-regulated genes as Wnt signaling (GO: 0035567, 0060070, 0060071), sister chromatid cohesion (GO: 0007062), and cell division (GO: 0000278, 0051301), while down-regulated genes were identified as Regulated genes were identified as enriched in rRNA processing (GO: 0006364), translation (GO: 0006412, 0006413), and nuclear transcribed mRNA catabolism (GO: 0000184) (see Fig. 1C). 28 up-regulated genes belonged to Wnt signaling genes or cell division genes, and 22 down-regulated genes belonged to rRNA processing genes.

Example 2: Comparative analysis of MTV-related gene expression in survival and death groups of the TCGA-PAAD data set

MUG and MDG between surviving and deceased patients in The Cancer Genome Atlas (TCGA-PAAD) dataset, a large dataset that did not consider information about MTV to evaluate its usefulness as a pancreatic cancer marker. The expression levels were compared and shown in a vertical scatter plot (see Figures 2a and 2b). At this time, genetic alteration analysis was performed in cBioPortal using genetic alterations from TCGA and PanCancer Atlas 10 shared by TCGA-PAAD and patient samples. The MUG (MTV-upregulated gene) refers to a gene upregulated in the MTV-high expression group compared to the MTV-low expression group, and the MDG (MTV-downregulated gene) refers to a gene upregulated in the MTV-high expression group compared to the MTV-low expression group. Means down-regulated genes in the group.

Referring to the experimental results, among the 43 MUGs (excluding BIPR, which is a gene not included in the data set), 12 genes were found to be significantly and positively correlated with the survival of pancreatic cancer patients, and 4 genes were significant but not The opposite correlation was shown, and it was confirmed that 27 genes did not show a correlation with patient survival (see Figure 2a). From this, among MUGs, CELSR1 (Cadherin EGF LAG Seven-Pass G-Type Receptor 1), CNOT1 (CCR4-NOT Transcription Complex Subunit 1), and DCLRE1B (DNA Cross-Link Repair 1B) were identified as markers significantly correlated with patient survival. , ITGA3 (Integrin Subunit Alpha 3), KIAA1217 (Sickle Tail Protein Homolog), KIF11 (kinesin family member 11), MBOAT2 (Membrane Bound O-Acyltransferase Domain Containing 2), RCC1 (Regulator Of Chromosome Condensation 1), SLC44A1 (Solute Carrier Family 44 Member 1), SON (SON DNA And RNA Binding Protein), TLDC1 (MTOR Associated Protein, Eak-7 Homolog), and ZFP69 (Zinc Finger Protein 69 Homolog) were selected, and the death group was compared with the survival group of pancreatic cancer patients. It was confirmed that the expression level of the gene was up-regulated.

In addition, among the 56 MDGs, 17 genes were confirmed to be significant and showed a negative correlation with the survival of pancreatic cancer patients, 7 genes showed a significant but inverse correlation, and 27 genes showed a significant but inverse correlation with patient survival. There was no correlation, and it was confirmed that the two genes were not expressed (see Figure 2b). From this, among MDGs as markers significantly correlated with patient survival, ADCY1 (Adenylate Cyclase 1), ARL6IP4 (ADP Ribosylation Factor Like GTPase 6 Interacting Protein 4), ATP8A1 (ATPase Phospholipid Transporting 8A1), and COX14 (Cytochrome C Oxidase Assembly) Factor COX14), EPOR (Erythropoietin Receptor), FAM110D (Family With Sequence Similarity 110 Member D), GADD45G (Growth Arrest And DNA Damage Inducible Gamma), HHEX (Hematopoietically Expressed Homeobox), INPP5B (Inositol Polyphosphate-5-Phosphatase B), KCNJ8 (Potassium Inwardly Rectifying Channel Subfamily J Member 8), LIN7B (Lin-7 homolog B), MSI1 (Musashi RNA Binding Protein 1), PAK3 (P21 Activated Kinase 3), RBP (Retinol Binding Protein 5), SDK1 (Sidekick Cell Adhesion Molecule 1), SNHG7 (Small Nucleolar RNA Host Gene 7), and SYNGR1 (Synaptogyrin 1) were able to be selected, and it was confirmed that the expression levels of these genes were downregulated in the deceased group compared to the surviving group of pancreatic cancer patients.

Example 3: Survival analysis between low and high expression groups of MTV-related genes

In order to verify whether the 12 MUG markers and 17 MDG markers selected in Example 2 were differentially expressed between the survival and death groups of the TCGA-PAAD data set and had an association with survival time, Kaplan Meier survival analysis (Kaplan -Meier Estimate) and shown in Figures 3a and 3b, and a P-value of less than 0.05 was considered statistically significant.

The experimental results showed that 10 of the 12 MUG genes (CELSR1, CNOT1, DCLRE1B, ITGA3, KIAA1217, KIF11, MBOAT2, RCC1, SLC44A1, TLDC1) were significantly associated with a worse prognosis in the high-expression group than in the low-expression group. It was confirmed that two genes (SON and ZFP69) were not (see Figure 3a). Meanwhile, 15 genes (ADCY1, ARL6IP4, COX14, EPOR, FAM110D, GADD45G, HHEX, INPP5B, KCNJ8, LIN7B, MSI1, PAK3, RBP5, SDK1, SYNGR1) among 17 MDGs performed worse in the low-expression group than in the high-expression group. Two genes (ATP8A1 and SNHG7) were found to be significantly associated with prognosis, but not (see Figure 3b). Summarizing the above results, the slope of the survival curve is determined by the survival period, and it can be predicted that a poor prognosis will occur when the MUG marker is highly expressed or the MDG marker is lowly expressed.

Example 4: Correlation analysis between MAG (MTV-associated genes)

The correlation coefficient, which represents the strength of the relationship between the MTV RNA-Seq results and the results of the TCGA-PAAD data set, is quantified by the r value, which is the sample correlation coefficient, and is shown in Figure 4a.

로 재분류하여 도 4b에 나타내었다. 이 과정을 통하여 MTV RNA-Seq 및 TCGA-PAAD 데이터 세트의 MAG로부터 상관 매트릭스 분석을 수행함으로써 개선된 바이오 마커 조합을 발굴할 수 있었다.Referring to MTV RNA-Seq in Figure 4a, it was confirmed that there was a clear positive correlation between MUGs or MDGs, and a negative correlation between MUGs and MDGs. Meanwhile, in the TCGA-PAAD data set, it can be seen that the general correlation pattern appears similar to MTV RNA-Seq. Significant correlations between MTV RNA-Seq, TCGA-PAAD, or MTV RNA-Seq and TCGA-PAAD data sets are indicated by MTV RNA-Seq only, TCGA-PAAD only, MTV

It is reclassified and shown in Figure 4b. Through this process, we were able to discover improved combinations of biomarkers by performing correlation matrix analysis from the MAGs of the MTV RNA-Seq and TCGA-PAAD data sets.

Example 5: Improved prognosis prediction by MAG single marker or MAG combination marker

In order to confirm the accuracy of prognosis prediction of the MAG marker discovered from the above example, survival rate prediction was compared and analyzed between the case of using only a single marker (MUG or MDG) and the MUG combination marker, MUG-MDG combination marker, or MDG combination marker (Figure see 5a). Groups that confirmed expression of single MAG (MUG or MDG) markers, respectively, are indicated by light blue and orange lines, and groups that confirmed expression of combined MAG (MUG, MUG-MDG, or MDG) combination markers, respectively, are indicated by dark blue and red lines. It is expressed as Black letters are single MAG markers, and red letters correspond to additional combined MAG markers (see FIGS. 5B to 5D).

To determine whether combinations of MAGs can better predict cancer prognosis than single MAGs, we compared the p-values of patient survival with single MAGs and combination MAGs and found that among the MUG combinations, CELSR1 (p = 0.0118) predicted survival better than ITGA3 ( p < 0.0001), KIF11 (p = 0.0004), or MBOAT2 (p < 0.0001), and the survival prediction of CNOT1 (p = 0.0183) was improved by combination with SLC44A1 (p = 0.0013). I was able to confirm that it was happening. Additionally, survival prediction of KIAA1217 (p: NS) improved in combination with SON (p = 0.0221) (see Figure 5b).

Among the combination of MUG and MDG, CELSR1 (p = 0.0118) predicted survival better than ADCY1 (p = 0.0035), ATP8A1 (p = 0.0072), FAM110D (p = 0.0029), GADD45G (p < 0.0001), and MSI1 (p = 0.0011). , improvement was observed in combination with PAK3 (p = 0.0021) or SDK1 (p = 0.0002), and survival prediction of CNOT1 (p = 0.0183) was significantly better than that of ADCY1 (p = 0.0005), GADD45G (p = 0.0002), or SDK1 ( p = 0.0002) (see Figure 5c).

Among MDG combinations, ADCY1 (p = 0.0138) was more predictive of survival in combination with FAM110D (p = 0.0012), KCNJ8 (p = 0.0017), RBP5 (p = 0.0034), SDK1 (p = 0.0012), or SYNGR1 (p = 0.0006). FAM110D (p = 0.0013) predicted survival better than GADD45G (p < 0.0001), KCNJ8 (p = 0.0010), RBP5 (p = 0.0013), SDK1 (p < 0.0001), or SYNGR1 (p < 0.0001). < 0.0001) improved by combination. The survival prediction of PAK3 (p = 0.0115) was improved in combination with SDK1 (p = 0.0014), and the survival prediction of RBP5 (p = 0.0113) was improved in combination with SYNGR1 (p = 0.0016). In particular, survival prediction of ATP8A1 (p: NS) was confirmed to be improved in combination with FAM110D (p = 0.0034), PAK3 (p = 0.0277), SDK1 (p = 0.0095), and SYNGR1 (p = 0.0039) (Figure 5d).

Example 6: Correlation matrix analysis between MAG and TCGA markers

To evaluate the usefulness of MAG as a pancreatic cancer marker, the correlation between MAG and TCGA markers among the top 20 unfavorable and favorable prognostic genes extracted from TCGA-PAAD data analysis was analyzed and shown in Figure 6a.

As a result, as shown in Figure 6a, most MUGs showed a positive correlation with unfriendly genes but a negative correlation with friendly genes. Meanwhile, it was confirmed that most MDGs showed a negative correlation with unfavorable genes but a positive correlation with favorable genes. Additionally, referring to Figure 6b, it can be seen that the pattern of correlation between MAG and TCGA markers was generally maintained even when filtered by statistical significance.

Example 7: Verification of the diagnostic potential of MAG markers in clinical practice

From the results confirmed above, the possibility of MAG markers (29 markers) as diagnostic and prognostic predictors of pancreatic cancer was confirmed, so we wanted to further verify whether there is a significant correlation with blood test markers that are widely used in the existing clinical diagnosis of pancreatic cancer. did. As a result of analyzing the correlation with the blood test markers CA19-9 and CEACAMB, it was confirmed that MAG, excluding CELSR1 and SON, was correlated with CA19-9, CEACAM1, CEACAM3, CEACAM4, CEACAM5, CEACAM6, CEACAM20 or CEACAM21. . In particular, CA19-9 and CEACAM6 showed a significant negative correlation with most MDGs, confirming their applicability in clinical practice (see Figure 7a).

Accordingly, as a result of applying the MAG marker to various factors applicable to actual clinical practice, in relation to the neoplastic disease stage of pancreatic cancer according to the AJCC staging criteria, the group with high-expressing MUG or It was confirmed that the group with low expression of MDG had a higher stage of disease. In particular, the distribution from stage I to stage IIB generally showed that the group with high expression of MUG or low expression of MDG compared to the group with low expression of MUG or high expression of MDG. An increasing trend was confirmed in the group. However, in some MUGs or MDGs, the distribution of stage III or IV was confirmed to be increased in the groups with high MUG expression or low MDG expression compared to the groups with low MUG expression or high MDG expression (see Figures 7b and 7c). .

In addition, as a result of applying treatment evaluation criteria indicating treatment prognosis, it was confirmed that favorable treatment results were reduced in the group with high MUG expression or low MDG expression compared to the group with low MUG expression or high MDG expression (Figure 7d).

Lastly, when comparing disease-free (DF) and recurrent or progressive (RP) cancers, the group with high MUG expression or low MDG compared to the group with low MUG expression or high MDG expression. It was confirmed that the distribution of recurrent or progressive cancer increased in the expressed group (see Figure 7e).

Summarizing the above results, it was verified that pancreatic cancer can be diagnosed using single markers such as 12 MUG markers and 17 MDG markers among the MAG markers. Furthermore, when some combinations of the 29 MAG markers are used for diagnosis, pancreatic cancer can be diagnosed. It was also confirmed that it has significance as a combination marker for more precise diagnosis. Therefore, when using the composition of the present invention, the occurrence or likelihood of developing pancreatic cancer can be predicted with excellent accuracy, so it is expected to be actively used in clinical practice.

As the specific parts of the present invention have been described in detail above, it is clear to those skilled in the art that these specific techniques are merely preferred implementation examples and do not limit the scope of the present invention. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

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Asn Gln Glu Gly Gly Phe Gln Asp Ile 165 170 175 Ala Ile Glu Val Leu His Leu Leu Leu Ser His Leu Leu Phe Gly Gln 180 185 190 Lys Gly Ala Phe Gly Val Gly Gln Glu Gln Ile Asp Ala Phe Leu Lys 195 200 205 Thr Leu Arg Arg Asp Phe Pro Gln Glu Arg Cys Pro Val Val Leu Ala 210 215 220 Pro Leu Leu Tyr Pro Glu Lys Arg Asp Ile Leu Met Asp Arg Ile Leu 225 230 235 240 Pro Asp Ser Gly Gly Val Ala Lys Thr Met Met Glu Ser Ser Leu Ala 245 250 255 Asp Phe Met Gln Glu Val Gly Tyr Gly Phe Cys Ala Ser Ile Glu Glu 260 265 270 Cys Arg Asn Ile Ile Val Gln Phe Gly Val Arg Glu Val Thr Ala Ala 275 280 285 Gln Val Ala Arg Val Leu Gly Met Met Ala Arg Thr His Ser Gly Leu 290 295 300 Thr Asp Gly Ile Pro Leu Gln Ser Ile Ser Ala Pro Gly Ser Gly Ile 305 310 315 320 Trp Ser Asp Gly Lys Asp Lys Ser Asp Gly Ala Gln Ala His Thr Trp 325 330 335 Asn Val Glu Val Leu Ile Asp Val Leu Lys Glu Leu Asn Pro Ser Leu 340 345 350 Asn Phe Lys Glu Val Thr Tyr Glu Leu Asp His Pro Gly Phe Gln Ile 355 360 365 Arg Asp Ser Lys Gly Leu His Asn Val Val Tyr Gly Ile Gln Arg Gly 370 375 380 Leu Gly Met Glu Val Phe Pro Val Asp Leu Ile Tyr Arg Pro Trp Lys 385 390 395 400 His Ala Glu Gly Gln Leu Ser Phe Ile Gln His Ser Leu Ile Asn Pro 405 410 415 Glu Ile Phe Cys Phe Ala Asp Tyr Pro Cys His Thr Val Ala Thr Asp 420 425 430 Ile Leu Lys Ala Pro Pro Glu Asp Asp Asn Arg Glu Ile Ala Thr Trp 435 440 445 Lys Ser Leu Asp Leu Ile Glu Ser Leu Leu Arg Leu Ala Glu Val Gly 450 455 460 Gln Tyr Glu Gln Val Lys Gln Leu Phe Ser Phe Pro Ile Lys His Cys 465 470 475 480 Pro Asp Met Leu Val Leu Ala Leu Leu Gln Ile Asn Thr Ser Trp His 485 490 495 Thr Leu Arg His Glu Leu Ile Ser Thr Leu Met Pro Ile Phe Leu Gly 500 505 510 Asn His Pro Asn Ser Ala Ile Ile Leu His Tyr Ala Trp His Gly Gln 515 520 525 Gly Gln Ser Pro Ser Ile Arg Gln Leu Ile Met His Ala Met Ala Glu 530 535 540 Trp Tyr Met Arg Gly Glu Gln Tyr Asp Gln Ala Lys Leu Ser Arg Ile 545 550 555 560 Leu Asp Val Ala Gln Asp Leu Lys Ala Leu Ser Met Leu Leu Asn Gly 565 570 575 Thr Pro Phe Ala Phe Val Ile Asp Leu Ala Ala Leu Ala Ser Arg Arg 580 585 590 Glu Tyr Leu Lys Leu Asp Lys Trp Leu Thr Asp Lys Ile Arg Glu His 595 600 605 Gly Glu Pro Phe Ile Gln Ala Cys Met Thr Phe Leu Lys Arg Arg Cys 610 615 620 Pro Ser Ile Leu Gly Gly Leu Ala Pro Glu Lys Asp Gln Pro Lys Ser 625 630 635 640 Ala Gln Leu Pro Pro Glu Thr Leu Ala Thr Met Leu Ala Cys Leu Gln 645 650 655 Ala Cys Ala Gly Ser Val Ser Gln Glu Leu Ser Glu Thr Ile Leu Thr 660 665 670 Met Val Ala Asn Cys Ser Asn Val Met Asn Lys Ala Arg Gln Pro Pro 675 680 685 Pro Gly Val Met Pro Lys Gly Arg Pro Pro Ser Ala Ser Ser Leu Asp 690 695 700 Ala Ile Ser Pro Val Gln Ile Asp Pro Leu Ala Gly Met Thr Ser Leu 705 710 715 720 Ser Ile Gly Gly Ser Ala Ala Pro His Thr Gln Ser Met Gln Gly Phe 725 730 735 Pro Pro Asn Leu Gly Ser Ala Phe Ser Thr Pro Gln Ser Pro Ala Lys 740 745 750 Ala Phe Pro Pro Leu Ser Thr Pro Asn Gln Thr Thr Ala Phe Ser Gly 755 760 765 Ile Gly Gly Leu Ser Ser Gln Leu Pro Val Gly Gly Leu Gly Thr Gly 770 775 780 Ser Leu Thr Gly Ile Gly Thr Gly Ala Leu Gly Leu Pro Ala Val Asn 785 790 795 800 Asn Asp Pro Phe Val Gln Arg Lys Leu Gly Thr Ser Gly Leu Asn Gln 805 810 815 Pro Thr Phe Gln Gln Thr Asp Leu Ser Gln Val Trp Pro Glu Ala Asn 820 825 830 Gln His Phe Ser Lys Glu Ile Asp Asp Glu Ala Asn Ser Tyr Phe Gln 835 840 845 Arg Ile Tyr Asn His Pro Pro His Pro Thr Met Ser Val Asp Glu Val 850 855 860 Leu Glu Met Leu Gln Arg Phe Lys Asp Ser Thr Ile Lys Arg Glu Arg 865 870 875 880 Glu Val Phe Asn Cys Met Leu Arg Asn Leu Phe Glu Glu Tyr Arg Phe 885 890 895 Phe Pro Gln Tyr Pro Asp Lys Glu Leu His Ile Thr Ala Cys Leu Phe 900 905 910 Gly Gly Ile Ile Glu Lys Gly Leu Val Thr Tyr Met Ala Leu Gly Leu 915 920 925 Ala Leu Arg Tyr Val Leu Glu Ala Leu Arg Lys Pro Phe Gly Ser Lys 930 935 940 Met Tyr Tyr Phe Gly Ile Ala Ala Leu Asp Arg Phe Lys Asn Arg Leu 945 950 955 960 Lys Asp Tyr Pro Gln Tyr Cys Gln His Leu Ala Ser Ile Ser His Phe 965 970 975 Met Gln Phe Pro His His Leu Gln Glu Tyr Ile Glu Tyr Gly Gln Gln 980 985 990 Ser Arg Asp Pro Pro Val Lys Met Gln Gly Ser Ile Thr Pro Gly 995 1000 1005 Ser Ile Ala Leu Ala Gln Ala Gln Ala Gln Ala Gln Val Pro Ala Lys 1010 1015 1020 Ala Pro Leu Ala Gly Gln Val Ser Thr Met Val Thr Thr Ser Thr Thr 1025 1030 1035 1040 Thr Thr Val Ala Lys Thr Val Thr Val Thr Arg Pro Thr Gly Val Ser 1045 1050 1055 Phe Lys Lys Asp Val Pro Pro Ser Ile Asn Thr Thr Asn Ile Asp Thr 1060 1065 1070 Leu Leu Val Ala Thr Asp Gln Thr Glu Arg Ile Val Glu Pro Pro Glu 1075 1080 1085 Asn Ile Gln Glu Lys Ile Ala Phe Ile Phe Asn Asn Leu Ser Gln Ser 1090 1095 1100 Asn Met Thr Gln Lys Val Glu Glu Leu Lys Glu Thr Val Lys Glu Glu 1105 1110 1115 1120 Phe Met Pro Trp Val Ser Gln Tyr Leu Val Met Lys Arg Val Ser Ile 1125 1130 1135 Glu Pro Asn Phe His Ser Leu Tyr Ser Asn Phe Leu Asp Thr Leu Lys 1140 1145 1150 Asn Pro Glu Phe Asn Lys Met Val Leu Asn Glu Thr Tyr Arg Asn Ile 1155 1160 1165 Lys Val Leu Leu Thr Ser Asp Lys Ala Ala Ala Asn Phe Ser Asp Arg 1170 1175 1180 Ser Leu Leu Lys Asn Leu Gly His Trp Leu Gly Met Ile Thr Leu Ala 1185 1190 1195 1200 Lys Asn Lys Pro Ile Leu His Thr Asp Leu Asp Val Lys Ser Leu Leu 1205 1210 1215 Leu Glu Ala Tyr Val Lys Gly Gln Gln Glu Leu Leu Tyr Val Val Pro 1220 1225 1230 Phe Val Ala Lys Val Leu Glu Ser Ser Ile Arg Ser Val Val Phe Arg 1235 1240 1245 Pro Pro Asn Pro Trp Thr Met Ala Ile Met Asn Val Leu Ala Glu Leu 1250 1255 1260 His Gln Glu His Asp Leu Lys Leu Asn Leu Lys Phe Glu Ile Glu Val 1265 1270 1275 1280 Leu Cys Lys Asn Leu Ala Leu Asp Ile Asn Glu Leu Lys Pro Gly Asn 1285 1290 1295 Leu Leu Lys Asp Lys Asp Arg Leu Lys Asn Leu Asp Glu Gln Leu Ser 1300 1305 1310 Ala Pro Lys Lys Asp Val Lys Gln Pro Glu Glu Leu Pro Pro Ile Thr 1315 1320 1325 Thr Thr Thr Thr Ser Thr Thr Pro Ala Thr Asn Thr Cys Thr Ala 1330 1335 1340 Thr Val Pro Pro Gln Pro Gln Tyr Ser Tyr His Asp Ile Asn Val Tyr 1345 1350 1355 1360 Ser Leu Ala Gly Leu Ala Pro His Ile Thr Leu Asn Pro Thr Ile Pro 1365 1370 1375 Leu Phe Gln Ala His Pro Gln Leu Lys Gln Cys Val Arg Gln Ala Ile 1380 1385 1390 Glu Arg Ala Val Gln Glu Leu Val His Pro Val Val Asp Arg Ser Ile 1395 1400 1405 Lys Ile Ala Met Thr Thr Cys Glu Gln Ile Val Arg Lys Asp Phe Ala 1410 1415 1420 Leu Asp Ser Glu Glu Ser Arg Met Arg Ile Ala Ala His His Met Met 1425 1430 1435 1440 Arg Asn Leu Thr Ala Gly Met Ala Met Ile Thr Cys Arg Glu Pro Leu 1445 1450 1455 Leu Met Ser Ile Ser Thr Asn Leu Lys Asn Ser Phe Ala Ser Ala Leu 1460 1465 1470 Arg Thr Ala Ser Pro Gln Gln Arg Glu Met Met Asp Gln Ala Ala Ala 1475 1480 1485 Gln Leu Ala Gln Asp Asn Cys Glu Leu Ala Cys Cys Phe Ile Gln Lys 1490 1495 1500 Thr Ala Val Glu Lys Ala Gly Pro Glu Met Asp Lys Arg Leu Ala Thr 1505 1510 1515 1520 Glu Phe Glu Leu Arg Lys His Ala Arg Gln Glu Gly Arg Arg Tyr Cys 1525 1530 1535 Asp Pro Val Val Leu Thr Tyr Gln Ala Glu Arg Met Pro Glu Gln Ile 1540 1545 1550 Arg Leu Lys Val Gly Gly Val Asp Pro Lys Gln Leu Ala Val Tyr Glu 1555 1560 1565 Glu Phe Ala Arg Asn Val Pro Gly Phe Leu Pro Thr Asn Asp Leu Ser 1570 1575 1580 Gln Pro Thr Gly Phe Leu Ala Gln Pro Met Lys Gln Ala Trp Ala Thr 1585 1590 1595 1600 Asp Asp Val Ala Gln Ile Tyr Asp Lys Cys Ile Thr Glu Leu Glu Gln 1605 1610 1615 His Leu His Ala Ile Pro Pro Thr Leu Ala Met Asn Pro Gln Ala Gln 1620 1625 1630 Ala Leu Arg Ser Leu Leu Glu Val Val Val Leu Ser Arg Asn Ser Arg 1635 1640 1645 1660 Leu Asp Ala Thr Ser Gly Ala Asp Ala Asp Leu Leu Leu Arg Tyr Arg 1665 1670 1675 1680 Glu Cys His Leu Leu Val Leu Lys Ala Leu Gln Asp Gly Arg Ala Tyr 1685 1690 1695 Gly Ser Pro Trp Cys Asn Lys Gln Ile Thr Arg Cys Leu Ile Glu Cys 1700 1705 1710 Arg Asp Glu Tyr Lys Tyr Asn Val Glu Ala Val Glu Leu Leu Ile Arg 1715 1720 1725 Asn His Leu Val Asn Met Gln Gln Tyr Asp Leu His Leu Ala Gln Ser 1730 1735 1740 Met Glu Asn Gly Leu Asn Tyr Met Ala Val Ala Phe Ala Met Gln Leu 1745 1750 1755 1760 Val Lys Ile Leu Leu Val Asp Glu Arg Ser Val Ala His Val Thr Glu 1765 1770 1775 Ala Asp Leu Phe His Thr Ile Glu Thr Leu Met Arg Ile Asn Ala His 1780 1785 1790 Ser Arg Gly Asn Ala Pro Glu Gly Leu Pro Gln Leu Met Glu Val Val 1795 1800 1805 Arg Ser Asn Tyr Glu Ala Met Ile Asp Arg Ala His Gly Gly Pro Asn 1810 1815 1820 Phe Met Met His Ser Gly Ile Ser Gln Ala Ser Glu Tyr Asp Asp Pro 1825 1830 1835 1840 Pro Gly Leu Arg Glu Lys Ala Glu Tyr Leu Leu Arg Glu Trp Val Asn 1845 1850 1855 Leu Tyr His Ser Ala Ala Ala Gly Arg Asp Ser Thr Lys Ala Phe Ser 1860 1865 1870 Ala Phe Val Gly Gln Met His Gln Gln Gly Ile Leu Lys Thr Asp Asp 1875 1880 1885 Leu Ile Thr Arg Phe Phe Arg Leu Cys Thr Glu Met Cys Val Glu Ile 1890 1895 1900 Ser Tyr Arg Ala Gln Ala Glu Gln Gln His Asn Pro Ala Ala Asn Pro 1905 1910 1915 1920 Thr Met Ile Arg Ala Lys Cys Tyr His Asn Leu Asp Ala Phe Val Arg 1925 1930 1935 Leu Ile Ala Leu Leu Val Lys His Ser Gly Glu Ala Thr Asn Thr Val 1940 1945 1950 Thr Lys Ile Asn Leu Leu Asn Lys Val Leu Gly Ile Val Val Gly Val 1955 1960 1965 Leu Leu Gln Asp His Asp Val Arg Gln Ser Glu Phe Gln Gln Leu Pro 1970 1975 1980 Tyr His Arg Ile Phe Ile Met Leu Leu Leu Glu Leu Asn Ala Pro Glu 1985 1990 1995 2000 His Val Leu Glu Thr Ile Asn Phe Gln Thr Leu Thr Ala Phe Cys Asn 2005 2010 2015 Thr Phe His Ile Leu Arg Pro Thr Lys Ala Pro Gly Phe Val Tyr Ala 2020 2025 2030 Trp Leu Glu Leu Ile Ser His Arg Ile Phe Ile Ala Arg Met Leu Ala 2035 2040 2045 His Thr Pro Gln Gln Lys Gly Trp Pro Met Tyr Ala Gln Leu Leu Ile 2050 2055 2060 Asp Leu Phe Lys Tyr Leu Ala Pro Phe Leu Arg Asn Val Glu Leu Thr 2065 2070 2075 2080 Lys Pro Met Gln Ile Leu Tyr Lys Gly Thr Leu Arg Val Leu Leu Val 2085 2090 2095 Leu Leu His Asp Phe Pro Glu Phe Leu Cys Asp Tyr His Tyr Gly Phe 2100 2105 2110 Cys Asp Val Ile Pro Pro Asn Cys Ile Gln Leu Arg Asn Leu Ile Leu 2115 2120 2125 Ser Ala Phe Pro Arg Asn Met Arg Leu Pro Asp Pro Phe Thr Pro Asn 2130 2135 2140 Leu Lys Val Asp Met Leu Ser Glu Ile Asn Ile Ala Pro Arg Ile Leu 2145 2150 2155 2160 Thr Asn Phe Thr Gly Val Met Pro Pro Gln Phe Lys Lys Asp Leu Asp 2165 2170 2175 Ser Tyr Leu Lys Thr Arg Ser Pro Val Thr Phe Leu Ser Asp Leu Arg 2180 2185 2190 Ser Asn Leu Gln Val Ser Asn Glu Pro Gly Asn Arg Tyr Asn Leu Gln 2195 2200 2205 Leu Ile Asn Ala Leu Val Leu Tyr Val Gly Thr Gln Ala Ile Ala His 2210 2215 2220 Ile His Asn Lys Gly Ser Thr Pro Ser Met Ser Thr Ile Thr His Ser 2225 2230 2235 2240 Ala His Met Asp Ile Phe Gln Asn Leu Ala Val Asp Leu Asp Thr Glu 2245 2250 2255 Gly Arg Tyr Leu Phe Leu Asn Ala Ile Ala Asn Gln Leu Arg Tyr Pro 2260 2265 2270 Asn Ser His Thr His Tyr Phe Ser Cys Thr Met Leu Tyr Leu Phe Ala 2275 2280 2285 Glu Ala Asn Thr Glu Ala Ile Gln Glu Gln Ile Thr Arg Val Leu Leu 2290 2295 2300 Glu Arg Leu Ile Val Asn Arg Pro His Pro Trp Gly Leu Leu Ile Thr 2305 2310 2315 2320 Phe Ile Glu Leu Ile Lys Asn Pro Ala Phe Lys Phe Trp Asn His Glu 2325 2330 2335 Phe Val His Cys Ala Pro Glu Ile Glu Lys Leu Phe Gln Ser Val Ala 2340 2345 2350 Gln Cys Cys Met Gly Gln Lys Gln Ala Gln Gln Val Met Glu Gly Thr 2355 2360 2365Gly Ala Ser 2370 <210> 2 <211> 1056 <212> PRT <213> homo sapiens <400> 2 Met Ala Ser Gln Pro Asn Ser Ser Ala Lys Lys Lys Glu Glu Lys Gly 1 5 10 15 Lys Asn Ile Gln Val Val Val Arg Cys Arg Pro Phe Asn Leu Ala Glu 20 25 30 Arg Lys Ala Ser Ala His Ser Ile Val Glu Cys Asp Pro Val Arg Lys 35 40 45 Glu Val Ser Val Arg Thr Gly Gly Leu Ala Asp Lys Ser Ser Arg Lys 50 55 60 Thr Tyr Thr Phe Asp Met Val Phe Gly Ala Ser Thr Lys Gln Ile Asp 65 70 75 80 Val Tyr Arg Ser Val Val Cys Pro Ile Leu Asp Glu Val Ile Met Gly 85 90 95 Tyr Asn Cys Thr Ile Phe Ala Tyr Gly Gln Thr Gly Thr Gly Lys Thr 100 105 110 Phe Thr Met Glu Gly Glu Arg Ser Pro Asn Glu Glu Tyr Thr Trp Glu 115 120 125 Glu Asp Pro Leu Ala Gly Ile Ile Pro Arg Thr Leu His Gln Ile Phe 130 135 140 Glu Lys Leu Thr Asp Asn Gly Thr Glu Phe Ser Val Lys Val Ser Leu 145 150 155 160 Leu Glu Ile Tyr Asn Glu Glu Leu Phe Asp Leu Leu Asn Pro Ser Ser 165 170 175 Asp Val Ser Glu Arg Leu Gln Met Phe Asp Asp Pro Arg Asn Lys Arg 180 185 190 Gly Val Ile Ile Lys Gly Leu Glu Glu Ile Thr Val His Asn Lys Asp 195 200 205 Glu Val Tyr Gln Ile Leu Glu Lys Gly Ala Ala Lys Arg Thr Thr Ala 210 215 220 Ala Thr Leu Met Asn Ala Tyr Ser Ser Arg Ser His Ser Val Phe Ser 225 230 235 240 Val Thr Ile His Met Lys Glu Thr Thr Ile Asp Gly Glu Glu Leu Val 245 250 255 Lys Ile Gly Lys Leu Asn Leu Val Asp Leu Ala Gly Ser Glu Asn Ile 260 265 270 Gly Arg Ser Gly Ala Val Asp Lys Arg Ala Arg Glu Ala Gly Asn Ile 275 280 285 Asn Gln Ser Leu Leu Thr Leu Gly Arg Val Ile Thr Ala Leu Val Glu 290 295 300 Arg Thr Pro His Val Pro Tyr Arg Glu Ser Lys Leu Thr Arg Ile Leu 305 310 315 320 Gln Asp Ser Leu Gly Gly Arg Thr Arg Thr Ser Ile Ile Ala Thr Ile 325 330 335 Ser Pro Ala Ser Leu Asn Leu Glu Glu Thr Leu Ser Thr Leu Glu Tyr 340 345 350 Ala His Arg Ala Lys Asn Ile Leu Asn Lys Pro Glu Val Asn Gln Lys 355 360 365 Leu Thr Lys Lys Ala Leu Ile Lys Glu Tyr Thr Glu Glu Ile Glu Arg 370 375 380 Leu Lys Arg Asp Leu Ala Ala Ala Arg Glu Lys Asn Gly Val Tyr Ile 385 390 395 400 Ser Glu Glu Asn Phe Arg Val Met Ser Gly Lys Leu Thr Val Gln Glu 405 410 415 Glu Gln Ile Val Glu Leu Ile Glu Lys Ile Gly Ala Val Glu Glu Glu 420 425 430 Leu Asn Arg Val Thr Glu Leu Phe Met Asp Asn Lys Asn Glu Leu Asp 435 440 445 Gln Cys Lys Ser Asp Leu Gln Asn Lys Thr Gln Glu Leu Glu Thr Thr 450 455 460 Gln Lys His Leu Gln Glu Thr Lys Leu Gln Leu Val Lys Glu Glu Tyr 465 470 475 480 Ile Thr Ser Ala Leu Glu Ser Thr Glu Glu Lys Leu His Asp Ala Ala 485 490 495 Ser Lys Leu Leu Asn Thr Val Glu Glu Thr Thr Lys Asp Val Ser Gly 500 505 510 Leu His Ser Lys Leu Asp Arg Lys Lys Ala Val Asp Gln His Asn Ala 515 520 525 Glu Ala Gln Asp Ile Phe Gly Lys Asn Leu Asn Ser Leu Phe Asn Asn 530 535 540 Met Glu Glu Leu Ile Lys Asp Gly Ser Ser Lys Gln Lys Ala Met Leu 545 550 555 560 Glu Val His Lys Thr Leu Phe Gly Asn Leu Leu Ser Ser Ser Val Ser 565 570 575 Ala Leu Asp Thr Ile Thr Thr Val Ala Leu Gly Ser Leu Thr Ser Ile 580 585 590 Pro Glu Asn Val Ser Thr His Val Ser Gln Ile Phe Asn Met Ile Leu 595 600 605 Lys Glu Gln Ser Leu Ala Ala Glu Ser Lys Thr Val Leu Gln Glu Leu 610 615 620 Ile Asn Val Leu Lys Thr Asp Leu Leu Ser Ser Leu Glu Met Ile Leu 625 630 635 640 Ser Pro Thr Val Val Ser Ile Leu Lys Ile Asn Ser Gln Leu Lys His 645 650 655 Ile Phe Lys Thr Ser Leu Thr Val Ala Asp Lys Ile Glu Asp Gln Lys 660 665 670 Lys Glu Leu Asp Gly Phe Leu Ser Ile Leu Cys Asn Asn Leu His Glu 675 680 685 Leu Gln Glu Asn Thr Ile Cys Ser Leu Val Glu Ser Gln Lys Gln Cys 690 695 700 Gly Asn Leu Thr Glu Asp Leu Lys Thr Ile Lys Gln Thr His Ser Gln 705 710 715 720 Glu Leu Cys Lys Leu Met Asn Leu Trp Thr Glu Arg Phe Cys Ala Leu 725 730 735 Glu Glu Lys Cys Glu Asn Ile Gln Lys Pro Leu Ser Ser Val Gln Glu 740 745 750 Asn Ile Gln Gln Lys Ser Lys Asp Ile Val Asn Lys Met Thr Phe His 755 760 765 Ser Gln Lys Phe Cys Ala Asp Ser Asp Gly Phe Ser Gln Glu Leu Arg 770 775 780 Asn Phe Asn Gln Glu Gly Thr Lys Leu Val Glu Glu Ser Val Lys His 785 790 795 800 Ser Asp Lys Leu Asn Gly Asn Leu Glu Lys Ile Ser Gln Glu Thr Glu 805 810 815 Gln Arg Cys Glu Ser Leu Asn Thr Arg Thr Val Tyr Phe Ser Glu Gln 820 825 830 Trp Val Ser Ser Leu Asn Glu Arg Glu Gln Glu Leu His Asn Leu Leu 835 840 845 Glu Val Val Ser Gln Cys Cys Glu Ala Ser Ser Ser Asp Ile Thr Glu 850 855 860 Lys Ser Asp Gly Arg Lys Ala Ala His Glu Lys Gln His Asn Ile Phe 865 870 875 880 Leu Asp Gln Met Thr Ile Asp Glu Asp Lys Leu Ile Ala Gln Asn Leu 885 890 895 Glu Leu Asn Glu Thr Ile Lys Ile Gly Leu Thr Lys Leu Asn Cys Phe 900 905 910 Leu Glu Gln Asp Leu Lys Leu Asp Ile Pro Thr Gly Thr Thr Pro Gln 915 920 925 Arg Lys Ser Tyr Leu Tyr Pro Ser Thr Leu Val Arg Thr Glu Pro Arg 930 935 940 Glu His Leu Leu Asp Gln Leu Lys Arg Lys Gln Pro Glu Leu Leu Met 945 950 955 960 Met Leu Asn Cys Ser Glu Asn Asn Lys Glu Glu Thr Ile Pro Asp Val 965 970 975 Asp Val Glu Glu Ala Val Leu Gly Gln Tyr Thr Glu Glu Pro Leu Ser 980 985 990 Gln Glu Pro Ser Val Asp Ala Gly Val Asp Cys Ser Ser Ile Gly Gly 995 1000 1005 Val Pro Phe Phe Gln His Lys Lys Ser His Gly Lys Asp Lys Glu Asn 1010 1015 1020 Arg Gly Ile Asn Thr Leu Glu Arg Ser Lys Val Glu Glu Thr Thr Glu 1025 1030 1035 1040 His Leu Val Thr Lys Ser Arg Leu Pro Leu Arg Ala Gln Ile Asn Leu 1045 1050 1055 <210> 3 <211> 657 <212> PRT <213> homo sapiens <400> 3 Met Gly Cys Cys Ser Ser Ala Ser Ser Ala Ala Gln Ser Ser Lys Arg 1 5 10 15 Glu Trp Lys Pro Leu Glu Asp Arg Ser Cys Thr Asp Ile Pro Trp Leu 20 25 30 Leu Leu Phe Ile Leu Phe Cys Ile Gly Met Gly Phe Ile Cys Gly Phe 35 40 45 Ser Ile Ala Thr Gly Ala Ala Ala Arg Leu Val Ser Gly Tyr Asp Ser 50 55 60 Tyr Gly Asn Ile Cys Gly Gln Lys Asn Thr Lys Leu Glu Ala Ile Pro 65 70 75 80 Asn Ser Gly Met Asp His Thr Gln Arg Lys Tyr Val Phe Phe Leu Asp 85 90 95 Pro Cys Asn Leu Asp Leu Ile Asn Arg Lys Ile Lys Ser Val Ala Leu 100 105 110 Cys Val Ala Ala Cys Pro Arg Gln Glu Leu Lys Thr Leu Ser Asp Val 115 120 125 Gln Lys Phe Ala Glu Ile Asn Gly Ser Ala Leu Cys Ser Tyr Asn Leu 130 135 140 Lys Pro Ser Glu Tyr Thr Thr Ser Pro Lys Ser Ser Val Leu Cys Pro 145 150 155 160 Lys Leu Pro Val Pro Ala Ser Ala Pro Ile Pro Phe Phe His Arg Cys 165 170 175 Ala Pro Val Asn Ile Ser Cys Tyr Ala Lys Phe Ala Glu Ala Leu Ile 180 185 190 Thr Phe Val Ser Asp Asn Ser Val Leu His Arg Leu Ile Ser Gly Val 195 200 205 Met Thr Ser Lys Glu Ile Ile Leu Gly Leu Cys Leu Leu Ser Leu Val 210 215 220 Leu Ser Met Ile Leu Met Val Ile Ile Arg Tyr Ile Ser Arg Val Leu 225 230 235 240 Val Trp Ile Leu Thr Ile Leu Val Ile Leu Gly Ser Leu Gly Gly Thr 245 250 255 Gly Val Leu Trp Trp Leu Tyr Ala Lys Gln Arg Arg Ser Pro Lys Glu 260 265 270 Thr Val Thr Pro Glu Gln Leu Gln Ile Ala Glu Asp Asn Leu Arg Ala 275 280 285 Leu Leu Ile Tyr Ala Ile Ser Ala Thr Val Phe Thr Val Ile Leu Phe 290 295 300 Leu Ile Met Leu Val Met Arg Lys Arg Val Ala Leu Thr Ile Ala Leu 305 310 315 320 Phe His Val Ala Gly Lys Val Phe Ile His Leu Pro Leu Leu Val Phe 325 330 335 Gln Pro Phe Trp Thr Phe Phe Ala Leu Val Leu Phe Trp Val Tyr Trp 340 345 350 Ile Met Thr Leu Leu Phe Leu Gly Thr Thr Gly Ser Pro Val Gln Asn 355 360 365 Glu Gln Gly Phe Val Glu Phe Lys Ile Ser Gly Pro Leu Gln Tyr Met 370 375 380 Trp Trp Tyr His Val Val Gly Leu Ile Trp Ile Ser Glu Phe Ile Leu 385 390 395 400 Ala Cys Gln Gln Met Thr Val Ala Gly Ala Val Val Thr Tyr Tyr Phe 405 410 415 Thr Arg Asp Lys Arg Asn Leu Pro Phe Thr Pro Ile Leu Ala Ser Val 420 425 430 Asn Arg Leu Ile Arg Tyr His Leu Gly Thr Val Ala Lys Gly Ser Phe 435 440 445 Ile Ile Thr Leu Val Lys Ile Pro Arg Met Ile Leu Met Tyr Ile His 450 455 460 Ser Gln Leu Lys Gly Lys Glu Asn Ala Cys Ala Arg Cys Val Leu Lys 465 470 475 480 Ser Cys Ile Cys Cys Leu Trp Cys Leu Glu Lys Cys Leu Asn Tyr Leu 485 490 495 Asn Gln Asn Ala Tyr Thr Ala Thr Ala Ile Asn Ser Thr Asn Phe Cys 500 505 510 Thr Ser Ala Lys Asp Ala Phe Val Ile Leu Val Glu Asn Ala Leu Arg 515 520 525 Val Ala Thr Ile Asn Thr Val Gly Asp Phe Met Leu Phe Leu Gly Lys 530 535 540 Val Leu Ile Val Cys Ser Thr Gly Leu Ala Gly Ile Met Leu Leu Asn 545 550 555 560 Tyr Gln Gln Asp Tyr Thr Val Trp Val Leu Pro Leu Ile Ile Val Cys 565 570 575 Leu Phe Ala Phe Leu Val Ala His Cys Phe Leu Ser Ile Tyr Glu Met 580 585 590 Val Val Asp Val Leu Phe Leu Cys Phe Ala Ile Asp Thr Lys Tyr Asn 595 600 605 Asp Gly Ser Pro Gly Arg Glu Phe Tyr Met Asp Lys Val Leu Met Glu 610 615 620 Phe Val Glu Asn Ser Arg Lys Ala Met Lys Glu Ala Gly Lys Gly Gly 625 630 635 640 Val Ala Asp Ser Arg Glu Leu Lys Pro Met Ala Ser Gly Ala Ser Ser 645 650 655 Ala <210> 4 <211> 362 <212> PRT <213> homo sapiens <400> 4 Met Glu Thr Asp Ala Pro Gln Pro Gly Leu Ala Ser Pro Asp Ser Pro 1 5 10 15 His Asp Pro Cys Lys Met Phe Ile Gly Gly Leu Ser Trp Gln Thr Thr 20 25 30 Gln Glu Gly Leu Arg Glu Tyr Phe Gly Gln Phe Gly Glu Val Lys Glu 35 40 45 Cys Leu Val Met Arg Asp Pro Leu Thr Lys Arg Ser Arg Gly Phe Gly 50 55 60 Phe Val Thr Phe Met Asp Gln Ala Gly Val Asp Lys Val Leu Ala Gln 65 70 75 80 Ser Arg His Glu Leu Asp Ser Lys Thr Ile Asp Pro Lys Val Ala Phe 85 90 95 Pro Arg Arg Ala Gln Pro Lys Met Val Thr Arg Thr Lys Lys Ile Phe 100 105 110 Val Gly Gly Leu Ser Val Asn Thr Thr Val Glu Asp Val Lys Gln Tyr 115 120 125 Phe Glu Gln Phe Gly Lys Val Asp Asp Ala Met Leu Met Phe Asp Lys 130 135 140 Thr Thr Asn Arg His Arg Gly Phe Gly Phe Val Thr Phe Glu Ser Glu 145 150 155 160 Asp Ile Val Glu Lys Val Cys Glu Ile His Phe His Glu Ile Asn Asn 165 170 175 Lys Met Val Glu Cys Lys Lys Ala Gln Pro Lys Glu Val Met Ser Pro 180 185 190 Thr Gly Ser Ala Arg Gly Arg Ser Arg Val Met Pro Tyr Gly Met Asp 195 200 205 Ala Phe Met Leu Gly Ile Gly Met Leu Gly Tyr Pro Gly Phe Gln Ala 210 215 220 Thr Thr Tyr Ala Ser Arg Ser Tyr Thr Gly Leu Ala Pro Gly Tyr Thr 225 230 235 240 Tyr Gln Phe Pro Glu Phe Arg Val Glu Arg Thr Pro Leu Pro Ser Ala 245 250 255 Pro Val Leu Pro Glu Leu Thr Ala Ile Pro Leu Thr Ala Tyr Gly Pro 260 265 270 Met Ala Ala Ala Ala Ala Ala Ala Val Val Arg Gly Thr Gly Ser 275 280 285 His Pro Trp Thr Met Ala Pro Pro Pro Gly Ser Thr Pro Ser Arg Thr 290 295 300 Gly Gly Phe Leu Gly Thr Thr Ser Pro Gly Pro Met Ala Glu Leu Tyr 305 310 315 320 Gly Ala Ala Asn Gln Asp Ser Gly Val Ser Ser Tyr Ile Ser Ala Ala 325 330 335 Ser Pro Ala Pro Ser Thr Gly Phe Gly His Ser Leu Gly Gly Pro Leu 340 345 350 Ile Ala Thr Ala Phe Thr Asn Gly Tyr His 355 360 <210> 5 <211> 2213 <212> PRT <213> homo sapiens <400> 5 Met Ala Arg Gly Ala Arg Pro Ser Ala Ala Gly Gly Gly Gly Gly Gly 1 5 10 15 Ala Glu Pro Pro Glu Arg Ala Gly Pro Gly Arg Pro Arg Gly Ser Pro 20 25 30 Pro Gly Arg Ala Arg Pro Ser Leu Ala Pro Arg Pro Gly Pro Glu Pro 35 40 45 Ser Arg Pro Arg Ala Ala Pro Glu Thr Ser Gly Gly Asp Thr Ala Gly 50 55 60 Ala Gly Arg Cys Gly Gly Arg Arg Ala Ala Lys Leu Gly Pro Gly Arg 65 70 75 80 Arg Gly Trp Trp Ala Leu Leu Ala Leu Gln Leu His Leu Leu Arg Ala 85 90 95 Leu Ala Gln Asp Asp Val Ala Pro Tyr Phe Lys Thr Glu Pro Gly Leu 100 105 110 Pro Gln Ile His Leu Glu Gly Asn Arg Leu Val Leu Thr Cys Leu Ala 115 120 125 Glu Gly Ser Trp Pro Leu Glu Phe Lys Trp Met Arg Asp Asp Ser Glu 130 135 140 Leu Thr Thr Tyr Ser Ser Glu Tyr Lys Tyr Ile Ile Pro Ser Leu Gln 145 150 155 160 Lys Leu Asp Ala Gly Phe Tyr Arg Cys Val Val Arg Asn Arg Met Gly 165 170 175 Ala Leu Leu Gln Arg Lys Ser Glu Val Gln Val Ala Tyr Met Gly Ser 180 185 190 Phe Met Asp Thr Asp Gln Arg Lys Thr Val Ser Gln Gly Arg Ala Ala 195 200 205 Ile Leu Asn Leu Leu Pro Ile Thr Ser Tyr Pro Arg Pro Gln Val Thr 210 215 220 Trp Phe Arg Glu Gly His Lys Ile Ile Pro Ser Asn Arg Ile Ala Ile 225 230 235 240 Thr Leu Glu Asn Gln Leu Val Ile Leu Ala Thr Thr Thr Ser Asp Ala 245 250 255 Gly Ala Tyr Tyr Val Gln Ala Val Asn Glu Lys Asn Gly Glu Asn Lys 260 265 270 Thr Ser Pro Phe Ile His Leu Ser Ile Ala Arg Asp Val Gly Thr Pro 275 280 285 Glu Thr Met Ala Pro Thr Ile Val Val Pro Pro Gly Asn Arg Ser Val 290 295 300 Val Ala Gly Ser Ser Glu Thr Thr Leu Glu Cys Ile Ala Ser Ala Arg 305 310 315 320 Pro Val Glu Asp Leu Ser Val Thr Trp Lys Arg Asn Gly Val Arg Ile 325 330 335 Thr Ser Gly Leu His Ser Phe Gly Arg Arg Leu Thr Ile Ser Asn Pro 340 345 350 Thr Ser Ala Asp Thr Gly Pro Tyr Val Cys Glu Ala Ala Leu Pro Gly 355 360 365 Ser Ala Phe Glu Pro Ala Arg Ala Thr Ala Phe Leu Phe Ile Ile Glu 370 375 380 Pro Pro Tyr Phe Thr Ala Glu Pro Glu Ser Arg Ile Ser Ala Glu Val 385 390 395 400 Glu Glu Thr Val Asp Ile Gly Cys Gln Ala Met Gly Val Pro Leu Pro 405 410 415 Thr Leu Gln Trp Tyr Lys Asp Ala Ile Ser Ile Ser Arg Leu Gln Asn 420 425 430 Pro Arg Tyr Lys Val Leu Ala Ser Gly Gly Leu Arg Ile Gln Lys Leu 435 440 445 Arg Pro Glu Asp Ser Gly Ile Phe Gln Cys Phe Ala Ser Asn Glu Gly 450 455 460 Gly Glu Ile Gln Thr His Thr Tyr Leu Asp Val Thr Asn Ile Ala Pro 465 470 475 480 Val Phe Thr Gln Arg Pro Val Asp Thr Thr Val Thr Asp Gly Met Thr 485 490 495 Ala Ile Leu Arg Cys Glu Val Ser Gly Ala Pro Lys Pro Ala Ile Thr 500 505 510 Trp Lys Arg Glu Asn His Ile Leu Ala Ser Gly Ser Val Arg Ile Pro 515 520 525 Arg Phe Met Leu Leu Glu Ser Gly Gly Leu Gln Ile Ala Pro Val Phe 530 535 540 Ile Gln Asp Ala Gly Asn Tyr Thr Cys Tyr Ala Ala Asn Thr Glu Gly 545 550 555 560 Ser Leu Asn Ala Ser Ala Thr Leu Thr Val Trp Asn Arg Thr Ser Ile 565 570 575 Val His Pro Pro Glu Asp His Val Val Ile Lys Gly Thr Thr Ala Thr 580 585 590 Leu His Cys Gly Ala Thr His Asp Pro Arg Val Ser Leu Arg Tyr Val 595 600 605 Trp Lys Lys Asp Asn Val Ala Leu Thr Pro Ser Ser Thr Ser Arg Ile 610 615 620 Val Glu Lys Asp Gly Ser Leu Leu Ile Ser Gln Thr Trp Ser Gly 625 630 635 640 Asp Ile Gly Asp Tyr Ser Cys Glu Ile Val Ser Glu Gly Gly Asn Asp 645 650 655 Ser Arg Met Ala Arg Leu Glu Val Ile Glu Leu Pro His Ser Pro Gln 660 665 670 Asn Leu Leu Val Ser Pro Asn Ser Ser His Ser His Ala Val Val Leu 675 680 685 Ser Trp Val Arg Pro Phe Asp Gly Asn Ser Pro Ile Leu Tyr Tyr Ile 690 695 700 Val Glu Leu Ser Glu Asn Asn Ser Pro Trp Lys Val His Leu Ser Asn 705 710 715 720 Val Gly Pro Glu Met Thr Gly Val Thr Val Ser Gly Leu Thr Pro Ala 725 730 735 Arg Thr Tyr Gln Phe Arg Val Cys Ala Val Asn Glu Val Gly Arg Gly 740 745 750 Gln Tyr Ser Ala Glu Thr Ser Arg Leu Met Leu Pro Glu Glu Pro Pro 755 760 765 Ser Ala Pro Pro Lys Asn Ile Val Ala Ser Gly Arg Thr Asn Gln Ser 770 775 780 Ile Met Val Gln Trp Gln Pro Pro Pro Glu Thr Glu His Asn Gly Val 785 790 795 800 Leu Arg Gly Tyr Ile Leu Arg Tyr Arg Leu Ala Gly Leu Pro Gly Glu 805 810 815 Tyr Gln Gln Arg Asn Ile Thr Ser Pro Glu Val Asn Tyr Cys Leu Val 820 825 830 Thr Asp Leu Ile Ile Trp Thr Gln Tyr Glu Ile Gln Val Ala Ala Tyr 835 840 845 Asn Gly Ala Gly Leu Gly Val Phe Ser Arg Ala Val Thr Glu Tyr Thr 850 855 860 Leu Gln Gly Val Pro Thr Ala Pro Pro Gln Asn Val Gln Thr Glu Ala 865 870 875 880 Val Asn Ser Thr Thr Ile Gln Phe Leu Trp Asn Pro Pro Pro Gln Gln 885 890 895 Phe Ile Asn Gly Ile Asn Gln Gly Tyr Lys Leu Leu Ala Trp Pro Ala 900 905 910 Asp Ala Pro Glu Ala Val Thr Val Val Thr Ile Ala Pro Asp Phe His 915 920 925 Gly Val His His Gly His Ile Thr Asn Leu Lys Lys Phe Thr Ala Tyr 930 935 940 Phe Thr Ser Val Leu Cys Phe Thr Thr Pro Gly Asp Gly Pro Pro Ser 945 950 955 960 Thr Pro Gln Leu Val Trp Thr Gln Glu Asp Lys Pro Gly Ala Val Gly 965 970 975 His Leu Ser Phe Thr Glu Ile Leu Asp Thr Ser Leu Lys Val Ser Trp 980 985 990 Gln Glu Pro Leu Glu Lys Asn Gly Ile Ile Thr Gly Tyr Gln Ile Ser 995 1000 1005 Trp Glu Val Tyr Gly Arg Asn Asp Ser Arg Leu Thr His Thr Leu Asn 1010 1015 1020 Ser Thr Thr His Glu Tyr Lys Ile Gln Gly Leu Ser Ser Leu Thr Thr 1025 1030 1035 1040 Tyr Thr Ile Asp Val Ala Ala Val Thr Ala Val Gly Thr Gly Leu Val 1045 1050 1055 Thr Ser Ser Thr Ile Ser Ser Gly Val Pro Pro Asp Leu Pro Gly Ala 1060 1065 1070 Pro Ser Asn Leu Val Ile Ser Asn Ile Ser Pro Arg Ser Ala Thr Leu 1075 1080 1085 Gln Phe Arg Pro Gly Tyr Asp Gly Lys Thr Ser Ile Ser Arg Trp Ile 1090 1095 1100 Val Glu Gly Gln Val Gly Ala Ile Gly Asp Glu Glu Glu Trp Val Thr 1105 1110 1115 1120 Leu Tyr Glu Glu Glu Asn Glu Pro Asp Ala Gln Met Leu Glu Ile Pro 1125 1130 1135 Asn Leu Thr Pro Tyr Thr His Tyr Arg Phe Arg Met Lys Gln Val Asn 1140 1145 1150 Ile Val Gly Pro Ser Pro Tyr Ser Pro Ser Ser Arg Val Ile Gln Thr 1155 1160 1165 Leu Gln Ala Pro Pro Asp Val Ala Pro Thr Ser Val Thr Val Arg Thr 1170 1175 1180 Ala Ser Glu Thr Ser Leu Arg Leu Arg Trp Val Pro Leu Pro Asp Ser 1185 1190 1195 1200 Gln Tyr Asn Gly Asn Pro Glu Ser Val Gly Tyr Arg Ile Lys Tyr Trp 1205 1210 1215 Arg Ser Asp Leu Gln Ser Ser Ala Val Ala Gln Val Val Ser Asp Arg 1220 1225 1230 Leu Glu Arg Glu Phe Thr Ile Glu Glu Leu Glu Glu Trp Met Glu Tyr 1235 1240 1245 Glu Leu Gln Met Gln Ala Phe Asn Ala Val Gly Ala Gly Pro Trp Ser 1250 1255 1260 Glu Val Val Arg Gly Arg Thr Arg Glu Ser Val Pro Ser Ala Ala Pro 1265 1270 1275 1280 Glu Asn Val Ser Ala Glu Ala Val Ser Ser Thr Gln Ile Leu Leu Thr 1285 1290 1295 Trp Thr Ser Val Pro Glu Gln Asp Gln Asn Gly Leu Ile Leu Gly Tyr 1300 1305 1310 Lys Ile Leu Phe Arg Ala Lys Asp Leu Asp Pro Glu Pro Arg Ser His 1315 1320 1325 Ile Val Arg Gly Asn His Thr Gln Ser Ala Leu Leu Ala Gly Leu Arg 1330 1335 1340 Lys Phe Val Leu Tyr Glu Leu Gln Val Leu Ala Phe Thr Arg Ile Gly 1345 1350 1355 1360 Asn Gly Val Pro Ser Thr Pro Leu Ile Leu Glu Arg Thr Lys Asp Asp 1365 1370 1375 Ala Pro Gly Pro Pro Val Arg Leu Val Phe Pro Glu Val Arg Leu Thr 1380 1385 1390 Ser Val Arg Ile Val Trp Gln Pro Pro Glu Glu Pro Asn Gly Ile Ile 1395 1400 1405 Leu Gly Tyr Gln Ile Ala Asp Leu Ala Pro Glu Ser Ala Tyr Ile Phe Arg Leu Ser Ala Lys Thr 1445 1450 1455 Arg Gln Gly Trp Gly Glu Pro Leu Glu Ala Thr Val Ile Thr Thr Glu 1460 1465 1470 Lys Arg Glu Arg Pro Ala Pro Pro Arg Glu Leu Leu Val Pro Gln Ala 1475 1480 1485 Glu Val Thr Ala Arg Ser Leu Arg Leu Gln Trp Val Pro Gly Ser Asp 1490 1495 1500 Gly Ala Ser Pro Ile Arg Tyr Phe Thr Met Gln Val Arg Glu Leu Pro 1505 1510 1515 1520 Arg Gly Glu Trp Gln Thr Tyr Ser Ser Ser Ile Ser His Glu Ala Thr 1525 1530 1535 Ala Cys Val Val Asp Arg Leu Arg Pro Phe Thr Ser Tyr Lys Leu Arg 1540 1545 1550 Leu Lys Ala Thr Asn Asp Ile Gly Asp Ser Asp Phe Ser Ser Glu Thr 1555 1560 1565 Glu Ala Val Thr Thr Leu Gln Asp Val Pro Gly Glu Pro Pro Gly Ser 1570 1575 1580 Val Ser Ala Thr Pro His Thr Thr Ser Ser Val Leu Ile Gln Trp Gln 1585 1590 1595 1600 Pro Pro Arg Asp Glu Ser Leu Asn Gly Leu Leu Gln Gly Tyr Arg Ile 1605 1610 1615 Tyr Tyr Arg Glu Leu Glu Tyr Glu Ala Gly Ser Gly Thr Glu Ala Lys 1620 1625 1630 Thr Leu Lys Asn Pro Ile Ala Leu His Ala Glu Leu Thr Ala Gln Ser 1635 1640 1645 Ser Phe Lys Thr Val Asn Ser Ser Ser Thr Ser Thr Met Cys Glu Leu 1650 1655 1660 Thr His Leu Lys Lys Tyr Arg Arg Tyr Glu Val Ile Met Thr Ala Tyr 1665 1670 1675 1680 Asn Ile Ile Gly Glu Ser Pro Ala Ser Ala Pro Val Glu Val Phe Val 1685 1690 1695 Gly Glu Ala Ala Pro Ala Met Ala Pro Gln Asn Val Gln Val Thr Pro 1700 1705 1710 Leu Thr Ala Ser Gln Leu Glu Val Thr Trp Asp Pro Pro Pro Pro Glu 1715 1720 1725 Ser Gln Asn Gly Asn Ile Gln Gly Tyr Lys Ile Tyr Tyr Trp Glu Ala 1730 1735 1740 Asp Ser Gln Asn Glu Thr Glu Lys Met Lys Val Leu Phe Leu Pro Glu 1745 1750 1755 1760 Pro Val Val Arg Leu Lys Asn Leu Thr Ser His Thr Lys Tyr Leu Val 1765 1770 1775 Ser Ile Ser Ala Phe Asn Ala Ala Gly Asp Gly Pro Lys Ser Asp Pro 1780 1785 1790 Gln Gln Gly Arg Thr His Gln Ala Ala Pro Gly Ala Pro Ser Phe Leu 1795 1800 1805 Ala Phe Ser Glu Ile Thr Ser Thr Thr Leu Asn Val Ser Trp Gly Glu 1810 1815 1820 Pro Ala Ala Ala Asn Gly Ile Leu Gln Gly Tyr Arg Val Val Tyr Glu 1825 1830 1835 1840 Pro Leu Ala Pro Val Gln Gly Val Ser Lys Val Val Thr Val Glu Val 1845 1850 1855 Arg Gly Asn Trp Gln Arg Trp Leu Lys Val Arg Asp Leu Thr Lys Gly 1860 1865 1870 Val Thr Tyr Phe Phe Arg Val Gln Ala Arg Thr Ile Thr Tyr Gly Pro 1875 1880 1885 Glu Leu Gln Ala Asn Ile Thr Ala Gly Pro Ala Glu Gly Ser Pro Gly 1890 1895 1900 Ser Pro Arg Asp Val Leu Val Thr Lys Ser Ala Ser Glu Leu Thr Leu 1905 1910 1915 1920 Gln Trp Thr Glu Gly His Ser Gly Asp Thr Pro Thr Thr Gly Tyr Val 1925 1930 1935 Ile Glu Ala Arg Pro Ser Asp Glu Gly Leu Trp Asp Met Phe Val Lys 1940 1945 1950 Asp Ile Pro Arg Ser Ala Thr Ser Tyr Thr Leu Ser Leu Asp Lys Leu 1955 1960 1965 Arg Gln Gly Val Thr Tyr Glu Phe Arg Val Val Ala Val Asn Glu Ala 1970 1975 1980 Gly Tyr Gly Glu Pro Ser Asn Pro Ser Thr Ala Val Ser Ala Gln Val 1985 1990 1995 2000 Glu Ala Pro Phe Tyr Glu Glu Trp Trp Phe Leu Leu Val Met Ala Leu 2005 2010 2015 Ser Ser Leu Ile Val Ile Leu Leu Val Val Phe Ala Leu Val Leu His 2020 2025 2030 Gly Gln Asn Lys Lys Tyr Lys Asn Cys Ser Thr Gly Lys Gly Ile Ser 2035 2040 2045 Thr Met Glu Glu Ser Val Thr Leu Asp Asn Gly Gly Phe Ala Ala Leu 2050 2055 2060 Glu Leu Ser Ser Arg His Leu Asn Val Lys Ser Thr Phe Ser Lys Lys 2065 2070 2075 2080 Asn Gly Thr Arg Ser Pro Pro Arg Pro Ser Pro Gly Gly Leu His Tyr 2085 2090 2095 Ser Asp Glu Asp Ile Cys Asn Lys Tyr Asn Gly Ala Val Leu Thr Glu 2100 2105 2110 Ser Val Ser Leu Lys Glu Lys Ser Ala Asp Ala Ser Glu Ser Glu Ala 2115 2120 2125 Thr Asp Ser Asp Tyr Glu Asp Ala Leu Pro Lys His Ser Phe Val Asn 2130 2135 2140 His Tyr Met Ser Asp Pro Thr Tyr Tyr Asn Ser Trp Lys Arg Arg Ala 2145 2150 2155 2160 Gln Gly Arg Ala Pro Ala Pro His Arg Tyr Glu Ala Val Ala Gly Ser 2165 2170 2175 Glu Ala Gly Ala Gln Leu His Pro Val Ile Thr Thr Gln Ser Ala Gly 2180 2185 2190 Gly Val Tyr Thr Pro Ala Gly Pro Gly Ala Arg Thr Pro Leu Thr Gly 2195 2200 2205Phe Ser Ser Phe Val 2210 <210> 6 <211> 233 <212> PRT <213> homo sapiens <400> 6 Met Glu Gly Gly Ala Tyr Gly Ala Gly Lys Ala Gly Gly Ala Phe Asp 1 5 10 15 Pro Tyr Thr Leu Val Arg Gln Pro His Thr Ile Leu Arg Val Val Ser 20 25 30 Trp Leu Phe Ser Ile Val Val Phe Gly Ser Ile Val Asn Glu Gly Tyr 35 40 45 Leu Asn Ser Ala Ser Glu Gly Glu Glu Phe Cys Ile Tyr Asn Arg Asn 50 55 60 Pro Asn Ala Cys Ser Tyr Gly Val Ala Val Gly Val Leu Ala Phe Leu 65 70 75 80 Thr Cys Leu Leu Tyr Leu Ala Leu Asp Val Tyr Phe Pro Gln Ile Ser 85 90 95 Ser Val Lys Asp Arg Lys Lys Ala Val Leu Ser Asp Ile Gly Val Ser 100 105 110 Ala Phe Trp Ala Phe Leu Trp Phe Val Gly Phe Cys Tyr Leu Ala Asn 115 120 125 Gln Trp Gln Val Ser Lys Pro Lys Asp Asn Pro Leu Asn Glu Gly Thr 130 135 140 Asp Ala Ala Arg Ala Ala Ile Ala Phe Ser Phe Phe Ser Ile Phe Thr 145 150 155 160 Trp Ala Gly Gln Ala Val Leu Ala Phe Gln Arg Tyr Gln Ile Gly Ala 165 170 175 Asp Ser Ala Leu Phe Ser Gln Asp Tyr Met Asp Pro Ser Gln Asp Ser 180 185 190 Ser Met Pro Tyr Ala Pro Tyr Val Glu Pro Thr Gly Pro Asp Pro Ala 195 200 205 Gly Met Gly Gly Thr Tyr Gln Gln Pro Ala Asn Thr Phe Asp Thr Glu 210 215 220 Pro Gln Gly Tyr Gln Ser Gln Gly Tyr 225 230 <210> 7 <211> 3014 <212> PRT <213> homo sapiens <400> 7 Met Ala Pro Pro Pro Pro Pro Val Leu Pro Val Leu Leu Leu Leu Ala 1 5 10 15 Ala Ala Ala Ala Leu Pro Ala Met Gly Leu Arg Ala Ala Ala Trp Glu 20 25 30 Pro Arg Val Pro Gly Gly Thr Arg Ala Phe Ala Leu Arg Pro Gly Cys 35 40 45 Thr Tyr Ala Val Gly Ala Ala Cys Thr Pro Arg Ala Pro Arg Glu Leu 50 55 60 Leu Asp Val Gly Arg Asp Gly Arg Leu Ala Gly Arg Arg Arg Val Ser 65 70 75 80 Gly Ala Gly Arg Pro Leu Pro Leu Gln Val Arg Leu Val Ala Arg Ser 85 90 95 Ala Pro Thr Ala Leu Ser Arg Arg Leu Arg Ala Arg Thr His Leu Pro 100 105 110 Gly Cys Gly Ala Arg Ala Arg Leu Cys Gly Thr Gly Ala Arg Leu Cys 115 120 125 Gly Ala Leu Cys Phe Pro Val Pro Gly Gly Cys Ala Ala Ala Gln His 130 135 140 Ser Ala Leu Ala Ala Pro Thr Thr Leu Pro Ala Cys Arg Cys Pro Pro 145 150 155 160 Arg Pro Arg Pro Arg Cys Pro Gly Arg Pro Ile Cys Leu Pro Pro Gly 165 170 175 Gly Ser Val Arg Leu Arg Leu Leu Cys Ala Leu Arg Arg Ala Ala Gly 180 185 190 Ala Val Arg Val Gly Leu Ala Leu Glu Ala Ala Thr Ala Gly Thr Pro 195 200 205 Ser Ala Ser Pro Ser Pro Ser Pro Pro Leu Pro Pro Asn Leu Pro Glu 210 215 220 Ala Arg Ala Gly Pro Ala Arg Arg Ala Arg Arg Gly Thr Ser Gly Arg 225 230 235 240 Gly Ser Leu Lys Phe Pro Met Pro Asn Tyr Gln Val Ala Leu Phe Glu 245 250 255 Asn Glu Pro Ala Gly Thr Leu Ile Leu Gln Leu His Ala His Tyr Thr 260 265 270 Ile Glu Gly Glu Glu Glu Arg Val Ser Tyr Tyr Met Glu Gly Leu Phe 275 280 285 Asp Glu Arg Ser Arg Gly Tyr Phe Arg Ile Asp Ser Ala Thr Gly Ala 290 295 300 Val Ser Thr Asp Ser Val Leu Asp Arg Glu Thr Lys Glu Thr His Val 305 310 315 320 Leu Arg Val Lys Ala Val Asp Tyr Ser Thr Pro Pro Arg Ser Ala Thr 325 330 335 Thr Tyr Ile Thr Val Leu Val Lys Asp Thr Asn Asp His Ser Pro Val 340 345 350 Phe Glu Gln Ser Glu Tyr Arg Glu Arg Val Arg Glu Asn Leu Glu Val 355 360 365 Gly Tyr Glu Val Leu Thr Ile Arg Ala Ser Asp Arg Asp Ser Pro Ile 370 375 380 Asn Ala Asn Leu Arg Tyr Arg Val Leu Gly Gly Ala Trp Asp Val Phe 385 390 395 400 Gln Leu Asn Glu Ser Ser Gly Val Val Ser Thr Arg Ala Val Leu Asp 405 410 415 Arg Glu Glu Ala Ala Glu Tyr Gln Leu Leu Val Glu Ala Asn Asp Gln 420 425 430 Gly Arg Asn Pro Gly Pro Leu Ser Ala Thr Ala Thr Val Tyr Ile Glu 435 440 445 Val Glu Asp Glu Asn Asp Asn Tyr Pro Gln Phe Ser Glu Gln Asn Tyr 450 455 460 Val Val Gln Val Pro Glu Asp Val Gly Leu Asn Thr Ala Val Leu Arg 465 470 475 480 Val Gln Ala Thr Asp Arg Asp Gln Gly Gln Asn Ala Ala Ile His Tyr 485 490 495 Ser Ile Leu Ser Gly Asn Val Ala Gly Gln Phe Tyr Leu His Ser Leu 500 505 510 Ser Gly Ile Leu Asp Val Ile Asn Pro Leu Asp Phe Glu Asp Val Gln 515 520 525 Lys Tyr Ser Leu Ser Ile Lys Ala Gln Asp Gly Gly Arg Pro Pro Leu 530 535 540 Ile Asn Ser Ser Gly Val Val Ser Val Gln Val Leu Asp Val Asn Asp 545 550 555 560 Asn Glu Pro Ile Phe Val Ser Ser Pro Phe Gln Ala Thr Val Leu Glu 565 570 575 Asn Val Pro Leu Gly Tyr Pro Val Val His Ile Gln Ala Val Asp Ala 580 585 590 Asp Ser Gly Glu Asn Ala Arg Leu His Tyr Arg Leu Val Asp Thr Ala 595 600 605 Ser Thr Phe Leu Gly Gly Gly Ser Ala Gly Pro Lys Asn Pro Ala Pro 610 615 620 Thr Pro Asp Phe Pro Phe Gln Ile His Asn Ser Ser Gly Trp Ile Thr 625 630 635 640 Val Cys Ala Glu Leu Asp Arg Glu Glu Val Glu His Tyr Ser Phe Gly 645 650 655 Val Glu Ala Val Asp His Gly Ser Pro Pro Met Ser Ser Ser Thr Ser 660 665 670 Val Ser Ile Thr Val Leu Asp Val Asn Asp Asn Asp Pro Val Phe Thr 675 680 685 Gln Pro Thr Tyr Glu Leu Arg Leu Asn Glu Asp Ala Ala Val Gly Ser 690 695 700 Ser Val Leu Thr Leu Gln Ala Arg Asp Arg Asp Ala Asn Ser Val Ile 705 710 715 720 Thr Tyr Gln Leu Thr Gly Gly Asn Thr Arg Asn Arg Phe Ala Leu Ser 725 730 735 Ser Gln Arg Gly Gly Gly Leu Ile Thr Leu Ala Leu Pro Leu Asp Tyr 740 745 750 Lys Gln Glu Gln Gln Tyr Val Leu Ala Val Thr Ala Ser Asp Gly Thr 755 760 765 Arg Ser His Thr Ala His Val Leu Ile Asn Val Thr Asp Ala Asn Thr 770 775 780 His Arg Pro Val Phe Gln Ser Ser His Tyr Thr Val Ser Val Ser Glu 785 790 795 800 Asp Arg Pro Val Gly Thr Ser Ile Ala Thr Leu Ser Ala Asn Asp Glu 805 810 815 Asp Thr Gly Glu Asn Ala Arg Ile Thr Tyr Val Ile Gln Asp Pro Val 820 825 830 Pro Gln Phe Arg Ile Asp Pro Asp Ser Gly Thr Met Tyr Thr Met Met 835 840 845 Glu Leu Asp Tyr Glu Asn Gln Val Ala Tyr Thr Leu Thr Ile Met Ala 850 855 860 Gln Asp Asn Gly Ile Pro Gln Lys Ser Asp Thr Thr Leu Glu Ile 865 870 875 880 Leu Ile Leu Asp Ala Asn Asp Asn Ala Pro Gln Phe Leu Trp Asp Phe 885 890 895 Tyr Gln Gly Ser Ile Phe Glu Asp Ala Pro Pro Ser Thr Ser Ile Leu 900 905 910 Gln Val Ser Ala Thr Asp Arg Asp Ser Gly Pro Asn Gly Arg Leu Leu 915 920 925 Tyr Thr Phe Gln Gly Gly Asp Asp Gly Asp Gly Asp Phe Tyr Ile Glu 930 935 940 Pro Thr Ser Gly Val Ile Arg Thr Gln Arg Arg Leu Asp Arg Glu Asn 945 950 955 960 Val Ala Val Tyr Asn Leu Trp Ala Leu Ala Val Asp Arg Gly Ser Pro 965 970 975 Thr Pro Leu Ser Ala Ser Val Glu Ile Gln Val Thr Ile Leu Asp Ile 980 985 990 Asn Asp Asn Ala Pro Met Phe Glu Lys Asp Glu Leu Glu Leu Phe Val 995 1000 1005 Glu Glu Asn Asn Pro Val Gly Ser Val Val Ala Lys Ile Arg Ala Asn 1010 1015 1020 Asp Pro Asp Glu Gly Pro Asn Ala Gln Ile Met Tyr Gln Ile Val Glu 1025 1030 1035 1040 Gly Asp Met Arg His Phe Phe Gln Leu Asp Leu Leu Asn Gly Asp Leu 1045 1050 1055 Arg Ala Met Val Glu Leu Asp Phe Glu Val Arg Arg Glu Tyr Val Leu 1060 1065 1070 Val Val Gln Ala Thr Ser Ala Pro Leu Val Ser Arg Ala Thr Val His 1075 1080 1085 Ile Leu Leu Val Asp Gln Asn Asp Asn Pro Pro Val Leu Pro Asp Phe 1090 1095 1100 Gln Ile Leu Phe Asn Asn Tyr Val Thr Asn Lys Ser Asn Ser Phe Pro 1105 1110 1115 1120 Thr Gly Val Ile Gly Cys Ile Pro Ala His Asp Pro Asp Val Ser Asp 1125 1130 1135 Ser Leu Asn Tyr Thr Phe Val Gln Gly Asn Glu Leu Arg Leu Leu Leu 1140 1145 1150 Leu Asp Pro Ala Thr Gly Glu Leu Gln Leu Ser Arg Asp Leu Asp Asn 1155 1160 1165 Asn Arg Pro Leu Glu Ala Leu Met Glu Val Ser Val Ser Asp Gly Ile 1170 1175 1180 His Ser Val Thr Ala Phe Cys Thr Leu Arg Val Thr Ile Ile Thr Asp 1185 1190 1195 1200 Asp Met Leu Thr Asn Ser Ile Thr Val Arg Leu Glu Asn Met Ser Gln 1205 1210 1215 Glu Lys Phe Leu Ser Pro Leu Leu Ala Leu Phe Val Glu Gly Val Ala 1220 1225 1230 Ala Val Leu Ser Thr Thr Lys Asp Asp Val Phe Val Phe Asn Val Gln 1235 1240 1245 Asn Asp Thr Asp Val Ser Ser Asn Ile Leu Asn Val Thr Phe Ser Ala 1250 1255 1260 Leu Leu Pro Gly Gly Val Arg Gly Gln Phe Phe Pro Ser Glu Asp Leu 1265 1270 1275 1280 Gln Glu Gln Ile Tyr Leu Asn Arg Thr Leu Leu Thr Thr Ile Ser Thr 1285 1290 1295 Gln Arg Val Leu Pro Phe Asp Asp Asn Ile Cys Leu Arg Glu Pro Cys 1300 1305 1310 Glu Asn Tyr Met Lys Cys Val Ser Val Leu Arg Phe Asp Ser Ser Ala 1315 1320 1325 Pro Phe Leu Ser Ser Thr Thr Val Leu Phe Arg Pro Ile His Pro Ile 1330 1335 1340 Asn Gly Leu Arg Cys Arg Cys Pro Pro Gly Phe Thr Gly Asp Tyr Cys 1345 1350 1355 1360 Glu Thr Glu Ile Asp Leu Cys Tyr Ser Asp Pro Cys Gly Ala Asn Gly 1365 1370 1375 Arg Cys Arg Ser Arg Glu Gly Gly Tyr Thr Cys Glu Cys Phe Glu Asp 1380 1385 1390 Phe Thr Gly Glu His Cys Glu Val Asp Ala Arg Ser Gly Arg Cys Ala 1395 1400 1405 Asn Gly Val Cys Lys Asn Gly Gly Thr Cys Val Asn Leu Leu Ile Gly 1410 1415 1420 Gly Phe His Cys Val Cys Pro Pro Gly Glu Tyr Glu Arg Pro Tyr Cys 1425 1430 1435 1440 Glu Val Thr Thr Arg Ser Phe Pro Pro Gln Ser Phe Val Thr Phe Arg 1445 1450 1455 Gly Leu Arg Gln Arg Phe His Phe Thr Ile Ser Leu Thr Phe Ala Thr 1460 1465 1470 Gln Glu Arg Asn Gly Leu Leu Leu Tyr Asn Gly Arg Phe Asn Glu Lys 1475 1480 1485 His Asp Phe Ile Ala Leu Glu Ile Val Asp Glu Gln Val Gln Leu Thr 1490 1495 1500 Phe Ser Ala Gly Glu Thr Thr Thr Thr Val Ala Pro Lys Val Pro Ser 1505 1510 1515 1520 Gly Val Ser Asp Gly Arg Trp His Ser Val Gln Val Gln Tyr Tyr Asn 1525 1530 1535 Lys Pro Asn Ile Gly His Leu Gly Leu Pro His Gly Pro Ser Gly Glu 1540 1545 1550 Lys Met Ala Val Val Thr Val Asp Asp Cys Asp Thr Thr Met Ala Val 1555 1560 1565 Arg Phe Gly Lys Asp Ile Gly Asn Tyr Ser Cys Ala Ala Gln Gly Thr 1570 1575 1580 Gln Thr Gly Ser Lys Lys Ser Leu Asp Leu Thr Gly Pro Leu Leu Leu 1585 1590 1595 1600 Gly Gly Val Pro Asn Leu Pro Glu Asp Phe Pro Val His Asn Arg Gln 1605 1610 1615 Phe Val Gly Cys Met Arg Asn Leu Ser Val Asp Gly Lys Asn Val Asp 1620 1625 1630 Met Ala Gly Phe Ile Ala Asn Asn Gly Thr Arg Glu Gly Cys Ala Ala 1635 1640 1645 Arg Arg Asn Phe Cys Asp Gly Arg Arg Cys Gln Asn Gly Gly Thr Cys 1650 1655 1660 Val Asn Arg Trp Asn Met Tyr Leu Cys Glu Cys Pro Leu Arg Phe Gly 1665 1670 1675 1680 Gly Lys Asn Cys Glu Gln Ala Met Pro His Pro Gln Leu Phe Ser Gly 1685 1690 1695 Glu Ser Val Val Ser Trp Ser Asp Leu Asn Ile Ile Ser Val Pro 1700 1705 1710 Trp Tyr Leu Gly Leu Met Phe Arg Thr Arg Lys Glu Asp Ser Val Leu 1715 1720 1725 Met Glu Ala Thr Ser Gly Gly Pro Thr Ser Phe Arg Leu Gln Ile Leu 1730 1735 1740 Asn Asn Tyr Leu Gln Phe Glu Val Ser His Gly Pro Ser Asp Val Glu 1745 1750 1755 1760 Ser Val Met Leu Ser Gly Leu Arg Val Thr Asp Gly Glu Trp His His 1765 1770 1775 Leu Leu Ile Glu Leu Lys Asn Val Lys Glu Asp Ser Glu Met Lys His 1780 1785 1790 Leu Val Thr Met Thr Leu Asp Tyr Gly Met Asp Gln Asn Lys Ala Asp 1795 1800 1805 Ile Gly Gly Met Leu Pro Gly Leu Thr Val Arg Ser Val Val Val Gly 1810 1815 1820 Gly Ala Ser Glu Asp Lys Val Ser Val Arg Arg Gly Phe Arg Gly Cys 1825 1830 1835 1840 Met Gln Gly Val Arg Met Gly Gly Thr Pro Thr Asn Val Ala Thr Leu 1845 1850 1855 Asn Met Asn Asn Ala Leu Lys Val Arg Val Lys Asp Gly Cys Asp Val 1860 1865 1870 Asp Asp Pro Cys Thr Ser Ser Pro Cys Pro Pro Asn Ser Arg Cys His 1875 1880 1885 Asp Ala Trp Glu Asp Tyr Ser Cys Val Cys Asp Lys Gly Tyr Leu Gly 1890 1895 1900 Ile Asn Cys Val Asp Ala Cys His Leu Asn Pro Cys Glu Asn Met Gly 1905 1910 1915 1920 Ala Cys Val Arg Ser Pro Gly Ser Pro Gln Gly Tyr Val Cys Glu Cys 1925 1930 1935 Gly Pro Ser His Tyr Gly Pro Tyr Cys Glu Asn Lys Leu Asp Leu Pro 1940 1945 1950 Cys Pro Arg Gly Trp Trp Gly Asn Pro Val Cys Gly Pro Cys His Cys 1955 1960 1965 Ala Val Ser Lys Gly Phe Asp Pro Asp Cys Asn Lys Thr Asn Gly Gln 1970 1975 1980 Cys Gln Cys Lys Glu Asn Tyr Tyr Lys Leu Leu Ala Gln Asp Thr Cys 1985 1990 1995 2000 Leu Pro Cys Asp Cys Phe Pro His Gly Ser His Ser Arg Thr Cys Asp 2005 2010 2015 Met Ala Thr Gly Gln Cys Ala Cys Lys Pro Gly Val Ile Gly Arg Gln 2020 2025 2030 Cys Asn Arg Cys Asp Asn Pro Phe Ala Glu Val Thr Thr Leu Gly Cys 2035 2040 2045 Glu Val Ile Tyr Asn Gly Cys Pro Lys Ala Phe Glu Ala Gly Ile Trp 2050 2055 2060 Trp Pro Gln Thr Lys Phe Gly Gln Pro Ala Ala Val Pro Cys Pro Lys 2065 2070 2075 2080 Gly Ser Val Gly Asn Ala Val Arg His Cys Ser Gly Glu Lys Gly Trp 2085 2090 2095 Leu Pro Pro Glu Leu Phe Asn Cys Thr Thr Ile Ser Phe Val Asp Leu 2100 2105 2110 Arg Ala Met Asn Glu Lys Leu Ser Arg Asn Glu Thr Gln Val Asp Gly 2115 2120 2125 Ala Arg Ala Leu Gln Leu Val Arg Ala Leu Arg Ser Ala Thr Gln His 2130 2135 2140 Thr Gly Thr Leu Phe Gly Asn Asp Val Arg Thr Ala Tyr Gln Leu Leu 2145 2150 2155 2160 Gly His Val Leu Gln His Glu Ser Trp Gln Gln Gly Phe Asp Leu Ala 2165 2170 2175 Ala Thr Gln Asp Ala Asp Phe His Glu Asp Val Ile His Ser Gly Ser 2180 2185 2190 Ala Leu Leu Ala Pro Ala Thr Arg Ala Ala Trp Glu Gln Ile Gln Arg 2195 2200 2205 Ser Glu Gly Gly Thr Ala Gln Leu Leu Arg Arg Leu Glu Gly Tyr Phe 2210 2215 2220 Ser Asn Val Ala Arg Asn Val Arg Arg Thr Tyr Leu Arg Pro Phe Val 2225 2230 2235 2240 Ile Val Thr Ala Asn Met Ile Leu Ala Val Asp Ile Phe Asp Lys Phe 2245 2250 2255 Asn Phe Thr Gly Ala Arg Val Pro Arg Phe Asp Thr Ile His Glu Glu 2260 2265 2270 Phe Pro Arg Glu Leu Glu Ser Ser Val Ser Phe Pro Ala Asp Phe Phe 2275 2280 2285 Arg Pro Pro Glu Glu Lys Glu Gly Pro Leu Leu Arg Pro Ala Gly Arg 2290 2295 2300 Arg Thr Thr Pro Gln Thr Thr Arg Pro Gly Pro Gly Thr Glu Arg Glu 2305 2310 2315 2320 Ala Pro Ile Ser Arg Arg Arg Arg His Pro Asp Asp Ala Gly Gln Phe 2325 2330 2335 Ala Val Ala Leu Val Ile Ile Tyr Arg Thr Leu Gly Gln Leu Leu Pro 2340 2345 2350 Glu Arg Tyr Asp Pro Asp Arg Arg Ser Leu Arg Leu Pro His Arg Pro 2355 2360 2365 Ile Ile Asn Thr Pro Met Val Ser Thr Leu Val Tyr Ser Glu Gly Ala 2370 2375 2380 Pro Leu Pro Arg Pro Leu Glu Arg Pro Val Leu Val Glu Phe Ala Leu 2385 2390 2395 2400 Leu Glu Val Glu Glu Arg Thr Lys Pro Val Cys Val Phe Trp Asn His 2405 2410 2415 Ser Leu Ala Val Gly Gly Thr Gly Gly Trp Ser Ala Arg Gly Cys Glu 2420 2425 2430 Leu Leu Ser Arg Asn Arg Thr His Val Ala Cys Gln Cys Ser His Thr 2435 2440 2445 Ala Ser Phe Ala Val Leu Met Asp Ile Ser Arg Arg Glu Asn Gly Glu 2450 2455 2460 Val Leu Pro Leu Lys Ile Val Thr Tyr Ala Ala Val Ser Leu Ser Leu 2465 2470 2475 2480 Ala Ala Leu Leu Val Ala Phe Val Leu Leu Ser Leu Val Arg Met Leu 2485 2490 2495 Arg Ser Asn Leu His Ser Ile His Lys His Leu Ala Val Ala Leu Phe 2500 2505 2510 Leu Ser Gln Leu Val Phe Val Ile Gly Ile Asn Gln Thr Glu Asn Pro 2515 2520 2525 Phe Leu Cys Thr Val Val Ala Ile Leu Leu His Tyr Ile Tyr Met Ser 2530 2535 2540 Thr Phe Ala Trp Thr Leu Val Glu Ser Leu His Val Tyr Arg Met Leu 2545 2550 2555 2560 Thr Glu Val Arg Asn Ile Asp Thr Gly Pro Met Arg Phe Tyr Tyr Val 2565 2570 2575 Val Gly Trp Gly Ile Pro Ala Ile Val Thr Gly Leu Ala Val Gly Leu 2580 2585 2590 Asp Pro Gln Gly Tyr Gly Asn Pro Asp Phe Cys Trp Leu Ser Leu Gln 2595 2600 2605 Asp Thr Leu Ile Trp Ser Phe Ala Gly Pro Ile Gly Ala Val Ile Ile 2610 2615 2620 Ile Asn Thr Val Thr Ser Val Leu Ser Ala Lys Val Ser Cys Gln Arg 2625 2630 2635 2640 Lys His His Tyr Tyr Gly Lys Lys Gly Ile Val Ser Leu Leu Arg Thr 2645 2650 2655 Ala Phe Leu Leu Leu Leu Leu Ile Ser Ala Thr Trp Leu Leu Gly Leu 2660 2665 2670 Leu Ala Val Asn Arg Asp Ala Leu Ser Phe His Tyr Leu Phe Ala Ile 2675 2680 2685 Phe Ser Gly Leu Gln Gly Pro Phe Val Leu Leu Phe His Cys Val Leu 2690 2695 2700 Asn Gln Glu Val Arg Lys His Leu Lys Gly Val Leu Gly Gly Arg Lys 2705 2710 2715 2720 Leu His Leu Glu Asp Ser Ala Thr Thr Arg Ala Thr Leu Leu Thr Arg 2725 2730 2735 Ser Leu Asn Cys Asn Thr Phe Gly Asp Gly Pro Asp Met Leu Arg 2740 2745 2750 Thr Asp Leu Gly Glu Ser Thr Ala Ser Leu Asp Ser Ile Val Arg Asp 2755 2760 2765 Glu Gly Ile Gln Lys Leu Gly Val Ser Ser Gly Leu Val Arg Gly Ser 2770 2775 2780 His Gly Glu Pro Asp Ala Ser Leu Met Pro Arg Ser Cys Lys Asp Pro 2785 2790 2795 2800 Pro Gly His Asp Ser Asp Ser Asp Ser Glu Leu Ser Leu Asp Glu Gln 2805 2810 2815 Ser Ser Ser Tyr Ala Ser Ser His Ser Ser Asp Ser Glu Asp Asp Gly 2820 2825 2830 Val Gly Ala Glu Glu Lys Trp Asp Pro Ala Arg Gly Ala Val His Ser 2835 2840 2845 Thr Pro Lys Gly Asp Ala Val Ala Asn His Val Pro Ala Gly Trp Pro 2850 2855 2860 Asp Gln Ser Leu Ala Glu Ser Asp Ser Glu Asp Pro Ser Gly Lys Pro 2865 2870 2875 2880 Arg Leu Lys Val Glu Thr Lys Val Ser Val Glu Leu His Arg Glu Glu 2885 2890 2895 Gln Gly Ser His Arg Gly Glu Tyr Pro Pro Asp Gln Glu Ser Gly Gly 2900 2905 2910 Ala Ala Arg Leu Ala Ser Ser Gln Pro Pro Glu Gln Arg Lys Gly Ile 2915 2920 2925 Leu Lys Asn Lys Val Thr Tyr Pro Pro Pro Leu Thr Leu Thr Glu Gln 2930 2935 2940 Thr Leu Lys Gly Arg Leu Arg Glu Lys Leu Ala Asp Cys Glu Gln Ser 2945 2950 2955 2960 Pro Thr Ser Ser Arg Thr Ser Ser Leu Gly Ser Gly Gly Pro Asp Cys 2965 2970 2975 Ala Ile Thr Val Lys Ser Pro Gly Arg Glu Pro Gly Arg Asp His Leu 2980 2985 2990 Asn Gly Val Ala Met Asn Val Arg Thr Gly Ser Ala Gln Ala Asp Gly 2995 3000 3005Ser Asp Ser Glu Lys Pro 3010 <210> 8 <211> 532 <212> PRT <213> homo sapiens <400> 8 Met Asn Gly Val Leu Ile Pro His Thr Pro Ile Ala Val Asp Phe Trp 1 5 10 15 Ser Leu Arg Arg Ala Gly Thr Ala Arg Leu Phe Phe Leu Ser His Met 20 25 30 His Ser Asp His Thr Val Gly Leu Ser Ser Thr Trp Ala Arg Pro Leu 35 40 45 Tyr Cys Ser Pro Ile Thr Ala His Leu Leu His Arg His Leu Gln Val 50 55 60 Ser Lys Gln Trp Ile Gln Ala Leu Glu Val Gly Glu Ser His Val Leu 65 70 75 80 Pro Leu Asp Glu Ile Gly Gln Glu Thr Met Thr Val Thr Leu Leu Asp 85 90 95 Ala Asn His Cys Pro Gly Ser Val Met Phe Leu Phe Glu Gly Tyr Phe 100 105 110 Gly Thr Ile Leu Tyr Thr Gly Asp Phe Arg Tyr Thr Pro Ser Met Leu 115 120 125 Lys Glu Pro Ala Leu Thr Leu Gly Lys Gln Ile His Thr Leu Tyr Leu 130 135 140 Asp Asn Thr Asn Cys Asn Pro Ala Leu Val Leu Pro Ser Arg Gln Glu 145 150 155 160 Ala Ala His Gln Ile Val Gln Leu Ile Arg Lys His Pro Gln His Asn 165 170 175 Ile Lys Ile Gly Leu Tyr Ser Leu Gly Lys Glu Ser Leu Leu Glu Gln 180 185 190 Leu Ala Leu Glu Phe Gln Thr Trp Val Val Leu Ser Pro Arg Arg Leu 195 200 205 Glu Leu Val Gln Leu Leu Gly Leu Ala Asp Val Phe Thr Val Glu Glu 210 215 220 Lys Ala Gly Arg Ile His Ala Val Asp His Met Glu Ile Cys His Ser 225 230 235 240 Asn Met Leu Arg Trp Asn Gln Thr His Pro Thr Ile Ala Ile Leu Pro 245 250 255 Thr Ser Arg Lys Ile His Ser Ser His Pro Asp Ile His Val Ile Pro 260 265 270 Tyr Ser Asp His Ser Ser Tyr Ser Glu Leu Arg Ala Phe Val Ala Ala 275 280 285 Leu Lys Pro Cys Gln Val Val Pro Ile Val Ser Arg Arg Pro Cys Gly 290 295 300 Gly Phe Gln Asp Ser Leu Ser Pro Arg Ile Ser Val Pro Leu Ile Pro 305 310 315 320 Asp Ser Val Gln Gln Tyr Met Ser Ser Ser Ser Arg Lys Pro Ser Leu 325 330 335 Leu Trp Leu Leu Glu Arg Arg Leu Lys Arg Pro Arg Thr Gln Gly Val 340 345 350 Val Phe Glu Ser Pro Glu Glu Ser Ala Asp Gln Ser Gln Ala Asp Arg 355 360 365 Asp Ser Lys Lys Ala Lys Lys Glu Lys Leu Ser Pro Trp Pro Ala Asp 370 375 380 Leu Glu Lys Gln Pro Ser His His Pro Leu Arg Ile Lys Lys Gln Leu 385 390 395 400 Phe Pro Asp Leu Tyr Ser Lys Glu Trp Asn Lys Ala Val Pro Phe Cys 405 410 415 Glu Ser Gln Lys Arg Val Thr Met Leu Thr Ala Pro Leu Gly Phe Ser 420 425 430 Val His Leu Arg Ser Thr Asp Glu Glu Phe Ile Ser Gln Lys Thr Arg 435 440 445 Glu Glu Ile Gly Leu Gly Ser Pro Leu Val Pro Met Gly Asp Asp Asp 450 455 460 Gly Gly Pro Glu Ala Thr Gly Asn Gln Ser Ala Trp Met Gly His Gly 465 470 475 480 Ser Pro Leu Ser His Ser Ser Lys Gly Thr Pro Leu Leu Ala Thr Glu 485 490 495 Phe Arg Gly Leu Ala Leu Lys Tyr Leu Leu Thr Pro Val Asn Phe Phe 500 505 510 Gln Ala Gly Tyr Ser Ser Arg Arg Phe Asp Gln Gln Val Glu Lys Tyr 515 520 525 His Lys Pro Cys 530 <210> 9 <211> 1051 <212> PRT <213> homo sapiens <400> 9 Met Gly Pro Gly Pro Ser Arg Ala Pro Arg Ala Pro Arg Leu Met Leu 1 5 10 15 Cys Ala Leu Ala Leu Met Val Ala Ala Gly Gly Cys Val Val Ser Ala 20 25 30 Phe Asn Leu Asp Thr Arg Phe Leu Val Val Lys Glu Ala Gly Asn Pro 35 40 45 Gly Ser Leu Phe Gly Tyr Ser Val Ala Leu His Arg Gln Thr Glu Arg 50 55 60 Gln Gln Arg Tyr Leu Leu Leu Ala Gly Ala Pro Arg Glu Leu Ala Val 65 70 75 80 Pro Asp Gly Tyr Thr Asn Arg Thr Gly Ala Val Tyr Leu Cys Pro Leu 85 90 95 Thr Ala His Lys Asp Asp Cys Glu Arg Met Asn Ile Thr Val Lys Asn 100 105 110 Asp Pro Gly His His Ile Ile Glu Asp Met Trp Leu Gly Val Thr Val 115 120 125 Ala Ser Gln Gly Pro Ala Gly Arg Val Leu Val Cys Ala His Arg Tyr 130 135 140 Thr Gln Val Leu Trp Ser Gly Ser Glu Asp Gln Arg Arg Met Val Gly 145 150 155 160 Lys Cys Tyr Val Arg Gly Asn Asp Leu Glu Leu Asp Ser Ser Asp Asp 165 170 175 Trp Gln Thr Tyr His Asn Glu Met Cys Asn Ser Asn Thr Asp Tyr Leu 180 185 190 Glu Thr Gly Met Cys Gln Leu Gly Thr Ser Gly Gly Phe Thr Gln Asn 195 200 205 Thr Val Tyr Phe Gly Ala Pro Gly Ala Tyr Asn Trp Lys Gly Asn Ser 210 215 220 Tyr Met Ile Gln Arg Lys Glu Trp Asp Leu Ser Glu Tyr Ser Tyr Lys 225 230 235 240 Asp Pro Glu Asp Gln Gly Asn Leu Tyr Ile Gly Tyr Thr Met Gln Val 245 250 255 Gly Ser Phe Ile Leu His Pro Lys Asn Ile Thr Ile Val Thr Gly Ala 260 265 270 Pro Arg His Arg His Met Gly Ala Val Phe Leu Leu Ser Gln Glu Ala 275 280 285 Gly Gly Asp Leu Arg Arg Arg Gln Val Leu Glu Gly Ser Gln Val Gly 290 295 300 Ala Tyr Phe Gly Ser Ala Ile Ala Leu Ala Asp Leu Asn Asn Asp Gly 305 310 315 320 Trp Gln Asp Leu Leu Val Gly Ala Pro Tyr Tyr Phe Glu Arg Lys Glu 325 330 335 Glu Val Gly Gly Ala Ile Tyr Val Phe Met Asn Gln Ala Gly Thr Ser 340 345 350 Phe Pro Ala His Pro Ser Leu Leu Leu His Gly Pro Ser Gly Ser Ala 355 360 365 Phe Gly Leu Ser Val Ala Ser Ile Gly Asp Ile Asn Gln Asp Gly Phe 370 375 380 Gln Asp Ile Ala Val Gly Ala Pro Phe Glu Gly Leu Gly Lys Val Tyr 385 390 395 400 Ile Tyr His Ser Ser Ser Lys Gly Leu Leu Arg Gln Pro Gln Gln Val 405 410 415 Ile His Gly Glu Lys Leu Gly Leu Pro Gly Leu Ala Thr Phe Gly Tyr 420 425 430 Ser Leu Ser Gly Gln Met Asp Val Asp Glu Asn Phe Tyr Pro Asp Leu 435 440 445 Leu Val Gly Ser Leu Ser Asp His Ile Val Leu Leu Arg Ala Arg Pro 450 455 460 Val Ile Asn Ile Val His Lys Thr Leu Val Pro Arg Pro Ala Val Leu 465 470 475 480 Asp Pro Ala Leu Cys Thr Ala Thr Ser Cys Val Gln Val Glu Leu Cys 485 490 495 Phe Ala Tyr Asn Gln Ser Ala Gly Asn Pro Asn Tyr Arg Arg Asn Ile 500 505 510 Thr Leu Ala Tyr Thr Leu Glu Ala Asp Arg Asp Arg Arg Pro Pro Arg 515 520 525 Phe Arg Phe Ala Gly Ser Glu Ser Ala Val Phe His Gly Phe Phe Ser 530 535 540 Met Pro Glu Met Arg Cys Gln Lys Leu Glu Leu Leu Leu Met Asp Asn 545 550 555 560 Leu Arg Asp Lys Leu Arg Pro Ile Ile Ile Ser Met Asn Tyr Ser Leu 565 570 575 Pro Leu Arg Met Pro Asp Arg Pro Arg Leu Gly Leu Arg Ser Leu Asp 580 585 590 Ala Tyr Pro Ile Leu Asn Gln Ala Gln Ala Leu Glu Asn His Thr Glu 595 600 605 Val Gln Phe Gln Lys Glu Cys Gly Pro Asp Asn Lys Cys Glu Ser Asn 610 615 620 Leu Gln Met Arg Ala Ala Phe Val Ser Glu Gln Gln Gln Lys Leu Ser 625 630 635 640 Arg Leu Gln Tyr Ser Arg Asp Val Arg Lys Leu Leu Leu Ser Ile Asn 645 650 655 Val Thr Asn Thr Arg Thr Ser Glu Arg Ser Gly Glu Asp Ala His Glu 660 665 670 Ala Leu Leu Thr Leu Val Val Pro Pro Ala Leu Leu Leu Ser Ser Val 675 680 685 Arg Pro Pro Gly Ala Cys Gln Ala Asn Glu Thr Ile Phe Cys Glu Leu 690 695 700 Gly Asn Pro Phe Lys Arg Asn Gln Arg Met Glu Leu Leu Ile Ala Phe 705 710 715 720 Glu Val Ile Gly Val Thr Leu His Thr Arg Asp Leu Gln Val Gln Leu 725 730 735 Gln Leu Ser Thr Ser Ser His Gln Asp Asn Leu Trp Pro Met Ile Leu 740 745 750 Thr Leu Leu Val Asp Tyr Thr Leu Gln Thr Ser Leu Ser Met Val Asn 755 760 765 His Arg Leu Gln Ser Phe Phe Gly Gly Thr Val Met Gly Glu Ser Gly 770 775 780 Met Lys Thr Val Glu Asp Val Gly Ser Pro Leu Lys Tyr Glu Phe Gln 785 790 795 800 Val Gly Pro Met Gly Glu Gly Leu Val Gly Leu Gly Thr Leu Val Leu 805 810 815 Gly Leu Glu Trp Pro Tyr Glu Val Ser Asn Gly Lys Trp Leu Leu Tyr 820 825 830 Pro Thr Glu Ile Thr Val His Gly Asn Gly Ser Trp Pro Cys Arg Pro 835 840 845 Pro Gly Asp Leu Ile Asn Pro Leu Asn Leu Thr Leu Ser Asp Pro Gly 850 855 860 Asp Arg Pro Ser Ser Pro Gln Arg Arg Arg Arg Gln Leu Asp Pro Gly 865 870 875 880 Gly Gly Gln Gly Pro Pro Pro Val Thr Leu Ala Ala Ala Lys Lys Ala 885 890 895 Lys Ser Glu Thr Val Leu Thr Cys Ala Thr Gly Arg Ala His Cys Val 900 905 910 Trp Leu Glu Cys Pro Ile Pro Asp Ala Pro Val Val Thr Asn Val Thr 915 920 925 Val Lys Ala Arg Val Trp Asn Ser Thr Phe Ile Glu Asp Tyr Arg Asp 930 935 940 Phe Asp Arg Val Arg Val Asn Gly Trp Ala Thr Leu Phe Leu Arg Thr 945 950 955 960 Ser Ile Pro Thr Ile Asn Met Glu Asn Lys Thr Thr Trp Phe Ser Val 965 970 975 Asp Ile Asp Ser Glu Leu Val Glu Glu Leu Pro Ala Glu Ile Glu Leu 980 985 990 Trp Leu Val Leu Val Ala Val Gly Ala Gly Leu Leu Leu Leu Gly Leu 995 1000 1005 Ile Ile Leu Leu Leu Trp Lys Cys Gly Phe Phe Lys Arg Ala Arg Thr 1010 1015 1020 Arg Ala Leu Tyr Glu Ala Lys Arg Gln Lys Ala Glu Met Lys Ser Gln 1025 1030 1035 1040 Pro Ser Glu Thr Glu Arg Leu Thr Asp Asp Tyr 1045 1050 <210> 10 <211> 866 <212> PRT <213> homo sapiens <400> 10 Met Gln Arg Glu Leu Val Tyr Ala Arg Gly Asp Gly Pro Gly Ala Pro 1 5 10 15 Arg Pro Gly Ser Thr Ala His Pro Pro His Ala Ile Pro Asn Ser Pro 20 25 30 Pro Ser Thr Pro Val Pro His Ser Met Pro Pro Ser Pro Ser Arg Ile 35 40 45 Pro Tyr Gly Gly Thr Arg Ser Met Val Val Pro Gly Asn Ala Thr Ile 50 55 60 Pro Arg Asp Arg Ile Ser Ser Leu Pro Val Ser Arg Pro Ile Ser Pro 65 70 75 80 Ser Pro Ser Ala Ile Leu Glu Arg Arg Asp Val Lys Pro Asp Glu Asp 85 90 95 Met Ser Gly Lys Asn Ile Ala Met Tyr Arg Asn Glu Gly Phe Tyr Ala 100 105 110 Asp Pro Tyr Leu Tyr His Glu Gly Arg Met Ser Ile Ala Ser Ser His 115 120 125 Gly Gly His Pro Leu Asp Val Pro Asp His Ile Ile Ala Tyr His Arg 130 135 140 Thr Ala Ile Arg Ser Ala Ser Ala Tyr Cys Asn Pro Ser Met Gln Ala 145 150 155 160 Glu Met His Met Glu Gln Ser Leu Tyr Arg Gln Lys Ser Arg Lys Tyr 165 170 175 Pro Asp Ser His Leu Pro Thr Leu Gly Ser Lys Thr Pro Pro Ala Ser 180 185 190 Pro His Arg Val Ser Asp Leu Arg Met Ile Asp Met His Ala His Tyr 195 200 205 Asn Ala His Gly Pro Pro His Thr Met Gln Pro Asp Arg Ala Ser Pro 210 215 220 Ser Arg Gln Ala Phe Lys Lys Glu Pro Gly Thr Leu Val Tyr Ile Glu 225 230 235 240 Lys Pro Arg Ser Ala Ala Gly Leu Ser Ser Leu Val Asp Leu Gly Pro 245 250 255 Pro Leu Met Glu Lys Gln Val Phe Ala Tyr Ser Thr Ala Thr Ile Pro 260 265 270 Lys Asp Arg Glu Thr Ser Glu Lys Met Met Lys Thr Thr Ala Asn Arg 275 280 285 Asn His Thr Asp Ser Ala Gly Thr Pro His Val Ser Gly Gly Lys Met 290 295 300 Leu Ser Ala Leu Glu Ser Thr Val Pro Pro Ser Gln Pro Pro Pro Val 305 310 315 320 Gly Thr Ser Ala Ile His Met Ser Leu Leu Glu Met Arg Arg Ser Val 325 330 335 Ala Glu Leu Arg Leu Gln Leu Gln Gln Met Arg Gln Leu Gln Leu Gln 340 345 350 Asn Gln Glu Leu Leu Arg Ala Met Met Lys Lys Ala Glu Leu Glu Ile 355 360 365 Ser Gly Lys Val Met Glu Thr Met Lys Arg Leu Glu Asp Pro Val Gln 370 375 380 Arg Gln Arg Val Leu Val Glu Gln Glu Arg Gln Lys Tyr Leu His Glu 385 390 395 400 Glu Glu Lys Ile Val Lys Lys Leu Cys Glu Leu Glu Asp Phe Val Glu 405 410 415 Asp Leu Lys Lys Asp Ser Thr Ala Ala Ser Arg Leu Val Thr Leu Lys 420 425 430 Asp Val Glu Asp Gly Ala Phe Leu Leu Arg Gln Val Gly Glu Ala Val 435 440 445 Ala Thr Leu Lys Gly Glu Phe Pro Thr Leu Gln Asn Lys Met Arg Ala 450 455 460 Ile Leu Arg Ile Glu Val Glu Ala Val Arg Phe Leu Lys Glu Glu Pro 465 470 475 480 His Lys Leu Asp Ser Leu Leu Lys Arg Val Arg Ser Met Thr Asp Val 485 490 495 Leu Thr Met Leu Arg Arg His Val Thr Asp Gly Leu Leu Lys Gly Thr 500 505 510 Asp Ala Ala Gln Ala Ala Gln Tyr Met Ala Met Glu Lys Ala Thr Ala 515 520 525 Ala Glu Val Leu Lys Ser Gln Glu Glu Ala Ala His Thr Ser Gly Gln 530 535 540 Pro Phe His Ser Thr Gly Ala Pro Gly Asp Ala Lys Ser Glu Val Val 545 550 555 560 Pro Leu Ser Gly Met Met Val Arg His Ala Gln Ser Ser Pro Val Val 565 570 575 Ile Gln Pro Ser Gln His Ser Val Ala Leu Leu Asn Pro Ala Gln Asn 580 585 590 Leu Pro His Val Ala Ser Ser Pro Ala Val Pro Gln Glu Ala Thr Ser 595 600 605 Thr Leu Gln Met Ser Gln Ala Pro Gln Ser Pro Gln Ile Pro Met Asn 610 615 620 Gly Ser Ala Met Gln Ser Leu Phe Ile Glu Glu Ile His Ser Val Ser 625 630 635 640 Ala Lys Asn Arg Ala Val Ser Ile Glu Lys Ala Glu Lys Lys Trp Glu 645 650 655 Glu Lys Arg Gln Asn Leu Asp His Tyr Asn Gly Lys Glu Phe Glu Lys 660 665 670 Leu Leu Glu Glu Ala Gln Ala Asn Ile Met Lys Ser Ile Pro Asn Leu 675 680 685 Glu Met Pro Pro Ala Thr Gly Pro Leu Pro Arg Gly Asp Ala Pro Val 690 695 700 Asp Lys Val Glu Leu Ser Glu Asp Ser Pro Asn Ser Glu Gln Asp Leu 705 710 715 720 Glu Lys Leu Gly Gly Lys Ser Pro Pro Pro Pro Pro Pro Pro Pro Arg 725 730 735 Arg Ser Tyr Leu Pro Gly Ser Gly Leu Thr Thr Thr Arg Ser Gly Asp 740 745 750 Val Val Tyr Thr Gly Arg Lys Glu Asn Ile Thr Ala Lys Ala Ser Ser 755 760 765 Glu Asp Ala Gly Pro Ser Pro Gln Thr Arg Ala Thr Lys Tyr Pro Ala 770 775 780 Glu Glu Pro Ala Ser Ala Trp Thr Pro Ser Pro Pro Pro Val Thr Thr 785 790 795 800 Ser Ser Ser Lys Asp Glu Glu Glu Glu Glu Glu Glu Gly Asp Lys Ile 805 810 815 Met Ala Glu Leu Gln Gly Ser Ser Gly Ala Pro Gln Thr Ser Arg Met 820 825 830 Pro Val Pro Met Ser Ala Lys Asn Arg Pro Gly Thr Leu Asp Lys Pro 835 840 845 Gly Lys Gln Ser Lys Leu Gln Asp Pro Arg Gln Tyr Arg Gln Val Val 850 855 860 Leu Pro 865 <210> 11 <211> 520 <212> PRT <213> homo sapiens <400> 11 Met Ala Thr Thr Ser Thr Thr Gly Ser Thr Leu Leu Gln Pro Leu Ser 1 5 10 15 Asn Ala Val Gln Leu Pro Ile Asp Gln Val Asn Phe Val Val Cys Gln 20 25 30 Leu Phe Ala Leu Leu Ala Ala Ile Trp Phe Arg Thr Tyr Leu His Ser 35 40 45 Ser Lys Thr Ser Ser Phe Ile Arg His Val Val Ala Thr Leu Leu Gly 50 55 60 Leu Tyr Leu Ala Leu Phe Cys Phe Gly Trp Tyr Ala Leu His Phe Leu 65 70 75 80 Val Gln Ser Gly Ile Ser Tyr Cys Ile Met Ile Ile Ile Gly Val Glu 85 90 95 Asn Met His Asn Tyr Cys Phe Val Phe Ala Leu Gly Tyr Leu Thr Val 100 105 110 Cys Gln Val Thr Arg Val Tyr Ile Phe Asp Tyr Gly Gln Tyr Ser Ala 115 120 125 Asp Phe Ser Gly Pro Met Met Ile Ile Thr Gln Lys Ile Thr Ser Leu 130 135 140 Ala Cys Glu Ile His Asp Gly Met Phe Arg Lys Asp Glu Glu Leu Thr 145 150 155 160 Ser Ser Gln Arg Asp Leu Ala Val Arg Arg Met Pro Ser Leu Leu Glu 165 170 175 Tyr Leu Ser Tyr Asn Cys Asn Phe Met Gly Ile Leu Ala Gly Pro Leu 180 185 190 Cys Ser Tyr Lys Asp Tyr Ile Thr Phe Ile Glu Gly Arg Ser Tyr His 195 200 205 Ile Thr Gln Ser Gly Glu Asn Gly Lys Glu Glu Thr Gln Tyr Glu Arg 210 215 220 Thr Glu Pro Ser Pro Asn Thr Ala Val Val Gln Lys Leu Leu Val Cys 225 230 235 240 Gly Leu Ser Leu Leu Phe His Leu Thr Ile Cys Thr Thr Leu Pro Val 245 250 255 Glu Tyr Asn Ile Asp Glu His Phe Gln Ala Thr Ala Ser Trp Pro Thr 260 265 270 Lys Ile Ile Tyr Leu Tyr Ile Ser Leu Leu Ala Ala Arg Pro Lys Tyr 275 280 285 Tyr Phe Ala Trp Thr Leu Ala Asp Ala Ile Asn Asn Ala Ala Gly Phe 290 295 300 Gly Phe Arg Gly Tyr Asp Glu Asn Gly Ala Ala Arg Trp Asp Leu Ile 305 310 315 320 Ser Asn Leu Arg Ile Gln Gln Ile Glu Met Ser Thr Ser Phe Lys Met 325 330 335 Phe Leu Asp Asn Trp Asn Ile Gln Thr Ala Leu Trp Leu Lys Arg Val 340 345 350 Cys Tyr Glu Arg Thr Ser Phe Ser Pro Thr Ile Gln Thr Phe Ile Leu 355 360 365 Ser Ala Ile Trp His Gly Val Tyr Pro Gly Tyr Tyr Leu Thr Phe Leu 370 375 380 Thr Gly Val Leu Met Thr Leu Ala Ala Arg Ala Met Arg Asn Asn Phe 385 390 395 400 Arg His Tyr Phe Ile Glu Pro Ser Gln Leu Lys Leu Phe Tyr Asp Val 405 410 415 Ile Thr Trp Ile Val Thr Gln Val Ala Ile Ser Tyr Thr Val Val Pro 420 425 430 Phe Val Leu Leu Ser Ile Lys Pro Ser Leu Thr Phe Tyr Ser Ser Trp 435 440 445 Tyr Tyr Cys Leu His Ile Leu Gly Ile Leu Val Leu Leu Leu Leu Pro 450 455 460 Val Lys Lys Thr Gln Arg Arg Lys Asn Thr His Glu Asn Ile Gln Leu 465 470 475 480 Ser Gln Ser Lys Lys Phe Asp Glu Gly Glu Asn Ser Leu Gly Gln Asn 485 490 495 Ser Phe Ser Thr Thr Asn Asn Val Cys Asn Gln Asn Gln Glu Ile Ala 500 505 510 Ser Arg His Ser Ser Leu Lys Gln 515 520 <210> 12 <211> 421 <212> PRT <213> homo sapiens <400> 12 Met Ser Pro Lys Arg Ile Ala Lys Arg Arg Ser Pro Pro Ala Asp Ala 1 5 10 15 Ile Pro Lys Ser Lys Lys Val Lys Val Ser His Arg Ser His Ser Thr 20 25 30 Glu Pro Gly Leu Val Leu Thr Leu Gly Gln Gly Asp Val Gly Gln Leu 35 40 45 Gly Leu Gly Glu Asn Val Met Glu Arg Lys Lys Pro Ala Leu Val Ser 50 55 60 Ile Pro Glu Asp Val Val Gln Ala Glu Ala Gly Gly Met His Thr Val 65 70 75 80 Cys Leu Ser Lys Ser Gly Gln Val Tyr Ser Phe Gly Cys Asn Asp Glu 85 90 95 Gly Ala Leu Gly Arg Asp Thr Ser Val Glu Gly Ser Glu Met Val Pro 100 105 110 Gly Lys Val Glu Leu Gln Glu Lys Val Val Gln Val Ser Ala Gly Asp 115 120 125 Ser His Thr Ala Ala Leu Thr Asp Asp Gly Arg Val Phe Leu Trp Gly 130 135 140 Ser Phe Arg Asp Asn Asn Gly Val Ile Gly Leu Leu Glu Pro Met Lys 145 150 155 160 Lys Ser Met Val Pro Val Gln Val Gln Leu Asp Val Pro Val Val Lys 165 170 175 Val Ala Ser Gly Asn Asp His Leu Val Met Leu Thr Ala Asp Gly Asp 180 185 190 Leu Tyr Thr Leu Gly Cys Gly Glu Gln Gly Gln Leu Gly Arg Val Pro 195 200 205 Glu Leu Phe Ala Asn Arg Gly Gly Arg Gln Gly Leu Glu Arg Leu Leu 210 215 220 Val Pro Lys Cys Val Met Leu Lys Ser Arg Gly Ser Arg Gly His Val 225 230 235 240 Arg Phe Gln Asp Ala Phe Cys Gly Ala Tyr Phe Thr Phe Ala Ile Ser 245 250 255 His Glu Gly His Val Tyr Gly Phe Gly Leu Ser Asn Tyr His Gln Leu 260 265 270 Gly Thr Pro Gly Thr Glu Ser Cys Phe Ile Pro Gln Asn Leu Thr Ser 275 280 285 Phe Lys Asn Ser Thr Lys Ser Trp Val Gly Phe Ser Gly Gly Gln His 290 295 300 His Thr Val Cys Met Asp Ser Glu Gly Lys Ala Tyr Ser Leu Gly Arg 305 310 315 320 Ala Glu Tyr Gly Arg Leu Gly Leu Gly Glu Gly Ala Glu Glu Lys Ser 325 330 335 Ile Pro Thr Leu Ile Ser Arg Leu Pro Ala Val Ser Ser Val Ala Cys 340 345 350 Gly Ala Ser Val Gly Tyr Ala Val Thr Lys Asp Gly Arg Val Phe Ala 355 360 365 Trp Gly Met Gly Thr Asn Tyr Gln Leu Gly Thr Gly Gln Asp Glu Asp 370 375 380 Ala Trp Ser Pro Val Glu Met Met Gly Lys Gln Leu Glu Asn Arg Val 385 390 395 400 Val Leu Ser Val Ser Ser Gly Gly Gln His Thr Val Leu Leu Val Lys 405 410 415 Asp Lys Glu Gln Ser 420 <210> 13 <211> 2426 <212> PRT <213> homo sapiens <400> 13 Met Ala Thr Asn Ile Glu Gln Ile Phe Arg Ser Phe Val Val Ser Lys 1 5 10 15 Phe Arg Glu Ile Gln Gln Glu Leu Ser Ser Gly Arg Asn Glu Gly Gln 20 25 30 Leu Asn Gly Glu Thr Asn Thr Pro Ile Glu Gly Asn Gln Ala Gly Asp 35 40 45 Ala Ala Ala Ser Ala Arg Ser Leu Pro Asn Glu Glu Ile Val Gln Lys 50 55 60 Ile Glu Glu Val Leu Ser Gly Val Leu Asp Thr Glu Leu Arg Tyr Lys 65 70 75 80 Pro Asp Leu Lys Glu Gly Ser Arg Lys Ser Arg Cys Val Ser Val Gln 85 90 95 Thr Asp Pro Thr Asp Glu Ile Pro Thr Lys Lys Ser Lys Lys His Lys 100 105 110 Lys His Lys Asn Lys Lys Lys Lys Lys Lys Lys Glu Lys Glu Lys Lys 115 120 125 Tyr Lys Arg Gln Pro Glu Glu Ser Glu Ser Lys Thr Lys Ser His Asp 130 135 140 Asp Gly Asn Ile Asp Leu Glu Ser Asp Ser Phe Leu Lys Phe Asp Ser 145 150 155 160 Glu Pro Ser Ala Val Ala Leu Glu Leu Pro Thr Arg Ala Phe Gly Pro 165 170 175 Ser Glu Thr Asn Glu Ser Pro Ala Val Val Leu Glu Pro Pro Val Val 180 185 190 Ser Met Glu Val Ser Glu Pro His Ile Leu Glu Thr Leu Lys Pro Ala 195 200 205 Thr Lys Thr Ala Glu Leu Ser Val Val Ser Thr Ser Val Ile Ser Glu 210 215 220 Gln Ser Glu Gln Ser Val Ala Val Met Pro Glu Pro Ser Met Thr Lys 225 230 235 240 Ile Leu Asp Ser Phe Ala Ala Ala Pro Val Pro Thr Thr Thr Leu Val 245 250 255 Leu Lys Ser Ser Glu Pro Val Val Thr Met Ser Val Glu Tyr Gln Met 260 265 270 Lys Ser Val Leu Lys Ser Val Glu Ser Thr Ser Pro Glu Pro Ser Lys 275 280 285 Ile Met Leu Val Glu Pro Pro Val Ala Lys Val Leu Glu Pro Ser Glu 290 295 300 Thr Leu Val Val Ser Ser Glu Thr Pro Thr Glu Val Tyr Pro Glu Pro 305 310 315 320 Ser Thr Ser Thr Thr Met Asp Phe Pro Glu Ser Ser Ala Ile Glu Ala 325 330 335 Leu Arg Leu Pro Glu Gln Pro Val Asp Val Pro Ser Glu Ile Ala Asp 340 345 350 Ser Ser Met Thr Arg Pro Gln Glu Leu Pro Glu Leu Pro Lys Thr Thr 355 360 365 Ala Leu Glu Leu Gln Glu Ser Ser Val Ala Ser Ala Met Glu Leu Pro 370 375 380 Gly Pro Pro Ala Thr Ser Met Pro Glu Leu Gln Gly Pro Pro Val Thr 385 390 395 400 Pro Val Leu Glu Leu Pro Gly Pro Ser Ala Thr Pro Val Pro Glu Leu 405 410 415 Pro Gly Pro Leu Ser Thr Pro Val Pro Glu Leu Pro Gly Pro Pro Pro Ala 420 425 430 Thr Ala Val Pro Glu Leu Pro Gly Pro Ser Val Thr Pro Val Pro Gln 435 440 445 Leu Ser Gln Glu Leu Pro Gly Leu Pro Ala Pro Ser Met Gly Leu Glu 450 455 460 Pro Pro Gln Glu Val Pro Glu Pro Pro Pro Val Met Ala Gln Glu Leu Pro 465 470 475 480 Gly Leu Pro Leu Val Thr Ala Ala Val Glu Leu Pro Glu Gln Pro Ala 485 490 495 Val Thr Val Ala Met Glu Leu Thr Glu Gln Pro Val Thr Thr Thr Glu 500 505 510 Leu Glu Gln Pro Val Gly Met Thr Thr Val Glu His Pro Gly His Pro 515 520 525 Glu Val Thr Thr Ala Thr Gly Leu Leu Gly Gln Pro Glu Ala Thr Met 530 535 540 Val Leu Glu Leu Pro Gly Gln Pro Val Ala Thr Thr Ala Leu Glu Leu 545 550 555 560 Pro Gly Gln Pro Ser Val Thr Gly Val Pro Glu Leu Pro Gly Leu Pro 565 570 575 Ser Ala Thr Arg Ala Leu Glu Leu Ser Gly Gln Pro Val Ala Thr Gly 580 585 590 Ala Leu Glu Leu Pro Gly Pro Leu Met Ala Ala Gly Ala Leu Glu Phe 595 600 605 Ser Gly Gln Ser Gly Ala Ala Gly Ala Leu Glu Leu Leu Gly Gln Pro 610 615 620 Leu Ala Thr Gly Val Leu Glu Leu Pro Gly Gln Pro Gly Ala Pro Glu 625 630 635 640 Leu Pro Gly Gln Pro Val Ala Thr Val Ala Leu Glu Ile Ser Val Gln 645 650 655 Ser Val Val Thr Thr Ser Glu Leu Ser Thr Met Thr Val Ser Gln Ser 660 665 670 Leu Glu Val Pro Ser Thr Thr Ala Leu Glu Ser Tyr Asn Thr Val Ala 675 680 685 Gln Glu Leu Pro Thr Leu Val Gly Glu Thr Ser Val Thr Val Gly 690 695 700 Val Asp Pro Leu Met Ala Pro Glu Ser His Ile Leu Ala Ser Asn Thr 705 710 715 720 Met Glu Thr His Ile Leu Ala Ser Asn Thr Met Asp Ser Gln Met Leu 725 730 735 Ala Ser Asn Thr Met Asp Ser Gln Met Leu Ala Ser Asn Thr Met Asp 740 745 750 Ser Gln Met Leu Ala Ser Ser Thr Met Asp Ser Gln Met Leu Ala Thr 755 760 765 Ser Ser Met Asp Ser Gln Met Leu Ala Thr Ser Ser Met Asp Ser Gln 770 775 780 Met Leu Ala Thr Ser Thr Met Asp Ser Gln Met Leu Ala Thr Ser Ser 785 790 795 800 Met Asp Ser Gln Met Leu Ala Thr Ser Ser Met Asp Ser Gln Met Leu 805 810 815 Ala Thr Ser Ser Met Asp Ser Gln Met Leu Ala Thr Ser Ser Met Asp 820 825 830 Ser Gln Met Leu Ala Thr Ser Thr Met Asp Ser Gln Met Leu Ala Thr 835 840 845 Ser Thr Met Asp Ser Gln Met Leu Ala Thr Ser Ser Met Asp Ser Gln 850 855 860 Met Leu Ala Ser Gly Thr Met Asp Ser Gln Met Leu Ala Ser Gly Thr 865 870 875 880 Met Asp Ala Gln Met Leu Ala Ser Gly Thr Met Asp Ala Gln Met Leu 885 890 895 Ala Ser Ser Thr Gln Asp Ser Ala Met Leu Gly Ser Lys Ser Pro Asp 900 905 910 Pro Tyr Arg Leu Ala Gln Asp Pro Tyr Arg Leu Ala Gln Asp Pro Tyr 915 920 925 Arg Leu Gly His Asp Pro Tyr Arg Leu Gly His Asp Ala Tyr Arg Leu 930 935 940 Gly Gln Asp Pro Tyr Arg Leu Gly His Asp Pro Tyr Arg Leu Thr Pro 945 950 955 960 Asp Pro Tyr Arg Met Ser Pro Arg Pro Tyr Arg Ile Ala Pro Arg Ser 965 970 975 Tyr Arg Ile Ala Pro Arg Pro Tyr Arg Leu Ala Pro Arg Pro Leu Met 980 985 990 Leu Ala Ser Arg Arg Ser Met Met Met Ser Tyr Ala Ala Glu Arg Ser 995 1000 1005 Met Met Ser Ser Tyr Glu Arg Ser Met Met Ser Tyr Glu Arg Ser Met 1010 1015 1020 Met Ser Pro Met Ala Glu Arg Ser Met Met Ser Ala Tyr Glu Arg Ser 1025 1030 1035 1040 Met Met Ser Ala Tyr Glu Arg Ser Met Met Ser Pro Met Ala Glu Arg 1045 1050 1055 Ser Met Met Ser Ala Tyr Glu Arg Ser Met Met Ser Ala Tyr Glu Arg 1060 1065 1070 Ser Met Met Ser Pro Met Ala Asp Arg Ser Met Met Ser Met Gly Ala 1075 1080 1085 Asp Arg Ser Met Met Ser Ser Tyr Ser Ala Ala Asp Arg Ser Met Met 1090 1095 1100 Ser Ser Tyr Ser Ala Ala Asp Arg Ser Met Met Ser Ser Tyr Thr Ala 1105 1110 1115 1120 Asp Arg Ser Met Met Ser Met Ala Ala Asp Ser Tyr Thr Asp Ser Tyr 1125 1130 1135 Thr Asp Thr Tyr Thr Glu Ala Tyr Met Val Pro Pro Leu Pro Pro Glu 1140 1145 1150 Glu Pro Pro Thr Met Pro Pro Leu Pro Pro Glu Glu Pro Pro Met Thr 1155 1160 1165 Pro Pro Leu Pro Pro Glu Glu Pro Pro Glu Gly Pro Ala Leu Pro Thr 1170 1175 1180 Glu Gln Ser Ala Leu Thr Ala Glu Asn Thr Trp Pro Thr Glu Val Pro 1185 1190 1195 1200 Ser Ser Pro Ser Glu Glu Ser Val Ser Gln Pro Glu Pro Pro Val Ser 1205 1210 1215 Gln Ser Glu Ile Ser Glu Pro Ser Ala Val Pro Thr Asp Tyr Ser Val 1220 1225 1230 Ser Ala Ser Asp Pro Ser Val Leu Val Ser Glu Ala Ala Val Thr Val 1235 1240 1245 Pro Glu Pro Pro Pro Glu Pro Glu Ser Ser Ile Thr Leu Thr Pro Val 1250 1255 1260 Glu Ser Ala Val Val Ala Glu Glu His Glu Val Val Pro Glu Arg Pro 1265 1270 1275 1280 Val Thr Cys Met Val Ser Glu Thr Pro Ala Met Ser Ala Glu Pro Thr 1285 1290 1295 Val Leu Ala Ser Glu Pro Pro Val Met Ser Glu Thr Ala Glu Thr Phe 1300 1305 1310 Asp Ser Met Arg Ala Ser Gly His Val Ala Ser Glu Val Ser Thr Ser 1315 1320 1325 Leu Leu Val Pro Ala Val Thr Thr Pro Val Leu Ala Glu Ser Ile Leu 1330 1335 1340 Glu Pro Ala Met Ala Ala Pro Glu Ser Ser Ala Met Ala Val Leu 1345 1350 1355 1360 Glu Ser Ser Ala Val Thr Val Leu Glu Ser Ser Thr Val Thr Val Leu 1365 1370 1375 Glu Ser Ser Thr Val Thr Val Leu Glu Pro Ser Val Val Thr Val Pro 1380 1385 1390 Glu Pro Pro Val Val Ala Glu Pro Asp Tyr Val Thr Ile Pro Val Pro 1395 1400 1405 Val Val Ser Ala Leu Glu Pro Ser Val Pro Val Leu Glu Pro Ala Val 1410 1415 1420 Ser Val Leu Gln Pro Ser Met Ile Val Ser Glu Pro Ser Val Ser Val 1425 1430 1435 1440 Gln Glu Ser Thr Val Thr Val Ser Glu Pro Ala Val Thr Val Ser Glu 1445 1450 1455 Gln Thr Gln Val Ile Pro Thr Glu Val Ala Ile Glu Ser Thr Pro Met 1460 1465 1470 Ile Leu Glu Ser Ser Ile Met Ser Ser His Val Met Lys Gly Ile Asn 1475 1480 1485 Leu Ser Ser Gly Asp Gln Asn Leu Ala Pro Glu Ile Gly Met Gln Glu 1490 1495 1500 Ile Ala Leu His Ser Gly Glu Glu Pro His Ala Glu Glu His Leu Lys 1505 1510 1515 1520 Gly Asp Phe Tyr Glu Ser Glu His Gly Ile Asn Ile Asp Leu Asn Ile 1525 1530 1535 Asn Asn His Leu Ile Ala Lys Glu Met Glu His Asn Thr Val Cys Ala 1540 1545 1550 Ala Gly Thr Ser Pro Val Gly Glu Ile Gly Glu Glu Lys Ile Leu Pro 1555 1560 1565 Thr Ser Glu Thr Lys Gln Arg Thr Val Leu Asp Thr Tyr Pro Gly Val 1570 1575 1580 Ser Glu Ala Asp Ala Gly Glu Thr Leu Ser Ser Thr Gly Pro Phe Ala 1585 1590 1595 1600 Leu Glu Pro Asp Ala Thr Gly Thr Ser Lys Gly Ile Glu Phe Thr Thr 1605 1610 1615 Ala Ser Thr Leu Ser Leu Val Asn Lys Tyr Asp Val Asp Leu Ser Leu 1620 1625 1630 Thr Thr Gln Asp Thr Glu His Asp Met Val Ile Ser Thr Ser Pro Ser 1635 1640 1645 Gly Gly Ser Glu Ala Asp Ile Glu Gly Pro Leu Pro Ala Lys Asp Ile 1650 1655 1660 His Leu Asp Leu Pro Ser Asn Asn Asn Leu Val Ser Lys Asp Thr Glu 1665 1670 1675 1680 Glu Pro Leu Pro Val Lys Glu Ser Asp Gln Thr Leu Ala Ala Leu Leu 1685 1690 1695 Ser Pro Lys Glu Ser Ser Gly Gly Glu Lys Glu Val Pro Pro Pro Pro 1700 1705 1710 Lys Glu Thr Leu Pro Asp Ser Gly Phe Ser Ala Asn Ile Glu Asp Ile 1715 1720 1725 Asn Glu Ala Asp Leu Val Arg Pro Leu Leu Pro Lys Asp Met Glu Arg 1730 1735 1740 Leu Thr Ser Leu Arg Ala Gly Ile Glu Gly Pro Leu Leu Ala Ser Asp 1745 1750 1755 1760 Val Gly Arg Asp Arg Ser Ala Ala Ser Pro Val Val Ser Ser Met Pro 1765 1770 1775 Glu Arg Ala Ser Glu Ser Ser Ser Glu Glu Lys Asp Asp Tyr Glu Ile 1780 1785 1790 Phe Val Lys Val Lys Asp Thr His Glu Lys Ser Lys Lys Asn Lys Asn 1795 1800 1805 Arg Asp Lys Gly Glu Lys Glu Lys Lys Arg Asp Ser Ser Leu Arg Ser 1810 1815 1820 Arg Ser Lys Arg Ser Lys Ser Ser Glu His Lys Ser Arg Lys Arg Thr 1825 1830 1835 1840 Ser Glu Ser Arg Ser Arg Ala Arg Lys Arg Ser Ser Lys Ser Lys Ser 1845 1850 1855 His Arg Ser Gln Thr Arg Ser Arg Ser Arg Ser Arg Arg Arg Arg Arg 1860 1865 1870 Ser Ser Arg Ser Arg Ser Lys Ser Arg Gly Arg Arg Ser Val Ser Lys 1875 1880 1885 Glu Lys Arg Lys Arg Ser Pro Lys His Arg Ser Lys Ser Arg Glu Arg 1890 1895 1900 Lys Arg Lys Arg Ser Ser Ser Arg Asp Asn Arg Lys Thr Val Arg Ala 1905 1910 1915 1920 Arg Ser Arg Thr Pro Ser Arg Arg Ser Arg Ser His Thr Pro Ser Arg 1925 1930 1935 Arg Arg Arg Ser Arg Ser Val Gly Arg Arg Arg Ser Phe Ser Ile Ser 1940 1945 1950 Pro Ser Arg Arg Ser Arg Thr Pro Ser Arg Arg Ser Arg Thr Pro Ser 1955 1960 1965 Arg Arg Ser Arg Thr Pro Ser Arg Arg Ser Arg Thr Pro Ser Arg Arg 1970 1975 1980 Ser Arg Thr Pro Ser Arg Arg Ser Arg Thr Pro Ser Arg Arg Arg Arg 1985 1990 1995 2000 Ser Arg Ser Val Val Arg Arg Arg Ser Phe Ser Ile Ser Pro Val Arg 2005 2010 2015 Leu Arg Arg Ser Arg Thr Pro Leu Arg Arg Arg Phe Ser Arg Ser Pro 2020 2025 2030 Ile Arg Arg Lys Arg Ser Arg Ser Ser Glu Arg Gly Arg Ser Pro Lys 2035 2040 2045 Arg Leu Thr Asp Leu Asp Lys Ala Gln Leu Leu Glu Ile Ala Lys Ala 2050 2055 2060 Asn Ala Ala Ala Met Cys Ala Lys Ala Gly Val Pro Leu Pro Pro Asn 2065 2070 2075 2080 Leu Lys Pro Ala Pro Pro Pro Thr Ile Glu Glu Lys Val Ala Lys Lys 2085 2090 2095 Ser Gly Gly Ala Thr Ile Glu Glu Leu Thr Glu Lys Cys Lys Gln Ile 2100 2105 2110 Ala Gln Ser Lys Glu Asp Asp Asp Val Ile Val Asn Lys Pro His Val 2115 2120 2125 Ser Asp Glu Glu Glu Glu Glu Pro Pro Phe Tyr His His Pro Phe Lys 2130 2135 2140 Leu Ser Glu Pro Lys Pro Ile Phe Phe Asn Leu Asn Ile Ala Ala Ala 2145 2150 2155 2160 Lys Pro Thr Pro Pro Lys Ser Gln Val Thr Leu Thr Lys Glu Phe Pro 2165 2170 2175 Val Ser Ser Gly Ser Gln His Arg Lys Lys Glu Ala Asp Ser Val Tyr 2180 2185 2190 Gly Glu Trp Val Pro Val Glu Lys Asn Gly Glu Glu Asn Lys Asp Asp 2195 2200 2205 Asp Asn Val Phe Ser Ser Asn Leu Pro Ser Glu Pro Val Asp Ile Ser 2210 2215 2220 Thr Ala Met Ser Glu Arg Ala Leu Ala Gln Lys Arg Leu Ser Glu Asn 2225 2230 2235 2240 Ala Phe Asp Leu Glu Ala Met Ser Met Leu Asn Arg Ala Gln Glu Arg 2245 2250 2255 Ile Asp Ala Trp Ala Gln Leu Asn Ser Ile Pro Gly Gln Phe Thr Gly 2260 2265 2270 Ser Thr Gly Val Gln Val Leu Thr Gln Glu Gln Leu Ala Asn Thr Gly 2275 2280 2285 Ala Gln Ala Trp Ile Lys Lys Asp Gln Phe Leu Arg Ala Ala Pro Val 2290 2295 2300 Thr Gly Gly Met Gly Ala Val Leu Met Arg Lys Met Gly Trp Arg Glu 2305 2310 2315 2320 Gly Glu Gly Leu Gly Lys Asn Lys Glu Gly Asn Lys Glu Pro Ile Leu 2325 2330 2335 Val Asp Phe Lys Thr Asp Arg Lys Gly Leu Val Ala Val Gly Glu Arg 2340 2345 2350 Ala Gln Lys Arg Ser Gly Asn Phe Ser Ala Ala Met Lys Asp Leu Ser 2355 2360 2365 Gly Lys His Pro Val Ser Ala Leu Met Glu Ile Cys Asn Lys Arg Arg 2370 2375 2380 Trp Gln Pro Pro Glu Phe Leu Leu Val His Asp Ser Gly Pro Asp His 2385 2390 2395 2400 Arg Lys His Phe Leu Phe Arg Val Leu Arg Asn Gly Ala Leu Thr Arg 2405 2410 2415Pro Asn Cys Met Phe Phe Leu Asn Arg Tyr 2420 2425 <210> 14 <211> 456 <212> PRT <213> homo sapiens <400> 14 Met Gly Asn Ser Arg Ser Arg Val Gly Arg Ser Phe Cys Ser Gln Phe 1 5 10 15 Leu Pro Glu Glu Gln Ala Glu Ile Asp Gln Leu Phe Asp Ala Leu Ser 20 25 30 Ser Asp Lys Asn Ser Pro Asn Val Ser Ser Lys Ser Phe Ser Leu Lys 35 40 45 Ala Leu Gln Asn His Val Gly Glu Ala Leu Pro Pro Glu Met Val Thr 50 55 60 Arg Leu Tyr Asp Gly Met Arg Arg Val Asp Leu Thr Gly Lys Ala Lys 65 70 75 80 Gly Pro Ser Glu Asn Val Ser Gln Glu Gln Phe Thr Ala Ser Met Ser 85 90 95 His Leu Leu Lys Gly Asn Ser Glu Glu Lys Ser Leu Met Ile Met Lys 100 105 110 Met Ile Ser Ala Thr Glu Gly Pro Val Lys Ala Arg Glu Val Gln Lys 115 120 125 Phe Thr Glu Asp Leu Val Gly Ser Val Val His Val Leu Ser His Arg 130 135 140 Gln Glu Leu Arg Gly Trp Thr Gly Lys Glu Ala Pro Gly Pro Asn Pro 145 150 155 160 Arg Val Gln Val Leu Ala Ala Gln Leu Leu Ser Asp Met Lys Leu Gln 165 170 175 Asp Gly Lys Arg Leu Leu Gly Pro Gln Trp Leu Asp Tyr Asp Cys Asp 180 185 190 Arg Ala Val Ile Glu Asp Trp Val Phe Arg Val Pro His Val Ala Ile 195 200 205 Phe Leu Ser Val Val Ile Cys Lys Gly Phe Leu Ile Leu Cys Ser Ser 210 215 220 Leu Asp Leu Thr Thr Leu Val Pro Glu Arg Gln Val Asp Gln Gly Arg 225 230 235 240 Gly Phe Glu Ser Ile Leu Asp Val Leu Ser Val Met Tyr Ile Asn Ala 245 250 255 Gln Leu Pro Arg Glu Gln Arg His Arg Trp Cys Leu Leu Phe Ser Ser 260 265 270 Glu Leu His Gly His Ser Phe Ser Gln Leu Cys Gly His Ile Thr His 275 280 285 Arg Gly Pro Cys Val Ala Val Leu Glu Asp His Asp Lys His Val Phe 290 295 300 Gly Gly Phe Ala Ser Cys Ser Trp Glu Val Lys Pro Gln Phe Gln Gly 305 310 315 320 Asp Asn Arg Cys Phe Leu Phe Ser Ile Cys Pro Ser Met Ala Val Tyr 325 330 335 Thr His Thr Gly Tyr Asn Asp His Tyr Met Tyr Leu Asn His Gly Gln 340 345 350 Gln Thr Ile Pro Asn Gly Leu Gly Met Gly Gly Gln His Asn Tyr Phe 355 360 365 Gly Leu Trp Val Asp Val Asp Phe Gly Lys Gly His Ser Arg Ala Lys 370 375 380 Pro Thr Cys Thr Thr Tyr Asn Ser Pro Gln Leu Ser Ala Gln Glu Asn 385 390 395 400 Phe Gln Phe Asp Lys Met Glu Val Trp Ala Val Gly Asp Pro Ser Glu 405 410 415 Glu Gln Leu Ala Lys Gly Asn Lys Ser Ile Leu Asp Ala Asp Pro Glu 420 425 430 Ala Gln Ala Leu Leu Glu Ile Ser Gly His Ser Arg His Ser Glu Gly 435 440 445 Leu Arg Glu Val Pro Asp Asp Glu 450 455 <210> 15 <211> 526 <212> PRT <213> homo sapiens <400> 15 Met Pro Gln Gln Leu Leu Ile Thr Leu Pro Thr Glu Ala Ser Thr Trp 1 5 10 15 Val Lys Leu Gln His Pro Lys Lys Ala Val Glu Gly Ala Pro Leu Trp 20 25 30 Glu Asp Val Thr Lys Met Phe Glu Gly Glu Ala Leu Leu Ser Gln Asp 35 40 45 Ala Glu Asp Val Lys Thr Gln Arg Glu Ser Leu Glu Asp Glu Val Thr 50 55 60 Pro Gly Leu Pro Thr Ala Glu Ser Gln Glu Leu Leu Thr Phe Lys Asp 65 70 75 80 Ile Ser Ile Asp Phe Thr Gln Glu Glu Trp Gly Gln Leu Ala Pro Ala 85 90 95 His Gln Asn Leu Tyr Arg Glu Val Met Leu Glu Asn Tyr Ser Asn Leu 100 105 110 Val Ser Val Gly Tyr Gln Leu Ser Lys Pro Ser Val Ile Ser Gln Leu 115 120 125 Glu Lys Gly Glu Glu Pro Trp Met Ala Glu Lys Glu Gly Pro Gly Asp 130 135 140 Pro Ser Ser Asp Leu Lys Ser Lys Ile Glu Thr Ile Glu Ser Thr Ala 145 150 155 160 Lys Ser Thr Ile Ser Gln Glu Arg Leu Tyr His Gly Ile Met Met Glu 165 170 175 Ser Phe Met Arg Asp Asp Ile Ile Tyr Ser Thr Leu Arg Lys Val Ser 180 185 190 Thr Tyr Asp Asp Val Leu Glu Arg His Gln Glu Thr Cys Met Arg Asp 195 200 205 Val Arg Gln Ala Ile Leu Thr His Lys Lys Arg Val Gln Glu Thr Asn 210 215 220 Lys Phe Gly Glu Asn Ile Ile Val His Ser Asn Val Ile Ile Glu Gln 225 230 235 240 Arg His His Lys Tyr Asp Thr Pro Thr Lys Arg Asn Thr Tyr Lys Leu 245 250 255 Asp Leu Ile Asn His Pro Thr Ser Tyr Ile Arg Thr Lys Thr Tyr Glu 260 265 270 Cys Asn Ile Cys Glu Lys Ile Phe Lys Gln Pro Ile His Leu Thr Glu 275 280 285 His Met Arg Ile His Thr Gly Glu Lys Pro Phe Arg Cys Lys Glu Cys 290 295 300 Gly Arg Ala Phe Ser Gln Ser Ala Ser Leu Ser Thr His Gln Arg Ile 305 310 315 320 His Thr Gly Glu Lys Pro Phe Glu Cys Glu Glu Cys Gly Lys Ala Phe 325 330 335 Arg His Arg Ser Ser Leu Asn Gln His His Arg Thr His Thr Gly Glu 340 345 350 Lys Pro Tyr Val Cys Asp Lys Cys Gln Lys Ala Phe Ser Gln Asn Ile 355 360 365 Ser Leu Val Gln His Leu Arg Thr His Ser Gly Glu Lys Pro Phe Thr 370 375 380 Cys Asn Glu Cys Gly Lys Thr Phe Arg Gln Ile Arg His Leu Ser Glu 385 390 395 400 His Ile Arg Ile His Thr Gly Glu Lys Pro Tyr Ala Cys Thr Ala Cys 405 410 415 Cys Lys Thr Phe Ser His Arg Ala Tyr Leu Thr His His Gln Arg Ile 420 425 430 His Thr Gly Glu Arg Pro Tyr Lys Cys Lys Glu Cys Gly Lys Ala Phe 435 440 445 Arg Gln Arg Ile His Leu Ser Asn His Lys Thr Val His Thr Gly Val 450 455 460 Lys Ala Tyr Glu Cys Asn Arg Cys Gly Lys Ala Tyr Arg His Asp Ser 465 470 475 480 Ser Phe Lys Lys His Gln Arg His His Thr Gly Glu Lys Pro Tyr Glu 485 490 495 Cys Asn Glu Cys Gly Lys Ala Phe Ser Tyr Asn Ser Ser Leu Ser Arg 500 505 510 His His Glu Ile His Arg Arg Asn Ala Phe Arg Asn Lys Val 515 520 525 <210> 16 <211> 1119 <212> PRT <213> homo sapiens <400> 16 Met Ala Gly Ala Pro Arg Gly Gly Gly Gly Gly Gly Gly Gly Ala Gly 1 5 10 15 Glu Pro Gly Gly Ala Glu Arg Ala Ala Gly Thr Ser Arg Arg Arg Gly 20 25 30 Leu Arg Ala Cys Asp Glu Glu Phe Ala Cys Pro Glu Leu Glu Ala Leu 35 40 45 Phe Arg Gly Tyr Thr Leu Arg Leu Glu Gln Ala Ala Thr Leu Lys Ala 50 55 60 Leu Ala Val Leu Ser Leu Leu Ala Gly Ala Leu Ala Leu Ala Glu Leu 65 70 75 80 Leu Gly Ala Pro Gly Pro Ala Pro Gly Leu Ala Lys Gly Ser His Pro 85 90 95 Val His Cys Val Leu Phe Leu Ala Leu Leu Val Val Thr Asn Val Arg 100 105 110 Ser Leu Gln Val Pro Gln Leu Gln Gln Val Gly Gln Leu Ala Leu Leu 115 120 125 Phe Ser Leu Thr Phe Ala Leu Leu Cys Cys Pro Phe Ala Leu Gly Gly 130 135 140 Pro Ala Arg Gly Ser Ala Gly Ala Ala Gly Gly Pro Ala Thr Ala Glu 145 150 155 160 Gln Gly Val Trp Gln Leu Leu Leu Val Thr Phe Val Ser Tyr Ala Leu 165 170 175 Leu Pro Val Arg Ser Leu Leu Ala Ile Gly Phe Gly Leu Val Val Ala 180 185 190 Ala Ser His Leu Leu Val Thr Ala Thr Leu Val Pro Ala Lys Arg Pro 195 200 205 Arg Leu Trp Arg Thr Leu Gly Ala Asn Ala Leu Leu Phe Val Gly Val 210 215 220 Asn Met Tyr Gly Val Phe Val Arg Ile Leu Thr Glu Arg Ser Gln Arg 225 230 235 240 Lys Ala Phe Leu Gln Ala Arg Ser Cys Ile Glu Asp Arg Leu Arg Leu 245 250 255 Glu Asp Glu Asn Glu Lys Gln Glu Arg Leu Leu Met Ser Leu Leu Pro 260 265 270 Arg Asn Val Ala Met Glu Met Lys Glu Asp Phe Leu Lys Pro Pro Glu 275 280 285 Arg Ile Phe His Lys Ile Tyr Ile Gln Arg His Asp Asn Val Ser Ile 290 295 300 Leu Phe Ala Asp Ile Val Gly Phe Thr Gly Leu Ala Ser Gln Cys Thr 305 310 315 320 Ala Gln Glu Leu Val Lys Leu Leu Asn Glu Leu Phe Gly Lys Phe Asp 325 330 335 Glu Leu Ala Thr Glu Asn His Cys Arg Arg Ile Lys Ile Leu Gly Asp 340 345 350 Cys Tyr Tyr Cys Val Ser Gly Leu Thr Gln Pro Lys Thr Asp His Ala 355 360 365 His Cys Cys Val Glu Met Gly Leu Asp Met Ile Asp Thr Ile Thr Ser 370 375 380 Val Ala Glu Ala Thr Glu Val Asp Leu Asn Met Arg Val Gly Leu His 385 390 395 400 Thr Gly Arg Val Leu Cys Gly Val Leu Gly Leu Arg Lys Trp Gln Tyr 405 410 415 Asp Val Trp Ser Asn Asp Val Thr Leu Ala Asn Val Met Glu Ala Ala 420 425 430 Gly Leu Pro Gly Lys Val His Ile Thr Lys Thr Thr Leu Ala Cys Leu 435 440 445 Asn Gly Asp Tyr Glu Val Glu Pro Gly Tyr Gly His Glu Arg Asn Ser 450 455 460 Phe Leu Lys Thr His Asn Ile Glu Thr Phe Phe Ile Val Pro Ser His 465 470 475 480 Arg Arg Lys Ile Phe Pro Gly Leu Ile Leu Ser Asp Ile Lys Pro Ala 485 490 495 Lys Arg Met Lys Phe Lys Thr Val Cys Tyr Leu Leu Val Gln Leu Met 500 505 510 His Cys Arg Lys Met Phe Lys Ala Glu Ile Pro Phe Ser Asn Val Met 515 520 525 Thr Cys Glu Asp Asp Asp Lys Arg Arg Ala Leu Arg Thr Ala Ser Glu 530 535 540 Lys Leu Arg Asn Arg Ser Ser Phe Ser Thr Asn Val Val Tyr Thr Thr 545 550 555 560 Pro Gly Thr Arg Val Asn Arg Tyr Ile Ser Arg Leu Leu Glu Ala Arg 565 570 575 Gln Thr Glu Leu Glu Met Ala Asp Leu Asn Phe Phe Thr Leu Lys Tyr 580 585 590 Lys His Val Glu Arg Glu Gln Lys Tyr His Gln Leu Gln Asp Glu Tyr 595 600 605 Phe Thr Ser Ala Val Val Leu Thr Leu Ile Leu Ala Ala Leu Phe Gly 610 615 620 Leu Val Tyr Leu Leu Ile Phe Pro Gln Ser Val Val Val Leu Leu Leu 625 630 635 640 Leu Val Phe Cys Ile Cys Phe Leu Val Ala Cys Val Leu Tyr Leu His 645 650 655 Ile Thr Arg Val Gln Cys Phe Pro Gly Cys Leu Thr Ile Gln Ile Arg 660 665 670 Thr Val Leu Cys Ile Phe Ile Val Val Leu Ile Tyr Ser Val Ala Gln 675 680 685 Gly Cys Val Val Gly Cys Leu Pro Trp Ala Trp Ser Ser Lys Pro Asn 690 695 700 Ser Ser Leu Val Val Leu Ser Ser Gly Gly Gln Arg Thr Ala Leu Pro 705 710 715 720 Thr Leu Pro Cys Glu Ser Thr His His Ala Leu Leu Cys Cys Leu Val 725 730 735 Gly Thr Leu Pro Leu Ala Ile Phe Phe Arg Val Ser Ser Leu Pro Lys 740 745 750 Met Ile Leu Leu Ser Gly Leu Thr Thr Ser Tyr Ile Leu Val Leu Glu 755 760 765 Leu Ser Gly Tyr Thr Arg Thr Gly Gly Gly Ala Val Ser Gly Arg Ser 770 775 780 Tyr Glu Pro Ile Val Ala Ile Leu Leu Phe Ser Cys Ala Leu Ala Leu 785 790 795 800 His Ala Arg Gln Val Asp Ile Arg Leu Arg Leu Asp Tyr Leu Trp Ala 805 810 815 Ala Gln Ala Glu Glu Glu Arg Glu Asp Met Glu Lys Val Lys Leu Asp 820 825 830 Asn Arg Arg Ile Leu Phe Asn Leu Leu Pro Ala His Val Ala Gln His 835 840 845 Phe Leu Met Ser Asn Pro Arg Asn Met Asp Leu Tyr Tyr Gln Ser Tyr 850 855 860 Ser Gln Val Gly Val Met Phe Ala Ser Ile Pro Asn Phe Asn Asp Phe 865 870 875 880 Tyr Ile Glu Leu Asp Gly Asn Asn Met Gly Val Glu Cys Leu Arg Leu 885 890 895 Leu Asn Glu Ile Ile Ala Asp Phe Asp Glu Leu Met Glu Lys Asp Phe 900 905 910 Tyr Lys Asp Ile Glu Lys Ile Lys Thr Ile Gly Ser Thr Tyr Met Ala 915 920 925 Ala Val Gly Leu Ala Pro Thr Ser Gly Thr Lys Ala Lys Lys Ser Ile 930 935 940 Ser Ser His Leu Ser Thr Leu Ala Asp Phe Ala Ile Glu Met Phe Asp 945 950 955 960 Val Leu Asp Glu Ile Asn Tyr Gln Ser Tyr Asn Asp Phe Val Leu Arg 965 970 975 Val Gly Ile Asn Val Gly Pro Val Val Ala Gly Val Ile Gly Ala Arg 980 985 990 Arg Pro Gln Tyr Asp Ile Trp Gly Asn Thr Val Asn Val Ala Ser Arg 995 1000 1005 Met Asp Ser Thr Gly Val Gln Gly Arg Ile Gln Val Thr Glu Glu Val 1010 1015 1020 His Arg Leu Leu Arg Arg Cys Pro Tyr His Phe Val Cys Arg Gly Lys 1025 1030 1035 1040 Val Ser Val Lys Gly Lys Gly Glu Met Leu Thr Tyr Phe Leu Glu Gly 1045 1050 1055 Arg Thr Asp Gly Asn Gly Ser Gln Ile Arg Ser Leu Gly Leu Asp Arg 1060 1065 1070 Lys Met Cys Pro Phe Gly Arg Ala Gly Leu Gln Gly Arg Arg Pro Pro 1075 1080 1085 Val Cys Pro Met Pro Gly Val Ser Val Arg Ala Gly Leu Pro Pro His 1090 1095 1100 Ser Pro Gly Gln Tyr Leu Pro Ser Ala Ala Ala Gly Lys Glu Ala 1105 1110 1115 <210> 17 <211> 218 <212> PRT <213> homo sapiens <400> 17 Met Ala His Val Gly Ser Arg Lys Arg Ser Arg Ser Arg Ser Arg Ser 1 5 10 15 Arg Gly Arg Gly Ser Glu Lys Arg Lys Lys Lys Ser Arg Lys Asp Thr 20 25 30 Ser Arg Asn Cys Ser Ala Ser Thr Ser Gln Glu Arg Ser Lys Gln Lys 35 40 45 Ala Arg Arg Arg Thr Arg Ser Ser Ser Ser Ser Ser Ser Ser Ser 50 55 60 Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Asp 65 70 75 80 Gly Arg Lys Lys Arg Gly Lys Tyr Lys Asp Lys Arg Arg Lys Lys Lys 85 90 95 Lys Lys Arg Lys Lys Leu Lys Lys Lys Gly Lys Glu Lys Ala Glu Ala 100 105 110 Gln Gln Val Glu Ala Leu Pro Gly Pro Ser Leu Asp Gln Trp His Arg 115 120 125 Ser Ala Gly Glu Glu Glu Asp Gly Pro Val Leu Thr Asp Glu Gln Lys 130 135 140 Ser Arg Ile Gln Ala Met Lys Pro Met Thr Lys Glu Glu Trp Asp Ala 145 150 155 160 Arg Gln Ser Ile Ile Arg Lys Val Val Asp Pro Glu Thr Gly Arg Thr 165 170 175 Arg Leu Ile Lys Gly Asp Gly Glu Val Leu Glu Glu Ile Val Thr Lys 180 185 190 Glu Arg His Arg Glu Ile Asn Lys Gln Ala Thr Arg Gly Asp Cys Leu 195 200 205 Ala Phe Gln Met Arg Ala Gly Leu Leu Pro 210 215 <210> 18 <211> 1149 <212> PRT <213> homo sapiens <400> 18 Met Pro Thr Met Arg Arg Thr Val Ser Glu Ile Arg Ser Arg Ala Glu 1 5 10 15 Gly Tyr Glu Lys Thr Asp Asp Val Ser Glu Lys Thr Ser Leu Ala Asp 20 25 30 Gln Glu Glu Val Arg Thr Ile Phe Ile Asn Gln Pro Gln Leu Thr Lys 35 40 45 Phe Cys Asn Asn His Val Ser Thr Ala Lys Tyr Asn Ile Ile Thr Phe 50 55 60 Leu Pro Arg Phe Leu Tyr Ser Gln Phe Arg Arg Ala Ala Asn Ser Phe 65 70 75 80 Phe Leu Phe Ile Ala Leu Leu Gln Gln Ile Pro Asp Val Ser Pro Thr 85 90 95 Gly Arg Tyr Thr Thr Leu Val Pro Leu Leu Phe Ile Leu Ala Val Ala 100 105 110 Ala Ile Lys Glu Ile Ile Glu Asp Ile Lys Arg His Lys Ala Asp Asn 115 120 125 Ala Val Asn Lys Lys Gln Thr Gln Val Leu Arg Asn Gly Ala Trp Glu 130 135 140 Ile Val His Trp Glu Lys Val Asn Val Gly Asp Ile Val Ile Ile Lys 145 150 155 160 Gly Lys Glu Tyr Ile Pro Ala Asp Thr Val Leu Leu Ser Ser Ser Glu 165 170 175 Pro Gln Ala Met Cys Tyr Ile Glu Thr Ser Asn Leu Asp Gly Glu Thr 180 185 190 Asn Leu Lys Ile Arg Gln Gly Leu Pro Ala Thr Ser Asp Ile Lys Asp 195 200 205 Val Asp Ser Leu Met Arg Ile Ser Gly Arg Ile Glu Cys Glu Ser Pro 210 215 220 Asn Arg His Leu Tyr Asp Phe Val Gly Asn Ile Arg Leu Asp Gly His 225 230 235 240 Gly Thr Val Pro Leu Gly Ala Asp Gln Ile Leu Leu Arg Gly Ala Gln 245 250 255 Leu Arg Asn Thr Gln Trp Val His Gly Ile Val Val Tyr Thr Gly His 260 265 270 Asp Thr Lys Leu Met Gln Asn Ser Thr Ser Pro Pro Leu Lys Leu Ser 275 280 285 Asn Val Glu Arg Ile Thr Asn Val Gln Ile Leu Ile Leu Phe Cys Ile 290 295 300 Leu Ile Ala Met Ser Leu Val Cys Ser Val Gly Ser Ala Ile Trp Asn 305 310 315 320 Arg Arg His Ser Gly Lys Asp Trp Tyr Leu Asn Leu Asn Tyr Gly Gly 325 330 335 Ala Ser Asn Phe Gly Leu Asn Phe Leu Thr Phe Ile Ile Leu Phe Asn 340 345 350 Asn Leu Ile Pro Ile Ser Leu Leu Val Thr Leu Glu Val Val Lys Phe 355 360 365 Thr Gln Ala Tyr Phe Ile Asn Trp Asp Leu Asp Met His Tyr Glu Pro 370 375 380 Thr Asp Thr Ala Ala Met Ala Arg Thr Ser Asn Leu Asn Glu Glu Leu 385 390 395 400 Gly Gln Val Lys Tyr Ile Phe Ser Asp Lys Thr Gly Thr Leu Thr Cys 405 410 415 Asn Val Met Gln Phe Lys Lys Cys Thr Ile Ala Gly Val Ala Tyr Gly 420 425 430 Gln Asn Ser Gln Phe Gly Asp Glu Lys Thr Phe Ser Asp Ser Ser Leu 435 440 445 Leu Glu Asn Leu Gln Asn Asn His Pro Thr Ala Pro Ile Ile Cys Glu 450 455 460 Phe Leu Thr Met Met Ala Val Cys His Thr Ala Val Pro Glu Arg Glu 465 470 475 480 Gly Asp Lys Ile Ile Tyr Gln Ala Ala Ser Pro Asp Glu Gly Ala Leu 485 490 495 Val Arg Ala Ala Lys Gln Leu Asn Phe Val Phe Thr Gly Arg Thr Pro 500 505 510 Asp Ser Val Ile Ile Asp Ser Leu Gly Gln Glu Glu Arg Tyr Glu Leu 515 520 525 Leu Asn Val Leu Glu Phe Thr Ser Ala Arg Lys Arg Met Ser Val Ile 530 535 540 Val Arg Thr Pro Ser Gly Lys Leu Arg Leu Tyr Cys Lys Gly Ala Asp 545 550 555 560 Thr Val Ile Tyr Asp Arg Leu Ala Glu Thr Ser Lys Tyr Lys Glu Ile 565 570 575 Thr Leu Lys His Leu Glu Gln Phe Ala Thr Glu Gly Leu Arg Thr Leu 580 585 590 Cys Phe Ala Val Ala Glu Ile Ser Glu Ser Asp Phe Gln Glu Trp Arg 595 600 605 Ala Val Tyr Gln Arg Ala Ser Thr Ser Val Gln Asn Arg Leu Leu Lys 610 615 620 Leu Glu Glu Ser Tyr Glu Leu Ile Glu Lys Asn Leu Gln Leu Leu Gly 625 630 635 640 Ala Thr Ala Ile Glu Asp Lys Leu Gln Asp Gln Val Pro Glu Thr Ile 645 650 655 Glu Thr Leu Met Lys Ala Asp Ile Lys Ile Trp Ile Leu Thr Gly Asp 660 665 670 Lys Gln Glu Thr Ala Ile Asn Ile Gly His Ser Cys Lys Leu Leu Lys 675 680 685 Lys Asn Met Gly Met Ile Val Ile Asn Glu Gly Ser Leu Asp Gly Thr 690 695 700 Arg Glu Thr Leu Ser Arg His Cys Thr Thr Leu Gly Asp Ala Leu Arg 705 710 715 720 Lys Glu Asn Asp Phe Ala Leu Ile Ile Asp Gly Lys Thr Leu Lys Tyr 725 730 735 Ala Leu Thr Phe Gly Val Arg Gln Tyr Phe Leu Asp Leu Ala Leu Ser 740 745 750 Cys Lys Ala Val Ile Cys Cys Arg Val Ser Pro Leu Gln Lys Ser Glu 755 760 765 Val Val Glu Met Val Lys Lys Gln Val Lys Val Val Thr Leu Ala Ile 770 775 780 Gly Asp Gly Ala Asn Asp Val Ser Met Ile Gln Thr Ala His Val Gly 785 790 795 800 Val Gly Ile Ser Gly Asn Glu Gly Leu Gln Ala Ala Asn Ser Ser Asp 805 810 815 Tyr Ser Ile Ala Gln Phe Lys Tyr Leu Lys Asn Leu Leu Met Ile His 820 825 830 Gly Ala Trp Asn Tyr Asn Arg Val Ser Lys Cys Ile Leu Tyr Cys Phe 835 840 845 Tyr Lys Asn Ile Val Leu Tyr Ile Ile Glu Ile Trp Phe Ala Phe Val 850 855 860 Asn Gly Phe Ser Gly Gln Ile Leu Phe Glu Arg Trp Cys Ile Gly Leu 865 870 875 880 Tyr Asn Val Met Phe Thr Ala Met Pro Pro Leu Thr Leu Gly Ile Phe 885 890 895 Glu Arg Ser Cys Arg Lys Glu Asn Met Leu Lys Tyr Pro Glu Leu Tyr 900 905 910 Lys Thr Ser Gln Asn Ala Leu Asp Phe Asn Thr Lys Val Phe Trp Val 915 920 925 His Cys Leu Asn Gly Leu Phe His Ser Val Ile Leu Phe Trp Phe Pro 930 935 940 Leu Lys Ala Leu Gln Tyr Gly Thr Ala Phe Gly Asn Gly Lys Thr Ser 945 950 955 960 Asp Tyr Leu Leu Leu Gly Asn Phe Val Tyr Thr Phe Val Val Ile Thr 965 970 975 Val Cys Leu Lys Ala Gly Leu Glu Thr Ser Tyr Trp Thr Trp Phe Ser 980 985 990 His Ile Ala Ile Trp Gly Ser Ile Ala Leu Trp Val Val Phe Phe Gly 995 1000 1005 Ile Tyr Ser Ser Leu Trp Pro Ala Ile Pro Met Ala Pro Asp Met Ser 1010 1015 1020 Gly Glu Ala Ala Met Leu Phe Ser Ser Gly Val Phe Trp Met Gly Leu 1025 1030 1035 1040 Leu Phe Ile Pro Val Ala Ser Leu Leu Leu Asp Val Val Tyr Lys Val 1045 1050 1055 Ile Lys Arg Thr Ala Phe Lys Thr Leu Val Asp Glu Val Gln Glu Leu 1060 1065 1070 Glu Ala Lys Ser Gln Asp Pro Gly Ala Val Val Leu Gly Lys Ser Leu 1075 1080 1085 Thr Glu Arg Ala Gln Leu Leu Lys Asn Val Phe Lys Lys Asn His Val 1090 1095 1100 Asn Leu Tyr Arg Ser Glu Ser Leu Gln Gln Asn Leu Leu His Gly Tyr 1105 1110 1115 1120 Ala Phe Ser Gln Asp Glu Asn Gly Ile Val Ser Gln Ser Glu Val Ile 1125 1130 1135 Arg Ala Tyr Asp Thr Thr Lys Gln Arg Pro Asp Glu Trp 1140 1145 <210> 19 <211> 57 <212> PRT <213> homo sapiens <400> 19 Met Pro Thr Gly Lys Gln Leu Ala Asp Ile Gly Tyr Lys Thr Phe Ser 1 5 10 15 Thr Ser Met Met Leu Leu Thr Val Tyr Gly Gly Tyr Leu Cys Ser Val 20 25 30 Arg Val Tyr His Tyr Phe Gln Trp Arg Arg Ala Gln Arg Gln Ala Ala 35 40 45 Glu Glu Gln Lys Thr Ser Gly Ile Met 50 55 <210> 20 <211> 335 <212> PRT <213> homo sapiens <400> 20 Met Thr Ser His Ile Arg Tyr Glu Val Asp Val Ser Ala Gly Asn Gly 1 5 10 15 Ala Gly Ser Val Gln Arg Val Glu Ile Leu Glu Gly Arg Thr Glu Cys 20 25 30 Val Leu Ser Asn Leu Arg Gly Arg Thr Arg Tyr Thr Phe Ala Val Arg 35 40 45 Ala Arg Met Ala Glu Pro Ser Phe Gly Gly Phe Trp Ser Ala Trp Ser 50 55 60 Glu Pro Val Ser Leu Leu Thr Pro Ser Asp Leu Asp Pro Leu Ile Leu 65 70 75 80 Thr Leu Ser Leu Ile Leu Val Val Ile Leu Val Leu Leu Thr Val Leu 85 90 95 Ala Leu Leu Ser His Arg Arg Ala Leu Lys Gln Lys Ile Trp Pro Gly 100 105 110 Ile Pro Ser Pro Glu Ser Glu Phe Glu Gly Leu Phe Thr Thr His Lys 115 120 125 Gly Asn Phe Gln Leu Trp Leu Tyr Gln Asn Asp Gly Cys Leu Trp Trp 130 135 140 Ser Pro Cys Thr Pro Phe Thr Glu Asp Pro Pro Ala Ser Leu Glu Val 145 150 155 160 Leu Ser Glu Arg Cys Trp Gly Thr Met Gln Ala Val Glu Pro Gly Thr 165 170 175 Asp Asp Glu Gly Pro Leu Leu Glu Pro Val Gly Ser Glu His Ala Gln 180 185 190 Asp Thr Tyr Leu Val Leu Asp Lys Trp Leu Leu Pro Arg Asn Pro Pro 195 200 205 Ser Glu Asp Leu Pro Gly Pro Gly Gly Ser Val Asp Ile Val Ala Met 210 215 220 Asp Glu Gly Ser Glu Ala Ser Ser Cys Ser Ser Ala Leu Ala Ser Lys 225 230 235 240 Pro Ser Pro Glu Gly Ala Ser Ala Ala Ser Phe Glu Tyr Thr Ile Leu 245 250 255 Asp Pro Ser Ser Gln Leu Leu Arg Pro Trp Thr Leu Cys Pro Glu Leu 260 265 270 Pro Pro Thr Pro Pro His Leu Lys Tyr Leu Tyr Leu Val Val Ser Asp 275 280 285 Ser Gly Ile Ser Thr Asp Tyr Ser Ser Gly Asp Ser Gln Gly Ala Gln 290 295 300 Gly Gly Leu Ser Asp Gly Pro Tyr Ser Asn Pro Tyr Glu Asn Ser Leu 305 310 315 320 Ile Pro Ala Ala Glu Pro Leu Pro Pro Ser Tyr Val Ala Cys Ser 325 330 335 <210> 21 <211> 271 <212> PRT <213> homo sapiens <400> 21 Met Leu Leu Ala Pro Pro Ser Thr Pro Ser Arg Gly Arg Thr Pro Ser 1 5 10 15 Ala Val Glu Arg Leu Glu Ala Asp Lys Ala Lys Tyr Val Lys Thr His 20 25 30 Gln Val Ile Ala Arg Arg Gln Glu Pro Ala Leu Arg Gly Ser Pro Gly 35 40 45 Pro Leu Thr Pro His Pro Cys Asn Glu Leu Gly Pro Pro Ala Ser Pro 50 55 60 Arg Thr Pro Arg Pro Val Arg Arg Gly Ser Gly Arg Arg Leu Pro Arg 65 70 75 80 Pro Asp Ser Leu Ile Phe Tyr Arg Gln Lys Arg Asp Cys Lys Ala Ser 85 90 95 Val Asn Lys Glu Asn Ala Lys Gly Gln Gly Leu Val Arg Arg Leu Phe 100 105 110 Leu Gly Ala Pro Arg Asp Ala Ala Pro Ser Ser Pro Ala Ser Thr Glu 115 120 125 Arg Pro Ala Ala Ser Gly Gly Trp Ala Ala Pro Gln Asp Ala Pro Glu 130 135 140 Ala Ala Gly Lys Arg Ala Leu Cys Pro Thr Cys Ser Leu Pro Leu Ser 145 150 155 160 Glu Lys Glu Arg Phe Phe Asn Tyr Cys Gly Leu Glu Arg Ala Leu Val 165 170 175 Glu Val Leu Gly Ala Glu Arg Phe Ser Pro Gln Ser Trp Gly Ala Asp 180 185 190 Ala Ser Pro Gln Ala Gly Thr Ser Pro Pro Pro Gly Ser Gly Asp Ala 195 200 205 Ser Asp Trp Thr Ser Ser Asp Arg Gly Val Asp Ser Pro Gly Gly Ala 210 215 220 Gly Gly Gly Gly Gly Ser Glu Ala Ala Gly Ser Ala Arg Asp Arg Arg 225 230 235 240 Pro Pro Val Ser Val Val Glu Arg Asn Ala Arg Val Ile Gln Trp Leu 245 250 255 Tyr Gly Cys Gln Arg Ala Arg Gly Pro Pro Arg Glu Ser Glu Val 260 265 270 <210> 22 <211> 159 <212> PRT <213> homo sapiens <400> 22 Met Thr Leu Glu Glu Val Arg Gly Gln Asp Thr Val Pro Glu Ser Thr 1 5 10 15 Ala Arg Met Gln Gly Ala Gly Lys Ala Leu His Glu Leu Leu Leu Ser 20 25 30 Ala Gln Arg Gln Gly Cys Leu Thr Ala Gly Val Tyr Glu Ser Ala Lys 35 40 45 Val Leu Asn Val Asp Pro Asp Asn Val Thr Phe Cys Val Leu Ala Ala 50 55 60 Gly Glu Glu Asp Glu Gly Asp Ile Ala Leu Gln Ile His Phe Thr Leu 65 70 75 80 Ile Gln Ala Phe Cys Cys Glu Asn Asp Ile Asp Ile Val Arg Val Gly 85 90 95 Asp Val Gln Arg Leu Ala Ala Ile Val Gly Ala Gly Glu Glu Ala Gly 100 105 110 Ala Pro Gly Asp Leu His Cys Ile Leu Ile Ser Asn Pro Asn Glu Asp 115 120 125 Ala Trp Lys Asp Pro Ala Leu Glu Lys Leu Ser Leu Phe Cys Glu Glu 130 135 140 Ser Arg Ser Val Asn Asp Trp Val Pro Ser Ile Thr Leu Pro Glu 145 150 155 <210> 23 <211> 270 <212> PRT <213> homo sapiens <400> 23 Met Gln Tyr Pro His Pro Gly Pro Ala Ala Gly Ala Val Gly Val Pro 1 5 10 15 Leu Tyr Ala Pro Thr Pro Leu Leu Gln Pro Ala His Pro Thr Pro Phe 20 25 30 Tyr Ile Glu Asp Ile Leu Gly Arg Gly Pro Ala Ala Pro Thr Pro Ala 35 40 45 Pro Thr Leu Pro Ser Pro Asn Ser Ser Phe Thr Ser Leu Val Ser Pro 50 55 60 Tyr Arg Thr Pro Val Tyr Glu Pro Thr Pro Ile His Pro Ala Phe Ser 65 70 75 80 His His Ser Ala Ala Ala Leu Ala Ala Ala Tyr Gly Pro Gly Gly Phe 85 90 95 Gly Gly Pro Leu Tyr Pro Phe Pro Arg Thr Val Asn Asp Tyr Thr His 100 105 110 Ala Leu Leu Arg His Asp Pro Leu Gly Lys Pro Leu Leu Trp Ser Pro 115 120 125 Phe Leu Gln Arg Pro Leu His Lys Arg Lys Gly Gly Gln Val Arg Phe 130 135 140 Ser Asn Asp Gln Thr Ile Glu Leu Glu Lys Lys Phe Glu Thr Gln Lys 145 150 155 160 Tyr Leu Ser Pro Pro Glu Arg Lys Arg Leu Ala Lys Met Leu Gln Leu 165 170 175 Ser Glu Arg Gln Val Lys Thr Trp Phe Gln Asn Arg Arg Ala Lys Trp 180 185 190 Arg Arg Leu Lys Gln Glu Asn Pro Gln Ser Asn Lys Lys Glu Glu Leu 195 200 205 Glu Ser Leu Asp Ser Ser Cys Asp Gln Arg Gln Asp Leu Pro Ser Glu 210 215 220 Gln Asn Lys Gly Ala Ser Leu Asp Ser Ser Gln Cys Ser Pro Ser Pro 225 230 235 240 Ala Ser Gln Glu Asp Leu Glu Ser Glu Ile Ser Glu Asp Ser Asp Gln 245 250 255 Glu Val Asp Ile Glu Gly Asp Lys Ser Tyr Phe Asn Ala Gly 260 265 270 <210> 24 <211> 749 <212> PRT <213> homo sapiens <400> 24 Met Ser Ala Ala Ala Gly Ser Arg Glu Arg Asn Thr Ala Gly Gly Ser 1 5 10 15 Asn Phe Asp Gly Leu Arg Pro Asn Gly Lys Gly Val Pro Met Asp Gln 20 25 30 Ser Ser Arg Gly Gln Asp Lys Pro Glu Ser Leu Gln Pro Arg Gln Asn 35 40 45 Lys Ser Lys Ser Glu Ile Thr Asp Met Val Arg Ser Ser Thr Ile Thr 50 55 60 Val Ser Asp Lys Ala His Ile Leu Ser Met Gln Lys Phe Gly Leu Arg 65 70 75 80 Asp Thr Ile Val Lys Ser His Leu Leu Gln Lys Glu Glu Asp Tyr Thr 85 90 95 Tyr Ile Gln Asn Phe Arg Phe Phe Ala Gly Thr Tyr Asn Val Asn Gly 100 105 110 Gln Ser Pro Lys Glu Cys Leu Arg Leu Trp Leu Ser Asn Gly Ile Gln 115 120 125 Ala Pro Asp Val Tyr Cys Val Gly Phe Gln Glu Leu Asp Leu Ser Lys 130 135 140 Glu Ala Phe Phe Phe His Asp Thr Pro Lys Glu Glu Glu Trp Phe Lys 145 150 155 160 Ala Val Ser Glu Gly Leu His Pro Asp Ala Lys Tyr Ala Lys Val Lys 165 170 175 Leu Ile Arg Leu Val Gly Ile Met Leu Leu Leu Tyr Val Lys Gln Glu 180 185 190 His Ala Ala Tyr Ile Ser Glu Val Glu Ala Glu Thr Val Gly Thr Gly 195 200 205 Ile Met Gly Arg Met Gly Asn Lys Gly Gly Val Ala Ile Arg Phe Gln 210 215 220 Phe His Asn Thr Ser Ile Cys Val Val Asn Ser His Leu Ala Ala His 225 230 235 240 Ile Glu Glu Tyr Glu Arg Arg Asn Gln Asp Tyr Lys Asp Ile Cys Ser 245 250 255 Arg Met Gln Phe Cys Gln Pro Asp Pro Ser Leu Pro Pro Leu Thr Ile 260 265 270 Ser Asn His Asp Val Ile Leu Trp Leu Gly Asp Leu Asn Tyr Arg Ile 275 280 285 Glu Glu Leu Asp Val Glu Lys Val Lys Lys Leu Ile Glu Glu Lys Asp 290 295 300 Phe Gln Met Leu Tyr Ala Tyr Asp Gln Leu Lys Ile Gln Val Ala Ala 305 310 315 320 Lys Thr Val Phe Glu Gly Phe Thr Glu Gly Glu Leu Thr Phe Gln Pro 325 330 335 Thr Tyr Lys Tyr Asp Thr Gly Ser Asp Asp Trp Asp Thr Ser Glu Lys 340 345 350 Cys Arg Ala Pro Ala Trp Cys Asp Arg Ile Leu Trp Lys Gly Lys Asn 355 360 365 Ile Thr Gln Leu Ser Tyr Gln Ser His Met Ala Leu Lys Thr Ser Asp 370 375 380 His Lys Pro Val Ser Ser Val Phe Asp Ile Gly Val Arg Val Val Asn 385 390 395 400 Asp Glu Leu Tyr Arg Lys Thr Leu Glu Glu Ile Val Arg Ser Leu Asp 405 410 415 Lys Met Glu Asn Ala Asn Ile Pro Ser Val Ser Leu Ser Lys Arg Glu 420 425 430 Phe Cys Phe Gln Asn Val Lys Tyr Met Gln Leu Lys Val Glu Ser Phe 435 440 445 Thr Ile His Asn Gly Gln Val Pro Cys His Phe Glu Phe Ile Asn Lys 450 455 460 Pro Asp Glu Glu Ser Tyr Cys Lys Gln Trp Leu Asn Ala Asn Pro Ser 465 470 475 480 Arg Gly Phe Leu Leu Pro Asp Ser Asp Val Glu Ile Asp Leu Glu Leu 485 490 495 Phe Val Asn Lys Met Thr Ala Thr Lys Leu Asn Ser Gly Glu Asp Lys 500 505 510 Ile Glu Asp Ile Leu Val Leu His Leu Asp Arg Gly Lys Asp Tyr Phe 515 520 525 Leu Ser Val Ser Gly Asn Tyr Leu Pro Ser Cys Phe Gly Ser Pro Ile 530 535 540 His Thr Leu Cys Tyr Met Arg Glu Pro Ile Leu Asp Leu Pro Leu Glu 545 550 555 560 Thr Ile Ser Glu Leu Thr Leu Met Pro Val Trp Thr Gly Asp Asp Gly 565 570 575 Ser Gln Leu Asp Ser Pro Met Glu Ile Pro Lys Glu Leu Trp Met Met 580 585 590 Val Asp Tyr Leu Tyr Arg Asn Ala Val Gln Gln Glu Asp Leu Phe Gln 595 600 605 Gln Pro Gly Leu Arg Ser Glu Phe Glu His Ile Arg Asp Cys Leu Asp 610 615 620 Thr Gly Met Ile Asp Asn Leu Ser Ala Ser Asn His Ser Val Ala Glu 625 630 635 640 Ala Leu Leu Leu Phe Leu Glu Ser Leu Pro Glu Pro Val Ile Cys Tyr 645 650 655 Ser Thr Tyr His Asn Cys Leu Glu Cys Ser Gly Asn Tyr Thr Ala Ser 660 665 670 Lys Gln Val Ile Ser Thr Leu Pro Ile Phe His Lys Asn Val Phe His 675 680 685 Tyr Leu Met Ala Phe Leu Arg Glu Leu Leu Lys Asn Ser Ala Lys Asn 690 695 700 His Leu Asp Glu Asn Ile Leu Ala Ser Ile Phe Gly Ser Leu Leu Leu 705 710 715 720 Arg Asn Pro Ala Gly His Gln Lys Leu Asp Met Thr Glu Lys Lys Lys 725 730 735 Ala Gln Glu Phe Ile His Gln Phe Leu Cys Asn Pro Leu 740 745 <210> 25 <211> 424 <212> PRT <213> homo sapiens <400> 25 Met Leu Ala Arg Lys Ser Ile Ile Pro Glu Glu Tyr Val Leu Ala Arg 1 5 10 15 Ile Ala Ala Glu Asn Leu Arg Lys Pro Arg Ile Arg Asp Arg Leu Pro 20 25 30 Lys Ala Arg Phe Ile Ala Lys Ser Gly Ala Cys Asn Leu Ala His Lys 35 40 45 Asn Ile Arg Glu Gln Gly Arg Phe Leu Gln Asp Ile Phe Thr Thr Leu 50 55 60 Val Asp Leu Lys Trp Arg His Thr Leu Val Ile Phe Thr Met Ser Phe 65 70 75 80 Leu Cys Ser Trp Leu Leu Phe Ala Ile Met Trp Trp Leu Val Ala Phe 85 90 95 Ala His Gly Asp Ile Tyr Ala Tyr Met Glu Lys Ser Gly Met Glu Lys 100 105 110 Ser Gly Leu Glu Ser Thr Val Cys Val Thr Asn Val Arg Ser Phe Thr 115 120 125 Ser Ala Phe Leu Phe Ser Ile Glu Val Gln Val Thr Ile Gly Phe Gly 130 135 140 Gly Arg Met Met Thr Glu Glu Cys Pro Leu Ala Ile Thr Val Leu Ile 145 150 155 160 Leu Gln Asn Ile Val Gly Leu Ile Ile Asn Ala Val Met Leu Gly Cys 165 170 175 Ile Phe Met Lys Thr Ala Gln Ala His Arg Arg Ala Glu Thr Leu Ile 180 185 190 Phe Ser Arg His Ala Val Ile Ala Val Arg Asn Gly Lys Leu Cys Phe 195 200 205 Met Phe Arg Val Gly Asp Leu Arg Lys Ser Met Ile Ile Ser Ala Ser 210 215 220 Val Arg Ile Gln Val Val Lys Lys Thr Thr Thr Pro Glu Gly Glu Val 225 230 235 240 Val Pro Ile His Gln Leu Asp Ile Pro Val Asp Asn Pro Ile Glu Ser 245 250 255 Asn Asn Ile Phe Leu Val Ala Pro Leu Ile Ile Cys His Val Ile Asp 260 265 270 Lys Arg Ser Pro Leu Tyr Asp Ile Ser Ala Thr Asp Leu Ala Asn Gln 275 280 285 Asp Leu Glu Val Ile Val Ile Leu Glu Gly Val Val Glu Thr Thr Gly 290 295 300 Ile Thr Thr Gln Ala Arg Thr Ser Tyr Ile Ala Glu Glu Ile Gln Trp 305 310 315 320 Gly His Arg Phe Val Ser Ile Val Thr Glu Glu Glu Gly Val Tyr Ser 325 330 335 Val Asp Tyr Ser Lys Phe Gly Asn Thr Val Lys Val Ala Ala Pro Arg 340 345 350 Cys Ser Ala Arg Glu Leu Asp Glu Lys Pro Ser Ile Leu Ile Gln Thr 355 360 365 Leu Gln Lys Ser Glu Leu Ser His Gln Asn Ser Leu Arg Lys Arg Asn 370 375 380 Ser Met Arg Arg Asn Asn Ser Met Arg Arg Asn Asn Ser Ile Arg Arg 385 390 395 400 Asn Asn Ser Ser Leu Met Val Pro Lys Val Gln Phe Met Thr Pro Glu 405 410 415 Gly Asn Gln Asn Thr Ser Glu Ser 420 <210> 26 <211> 207 <212> PRT <213> homo sapiens <400> 26 Met Ala Ala Leu Val Glu Pro Leu Gly Leu Glu Arg Asp Val Ser Arg 1 5 10 15 Ala Val Glu Leu Leu Glu Arg Leu Gln Arg Ser Gly Glu Leu Pro Pro 20 25 30 Gln Lys Leu Gln Ala Leu Gln Arg Val Leu Gln Ser Arg Phe Cys Ser 35 40 45 Ala Ile Arg Glu Val Tyr Glu Gln Leu Tyr Asp Thr Leu Asp Ile Thr 50 55 60 Gly Ser Ala Glu Ile Arg Ala His Ala Thr Ala Lys Ala Thr Val Ala 65 70 75 80 Ala Phe Thr Ala Ser Glu Gly His Ala His Pro Arg Val Val Glu Leu 85 90 95 Pro Lys Thr Asp Glu Gly Leu Gly Phe Asn Ile Met Gly Gly Lys Glu 100 105 110 Gln Asn Ser Pro Ile Tyr Ile Ser Arg Val Ile Pro Gly Gly Val Ala 115 120 125 Asp Arg His Gly Gly Leu Lys Arg Gly Asp Gln Leu Leu Ser Val Asn 130 135 140 Gly Val Ser Val Glu Gly Glu Gln His Glu Lys Ala Val Glu Leu Leu 145 150 155 160 Lys Ala Ala Gln Gly Ser Val Lys Leu Val Val Arg Tyr Thr Pro Arg 165 170 175 Val Leu Glu Glu Met Glu Ala Arg Phe Glu Lys Met Arg Ser Ala Arg 180 185 190 Arg Arg Gln Gln His Gln Ser Tyr Ser Ser Leu Glu Ser Arg Gly 195 200 205 <210> 27 <211> 544 <212> PRT <213> homo sapiens <400> 27 Met Ser Asp Gly Leu Asp Asn Glu Glu Lys Pro Pro Ala Pro Pro Leu 1 5 10 15 Arg Met Asn Ser Asn Asn Arg Asp Ser Ser Ala Leu Asn His Ser Ser 20 25 30 Lys Pro Leu Pro Met Ala Pro Glu Glu Lys Asn Lys Lys Ala Arg Leu 35 40 45 Arg Ser Ile Phe Pro Gly Gly Gly Asp Lys Thr Asn Lys Lys Lys Glu 50 55 60 Lys Glu Arg Pro Glu Ile Ser Leu Pro Ser Asp Phe Glu His Thr Ile 65 70 75 80 His Val Gly Phe Asp Ala Val Thr Gly Glu Phe Thr Gly Ile Pro Glu 85 90 95 Gln Trp Ala Arg Leu Leu Gln Thr Ser Asn Ile Thr Lys Leu Glu Gln 100 105 110 Lys Lys Asn Pro Gln Ala Val Leu Asp Val Leu Lys Phe Tyr Asp Ser 115 120 125 Lys Glu Thr Val Asn Asn Gln Lys Tyr Met Ser Phe Thr Ser Gly Asp 130 135 140 Lys Ser Ala His Gly Tyr Ile Ala Ala His Pro Ser Ser Thr Lys Thr 145 150 155 160 Ala Ser Glu Pro Pro Leu Ala Pro Pro Val Ser Glu Glu Glu Asp Glu 165 170 175 Glu Glu Glu Glu Glu Glu Asp Glu Asn Glu Pro Pro Pro Val Ile Ala 180 185 190 Pro Arg Pro Glu His Thr Lys Ser Ile Tyr Thr Arg Ser Val Val Glu 195 200 205 Ser Ile Ala Ser Pro Ala Val Pro Asn Lys Glu Val Thr Pro Pro Ser 210 215 220 Ala Glu Asn Ala Asn Ser Ser Thr Leu Tyr Arg Asn Thr Asp Arg Gln 225 230 235 240 Arg Lys Lys Ser Lys Met Thr Asp Glu Glu Ile Leu Glu Lys Leu Arg 245 250 255 Ser Ile Val Ser Val Gly Asp Pro Lys Lys Lys Tyr Thr Arg Phe Glu 260 265 270 Lys Ile Gly Gln Gly Ala Ser Gly Thr Val Tyr Thr Ala Leu Asp Ile 275 280 285 Ala Thr Gly Gln Glu Val Ala Ile Lys Gln Met Asn Leu Gln Gln Gln 290 295 300 Pro Lys Lys Glu Leu Ile Ile Asn Glu Ile Leu Val Met Arg Glu Asn 305 310 315 320 Lys Asn Pro Asn Ile Val Asn Tyr Leu Asp Ser Tyr Leu Val Gly Asp 325 330 335 Glu Leu Trp Val Val Met Glu Tyr Leu Ala Gly Gly Ser Leu Thr Asp 340 345 350 Val Val Thr Glu Thr Cys Met Asp Glu Gly Gln Ile Ala Ala Val Cys 355 360 365 Arg Glu Cys Leu Gln Ala Leu Asp Phe Leu His Ser Asn Gln Val Ile 370 375 380 His Arg Asp Ile Lys Ser Asp Asn Ile Leu Leu Gly Met Asp Gly Ser 385 390 395 400 Val Lys Leu Thr Asp Phe Gly Phe Cys Ala Gln Ile Thr Pro Glu Gln 405 410 415 Ser Lys Arg Ser Thr Met Val Gly Thr Pro Tyr Trp Met Ala Pro Glu 420 425 430 Val Val Thr Arg Lys Ala Tyr Gly Pro Lys Val Asp Ile Trp Ser Leu 435 440 445 Gly Ile Met Ala Ile Glu Met Val Glu Gly Glu Pro Pro Pro Tyr Leu Asn 450 455 460 Glu Asn Pro Leu Arg Ala Leu Tyr Leu Ile Ala Thr Asn Gly Thr Pro 465 470 475 480 Glu Leu Gln Asn Pro Glu Arg Leu Ser Ala Val Phe Arg Asp Phe Leu 485 490 495 Asn Arg Cys Leu Glu Met Asp Val Asp Arg Arg Gly Ser Ala Lys Glu 500 505 510 Leu Leu Gln His Pro Phe Leu Lys Leu Ala Lys Pro Leu Ser Ser Leu 515 520 525 Thr Pro Leu Ile Ile Ala Ala Lys Glu Ala Ile Lys Asn Ser Ser Arg 530 535 540 <210> 28 <211> 135 <212> PRT <213> homo sapiens <400> 28 Met Pro Pro Asn Leu Thr Gly Tyr Tyr Arg Phe Val Ser Gln Lys Asn 1 5 10 15 Met Glu Asp Tyr Leu Gln Ala Leu Asn Ile Ser Leu Ala Val Arg Lys 20 25 30 Ile Ala Leu Leu Leu Lys Pro Asp Lys Glu Ile Glu His Gln Gly Asn 35 40 45 His Met Thr Val Arg Thr Leu Ser Thr Phe Arg Asn Tyr Thr Val Gln 50 55 60 Phe Asp Val Gly Val Glu Phe Glu Glu Asp Leu Arg Ser Val Asp Gly 65 70 75 80 Arg Lys Cys Gln Thr Ile Val Thr Trp Glu Glu Glu His Leu Val Cys 85 90 95 Val Gln Lys Gly Glu Val Pro Asn Arg Gly Trp Arg His Trp Leu Glu 100 105 110 Gly Glu Met Leu Tyr Leu Glu Leu Thr Ala Arg Asp Ala Val Cys Glu 115 120 125 Gln Val Phe Arg Lys Val Arg 130 135 <210> 29 <211> 79 <212> PRT <213> homo sapiens <400> 29 Met Leu Ser Trp Thr Cys Trp His His Arg Gln Leu Leu Cys Cys Ala 1 5 10 15 Cys Gly Leu Gly Ala Lys Arg Lys Trp Arg Phe Leu His Ser Val Leu 20 25 30 Gly Asn Gln Trp Ala Leu Arg Met Val Tyr Gly Leu Thr Leu Leu Ala 35 40 45 Thr Lys Ala Arg Gln His Leu Asp Phe Arg Phe Trp Lys Pro Pro Tyr 50 55 60 Leu Val Cys Ser Met Arg Glu Gly Gln Gln His Arg Trp Glu Pro 65 70 75

Claims (28)

CNOT1 (CCR4-NOT Transcription Complex Subunit 1), KIF11 (kinesin family member 11), SLC44A1 (Solute Carrier Family 44 Member 1), MSI1 (Musashi RNA Binding Protein 1), SDK1 (Sidekick Cell Adhesion Molecule 1), and SYNGR1 (Synaptogyrin 1) at least one protein selected from the group consisting of; Or an agent for measuring the expression level of the gene encoding the same; A composition for diagnosing cancer comprising as an active ingredient. According to clause 1,
The agent for measuring the expression level of the protein is a composition comprising at least one selected from the group consisting of antibodies, oligopeptides, ligands, PNA (peptide nucleic acids), and aptamers that specifically bind to the protein. . According to clause 1,
A composition for measuring the expression level of the gene, comprising at least one selected from the group consisting of primers, probes, and antisense nucleotides that specifically bind to the gene. According to clause 1,
The composition is for application to a biological sample isolated from a subject of interest. According to clause 4,
The biological sample includes whole blood, leukocytes, peripheral blood mononuclear cells, buffy coat, plasma, serum, sputum, and tears ( tears, mucus, nasal washes, nasal aspirate, breath, urine, semen, saliva, peritoneal washings, Ascites, cystic fluid, meningeal fluid, amniotic fluid, glandular fluid, pancreatic fluid, lymph fluid, pleural fluid, nipple Nipple aspirate, bronchial aspirate, synovial fluid, joint aspirate, organ secretions, cells, cell extract and cerebrospinal fluid ( A composition comprising at least one member selected from the group consisting of cerebrospinal fluid. According to clause 1,
The above cancers include pancreatic cancer, thyroid cancer, parathyroid cancer, stomach cancer, ovarian cancer, colon cancer, liver cancer, breast cancer, cervical cancer, lung cancer, non-small cell lung cancer, prostate cancer, gallbladder cancer, biliary tract cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, and blood cancer. , bladder cancer, kidney cancer, melanoma, colon cancer, bone cancer, skin cancer, head cancer, uterine cancer, rectal cancer, brain tumor, perianal cancer, fallopian tube carcinoma, endometrial carcinoma, vaginal cancer, vulvar carcinoma, esophageal cancer, small intestine cancer, endocrine cancer, adrenal cancer. , soft tissue sarcoma, urethral cancer, penile cancer, ureteral cancer, renal cell carcinoma, renal pelvic carcinoma, CNS central nervous system tumor, primary CNS lymphoma, spinal cord tumor, brainstem glioma or pituitary adenoma. According to clause 1,
The composition includes CELSR1 (Cadherin EGF LAG Seven-Pass G-Type Receptor 1), DCLRE1B (DNA Cross-Link Repair 1B), ITGA3 (Integrin Subunit Alpha 3), KIAA1217 (Sickle Tail Protein Homolog), and MBOAT2 (Membrane Bound O- Acyltransferase Domain Containing 2), RCC1 (Regulator Of Chromosome Condensation 1), SON (SON DNA And RNA Binding Protein), TLDC1 (MTOR Associated Protein, Eak-7 Homolog), ZFP69 (Zinc Finger Protein 69 Homolog), ADCY1 (Adenylate Cyclase) 1), ARL6IP4 (ADP Ribosylation Factor Like GTPase 6 Interacting Protein 4), ATP8A1 (ATPase Phospholipid Transporting 8A1), COX14 (Cytochrome C Oxidase Assembly Factor COX14), EPOR (Erythropoietin Receptor), FAM110D (Family With Sequence Similarity 110 Member D) , GADD45G (Growth Arrest And DNA Damage Inducible Gamma), HHEX (Hematopoietically Expressed Homeobox), INPP5B (Inositol Polyphosphate-5-Phosphatase B), KCNJ8 (Potassium Inwardly Rectifying Channel Subfamily J Member 8), LIN7B (Lin-7 homolog B) , at least one protein selected from the group consisting of P21 Activated Kinase 3 (PAK3), Retinol Binding Protein 5 (RBP5), and Small Nucleolar RNA Host Gene 7 (SNHG7); Or an agent for measuring the expression level of the gene encoding the same. A kit for diagnosing cancer, comprising the composition of any one of claims 1 to 7. According to clause 8,
The kit is an RT-PCR kit, a DNA chip kit, an ELISA kit, a protein chip kit, a rapid kit, or a multiple reaction monitoring (MRM) kit. In biological samples isolated from the subject of interest,
CNOT1 (CCR4-NOT Transcription Complex Subunit 1), KIF11 (kinesin family member 11), SLC44A1 (Solute Carrier Family 44 Member 1), MSI1 (Musashi RNA Binding Protein 1), SDK1 (Sidekick Cell Adhesion Molecule 1), and SYNGR1 (Synaptogyrin 1) at least one protein selected from the group consisting of; Or a method of providing information for the diagnosis of cancer, comprising; measuring the expression level of the gene encoding the protein. According to clause 10,
The biological sample includes whole blood, leukocytes, peripheral blood mononuclear cells, buffy coat, plasma, serum, sputum, and tears ( tears, mucus, nasal washes, nasal aspirate, breath, urine, semen, saliva, peritoneal washings, Ascites, cystic fluid, meningeal fluid, amniotic fluid, glandular fluid, pancreatic fluid, lymph fluid, pleural fluid, nipple Nipple aspirate, bronchial aspirate, synovial fluid, joint aspirate, organ secretions, cells, cell extract and cerebrospinal fluid ( A method of at least one selected from the group consisting of cerebrospinal fluid. According to clause 10,
At least one protein selected from the group consisting of CNOT1, KIF11, and SLC44A1 measured in the biological sample; or at least one protein selected from the group consisting of MSI1, SDK1, and SYNGR1, where the expression level of the gene encoding it is higher than that of the control group, or measured; Or, a method of predicting that the subject of interest has developed or is highly likely to develop cancer when the expression level of the gene encoding it is lower than that of the control group. According to clause 10,
The method includes CELSR1 (Cadherin EGF LAG Seven-Pass G-Type Receptor 1), DCLRE1B (DNA Cross-Link Repair 1B), ITGA3 (Integrin Subunit Alpha 3), KIAA1217 (Sickle Tail Protein Homolog), and MBOAT2 (Membrane Bound O- Acyltransferase Domain Containing 2), RCC1 (Regulator Of Chromosome Condensation 1), SON (SON DNA And RNA Binding Protein), TLDC1 (MTOR Associated Protein, Eak-7 Homolog), ZFP69 (Zinc Finger Protein 69 Homolog), ADCY1 (Adenylate Cyclase) 1), ARL6IP4 (ADP Ribosylation Factor Like GTPase 6 Interacting Protein 4), ATP8A1 (ATPase Phospholipid Transporting 8A1), COX14 (Cytochrome C Oxidase Assembly Factor COX14), EPOR (Erythropoietin Receptor), FAM110D (Family With Sequence Similarity 110 Member D) , GADD45G (Growth Arrest And DNA Damage Inducible Gamma), HHEX (Hematopoietically Expressed Homeobox), INPP5B (Inositol Polyphosphate-5-Phosphatase B), KCNJ8 (Potassium Inwardly Rectifying Channel Subfamily J Member 8), LIN7B (Lin-7 homolog B) , at least one protein selected from the group consisting of P21 Activated Kinase 3 (PAK3), Retinol Binding Protein 5 (RBP5), and Small Nucleolar RNA Host Gene 7 (SNHG7); Or a method further comprising measuring the expression level of the gene encoding the same. According to clause 13,
At least one protein selected from the group consisting of CELSR1, DCLRE1B, ITGA3, KIAA1217, MBOAT2, RCC1, SON, TLDC1 and ZFP69 measured; Or the expression level of the gene encoding this is higher than the control group, or selected from the group consisting of ADCY1, ARL6IP4, ATP8A1, COX14, EPOR, FAM110D, GADD45G, HHEX, INPP5B, KCNJ8, LIN7B, PAK3, RBP5 and SNHG7 at least one protein; Or, a method of predicting that the subject of interest has developed or is highly likely to develop cancer when the expression level of the gene encoding it is lower than that of the control group. According to clause 10,
The expression level of the protein can be measured using protein chip analysis, immunoassay, ligand binding assay, Matrix Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF) analysis, and Surface Enhanced Laser Desorption/Ionization Time of SELDI-TOF (SELDI-TOF). Flight Mass Spectrometry analysis, radioimmunoassay, radioimmunodiffusion method, Ouchteroni immunodiffusion method, rocket immunoelectrophoresis, tissue immunostaining, complement fixation assay, two-dimensional electrophoresis analysis, liquid chromatography-mass spectrometry. Mass Spectrometry, LC-MS), LC-MS/MS (liquid chromatography-Mass Spectrometry/Mass Spectrometry), Western blotting, ELISA (enzyme linked immunosorbent assay), or multiple reaction monitoring (MRM) methods, method. According to clause 10,
The expression level of the gene can be measured using reverse transcription polymerase reaction (RT-PCR), competitive reverse transcription polymerase reaction (Competitive RT-PCR), real-time reverse transcription polymerase reaction (Real-time RT-PCR), and RNase protection assay (RPA). RNase protection assay), Northern blotting or DNA chip method. According to clause 10,
The above cancers include pancreatic cancer, thyroid cancer, parathyroid cancer, stomach cancer, ovarian cancer, colon cancer, liver cancer, breast cancer, cervical cancer, lung cancer, non-small cell lung cancer, prostate cancer, gallbladder cancer, biliary tract cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, and blood cancer. , bladder cancer, kidney cancer, melanoma, colon cancer, bone cancer, skin cancer, head cancer, uterine cancer, rectal cancer, brain tumor, perianal cancer, fallopian tube carcinoma, endometrial carcinoma, vaginal cancer, vulvar carcinoma, esophageal cancer, small intestine cancer, endocrine cancer, adrenal cancer. , soft tissue sarcoma, urethral cancer, penile cancer, ureteral cancer, renal cell carcinoma, renal pelvic carcinoma, CNS central nervous system tumor, primary CNS lymphoma, spinal cord tumor, brainstem glioma, or pituitary adenoma. CNOT1 (CCR4-NOT Transcription Complex Subunit 1), KIF11 (kinesin family member 11), SLC44A1 (Solute Carrier Family 44 Member 1), MSI1 (Musashi RNA Binding Protein 1), SDK1 (Sidekick Cell Adhesion Molecule 1), and SYNGR1 (Synaptogyrin 1) at least one protein selected from the group consisting of; Or an agent for measuring the expression level of the gene encoding the same; A composition for predicting the prognosis of cancer comprising as an active ingredient. According to clause 18,
The above cancers include pancreatic cancer, thyroid cancer, parathyroid cancer, stomach cancer, ovarian cancer, colon cancer, liver cancer, breast cancer, cervical cancer, lung cancer, non-small cell lung cancer, prostate cancer, gallbladder cancer, biliary tract cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, and blood cancer. , bladder cancer, kidney cancer, melanoma, colon cancer, bone cancer, skin cancer, head cancer, uterine cancer, rectal cancer, brain tumor, perianal cancer, fallopian tube carcinoma, endometrial carcinoma, vaginal cancer, vulvar carcinoma, esophageal cancer, small intestine cancer, endocrine cancer, adrenal cancer. , soft tissue sarcoma, urethral cancer, penile cancer, ureteral cancer, renal cell carcinoma, renal pelvic carcinoma, CNS central nervous system tumor, primary CNS lymphoma, spinal cord tumor, brainstem glioma or pituitary adenoma. A kit for predicting the prognosis of cancer, comprising the composition of claim 18. In biological samples isolated from the subject of interest,
CNOT1 (CCR4-NOT Transcription Complex Subunit 1), KIF11 (kinesin family member 11), SLC44A1 (Solute Carrier Family 44 Member 1), MSI1 (Musashi RNA Binding Protein 1), SDK1 (Sidekick Cell Adhesion Molecule 1), and SYNGR1 (Synaptogyrin 1) at least one protein selected from the group consisting of; Or a method of providing information for predicting the prognosis of cancer, comprising; measuring the expression level of the gene encoding the protein. According to clause 21,
The above cancers include pancreatic cancer, thyroid cancer, parathyroid cancer, stomach cancer, ovarian cancer, colon cancer, liver cancer, breast cancer, cervical cancer, lung cancer, non-small cell lung cancer, prostate cancer, gallbladder cancer, biliary tract cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, and blood cancer. , bladder cancer, kidney cancer, melanoma, colon cancer, bone cancer, skin cancer, head cancer, uterine cancer, rectal cancer, brain tumor, perianal cancer, fallopian tube carcinoma, endometrial carcinoma, vaginal cancer, vulvar carcinoma, esophageal cancer, small intestine cancer, endocrine cancer, adrenal cancer. , soft tissue sarcoma, urethral cancer, penile cancer, ureteral cancer, renal cell carcinoma, renal pelvic carcinoma, CNS central nervous system tumor, primary CNS lymphoma, spinal cord tumor, brainstem glioma, or pituitary adenoma. According to clause 21,
At least one protein selected from the group consisting of CNOT1, KIF11, and SLC44A1 measured in the biological sample; or at least one protein selected from the group consisting of MSI1, SDK1, and SYNGR1, where the expression level of the gene encoding it is higher than that of the control group, or measured; Or, a method of predicting that the prognosis of cancer is poor when the expression level of the gene encoding it is lower than that of the control group. According to clause 21,
The method includes CELSR1 (Cadherin EGF LAG Seven-Pass G-Type Receptor 1), DCLRE1B (DNA Cross-Link Repair 1B), ITGA3 (Integrin Subunit Alpha 3), KIAA1217 (Sickle Tail Protein Homolog), and MBOAT2 (Membrane Bound O- Acyltransferase Domain Containing 2), RCC1 (Regulator Of Chromosome Condensation 1), SON (SON DNA And RNA Binding Protein), TLDC1 (MTOR Associated Protein, Eak-7 Homolog), ZFP69 (Zinc Finger Protein 69 Homolog), ADCY1 (Adenylate Cyclase) 1), ARL6IP4 (ADP Ribosylation Factor Like GTPase 6 Interacting Protein 4), ATP8A1 (ATPase Phospholipid Transporting 8A1), COX14 (Cytochrome C Oxidase Assembly Factor COX14), EPOR (Erythropoietin Receptor), FAM110D (Family With Sequence Similarity 110 Member D) , GADD45G (Growth Arrest And DNA Damage Inducible Gamma), HHEX (Hematopoietically Expressed Homeobox), INPP5B (Inositol Polyphosphate-5-Phosphatase B), KCNJ8 (Potassium Inwardly Rectifying Channel Subfamily J Member 8), LIN7B (Lin-7 homolog B) , at least one protein selected from the group consisting of P21 Activated Kinase 3 (PAK3), Retinol Binding Protein 5 (RBP5), and Small Nucleolar RNA Host Gene 7 (SNHG7); or measuring the expression level of the gene encoding the same. According to clause 24,
At least one protein selected from the group consisting of CELSR1, DCLRE1B, ITGA3, KIAA1217, MBOAT2, RCC1, SON, TLDC1 and ZFP69 measured; Or the expression level of the gene encoding this is higher than the control group, or selected from the group consisting of ADCY1, ARL6IP4, ATP8A1, COX14, EPOR, FAM110D, GADD45G, HHEX, INPP5B, KCNJ8, LIN7B, PAK3, RBP5 and SNHG7 at least one protein; Or, a method of predicting that the prognosis of cancer is poor when the expression level of the gene encoding it is lower than that of the control group. CNOT1 (CCR4-NOT Transcription Complex Subunit 1), KIF11 (kinesin family member 11), SLC44A1 (Solute Carrier Family 44 Member 1), MSI1 (Musashi RNA Binding Protein 1), SDK1 (Sidekick Cell Adhesion Molecule 1), and SYNGR1 (Synaptogyrin 1) at least one protein selected from the group consisting of; Or an agent for measuring the expression level of the gene encoding the same; a panel for diagnosing cancer or predicting the prognosis of cancer, comprising a. According to clause 26,
The above cancers include pancreatic cancer, thyroid cancer, parathyroid cancer, stomach cancer, ovarian cancer, colon cancer, liver cancer, breast cancer, cervical cancer, lung cancer, non-small cell lung cancer, prostate cancer, gallbladder cancer, biliary tract cancer, non-Hodgkin lymphoma, Hodgkin lymphoma, and blood cancer. , bladder cancer, kidney cancer, melanoma, colon cancer, bone cancer, skin cancer, head cancer, uterine cancer, rectal cancer, brain tumor, perianal cancer, fallopian tube carcinoma, endometrial carcinoma, vaginal cancer, vulvar carcinoma, esophageal cancer, small intestine cancer, endocrine cancer, adrenal cancer. , soft tissue sarcoma, urethral cancer, penile cancer, ureteral cancer, renal cell carcinoma, renal pelvic carcinoma, CNS central nervous system tumor, primary CNS lymphoma, spinal cord tumor, brainstem glioma, or pituitary adenoma, panel. According to clause 26,
The panel includes CELSR1 (Cadherin EGF LAG Seven-Pass G-Type Receptor 1), DCLRE1B (DNA Cross-Link Repair 1B), ITGA3 (Integrin Subunit Alpha 3), KIAA1217 (Sickle Tail Protein Homolog), and MBOAT2 (Membrane Bound O- Acyltransferase Domain Containing 2), RCC1 (Regulator Of Chromosome Condensation 1), SON (SON DNA And RNA Binding Protein), TLDC1 (MTOR Associated Protein, Eak-7 Homolog), ZFP69 (Zinc Finger Protein 69 Homolog), ADCY1 (Adenylate Cyclase) 1), ARL6IP4 (ADP Ribosylation Factor Like GTPase 6 Interacting Protein 4), ATP8A1 (ATPase Phospholipid Transporting 8A1), COX14 (Cytochrome C Oxidase Assembly Factor COX14), EPOR (Erythropoietin Receptor), FAM110D (Family With Sequence Similarity 110 Member D) , GADD45G (Growth Arrest And DNA Damage Inducible Gamma), HHEX (Hematopoietically Expressed Homeobox), INPP5B (Inositol Polyphosphate-5-Phosphatase B), KCNJ8 (Potassium Inwardly Rectifying Channel Subfamily J Member 8), LIN7B (Lin-7 homolog B) , at least one protein selected from the group consisting of P21 Activated Kinase 3 (PAK3), Retinol Binding Protein 5 (RBP5), and Small Nucleolar RNA Host Gene 7 (SNHG7); Or an agent for measuring the expression level of the gene encoding the same; a panel further comprising a.