KR20210129616A - Composition And Kit For Diagnosing Prognosis Of Bladder Cancer According To Pathologic Stage - Google Patents

Abstract

The present invention provides a composition for diagnosing the prognosis of bladder cancer depending on the pathologic stage of bladder cancer, a kit for diagnosing the prognosis of bladder cancer, and a method for providing the information necessary for diagnosing the prognosis of bladder cancer using the same. The composition and the kit for diagnosing the prognosis of bladder cancer according to the present invention enable users to diagnose and predict the prognosis of bladder cancer, such as the survival rate and recurrence rate after treatment, depending on the pathologic stage of bladder cancer, thereby helping them to establish a treatment strategy for a bladder cancer patient.

Description

Composition And Kit For Diagnosing Prognosis Of Bladder Cancer According To Pathologic Stage

The present invention relates to a composition for prognostic diagnosis of bladder cancer according to the pathological stage of bladder cancer, a kit for prognostic diagnosis of bladder cancer, and a method for providing information necessary for prognostic diagnosis of a bladder cancer patient using the same.

Bladder cancer (BC) is the most frequently occurring cancer in the urinary system. As such, the incidence rate is lower than in the West, but the incidence rate is increasing every year, and it is known as the cancer with the highest incidence among cancers of the urinary system in Korea (Lee C, et al., 1992).

Bladder cancer is largely divided into non-muscle invasive bladder cancer (NMIBC) and invasive (muscle invasive bladder cancer, MIBC) bladder cancer according to the degree of invasiveness. Noninvasive bladder cancer is a lesion in which the cancer is confined to the mucous membrane without invasion of the muscle layer. recurrence and progression to invasive cancer are problematic.

On the other hand, invasive bladder cancer refers to a state in which the cancer has penetrated to the muscle layer, and for its treatment, it is necessary to perform complex urinary diversion along with radical cystectomy, and it may lead to fatal results for the patient. Therefore, it is very important to predict, early detection and prevention of recurrence and progression after primary treatment.

For this reason, early diagnosis of bladder cancer and development of markers that can check the remaining lifespan after cancer onset is required. Patent Document 1 discloses a series of genetic markers that can be used for detection or diagnosis of human bladder cancer.

Although markers for diagnosing bladder cancer and other cancers have been developed, research has not yet been made on the relationship between the recurrence of bladder cancer patients or the survival rate of patients with recurrent bladder cancer and mutations in specific genes.

In order to diagnose bladder cancer or to discover a therapeutic agent for bladder cancer and determine a treatment strategy, the present inventors focused on the need to develop a marker capable of diagnosing the prognosis of a bladder cancer patient, The association with pathological stage was studied.

Korean Patent Publication No. 2014-0092905 (2014.07.24)

In order to apply a therapeutic strategy suitable for bladder cancer patients, it is necessary to develop a marker that can predict the prognosis of bladder cancer patients and provide information to determine a treatment strategy. An object of the present invention is to provide a marker that helps in prognostic diagnosis of bladder cancer patients and determination of treatment strategies for bladder cancer patients based on the pathological stage of bladder cancer.

One aspect of the present invention is a mutation in the AKAP9 gene, mutation in the BPIFB6 gene, mutation in the CHD4 gene, mutation in the DNMT3A gene, mutation in the DPM1 gene, mutation in the FRY gene, mutation in the GRM6 gene, mutation in the KIF4A gene, mutation in the KLHL36 gene , LTN1 gene mutation, MAP3K5 gene mutation, MED1 gene mutation, NAV3 gene mutation, NDNF gene mutation, NKRF gene mutation, OLFM4 gene mutation, OR13C3 gene mutation, PLEC gene mutation, RADIL gene mutation , RELN gene mutation, RIPK1 gene mutation, RNF123 gene mutation, RNF215 gene mutation, RSRC2 gene mutation, SIN3A gene mutation, SLC23A3 gene mutation, STAM gene mutation, TRIM59 gene mutation, USPL1 gene mutation , It provides a composition for prognostic diagnosis of bladder cancer comprising a reagent capable of detecting a pathological stage-specific marker of a bladder cancer patient comprising at least one selected from the group consisting of a mutation of the WNK1 gene and a mutation of the ZNF485 gene.

Another aspect of the present invention is an AKAP9 gene mutation, a BPIFB6 gene mutation, a CHD4 gene mutation, a DNMT3A gene mutation, a DPM1 gene mutation, a FRY gene mutation, a GRM6 gene mutation, a KIF4A gene mutation, and a KLHL36 gene mutation. , LTN1 gene mutation, MAP3K5 gene mutation, MED1 gene mutation, NAV3 gene mutation, NDNF gene mutation, NKRF gene mutation, OLFM4 gene mutation, OR13C3 gene mutation, PLEC gene mutation, RADIL gene mutation , RELN gene mutation, RIPK1 gene mutation, RNF123 gene mutation, RNF215 gene mutation, RSRC2 gene mutation, SIN3A gene mutation, SLC23A3 gene mutation, STAM gene mutation, TRIM59 gene mutation, USPL1 gene mutation , It provides a kit for prognostic diagnosis of bladder cancer comprising a reagent capable of detecting a pathological stage-specific marker of a bladder cancer patient comprising at least one selected from the group consisting of a mutation in the WNK1 gene and a mutation in the ZNF485 gene.

Another aspect of the present invention comprises the steps of preparing a sample DNA from a sample of a bladder cancer patient; and confirming the presence or absence of pathological stage-specific markers using the composition for prognosis diagnosis of bladder cancer or the kit for prognosis diagnosis of bladder cancer with respect to the sample DNA; providing information necessary for prognostic diagnosis of bladder cancer patients comprising a; provide a way

Using the composition for diagnosis of prognosis of bladder cancer of the present invention and a kit for diagnosis of prognosis of bladder cancer including the same, prognosis such as viability or recurrence after treatment can be diagnosed and predicted based on the pathological stage of bladder cancer. This can help establish a treatment strategy for bladder cancer patients.

In this specification, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In general, the nomenclature used herein and the experimental methods described below are those well known and commonly used in the art.

In the present invention, the term 'gene' and its variants include DNA fragments involved in polypeptide chain generation; It includes regions before and after the coding region, eg promoters and 3'-untranslated regions, respectively, as well as intervening sequences (introns) between individual coding fragments (exons).

As used herein, the term 'cancer' includes any member of a class of diseases characterized by the uncontrolled growth of abnormal cells. The term includes all known cancers and neoplastic conditions, whether characterized as malignant, benign, soft tissue or solid, and cancers of all stages and grades, including cancers before and after metastasis.

In the present invention, the term 'prognosis' refers to the progress and cure of neoplastic diseases such as cancer, such as the possibility of cancer-caused death or progression, including recurrence, metastatic spread, and drug resistance, for example. For the purpose of the present invention, it may be to predict the prognosis of bladder cancer, preferably to predict the disease-free survival rate or survival rate of bladder cancer patients.

In the present invention, the term 'diagnosis' refers to confirming the presence or characteristics of a pathological condition, and for the purpose of the present invention, not only confirming whether or not cancer occurs, but also recurrence, metastasis, drug reactivity, resistance of the subject after treatment of cancer It means judging whether or not Preferably, when using the mutation of the gene of the present invention, it is possible to predict whether or not the subject will develop cancer, as well as whether the prognosis of the subject will be good in the future by checking whether the mutation is present from the subject's sample.

In the present invention, the term 'pathological stage-specific marker' may refer to a mutation in a gene or mutations in a gene that can be an indicator for predicting the prognosis of bladder cancer in a subject after treatment based on the pathological stage of bladder cancer. Also, in the present invention, the 'marker gene' may be used to refer to each gene mutation included in the pathological stage-specific marker.

1. Composition and kit for prognostic diagnosis of bladder cancer

One aspect of the present invention provides a composition for prognostic diagnosis of bladder cancer comprising a reagent capable of detecting a pathological stage-specific marker of a bladder cancer patient. The pathological stage-specific marker of the composition for prognostic diagnosis of bladder cancer of the present invention may be an index predicting the prognosis of bladder cancer in a subject after treatment, depending on the pathological stage of bladder cancer.

For example, when the pathological stage-specific marker is identified and a specific pathological stage of bladder cancer is identified in a bladder cancer patient, the individual has a lower survival rate or a higher recurrence rate than a person for which the pathological stage-specific marker is not identified. can judge

Or, vice versa, when the pathological stage-specific marker is identified and a specific pathological stage of bladder cancer is identified in a bladder cancer patient, the survival rate of the individual is higher than that of a person for which the pathological stage-specific marker is not identified. Or it can be judged that the recurrence rate is low.

Specifically, the pathological stage-specific marker is a mutation of the AKAP9 gene (Gene bank accession number: NM_147185.3), a mutation of the BPIFB6 gene (Gene bank accession number: NM_174897.2), and the CHD4 gene (Gene bank accession number: NM_001273) .5) mutation, DNMT3A gene (Gene bank accession number: NM_022552.4) mutation, DPM1 gene (Gene bank accession number: NM_003859.2) mutation, FRY gene (Gene bank accession number: NM_023037.3) mutation , GRM6 gene (Gene bank accession number: NM_000843.4) mutation, KIF4A gene (Gene bank accession number: NM_012310.5) mutation, KLHL36 gene (Gene bank accession number: NM_024731.4) mutation, LTN1 gene (Gene) bank accession number: NM_015565.3) mutation, MAP3K5 gene (Gene bank accession number: NM_005923.4) mutation, MED1 gene (Gene bank accession number: NM_004774.4) mutation, NAV3 gene (Gene bank accession number: NM_001024383) .2) mutation, NDNF gene (Gene bank accession number: NM_024574.4) mutation, NKRF gene (Gene bank accession number: NM_017544.5) mutation, OLFM4 gene (Gene bank accession number: NM_006418.5) mutation , OR13C3 gene (Gene bank accession number: NM_00100196 1.1) mutation, PLEC gene (Gene bank accession number: NM_201380.4) mutation, RADIL gene (Gene bank accession number: NM_018059.5) mutation, RELN gene (Gene bank accession number: NM_005045.4) mutation, RIPK1 gene (Gene bank accession number: NM_003804.6) mutation, RNF123 gene (Gene bank accession number: NM_022064.5) mutation, RNF215 gene (Gene bank accession number: NM_001017981.2) mutation, RSRC2 gene (Gene bank accession number: NM_023012.6) mutation, SIN3A gene (Gene bank accession number: NM_001145357.2) mutation, SLC23A3 gene (Gene bank accession number: NM_001144889.2) mutation, STAM gene (Gene bank accession number: NM_003473). 4) mutation, TRIM59 gene (Gene bank accession number: NM_173084.3) mutation, USPL1 gene (Gene bank accession number: NM_005800.5) mutation, WNK1 gene (Gene bank accession number: NM_018979.4) mutation, It may include at least one selected from the group consisting of a mutation of the ZNF485 gene (Gene bank accession number: NM_145312.4).

In addition, the pathological stage-specific markers include a mutation in the AEBP1 gene (Gene bank accession number: NM_001129.5), a mutation in the LPCAT1 gene (Gene bank accession number: NM_024830.5), and a CCAR2 gene (Gene bank accession number: NM_021174. 6) mutation, CELA1 gene (Gene bank accession number: NM_001971.6) mutation, CPEB3 gene (Gene bank accession number: NM_014912.5) mutation, FDPS gene (Gene bank accession number: NM_001135821.2) mutation, Mutation of GPI gene (Gene bank accession number: NM_000175.5), PMS1 gene (Gene bank accession number: NM_000534.4) mutation, PPM1J gene (Gene bank accession number: NM_005167.5) mutation, SRRM2 gene (Gene bank accession number: NM_016333.4) mutation, SYT1 gene (Gene bank accession number: NM_001135805.2) mutation, TCFL5 gene (Gene bank accession number: NM_006602.4) mutation, TRIM24 gene (Gene bank accession number: NM_015905). 3) may further include at least one selected from the group consisting of mutations.

The full names of the abbreviations of the genes are, respectively, AKAP9 (A-kinase anchoring protein 9), BPIFB6 (BPI fold containing family B member 6), CHD4 (chromodomain helicase DNA binding protein 4), DNMT3A (DNA methyltransferase 3 alpha), DPM1 ( dolichyl-phosphate mannosyltransferase subunit 1, catalytic), FRY (FRY microtubule binding protein), GRM6 (glutamate metabotropic receptor 6), KIF4A (kinesin family member 4A), KLHL36 (kelch like family member 36), LTN1 (listerin E3 ubiquitin protein ligase) 1), MAP3K5 (mitogen-activated protein kinase kinase kinase 5), MED1 (mediator complex subunit 1), NAV3 (neuron navigator 3), NDNF (neuron derived neurotrophic factor), NKRF (NFKB repressing factor), OLFM4 (olfactomedin 4) , OR13C3 (olfactory receptor family 13 subfamily C member 3), PLEC (plectin), RADIL (Rap associating with DIL domain), RELN (reelin), RIPK1 (receptor interacting serine/threonine kinase 1), RNF123 (ring finger protein 123) , RNF215 (ring finger protein 215), RSRC2 (arginine and serine rich coiled-coil 2), SIN3A (SIN3 transcription regulator) r family member A), SLC23A3 (solute carrier family 23 member 3), STAM (signal transducing adapter molecule), TRIM59 (tripartite motif containing 59), USPL1 (ubiquitin specific peptidase like 1), WNK1 (WNK lysine deficient protein kinase 1) , ZNF485 (zinc finger protein 485).

In the present invention, the reagent capable of detecting the pathological stage-specific marker may include at least one selected from the group consisting of primers, probes, antibodies, and aptamers for the pathological stage-specific marker. The primer, probe, antibody or aptamer can be manufactured using a known technique, and a primer, probe, antibody or aptamer capable of detecting a mutation of a gene of the present invention is included in the scope of the present invention.

In the present invention, the term 'primer' is a nucleic acid sequence having a short free 3' hydroxyl group, which can form a base pair with a complementary template and is a starting point for template strand copying. It refers to a short nucleic acid sequence that functions as The primers are capable of initiating DNA synthesis in the presence of reagents for the polymerization reaction (ie, DNA polymerase or reverse transcriptase) and the four different nucleoside triphosphates in appropriate buffer solutions and temperatures. In the present invention, PCR amplification is performed using the forward and reverse primers of the mutant gene to determine the presence or absence of a corresponding gene marker through the generation of a desired product, and it can be used for diagnosis. For example, in the case of a forward primer, a primer corresponding to a mutant in which deletion, substitution, or insertion has occurred is designed, and a reverse primer is designed and PCR corresponding to a position where mutation does not occur, mutation of the gene of the present invention In the case of a chain, an amplification product will be generated by PCR, but if it is not a mutant of the gene of the present invention, no amplification product will be generated. PCR conditions, forward and reverse primer lengths can be modified based on those known in the art.

In the present invention, the term 'probe' refers to a nucleic acid fragment such as RNA or DNA capable of forming a specific binding with DNA, and consists of several bases to several hundred bases as long as possible. Since the probe is labeled, the presence or absence of a specific DNA can be confirmed. The probe may be manufactured in the form of an oligonucleotide probe, a single stranded DNA probe, a double stranded DNA probe, an RNA probe, or the like. In the present invention, hybridization is performed using a probe complementary to a mutation of a gene, and the presence or absence of a mutation in a gene can be diagnosed based on whether or not hybridization occurs. For example, when a probe corresponding to a mutant having a deletion, substitution or insertion is synthesized and the probe is hybridized with the genomic DNA of a bladder cancer patient, hybridization will occur in the case of a mutant of the gene of the present invention, but If the gene is not a mutant, hybridization will not occur. Selection of suitable probes and hybridization conditions can be modified based on those known in the art.

In the present invention, the term 'antibody' is a term known in the art and refers to a specific protein molecule directed against an antigenic site. In the present invention, the antibody may refer to an antibody that specifically binds to each marker gene. Such an antibody can be prepared by cloning each marker gene into an expression vector according to a conventional method to obtain a protein encoded by the marker gene, and from the obtained protein by a conventional method. This also includes a partial peptide that can be made from the protein, and the partial peptide of the present invention contains at least 7 amino acids, preferably 9 amino acids, more preferably 12 or more amino acids. The form of the antibody of the present invention is not particularly limited, and a part thereof is included in the antibody of the present invention as long as it has polyclonal antibody, monoclonal antibody, or antigen-binding property, and all immunoglobulin antibodies are included. Furthermore, the antibody of the present invention includes a special antibody such as a humanized antibody. Antibodies used for the detection of marker genes of the present invention include functional fragments of antibody molecules as well as complete forms having two full-length light chains and two full-length heavy chains. A functional fragment of an antibody molecule refers to a fragment having at least an antigen-binding function, and includes Fab, F(ab'), F(ab') ₂ and Fv.

As used herein, the term 'aptamer' refers to a single-stranded nucleic acid (DNA, RNA, or modified nucleic acid) that has a stable tertiary structure by itself and can bind to a target molecule with high affinity and specificity. Aptamers can be synthesized by known chemical methods, for example, by a method called SELEX (Systematic Evolution of Ligands of Exponential enrichment) for various target substances (proteins, sugars, dyes, DNA, metal ions, cells, etc.) You can develop aptamers.

The mutation of the gene may include any one or more mutations, for example, a truncating mutation, a missense mutation (or a missense mutation), a nonsense mutation, a frame shift. ) mutation, in-frame mutation (or in-frame mutation), splice mutation, and splice_region mutation may have at least one mutation selected from the group consisting of mutations. The frameshift mutation may be at least one of a frame shift insert (FS ins) mutation and a frame shift delete mutation (FS del). The in-frame mutation may be at least one of an in-frame insertion (IF ins) mutation and an in-frame delete (IF del) mutation.

The term "X#Y" with respect to a mutation in a polypeptide sequence is self-recognized in the art, where "#" indicates the mutation site with respect to the amino acid number of the polypeptide, and "X" is that of the wild-type amino acid sequence. indicates the amino acid found at that position, and "Y" indicates the mutant amino acid at that position. For example, the designation "E514K" with respect to an AKAP9 polypeptide indicates that glutamic acid is present at amino acid number 514 of the wild-type AKAP9 sequence and that glutamic acid has been replaced with lysine in the mutant AKAP9 sequence. Mutations in these genes are as follows:

The mutation of the AKAP9 gene is, in the amino acid sequence of SEQ ID NO: 1, E514K missense mutation, E2596K missense mutation, Q365H missense mutation, L3448Tfs*10 frameshift insertion mutation, S60L missense mutation, E1898K missense mutation, D657H missense mutation Mutation, Q3132E missense mutation, Q3847H missense mutation, L301S missense mutation, E774K missense mutation, E2043Q missense mutation, E2071K missense mutation, L2786R missense mutation, E461Q missense mutation, E1961Q missense mutation, R2109K missense mutation Mutation, F3547L missense mutation, H3016D missense mutation, E1921K missense mutation, H3016Y missense mutation, I3647M missense mutation, S1200C missense mutation, L214S missense mutation, E3365Q missense mutation, E1940Q missense mutation, E3586K missense mutation Mutation, R1562T missense mutation, M3312I missense mutation, D3011N missense mutation, M2002I missense mutation, P1381S missense mutation, X1447_splice Splice_Site mutation, R3478T missense mutation, T2825P missense mutation, R3476T missense mutation, E3365* nonsense mutation , H2891P missense mutation, D570H missense mutation, E734K missense mutation, E1916Q missense mutation, Q1192E missense mutation, S1278R missense mutation, M1451I missense mutation, S1760Y missense mutation, E2218K missense mutation, E3365K missense mutation , E940Tfs*6 frameshift deletion, H1904Y missense mutation, S2240C missense mutation, R3798K missense mutation or S2932R missense mutation. The notation method for frameshift mutations is amino acid type (amino acid position) amino acid type fs* (number of nucleotides from the amino acid position to the stop codon in the downstream direction) explanation is omitted). In the nonsense mutation, * indicates that the amino acid synthesis at the corresponding amino acid position is terminated (the description is omitted below).

The mutation of the BPIFB6 gene is, in the amino acid sequence of SEQ ID NO: 2, S391L missense mutation, X381_splice Splice_Site mutation (c.1143-1G>A), S390L missense mutation, S378Y missense mutation, G15S missense mutation, Q421* nonsense mutation, L256M missense mutation, P306S missense mutation, S216I missense mutation, X33_splice Splice_Site mutation (c.97+1G>T), F360L missense mutation or G104E missense mutation.

The mutation of the CHD4 gene is, in the amino acid sequence of SEQ ID NO: 3, R1877Q missense mutation, E1776Q missense mutation, E1371Q missense mutation, E1299Q missense mutation, P1387L missense mutation, L641F missense mutation, K634N missense mutation, E1469Q Missense mutation, P1541A missense mutation, L1333V missense mutation, E540K missense mutation, X1075_splice Splice_Site mutation (c.3223-1G>A), R305H missense mutation, R1000P missense mutation, S1808* nonsense mutation, E592K missense mutation Mutation, E357K missense mutation, L498V missense mutation, E1523Q missense mutation, E698* nonsense mutation, S785C missense mutation, Y574Sfs*43 frameshift deletion mutation, D386H missense mutation, D386N missense mutation, E425Q missense mutation, L1789V missense mutation, E752K missense mutation, S108N missense mutation, D104Y missense mutation or Q1155E missense mutation. In the notation method of in-frame deletion mutations, del indicates that the corresponding amino acid is deleted at the corresponding amino acid sequence position (the description is omitted below).

The mutation of the DNMT3A gene is, in the amino acid sequence of SEQ ID NO: 4, M880I missense mutation, F827=Splice_Region mutation (c.2481C>T), G890D missense mutation, E863K missense mutation, T834N missense mutation, H821R missense mutation , G543V missense mutation, A760T missense mutation, R309P missense mutation or K299I missense mutation.

The mutation of the DPM1 gene may be an E38Q missense mutation, an E59K missense mutation or an E53Q missense mutation in the amino acid sequence of SEQ ID NO: 5.

The mutation of the FRY gene is, in the amino acid sequence of SEQ ID NO: 6, R417Q missense mutation, S1398C missense mutation, D1789V missense mutation, S1882* nonsense mutation, E2059Q missense mutation, D49N missense mutation, S1938A missense mutation, E1004Q Missense mutation, P2300L missense mutation, L373V missense mutation, T73P missense mutation, K2391= Splice_Region mutation (c.7173G>A), Q510* nonsense mutation, L791P missense mutation, S135L missense mutation, Q108E missense mutation , S1698C missense mutation, D2470H missense mutation, X1107_splice Splice_Site mutation (c.3319+1G>A), E1434K missense mutation, S2237T missense mutation, S1756* nonsense mutation, L2403V missense mutation, W824* nonsense mutation, G1306E missense mutation, E285* nonsense mutation, G528E missense mutation, Q199H missense mutation, S28F missense mutation, E191K missense mutation, H642Rfs*26 frameshift deletion mutation or S2451Rfs*5 frameshift deletion mutation.

The mutation of the GRM6 gene is, in the amino acid sequence of SEQ ID NO: 7, V775M missense mutation, A782V missense mutation, D340N missense mutation, G338E missense mutation, A636T missense mutation, D406V missense mutation, P521L missense mutation, P847S It may be a missense mutation or an S507C missense mutation.

The mutation of the KIF4A gene is, in the amino acid sequence of SEQ ID NO: 8, R295G missense mutation, K586N missense mutation or K128R It may be a missense mutation.

The mutation of the KLHL36 gene may be an E407K missense mutation, an R387L missense mutation, or an E233Q missense mutation in the amino acid sequence of SEQ ID NO: 9.

The mutation of the LTN1 gene is, in the amino acid sequence of SEQ ID NO: 10, D825Y missense mutation, K1372R missense mutation, E561Q missense mutation, W712C missense mutation, W712S missense mutation, D825H missense mutation, Q1339E missense mutation, A1028S missense mutation, H897Y missense mutation, E551D missense mutation, L715F missense mutation, D951N missense mutation, Q1674* nonsense mutation, E328Q missense mutation, E477K missense mutation or L994V missense mutation.

The mutation of the MAP3K5 gene is, in the amino acid sequence of SEQ ID NO: 11, T1108I missense mutation, L192V missense mutation, D344H missense mutation, X1292_splice Splice_Site mutation (c.3875-1G>A), Q496* nonsense mutation, R683K missense mutation, P880L missense mutation, S329C missense mutation, P593S missense mutation, S72Y missense mutation, G790A missense mutation, D1233N missense mutation, E291Q missense mutation, H1145Y missense mutation or E1183K missense mutation.

The mutation of the MED1 gene is, in the amino acid sequence of SEQ ID NO: 12, H1526D missense mutation, S387T missense mutation, S1227L missense mutation, S1379L missense mutation, S1218C missense mutation, K202N missense mutation, L69I missense mutation, K283T Missense mutation, S1375C missense mutation, P1208A missense mutation, S256* nonsense mutation, S682L missense mutation, S1363* nonsense mutation, S1439F missense mutation, S1558* nonsense mutation, P381A missense mutation, S1368F missense mutation, E8K missense mutation, S1111L missense mutation, S349L missense mutation or M1172I missense mutation.

The mutation of the NAV3 gene is, in the amino acid sequence of SEQ ID NO: 13, S1262C missense mutation, S1273L missense mutation, E48* nonsense mutation, E1023Q missense mutation, S1090F missense mutation, S1106L missense mutation, D1690H missense mutation, S1170C Missense mutation, E1603K missense mutation, L692F missense mutation, Q2363L missense mutation, Y2151C missense mutation, D1969H missense mutation, A1679V missense mutation, L29V missense mutation, S1262F missense mutation, S1217F missense mutation, S461C Missense mutation, S1722F missense mutation, S532Y missense mutation, I100M missense mutation, S210L missense mutation, R1402T missense mutation, N732S missense mutation, S1142L missense mutation, S136F missense mutation, T1080S missense mutation, E1563K missense mutation, Y820Vfs*20 frameshift deletion mutation, G1384D missense mutation or S2364C missense mutation.

The mutation of the NDNF gene may be an M323R missense mutation, a Q269* nonsense mutation, a Y481S missense mutation, a K412N missense mutation or an I453M missense mutation in the amino acid sequence of SEQ ID NO: 14.

The mutation of the NKRF gene may be an N690S missense mutation, a Q30* nonsense mutation, a Q585K missense mutation or an R56C missense mutation in the amino acid sequence of SEQ ID NO: 15.

The mutation of the OLFM4 gene may be an L415R missense mutation, a V378I missense mutation, a Q381E missense mutation, a P257Q missense mutation or an S56Y missense mutation in the amino acid sequence of SEQ ID NO: 16.

The mutation of the OR13C3 gene is, in the amino acid sequence of SEQ ID NO: 17, R329I missense mutation, A218S missense mutation, I255M missense mutation, A136V missense mutation, S83F missense mutation, G200W missense mutation, S117* nonsense mutation, L145V missense mutation, L69V missense mutation, T8I missense mutation or S311C missense mutation.

The mutation of the PLEC gene is, in the amino acid sequence of SEQ ID NO: 18, E2845D missense mutation, E2252K missense mutation, S4365F missense mutation, E2458K missense mutation, E3767Q missense mutation, E3360* nonsense mutation, A3072E missense mutation, E2061K Missense mutation, E689Q missense mutation, D677N missense mutation, E1609K missense mutation, E1057Q missense mutation, E985* nonsense mutation, E3010Q missense mutation, E2997K missense mutation, E2595D missense mutation, E2405* nonsense mutation, R3838S Missense mutation, S4272Y missense mutation, L1259V missense mutation, Q3962H missense mutation, R179H missense mutation, R3804L missense mutation, E2624D missense mutation, L3478V missense mutation, I3611V missense mutation, E4212Q missense mutation, E2446K Missense mutation, E2063K missense mutation, L3157F missense mutation, A1513S missense mutation, S1181F missense mutation, K2409N missense mutation, E3634D missense mutation, G3279S missense mutation, E3665K missense mutation, Q4509Rfs*3 frameshift deletion Mutation, Q3266R missense mutation, S4374L missense mutation, S2634F missense mutation, K298N missense mutation, E413K missense mutation, V3780L missense mutation, R316Q missense mutation, L4545M missense mutation, E1185K missense mutation, E1137K missense mutation mutation, E3236Q missense mutation, S558L missense mutation or E364Q missense mutation.

The mutation of the RADIL gene may be S715T missense mutation, Y100* nonsense mutation, A437T missense mutation, R595H missense mutation, S289L missense mutation, S1060F missense mutation or S984C missense mutation in the amino acid sequence of SEQ ID NO: 19. have.

The mutation of the RELN gene is, in the amino acid sequence of SEQ ID NO: 20, R2639H missense mutation, R2524Q missense mutation, V240I missense mutation, E397K missense mutation, S1879C missense mutation, M1070T missense mutation, L2213F missense mutation, E1449K missense mutation, D802H missense mutation, R1491G missense mutation, W1770* nonsense mutation, D1563N missense mutation, I1978M missense mutation, R2106T missense mutation, S34P missense mutation, R755H missense mutation, V2623M missense mutation, F1841C missense mutation, D3416A missense mutation, Y339H missense mutation, D2180H missense mutation, E1366K missense mutation, D2381N missense mutation, D185H missense mutation, T2963S missense mutation, S2841L missense mutation, E3052K missense mutation, I3246V Missense mutation, A1341S missense mutation, D1246H missense mutation, G1405A missense mutation, D1693N missense mutation, L3234V missense mutation, G2129S missense mutation, E425Q missense mutation, R1825Kfs*7 frameshift insertion mutation or C1416G missense mutation It may be a mutation.

The mutation of the RIPK1 gene is, in the amino acid sequence of SEQ ID NO: 21, R317T missense mutation, M42V missense mutation, M637I missense mutation, E368K missense mutation, M517Ifs*11 frameshift insertion mutation, R275W missense mutation or N310T missense mutation. It may be a mutation.

The mutation of the RNF123 gene is, in the amino acid sequence of SEQ ID NO: 22, L209V missense mutation, E1169Q missense mutation, V661A missense mutation, E778K missense mutation, L904V missense mutation, X1215_splice Splice_Site mutation (c.3644-1G>A ), S563C missense mutation, S1263C missense mutation, E22Q missense mutation, R390* nonsense mutation, E995K missense mutation, F1289C missense mutation or S540N missense mutation.

The mutation of the RNF215 gene may be a D229H missense mutation, a G225D missense mutation, an R166Q missense mutation or an R295H missense mutation in the amino acid sequence of SEQ ID NO: 23.

The mutation of the RSRC2 gene is, in the amino acid sequence of SEQ ID NO: 24, S165L missense mutation, A322T missense mutation, N365S missense mutation, R66T missense mutation, S145C missense mutation, S350C missense mutation, D19H missense mutation, R242T missense mutation, E332Q missense mutation, F213C missense mutation, K255N missense mutation or D96H missense mutation.

The mutation of the SIN3A gene is, in the amino acid sequence of SEQ ID NO: 25, R471Q missense mutation, F1169L missense mutation, I1133V missense mutation, T1049K missense mutation, Q100H missense mutation, E540K missense mutation, K1148N missense mutation, E513Q missense mutation, Q805E missense mutation, H333R missense mutation, D1090Y missense mutation, N423K missense mutation, Q1208E missense mutation or R428C missense mutation.

The mutation of the SLC23A3 gene is, in the amino acid sequence of SEQ ID NO: 26, P114A missense mutation, P199S missense mutation, S251* nonsense mutation, P25S missense mutation, P25Q missense mutation, R148M missense mutation, P22R missense mutation, Q85 * may be nonsense mutation, L51M missense mutation or S207F missense mutation.

The mutation of the STAM gene may be an M422L missense mutation, a W115* nonsense mutation, a W115* nonsense mutation, a I32M missense mutation, a D117N missense mutation or a D10N missense mutation in the amino acid sequence of SEQ ID NO: 27.

The mutation of the TRIM59 gene may be Q39* nonsense mutation, S72C missense mutation, R60K missense mutation, V95F missense mutation or F348L missense mutation in the amino acid sequence of SEQ ID NO: 28.

The mutation of the USPL1 gene is, in the amino acid sequence of SEQ ID NO: 29, S298L missense mutation, S546L missense mutation, S1069L missense mutation, Q284* nonsense mutation, P833S missense mutation, R916Q missense mutation, E697K missense mutation, I461N missense mutation, I265M missense mutation, D581N missense mutation, Q369* nonsense mutation, X371_splice Splice_Site mutation (c.1113-1G>A) or S603F missense mutation.

The mutation of the WNK1 gene is, in the amino acid sequence of SEQ ID NO: 30, D349N missense mutation, R341G missense mutation, A22S missense mutation, E1637K missense mutation, E1665K missense mutation, M2320V missense mutation, Q2044H missense mutation, A918S Missense mutation, A1977V missense mutation, H1534D missense mutation, E586D missense mutation, E1049Q missense mutation, Q276* nonsense mutation, S732C missense mutation, T74A missense mutation, I558M missense mutation, S847* nonsense mutation, S731L Missense mutation, Q838E missense mutation, D2013H missense mutation, H1296D missense mutation, K2104T missense mutation, S1918F missense mutation, L1303I missense mutation, G1771A missense mutation, D2013N missense mutation, E122K missense mutation, E548Q It may be a missense mutation or a K1531N missense mutation.

The mutation of the ZNF485 gene may be an S143L missense mutation, S227* nonsense mutation, R436K missense mutation, N245H missense mutation or F335L missense mutation in the amino acid sequence of SEQ ID NO: 31.

The mutation of the AEBP1 gene may be, in the amino acid sequence of SEQ ID NO: 32, R1000Q missense mutation, E799K missense mutation, G6W missense mutation, E1096K missense mutation, R831C missense mutation or G832R missense mutation.

The mutation of the LPCAT1 gene may be a Q268L missense mutation, a V94F missense mutation or an L166V missense mutation in the amino acid sequence of SEQ ID NO: 33.

The mutation of the CCAR2 gene may be a D696N missense mutation, a S671L missense mutation or a P30S missense mutation in the amino acid sequence of SEQ ID NO: 34.

The mutation of the CELA1 gene may be a G231S missense mutation or a D84A missense mutation in the amino acid sequence of SEQ ID NO: 35.

The mutation of the CPEB3 gene is a T359S missense mutation, Q601* nonsense mutation, R435Q missense mutation, S241Rfs*77 frameshift deletion mutation, E493* nonsense mutation or A225Gfs*24 frameshift deletion mutation in the amino acid sequence of SEQ ID NO: 36. can

The mutation of the FDPS gene may be, in the amino acid sequence of SEQ ID NO: 37, P275A missense mutation, K332T missense mutation, G38W missense mutation, Q85H missense mutation, S230F missense mutation or Q232E missense mutation.

The mutation of the GPI gene may be R180H missense mutation, S298L missense mutation, H306Q missense mutation or D458V missense mutation in the amino acid sequence of SEQ ID NO: 38.

The mutation of the PMS1 gene is, in the amino acid sequence of SEQ ID NO: 39, Q132* nonsense mutation, N531S missense mutation, L282V missense mutation, L329F missense mutation, S673C missense mutation, K711N missense mutation, D397H missense mutation, K667N missense mutation or S426C missense mutation.

The mutation of the PPM1J gene may be a P473T missense mutation or an E296Q missense mutation in the amino acid sequence of SEQ ID NO: 40.

The mutation of the SRRM2 gene is, in the amino acid sequence of SEQ ID NO: 41, R1853C missense mutation, R1448T missense mutation, E1515Q missense mutation, S669L missense mutation, S2535W missense mutation, S2640C missense mutation, E396K missense mutation, R546T Missense mutation, D1408H missense mutation, S177C missense mutation, E1047K missense mutation, R650K missense mutation, R2356K missense mutation, E201K missense mutation, S2706L missense mutation, R948Q missense mutation, Q1554* nonsense mutation, S2544F Missense mutation, E1479A missense mutation, R2097I missense mutation, R1719I missense mutation, L1055V missense mutation, S536F missense mutation, E2573K missense mutation, S2512C missense mutation, S2335C missense mutation, Q833R missense mutation, D1429H Can be missense mutation, R643T missense mutation, D1481N missense mutation, R693W missense mutation, S931F missense mutation, S931F missense mutation, S1581L missense mutation, E1259Q missense mutation, R1475T missense mutation or E100K missense mutation have.

The mutation of the SYT1 gene is, in the amino acid sequence of SEQ ID NO: 42, D364_Y365insN in-frame insertion mutation, Y181* nonsense mutation, K326N missense mutation, S41Y missense mutation, E140K missense mutation, D122N missense mutation or D415N missense mutation. can In the notation of in-frame insertional mutations, ins indicates that the corresponding amino acid is inserted at the corresponding amino acid sequence position (the description will be omitted below).

The mutation of the TCFL5 gene may be S282A missense mutation, Q391H missense mutation, I450M missense mutation, Q400E missense mutation, E403D missense mutation, E380K missense mutation or R401H missense mutation in the amino acid sequence of SEQ ID NO: 43 have.

The mutation of the TRIM24 gene is, in the amino acid sequence of SEQ ID NO: 44, R1046C missense mutation, D781N missense mutation, E136K missense mutation, E150K missense mutation, M340I missense mutation, H226Y missense mutation, R721Q missense mutation, D872H missense mutation, D626G missense mutation, Q64R missense mutation, C187S missense mutation, E994Q missense mutation or M498V missense mutation.

Next generation sequencing (NGS), RT-PCR, direct nucleic acid sequencing method, and microarray can be used as an analysis method for diagnosing the prognosis of bladder cancer using the mutation of the gene, and the gene of the present invention Any method that can confirm the presence of a mutation using a mutation of In one embodiment, the presence of a mutation is determined using an anti-(mutant of each gene) antibody or nucleic acid probe that hybridizes under stringent conditions to the polynucleotide of the mutant of each gene. In another embodiment, the antibody or nucleic acid probe is detectably labeled. In another embodiment, the label is selected from the group consisting of an immunofluorescent label, a chemiluminescent label, a phosphorescent label, an enzymatic label, a radioactive label, avidin/biotin, colloidal gold particles, colored particles, and magnetic particles. In another embodiment, the presence of the mutation is determined by radioimmunoassay, western blot assay, immunofluorescence assay, enzymatic immunoassay, immunoprecipitation assay, chemiluminescence assay, immunohistochemical assay, dot blot assay, slot blot assay or flow cytometry. determined by the assay. In another embodiment, the presence of the mutation is determined by RT-PCR. In another embodiment, the presence of a mutation is determined by nucleic acid sequencing.

As used herein, the term 'polynucleotide' generally refers to any polyribonucleotide or polydeoxyribonucleotide, which may be unmodified RNA or DNA or modified RNA or DNA. Thus, for example, polynucleotides as defined herein include, but are not limited to, single- and double-stranded DNA, DNA comprising single- and double-stranded regions, single- and double-stranded RNA, and single- and double-stranded DNA. - RNA comprising a region, single-stranded or more typically double-stranded, or hybrid molecule comprising DNA and RNA, which may comprise single- and double-stranded regions. Thus, DNA or RNA having a backbone that has been modified for stability or other reasons is a 'polynucleotide' as the term is intended herein. Also included in the term 'polynucleotide' as defined herein is DNA or RNA comprising an unconventional base such as inosine or a modified base such as a tritiated base. In general, the term 'polynucleotide' includes all chemically, enzymatically and/or metabolically modified forms of unmodified polynucleotides. Polynucleotides can be prepared by a variety of methods, including in vitro recombinant DNA-mediated techniques, and by expression of DNA in cells and organisms.

Another aspect of the present invention is an AKAP9 gene mutation, a BPIFB6 gene mutation, a CHD4 gene mutation, a DNMT3A gene mutation, a DPM1 gene mutation, a FRY gene mutation, a GRM6 gene mutation, a KIF4A gene mutation, and a KLHL36 gene mutation. , LTN1 gene mutation, MAP3K5 gene mutation, MED1 gene mutation, NAV3 gene mutation, NDNF gene mutation, NKRF gene mutation, OLFM4 gene mutation, OR13C3 gene mutation, PLEC gene mutation, RADIL gene mutation , RELN gene mutation, RIPK1 gene mutation, RNF123 gene mutation, RNF215 gene mutation, RSRC2 gene mutation, SIN3A gene mutation, SLC23A3 gene mutation, STAM gene mutation, TRIM59 gene mutation, USPL1 gene mutation , It provides a kit for prognostic diagnosis of bladder cancer comprising a reagent capable of detecting a pathological stage-specific marker of a bladder cancer patient comprising at least one selected from the group consisting of a mutation in the WNK1 gene and a mutation in the ZNF485 gene.

In addition, the pathological stage-specific marker is AEBP1 gene mutation, LPCAT1 gene mutation, CCAR2 gene mutation, CELA1 gene mutation, CPEB3 gene mutation, FDPS gene mutation, GPI gene mutation, PMS1 gene mutation, It may further include at least one selected from the group consisting of a mutation of the PPM1J gene, a mutation of the SRRM2 gene, a mutation of the SYT1 gene, a mutation of the TCFL5 gene, and a mutation of the TRIM24 gene.

For example, when the pathological stage-specific marker is identified, it may be determined that the survival rate is lower or the recurrence rate is higher than that of a person for which the pathological stage-specific marker is not identified. Or vice versa.

The reagent capable of detecting the pathological stage-specific marker may include one or more selected from the group consisting of a primer, a probe, an antibody, and an aptamer, and the specific details are the same as described above, and thus a detailed description thereof will be omitted.

The kit of the present invention may be an RT-PCR kit, a DNA chip kit or a protein chip kit. As an example, the RT-PCR kit for measuring the mRNA expression level of the marker gene of the present invention may be a kit including essential elements necessary for performing RT-PCR. The RT-PCR kit contains, in addition to each primer pair specific for the marker gene, a test tube or other suitable container, reaction buffer (with varying pH and magnesium concentration), deoxynucleotides (dNTPs), Taq-polymerase and enzymes such as reverse transcriptase, DNase, RNAse inhibitors, DEPC-water, sterile water, and the like. In addition, a pair of primers specific to a gene used as a quantitative control may be included.

As another example, the DNA chip kit of the present invention may include essential elements necessary for performing a DNA chip analysis method. The DNA chip kit may include a substrate to which cDNA corresponding to a marker gene or a fragment thereof is attached as a probe, and reagents, agents, enzymes, and the like for producing a fluorescently labeled probe. In addition, the substrate may include cDNA corresponding to a quantitative control gene or a fragment thereof.

As another example, the kit of the present invention is a protein chip kit for measuring the level of a protein expressed from the marker gene, and the kit is not particularly limited thereto, but includes a substrate, an appropriate buffer, It may include a chromogenic enzyme or a secondary antibody labeled with a fluorescent substance, a chromogenic substrate, and the like. The substrate is not particularly limited thereto, but a nitrocellulose membrane, a 96-well plate synthesized from a polyvinyl resin, a 96-well plate synthesized from a polystyrene resin, a glass slide glass, etc. may be used, and the chromogenic enzyme is not particularly limited thereto. However, peroxidase and alkaline phosphatase may be used, and the fluorescent material may be FITC, RITC, etc., but is not particularly limited thereto, and the color development substrate solution is not particularly limited thereto, but ABTS (2, 2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)) or OPD (o-phenylenediamine), TMB (tetramethyl benzidine).

In addition, the kit of the present invention may further include a buffer, an indicator, or a combination thereof as a reagent.

The kit for prognostic diagnosis of bladder cancer of the present invention is very economical because it saves time and money compared to the existing general gene mutation detection method. Using existing gene mutation detection methods such as Single Strand Conformational Polymorphism (SSCP), Protein Truncation Test (PTT), cloning, and direct sequencing, it takes several days on average to test all one gene. It takes several months. In addition, gene mutations can be precisely tested quickly and simply through next generation sequencing (NGS). When mutations are tested by conventional analysis methods such as SSCP, cloning, direct sequencing, and Restriction Fragment Length Polymorphism (RFLP), it takes about a month to complete the test, whereas using the kit of the present invention, sample DNA is prepared If it is done, results can be obtained within about 10 to 11 hours, and since a primer set capable of detecting mutations is integrated on one chip, not only time but also cost can be reduced compared to the conventional method. Compared to the conventional method, the average cost of reagents is less than half per experiment, so even greater cost savings can be expected when the researcher's labor costs are taken into account.

2. A method of providing necessary information for prognostic diagnosis of bladder cancer

Another aspect of the present invention comprises the steps of preparing a sample DNA from a sample of a bladder cancer patient; It provides a method for providing information necessary for prognostic diagnosis of bladder cancer patients, including: confirming the presence or absence of a pathological stage-specific marker using the sample DNA for prognosis diagnosis of bladder cancer.

The method may further include amplifying the sample DNA prepared from the bladder cancer patient's sample using the composition or kit for prognostic diagnosis of bladder cancer.

The description of the ' composition and kit for prognostic diagnosis of bladder cancer' is the same as that described in '1. Composition and kit for prognostic diagnosis of bladder cancer ', so a detailed description will be omitted.

The term 'patient' usually includes humans as well as other animals, such as other primates, rodents, dogs, cats, horses, sheep, pigs, and the like.

The term 'sample' refers to a sample of an individual or tissue in which cancer or tumor has already occurred or is expected to occur, and a target sample for diagnosing its prognosis. Specifically, it may refer to a tumor lysate or extract prepared from frozen tissue obtained from a patient with bladder cancer.

The term 'subject' includes a subject diagnosed with or suspected of having bladder cancer.

The method can predict the overall survival or disease-free survival of bladder cancer patients.

In the present invention, the term 'overall survival (OS)' includes a clinical endpoint that describes a patient who is alive for a limited time after being diagnosed with or treated for a disease, such as cancer, and is related to whether or not the cancer recurs. the possibility of surviving without it.

In the present invention, the term 'disease-free survival (DFS)' includes a period in which a patient survives without cancer recurrence after treatment for a specific disease (eg, cancer).

According to the present invention, by confirming the presence of a mutation in the gene of the present invention in a sample of a bladder cancer patient, it is possible to predict what prognosis an individual having the target sample has for cancer. In addition, this method can be achieved by comparing the p-value of total survival or disease-free survival with an individual in a control group that does not have a mutation known to have a good prognosis. In the present invention, an individual known to have a good prognosis means an individual without a history of metastasis, recurrence, death, etc. after cancer has developed.

The pathological stage-specific marker is AKAP9 gene mutation, BPIFB6 gene mutation, CHD4 gene mutation, DNMT3A gene mutation, DPM1 gene mutation, FRY gene mutation, GRM6 gene mutation, KIF4A gene mutation, KLHL36 gene mutation in LTN1 gene, MAP3K5 gene mutation, MED1 gene mutation, NAV3 gene mutation, NDNF gene mutation, NKRF gene mutation, OLFM4 gene mutation, OR13C3 gene mutation, PLEC gene mutation, RADIL gene mutation, RELN gene mutation, RIPK1 gene mutation, RNF123 gene mutation, RNF215 gene mutation, RSRC2 gene mutation, SIN3A gene mutation, SLC23A3 gene mutation, STAM gene mutation, TRIM59 gene mutation, USPL1 gene It may include at least one selected from the group consisting of a mutation, a mutation of the WNK1 gene, and a mutation of the ZNF485 gene.

In addition, the pathological stage-specific marker is AEBP1 gene mutation, LPCAT1 gene mutation, CCAR2 gene mutation, CELA1 gene mutation, CPEB3 gene mutation, FDPS gene mutation, GPI gene mutation, PMS1 gene mutation, PPM1J gene mutation, SRRM2 gene mutation, It may further include at least one selected from the group consisting of a mutation of the SYT1 gene, a mutation of the TCFL5 gene, and a mutation of the TRIM24 gene.

The method of providing information necessary for prognostic diagnosis of the bladder cancer patient may predict the total survival rate or disease-free survival rate of the bladder cancer patient. For example, in the method, when the pathological stage-specific marker is identified and a specific pathological stage of bladder cancer is identified in a bladder cancer patient, the survival rate is lower than that of a person in which the pathological stage-specific marker is not identified, or Determining that the recurrence rate is high; may include.

In addition, in the method, when the pathological stage-specific marker is identified and a specific pathological stage of bladder cancer is identified in a bladder cancer patient, the survival rate is higher than that of a person in which the pathological stage-specific marker is not identified, or the recurrence rate of bladder cancer is lower Determining that it is low; may include.

For example, the method of the present invention includes a mutation of the DPM1 gene, a mutation of the GRM6 gene, a mutation of the KIF4A gene, a mutation of the KLHL36 gene, a mutation of the NDNF gene, mutation of the NKRF gene, and mutation of the RADIL gene among the pathological stage-specific markers. When at least one is identified from the group consisting of a mutation, a mutation of the RIPK1 gene, a mutation of the RNF215 gene, a mutation of the STAM gene, a mutation of the TRIM59 gene, and a mutation of the ZNF485 gene It may further include; determining that the survival rate is low or the recurrence rate is high.

In addition, the method of the present invention includes a mutation of the AKAP9 gene, a mutation of the BPIFB6 gene, a mutation of the CHD4 gene, a mutation of the DNMT3A gene, a mutation of the FRY gene, a mutation of the LTN1 gene, mutation of the MAP3K5 gene, MED1 gene mutation, NAV3 gene mutation, OLFM4 gene mutation, OR13C3 gene mutation, PLEC gene mutation, RELN gene mutation, RNF123 gene mutation, RSRC2 gene mutation, SIN3A gene mutation, SLC23A3 gene mutation, When at least one selected from the group consisting of a mutation of the USPL1 gene and a mutation of the WNK1 gene is confirmed, determining that the survival rate is higher or the recurrence rate is lower than that of a person for which the pathological stage-specific marker is not identified; can

As such, mutants of the genes of the present invention are AKAP9, BPIFB6, CHD4, DNMT3A, DPM1, FRY, GRM6, KIF4A, KLHL36, LTN1, MAP3K5, MED1, NAV3, NDNF, NKRF, OLFM4, OR13C3, PLEC, RADIL, RELN, RADIL, Viability or recurrence of bladder cancer according to the pathological stage of bladder cancer using mutation of at least one gene selected from the gene group consisting of RIPK1, RNF123, RNF215, RSRC2, SIN3A, SLC23A3, STAM, TRIM59, USPL1, WNK1 and ZNF485 The content that can diagnose the prognosis, such as possibility, has not yet been revealed. In addition, it has not been reported that the total survival rate or disease-free survival rate may be different for each gene. The present inventors have identified for the first time that mutations of the above genes can be used as diagnostic markers for predicting differences in therapeutic effects depending on the pathological stage of bladder cancer or diagnosing the prognosis of bladder cancer patients.

The method of providing information necessary for predicting the difference in the treatment effect of bladder cancer patients of the present invention can be used to diagnose a bladder cancer gene mutation, increase the survival rate of bladder cancer patients, or lower the recurrence rate. Through the method for prognostic diagnosis of bladder cancer patients of the present invention, the treatment effect can be predicted according to the pathological stage of the bladder cancer patient using the mutational information of the bladder cancer gene, or the survival rate or recurrence rate of bladder cancer patients can be predicted, so each It can provide information on the selection of a treatment as well as the discovery of a suitable treatment for the patient, so that a treatment strategy for bladder cancer can be efficiently designed.

Hereinafter, the present invention will be described in detail by way of Examples and Experimental Examples.

However, the following Examples and Experimental Examples are only for illustrating the present invention, and the content of the present invention is not limited by the following Examples and Experimental Examples.

Example

Securing genetic and clinical information

In order to derive pathological stage-specific markers that can diagnose the prognosis after treatment according to the pathological stage of bladder cancer, bladder cancer patients who have both genetic information and clinical information from TCGA (The Cancer Genome Atlas) 411 Data on recurrence, metastasis, death, observation time, etc. were obtained and used for analysis.

Pathological staging group of bladder cancer patients pathological stage group number of patients Patient rate (%) STAGE-Ⅰ 2 0.48 STAGE-II 131 31.9 STAGE-III 141 34.3 STAGE-IV 135 32.8 etc 2 0.48

Selection of genes associated with pathological stage

Among the above data, 411 data that can confirm the pathological stage were collected. According to the pathological stage, it was classified into 4 groups (see Table 1 above), and as shown in Table 2 below, three Feature Selection (Information Gain, Chi-Square, MR) methods were performed for test sets 1-4. Through training, a total of 233 genes related to pathologic stage were derived. Among them, the genes associated with the pathological stage for each test set are shown in Table 2.

Comparison between groups of pathological staging test set type Detail note test set 1 STAGE-Ⅰvs Ⅱ vs Ⅲ vs Ⅳ Comparative analysis between stages test set 2 STAGE-Ⅰvs Ⅱ, Ⅲ, Ⅳ Comparative analysis before and after Stage I test set 3 STAGE-Ⅰ,Ⅱ vs Ⅲ, Ⅳ Comparative analysis before and after Stage II test set 4 STAGE-Ⅰ, Ⅱ, Ⅲ vs Ⅳ Comparative analysis before and after Stage III Results of comparative analysis between pathological stage groups test set type Genes Associated with Pathological Stages test set 1 ADK, BAG5, CACNA2D2, CAPN10, CDR2, CNGA1, COL9A2, CSDE1, CSF3, FBXO8, FGD1, GPN3, HIST1H3F, HLCS, HSPB11, LARP1, OR LAT, LRFN3, MAN2A2, ORT2, OR4T, OLFM4, NVL10 OR6C70, OTUD7A, PLSCR4, PLXNA4, PURB, PVRL4, RAB5A, RIPK1, RNF123, SLC23A3, SNX22, TCP11L2, TELO2, TMEM209, USO1, ZNF202 test set 2 ADK, CACNA2D2, CAPN10, CDR2, CNGA1, COL9A2, CSF3, EIF2S1, FAM50B, FBXO8, FGD1, FMO2, GABBR2, GPN3, HIST1H3F, HSPB11, IPPK, LARP1, LATMAN2, LRFN3, ORVL4, LRFN3, N FM OR6C70, PLAUR, PLSCR4, PVRL4, RAB5A, RADIL, RIPK1,SLMAP, SNX22, SPATS2, SRC, TARSL2, TSKU, USO1, ZNF221 test set 3 ADA, ALKBH1, BPIFB6, BRAF, CKB, CNTN4, DAPK1, DNMT3A, ERLEC1, EXOC4, FAM111A, FGFR3, GLP1R, GPRIN3, HCN3, HELLS, HOXC13, HYOU1, KCND3, OR10G7, ORKLK13, KP, ORKLK13, KP107 PAK1IP1, PHF1, PHF17, PITRM1, PLXNA4, POLR1C, PPP1R3B, PPP2R5B, PROCA1, RELN, RSRC1, SCMH1, SEMA6D, SIN3A, SLC25A31, SLC43A2, STAM, SMTON1, TPEMAL, TM21, TEMPO1, TBC1D12, USMPO USP24, ZNF274, ZNF382, ZNF665 test set 4 A2M, ACBD7, ADAM7, AKAP9, ALDH1L1, ARHGAP35, C11orf16, CHD4, CLK1, DAAM2, DNAH8, DPM1, DSG1, EXOC4, EYA1, FRY, GNA15, GRIK3, GRM6, KIK5, HL36, LRR MAP1, LAA1407, KIF4A MED1, MTBP, NAV3, NDNF, NF1, NKRF, NUDT14, NUP107, OR10T2, OTOP3, PLEC, PRR5, PRRG4, RNF215, RSRC2, SLC13A5, SLC37A3, SYPL2, TRIM59, USP15, ZFP1, WNK1, ZFP1, WNK1 ZNF485

The results for each of the test sets 1 to 4 are specifically shown in Tables 3 to 6 below. In addition, for convenience in data interpretation, the p values of total survival (Overall Survival) and disease-free survival (Disease Free Survival) according to the Kaplan Meier survival analysis method performed in Example 2 to be described later are shown together.

(Analysis result of test set 1) gene Stage number of mutations Mutation (%) Mutation type Cyto band Fisher's test (p-value) Total survival (p-value) Disease-free survival (p-value) I II Ⅲ IV NA cut missense in-frame etc ADK One 0 One One 0 3 0.7% 0 3 0 0 10q22.2|10q11-q24 0.02149 0.159 0.869 AEBP1 0 One 5 0 0 6 1.5% 0 6 0 0 7p13 0.1041 0.0475 0.0418 BAG5 0 0 5 0 0 5 1.2% One 4 0 0 14q32.33 0.03711 0.915 0.659 CACNA2D2 One One One 3 0 6 1.5% One 5 0 0 2q37.3 0.02899 0.931 0.545 CAPN10 One 2 0 0 0 3 0.7% 0 3 0 0 2q37.3 0.00606 0.17 0.557 CDR2 One 0 2 0 0 3 0.7% 0 3 0 0 16p12.2 0.009465 0.0922 0.305 CNGA1 One 0 One 2 0 4 1.0% 0 4 0 0 4p12 0.01163 0.473 0.55 COL9A2 One One One One 0 4 1.0% One 3 0 0 1p34.2 0.04556 0.458 0.568 CSDE1 0 0 6 0 0 6 1.5% One 5 0 0 1p13.2 0.01152 0.499 0.803 CSF3 One 0 0 0 0 One 0.2% 0 One 0 0 1p34.3 0.009479 0.61 0.564 EHMT1 One 4 2 One 0 8 1.9% One 7 0 0 9q34.3 0.05333 0.123 0.577 EIF2S1 One 2 One One 0 5 1.2% 0 5 0 0 14q23.3 0.05068 0.231 0.179 FBXO8 One 0 2 0 0 3 0.7% 0 3 0 0 4q34.1 0.009465 0.135 0.453 FGD1 One 0 4 2 0 7 1.7% 0 7 0 0 Xp11.22 0.009862 0.222 0.118 GPN3 One 0 0 One 0 2 0.5% 0 2 0 0 12q24.11 0.005823 0.269 0.108 HIST1H3F One One 0 One One 4 1.0% 0 4 0 0 6p22.2 0.01544 0.599 0.686 HLCS 0 0 11 One 0 12 2.9% One 11 0 0 21q22.13 0.000317 0.0577 0.159 HSPB11 One 0 0 2 0 3 0.7% 0 3 0 0 1p32.3 0.002748 0.637 0.884 IPPK One One 2 One 0 5 1.2% One 4 0 0 9q22.31 0.05797 0.282 0.833 IREB2 One 3 5 One 0 10 2.4% 4 6 0 0 15q25.1 0.07109 0.257 0.342 KRT1 0 0 One One 0 2 0.5% 0 2 0 0 12q13.13 0.7628 0.548 0.733 LARP1 One 3 2 0 One 7 1.7% One 6 0 0 5q33.2 0.02236 0.152 0.234 LAT One 0 0 0 0 One 0.2% 0 One 0 0 16p11.2 0.009479 0.392 0.578 LRFN3 One 2 4 0 0 7 1.7% 2 5 0 0 19q13.12 0.01944 0.164 0.49 MAN2A2 One 0 3 One 0 5 1.2% 0 5 0 0 15q26.1 0.01273 0.395 0.813 MED1 0 6 13 2 0 21 5.1% 3 18 0 0 17q12 0.03315 0.005 0.0154 NELL1 One 3 4 2 0 10 2.4% 3 7 0 0 11p15.1 0.1565 0.578 0.446 NVL One 0 5 One 0 7 1.7% One 6 0 0 1q42.11 0.004076 0.315 0.462 OLFM4 2 0 One 2 0 5 1.2% 0 5 0 0 13q14.3 0.000137 0.004 0.14 OR10T2 0 0 0 4 0 4 1.0% 0 4 0 0 1q23.1 0.03718 0.204 0.874 OR2T6 One One 0 3 0 5 1.2% 0 5 0 0 1q44 0.003914 0.808 0.591 OR4L1 One 0 One One 0 3 0.7% 0 3 0 0 14q11.2 0.02149 0.868 0.618 OR6C70 One One 0 0 0 2 0.5% 0 2 0 0 12q13.2 0.01232 0.212 0.73 OTUD7A One One One 5 0 8 1.9% One 7 0 0 15q13.3 0.01088 0.244 0.167 PEAR1 0 0 One One 0 2 0.5% 0 2 0 0 1q23.1 0.7628 0.329 0.607 PLSCR4 One 0 One 0 0 2 0.5% 0 2 0 0 3q24 0.01891 0.225 0.77 PLXNA4 One 17 3 3 One 25 6.1% One 23 One 0 7q32.3 0.000171 0.135 0.208 PURB 0 2 8 0 0 10 2.4% 0 10 0 0 7p13 0.01606 0.954 0.788 PVRL4 One 0 0 2 One 4 1.0% One 3 0 0 1q23.3 0.002748 0.683 0.77 RAB5A One One 0 0 0 2 0.5% 0 2 0 0 3p24.3 0.01232 0.212 0.73 RADIL One One 3 2 0 7 1.7% One 6 0 0 7p22.1 0.06291 0.847 0.0368 RIPK1 One One One 4 0 7 1.7% One 6 0 0 6p25.2 0.02144 0.844 3.70E-04 RNF123 One One 9 2 One 14 3.4% 2 12 0 0 3p21.31 0.004791 0.0306 0.147 RSPH4A One 2 4 One 0 8 1.9% 2 6 0 0 6q22.1 0.05751 0.391 0.16 SLC23A3 One 3 6 0 0 10 2.4% 2 8 0 0 2q35 0.009411 0.0221 0.0711 SNX22 One 2 One 0 0 4 1.0% One 3 0 0 15q22.31 0.02455 0.113 0.891 TCP11L2 One 2 5 0 0 8 1.9% One 7 0 0 12q23.3 0.009015 0.958 0.737 TELO2 0 One 8 0 0 9 2.2% 0 7 One One 16p13.3 0.007785 0.495 0.816 TFAP2D 0 2 One 0 0 3 0.7% One 2 0 0 6p12.3 0.6595 0.278 0.827 TMEM209 0 6 0 One 0 7 1.7% One 6 0 0 7q32.2 0.02953 0.249 0.708 UBE2U 0 One 2 0 0 3 0.7% 0 3 0 0 1p31.3 0.7821 0.489 0.156 USO1 One 2 One 0 0 4 1.0% 0 4 0 0 4q21.1 0.02455 0.105 0.794 ZNF202 0 0 One 6 0 7 1.7% One 6 0 0 11q24.1 0.01777 0.862 0.316

(Analysis result of test set 2) number of mutations Mutation (%) Cyto band Mutation type Stage Fisher's test (p-value) Total survival (p-value) Disease-free survival (p-value) cut missense in-frame etc I II+III+IV NA II+III+IV(%) ADAMTS14 11 2.7% 10q22.1 2 9 0 0 One 10 0 90.9% 0.077 0.0923 0.474 ADK 3 0.7% 10q22.2|10q11-q24 0 3 0 0 One 2 0 66.7% 0.022 0.159 0.869 AMIGO3 10 2.4% 3p21.31 One 9 0 0 One 9 0 90.0% 0.07 0.957 0.735 AQPEP 7 1.7% 5q23.1 0 7 0 0 0 7 0 100.0% One 0.0723 0.944 BMP2K 9 2.2% 4q21.21 2 7 0 0 One 8 0 88.9% 0.064 0.407 0.492 C2orf44 9 2.2% 2p23.3 0 9 0 0 One 8 0 88.9% 0.064 0.148 0.685 CACNA2D2 6 1.5% 3p21.31 One 5 0 0 One 5 0 83.3% 0.043 0.931 0.545 CAPN10 3 0.7% 2q37.3 0 3 0 0 One 2 0 66.7% 0.022 0.17 0.557 CCAR2 3 0.7% 8p21.3 0 3 0 0 0 3 0 100.0% One 0.0301 0.231 CCDC88B 13 3.2% 11q13.1 One 11 0 One One 12 0 92.3% 0.09 0.172 0.353 CDR2 3 0.7% 16p12.2 0 3 0 0 One 2 0 66.7% 0.022 0.0922 0.305 CNGA1 4 1.0% 4p12 0 4 0 0 One 3 0 75.0% 0.029 0.473 0.55 CNTN6 18 4.4% 3p26.3 2 16 0 0 One 17 0 94.4% 0.122 0.98 0.477 COL1A2 11 2.7% 7q21.3 2 9 0 0 One 10 0 90.9% 0.077 0.739 0.512 COL27A1 12 2.9% 9q32 0 12 0 0 One 11 0 91.7% 0.084 0.911 0.506 COL9A2 4 1.0% 1p34.2 One 3 0 0 One 3 0 75.0% 0.029 0.458 0.568 CRAT 10 2.4% 9q34.11 One 9 0 0 One 8 One 80.0% 0.064 0.688 0.649 CSF3 One 0.2% 17q21.1 0 One 0 0 One 0 0 0.0% 0.007 0.61 0.564 DCAF8L1 9 2.2% Xp21.3 0 9 0 0 One 8 0 88.9% 0.064 0.903 0.981 ECE2 13 3.2% 3q27.1 One 12 0 0 One 12 0 92.3% 0.09 0.666 0.516 EHMT1 8 1.9% 9q34.3 One 7 0 0 One 7 0 87.5% 0.057 0.123 0.577 EIF2S1 5 1.2% 14q23.3 0 5 0 0 One 4 0 80.0% 0.036 0.231 0.179 ESRP1 9 2.2% 8q22.1 One 8 0 0 One 8 0 88.9% 0.064 0.356 0.908 FAM50B 4 1.0% 6p25.2 0 4 0 0 One 3 0 75.0% 0.029 0.668 0.518 FBXO8 3 0.7% 4q34.1 0 3 0 0 One 2 0 66.7% 0.022 0.135 0.453 FGD1 7 1.7% Xp11.22 0 7 0 0 One 6 0 85.7% 0.05 0.222 0.118 FIGN 10 2.4% 2q24.3 2 8 0 0 One 9 0 90.0% 0.07 0.723 0.299 FMO2 7 1.7% 1q24.3 0 7 0 0 One 6 0 85.7% 0.05 0.484 0.271 GABBR2 7 1.7% 9q22.33 0 7 0 0 One 6 0 85.7% 0.05 0.656 0.443 GPI 4 1.0% 19q13.11 0 4 0 0 0 4 0 100.0% One 0.457 0.0417 GPN3 2 0.5% 12q24.11 0 2 0 0 One One 0 50.0% 0.015 0.269 0.108 GUCY1A3 11 2.7% 4q32.1 2 9 0 0 One 10 0 90.9% 0.077 0.947 0.573 HIP1R 9 2.2% 12q24.31 One 8 0 0 One 8 0 88.9% 0.064 0.598 0.495 HIST1H3F 4 1.0% 6p22.2 0 4 0 0 One 2 One 50.0% 0.022 0.599 0.686 HSPB11 3 0.7% 1p32.3 0 3 0 0 One 2 0 66.7% 0.022 0.637 0.884 IKBKAP 11 2.7% 9q31.3 One 10 0 0 One 10 0 90.9% 0.077 0.691 0.711 IPPK 5 1.2% 9q22.31 One 4 0 0 One 4 0 80.0% 0.036 0.282 0.833 IREB2 10 2.4% 15q25.1 4 6 0 0 One 9 0 90.0% 0.07 0.257 0.342 KIAA1468 8 1.9% 18q21.33 2 6 0 0 One 7 0 87.5% 0.057 0.989 0.0988 KIF23 11 2.7% 15q23 One 10 0 0 One 10 0 90.9% 0.077 0.237 0.46 KRT1 2 0.5% 12q13.13 0 2 0 0 0 2 0 100.0% One 0.548 0.733 LARP1 7 1.7% 5q33.2 One 6 0 0 One 5 One 71.4% 0.043 0.152 0.234 LAT One 0.2% 16p11.2 0 One 0 0 One 0 0 0.0% 0.007 0.392 0.578 LDLR 10 2.4% 19p13.2 4 6 0 0 One 9 0 90.0% 0.07 0.72 0.68 LRFN3 7 1.7% 19q13.12 2 5 0 0 One 6 0 85.7% 0.05 0.164 0.49 MAN2A2 5 1.2% 15q26.1 0 5 0 0 One 4 0 80.0% 0.036 0.395 0.813 MYO7B 15 3.6% 2q14.3 2 13 0 0 0 15 0 100.0% One 0.999 0.396 NBR1 16 3.9% 17q21.31 2 14 0 0 One 15 0 93.8% 0.109 0.336 0.282 NELL1 10 2.4% 11p15.1 3 7 0 0 One 9 0 90.0% 0.07 0.578 0.446 NOTCH4 14 3.4% 6p21.32 2 12 0 0 One 13 0 92.9% 0.097 0.109 0.878 NUP153 14 3.4% 6p22.3 One 13 0 0 One 13 0 92.9% 0.097 0.0564 0.458 NVL 7 1.7% 1q42.11 One 6 0 0 One 6 0 85.7% 0.05 0.315 0.462 OBSL1 10 2.4% 2q35 One 9 0 0 One 9 0 90.0% 0.07 0.171 0.27 OLFM4 5 1.2% 13q14.3 0 5 0 0 2 3 0 60.0% 0.001 0.04 0.14 OR2T6 5 1.2% 1q44 0 5 0 0 One 4 0 80.0% 0.036 0.808 0.591 OR4L1 3 0.7% 14q11.2 0 3 0 0 One 2 0 66.7% 0.022 0.868 0.618 OR6C70 2 0.5% 12q13.2 0 2 0 0 One One 0 50.0% 0.015 0.212 0.73 OR8H1 10 2.4% 11q12.1 One 9 0 0 One 9 0 90.0% 0.07 0.894 0.437 OTUD7A 8 1.9% 15q13.3 One 7 0 0 One 7 0 87.5% 0.057 0.244 0.167 PCDHB1 10 2.4% 5q31.3 One 9 0 0 One 9 0 90.0% 0.07 0.457 0.0988 PDZRN3 11 2.7% 3p13 One 10 0 0 One 10 0 90.9% 0.077 0.347 0.793 PEAR1 2 0.5% 1q23.1 0 2 0 0 0 2 0 100.0% One 0.329 0.607 PLAUR 8 1.9% 19q13.31 One 7 0 0 2 6 0 75.0% 0.02 0.53 0.637 PLSCR4 2 0.5% 3q24 0 2 0 0 One One 0 50.0% 0.015 0.225 0.77 PMS1 9 2.2% 2q32.2 One 8 0 0 One 8 0 88.9% 0.064 0.0467 0.288 POLN 12 2.9% 4p16.3 0 12 0 0 One 11 0 91.7% 0.084 0.21 0.783 PVRL4 4 1.0% 1q23.3 One 3 0 0 One 2 One 50.0% 0.022 0.683 0.77 RAB5A 2 0.5% 3p24.3 0 2 0 0 One One 0 50.0% 0.015 0.212 0.73 RADIL 7 1.7% 7p22.1 One 6 0 0 One 6 0 85.7% 0.05 0.847 0.0368 RIPK1 7 1.7% 6p25.2 One 6 0 0 One 6 0 85.7% 0.05 0.844 3.70E-04 RNF123 14 3.4% 3p21.31 2 12 0 0 One 12 One 85.7% 0.09 0.0306 0.147 RSPH4A 8 1.9% 6q22.1 2 6 0 0 One 7 0 87.5% 0.057 0.391 0.16 SCAMP3 5 1.2% 1q22 One 4 0 0 0 4 One 80.0% One 0.787 0.554 SDCCAG8 9 2.2% 1q43-q44 One 8 0 0 One 8 0 88.9% 0.064 0.0848 0.228 SEC24A 10 2.4% 5q31.1 One 9 0 0 One 9 0 90.0% 0.07 0.33 0.503 SLC23A3 10 2.4% 2q35 2 8 0 0 One 9 0 90.0% 0.07 0.0221 0.0711 SLC6A9 8 1.9% 1p34.1 0 8 0 0 One 7 0 87.5% 0.057 0.0877 0.208 SLMAP 7 1.7% 3p14.3 6 One 0 0 One 6 0 85.7% 0.05 0.525 0.979 SNX22 4 1.0% 15q22.31 One 3 0 0 One 3 0 75.0% 0.029 0.113 0.891 SPATS2 8 1.9% 12q13.12 2 6 0 0 2 6 0 75.0% 0.02 0.872 0.619 SRC 7 1.7% 20q11.23 0 7 0 0 One 6 0 85.7% 0.05 0.578 0.336 SUCO 11 2.7% 1q24.3 One 10 0 0 One 10 0 90.9% 0.077 0.801 0.79 TARSL2 6 1.5% 15q26.3 0 6 0 0 One 5 0 83.3% 0.043 0.843 0.499 TCFL5 8 1.9% 20q13.33 0 8 0 0 One 7 0 87.5% 0.057 0.0465 0.055 TCP11L2 8 1.9% 12q23.3 One 7 0 0 One 7 0 87.5% 0.057 0.958 0.737 TFAP2D 3 0.7% 6p12.3 One 2 0 0 0 3 0 100.0% One 0.278 0.827 TOPORS 10 2.4% 9p21.1 One 9 0 0 2 8 0 80.0% 0.064 0.392 0.601 TRIM24 13 3.2% 7q33-q34 0 13 0 0 One 12 0 92.3% 0.09 0.518 0.0393 TSKU 5 1.2% 11q13.5 0 5 0 0 One 4 0 80.0% 0.036 0.0849 0.593 UBE2U 3 0.7% 1p31.3 0 3 0 0 0 3 0 100.0% One 0.489 0.156 USO1 4 1.0% 4q21.1 0 4 0 0 One 3 0 75.0% 0.029 0.105 0.794 XPO5 11 2.7% 6p21.1 2 8 0 One One 10 0 90.9% 0.077 0.26 0.488 ZNF221 7 1.7% 19q13.31 0 7 0 0 One 6 0 85.7% 0.05 0.0952 0.918

(Analysis result of test set 3) number of mutations Mutation (%) Cyto band Mutation type Stage Fisher's test (p-value) Total survival (p-value) Disease-free survival (p-value) cut missense in-frame etc I+II III+IV NA III+IV(%) ADA 4 1.0% 20q13.12 0 4 0 0 4 0 0 0.0% 0.011 0.153 0.449 ALKBH1 4 1.0% 14q24.3 0 4 0 0 4 0 0 0.0% 0.011 0.594 0.192 BPIFB6 12 2.9% 20q11.21 3 9 0 0 7 4 One 33.3% 0.046 0.0364 0.124 BRAF 11 2.7% 7q34 2 9 0 0 8 3 0 27.3% 0.008 0.287 0.249 CKB 5 1.2% 14q32.33 0 4 One 0 5 0 0 0.0% 0.004 0.139 0.262 CNTN4 11 2.7% 3p26.3-p26.2 0 10 0 One 0 10 0 100.0% 0.022 0.839 0.945 COL24A1 16 3.9% 1p22.3 0 16 0 0 8 7 0 46.7% 0.080 0.916 0.453 DAPK1 14 3.4% 9q21.33 One 13 0 0 One 12 0 92.3% 0.048 0.484 0.838 DNMT3A 10 2.4% 2p23.3 One 9 0 0 7 2 0 22.2% 0.008 0.0236 0.057 EPCAM 2 0.5% 2p21 0 2 0 0 2 One 0 33.3% 0.248 0.237 0.762 ERLEC1 5 1.2% 2p16.2 0 4 0 One 4 One 0 20.0% 0.042 0.915 0.895 EXOC4 13 3.2% 7q33 One 12 0 0 10 3 0 23.1% 0.002 0.0984 0.121 FAM111A 5 1.2% 11q12.1 0 5 0 0 5 0 0 0.0% 0.004 0.218 0.205 FBXO7 2 0.5% 22q12.3 0 2 0 0 2 One 0 33.3% 0.248 0.232 0.803 FDPS 6 1.5% 1q22 0 6 0 0 4 2 0 33.3% 0.093 0.0199 0.0368 FGFR3 67 16.3% 4p16.3 3 64 0 0 31 35 0 53.0% 0.025 0.115 0.425 GLP1R 3 0.7% 6p21.2 0 3 0 0 3 0 0 0.0% 0.035 0.0986 0.101 GPRIN3 4 1.0% 4q22.1 0 4 0 0 4 0 0 0.0% 0.011 0.711 0.732 HCN3 5 1.2% 1q22 0 5 0 0 4 One 0 20.0% 0.042 0.826 0.41 HELLS 5 1.2% 10q23.33 One 4 0 0 4 One 0 20.0% 0.042 0.139 0.12 HOXC13 4 1.0% 12q13.13 0 4 0 0 4 0 0 0.0% 0.011 0.151 0.416 HYOU1 6 1.5% 11q23.3 0 6 0 0 4 One 0 20.0% 0.042 0.355 0.575 KCND3 4 1.0% 1p13.2 0 4 0 0 4 0 0 0.0% 0.011 0.296 0.166 KIF13A 16 3.9% 6p22.3 2 14 0 0 One 14 0 93.3% 0.045 0.958 0.907 KLK13 5 1.2% 19q13.41 One 4 0 0 4 One 0 20.0% 0.042 0.0702 0.0638 KPNA2 8 1.9% KPNA2 0 8 0 0 7 0 One 0.0% 0 0.448 0.285 MBNL2 6 1.5% 13q32.1 2 4 0 0 4 2 0 33.3% 0.093 0.263 0.139 NUP107 12 2.9% 12q15 3 9 0 0 0 10 One 90.9% 0.022 0.071 0.08 OR10G7 5 1.2% 11q24.2 0 5 0 0 5 0 0 0.0% 0.004 0.0791 0.0702 OR13C3 11 2.7% 9q31.1 One 10 0 0 9 One One 9.1% 0 0.0134 0.11 OR5D13 4 1.0% 11q11 One 3 0 0 3 One 0 25.0% 0.104 0.467 0.923 OR5H15 4 1.0% 3q11.2 0 4 0 0 3 One 0 25.0% 0.104 0.587 0.182 PAK1IP1 4 1.0% 6p24.2 0 4 0 0 4 0 0 0.0% 0.011 0.371 0.366 PAPPA2 25 6.1% 1q25.2 3 22 0 0 12 12 0 50.0% 0.079 0.666 0.922 PHF1 10 2.4% 6p21.32 2 8 0 0 0 9 0 100.0% 0.032 0.857 0.567 PHF17 5 1.2% One 4 0 0 4 One 0 20.0% 0.042 0.638 0.919 PITRM1 5 1.2% 10p15.2 0 5 0 0 4 One 0 20.0% 0.042 0.598 0.586 PLXNA4 25 6.1% 7q32.3 One 23 One 0 18 6 One 24.0% 0 0.135 0.208 POLR1C 5 1.2% 6p21.1 0 5 0 0 5 0 0 0.0% 0.004 0.216 0.557 PPP1R3B 3 0.7% 8p23.1 0 3 0 0 3 0 0 0.0% 0.035 0.375 0.322 PPP2R5B 5 1.2% 11q13.1 One 4 0 0 4 One 0 20.0% 0.042 0.0933 0.0891 PROCA1 5 1.2% 17q11.2 0 5 0 0 4 One 0 20.0% 0.042 0.421 0.259 RELN 37 9.0% 7q22.1 2 35 0 0 21 15 0 41.7% 0.002 0.0206 0.0423 RSRC1 5 1.2% 3q25.32 One 4 0 0 4 One 0 20.0% 0.042 0.0802 0.0785 SCMH1 4 1.0% 1p34.2 0 4 0 0 4 0 0 0.0% 0.011 0.263 0.437 SEMA6D 12 2.9% 15q21.1 One 11 0 0 9 3 0 25.0% 0.004 0.0827 0.122 SESTD1 7 1.7% 2q31.2 5 2 0 0 3 4 0 57.1% 0.687 0.158 0.0862 SIN3A 14 3.4% 15q24.2 0 14 0 0 10 4 0 28.6% 0.004 0.00744 0.00345 SLC25A31 4 1.0% 4q28.1 0 4 0 0 4 0 0 0.0% 0.011 0.248 0.209 SLC43A2 5 1.2% 17p13.3 One 4 0 0 4 One 0 20.0% 0.042 0.191 0.102 SLC5A2 4 1.0% 16p11.2 0 4 0 0 3 One 0 25.0% 0.104 0.458 0.438 SRRM2 38 9.2% 16p13.3 One 37 0 0 17 21 0 55.3% 0.149 0.00237 0.00219 STAM 6 1.5% 10p12.33 2 4 0 0 4 One 0 20.0% 0.042 0.0123 0.246 STON1 14 3.4% 2p16.3 One 13 0 0 9 5 0 35.7% 0.019 0.586 0.645 SYT1 7 1.7% 12q21.2 One 5 One 0 4 3 0 42.9% 0.223 0.457 0.0497 TBC1D12 9 2.2% 10q23.33 0 3 0 6 7 2 0 22.2% 0.008 0.299 0.536 TMEM209 7 1.7% 7q32.2 One 6 0 0 6 One 0 14.3% 0.006 0.249 0.708 TMEM67 13 3.2% 8q22.1 2 11 0 0 0 12 0 100.0% 0.010 0.795 0.285 TNPO1 12 2.9% 5q13.2 4 7 One 0 0 11 0 100.0% 0.020 0.808 0.81 TRIM4 3 0.7% 7q22.1 0 3 0 0 3 0 0 0.0% 0.035 0.406 0.229 TTPAL 5 1.2% 20q13.12 0 5 0 0 5 0 0 0.0% 0.004 0.116 0.362 USP21 9 2.2% 1q23.3 0 9 0 0 7 2 0 22.2% 0.008 0.237 0.538 USP24 15 3.6% 1p32.3 3 12 0 0 9 6 0 40.0% 0.046 0.419 0.645 ZMIZ2 10 2.4% 7p13 0 10 0 0 One 9 0 90.0% 0.180 0.546 0.587 ZNF274 5 1.2% 19q13.43 0 5 0 0 5 0 0 0.0% 0.004 0.206 0.497 ZNF382 10 2.4% 19q13.12 0 10 0 0 7 2 0 22.2% 0.008 0.232 0.551 ZNF665 20 4.9% 19q13.42 4 15 0 One 16 4 0 20.0% 0 0.217 0.365

(Analysis result of test set 4) number of mutations Mutation (%) Cyto band Mutation type Stage Fisher's test (p-value) Total survival (p-value) Disease-free survival (p-value) cut missense in-frame etc I+II+III IV NA IV (%) A2M 15 3.6% 12p13.31 3 12 0 0 14 One 0 6.7% 0.045 0.208 0.848 ACBD7 3 0.7% 10p13 0 3 0 0 0 3 0 100.0% 0.037 0.195 0.127 ADAM7 5 1.2% 8p21.2 One 4 0 0 One 4 0 80.0% 0.045 0.359 0.653 LPCAT1 3 0.7% 5p15.33 0 3 0 0 One 2 0 66.7% 0.258 0.151 0.0114 AKAP9 52 12.7% 7q21.2 4 48 0 0 45 7 0 13.5% 0.004 0.0216 0.00399 ALDH1L1 3 0.7% 3q21.3 0 3 0 0 0 3 0 100.0% 0.037 0.0973 0.264 ARHGAP35 30 7.3% 19q13.32 9 21 0 0 28 2 0 6.7% 0.002 0.818 0.909 ATR 36 8.8% 3q23 3 33 0 0 29 7 0 19.4% 0.134 0.128 0.069 C11orf16 5 1.2% 11p15.4 0 5 0 0 One 4 0 80.0% 0.045 0.739 0.17 CELA1 2 0.5% 12q13.13 0 2 0 0 0 2 0 100.0% 0.111 0.0488 0.828 CHD4 30 7.3% 12p13.31 4 26 0 0 27 2 One 6.7% 0.003 0.0356 0.59 CLINT1 4 1.0% 5q33.3 0 4 0 0 One 3 0 75.0% 0.111 0.595 0.0651 CLK1 7 1.7% 2q33.1 0 7 0 0 One 6 0 85.7% 0.007 0.321 0.705 CPEB3 6 1.5% 10q23.32 4 2 0 0 3 3 0 50.0% 0.404 0.105 0.00335 CTAGE5 3 0.7% 14q13.2 0 3 0 0 2 One 0 33.3% 1.000 0.726 0.887 DAAM2 9 2.2% 6p21.2 One 8 0 0 2 7 0 77.8% 0.009 0.632 0.284 DNAH8 50 12.2% 6p21.2 8 42 0 0 43 7 0 14.0% 0.006 0.132 0.242 DNASE2 2 0.5% 19p13.13 0 2 0 0 0 2 0 100.0% 0.111 0.137 0.298 DPM1 3 0.7% 20q13.13 0 3 0 0 0 3 0 100.0% 0.037 5.42E-04 0.237 DSG1 12 2.9% 18q12.1 One 11 0 0 12 0 0 0.0% 0.011 0.796 0.963 EXOC4 13 3.2% 7q33 One 12 0 0 13 0 0 0.0% 0.012 0.0984 0.121 EYA1 7 1.7% 8q13.3 2 5 0 0 2 5 0 71.4% 0.046 0.0559 0.336 FRY 33 8.0% 13q13.1 9 24 0 0 28 5 0 15.2% 0.003 0.0863 0.0143 GLE1 2 0.5% 9q34.11 One One 0 0 0 2 0 100.0% 0.111 0.992 0.347 GNA15 5 1.2% 19p13.3 2 3 0 0 One 4 0 80.0% 0.045 0.4 0.0941 GRIK3 15 3.6% 1p34.3 3 12 0 0 14 One 0 6.7% 0.045 0.221 0.203 GRM6 9 2.2% 5q35.3 0 9 0 0 2 7 0 77.8% 0.009 0.0436 0.114 GSK3B 4 1.0% 3q13.33 2 2 0 0 One 3 0 75.0% 0.111 0.644 0.787 HLCS 12 2.9% 21q22.13 One 11 0 0 0 0 0 #DIV/0! 0.114 0.0577 0.159 KIAA1407 8 1.9% 3q13.31 One 7 0 0 2 6 0 75.0% 0.020 0.712 0.618 KIF4A 3 0.7% Xq13.1 0 3 0 0 0 3 0 100.0% 0.037 0.0431 0.609 KLHL36 3 0.7% 16q24.1 0 3 0 0 0 3 0 100.0% 0.037 0.0229 0.828 LRRCC1 17 4.1% 8q21.2 0 17 0 0 16 One 0 5.9% 0.016 0.0931 0.256 LTN1 18 4.4% 21q21.3 One 15 0 2 17 One 0 5.6% 0.017 0.0454 0.323 MAGEA10 3 0.7% Xq28 0 3 0 0 One 2 0 66.7% 0.258 0.0632 0.937 MAMLD1 2 0.5% Xq28 0 2 0 0 0 2 0 100.0% 0.111 0.472 0.458 MAP3K5 15 3.6% 6q23.3 2 13 0 0 14 One 0 6.7% 0.045 0.0449 0.12 MED1 21 5.1% 17q12 3 18 0 0 19 2 0 9.5% 0.029 0.005 0.0154 MTBP 8 1.9% 8q24.12 One 6 One 0 2 6 0 75.0% 0.020 0.485 0.105 MTF2 5 1.2% 1p22.1 2 3 0 0 2 3 0 60.0% 0.339 0.177 0.659 MXD4 3 0.7% 4p16.3 0 3 0 0 One 2 0 66.7% 0.258 0.31 0.323 NACA 3 0.7% 12q13.3 0 3 0 0 3 0 0 0.0% 0.554 0.137 0.144 NAV3 31 7.5% 12q21.2 2 29 0 0 28 2 One 6.5% 0.002 0.00235 0.0266 NDNF 5 1.2% 4q27 One 4 0 0 0 5 0 100.0% 0.004 0.539 5.75E-04 NF1 41 10.0% 17q11.2 17 24 0 0 36 5 0 12.2% 0.005 0.371 0.947 NKRF 4 1.0% Xq24 One 3 0 0 0 4 0 100.0% 0.012 0.03 0.0343 NUDT14 4 1.0% 14q32.33 One 3 0 0 0 4 0 100.0% 0.012 0.842 0.619 NUP107 12 2.9% 12q15 3 9 0 0 2 9 One 75.0% 0.002 0.071 0.08 OR10T2 4 1.0% 1q23.1 0 4 0 0 0 4 0 100.0% 0.012 0.204 0.874 OTOP3 6 1.5% 17q25.1 0 6 0 0 One 5 0 83.3% 0.018 0.344 0.981 PLEC 50 12.2% 8q24.3 4 46 0 0 45 4 One 8.0% 0 0.024 0.438 PPM1J 2 0.5% 1p13.2 0 2 0 0 0 2 0 100.0% 0.111 3.56E-05 PRR5 7 1.7% 22q13.31 0 7 0 0 2 5 0 71.4% 0.046 0.484 0.788 PRRG4 3 0.7% 11p13 0 3 0 0 0 3 0 100.0% 0.037 0.249 0.322 RAC1 4 1.0% 7p22.1 0 4 0 0 One 3 0 75.0% 0.111 0.643 0.598 RNF215 5 1.2% 22q12.2 0 5 0 0 0 5 0 100.0% 0.004 7.41E-07 2.72E-05 RPL10 3 0.7% Xq28 0 3 0 0 One 2 0 66.7% 0.258 0.825 0.787 RSRC2 12 2.9% 12q24.31 0 12 0 0 11 0 One 0.0% 0.019 0.0507 0.0449 SEZ6L 12 2.9% 22q12.1 2 10 0 0 10 One One 8.3% 0.113 0.0598 0.425 SLC13A5 5 1.2% 17p13.1 2 3 0 0 One 4 0 80.0% 0.045 0.912 0.861 SLC37A3 8 1.9% 7q34 0 7 0 One One 7 0 87.5% 0.003 0.39 0.0878 SYPL2 3 0.7% 1p13.3 0 3 0 0 0 3 0 100.0% 0.037 0.102 0.719 TRIM59 5 1.2% 3q25.33 One 4 0 0 One 4 0 80.0% 0.045 1.34E-04 7.29E-04 USP15 10 2.4% 12q14.1 0 10 0 0 9 0 One 0.0% 0.029 0.887 0.936 USPL1 13 3.2% 13q12.3 3 10 0 0 12 One 0 7.7% 0.043 0.0189 0.00297 WNK1 30 7.3% 12p13.33 2 28 0 0 28 2 0 6.7% 0.002 0.075 0.00575 YBX3 3 0.7% 12p13.2 0 3 0 0 0 2 One 66.7% 0.111 0.834 0.38 ZFP36L1 32 7.8% 14q24.1 21 8 2 One 15 17 0 53.1% 0.032 0.324 0.988 ZMIZ2 10 2.4% 7p13 0 10 0 0 3 7 0 70.0% 0.035 0.546 0.587 ZNF202 7 1.7% 11q24.1 One 6 0 0 One 6 0 85.7% 0.007 0.862 0.316 ZNF485 5 1.2% 10q11.21 One 4 0 0 0 5 0 100.0% 0.004 0.125 0.0218

In summary, if the p value of Fisher's exact test among the genes in Tables 3 to 6 is 0.05 or more, it is related to the pathological stage, but it is determined that the association is low, and the following 152 genes with a p value of less than 0.05 (Candidate gene group 1) is considered to be a gene associated with the pathological stage.

Candidate gene group 1: A2M, ACBD7, ADA, ADAM7, ADK, AKAP9, ALDH1L1, ALKBH1, ARHGAP35, BAG5, BPIFB6, BRAF, C11orf16, CACNA2D2, CAPN10, CDR2, CHD4, CKB, CLK1, CN4 CSDE1, CSF3, DAAM2, DAPK1, DNAH8, DNMT3A, DPM1, DSG1, EIF2S1, ERLEC1, EXOC4, EYA1, FAM111A, FAM50B, FBXO8, FGD1, FGFR3, FMO2, FRY, GABBR3, GPRIK3, GNA15, GLP1 GRM6, HCN3, HELLS, HIST1H3F, HLCS, HOXC13, HSPB11, HYOU1, IPPK, KCND3, KIAA1407, KIF13A, KIF4A, KLHL36, KLK13, KPNA2, LARP1, LAT, MLRFN3, BP, LRRCC1, LTN1K BP, MANED1, LRRCC2A NAV3, NDNF, NF1, NKRF, NUDT14, NUP107, NVL, OLFM4, OR10G7, OR10T2, OR13C3, OR2T6, OR4L1, OR6C70, OTOP3, OTUD7A, PAK1IP1, PHF1, PHFP17, PHF1, PHFPOLR4 PPP1R3B; PPP2R5B; SPATS2, SRC, STAM, STON1, SYPL2, TARSL2, TBC1D12, TCP11L2, TELO2, TMEM209, TMEM67, TNPO1, TRIM4, TRIM59, TSKU , TTPAL, USO1, USP15, USP21, USP24, USPL1, WNK1, ZFP36L1, ZMIZ2, ZNF202, ZNF221, ZNF274, ZNF382, ZNF485, ZNF665

Selection and review of pathologic stage-specific markers for prognosis

In order to confirm the possibility of use as a pathological stage-specific marker for prognosis prediction, comparative analysis was performed on the data of the 411 subjects for these genes, and missing values and outliers were excluded.

Based on the clinical information (event (death or recurrence), observation time) of the patients, overall survival or disease-free survival was calculated by Kaplan Meier survival analysis using SPSS. In the total survival period, the event was defined as death, and in the disease-free survival period, the event was defined as bladder cancer recurrence. In order to determine whether mutation in each of the genes is correlated with bladder cancer-caused death or bladder cancer recurrence, mutation occurrence and total survival were based on the event time of each group obtained in the Kaplan Meier survival assay. The association of duration, and association of mutagenesis and disease-free survival, was confirmed by log rank test. A p-value of less than 0.05 was considered statistically significant.

The experimental group was defined as the case with alterations in query gene, and the control group was the case without alterations in query gene. The median months survival means a value located at the center when the survival periods of patients in the corresponding group are listed. The slope in the survival curve by the Kaplan Meier survival assay is determined by the duration of survival.

As a result of the above analysis, the following 44 genes (candidate gene group 2) with a p-value of less than 0.05 for total survival or disease-free survival are considered to be highly correlated with survival or recurrence rates.

Candidate gene class 2: AEBP1, LPCAT1, AKAP9, BPIFB6, CCAR2, CELA1, CHD4, CPEB3, DNMT3A, DPM1, FDPS, FRY, GPI, GRM6, KIF4A, KLHL36, LTN1, MAP3K5, MED1, NKRF3, NDNF, NAV3, OLFM4, OR13C3, PLEC, PMS1, PPM1J, RADIL, RELN, RIPK1, RNF123, RNF215, RSRC2, SIN3A, SLC23A3, SRRM2, STAM, SYT1, TCFL5, TRIM24, TRIM59, USPL1, WNK1, ZNF485.

Table 7 below shows the Kaplan Meier analysis results for 32 genes having a p-value of less than 0.05 in total survival among the second group of candidate genes.

gene Total survival (p-value) no mutation with mutation Total number of people (persons) Number of deaths (persons) death rate(%) Median survival (months) Total number of people (persons) Number of deaths (persons) death rate(%) Median survival (months) AEBP1 0.0475 403 179 44.42 33.11 6 0 0 NA AKAP9 0.0216 366 166 45.36 31.18 43 13 30.23 NA BPIFB6 0.0364 399 178 44.61 33.02 10 One 10 NA CCAR2 0.0301 406 177 43.6 34.95 3 2 66.67 9.66 CELA1 0.0488 407 178 43.73 34.03 2 One 50 8.08 CHD4 0.0356 386 173 44.82 33.02 23 6 26.09 NA DNMT3A 0.0236 399 178 44.61 33.02 10 One 10 NA DPM1 5.416E-04 406 176 43.35 34.95 3 3 100 7.1 FDPS 0.0199 403 179 44.42 33.02 6 0 0 NA GRM6 0.0436 401 173 43.14 35.38 8 6 75 17.97 KIF4A 0.0431 406 177 43.6 34.03 3 2 66.67 11.96 KLHL36 0.0229 406 177 43.6 34.95 3 2 66.67 17.61 LTN1 0.0454 393 176 44.78 33.02 16 3 18.75 NA MAP3K5 0.0449 394 176 44.67 33.02 15 3 20 NA MED1 0.00500 392 177 45.15 32.98 17 2 11.76 NA NAV3 0.00235 381 173 45.41 31.18 28 6 21.43 NA NKRF 0.0300 406 176 43.35 34.95 3 3 100 15.11 OLFM4 0.0400 404 179 44.31 33.11 5 0 0 NA OR13C3 0.0134 401 179 44.64 33.02 8 0 0 NA PLEC 0.0240 375 171 45.6 32.98 34 8 23.53 NA PMS1 0.0467 401 178 44.39 33.02 8 One 12.5 NA PPM1J 3.56E-05 407 177 43.49 34.95 2 2 100 4.73 RELN 0.0206 376 171 45.48 32 33 8 24.24 NA RNF123 0.0306 396 177 44.7 33.02 13 2 15.38 97.04 RNF215 7.41E-07 404 174 43.07 34.95 5 5 100 5.68 SIN3A 0.00744 397 178 44.84 32.98 12 One 8.33 NA SLC23A3 0.0221 401 179 44.64 33.02 8 0 0 NA SRRM2 0.00237 381 173 45.41 31.18 28 6 21.43 NA STAM 0.0123 404 175 43.32 34.95 5 4 80 14.36 TCFL5 0.0465 401 178 44.39 33.11 8 One 12.5 NA TRIM59 1.34E-04 404 174 43.04 34.95 5 5 100 12.84 USPL1 0.0189 396 176 44.44 32.98 13 3 23.08 NA

In Table 7 above, in the case of AEBP1, AKAP9, BPIFB6, CHD4, DNMT3A, FDPS, LTN1, MAP3K5, MED1, NAV3, OLFM4, OR13C3, PLEC, PMS1, RELN, RNF123, SIN3A, SLC23A3, SRRM2, TCFL1 genes, If there is a mutation in the gene, the mortality rate is less than 50%, and it is considered a marker with a good prognosis.

On the other hand, in the case of LPCAT1, CCAR2, CELA1, CPEB3, DPM1, GPI, GRM6, KIF4A, KLHL36, NDNF, NKRF, PPM1J, RNF215, STAM, TRIM59, ZNF485 genes, if there is a mutation in the corresponding gene, the mortality rate is 50% or more. is a bad marker.

In addition, the results of Kaplan Meier analysis for 24 genes having a p-value of less than 0.05 for disease-free survival are shown in Table 8 below.

gene Disease-free survival (p-value) no mutation with mutation Total number of people (persons) Number of recurrences (persons) Relapse rate (%) Median disease-free survival (months) Total number of people (persons) Number of recurrences (persons) Relapse rate (%) Median disease-free survival (months) AEBP1 0.0418 316 143 45.25 29.89 6 0 0 NA LPCAT1 0.0114 319 140 43.89 32.59 3 3 100 8.54 AKAP9 0.00399 287 134 46.69 29.07 35 9 25.71 NA CPEB3 0.00335 317 139 43.85 32.59 5 4 80 5.35 FDPS 0.0368 316 142 44.94 29.89 6 One 16.67 161.2 FRY 0.0143 297 138 46.46 29.8 25 5 20 NA GPI 0.0417 318 141 44.34 30.22 4 2 50 4.73 MED1 0.0154 305 140 45.9 29.8 17 3 17.65 NA NAV3 0.0266 296 135 45.61 29.47 26 8 30.77 NA NDNF 5.748E-04 317 138 43.53 32.59 5 5 100 11.66 NKRF 0.0343 321 142 44.24 30.22 One One 100 7.56 RADIL 0.0368 315 137 43.49 32.59 7 6 85.71 11.27 RELN 0.0423 294 135 45.92 29.8 28 8 28.57 NA RIPK1 3.70E-04 315 137 43.49 35.68 7 6 85.71 11.66 RNF215 2.723E-05 319 140 43.89 32.59 3 3 100 4.99 RSRC2 0.0449 311 141 45.34 29.8 11 2 18.18 101.38 SIN3A 0.00345 311 143 45.98 29.8 11 0 0 NA SRRM2 0.00219 298 138 46.31 29.07 24 5 20.83 NA SYT1 0.0497 318 143 44.97 29.89 4 0 0 NA TRIM24 0.0393 315 143 45.4 29.89 7 0 0 NA TRIM59 7.294E-04 318 139 43.71 32.59 4 4 100 10.18 USPL1 0.00297 312 143 45.83 29.8 10 0 0 NA WNK1 0.00575 302 140 46.36 29.47 20 3 15 NA ZNF485 0.0218 318 139 43.71 30.22 4 4 100 4.99

In Table 8 above, AEBP1, AKAP9, FDPS, FRY, MED1, NAV3, RELN, RSRC2, SIN3A, SRRM2, SYT1, TRIM24, USPL1, and WNK1 genes are considered good prognostic markers with a recurrence rate of less than 50% if there is a mutation in the corresponding gene.

On the other hand, in the case of LPCAT1, CCAR2, CPEB3, DPM1, GPI, GRM6, KIF4A, NDNF, NKRF, RADIL, RIPK1, RNF215, STAM, TRIM59, ZNF485 genes, if there is a mutation in the corresponding gene, the recurrence rate is more than 50%, and the prognosis is poor. corresponds to the marker.

In addition, in the case of the following 31 genes (candidate gene group 1 & 2) overlappingly included in the first candidate gene group and the second candidate gene group, there is a mutation in the gene and a specific pathology in the subject When an enemy stage is identified, the survival rate or recurrence rate can be determined based on this. Therefore, in the case of the corresponding 31 genes, it is considered that the potential for use as a pathological stage-specific marker that can predict the prognosis is high.

Candidate Genes Groups 1 & 2: AKAP9, BPIFB6, CHD4, DNMT3A, DPM1, FRY, GRM6, KIF4A, KLHL36, LTN1, MAP3K5, MED1, NAV3, NDNF, NKRF, OLFM4, OR13C3, PLEC, RADIL, RELN, RADIL RIPK1, RNF123, RNF215, RSRC2, SIN3A, SLC23A3, STAM, TRIM59, USPL1, WNK1, ZNF485.

On the other hand, among the second group of candidate genes, if there is a mutation in the following 13 genes, it is related to the pathological stage (gender related) and has a correlation with whether or not total survival or disease-free survival. These are designated as the third group of candidate genes.

Candidate gene group 3: AEBP1, LPCAT1, CCAR2, CELA1, CPEB3, FDPS, GPI, PMS1, PPM1J, SRRM2, SYT1, TCFL5, TRIM24.

In addition, when there is a mutation in the following 12 genes among the second group of candidate genes, there is a correlation with both total survival and disease-free survival. These are designated as the 4th group of candidate genes.

Candidate gene group 4: AEBP1, AKAP9, FDPS, MED1, NAV3, NKRF, RELN, RNF215, SIN3A, SRRM2, TRIM59, USPL1.

Detection of marker genes using mutation position information

Mutation position information of the genes of the second group of candidate genes is shown below.

Gene AA change Type Copy # COSMIC Chr Start Pos End Pos HGVSc AEBP1 R1000Q Missense gain One chr7 44153382 44153382 ENST00000223357.3:c.2999G>A E799K Missense gain 2 chr7 44152334 44152334 ENST00000223357.3:c.2395G>A G6W Missense gain One chr7 44144280 44144280 ENST000002223357.3:c.16G>T E1096K Missense gain One chr7 44153669 44153669 ENST00000223357.3:c.3286G>A R831C Missense diploid chr7 44152430 44152430 ENST000002223357.3:c.2491C>T G832R Missense diploid chr7 44152433 44152433 ENST000002223357.3:c.2494G>A AKAP9 E514K Missense diploid chr7 91630771 91630771 ENST00000356239.3:c.1540G>A E2596K Missense diploid chr7 91709233 91709233 ENST00000356239.3:c.7786G>A Q365H Missense diploid chr7 91630326 91630326 ENST00000356239.3:c.1095G>C L3448Tfs*10 Frame_Shift_Ins gain chr7 91726612 91726613 ENST00000356239.3:c.10341dup S60L Missense shallowdel chr7 91603155 91603155 ENST00000356239.3:c.179C>T E1898K Missense diploid chr7 91690664 91690664 ENST00000356239.3:c.5692G>A D657H Missense shallowdel chr7 91631200 91631200 ENST00000356239.3:c.1969G>C Q3132E Missense shallowdel chr7 91722446 91722446 ENST00000356239.3:c.9394C>G Q3847H Missense gain chr7 91736731 91736731 ENST00000356239.3:c.11541G>C L301S Missense diploid chr7 91625086 91625086 ENST00000356239.3:c.902T>C E774K Missense shallowdel chr7 91631551 91631551 ENST00000356239.3:c.2320G>A E2043Q Missense diploid chr7 91694694 91694694 ENST00000356239.3:c.6127G>C E2071K Missense diploid chr7 91695741 91695741 ENST00000356239.3:c.6211G>A L2786R Missense gain One chr7 91712680 91712680 ENST00000356239.3:c.8357T>G E461Q Missense gain chr7 91630612 91630612 ENST00000356239.3:c.1381G>C E1961Q Missense diploid chr7 91691704 91691704 ENST00000356239.3:c.5881G>C R2109K Missense diploid chr7 91695856 91695856 ENST00000356239.3:c.6326G>A F3547L Missense diploid chr7 91727456 91727456 ENST00000356239.3:c.10641C>A H3016D Missense gain chr7 91715563 91715563 ENST00000356239.3:c.9046C>G E1921K Missense diploid chr7 91690733 91690733 ENST00000356239.3:c.5761G>A H3016Y Missense gain chr7 91715563 91715563 ENST00000356239.3:c.9046C>T I3647M Missense diploid chr7 91730214 91730214 ENST00000356239.3:c.10941C>G S1200C Missense diploid chr7 91643629 91643629 ENST00000356239.3:c.3599C>G L214S Missense shallowdel chr7 91623999 91623999 ENST00000356239.3:c.641T>C E3365Q Missense gain chr7 91726366 91726366 ENST00000356239.3:c.10093G>C E1940Q Missense gain chr7 91691641 91691641 ENST00000356239.3:c.5818G>C E3586K Missense diploid chr7 91729043 91729043 ENST00000356239.3:c.10756G>A R1562T Missense gain chr7 91668079 91668079 ENST00000356239.3:c.4685G>C M3312I Missense gain chr7 91726209 91726209 ENST00000356239.3:c.9936G>A D3011N Missense gain chr7 91715548 91715548 ENST00000356239.3:c.9031G>A M2002I Missense gain chr7 91694573 91694573 ENST00000356239.3:c.6006G>C P1381S Missense gain chr7 91652316 91652316 ENST00000356239.3:c.4141C>T X1447_splice Splice_Site gain chr7 91667732 91667732 ENST00000356239.3:c.4339-1G>A R3478T Missense diploid chr7 91726934 91726934 ENST00000356239.3:c.10433G>C T2825P Missense gain chr7 91712796 91712796 ENST00000356239.3:c.8473A>C R3476T Missense shallowdel chr7 91726928 91726928 ENST00000356239.3:c.10427G>C E3365* Nonsense gain chr7 91726366 91726366 ENST00000356239.3:c.10093G>T H2891P Missense diploid chr7 91713979 91713979 ENST00000356239.3:c.8672A>C D570H Missense diploid chr7 91630939 91630939 ENST00000356239.3:c.1708G>C E734K Missense diploid chr7 91631431 91631431 ENST00000356239.3:c.2200G>A E1916Q Missense diploid chr7 91690718 91690718 ENST00000356239.3:c.5746G>C Q1192E Missense gain chr7 91643604 91643604 ENST00000356239.3:c.3574C>G S1278R Missense gain chr7 91646413 91646413 ENST00000356239.3:c.3834C>G M1451I Missense diploid chr7 91667747 91667747 ENST00000356239.3:c.4353G>C S1760Y Missense diploid chr7 91674438 91674438 ENST00000356239.3:c.5279C>A E2218K Missense diploid chr7 91706208 91706208 ENST00000356239.3:c.6652G>A E3365K Missense diploid chr7 91726366 91726366 ENST00000356239.3:c.10093G>A E940Tfs*6 Frame_Shift_Del diploid chr7 91632048 91632049 ENST00000356239.3:c.2818_2819del H1904Y Missense diploid chr7 91690682 91690682 ENST00000356239.3:c.5710C>T S2240C Missense diploid chr7 91706275 91706275 ENST00000356239.3:c.6719C>G R3798K Missense diploid chr7 91735054 91735054 ENST00000356239.3:c.11393G>A S2932R Missense gain chr7 91714218 91714218 ENST00000356239.3:c.8796T>G BPIFB6 S391L Missense diploid chr20 31629805 31629805 ENST000000349552.1:c.1172C>T X381_splice Splice_Site diploid chr20 31629775 31629775 ENST000000349552.1:c.1143-1G>A S390L Missense gain chr20 31629802 31629802 ENST000000349552.1:c.1169C>T S378Y Missense diploid chr20 31628115 31628115 ENST000000349552.1:c.1133C>A G15S Missense gain chr20 31619496 31619496 ENST000000349552.1:c.43G>A Q421* Nonsense gain chr20 31631105 31631105 ENST000000349552.1:c.1261C>T L256M Missense gain chr20 31625464 31625464 ENST000000349552.1:c.766C>A P306S Missense gain chr20 31627168 31627168 ENST000000349552.1:c.916C>T S216I Missense diploid chr20 31624320 31624320 ENST000000349552.1:c.647G>T X33_splice Splice_Site gain chr20 31619551 31619551 ENST000000349552.1:c.97+1G>T F360L Missense gain chr20 31628062 31628062 ENST000000349552.1:c.1080C>A G104E Missense gain chr20 31622577 31622577 ENST000000349552.1:c.311G>A CCAR2 D696N Missense diploid chr8 22475874 22475874 ENST00000308511.4:c.2086G>A S671L Missense gain chr8 22475230 22475230 ENST00000308511.4:c.2012C>T P30S Missense shallowdel chr8 22463627 22463627 ENST00000308511.4:c.88C>T CELA1 G231S Missense diploid One chr12 51723536 51723536 ENST00000293636.1:c.691G>A D84A Missense diploid chr12 51736434 51736434 ENST00000293636.1:c.251A>C CHD4 R1877Q Missense diploid chr12 6680126 6680126 ENST00000357008.2:c.5630G>A E1776Q Missense diploid chr12 6686986 6686986 ENST00000357008.2:c.5326G>C E1371Q Missense diploid One chr12 6692229 6692229 ENST00000357008.2:c.4111G>C E1299Q Missense diploid One chr12 6692529 6692529 ENST00000357008.2:c.3895G>C P1387L Missense diploid One chr12 6692090 6692090 ENST00000357008.2:c.4160C>T L641F Missense gain One chr12 6705273 6705273 ENST00000357008.2:c.1923G>C K634N Missense gain One chr12 6705294 6705294 ENST00000357008.2:c.1902G>C E1469Q Missense One chr12 6691413 6691413 ENST00000357008.2:c.4405G>C P1541A Missense diploid 3 chr12 6690875 6690875 ENST00000357008.2:c.4621C>G L1333V Missense diploid One chr12 6692427 6692427 ENST00000357008.2:c.3997C>G E540K Missense gain 2 chr12 6707456 6707456 ENST00000357008.2:c.1618G>A X1075_splice Splice_Site diploid chr12 6700750 6700750 ENST00000357008.2:c.3223-1G>A R305H Missense diploid One chr12 6710105 6710105 ENST00000357008.2:c.914G>A R1000P Missense diploid chr12 6701173 6701173 ENST00000357008.2:c.2999G>C S1808* Nonsense diploid chr12 6682374 6682374 ENST00000357008.2:c.5423C>G E592K Missense gain chr12 6707178 6707178 ENST00000357008.2:c.1774G>A E357K Missense amp chr12 6709556 6709556 ENST00000357008.2:c.1069G>A L498V Missense diploid chr12 6707582 6707582 ENST00000357008.2:c.1492C>G E1523Q Missense gain chr12 6690929 6690929 ENST00000357008.2:c.4567G>C E698* Nonsense diploid chr12 6704529 6704529 ENST00000357008.2:c.2092G>T S785C Missense gain chr12 6702742 6702742 ENST00000357008.2:c.2354C>G Y574Sfs*43 Frame_Shift_Del diploid chr12 6707229 6707232 ENST00000357008.2:c.1720_1723del D386H Missense gain chr12 6709469 6709469 ENST00000357008.2:c.1156G>C D386N Missense diploid chr12 6709469 6709469 ENST00000357008.2:c.1156G>A E425Q Missense diploid chr12 6709148 6709148 ENST00000357008.2:c.1273G>C L1789V Missense diploid chr12 6682432 6682432 ENST00000357008.2:c.5365T>G E752K Missense diploid chr12 6703684 6703684 ENST00000357008.2:c.2254G>A S108N Missense shallowdel chr12 6711241 6711241 ENST00000357008.2:c.323G>A D104Y Missense shallowdel chr12 6711254 6711254 ENST00000357008.2:c.310G>T Q1155E Missense diploid chr12 6697466 6697466 ENST00000357008.2:c.3463C>G CPEB3 T359S Missense shallowdel One chr10 93952323 93952323 ENST00000265997.4:c.1076C>G Q601* Nonsense shallowdel chr10 93841145 93841145 ENST00000265997.4:c.1801C>T R435Q Missense diploid chr10 93904761 93904761 ENST00000265997.4:c.1304G>A S241Rfs*77 Frame_Shift_Del diploid chr10 93999375 93999385 ENST00000265997.4:c.723_733del E493* Nonsense diploid chr10 93870928 93870928 ENST00000265997.4:c.1477G>T A225Gfs*24 Frame_Shift_Del diploid chr10 93999434 93999434 ENST00000265997.4:c.674del DNMT3A M880I Missense diploid 4 chr2 25457247 25457247 ENST00000264709.3:c.2640G>A F827= Splice_Region shallowdel chr2 25458692 25458692 ENST00000264709.3:c.2481C>T G890D Missense diploid 2 chr2 25457218 25457218 ENST00000264709.3:c.2669G>A E863K Missense diploid One chr2 25458586 25458586 ENST00000264709.3:c.2587G>A T834N Missense diploid 2 chr2 25458672 25458672 ENST00000264709.3:c.2501C>A H821R Missense diploid chr2 25459821 25459821 ENST00000264709.3:c.2462A>G G543V Missense gain 14 chr2 25467448 25467448 ENST00000264709.3:c.1628G>T A760T Missense diploid One chr2 25463215 25463215 ENST00000264709.3:c.2278G>A R309P Missense diploid chr2 25470548 25470548 ENST00000264709.3:c.926G>C K299I Missense amp chr2 25470578 25470578 ENST00000264709.3:c.896A>T DPM1 E38Q Missense diploid 3 chr20 49574949 49574949 ENST00000371588.5:c.112G>C E59K Missense gain chr20 49571809 49571809 ENST00000371588.5:c.175G>A E53Q Missense amp chr20 49574904 49574904 ENST00000371588.5:c.157G>C FDPS P275A Missense gain One chr1 155288696 155288696 ENST00000356657.6:c.823C>G K332T Missense amp chr1 155289655 155289655 ENST00000356657.6:c.995A>C G38W Missense gain chr1 155279692 155279692 ENST00000356657.6:c.112G>T Q85H Missense gain chr1 155279912 155279912 ENST00000356657.6:c.255G>T S230F Missense gain One chr1 155288460 155288460 ENST00000356657.6:c.689C>T Q232E Missense gain chr1 155288465 155288465 ENST00000356657.6:c.694C>G FRY R417Q Missense diploid 4 chr13 32721489 32721489 ENST00000380250.3:c.1250G>A S1398C Missense gain One chr13 32783164 32783164 ENST00000380250.3:c.4193C>G D1789V Missense diploid 2 chr13 32802752 32802752 ENST00000380250.3:c.5366A>T S1882* Nonsense diploid One chr13 32808828 32808828 ENST00000380250.3:c.5645C>A E2059Q Missense gain One chr13 32811880 32811880 ENST00000380250.3:c.6175G>C D49N Missense gain chr13 32841395 32841395 ENST00000542859.1:c.145G>A S1938A Missense shallowdel One chr13 32811517 32811517 ENST00000380250.3:c.5812T>G E1004Q Missense gain One chr13 32757127 32757127 ENST00000380250.3:c.3010G>C P2300L Missense gain One chr13 32821530 32821530 ENST00000380250.3:c.6899C>T L373V Missense amp chr13 32869562 32869562 ENST00000542859.1:c.1117C>G T73P Missense diploid chr13 32841467 32841467 ENST00000542859.1:c.217A>C K2391= Splice_Region gain chr13 32826017 32826017 ENST00000380250.3:c.7173G>A Q510* Nonsense diploid chr13 32729676 32729676 ENST00000380250.3:c.1528C>T L791P Missense diploid 2 chr13 32749720 32749720 ENST00000380250.3:c.2372T>C S135L Missense gain chr13 32850608 32850608 ENST00000542859.1:c.404C>T Q108E Missense shallowdel chr13 32676151 32676151 ENST00000380250.3:c.322C>G S1698C Missense diploid chr13 32799998 32799998 ENST00000380250.3:c.5093C>G D2470H Missense gain chr13 32828523 32828523 ENST00000380250.3:c.7408G>C X1107_splice Splice_Site shallowdel chr13 32759286 32759286 ENST00000380250.3:c.3319+1G>A E1434K Missense shallowdel chr13 32783746 32783746 ENST00000380250.3:c.4300G>A S2237T Missense gain chr13 32818201 32818201 ENST00000380250.3:c.6710G>C S1756* Nonsense diploid chr13 32802653 32802653 ENST00000380250.3:c.5267C>G L2403V Missense shallowdel chr13 32826051 32826051 ENST00000380250.3:c.7207C>G W824* Nonsense diploid chr13 32752364 32752364 ENST00000380250.3:c.2472G>A G1306E Missense diploid chr13 32776563 32776563 ENST00000380250.3:c.3917G>A E285* Nonsense diploid chr13 32705945 32705945 ENST00000380250.3:c.853G>T G528E Missense shallowdel chr13 32729731 32729731 ENST00000380250.3:c.1583G>A Q199H Missense gain chr13 32863787 32863787 ENST00000542859.1:c.597G>C S28F Missense gain chr13 32841333 32841333 ENST00000542859.1:c.83C>T E191K Missense diploid chr13 32852677 32852677 ENST00000542859.1:c.571G>A H642Rfs*26 Frame_Shift_Del chr13 32745180 32745201 ENST00000380250.3:c.1924_1945del S2451Rfs*5 Frame_Shift_Del diploid chr13 32828466 32828467 ENST00000380250.3:c.7351_7352del GPI R180H Missense diploid One chr19 34868692 34868692 ENST00000356487.5:c.539G>A S298L Missense gain One chr19 34884660 34884660 ENST00000356487.5:c.893C>T H306Q Missense gain One chr19 34884827 34884827 ENST00000356487.5:c.918C>G D458V Missense diploid chr19 34890215 34890215 ENST00000356487.5:c.1373A>T GRM6 V775M Missense gain 3 chr5 178410024 178410024 ENST00000231188.5:c.2323G>A A782V Missense shallowdel One chr5 178410002 178410002 ENST00000231188.5:c.2345C>T D340N Missense deepdel One chr5 178416401 178416401 ENST00000231188.5:c.1018G>A G338E Missense deepdel One chr5 178416406 178416406 ENST00000231188.5:c.1013G>A A636T Missense diploid chr5 178413349 178413349 ENST00000231188.5:c.1906G>A D406V Missense diploid chr5 178416073 178416073 ENST00000231188.5:c.1217A>T P521L Missense shallowdel One chr5 178413693 178413693 ENST00000231188.5:c.1562C>T P847S Missense diploid chr5 178408753 178408753 ENST00000231188.5:c.2539C>T S507C Missense diploid chr5 178413735 178413735 ENST00000231188.5:c.1520C>G KIF4A R295G Missense diploid chrX 69549359 69549359 ENST00000374403.3:c.883C>G K586N Missense gain chrX 69594084 69594084 ENST00000374403.3:c.1758G>C K128R Missense amp chrX 69516995 69516995 ENST00000374403.3:c.383A>G KLHL36 E407K Missense amp chr16 84693447 84693447 ENST00000564996.1:c.1219G>A R387L Missense diploid chr16 84693388 84693388 ENST00000564996.1:c.1160G>T E233Q Missense shallowdel chr16 84691110 84691110 ENST00000564996.1:c.697G>C LPCAT1 Q268L Missense gain One chr5 1479749 1479749 ENST00000283415.3:c.803A>T V94F Missense shallowdel chr5 1495028 1495028 ENST00000283415.3:c.280G>T L166V Missense amp chr5 1489971 1489971 ENST00000283415.3:c.496C>G LTN1 D825Y Missense gain One chr21 30331900 30331900 ENST00000361371.5:c.2473G>T K1372R Missense gain One chr21 30316094 30316094 ENST00000361371.5:c.4115A>G E561Q Missense diploid One chr21 30339132 30339132 ENST00000361371.5:c.1681G>C W712C Missense gain chr21 30338214 30338214 ENST00000361371.5:c.2136G>T W712S Missense gain chr21 30338215 30338215 ENST00000361371.5:c.2135G>C D825H Missense diploid One chr21 30331900 30331900 ENST00000361371.5:c.2473G>C Q1339E Missense shallowdel One chr21 30316194 30316194 ENST00000361371.5:c.4015C>G A1028S Missense shallowdel chr21 30325696 30325696 ENST00000361371.5:c.3082G>T H897Y Missense diploid chr21 30330766 30330766 ENST00000361371.5:c.2689C>T E551D Missense diploid chr21 30339160 30339160 ENST00000361371.5:c.1653G>C L715F Missense gain chr21 30338207 30338207 ENST00000361371.5:c.2143C>T D951N Missense gain chr21 30329695 30329695 ENST00000361371.5:c.2851G>A Q1674* Nonsense diploid chr21 30304842 30304842 ENST00000361371.5:c.5020C>T E328Q Missense diploid chr21 30343595 30343595 ENST00000361371.5:c.982G>C E477K Missense gain chr21 30339384 30339384 ENST00000361371.5:c.1429G>A L994V Missense diploid chr21 30329183 30329183 ENST00000361371.5:c.2980C>G MAP3K5 T1108I Missense diploid One chr6 136904781 136904781 ENST00000359015.4:c.3323C>T L192V Missense diploid One chr6 137041602 137041602 ENST00000359015.4:c.574C>G D344H Missense gain One chr6 137017141 137017141 ENST00000359015.4:c.1030G>C X1292_splice Splice_Site shallowdel chr6 136882784 136882784 ENST00000359015.4:c.3875-1G>A Q496* Nonsense shallowdel chr6 136980397 136980397 ENST00000359015.4:c.1486C>T R683K Missense diploid chr6 136944088 136944088 ENST00000359015.4:c.2048G>A P880L Missense gain chr6 136926387 136926387 ENST00000359015.4:c.2639C>T S329C Missense shallowdel chr6 137017185 137017185 ENST00000359015.4:c.986C>G P593S Missense shallowdel chr6 136972133 136972133 ENST00000359015.4:c.1777C>T S72Y Missense shallowdel chr6 137113081 137113081 ENST00000359015.4:c.215C>A G790A Missense gain chr6 136934304 136934304 ENST00000359015.4:c.2369G>C D1233N Missense deepdel chr6 136888833 136888833 ENST00000359015.4:c.3697G>A E291Q Missense gain chr6 137018461 137018461 ENST00000359015.4:c.871G>C H1145Y Missense diploid chr6 136901523 136901523 ENST00000359015.4:c.3433C>T E1183K Missense shallowdel One chr6 136888983 136888983 ENST00000359015.4:c.3547G>A MED1 H1526D Missense gain 2 chr17 37563898 37563898 ENST00000300651.6:c.4576C>G S387T Missense diploid One chr17 37576107 37576107 ENST00000300651.6:c.1160G>C S1227L Missense diploid One chr17 37564794 37564794 ENST00000300651.6:c.3680C>T S1379L Missense diploid One chr17 37564338 37564338 ENST00000300651.6:c.4136C>T S1218C Missense diploid One chr17 37564821 37564821 ENST00000300651.6:c.3653C>G K202N Missense diploid 2 chr17 37587411 37587411 ENST00000300651.6:c.606G>C L69I Missense diploid One chr17 37599809 37599809 ENST00000300651.6:c.205C>A K283T Missense diploid chr17 37580883 37580883 ENST00000300651.6:c.848A>C S1375C Missense gain chr17 37564350 37564350 ENST00000300651.6:c.4124C>G P1208A Missense gain chr17 37564852 37564852 ENST00000300651.6:c.3622C>G S256* Nonsense amp chr17 37580964 37580964 ENST00000300651.6:c.767C>A S682L Missense gain chr17 37566429 37566429 ENST00000300651.6:c.2045C>T S1363* Nonsense gain chr17 37564386 37564386 ENST00000300651.6:c.4088C>G S1439F Missense gain chr17 37564158 37564158 ENST00000300651.6:c.4316C>T S1558* Nonsense diploid chr17 37563801 37563801 ENST00000300651.6:c.4673C>G P381A Missense gain chr17 37576126 37576126 ENST00000300651.6:c.1141C>G S1368F Missense diploid chr17 37564371 37564371 ENST00000300651.6:c.4103C>T E8K Missense amp chr17 37607294 37607294 ENST00000300651.6:c.22G>A S1111L Missense gain chr17 37565142 37565142 ENST00000300651.6:c.3332C>T S349L Missense gain chr17 37579629 37579629 ENST00000300651.6:c.1046C>T M1172I Missense diploid chr17 37564958 37564958 ENST00000300651.6:c.3516G>A NAV3 S1262C Missense diploid 2 chr12 78515755 78515755 ENST00000397909.2:c.3785C>G S1273L Missense diploid One chr12 78515788 78515788 ENST00000397909.2:c.3818C>T E48* Nonsense diploid One chr12 78225383 78225383 ENST00000397909.2:c.142G>T E1023Q Missense gain One chr12 78513043 78513043 ENST00000397909.2:c.3067G>C S1090F Missense gain One chr12 78513245 78513245 ENST00000397909.2:c.3269C>T S1106L Missense shallowdel One chr12 78513293 78513293 ENST00000397909.2:c.3317C>T D1690H Missense diploid One chr12 78569172 78569172 ENST00000397909.2:c.5068G>C S1170C Missense shallowdel One chr12 78513485 78513485 ENST00000397909.2:c.3509C>G E1603K Missense shallowdel One chr12 78553004 78553004 ENST00000397909.2:c.4807G>A L692F Missense diploid One chr12 78443825 78443825 ENST00000397909.2:c.2076G>C Q2363L Missense amp chr12 78604227 78604227 ENST00000397909.2:c.7088A>T Y2151C Missense diploid chr12 78592390 78592390 ENST00000397909.2:c.6452A>G D1969H Missense diploid chr12 78582407 78582407 ENST00000397909.2:c.5905G>C A1679V Missense diploid chr12 78569140 78569140 ENST00000397909.2:c.5036C>T L29V Missense diploid One chr12 78225326 78225326 ENST00000397909.2:c.85C>G S1262F Missense gain 2 chr12 78515755 78515755 ENST00000397909.2:c.3785C>T S1217F Missense gain One chr12 78513626 78513626 ENST00000397909.2:c.3650C>T S461C Missense gain One chr12 78400700 78400700 ENST00000397909.2:c.1382C>G S1722F Missense diploid chr12 78570961 78570961 ENST00000397909.2:c.5165C>T S532Y Missense shallowdel chr12 78400913 78400913 ENST00000397909.2:c.1595C>A I100M Missense diploid chr12 78334155 78334155 ENST00000397909.2:c.300C>G S210L Missense shallowdel chr12 78362440 78362440 ENST00000397909.2:c.629C>T R1402T Missense amp chr12 78516175 78516175 ENST00000397909.2:c.4205G>C N732S Missense shallowdel chr12 78444606 78444606 ENST00000397909.2:c.2195A>G S1142L Missense diploid chr12 78513401 78513401 ENST00000397909.2:c.3425C>T S136F Missense gain chr12 78334906 78334906 ENST00000397909.2:c.407C>T T1080S Missense gain chr12 78513215 78513215 ENST00000397909.2:c.3239C>G E1563K Missense diploid chr12 78540152 78540152 ENST00000397909.2:c.4687G>A Y820Vfs*20 Frame_Shift_Del gain chr12 78444867 78444873 ENST00000397909.2:c.2458_2464del G1384D Missense shallowdel chr12 78516121 78516121 ENST00000397909.2:c.4151G>A S2364C Missense gain chr12 78604229 78604229 ENST00000397909.2:c.7090A>T NDNF M323R Missense shallowdel One chr4 121958158 121958158 ENST00000379692.4:c.968T>G Q269* Nonsense diploid One chr4 121958321 121958321 ENST00000379692.4:c.805C>T Y481S Missense diploid chr4 121957684 121957684 ENST00000379692.4:c.1442A>C K412N Missense diploid chr4 121957890 121957890 ENST00000379692.4:c.1236A>C I453M Missense diploid chr4 121957767 121957767 ENST00000379692.4:c.1359C>G NKRF N690S Missense diploid One chrX 118723319 118723319 ENST00000304449.5:c.2069A>G Q30* Nonsense gain chrX 118726373 118726373 ENST00000304449.5:c.88C>T Q585K Missense gain chrX 118723635 118723635 ENST00000304449.5:c.1753C>A R56C Missense diploid chrX 118725222 118725222 ENST00000304449.5:c.166C>T OLFM4 L415R Missense diploid One chr13 53624617 53624617 ENST00000219022.2:c.1244T>G V378I Missense diploid One chr13 53624505 53624505 ENST00000219022.2:c.1132G>A Q381E Missense shallowdel One chr13 53624514 53624514 ENST00000219022.2:c.1141C>G P257Q Missense diploid chr13 53624143 53624143 ENST00000219022.2:c.770C>A S56Y Missense gain chr13 53603138 53603138 ENST00000219022.2:c.167C>A OR13C3 R329I Missense diploid One chr9 107298109 107298109 ENST00000374781.2:c.986G>T A218S Missense gain One chr9 107298443 107298443 ENST00000374781.2:c.652G>T I255M Missense shallowdel One chr9 107298330 107298330 ENST00000374781.2:c.765C>G A136V Missense shallowdel One chr9 107298688 107298688 ENST00000374781.2:c.407C>T S83F Missense gain chr9 107298847 107298847 ENST00000374781.2:c.248C>T G200W Missense diploid chr9 107298497 107298497 ENST00000374781.2:c.598G>T S117* Nonsense shallowdel chr9 107298745 107298745 ENST00000374781.2:c.350C>G L145V Missense diploid chr9 107298662 107298662 ENST00000374781.2:c.433C>G L69V Missense diploid chr9 107298890 107298890 ENST00000374781.2:c.205C>G T8I Missense diploid chr9 107299072 107299072 ENST00000374781.2:c.23C>T S311C Missense diploid chr9 107298163 107298163 ENST00000374781.2:c.932C>G PLEC E2845D Missense diploid 2 chr8 144995865 144995865 ENST00000322810.4:c.8535G>C E2252K Missense gain One chr8 144997754 144997754 ENST00000322810.4:c.6754G>A S4365F Missense gain One chr8 144991306 144991306 ENST00000322810.4:c.13094C>T E2458K Missense gain One chr8 144997136 144997136 ENST00000322810.4:c.7372G>A E3767Q Missense gain One chr8 144993101 144993101 ENST00000322810.4:c.11299G>C E3360* Nonsense gain One chr8 144994322 144994322 ENST00000322810.4:c.10078G>T A3072E Missense gain One chr8 144995185 144995185 ENST00000322810.4:c.9215C>A E2061K Missense gain One chr8 144998327 144998327 ENST00000322810.4:c.6181G>A E689Q Missense gain One chr8 145007044 145007044 ENST00000322810.4:c.2065G>C D677N Missense gain One chr8 145007080 145007080 ENST00000322810.4:c.2029G>A E1609K Missense amp One chr8 144999683 144999683 ENST00000322810.4:c.4825G>A E1057Q Missense diploid One chr8 145003979 145003979 ENST00000322810.4:c.3169G>C E985* Nonsense diploid One chr8 145004382 145004382 ENST00000322810.4:c.2953G>T E3010Q Missense diploid One chr8 144995372 144995372 ENST00000322810.4:c.9028G>C E2997K Missense diploid One chr8 144995411 144995411 ENST00000322810.4:c.8989G>A E2595D Missense diploid One chr8 144996723 144996723 ENST00000322810.4:c.7785G>C E2405* Nonsense diploid One chr8 144997295 144997295 ENST00000322810.4:c.7213G>T R3838S Missense gain One chr8 144992886 144992886 ENST00000322810.4:c.11514G>C S4272Y Missense diploid 2 chr8 144991585 144991585 ENST00000322810.4:c.12815C>A L1259V Missense diploid One chr8 145002057 145002057 ENST00000322810.4:c.3775C>G Q3962H Missense diploid One chr8 144992514 144992514 ENST00000322810.4:c.11886G>C R179H Missense gain chr8 145012848 145012848 ENST00000322810.4:c.536G>A R3804L Missense gain chr8 144992989 144992989 ENST00000322810.4:c.11411G>T E2624D Missense gain chr8 144996528 144996528 ENST00000322810.4:c.7872G>C L3478V Missense diploid chr8 144993968 144993968 ENST00000322810.4:c.10432C>G I3611V Missense gain One chr8 144993569 144993569 ENST00000322810.4:c.10831A>G E4212Q Missense gain chr8 144991766 144991766 ENST00000322810.4:c.12634G>C E2446K Missense diploid One chr8 144997172 144997172 ENST00000322810.4:c.7336G>A E2063K Missense diploid chr8 144998321 144998321 ENST00000322810.4:c.6187G>A L3157F Missense diploid chr8 144994931 144994931 ENST00000322810.4:c.9469C>T A1513S Missense gain One chr8 14499971 14499971 ENST00000322810.4:c.4537G>T S1181F Missense gain chr8 145003400 145003400 ENST00000322810.4:c.3542C>T K2409N Missense gain chr8 144997281 144997281 ENST00000322810.4:c.7227G>C E3634D Missense gain chr8 144993498 144993498 ENST00000322810.4:c.10902G>C G3279S Missense amp chr8 144994565 144994565 ENST00000322810.4:c.9835G>A E3665K Missense shallowdel chr8 144993407 144993407 ENST00000322810.4:c.10993G>A Q4509Rfs*3 Frame_Shift_Del diploid chr8 144990875 144990875 ENST00000322810.4:c.13525del Q3266R Missense diploid One chr8 144994603 144994603 ENST00000322810.4:c.9797A>G S4374L Missense gain chr8 144991279 144991279 ENST00000322810.4:c.13121C>T S2634F Missense gain chr8 144996499 144996499 ENST00000322810.4:c.7901C>T K298N Missense gain chr8 145010135 145010135 ENST00000322810.4:c.894G>C E413K Missense gain chr8 145009097 145009097 ENST00000322810.4:c.1237G>A V3780L Missense amp chr8 144993062 144993062 ENST00000322810.4:c.11338G>T R316Q Missense amp chr8 145010082 145010082 ENST00000322810.4:c.947G>A L4545M Missense gain chr8 144990767 144990767 ENST00000322810.4:c.13633C>A E1185K Missense gain chr8 145003389 145003389 ENST00000322810.4:c.3553G>A E1137K Missense gain chr8 145003665 145003665 ENST00000322810.4:c.3409G>A E3236Q Missense amp chr8 144994694 144994694 ENST00000322810.4:c.9706G>C S558L Missense gain chr8 145008167 145008167 ENST00000322810.4:c.1673C>T E364Q Missense gain chr8 145009405 145009405 ENST00000322810.4:c.1090G>C PMS1 Q132* Nonsense diploid chr2 190670456 190670456 ENST00000441310.2:c.394C>T N531S Missense diploid One chr2 190719590 190719590 ENST00000441310.2:c.1592A>G L282V Missense gain chr2 190718686 190718686 ENST00000441310.2:c.844C>G L329F Missense gain chr2 190718983 190718983 ENST00000441310.2:c.985C>T S673C Missense diploid One chr2 190728630 190728630 ENST00000441310.2:c.2018C>G K711N Missense diploid chr2 190728745 190728745 ENST00000441310.2:c.2133G>T D397H Missense diploid chr2 190719187 190719187 ENST00000441310.2:c.1189G>C K667N Missense diploid chr2 190728613 190728613 ENST00000441310.2:c.2001G>T S426C Missense shallowdel chr2 190719275 190719275 ENST00000441310.2:c.1277C>G PPM1J P473T Missense diploid chr1 113252886 113252886 ENST00000309276.6:c.1417C>A E296Q Missense gain chr1 113254634 113254634 ENST00000309276.6:c.886G>C RADIL S715T Missense gain One chr7 4845343 4845343 ENST00000399583.3:c.2144G>C Y100* Nonsense gain One chr7 4917471 4917471 ENST00000399583.3:c.300C>A A437T Missense gain chr7 4874345 4874345 ENST00000399583.3:c.1309G>A R595H Missense diploid One chr7 4856041 4856041 ENST00000399583.3:c.1784G>A S289L Missense diploid chr7 4874788 4874788 ENST00000399583.3:c.866C>T S1060F Missense gain chr7 4839058 4839058 ENST00000399583.3:c.3179C>T S984C Missense gain chr7 4839833 4839833 ENST00000399583.3:c.2951C>G RELN R2639H Missense diploid 2 chr7 103155835 103155835 ENST00000428762.1:c.7916G>A R2524Q Missense gain One chr7 103162566 103162566 ENST00000428762.1:c.7571G>A V240I Missense gain 2 chr7 103368593 103368593 ENST00000428762.1:c.718G>A E397K Missense diploid 2 chr7 103322663 103322663 ENST00000428762.1:c.1189G>A S1879C Missense shallowdel chr7 103197585 103197585 ENST00000428762.1:c.5636C>G M1070T Missense diploid One chr7 103243875 103243875 ENST00000428762.1:c.3209T>C L2213F Missense shallowdel One chr7 103183210 103183210 ENST00000428762.1:c.6639G>C E1449K Missense gain One chr7 103214705 103214705 ENST00000428762.1:c.4345G>A D802H Missense gain One chr7 103275933 103275933 ENST00000428762.1:c.2404G>C R1491G Missense gain One chr7 103214579 103214579 ENST00000428762.1:c.4471A>G W1770* Nonsense gain One chr7 103202301 103202301 ENST00000428762.1:c.5310G>A D1563N Missense gain 2 chr7 103207108 103207108 ENST00000428762.1:c.4687G>A I1978M Missense diploid One chr7 103194142 103194142 ENST00000428762.1:c.5934C>G R2106T Missense gain One chr7 103185777 103185777 ENST00000428762.1:c.6317G>C S34P Missense gain chr7 103629704 103629704 ENST00000428762.1:c.100T>C R755H Missense shallowdel One chr7 103276721 103276721 ENST00000428762.1:c.2264G>A V2623M Missense gain chr7 103155884 103155884 ENST00000428762.1:c.7867G>A F1841C Missense diploid chr7 103201986 103201986 ENST00000428762.1:c.5522T>G D3416A Missense diploid chr7 103123353 103123353 ENST00000428762.1:c.10247A>C Y339H Missense gain chr7 103338428 103338428 ENST00000428762.1:c.1015T>C D2180H Missense gain chr7 103183311 103183311 ENST00000428762.1:c.6538G>C E1366K Missense gain chr7 103230092 103230092 ENST00000428762.1:c.4096G>A D2381N Missense diploid chr7 103179564 103179564 ENST00000428762.1:c.7141G>A D185H Missense gain chr7 103393653 103393653 ENST00000428762.1:c.553G>C T2963S Missense diploid chr7 103138329 103138329 ENST00000428762.1:c.8888C>G S2841L Missense gain One chr7 103141337 103141337 ENST00000428762.1:c.8522C>T E3052K Missense diploid chr7 103137012 103137012 ENST00000428762.1:c.9154G>A I3246V Missense gain chr7 103130216 103130216 ENST00000428762.1:c.9736A>G A1341S Missense diploid chr7 103230167 103230167 ENST00000428762.1:c.4021G>T D1246H Missense gain chr7 103234305 103234305 ENST00000428762.1:c.3736G>C G1405A Missense diploid chr7 103216084 103216084 ENST00000428762.1:c.4214G>C D1693N Missense gain chr7 103205858 103205858 ENST00000428762.1:c.5077G>A L3234V Missense diploid chr7 103130252 103130252 ENST00000428762.1:c.9700C>G G2129S Missense shallowdel chr7 103185709 103185709 ENST00000428762.1:c.6385G>A E425Q Missense gain chr7 103322579 103322579 ENST00000428762.1:c.1273G>C R1825Kfs*7 Frame_Shift_Ins diploid chr7 103202034 103202035 ENST00000428762.1:c.5473dup C1416G Missense chr7 103216052 103216052 ENST00000428762.1:c.4246T>G RIPK1 R317T Missense diploid One chr6 3104493 3104493 ENST00000259808.4:c.950G>C M42V Missense diploid One chr6 3077181 3077181 ENST00000259808.4:c.124A>G M637I Missense diploid chr6 3113468 3113468 ENST00000259808.4:c.1911G>A E368K Missense gain chr6 3105811 3105811 ENST00000259808.4:c.1102G>A M517Ifs*11 Frame_Shift_Ins shallowdel chr6 3106258 3106259 ENST00000259808.4:c.1550dup R275W Missense shallowdel chr6 3085627 3085627 ENST00000259808.4:c.823C>T N310T Missense shallowdel chr6 3104472 3104472 ENST00000259808.4:c.929A>C RNF123 L209V Missense gain One chr3 49736242 49736242 ENST00000327697.6:c.625C>G E1169Q Missense diploid One chr3 49757948 49757948 ENST00000327697.6:c.3505G>C E1169Q Missense diploid One chr3 49757948 49757948 ENST00000327697.6:c.3505G>C V661A Missense diploid One chr3 49742439 49742439 ENST00000327697.6:c.1982T>C E778K Missense diploid chr3 49743442 49743442 ENST00000327697.6:c.2332G>A L904V Missense diploid chr3 49750981 49750981 ENST00000327697.6:c.2710C>G X1215_splice Splice_Site deepdel chr3 49758232 49758232 ENST00000327697.6:c.3644-1G>A S563C Missense shallowdel chr3 49740124 49740124 ENST00000327697.6:c.1688C>G S1263C Missense gain chr3 49758502 49758502 ENST00000327697.6:c.3788C>G E22Q Missense gain chr3 49728662 49728662 ENST00000327697.6:c.64G>C R390* Nonsense gain chr3 49737962 49737962 ENST00000327697.6:c.1168C>T E995K Missense diploid chr3 49751580 49751580 ENST00000327697.6:c.2983G>A F1289C Missense shallowdel chr3 49758659 49758659 ENST00000327697.6:c.3866T>G S540N Missense amp chr3 49739828 49739828 ENST00000327697.6:c.1619G>A RNF215 D229H Missense diploid 2 chr22 30780387 30780387 ENST00000382363.3:c.685G>C G225D Missense diploid One chr22 30780398 30780398 ENST00000382363.3:c.674G>A R166Q Missense diploid chr22 30782063 30782063 ENST00000382363.3:c.497G>A R166Q Missense diploid chr22 30782063 30782063 ENST00000382363.3:c.497G>A R295H Missense diploid chr22 30776175 30776175 ENST00000382363.3:c.884G>A RSRC2 S165L Missense gain 2 chr12 123001882 123001882 ENST00000331738.7:c.494C>T A322T Missense 2 chr12 122992836 122992836 ENST00000331738.7:c.964G>A N365S Missense diploid One chr12 122991412 122991412 ENST00000331738.7:c.1094A>G R66T Missense gain One chr12 123005942 123005942 ENST00000331738.7:c.197G>C S145C Missense diploid chr12 123001942 123001942 ENST00000331738.7:c.434C>G S350C Missense shallowdel chr12 122991457 122991457 ENST00000331738.7:c.1049C>G D19H Missense gain chr12 123006798 123006798 ENST00000331738.7:c.55G>C R242T Missense diploid chr12 122999652 122999652 ENST00000331738.7:c.725G>C E332Q Missense shallowdel chr12 122992806 122992806 ENST00000331738.7:c.994G>C F213C Missense diploid chr12 122999739 122999739 ENST00000331738.7:c.638T>G K255N Missense diploid chr12 122995696 122995696 ENST00000331738.7:c.765G>C D96H Missense diploid chr12 123003498 123003498 ENST00000331738.7:c.286G>C SIN3A R471Q Missense diploid One chr15 75694307 75694307 ENST00000360439.4:c.1412G>A F1169L Missense diploid One chr15 75668090 75668090 ENST00000360439.4:c.3507C>A I1133V Missense gain One chr15 75668200 75668200 ENST00000360439.4:c.3397A>G T1049K Missense gain One chr15 75676654 75676654 ENST00000360439.4:c.3146C>A Q100H Missense diploid One chr15 75715054 75715054 ENST00000360439.4:c.300G>C E540K Missense diploid chr15 75693190 75693190 ENST00000360439.4:c.1618G>A K1148N Missense shallowdel chr15 75668153 75668153 ENST00000360439.4:c.3444G>C E513Q Missense diploid chr15 75693271 75693271 ENST00000360439.4:c.1537G>C Q805E Missense diploid chr15 75685021 75685021 ENST00000360439.4:c.2413C>G H333R Missense shallowdel chr15 75703843 75703843 ENST00000360439.4:c.998A>G D1090Y Missense shallowdel chr15 75673974 75673974 ENST00000360439.4:c.3268G>T N423K Missense diploid One chr15 75702225 75702225 ENST00000360439.4:c.1269T>A Q1208E Missense diploid chr15 75664520 75664520 ENST00000360439.4:c.3622C>G R428C Missense chr15 75702212 75702212 ENST00000360439.4:c.1282C>T SLC23A3 P114A Missense diploid One chr2 220034109 220034109 ENST00000409878.3:c.340C>G P199S Missense shallowdel One chr2 220033453 220033453 ENST00000409878.3:c.595C>T S251* Nonsense diploid chr2 220032963 220032963 ENST00000409878.3:c.752C>G P25S Missense shallowdel chr2 220034634 220034634 ENST00000409878.3:c.73C>T P25Q Missense shallowdel chr2 220034633 220034633 ENST00000409878.3:c.74C>A R148M Missense diploid chr2 220033800 220033800 ENST00000409878.3:c.443G>T P22R Missense diploid chr2 220034642 220034642 ENST00000409878.3:c.65C>G Q85* Nonsense diploid chr2 220034310 220034310 ENST00000409878.3:c.253C>T L51M Missense diploid chr2 220034556 220034556 ENST00000409878.3:c.151C>A S207F Missense shallowdel One chr2 220033428 220033428 ENST00000409878.3:c.620C>T SRRM2 R1853C Missense diploid One chr16 2816086 2816086 ENST00000301740.8:c.5557C>T R1448T Missense shallowdel One chr16 2814872 2814872 ENST00000301740.8:c.4343G>C E1515Q Missense shallowdel One chr16 2815072 2815072 ENST00000301740.8:c.4543G>C S669L Missense shallowdel One chr16 2812535 2812535 ENST00000301740.8:c.2006C>T S2535W Missense shallowdel 2 chr16 2818133 2818133 ENST00000301740.8:c.7604C>G S2640C Missense shallowdel One chr16 2819183 2819183 ENST00000301740.8:c.7919C>G E396K Missense shallowdel One chr16 2811715 2811715 ENST00000301740.8:c.1186G>A R546T Missense shallowdel One chr16 2812166 2812166 ENST00000301740.8:c.1637G>C D1408H Missense shallowdel One chr16 2814751 2814751 ENST00000301740.8:c.4222G>C S177C Missense gain One chr16 2808485 2808485 ENST00000301740.8:c.530C>G E1047K Missense diploid One chr16 2813668 2813668 ENST00000301740.8:c.3139G>A R650K Missense diploid One chr16 2812478 2812478 ENST00000301740.8:c.1949G>A R2356K Missense diploid One chr16 2817596 2817596 ENST00000301740.8:c.7067G>A E201K Missense diploid One chr16 2808993 2808993 ENST00000301740.8:c.601G>A S2706L Missense diploid One chr16 2820448 2820448 ENST00000301740.8:c.8117C>T R948Q Missense diploid One chr16 2813372 2813372 ENST00000301740.8:c.2843G>A Q1554* Nonsense shallowdel chr16 2815189 2815189 ENST00000301740.8:c.4660C>T S2544F Missense gain chr16 2818160 2818160 ENST00000301740.8:c.7631C>T E1479A Missense diploid One chr16 2814965 2814965 ENST00000301740.8:c.4436A>C R2097I Missense diploid chr16 2816819 2816819 ENST00000301740.8:c.6290G>T R1719I Missense diploid chr16 2815685 2815685 ENST00000301740.8:c.5156G>T L1055V Missense shallowdel chr16 2813692 2813692 ENST00000301740.8:c.3163C>G S536F Missense diploid chr16 2812136 2812136 ENST00000301740.8:c.1607C>T S536F Missense diploid chr16 2812136 2812136 ENST00000301740.8:c.1607C>T E2573K Missense diploid chr16 2818246 2818246 ENST00000301740.8:c.7717G>A S2512C Missense diploid chr16 2818064 2818064 ENST00000301740.8:c.7535C>G S2335C Missense diploid chr16 2817533 2817533 ENST00000301740.8:c.7004C>G Q833R Missense shallowdel chr16 2813027 2813027 ENST00000301740.8:c.2498A>G D1429H Missense diploid chr16 2814814 2814814 ENST00000301740.8:c.4285G>C R643T Missense gain chr16 2812457 2812457 ENST00000301740.8:c.1928G>C D1481N Missense diploid chr16 2814970 2814970 ENST00000301740.8:c.4441G>A R693W Missense gain One chr16 2812606 2812606 ENST00000301740.8:c.2077C>T S931F Missense shallowdel chr16 2813321 2813321 ENST00000301740.8:c.2792C>T S931F Missense gain chr16 2813321 2813321 ENST00000301740.8:c.2792C>T S1581L Missense shallowdel chr16 2815271 2815271 ENST00000301740.8:c.4742C>T E1259Q Missense gain chr16 2814304 2814304 ENST00000301740.8:c.3775G>C R1475T Missense gain chr16 2814953 2814953 ENST00000301740.8:c.4424G>C E100K Missense shallowdel chr16 2807528 2807528 ENST00000301740.8:c.298G>A STAM M422L Missense gain One chr16 17750829 17750829 ENST00000377524.3:c.1264A>T W115* Nonsense amp chr16 17730072 17730072 ENST00000377524.3:c.344G>A W115* Nonsense amp chr16 17730073 17730073 ENST00000377524.3:c.345G>A I32M Missense gain chr16 17702518 17702518 ENST00000377524.3:c.96C>G D117N Missense gain chr16 17730077 17730077 ENST00000377524.3:c.349G>A D10N Missense diploid chr16 17686366 17686366 ENST00000377524.3:c.28G>A SYT1 D364_Y365insN In_Frame_Ins diploid chr16 79842725 79842726 Y181* Nonsense gain 2 chr16 79689917 79689917 ENST00000261205.4:c.543C>G K326N Missense diploid chr16 79837902 79837902 ENST00000261205.4:c.978G>T S41Y Missense diploid chr16 79611421 79611421 ENST00000261205.4:c.122C>A E140K Missense diploid One chr16 79685854 79685854 ENST00000261205.4:c.418G>A D122N Missense gain chr16 79685800 79685800 ENST00000261205.4:c.364G>A D415N Missense gain chr16 79842878 79842878 ENST00000261205.4:c.1243G>A TCFL5 S282A Missense gain One chr16 61490866 61490866 ENST00000335351.3:c.844T>G Q391H Missense gain chr16 61488812 61488812 ENST00000335351.3:c.1173G>C Q391H Missense gain chr16 61488812 61488812 ENST00000335351.3:c.1173G>C I450M Missense diploid chr16 61485398 61485398 ENST00000335351.3:c.1350C>G Q400E Missense gain chr16 61488787 61488787 ENST00000335351.3:c.1198C>G E403D Missense diploid chr16 61488776 61488776 ENST00000335351.3:c.1209G>C E380K Missense gain One chr16 61488847 61488847 ENST00000335351.3:c.1138G>A R401H Missense diploid chr16 61488783 61488783 ENST00000335351.3:c.1202G>A TRIM24 R1046C Missense gain One chr7 138269679 138269679 ENST00000343526.4:c.3136C>T D781N Missense gain chr7 138264033 138264033 ENST00000343526.4:c.2341G>A E136K Missense gain chr7 138189076 138189076 ENST00000343526.4:c.406G>A E150K Missense gain chr7 138189118 138189118 ENST00000343526.4:c.448G>A M340I Missense gain chr7 138223425 138223425 ENST00000343526.4:c.1020G>A H226Y Missense diploid One chr7 138203978 138203978 ENST00000343526.4:c.676C>T R721Q Missense diploid chr7 138262239 138262239 ENST00000343526.4:c.2162G>A D872H Missense gain chr7 138265335 138265335 ENST00000343526.4:c.2614G>C D626G Missense diploid chr7 138255747 138255747 ENST00000343526.4:c.1877A>G Q64R Missense diploid chr7 138145484 138145484 ENST00000343526.4:c.191A>G C187S Missense diploid chr7 138200032 138200032 ENST00000343526.4:c.559T>A E994Q Missense diploid chr7 138269523 138269523 ENST00000343526.4:c.2980G>C M498V Missense diploid chr7 138239673 138239673 ENST00000343526.4:c.1492A>G TRIM59 Q39* Nonsense gain One chr3 160156857 160156857 ENST00000309784.4:c.115C>T S72C Missense diploid One chr3 160156757 160156757 ENST00000309784.4:c.215C>G R60K Missense diploid One chr3 160156793 160156793 ENST00000309784.4:c.179G>A V95F Missense gain One chr3 160156689 160156689 ENST00000309784.4:c.283G>T F348L Missense diploid chr3 160155928 160155928 ENST00000309784.4:c.1044C>A USPL1 S298L Missense diploid One chr13 31211905 31211905 ENST00000255304.4:c.893C>T S546L Missense diploid One chr13 31231851 31231851 ENST00000255304.4:c.1637C>T S1069L Missense diploid One chr13 31233420 31233420 ENST00000255304.4:c.3206C>T Q284* Nonsense diploid One chr13 31205593 31205593 ENST00000255304.4:c.850C>T P833S Missense shallowdel One chr13 31232711 31232711 ENST00000255304.4:c.2497C>T R916Q Missense gain chr13 31232961 31232961 ENST00000255304.4:c.2747G>A E697K Missense gain chr13 31232303 31232303 ENST00000255304.4:c.2089G>A I461N Missense shallowdel chr13 31227428 31227428 ENST00000255304.4:c.1382T>A I265M Missense diploid chr13 31205538 31205538 ENST00000255304.4:c.795A>G D581N Missense gain chr13 31231955 31231955 ENST00000255304.4:c.1741G>A Q369* Nonsense gain chr13 31216887 31216887 ENST00000255304.4:c.1105C>T X371_splice Splice_Site diploid chr13 31221068 31221068 ENST00000255304.4:c.1113-1G>A S603F Missense gain chr13 31232022 31232022 ENST00000255304.4:c.1808C>T WNK1 D349N Missense diploid One chr12 936320 936320 ENST00000315939.6:c.1045G>A R341G Missense gain 2 chr12 936296 936296 ENST00000315939.6:c.1021C>G R341G Missense gain 2 chr12 936296 936296 ENST00000315939.6:c.1021C>G A22S Missense gain One chr12 862795 862795 ENST00000315939.6:c.64G>T E1637K Missense shallowdel chr12 994879 994879 ENST00000315939.6:c.4909G>A E1665K Missense shallowdel chr12 994963 994963 ENST00000315939.6:c.4993G>A M2320V Missense gain One chr12 1017767 1017767 ENST00000315939.6:c.6958A>G Q2044H Missense diploid One chr12 1005785 1005785 ENST00000315939.6:c.6132G>C A918S Missense diploid One chr12 989117 989117 ENST00000315939.6:c.2752G>T A1977V Missense diploid One chr12 1005583 1005583 ENST00000315939.6:c.5930C>T H1534D Missense gain One chr12 994570 994570 ENST00000315939.6:c.4600C>G E586D Missense diploid chr12 970316 970316 ENST00000315939.6:c.1758G>C E1049Q Missense diploid chr12 990891 990891 ENST00000315939.6:c.3145G>C Q276* Nonsense diploid chr12 922874 922874 ENST00000315939.6:c.826C>T S732C Missense amp chr12 980486 980486 ENST00000315939.6:c.2195C>G T74A Missense diploid chr12 862951 862951 ENST00000315939.6:c.220A>G I558M Missense gain chr12 970232 970232 ENST00000315939.6:c.1674C>G S847* Nonsense gain chr12 988905 988905 ENST00000315939.6:c.2540C>G S731L Missense diploid One chr12 980483 980483 ENST00000315939.6:c.2192C>T Q838E Missense diploid chr12 988877 988877 ENST00000315939.6:c.2512C>G D2013H Missense gain chr12 1005690 1005690 ENST00000315939.6:c.6037G>C H1296D Missense diploid chr12 993856 993856 ENST00000315939.6:c.3886C>G K2104T Missense diploid chr12 1006710 1006710 ENST00000315939.6:c.6311A>C S1918F Missense shallowdel chr12 1005406 1005406 ENST00000315939.6:c.5753C>T L1303I Missense shallowdel chr12 993877 993877 ENST00000315939.6:c.3907C>A G1771A Missense gain chr12 996418 996418 ENST00000315939.6:c.5312G>C D2013N Missense diploid chr12 1005690 1005690 ENST00000315939.6:c.6037G>A E122K Missense diploid chr12 863095 863095 ENST00000315939.6:c.364G>A E548Q Missense diploid chr12 970200 970200 ENST00000315939.6:c.1642G>C K1531N Missense gain chr12 994563 994563 ENST00000315939.6:c.4593G>C ZNF485 S143L Missense shallowdel chr10 44111919 44111919 ENST00000361807.3:c.428C>T S227* Nonsense diploid chr10 44112171 44112171 ENST00000361807.3:c.680C>G R436K Missense gain chr10 44112798 44112798 ENST00000361807.3:c.1307G>A N245H Missense shallowdel chr10 44112224 44112224 ENST00000361807.3:c.733A>C F335L Missense diploid chr10 44112496 44112496 ENST00000361807.3:c.1005C>G

Based on the mutation position information, it is possible to manufacture a microchip using a primer, a probe, an antibody, or an aptamer capable of detecting the marker gene, and the specific method may be according to a conventional technique.

In the above, preferred embodiments of the present invention have been exemplarily described, but the scope of the present invention is not limited to the specific embodiments as described above, and those of ordinary skill in the art will It can be appropriately changed within.

<110> THE CATHOLIC UNIVERSITY OF KOREA INDUSTRY-ACADEMIC COOPERATION FOUNDATION <120> Composition And Kit For Diagnosing Prognosis Of Bladder Cancer According To Pathologic Stage <130> 2021-DPA-4422D <150> KR 10-2020-0037737 <151> 2020-03-27 <160> 44 <170> KoPatentIn 3.0 <210> 1 <211> 3899 <212> PRT <213> Homo sapiens <400> 1 Met Glu Asp Glu Glu Arg Gln Lys Lys Leu Glu Ala Gly Lys Ala Lys 1 5 10 15 Leu Ala Gln Phe Arg Gln Arg Lys Ala Gln Ser Asp Gly Gln Ser Pro 20 25 30 Ser Lys Lys Gln Lys Lys Lys Arg Lys Thr Ser Ser Ser Lys His Asp 35 40 45 Val Ser Ala His His Asp Leu Asn Ile Asp Gln Ser Gln Cys Asn Glu 50 55 60 Met Tyr Ile Asn Ser Ser Gln Arg Val Glu Ser Thr Val Ile Pro Glu 65 70 75 80 Ser Thr Ile Met Arg Thr Leu His Ser Gly Glu Ile Thr Ser His Glu 85 90 95 Gln Gly Phe Ser Val Glu Leu Glu Ser Glu Ile Ser Thr Thr Ala Asp 100 105 110 Asp Cys Ser Ser Glu Val Asn Gly Cys Ser Phe Val Met Arg Thr Gly 115 120 125 Lys Pro Thr Asn Leu Leu Arg Glu Glu Glu Phe Gly Val Asp Asp Ser 130 135 140 Tyr Ser Glu Gln Gly Ala Gln Asp Ser Pro Thr His Leu Glu Met Met 145 150 155 160 Glu Ser Glu Leu Ala Gly Lys Gln His Glu Ile Glu Glu Leu Asn Arg 165 170 175 Glu Leu Glu Glu Met Arg Val Thr Tyr Gly Thr Glu Gly Leu Gln Gln 180 185 190 Leu Gln Glu Phe Glu Ala Ala Ile Lys Gln Arg Asp Gly Ile Ile Thr 195 200 205 Gln Leu Thr Ala Asn Leu Gln Gln Ala Arg Arg Glu Lys Asp Glu Thr 210 215 220 Met Arg Glu Phe Leu Glu Leu Thr Glu Gln Ser Gln Lys Leu Gln Ile 225 230 235 240 Gln Phe Gln Gln Leu Gln Ala Ser Glu Thr Leu Arg Asn Ser Thr His 245 250 255 Ser Ser Thr Ala Ala Asp Leu Leu Gln Ala Lys Gln Gln Ile Leu Thr 260 265 270 His Gln Gln Gln Leu Glu Glu Gln Asp His Leu Leu Glu Asp Tyr Gln 275 280 285 Lys Lys Lys Glu Asp Phe Thr Met Gln Ile Ser Phe Leu Gln Glu Lys 290 295 300 Ile Lys Val Tyr Glu Met Glu Gln Asp Lys Lys Val Glu Asn Ser Asn 305 310 315 320 Lys Glu Glu Ile Gln Glu Lys Glu Thr Ile Ile Glu Glu Leu Asn Thr 325 330 335 Lys Ile Ile Glu Glu Glu Lys Lys Thr Leu Glu Leu Lys Asp Lys Leu 340 345 350 Thr Thr Ala Asp Lys Leu Leu Gly Glu Leu Gln Glu Gln Ile Val Gln 355 360 365 Lys Asn Gln Glu Ile Lys Asn Met Lys Leu Glu Leu Thr Asn Ser Lys 370 375 380 Gln Lys Glu Arg Gln Ser Ser Glu Glu Ile Lys Gln Leu Met Gly Thr 385 390 395 400 Val Glu Glu Leu Gln Lys Arg Asn His Lys Asp Ser Gln Phe Glu Thr 405 410 415 Asp Ile Val Gln Arg Met Glu Gln Glu Thr Gln Arg Lys Leu Glu Gln 420 425 430 Leu Arg Ala Glu Leu Asp Glu Met Tyr Gly Gln Gln Ile Val Gln Met 435 440 445 Lys Gln Glu Leu Ile Arg Gln His Met Ala Gln Met Glu Glu Met Lys 450 455 460 Thr Arg His Lys Gly Glu Met Glu Asn Ala Leu Arg Ser Tyr Ser Asn 465 470 475 480 Ile Thr Val Asn Glu Asp Gln Ile Lys Leu Met Asn Val Ala Ile Asn 485 490 495 Glu Leu Asn Ile Lys Leu Gln Asp Thr Asn Ser Gln Lys Glu Lys Leu 500 505 510 Lys Glu Glu Leu Gly Leu Ile Leu Glu Glu Lys Cys Ala Leu Gln Arg 515 520 525 Gln Leu Glu Asp Leu Val Glu Glu Leu Ser Phe Ser Arg Glu Gln Ile 530 535 540 Gln Arg Ala Arg Gln Thr Ile Ala Glu Gln Glu Ser Lys Leu Asn Glu 545 550 555 560 Ala His Lys Ser Leu Ser Thr Val Glu Asp Leu Lys Ala Glu Ile Val 565 570 575 Ser Ala Ser Glu Ser Arg Lys Glu Leu Glu Leu Lys His Glu Ala Glu 580 585 590 Val Thr Asn Tyr Lys Ile Lys Leu Glu Met Leu Glu Lys Glu Lys Asn 595 600 605 Ala Val Leu Asp Arg Met Ala Glu Ser Gln Glu Ala Glu Leu Glu Arg 610 615 620 Leu Arg Thr Gln Leu Leu Phe Ser His Glu Glu Glu Leu Ser Lys Leu 625 630 635 640 Lys Glu Asp Leu Glu Ile Glu His Arg Ile Asn Ile Glu Lys Leu Lys 645 650 655 Asp Asn Leu Gly Ile His Tyr Lys Gln Gln Ile Asp Gly Leu Gln Asn 660 665 670 Glu Met Ser Gln Lys Ile Glu Thr Met Gln Phe Glu Lys Asp Asn Leu 675 680 685 Ile Thr Lys Gln Asn Gln Leu Ile Leu Glu Ile Ser Lys Leu Lys Asp 690 695 700 Leu Gln Gln Ser Leu Val Asn Ser Lys Ser Glu Glu Met Thr Leu Gln 705 710 715 720 Ile Asn Glu Leu Gln Lys Glu Ile Glu Ile Leu Arg Gln Glu Glu Lys 725 730 735 Glu Lys Gly Thr Leu Glu Gln Glu Val Gln Glu Leu Gln Leu Lys Thr 740 745 750 Glu Leu Leu Glu Lys Gln Met Lys Glu Lys Glu Asn Asp Leu Gln Glu 755 760 765 Lys Phe Ala Gln Leu Glu Ala Glu Asn Ser Ile Leu Lys Asp Glu Lys 770 775 780 Lys Thr Leu Glu Asp Met Leu Lys Ile His Thr Pro Val Ser Gln Glu 785 790 795 800 Glu Arg Leu Ile Phe Leu Asp Ser Ile Lys Ser Lys Ser Lys Asp Ser 805 810 815 Val Trp Glu Lys Glu Ile Glu Ile Leu Ile Glu Glu Asn Glu Asp Leu 820 825 830 Lys Gln Gln Cys Ile Gln Leu Asn Glu Glu Ile Glu Lys Gln Arg Asn 835 840 845 Thr Phe Ser Phe Ala Glu Lys Asn Phe Glu Val Asn Tyr Gln Glu Leu 850 855 860 Gln Glu Glu Tyr Ala Cys Leu Leu Lys Val Lys Asp Asp Leu Glu Asp 865 870 875 880 Ser Lys Asn Lys Gln Glu Leu Glu Tyr Lys Ser Lys Leu Lys Ala Leu 885 890 895 Asn Glu Glu Leu His Leu Gln Arg Ile Asn Pro Thr Thr Val Lys Met 900 905 910 Lys Ser Ser Val Phe Asp Glu Asp Lys Thr Phe Val Ala Glu Thr Leu 915 920 925 Glu Met Gly Glu Val Val Glu Lys Asp Thr Thr Glu Leu Met Glu Lys 930 935 940 Leu Glu Val Thr Lys Arg Glu Lys Leu Glu Leu Ser Gln Arg Leu Ser 945 950 955 960 Asp Leu Ser Glu Gln Leu Lys Gln Lys His Gly Glu Ile Ser Phe Leu 965 970 975 Asn Glu Glu Val Lys Ser Leu Lys Gln Glu Lys Glu Gln Val Ser Leu 980 985 990 Arg Cys Arg Glu Leu Glu Ile Ile Ile Asn His Asn Arg Ala Glu Asn 995 1000 1005 Val Gln Ser Cys Asp Thr Gln Val Ser Ser Leu Leu Asp Gly Val Val 1010 1015 1020 Thr Met Thr Ser Arg Gly Ala Glu Gly Ser Val Ser Lys Val Asn Lys 1025 1030 1035 1040 Ser Phe Gly Glu Glu Ser Lys Ile Met Val Glu Asp Lys Val Ser Phe 1045 1050 1055 Glu Asn Met Thr Val Gly Glu Glu Ser Lys Gln Glu Gln Leu Ile Leu 1060 1065 1070 Asp His Leu Pro Ser Val Thr Lys Glu Ser Ser Leu Arg Ala Thr Gln 1075 1080 1085 Pro Ser Glu Asn Asp Lys Leu Gln Lys Glu Leu Asn Val Leu Lys Ser 1090 1095 1100 Glu Gln Asn Asp Leu Arg Leu Gln Met Glu Ala Gln Arg Ile Cys Leu 1105 1110 1115 1120 Ser Leu Val Tyr Ser Thr His Val Asp Gln Val Arg Glu Tyr Met Glu 1125 1130 1135 Asn Glu Lys Asp Lys Ala Leu Cys Ser Leu Lys Glu Glu Leu Ile Phe 1140 1145 1150 Ala Gln Glu Glu Lys Ile Lys Glu Leu Gln Lys Ile His Gln Leu Glu 1155 1160 1165 Leu Gln Thr Met Lys Thr Gln Glu Thr Gly Asp Glu Gly Lys Pro Leu 1170 1175 1180 His Leu Leu Ile Gly Lys Leu Gln Lys Ala Val Ser Glu Glu Cys Ser 1185 1190 1195 1200 Tyr Phe Leu Gln Thr Leu Cys Ser Val Leu Gly Glu Tyr Tyr Thr Pro 1205 1210 1215 Ala Leu Lys Cys Glu Val Asn Ala Glu Asp Lys Glu Asn Ser Gly Asp 1220 1225 1230 Tyr Ile Ser Glu Asn Glu Asp Pro Glu Leu Gln Asp Tyr Arg Tyr Glu 1235 1240 1245 Val Gln Asp Phe Gln Glu Asn Met His Thr Leu Leu Asn Lys Val Thr 1250 1255 1260 Glu Glu Tyr Asn Lys Leu Leu Val Leu Gln Thr Arg Leu Ser Lys Ile 1265 1270 1275 1280 Trp Gly Gln Gln Thr Asp Gly Met Lys Leu Glu Phe Gly Glu Glu Asn 1285 1290 1295 Leu Pro Lys Glu Glu Thr Glu Phe Leu Ser Ile His Ser Gln Met Thr 1300 1305 1310 Asn Leu Glu Asp Ile Asp Val Asn His Lys Ser Lys Leu Ser Ser Leu 1315 1320 1325 Gln Asp Leu Glu Lys Thr Lys Leu Glu Glu Gln Val Gln Glu Leu Glu 1330 1335 1340 Ser Leu Ile Ser Ser Leu Gln Gln Gln Leu Lys Glu Thr Glu Gln Asn 1345 1350 1355 1360 Tyr Glu Ala Glu Ile His Cys Leu Gln Lys Arg Leu Gln Ala Val Ser 1365 1370 1375 Glu Ser Thr Val Pro Pro Ser Leu Pro Val Asp Ser Val Val Ile Thr 1380 1385 1390 Glu Ser Asp Ala Gln Arg Thr Met Tyr Pro Gly Ser Cys Val Lys Lys 1395 1400 1405 Asn Ile Asp Gly Thr Ile Glu Phe Ser Gly Glu Phe Gly Val Lys Glu 1410 1415 1420 Glu Thr Asn Ile Val Lys Leu Leu Glu Lys Gln Tyr Gln Glu Gln Leu 1425 1430 1435 1440 Glu Glu Glu Val Ala Lys Val Ile Val Ser Met Ser Ile Ala Phe Ala 1445 1450 1455 Gln Gln Thr Glu Leu Ser Arg Ile Ser Gly Gly Lys Glu Asn Thr Ala 1460 1465 1470 Ser Ser Lys Gln Ala His Ala Val Cys Gln Gln Glu Gln His Tyr Phe 1475 1480 1485 Asn Glu Met Lys Leu Ser Gln Asp Gln Ile Gly Phe Gln Thr Phe Glu 1490 1495 1500 Thr Val Asp Val Lys Phe Lys Glu Glu Phe Lys Pro Leu Ser Lys Glu 1505 1510 1515 1520 Leu Gly Glu His Gly Lys Glu Ile Leu Leu Ser Asn Ser Asp Pro His 1525 1530 1535 Asp Ile Pro Glu Ser Lys Asp Cys Val Leu Thr Ile Ser Glu Glu Met 1540 1545 1550 Phe Ser Lys Asp Lys Thr Phe Ile Val Arg Gln Ser Ile His Asp Glu 1555 1560 1565 Ile Ser Val Ser Ser Met Asp Ala Ser Arg Gln Leu Met Leu Asn Glu 1570 1575 1580 Glu Gln Leu Glu Asp Met Arg Gln Glu Leu Val Arg Gln Tyr Gln Glu 1585 1590 1595 1600 His Gln Gln Ala Thr Glu Leu Leu Arg Gln Ala His Met Arg Gln Met 1605 1610 1615 Glu Arg Gln Arg Glu Asp Gln Glu Gln Leu Gln Glu Glu Ile Lys Arg 1620 1625 1630 Leu Asn Arg Gln Leu Ala Gln Arg Ser Ser Ile Asp Asn Glu Asn Leu 1635 1640 1645 Val Ser Glu Arg Glu Arg Val Leu Leu Glu Glu Leu Glu Ala Leu Lys 1650 1655 1660 Gln Leu Ser Leu Ala Gly Arg Glu Lys Leu Cys Cys Glu Leu Arg Asn 1665 1670 1675 1680 Ser Ser Thr Gln Thr Gln Asn Gly Asn Glu Asn Gln Gly Glu Val Glu 1685 1690 1695 Glu Gln Thr Phe Lys Glu Lys Glu Leu Asp Arg Lys Pro Glu Asp Val 1700 1705 1710 Pro Pro Glu Ile Leu Ser Asn Glu Arg Tyr Ala Leu Gln Lys Ala Asn 1715 1720 1725 Asn Arg Leu Leu Lys Ile Leu Leu Glu Val Val Lys Thr Thr Ala Ala 1730 1735 1740 Val Glu Glu Thr Ile Gly Arg His Val Leu Gly Ile Leu Asp Arg Ser 1745 1750 1755 1760 Ser Lys Ser Gln Ser Ser Ala Ser Leu Ile Trp Arg Ser Glu Ala Glu 1765 1770 1775 Ala Ser Val Lys Ser Cys Val His Glu Glu His Thr Arg Val Thr Asp 1780 1785 1790 Glu Ser Ile Pro Ser Tyr Ser Gly Ser Asp Met Pro Arg Asn Asp Ile 1795 1800 1805 Asn Met Trp Ser Lys Val Thr Glu Glu Gly Thr Glu Leu Ser Gln Arg 1810 1815 1820 Leu Val Arg Ser Gly Phe Ala Gly Thr Glu Ile Asp Pro Glu Asn Glu 1825 1830 1835 1840 Glu Leu Met Leu Asn Ile Ser Ser Arg Leu Gln Ala Ala Val Glu Lys 1845 1850 1855 Leu Leu Glu Ala Ile Ser Glu Thr Ser Ser Gln Leu Glu His Ala Lys 1860 1865 1870 Val Thr Gln Thr Glu Leu Met Arg Glu Ser Phe Arg Gln Lys Gln Glu 1875 1880 1885 Ala Thr Glu Ser Leu Lys Cys Gin Glu Glu Leu Arg Glu Arg Leu His 1890 1895 1900 Glu Glu Ser Arg Ala Arg Glu Gln Leu Ala Val Glu Leu Ser Lys Ala 1905 1910 1915 1920 Glu Gly Val Ile Asp Gly Tyr Ala Asp Glu Lys Thr Leu Phe Glu Arg 1925 1930 1935 Gln Ile Gln Glu Lys Thr Asp Ile Ile Asp Arg Leu Glu Gln Glu Leu 1940 1945 1950 Leu Cys Ala Ser Asn Arg Leu Gln Glu Leu Glu Ala Glu Gln Gln Gln 1955 1960 1965 Ile Gln Glu Glu Arg Glu Leu Leu Ser Arg Gln Lys Glu Ala Met Lys 1970 1975 1980 Ala Glu Ala Gly Pro Val Glu Gln Gln Leu Leu Gln Glu Thr Glu Lys 1985 1990 1995 2000 Leu Met Lys Glu Lys Leu Glu Val Gln Cys Gln Ala Glu Lys Val Arg 2005 2010 2015 Asp Asp Leu Gln Lys Gln Val Lys Ala Leu Glu Ile Asp Val Glu Glu 2020 2025 2030 Gln Val Ser Arg Phe Ile Glu Leu Glu Gln Glu Lys Asn Thr Glu Leu 2035 2040 2045 Met Asp Leu Arg Gln Gln Asn Gln Ala Leu Glu Lys Gln Leu Glu Lys 2050 2055 2060 Met Arg Lys Phe Leu Asp Glu Gln Ala Ile Asp Arg Glu His Glu Arg 2065 2070 2075 2080 Asp Val Phe Gln Gln Glu Ile Gln Lys Leu Glu Gln Gln Leu Lys Val 2085 2090 2095 Val Pro Arg Phe Gln Pro Ile Ser Glu His Gln Thr Arg Glu Val Glu 2100 2105 2110 Gln Leu Ala Asn His Leu Lys Glu Lys Thr Asp Lys Cys Ser Glu Leu 2115 2120 2125 Leu Leu Ser Lys Glu Gln Leu Gln Arg Asp Ile Gln Glu Arg Asn Glu 2130 2135 2140 Glu Ile Glu Lys Leu Glu Phe Arg Val Arg Glu Leu Glu Gln Ala Leu 2145 2150 2155 2160 Leu Val Glu Asp Arg Lys His Phe Gly Ala Val Glu Ala Lys Pro Glu 2165 2170 2175 Leu Ser Leu Glu Val Gln Leu Gln Ala Glu Arg Asp Ala Ile Asp Arg 2180 2185 2190 Lys Glu Lys Glu Ile Thr Asn Leu Glu Glu Gln Leu Glu Gln Phe Arg 2195 2200 2205 Glu Glu Leu Glu Asn Lys Asn Glu Glu Val Gln Gln Leu His Met Gln 2210 2215 2220 Leu Glu Ile Gln Lys Lys Glu Ser Thr Thr Arg Leu Gln Glu Leu Glu 2225 2230 2235 2240 Gln Glu Asn Lys Leu Phe Lys Asp Asp Met Glu Lys Leu Gly Leu Ala 2245 2250 2255 Ile Lys Glu Ser Asp Ala Met Ser Thr Gln Asp Gln His Val Leu Phe 2260 2265 2270 Gly Lys Phe Ala Gln Ile Ile Gln Glu Lys Glu Val Glu Ile Asp Gln 2275 2280 2285 Leu Asn Glu Gln Val Thr Lys Leu Gln Gln Gln Leu Lys Ile Thr Thr 2290 2295 2300 Asp Asn Lys Val Ile Glu Glu Lys Asn Glu Leu Ile Arg Asp Leu Glu 2305 2310 2315 2320 Thr Gln Ile Glu Cys Leu Met Ser Asp Gln Glu Cys Val Lys Arg Asn 2325 2330 2335 Arg Glu Glu Glu Ile Glu Gln Leu Asn Glu Val Ile Glu Lys Leu Gln 2340 2345 2350 Gln Glu Leu Ala Asn Ile Gly Gln Lys Thr Ser Met Asn Ala His Ser 2355 2360 2365 Leu Ser Glu Glu Ala Asp Ser Leu Lys His Gln Leu Asp Val Val Ile 2370 2375 2380 Ala Glu Lys Leu Ala Leu Glu Gln Gln Val Glu Thr Ala Asn Glu Glu 2385 2390 2395 2400 Met Thr Phe Met Lys Asn Val Leu Lys Glu Thr Asn Phe Lys Met Asn 2405 2410 2415 Gln Leu Thr Gln Glu Leu Phe Ser Leu Lys Arg Glu Arg Glu Ser Val 2420 2425 2430 Glu Lys Ile Gln Ser Ile Pro Glu Asn Ser Val Asn Val Ala Ile Asp 2435 2440 2445 His Leu Ser Lys Asp Lys Pro Glu Leu Glu Val Val Leu Thr Glu Asp 2450 2455 2460 Ala Leu Lys Ser Leu Glu Asn Gln Thr Tyr Phe Lys Ser Phe Glu Glu 2465 2470 2475 2480 Asn Gly Lys Gly Ser Ile Ile Asn Leu Glu Thr Arg Leu Leu Gln Leu 2485 2490 2495 Glu Ser Thr Val Ser Ala Lys Asp Leu Glu Leu Thr Gln Cys Tyr Lys 2500 2505 2510 Gln Ile Lys Asp Met Gln Glu Gln Gly Gln Phe Glu Thr Glu Met Leu 2515 2520 2525 Gln Lys Lys Ile Val Asn Leu Gln Lys Ile Val Glu Glu Lys Val Ala 2530 2535 2540 Ala Ala Leu Val Ser Gln Ile Gln Leu Glu Ala Val Gln Glu Tyr Ala 2545 2550 2555 2560 Lys Phe Cys Gln Asp Asn Gln Thr Ile Ser Ser Glu Pro Glu Arg Thr 2565 2570 2575 Asn Ile Gln Asn Leu Asn Gln Leu Arg Glu Asp Glu Leu Gly Ser Asp 2580 2585 2590 Ile Ser Ala Leu Thr Leu Arg Ile Ser Glu Leu Glu Ser Gln Val Val 2595 2600 2605 Glu Met His Thr Ser Leu Ile Leu Glu Lys Glu Gln Val Glu Ile Ala 2610 2615 2620 Glu Lys Asn Val Leu Glu Lys Glu Lys Lys Leu Leu Glu Leu Gln Lys 2625 2630 2635 2640 Leu Leu Glu Gly Asn Glu Lys Lys Gln Arg Glu Lys Glu Lys Lys Arg 2645 2650 2655 Ser Pro Gln Asp Val Glu Val Leu Lys Thr Thr Thr Glu Leu Phe His 2660 2665 2670 Ser Asn Glu Glu Ser Gly Phe Phe Asn Glu Leu Glu Ala Leu Arg Ala 2675 2680 2685 Glu Ser Val Ala Thr Lys Ala Glu Leu Ala Ser Tyr Lys Glu Lys Ala 2690 2695 2700 Glu Lys Leu Gln Glu Glu Leu Leu Val Lys Glu Thr Asn Met Thr Ser 2705 2710 2715 2720 Leu Gln Lys Asp Leu Ser Gln Val Arg Asp His Leu Ala Glu Ala Lys 2725 2730 2735 Glu Lys Leu Ser Ile Leu Glu Lys Glu Asp Glu Thr Glu Val Gln Glu 2740 2745 2750 Ser Lys Lys Ala Cys Met Phe Glu Pro Leu Pro Ile Lys Leu Ser Lys 2755 2760 2765 Ser Ile Ala Ser Gln Thr Asp Gly Thr Leu Lys Ile Ser Ser Ser Asn 2770 2775 2780 Gln Thr Pro Gln Ile Leu Val Lys Asn Ala Gly Ile Gln Ile Asn Leu 2785 2790 2795 2800 Gln Ser Glu Cys Ser Ser Glu Glu Val Thr Glu Ile Ile Ser Gln Phe 2805 2810 2815 Thr Glu Lys Ile Glu Lys Met Gln Glu Leu His Ala Ala Glu Ile Leu 2820 2825 2830 Asp Met Glu Ser Arg His Ile Ser Glu Thr Glu Thr Leu Lys Arg Glu 2835 2840 2845 His Tyr Val Ala Val Gln Leu Leu Lys Glu Glu Cys Gly Thr Leu Lys 2850 2855 2860 Ala Val Ile Gln Cys Leu Arg Ser Lys Glu Gly Ser Ser Ile Pro Glu 2865 2870 2875 2880 Leu Ala His Ser Asp Ala Tyr Gln Thr Arg Glu Ile Cys Ser Ser Asp 2885 2890 2895 Ser Gly Ser Asp Trp Gly Gln Gly Ile Tyr Leu Thr His Ser Gln Gly 2900 2905 2910 Phe Asp Ile Ala Ser Glu Gly Arg Gly Glu Glu Ser Glu Ser Ala Thr 2915 2920 2925 Asp Ser Phe Pro Lys Lys Ile Lys Gly Leu Leu Arg Ala Val His Asn 2930 2935 2940 Glu Gly Met Gln Val Leu Ser Leu Thr Glu Ser Pro Tyr Ser Asp Gly 2945 2950 2955 2960 Glu Asp His Ser Ile Gln Gln Val Ser Glu Pro Trp Leu Glu Glu Arg 2965 2970 2975 Lys Ala Tyr Ile Asn Thr Ile Ser Ser Leu Lys Asp Leu Ile Thr Lys 2980 2985 2990 Met Gln Leu Gln Arg Glu Ala Glu Val Tyr Asp Ser Ser Gln Ser His 2995 3000 3005 Glu Ser Phe Ser Asp Trp Arg Gly Glu Leu Leu Leu Ala Leu Gln Gln 3010 3015 3020 Val Phe Leu Glu Glu Arg Ser Val Leu Leu Ala Ala Phe Arg Thr Glu 3025 3030 3035 3040 Leu Thr Ala Leu Gly Thr Thr Asp Ala Val Gly Leu Leu Asn Cys Leu 3045 3050 3055 Glu Gln Arg Ile Gln Glu Gln Gly Val Glu Tyr Gln Ala Ala Met Glu 3060 3065 3070 Cys Leu Gln Lys Ala Asp Arg Arg Ser Leu Leu Ser Glu Ile Gln Ala 3075 3080 3085 Leu His Ala Gln Met Asn Gly Arg Lys Ile Thr Leu Lys Arg Glu Gln 3090 3095 3100 Glu Ser Glu Lys Pro Ser Gln Glu Leu Leu Glu Tyr Asn Ile Gln Gln 3105 3110 3115 3120 Lys Gln Ser Gln Met Leu Glu Met Gln Val Glu Leu Ser Ser Met Lys 3125 3130 3135 Asp Arg Ala Thr Glu Leu Gln Glu Gln Leu Ser Ser Glu Lys Met Val 3140 3145 3150 Val Ala Glu Leu Lys Ser Glu Leu Ala Gln Thr Lys Leu Glu Leu Glu 3155 3160 3165 Thr Thr Leu Lys Ala Gln His Lys His Leu Lys Glu Leu Glu Ala Phe 3170 3175 3180 Arg Leu Glu Val Lys Asp Lys Thr Asp Glu Val His Leu Leu Asn Asp 3185 3190 3195 3200 Thr Leu Ala Ser Glu Gln Lys Lys Ser Arg Glu Leu Gln Trp Ala Leu 3205 3210 3215 Glu Lys Glu Lys Ala Lys Leu Gly Arg Ser Glu Glu Arg Asp Lys Glu 3220 3225 3230 Glu Leu Glu Asp Leu Lys Phe Ser Leu Glu Ser Gln Lys Gln Arg Asn 3235 3240 3245 Leu Gln Leu Asn Leu Leu Leu Glu Gln Gln Lys Gln Leu Leu Asn Glu 3250 3255 3260 Ser Gln Gln Lys Ile Glu Ser Gln Arg Met Leu Tyr Asp Ala Gln Leu 3265 3270 3275 3280 Ser Glu Glu Gln Gly Arg Asn Leu Glu Leu Gln Val Leu Leu Glu Ser 3285 3290 3295 Glu Lys Val Arg Ile Arg Glu Met Ser Ser Thr Leu Asp Arg Glu Arg 3300 3305 3310 Glu Leu His Ala Gln Leu Gln Ser Ser Asp Gly Thr Gly Gln Ser Arg 3315 3320 3325 Pro Pro Leu Pro Ser Glu Asp Leu Leu Lys Glu Leu Gln Lys Gln Leu 3330 3335 3340 Glu Glu Lys His Ser Arg Ile Val Glu Leu Leu Asn Glu Thr Glu Lys 3345 3350 3355 3360 Tyr Lys Leu Asp Ser Leu Gln Thr Arg Gln Gln Met Glu Lys Asp Arg 3365 3370 3375 Gln Val His Arg Lys Thr Leu Gln Thr Glu Gln Glu Ala Asn Thr Glu 3380 3385 3390 Gly Gln Lys Lys Met His Glu Leu Gln Ser Lys Val Glu Asp Leu Gln 3395 3400 3405 Arg Gln Leu Glu Glu Lys Arg Gln Gln Val Tyr Lys Leu Asp Leu Glu 3410 3415 3420 Gly Gln Arg Leu Gln Gly Ile Met Gln Glu Phe Gln Lys Gln Glu Leu 3425 3430 3435 3440 Glu Arg Glu Glu Lys Arg Glu Ser Arg Arg Ile Leu Tyr Gln Asn Leu 3445 3450 3455 Asn Glu Pro Thr Thr Trp Ser Leu Thr Ser Asp Arg Thr Arg Asn Trp 3460 3465 3470 Val Leu Gln Gln Lys Ile Glu Gly Glu Thr Lys Glu Ser Asn Tyr Ala 3475 3480 3485 Lys Leu Ile Glu Met Asn Gly Gly Gly Thr Gly Cys Asn His Glu Leu 3490 3495 3500 Glu Met Ile Arg Gln Lys Leu Gln Cys Val Ala Ser Lys Leu Gln Val 3505 3510 3515 3520 Leu Pro Gln Lys Ala Ser Glu Arg Leu Gln Phe Glu Thr Ala Asp Asp 3525 3530 3535 Glu Asp Phe Ile Trp Val Gln Glu Asn Ile Asp Glu Ile Ile Leu Gln 3540 3545 3550 Leu Gln Lys Leu Thr Gly Gln Gln Gly Glu Glu Pro Ser Leu Val Ser 3555 3560 3565 Pro Ser Thr Ser Cys Gly Ser Leu Thr Glu Arg Leu Leu Arg Gln Asn 3570 3575 3580 Ala Glu Leu Thr Gly His Ile Ser Gln Leu Thr Glu Glu Lys Asn Asp 3585 3590 3595 3600 Leu Arg Asn Met Val Met Lys Leu Glu Glu Gln Ile Arg Trp Tyr Arg 3605 3610 3615 Gln Thr Gly Ala Gly Arg Asp Asn Ser Ser Arg Phe Ser Leu Asn Gly 3620 3625 3630 Gly Ala Asn Ile Glu Ala Ile Ile Ala Ser Glu Lys Glu Val Trp Asn 3635 3640 3645 Arg Glu Lys Leu Thr Leu Gln Lys Ser Leu Lys Arg Ala Glu Ala Glu 3650 3655 3660 Val Tyr Lys Leu Lys Ala Glu Leu Arg Asn Asp Ser Leu Leu Gln Thr 3665 3670 3675 3680 Leu Ser Pro Asp Ser Glu His Val Thr Leu Lys Arg Ile Tyr Gly Lys 3685 3690 3695 Tyr Leu Arg Ala Glu Ser Phe Arg Lys Ala Leu Ile Tyr Gln Lys Lys 3700 3705 3710 Tyr Leu Leu Leu Leu Leu Gly Gly Phe Gln Glu Cys Glu Asp Ala Thr 3715 3720 3725 Leu Ala Leu Leu Ala Arg Met Gly Gly Gln Pro Ala Phe Thr Asp Leu 3730 3735 3740 Glu Val Ile Thr Asn Arg Pro Lys Gly Phe Thr Arg Phe Arg Ser Ala 3745 3750 3755 3760 Val Arg Val Ser Ile Ala Ile Ser Arg Met Lys Phe Leu Val Arg Arg 3765 3770 3775 Trp His Arg Val Thr Gly Ser Val Ser Ile Asn Ile Asn Arg Asp Gly 3780 3785 3790 Phe Gly Leu Asn Gln Gly Ala Glu Lys Thr Asp Ser Phe Tyr His Ser 3795 3800 3805 Ser Gly Gly Leu Glu Leu Tyr Gly Glu Pro Arg His Thr Thr Tyr Arg 3810 3815 3820 Ser Arg Ser Asp Leu Asp Tyr Ile Arg Ser Pro Leu Pro Phe Gln Asn 3825 3830 3835 3840 Arg Tyr Pro Gly Thr Pro Ala Asp Phe Asn Pro Gly Ser Leu Ala Cys 3845 3850 3855 Ser Gln Leu Gln Asn Tyr Asp Pro Asp Arg Ala Leu Thr Asp Tyr Ile 3860 3865 3870 Thr Arg Leu Glu Ala Leu Gln Arg Arg Leu Gly Thr Ile Gln Ser Gly 3875 3880 3885 Ser Thr Thr Gln Phe His Ala Gly Met Arg Arg 3890 3895 <210> 2 <211> 453 <212> PRT <213> Homo sapiens <400> 2 Met Leu Arg Ile Leu Cys Leu Ala Leu Cys Ser Leu Leu Thr Gly Thr 1 5 10 15 Arg Ala Asp Pro Gly Ala Leu Leu Arg Leu Gly Met Asp Ile Met Asn 20 25 30 Gln Val Gln Ser Ala Met Asp Glu Ser His Ile Leu Glu Lys Met Ala 35 40 45 Ala Glu Ala Gly Lys Lys Gln Pro Gly Met Lys Pro Ile Lys Gly Ile 50 55 60 Thr Asn Leu Lys Val Lys Asp Val Gln Leu Pro Val Ile Thr Leu Asn 65 70 75 80 Phe Val Pro Gly Val Gly Ile Phe Gln Cys Val Ser Thr Gly Met Thr 85 90 95 Val Thr Gly Lys Ser Phe Met Gly Gly Asn Met Glu Ile Ile Val Ala 100 105 110 Leu Asn Ile Thr Ala Thr Asn Arg Leu Leu Arg Asp Glu Glu Thr Gly 115 120 125 Leu Pro Val Phe Lys Ser Glu Gly Cys Glu Val Ile Leu Val Asn Val 130 135 140 Lys Thr Asn Leu Pro Ser Asn Met Leu Pro Lys Met Val Asn Lys Phe 145 150 155 160 Leu Asp Ser Thr Leu His Lys Val Leu Pro Gly Leu Met Cys Pro Ala 165 170 175 Ile Asp Ala Val Leu Val Tyr Val Asn Arg Lys Trp Thr Asn Leu Ser 180 185 190 Asp Pro Met Pro Val Gly Gln Met Gly Thr Val Lys Tyr Val Leu Met 195 200 205 Ser Ala Pro Ala Thr Thr Ala Ser Tyr Ile Gln Leu Asp Phe Ser Pro 210 215 220 Val Val Gln Gln Gln Lys Gly Lys Thr Ile Lys Leu Ala Asp Ala Gly 225 230 235 240 Glu Ala Leu Thr Phe Pro Glu Gly Tyr Ala Lys Gly Ser Ser Gln Leu 245 250 255 Leu Leu Pro Ala Thr Phe Leu Ser Ala Glu Leu Ala Leu Leu Gln Lys 260 265 270 Ser Phe His Val Asn Ile Gln Asp Thr Met Ile Gly Glu Leu Pro Pro 275 280 285 Gln Thr Thr Lys Thr Leu Ala Arg Phe Ile Pro Glu Val Ala Val Ala 290 295 300 Tyr Pro Lys Ser Lys Pro Leu Thr Thr Gln Ile Lys Ile Lys Lys Pro 305 310 315 320 Pro Lys Val Thr Met Lys Thr Gly Lys Ser Leu Leu His Leu His Ser 325 330 335 Thr Leu Glu Met Phe Ala Ala Arg Trp Arg Ser Lys Ala Pro Met Ser 340 345 350 Leu Phe Leu Leu Glu Val His Phe Asn Leu Lys Val Gln Tyr Ser Val 355 360 365 His Glu Asn Gln Leu Gln Met Ala Thr Ser Leu Asp Arg Leu Leu Ser 370 375 380 Leu Ser Arg Lys Ser Ser Ser Ile Gly Asn Phe Asn Glu Arg Glu Leu 385 390 395 400 Thr Gly Phe Ile Thr Ser Tyr Leu Glu Glu Ala Tyr Ile Pro Val Val 405 410 415 Asn Asp Val Leu Gln Val Gly Leu Pro Leu Pro Asp Phe Leu Ala Met 420 425 430 Asn Tyr Asn Leu Ala Glu Leu Asp Ile Val Glu Asn Ala Leu Met Leu 435 440 445 Asp Leu Lys Leu Gly 450 <210> 3 <211> 1912 <212> PRT <213> Homo sapiens <400> 3 Met Ala Ser Gly Leu Gly Ser Pro Ser Pro Cys Ser Ala Gly Ser Glu 1 5 10 15 Glu Glu Asp Met Asp Ala Leu Leu Asn Asn Ser Leu Pro Pro His 20 25 30 Pro Glu Asn Glu Glu Asp Pro Glu Glu Asp Leu Ser Glu Thr Glu Thr 35 40 45 Pro Lys Leu Lys Lys Lys Lys Lys Pro Lys Lys Pro Arg Asp Pro Lys 50 55 60 Ile Pro Lys Ser Lys Arg Gln Lys Lys Glu Arg Met Leu Leu Cys Arg 65 70 75 80 Gln Leu Gly Asp Ser Ser Gly Glu Gly Pro Glu Phe Val Glu Glu Glu 85 90 95 Glu Glu Val Ala Leu Arg Ser Asp Ser Glu Gly Ser Asp Tyr Thr Pro 100 105 110 Gly Lys Lys Lys Lys Lys Lys Leu Gly Pro Lys Lys Glu Lys Lys Ser 115 120 125 Lys Ser Lys Arg Lys Glu Glu Glu Glu Glu Glu Asp Asp Asp Asp Asp 130 135 140 Ser Lys Glu Pro Lys Ser Ser Ala Gln Leu Leu Glu Asp Trp Gly Met 145 150 155 160 Glu Asp Ile Asp His Val Phe Ser Glu Glu Asp Tyr Arg Thr Leu Thr 165 170 175 Asn Tyr Lys Ala Phe Ser Gln Phe Val Arg Pro Leu Ile Ala Ala Lys 180 185 190 Asn Pro Lys Ile Ala Val Ser Lys Met Met Met Val Leu Gly Ala Lys 195 200 205 Trp Arg Glu Phe Ser Thr Asn Asn Pro Phe Lys Gly Ser Ser Gly Ala 210 215 220 Ser Val Ala Ala Ala Ala Ala Ala Ala Val Ala Val Val Glu Ser Met 225 230 235 240 Val Thr Ala Thr Glu Val Ala Pro Pro Pro Pro Val Glu Val Pro 245 250 255 Ile Arg Lys Ala Lys Thr Lys Glu Gly Lys Gly Pro Asn Ala Arg Arg 260 265 270 Lys Pro Lys Gly Ser Pro Arg Val Pro Asp Ala Lys Lys Pro Lys Pro 275 280 285 Lys Lys Val Ala Pro Leu Lys Ile Lys Leu Gly Gly Phe Gly Ser Lys 290 295 300 Arg Lys Arg Ser Ser Ser Glu Asp Asp Asp Leu Asp Val Glu Ser Asp 305 310 315 320 Phe Asp Asp Ala Ser Ile Asn Ser Tyr Ser Val Ser Asp Gly Ser Thr 325 330 335 Ser Arg Ser Ser Arg Ser Arg Lys Lys Leu Arg Thr Thr Lys Lys Lys 340 345 350 Lys Lys Gly Glu Glu Glu Val Thr Ala Val Asp Gly Tyr Glu Thr Asp 355 360 365 His Gln Asp Tyr Cys Glu Val Cys Gln Gin Gly Gly Glu Ile Ile Leu 370 375 380 Cys Asp Thr Cys Pro Arg Ala Tyr His Met Val Cys Leu Asp Pro Asp 385 390 395 400 Met Glu Lys Ala Pro Glu Gly Lys Trp Ser Cys Pro His Cys Glu Lys 405 410 415 Glu Gly Ile Gln Trp Glu Ala Lys Glu Asp Asn Ser Glu Gly Glu Glu 420 425 430 Ile Leu Glu Glu Val Gly Gly Asp Leu Glu Glu Glu Asp Asp His His 435 440 445 Met Glu Phe Cys Arg Val Cys Lys Asp Gly Gly Glu Leu Leu Cys Cys 450 455 460 Asp Thr Cys Pro Ser Ser Tyr His Ile His Cys Leu Asn Pro Pro Leu 465 470 475 480 Pro Glu Ile Pro Asn Gly Glu Trp Leu Cys Pro Arg Cys Thr Cys Pro 485 490 495 Ala Leu Lys Gly Lys Val Gln Lys Ile Leu Ile Trp Lys Trp Gly Gln 500 505 510 Pro Pro Ser Pro Thr Pro Val Pro Arg Pro Pro Asp Ala Asp Pro Asn 515 520 525 Thr Pro Ser Pro Lys Pro Leu Glu Gly Arg Pro Glu Arg Gln Phe Phe 530 535 540 Val Lys Trp Gln Gly Met Ser Tyr Trp His Cys Ser Trp Val Ser Glu 545 550 555 560 Leu Gln Leu Glu Leu His Cys Gln Val Met Phe Arg Asn Tyr Gln Arg 565 570 575 Lys Asn Asp Met Asp Glu Pro Ser Gly Asp Phe Gly Gly Asp Glu 580 585 590 Glu Lys Ser Arg Lys Arg Lys Asn Lys Asp Pro Lys Phe Ala Glu Met 595 600 605 Glu Glu Arg Phe Tyr Arg Tyr Gly Ile Lys Pro Glu Trp Met Met Ile 610 615 620 His Arg Ile Leu Asn His Ser Val Asp Lys Lys Gly His Val His Tyr 625 630 635 640 Leu Ile Lys Trp Arg Asp Leu Pro Tyr Asp Gln Ala Ser Trp Glu Ser 645 650 655 Glu Asp Val Glu Ile Gln Asp Tyr Asp Leu Phe Lys Gln Ser Tyr Trp 660 665 670 Asn His Arg Glu Leu Met Arg Gly Glu Glu Gly Arg Pro Gly Lys Lys 675 680 685 Leu Lys Lys Val Lys Leu Arg Lys Leu Glu Arg Pro Pro Glu Thr Pro 690 695 700 Thr Val Asp Pro Thr Val Lys Tyr Glu Arg Gln Pro Glu Tyr Leu Asp 705 710 715 720 Ala Thr Gly Gly Thr Leu His Pro Tyr Gln Met Glu Gly Leu Asn Trp 725 730 735 Leu Arg Phe Ser Trp Ala Gln Gly Thr Asp Thr Ile Leu Ala Asp Glu 740 745 750 Met Gly Leu Gly Lys Thr Val Gln Thr Ala Val Phe Leu Tyr Ser Leu 755 760 765 Tyr Lys Glu Gly His Ser Lys Gly Pro Phe Leu Val Ser Ala Pro Leu 770 775 780 Ser Thr Ile Ile Asn Trp Glu Arg Glu Phe Glu Met Trp Ala Pro Asp 785 790 795 800 Met Tyr Val Val Thr Tyr Val Gly Asp Lys Asp Ser Arg Ala Ile Ile 805 810 815 Arg Glu Asn Glu Phe Ser Phe Glu Asp Asn Ala Ile Arg Gly Gly Lys 820 825 830 Lys Ala Ser Arg Met Lys Lys Glu Ala Ser Val Lys Phe His Val Leu 835 840 845 Leu Thr Ser Tyr Glu Leu Ile Thr Ile Asp Met Ala Ile Leu Gly Ser 850 855 860 Ile Asp Trp Ala Cys Leu Ile Val Asp Glu Ala His Arg Leu Lys Asn 865 870 875 880 Asn Gln Ser Lys Phe Phe Arg Val Leu Asn Gly Tyr Ser Leu Gln His 885 890 895 Lys Leu Leu Leu Thr Gly Thr Pro Leu Gln Asn Asn Leu Glu Glu Leu 900 905 910 Phe His Leu Leu Asn Phe Leu Thr Pro Glu Arg Phe His Asn Leu Glu 915 920 925 Gly Phe Leu Glu Glu Phe Ala Asp Ile Ala Lys Glu Asp Gln Ile Lys 930 935 940 Lys Leu His Asp Met Leu Gly Pro His Met Leu Arg Arg Leu Lys Ala 945 950 955 960 Asp Val Phe Lys Asn Met Pro Ser Lys Thr Glu Leu Ile Val Arg Val 965 970 975 Glu Leu Ser Pro Met Gln Lys Lys Tyr Tyr Lys Tyr Ile Leu Thr Arg 980 985 990 Asn Phe Glu Ala Leu Asn Ala Arg Gly Gly Gly Asn Gln Val Ser Leu 995 1000 1005 Leu Asn Val Val Met Asp Leu Lys Lys Cys Cys Asn His Pro Tyr Leu 1010 1015 1020 Phe Pro Val Ala Ala Met Glu Ala Pro Lys Met Pro Asn Gly Met Tyr 1025 1030 1035 1040 Asp Gly Ser Ala Leu Ile Arg Ala Ser Gly Lys Leu Leu Leu Leu Gln 1045 1050 1055 Lys Met Leu Lys Asn Leu Lys Glu Gly Gly His Arg Val Leu Ile Phe 1060 1065 1070 Ser Gln Met Thr Lys Met Leu Asp Leu Leu Glu Asp Phe Leu Glu His 1075 1080 1085 Glu Gly Tyr Lys Tyr Glu Arg Ile Asp Gly Gly Ile Thr Gly Asn Met 1090 1095 1100 Arg Gln Glu Ala Ile Asp Arg Phe Asn Ala Pro Gly Ala Gln Gln Phe 1105 1110 1115 1120 Cys Phe Leu Leu Ser Thr Arg Ala Gly Gly Leu Gly Ile Asn Leu Ala 1125 1130 1135 Thr Ala Asp Thr Val Ile Ile Tyr Asp Ser Asp Trp Asn Pro His Asn 1140 1145 1150 Asp Ile Gln Ala Phe Ser Arg Ala His Arg Ile Gly Gln Asn Lys Lys 1155 1160 1165 Val Met Ile Tyr Arg Phe Val Thr Arg Ala Ser Val Glu Glu Arg Ile 1170 1175 1180 Thr Gln Val Ala Lys Lys Lys Met Met Leu Thr His Leu Val Val Arg 1185 1190 1195 1200 Pro Gly Leu Gly Ser Lys Thr Gly Ser Met Ser Lys Gln Glu Leu Asp 1205 1210 1215 Asp Ile Leu Lys Phe Gly Thr Glu Glu Leu Phe Lys Asp Glu Ala Thr 1220 1225 1230 Asp Gly Gly Gly Asp Asn Lys Glu Gly Glu Asp Ser Ser Val Ile His 1235 1240 1245 Tyr Asp Asp Lys Ala Ile Glu Arg Leu Leu Asp Arg Asn Gln Asp Glu 1250 1255 1260 Thr Glu Asp Thr Glu Leu Gln Gly Met Asn Glu Tyr Leu Ser Ser Phe 1265 1270 1275 1280 Lys Val Ala Gln Tyr Val Val Arg Glu Glu Glu Met Gly Glu Glu Glu 1285 1290 1295 Glu Val Glu Arg Glu Ile Ile Lys Gln Glu Glu Ser Val Asp Pro Asp 1300 1305 1310 Tyr Trp Glu Lys Leu Leu Arg His His Tyr Glu Gln Gln Gln Glu Asp 1315 1320 1325 Leu Ala Arg Asn Leu Gly Lys Gly Lys Arg Ile Arg Lys Gln Val Asn 1330 1335 1340 Tyr Asn Asp Gly Ser Gln Glu Asp Arg Asp Trp Gln Asp Asp Gln Ser 1345 1350 1355 1360 Asp Asn Gln Ser Asp Tyr Ser Val Ala Ser Glu Glu Gly Asp Glu Asp 1365 1370 1375 Phe Asp Glu Arg Ser Glu Ala Pro Arg Arg Pro Ser Arg Lys Gly Leu 1380 1385 1390 Arg Asn Asp Lys Asp Lys Pro Leu Pro Pro Leu Leu Ala Arg Val Gly 1395 1400 1405 Gly Asn Ile Glu Val Leu Gly Phe Asn Ala Arg Gln Arg Lys Ala Phe 1410 1415 1420 Leu Asn Ala Ile Met Arg Tyr Gly Met Pro Pro Gln Asp Ala Phe Thr 1425 1430 1435 1440 Thr Gln Trp Leu Val Arg Asp Leu Arg Gly Lys Ser Glu Lys Glu Phe 1445 1450 1455 Lys Ala Tyr Val Ser Leu Phe Met Arg His Leu Cys Glu Pro Gly Ala 1460 1465 1470 Asp Gly Ala Glu Thr Phe Ala Asp Gly Val Pro Arg Glu Gly Leu Ser 1475 1480 1485 Arg Gln His Val Leu Thr Arg Ile Gly Val Met Ser Leu Ile Arg Lys 1490 1495 1500 Lys Val Gln Glu Phe Glu His Val Asn Gly Arg Trp Ser Met Pro Glu 1505 1510 1515 1520 Leu Ala Glu Val Glu Glu Asn Lys Lys Met Ser Gln Pro Gly Ser Pro 1525 1530 1535 Ser Pro Lys Thr Pro Thr Pro Ser Thr Pro Gly Asp Thr Gln Pro Asn 1540 1545 1550 Thr Pro Ala Pro Val Pro Pro Ala Glu Asp Gly Ile Lys Ile Glu Glu 1555 1560 1565 Asn Ser Leu Lys Glu Glu Glu Ser Ile Glu Gly Glu Lys Glu Val Lys 1570 1575 1580 Ser Thr Ala Pro Glu Thr Ala Ile Glu Cys Thr Gln Ala Pro Ala Pro 1585 1590 1595 1600 Ala Ser Glu Asp Glu Lys Val Val Val Glu Pro Glu Gly Glu Glu 1605 1610 1615 Lys Val Glu Lys Ala Glu Val Lys Glu Arg Thr Glu Glu Pro Met Glu 1620 1625 1630 Thr Glu Pro Lys Gly Ala Ala Asp Val Glu Lys Val Glu Glu Lys Ser 1635 1640 1645 Ala Ile Asp Leu Thr Pro Ile Val Val Glu Asp Lys Glu Glu Lys Lys 1650 1655 1660 Glu Glu Glu Glu Lys Lys Glu Val Met Leu Gln Asn Gly Glu Thr Pro 1665 1670 1675 1680 Lys Asp Leu Asn Asp Glu Lys Gln Lys Lys Asn Ile Lys Gln Arg Phe 1685 1690 1695 Met Phe Asn Ile Ala Asp Gly Gly Phe Thr Glu Leu His Ser Leu Trp 1700 1705 1710 Gln Asn Glu Glu Arg Ala Ala Thr Val Thr Lys Lys Thr Tyr Glu Ile 1715 1720 1725 Trp His Arg Arg His Asp Tyr Trp Leu Leu Ala Gly Ile Ile Asn His 1730 1735 1740 Gly Tyr Ala Arg Trp Gln Asp Ile Gln Asn Asp Pro Arg Tyr Ala Ile 1745 1750 1755 1760 Leu Asn Glu Pro Phe Lys Gly Glu Met Asn Arg Gly Asn Phe Leu Glu 1765 1770 1775 Ile Lys Asn Lys Phe Leu Ala Arg Arg Phe Lys Leu Leu Glu Gln Ala 1780 1785 1790 Leu Val Ile Glu Glu Gln Leu Arg Arg Ala Ala Tyr Leu Asn Met Ser 1795 1800 1805 Glu Asp Pro Ser His Pro Ser Met Ala Leu Asn Thr Arg Phe Ala Glu 1810 1815 1820 Val Glu Cys Leu Ala Glu Ser His Gln His Leu Ser Lys Glu Ser Met 1825 1830 1835 1840 Ala Gly Asn Lys Pro Ala Asn Ala Val Leu His Lys Val Leu Lys Gln 1845 1850 1855 Leu Glu Glu Leu Leu Ser Asp Met Lys Ala Asp Val Thr Arg Leu Pro 1860 1865 1870 Ala Thr Ile Ala Arg Ile Pro Val Ala Val Arg Leu Gln Met Ser 1875 1880 1885 Glu Arg Asn Ile Leu Ser Arg Leu Ala Asn Arg Ala Pro Glu Pro Thr 1890 1895 1900 Pro Gln Gln Val Ala Gln Gln Gln 1905 1910 <210> 4 <211> 912 <212> PRT <213> Homo sapiens <400> 4 Met Pro Ala Met Pro Ser Ser Gly Pro Gly Asp Thr Ser Ser Ser Ala 1 5 10 15 Ala Glu Arg Glu Glu Asp Arg Lys Asp Gly Glu Glu Gln Glu Glu Pro 20 25 30 Arg Gly Lys Glu Glu Arg Gln Glu Pro Ser Thr Thr Ala Arg Lys Val 35 40 45 Gly Arg Pro Gly Arg Lys Arg Lys His Pro Val Glu Ser Gly Asp 50 55 60 Thr Pro Lys Asp Pro Ala Val Ile Ser Lys Ser Pro Ser Met Ala Gln 65 70 75 80 Asp Ser Gly Ala Ser Glu Leu Leu Pro Asn Gly Asp Leu Glu Lys Arg 85 90 95 Ser Glu Pro Gln Pro Glu Glu Gly Ser Pro Ala Gly Gly Gln Lys Gly 100 105 110 Gly Ala Pro Ala Glu Gly Glu Gly Ala Ala Glu Thr Leu Pro Glu Ala 115 120 125 Ser Arg Ala Val Glu Asn Gly Cys Cys Thr Pro Lys Glu Gly Arg Gly 130 135 140 Ala Pro Ala Glu Ala Gly Lys Glu Gln Lys Glu Thr Asn Ile Glu Ser 145 150 155 160 Met Lys Met Glu Gly Ser Arg Gly Arg Leu Arg Gly Gly Leu Gly Trp 165 170 175 Glu Ser Ser Leu Arg Gln Arg Pro Met Pro Arg Leu Thr Phe Gln Ala 180 185 190 Gly Asp Pro Tyr Tyr Ile Ser Lys Arg Lys Arg Asp Glu Trp Leu Ala 195 200 205 Arg Trp Lys Arg Glu Ala Glu Lys Lys Ala Lys Val Ile Ala Gly Met 210 215 220 Asn Ala Val Glu Glu Asn Gln Gly Pro Gly Glu Ser Gln Lys Val Glu 225 230 235 240 Glu Ala Ser Pro Ala Val Gln Gln Pro Thr Asp Pro Ala Ser Pro 245 250 255 Thr Val Ala Thr Thr Pro Glu Pro Val Gly Ser Asp Ala Gly Asp Lys 260 265 270 Asn Ala Thr Lys Ala Gly Asp Asp Glu Pro Glu Tyr Glu Asp Gly Arg 275 280 285 Gly Phe Gly Ile Gly Glu Leu Val Trp Gly Lys Leu Arg Gly Phe Ser 290 295 300 Trp Trp Pro Gly Arg Ile Val Ser Trp Trp Met Thr Gly Arg Ser Arg 305 310 315 320 Ala Ala Glu Gly Thr Arg Trp Val Met Trp Phe Gly Asp Gly Lys Phe 325 330 335 Ser Val Val Cys Val Glu Lys Leu Met Pro Leu Ser Ser Phe Cys Ser 340 345 350 Ala Phe His Gln Ala Thr Tyr Asn Lys Gln Pro Met Tyr Arg Lys Ala 355 360 365 Ile Tyr Glu Val Leu Gln Val Ala Ser Ser Arg Ala Gly Lys Leu Phe 370 375 380 Pro Val Cys His Asp Ser Asp Glu Ser Asp Thr Ala Lys Ala Val Glu 385 390 395 400 Val Gln Asn Lys Pro Met Ile Glu Trp Ala Leu Gly Gly Phe Gln Pro 405 410 415 Ser Gly Pro Lys Gly Leu Glu Pro Pro Glu Glu Glu Lys Asn Pro Tyr 420 425 430 Lys Glu Val Tyr Thr Asp Met Trp Val Glu Pro Glu Ala Ala Ala Tyr 435 440 445 Ala Pro Pro Pro Pro Ala Lys Lys Pro Arg Lys Ser Thr Ala Glu Lys 450 455 460 Pro Lys Val Lys Glu Ile Ile Asp Glu Arg Thr Arg Glu Arg Leu Val 465 470 475 480 Tyr Glu Val Arg Gln Lys Cys Arg Asn Ile Glu Asp Ile Cys Ile Ser 485 490 495 Cys Gly Ser Leu Asn Val Thr Leu Glu His Pro Leu Phe Val Gly Gly 500 505 510 Met Cys Gln Asn Cys Lys Asn Cys Phe Leu Glu Cys Ala Tyr Gln Tyr 515 520 525 Asp Asp Asp Gly Tyr Gln Ser Tyr Cys Thr Ile Cys Cys Gly Gly Arg 530 535 540 Glu Val Leu Met Cys Gly Asn Asn Asn Cys Cys Arg Cys Phe Cys Val 545 550 555 560 Glu Cys Val Asp Leu Leu Val Gly Pro Gly Ala Ala Gln Ala Ala Ile 565 570 575 Lys Glu Asp Pro Trp Asn Cys Tyr Met Cys Gly His Lys Gly Thr Tyr 580 585 590 Gly Leu Leu Arg Arg Arg Glu Asp Trp Pro Ser Arg Leu Gln Met Phe 595 600 605 Phe Ala Asn Asn His Asp Gln Glu Phe Asp Pro Pro Lys Val Tyr Pro 610 615 620 Pro Val Pro Ala Glu Lys Arg Lys Pro Ile Arg Val Leu Ser Leu Phe 625 630 635 640 Asp Gly Ile Ala Thr Gly Leu Leu Val Leu Lys Asp Leu Gly Ile Gln 645 650 655 Val Asp Arg Tyr Ile Ala Ser Glu Val Cys Glu Asp Ser Ile Thr Val 660 665 670 Gly Met Val Arg His Gln Gly Lys Ile Met Tyr Val Gly Asp Val Arg 675 680 685 Ser Val Thr Gln Lys His Ile Gln Glu Trp Gly Pro Phe Asp Leu Val 690 695 700 Ile Gly Gly Ser Pro Cys Asn Asp Leu Ser Ile Val Asn Pro Ala Arg 705 710 715 720 Lys Gly Leu Tyr Glu Gly Thr Gly Arg Leu Phe Phe Glu Phe Tyr Arg 725 730 735 Leu Leu His Asp Ala Arg Pro Lys Glu Gly Asp Asp Arg Pro Phe Phe 740 745 750 Trp Leu Phe Glu Asn Val Val Ala Met Gly Val Ser Asp Lys Arg Asp 755 760 765 Ile Ser Arg Phe Leu Glu Ser Asn Pro Val Met Ile Asp Ala Lys Glu 770 775 780 Val Ser Ala Ala His Arg Ala Arg Tyr Phe Trp Gly Asn Leu Pro Gly 785 790 795 800 Met Asn Arg Pro Leu Ala Ser Thr Val Asn Asp Lys Leu Glu Leu Gln 805 810 815 Glu Cys Leu Glu His Gly Arg Ile Ala Lys Phe Ser Lys Val Arg Thr 820 825 830 Ile Thr Thr Arg Ser Asn Ser Ile Lys Gln Gly Lys Asp Gln His Phe 835 840 845 Pro Val Phe Met Asn Glu Lys Glu Asp Ile Leu Trp Cys Thr Glu Met 850 855 860 Glu Arg Val Phe Gly Phe Pro Val His Tyr Thr Asp Val Ser Asn Met 865 870 875 880 Ser Arg Leu Ala Arg Gln Arg Leu Leu Gly Arg Ser Trp Ser Val Pro 885 890 895 Val Ile Arg His Leu Phe Ala Pro Leu Lys Glu Tyr Phe Ala Cys Val 900 905 910 <210> 5 <211> 260 <212> PRT <213> Homo sapiens <400> 5 Met Ala Ser Leu Glu Val Ser Arg Ser Pro Arg Arg Ser Arg Arg Glu 1 5 10 15 Leu Glu Val Arg Ser Pro Arg Gln Asn Lys Tyr Ser Val Leu Leu Pro 20 25 30 Thr Tyr Asn Glu Arg Glu Asn Leu Pro Leu Ile Val Trp Leu Leu Val 35 40 45 Lys Ser Phe Ser Glu Ser Gly Ile Asn Tyr Glu Ile Ile Ile Ile Asp 50 55 60 Asp Gly Ser Pro Asp Gly Thr Arg Asp Val Ala Glu Gln Leu Glu Lys 65 70 75 80 Ile Tyr Gly Ser Asp Arg Ile Leu Leu Arg Pro Arg Glu Lys Lys Leu 85 90 95 Gly Leu Gly Thr Ala Tyr Ile His Gly Met Lys His Ala Thr Gly Asn 100 105 110 Tyr Ile Ile Ile Met Asp Ala Asp Leu Ser His His Pro Lys Phe Ile 115 120 125 Pro Glu Phe Ile Arg Lys Gln Lys Glu Gly Asn Phe Asp Ile Val Ser 130 135 140 Gly Thr Arg Tyr Lys Gly Asn Gly Gly Val Tyr Gly Trp Asp Leu Lys 145 150 155 160 Arg Lys Ile Ile Ser Arg Gly Ala Asn Phe Leu Thr Gln Ile Leu Leu 165 170 175 Arg Pro Gly Ala Ser Asp Leu Thr Gly Ser Phe Arg Leu Tyr Arg Lys 180 185 190 Glu Val Leu Glu Lys Leu Ile Glu Lys Cys Val Ser Lys Gly Tyr Val 195 200 205 Phe Gln Met Glu Met Ile Val Arg Ala Arg Gln Leu Asn Tyr Thr Ile 210 215 220 Gly Glu Val Pro Ile Ser Phe Val Asp Arg Val Tyr Gly Glu Ser Lys 225 230 235 240 Leu Gly Gly Asn Glu Ile Val Ser Phe Leu Lys Gly Leu Leu Thr Leu 245 250 255 Phe Ala Thr Thr 260 <210> 6 <211> 3013 <212> PRT <213> Homo sapiens <400> 6 Met Ala Ser Gln Gln Asp Ser Gly Phe Phe Glu Ile Ser Ile Lys Tyr 1 5 10 15 Leu Leu Lys Ser Trp Ser Asn Thr Ser Pro Val Gly Asn Gly Tyr Ile 20 25 30 Lys Pro Pro Val Pro Pro Ala Ser Gly Thr His Arg Glu Lys Gly Pro 35 40 45 Pro Thr Met Leu Pro Ile Asn Val Asp Pro Asp Ser Lys Pro Gly Glu 50 55 60 Tyr Val Leu Lys Ser Leu Phe Val Asn Phe Thr Thr Gln Ala Glu Arg 65 70 75 80 Lys Ile Arg Ile Ile Met Ala Glu Pro Leu Glu Lys Pro Leu Thr Lys 85 90 95 Ser Leu Gln Arg Gly Glu Asp Pro Gln Phe Asp Gln Val Ile Ser Ser 100 105 110 Met Ser Ser Leu Ser Glu Tyr Cys Leu Pro Ser Ile Leu Arg Thr Leu 115 120 125 Phe Asp Trp Tyr Lys Arg Gln Asn Gly Ile Glu Asp Glu Ser His Glu 130 135 140 Tyr Arg Pro Arg Thr Ser Asn Lys Ser Lys Ser Asp Glu Gln Gln Arg 145 150 155 160 Asp Tyr Leu Met Glu Arg Arg Asp Leu Ala Ile Asp Phe Ile Phe Ser 165 170 175 Leu Val Leu Ile Glu Val Leu Lys Gln Ile Pro Leu His Pro Val Ile 180 185 190 Asp Ser Leu Ile His Asp Val Ile Asn Leu Ala Phe Lys His Phe Lys 195 200 205 Tyr Lys Glu Gly Tyr Leu Gly Pro Asn Thr Gly Asn Met His Ile Val 210 215 220 Ala Asp Leu Tyr Ala Glu Val Ile Gly Val Leu Ala Gln Ala Lys Phe 225 230 235 240 Pro Ala Val Lys Lys Lys Lys Phe Met Ala Glu Leu Lys Glu Leu Arg His 245 250 255 Lys Glu Gln Asn Pro Tyr Val Val Gln Ser Ile Ile Ser Leu Ile Met 260 265 270 Gly Met Lys Phe Phe Arg Ile Lys Met Tyr Pro Val Glu Asp Phe Glu 275 280 285 Ala Ser Leu Gln Phe Met Gln Glu Cys Ala His Tyr Phe Leu Glu Val 290 295 300 Lys Asp Lys Asp Ile Lys His Ala Leu Ala Gly Leu Phe Val Glu Ile 305 310 315 320 Leu Val Pro Val Ala Ala Ala Val Lys Asn Glu Val Asn Val Pro Cys 325 330 335 Leu Arg Asn Phe Val Glu Ser Leu Tyr Asp Thr Thr Leu Glu Leu Ser 340 345 350 Ser Arg Lys Lys His Ser Leu Ala Leu Tyr Pro Leu Val Thr Cys Leu 355 360 365 Leu Cys Val Ser Gln Lys Gln Leu Phe Leu Asn Arg Trp His Ile Phe 370 375 380 Leu Asn Asn Cys Leu Ser Asn Leu Lys Asn Lys Asp Pro Lys Met Ala 385 390 395 400 Arg Val Ala Leu Glu Ser Leu Tyr Arg Leu Leu Trp Val Tyr Met Ile 405 410 415 Arg Ile Lys Cys Glu Ser Asn Thr Ala Thr Gln Ser Arg Leu Ile Thr 420 425 430 Ile Ile Thr Thr Leu Phe Pro Lys Gly Ser Arg Gly Val Val Pro Arg 435 440 445 Asp Met Pro Leu Asn Ile Phe Val Lys Ile Ile Gln Phe Ile Ala Gln 450 455 460 Glu Arg Leu Asp Phe Ala Met Lys Glu Ile Ile Phe Asp Phe Leu Cys 465 470 475 480 Val Gly Lys Pro Ala Lys Ala Phe Ser Leu Asn Pro Glu Arg Met Asn 485 490 495 Ile Gly Leu Arg Ala Phe Leu Val Ile Ala Asp Ser Leu Gln Gln Lys 500 505 510 Asp Gly Glu Pro Pro Met Pro Val Thr Gly Ala Val Leu Pro Ser Gly 515 520 525 Asn Thr Leu Arg Val Lys Lys Thr Tyr Leu Ser Lys Thr Leu Thr Glu 530 535 540 Glu Glu Ala Lys Met Ile Gly Met Ser Leu Tyr Tyr Ser Gln Val Arg 545 550 555 560 Lys Ala Val Asp Asn Ile Leu Arg His Leu Asp Lys Glu Val Gly Arg 565 570 575 Cys Met Met Leu Thr Asn Val Gln Met Leu Asn Lys Glu Pro Glu Asp 580 585 590 Met Ile Thr Gly Glu Arg Lys Pro Lys Ile Asp Leu Phe Arg Thr Cys 595 600 605 Val Ala Ala Ile Pro Arg Leu Leu Pro Asp Gly Met Ser Lys Leu Glu 610 615 620 Leu Ile Asp Leu Leu Ala Arg Leu Ser Ile His Met Asp Asp Glu Leu 625 630 635 640 Arg His Ile Ala Gln Asn Ser Leu Gln Gly Leu Leu Val Asp Phe Ser 645 650 655 Asp Trp Arg Glu Asp Val Leu Phe Gly Phe Thr Asn Phe Leu Leu Arg 660 665 670 Glu Val Asn Asp Met His His Thr Leu Leu Asp Ser Ser Leu Lys Leu 675 680 685 Leu Leu Gln Leu Leu Thr Gln Trp Lys Leu Val Ile Gln Thr Gln Gly 690 695 700 Lys Val Tyr Glu Gln Ala Asn Lys Ile Arg Asn Ser Glu Leu Ile Ala 705 710 715 720 Asn Gly Ser Ser His Arg Ile Gln Ser Glu Arg Gly Pro His Cys Ser 725 730 735 Val Leu His Ala Val Glu Gly Phe Ala Leu Val Leu Leu Cys Ser Phe 740 745 750 Gln Val Ala Thr Arg Lys Leu Ser Val Leu Ile Leu Lys Glu Ile Arg 755 760 765 Ala Leu Phe Ile Ala Leu Gly Gln Pro Glu Asp Asp Asp Arg Pro Met 770 775 780 Ile Asp Val Met Asp Gln Leu Ser Ser Ser Ile Leu Glu Ser Phe Ile 785 790 795 800 His Val Ala Val Ser Asp Ser Ala Thr Leu Pro Leu Thr His Asn Val 805 810 815 Asp Leu Gln Trp Leu Val Glu Trp Asn Ala Val Leu Val Asn Ser His 820 825 830 Tyr Asp Val Lys Ser Pro Ser His Val Trp Ile Phe Ala Gln Ser Val 835 840 845 Lys Asp Pro Trp Val Leu Cys Leu Phe Ser Phe Leu Arg Gln Glu Asn 850 855 860 Leu Pro Lys His Cys Pro Thr Ala Leu Ser Tyr Ala Trp Pro Tyr Ala 865 870 875 880 Phe Thr Arg Leu Gln Ser Val Met Pro Leu Val Asp Pro Asn Ser Pro 885 890 895 Ile Asn Ala Lys Lys Thr Ser Thr Ala Gly Ser Gly Asp Asn Tyr Val 900 905 910 Thr Leu Trp Arg Asn Tyr Leu Ile Leu Cys Phe Gly Val Ala Lys Pro 915 920 925 Ser Ile Met Ser Pro Gly His Leu Arg Ala Ser Thr Pro Glu Ile Met 930 935 940 Ala Thr Thr Pro Asp Gly Thr Val Ser Tyr Asp Asn Lys Ala Ile Gly 945 950 955 960 Thr Pro Ser Val Gly Val Leu Leu Lys Gln Leu Val Pro Leu Met Arg 965 970 975 Leu Glu Ser Ile Glu Ile Thr Glu Ser Leu Val Leu Gly Phe Gly Arg 980 985 990 Thr Asn Ser Leu Val Phe Arg Glu Leu Val Glu Glu Leu His Pro Leu 995 1000 1005 Met Lys Glu Ala Leu Glu Arg Arg Pro Glu Asn Lys Lys Arg Arg Glu 1010 1015 1020 Arg Arg Asp Leu Leu Arg Leu Gln Leu Leu Arg Ile Phe Glu Leu Leu 1025 1030 1035 1040 Ala Asp Ala Gly Val Ile Ser Asp Ser Thr Asn Gly Ala Leu Glu Arg 1045 1050 1055 Asp Thr Leu Ala Leu Gly Ala Leu Phe Leu Glu Tyr Val Asp Leu Thr 1060 1065 1070 Arg Met Leu Leu Glu Ala Glu Asn Asp Lys Glu Val Glu Ile Leu Lys 1075 1080 1085 Asp Ile Arg Ala His Phe Ser Ala Met Val Ala Asn Leu Ile Gln Cys 1090 1095 1100 Val Pro Val His His Arg Arg Phe Leu Phe Pro Gln Gln Ser Leu Arg 1105 1110 1115 1120 His His Leu Phe Ile Leu Phe Ser Gln Trp Ala Gly Pro Phe Ser Ile 1125 1130 1135 Met Phe Thr Pro Leu Asp Arg Tyr Ser Asp Arg Asn His Gln Ile Thr 1140 1145 1150 Arg Tyr Gln Tyr Cys Ala Leu Lys Ala Met Ser Ala Val Leu Cys Cys 1155 1160 1165 Gly Pro Val Phe Asp Asn Val Gly Leu Ser Pro Asp Gly Tyr Leu Tyr 1170 1175 1180 Lys Trp Leu Asp Asn Ile Leu Ala Cys Gln Asp Leu Arg Val His Gln 1185 1190 1195 1200 Leu Gly Cys Glu Val Val Val Leu Leu Leu Leu Glu Leu Asn Pro Asp Gln 1205 1210 1215 Ile Asn Leu Phe Asn Trp Ala Ile Asp Arg Cys Tyr Thr Gly Ser Tyr 1220 1225 1230 Gln Leu Ala Ser Gly Cys Phe Lys Ala Ile Ala Thr Val Cys Gly Ser 1235 1240 1245 Arg Asn Tyr Pro Phe Asp Ile Val Thr Leu Leu Asn Leu Val Leu Phe 1250 1255 1260 Lys Ala Ser Asp Thr Asn Arg Glu Ile Tyr Glu Ile Ser Met Gln Leu 1265 1270 1275 1280 Met Gln Ile Leu Glu Ala Lys Leu Phe Val Tyr Ser Lys Lys Val Ala 1285 1290 1295 Glu Gln Arg Pro Gly Ser Ile Leu Tyr Gly Thr His Gly Pro Leu Pro 1300 1305 1310 Pro Leu Tyr Ser Val Ser Leu Ala Leu Leu Ser Cys Glu Leu Ala Arg 1315 1320 1325 Met Tyr Pro Glu Leu Thr Leu Pro Leu Phe Ser Glu Val Ser Gln Arg 1330 1335 1340 Phe Pro Thr Thr His Pro Asn Gly Arg Gln Ile Met Leu Thr Tyr Leu 1345 1350 1355 1360 Leu Pro Trp Leu His Asn Ile Glu Leu Val Asp Ser Arg Leu Leu Leu 1365 1370 1375 Pro Gly Ser Ser Pro Ser Ser Pro Glu Asp Glu Val Lys Asp Arg Glu 1380 1385 1390 Gly Asp Val Thr Ala Ser His Gly Leu Arg Gly Asn Gly Trp Gly Ser 1395 1400 1405 Pro Glu Ala Thr Ser Leu Val Leu Asn Asn Leu Met Tyr Met Thr Ala 1410 1415 1420 Lys Tyr Gly Asp Glu Val Pro Gly Pro Glu Met Glu Asn Ala Trp Asn 1425 1430 1435 1440 Ala Leu Ala Asn Asn Glu Lys Trp Ser Asn Asn Leu Arg Ile Thr Leu 1445 1450 1455 Gln Phe Leu Ile Ser Leu Cys Gly Val Ser Ser Asp Thr Val Leu Leu 1460 1465 1470 Pro Tyr Ile Lys Lys Val Ala Ile Tyr Leu Cys Arg Asn Asn Thr Ile 1475 1480 1485 Gln Thr Met Glu Glu Leu Leu Phe Glu Leu Gln Gln Thr Glu Pro Val 1490 1495 1500 Asn Pro Ile Val Gln His Cys Asp Asn Pro Pro Phe Tyr Arg Phe Thr 1505 1510 1515 1520 Ala Ser Ser Lys Ala Ser Ala Ala Ala Ser Gly Thr Thr Ser Ser Ser Ser 1525 1530 1535 Asn Thr Val Val Ala Gly Gin Glu Asn Phe Pro Asp Ala Glu Glu Asn 1540 1545 1550 Lys Ile Leu Lys Glu Ser Asp Glu Arg Phe Ser Asn Val Ile Arg Ala 1555 1560 1565 His Thr Arg Leu Glu Ser Arg Tyr Ser Asn Ser Ser Gly Gly Ser Tyr 1570 1575 1580 Asp Glu Asp Lys Asn Asp Pro Ile Ser Pro Tyr Thr Gly Trp Leu Leu 1585 1590 1595 1600 Thr Ile Thr Glu Thr Lys Gln Pro Gln Pro Leu Pro Met Pro Cys Thr 1605 1610 1615 Gly Gly Cys Trp Ala Pro Leu Val Asp Tyr Leu Pro Glu Thr Ile Thr 1620 1625 1630 Pro Arg Gly Pro Leu His Arg Cys Asn Ile Ala Val Ile Phe Met Thr 1635 1640 1645 Glu Met Val Val Asp His Ser Val Arg Glu Asp Trp Ala Leu His Leu 1650 1655 1660 Pro Leu Leu Leu His Ala Val Phe Leu Gly Leu Asp His Tyr Arg Pro 1665 1670 1675 1680 Glu Val Phe Glu His Ser Lys Lys Leu Leu Leu His Leu Leu Ile Ala 1685 1690 1695 Leu Ser Cys Asn Ser Asn Phe His Ser Ile Ala Ser Val Leu Leu Gln 1700 1705 1710 Thr Arg Glu Met Gly Glu Ala Lys Thr Leu Thr Val Gln Pro Ala Tyr 1715 1720 1725 Gln Pro Glu Tyr Leu Tyr Thr Gly Gly Phe Asp Phe Leu Arg Glu Asp 1730 1735 1740 Gln Ser Ser Pro Val Pro Asp Ser Gly Leu Ser Ser Ser Ser Thr Ser 1745 1750 1755 1760 Ser Ser Ile Ser Leu Gly Gly Ser Ser Gly Asn Leu Pro Gln Met Thr 1765 1770 1775 Gln Glu Val Glu Asp Val Asp Thr Ala Ala Glu Thr Asp Glu Lys Ala 1780 1785 1790 Asn Lys Leu Ile Glu Phe Leu Thr Thr Arg Ala Phe Gly Pro Leu Trp 1795 1800 1805 Cys His Glu Asp Ile Thr Pro Lys Asn Gln Asn Ser Lys Ser Ala Glu 1810 1815 1820 Gln Leu Thr Asn Phe Leu Arg His Val Val Ser Val Phe Lys Asp Ser 1825 1830 1835 1840 Lys Ser Gly Phe His Leu Glu His Gln Leu Ser Glu Val Ala Leu Gln 1845 1850 1855 Thr Ala Leu Ala Ser Ser Ser Arg His Tyr Ala Gly Arg Ser Phe Gln 1860 1865 1870 Ile Phe Arg Ala Leu Lys Gln Pro Leu Ser Ala His Ala Leu Ser Asp 1875 1880 1885 Leu Leu Ser Arg Leu Val Glu Val Ile Gly Glu His Gly Asp Glu Ile 1890 1895 1900 Gln Gly Tyr Val Met Glu Ala Leu Leu Thr Leu Glu Ala Ala Val Asp 1905 1910 1915 1920 Asn Leu Ser Asp Cys Leu Lys Asn Ser Asp Leu Leu Thr Val Leu Ser 1925 1930 1935 Arg Ser Ser Ser Pro Asp Leu Ser Ser Ser Ser Lys Leu Thr Ala Ser 1940 1945 1950 Arg Lys Ser Thr Gly Gln Leu Asn Met Asn Pro Gly Thr Thr Ser Gly 1955 1960 1965 Asn Thr Ala Thr Ala Glu Arg Ser Arg His Gln Arg Ser Phe Ser Val 1970 1975 1980 Pro Lys Lys Phe Gly Val Ile Asp Arg Ser Ser Asp Pro Pro Arg Ser 1985 1990 1995 2000 Ala Thr Leu Asp Arg Ile Gln Ala Cys Thr Gln Gln Gly Leu Ser Ser 2005 2010 2015 Lys Thr Arg Ser Ser Ser Ser Leu Lys Asp Ser Leu Thr Asp Pro Ser 2020 2025 2030 His Ile Asn His Pro Thr Asn Leu Leu Ala Thr Ile Phe Trp Val Thr 2035 2040 2045 Val Ala Leu Met Glu Ser Asp Phe Glu Phe Glu Tyr Leu Met Ala Leu 2050 2055 2060 Arg Leu Leu Ser Arg Leu Leu Ala His Met Pro Leu Asp Lys Ala Glu 2065 2070 2075 2080 Asn Arg Glu Lys Leu Glu Lys Leu Gln Ala Gln Leu Lys Trp Ala Asp 2085 2090 2095 Phe Ser Gly Leu Gln Gln Leu Leu Leu Lys Gly Phe Thr Ser Leu Thr 2100 2105 2110 Thr Thr Asp Leu Thr Leu Gln Leu Phe Ser Leu Leu Thr Pro Val Ser 2115 2120 2125 Lys Ile Ser Met Val Asp Ala Ser His Ala Ile Gly Phe Pro Leu Asn 2130 2135 2140 Val Leu Cys Leu Leu Pro Gln Leu Ile Gln His Phe Glu Asn Pro Asn 2145 2150 2155 2160 Gln Phe Cys Lys Asp Ile Ala Glu Arg Ile Ala Gln Val Cys Leu Glu 2165 2170 2175 Glu Lys Asn Pro Lys Leu Ser Asn Leu Ala His Val Met Thr Leu Tyr 2180 2185 2190 Lys Thr His Ser Tyr Thr Arg Asp Cys Ala Thr Trp Val Asn Val Val 2195 2200 2205 Cys Arg Tyr Leu His Glu Ala Tyr Ala Asp Ile Thr Leu Asn Met Val 2210 2215 2220 Thr Tyr Leu Ala Glu Leu Leu Glu Lys Gly Leu Pro Ser Val Gln Gln 2225 2230 2235 2240 Pro Leu Leu Gln Val Ile Tyr Ser Leu Leu Ser Tyr Met Asp Leu Ser 2245 2250 2255 Val Val Pro Val Lys Gln Phe Asn Val Glu Val Leu Lys Thr Ile Glu 2260 2265 2270 Lys Tyr Val Gln Ser Val His Trp Arg Glu Ala Leu Asn Ile Leu Lys 2275 2280 2285 Leu Val Val Ser Arg Ser Ala Ser Leu Val Leu Pro Ser Tyr Gln His 2290 2295 2300 Ser Asp Leu Ser Lys Ile Glu Ile His Arg Val Trp Thr Ser Ala Ser 2305 2310 2315 2320 Lys Glu Leu Pro Gly Lys Thr Leu Asp Phe His Phe Asp Ile Ser Glu 2325 2330 2335 Thr Pro Ile Ile Gly Arg Arg Tyr Asp Glu Leu Gln Asn Ser Ser Gly 2340 2345 2350 Arg Asp Gly Lys Pro Arg Ala Met Ala Val Thr Arg Ser Thr Ser Ser 2355 2360 2365 Thr Ser Ser Gly Ser Asn Ser Asn Val Leu Val Pro Val Ser Trp Lys 2370 2375 2380 Arg Pro Gln Tyr Ser Gln Lys Arg Thr Lys Glu Lys Leu Val His Val 2385 2390 2395 2400 Leu Ser Leu Cys Gly Gln Glu Val Gly Leu Ser Lys Asn Pro Ser Val 2405 2410 2415 Ile Phe Ser Ser Cys Gly Asp Leu Asp Leu Leu Glu His Gln Thr Ser 2420 2425 2430 Leu Val Ser Ser Glu Asp Gly Ala Arg Glu Gln Glu Asn Met Asp Asp 2435 2440 2445 Thr Asn Ser Glu Gln Gln Phe Arg Val Phe Arg Asp Phe Asp Phe Leu 2450 2455 2460 Asp Val Glu Leu Glu Asp Gly Glu Gly Glu Ser Met Asp Asn Phe Asn 2465 2470 2475 2480 Trp Gly Val Arg Arg Arg Ser Leu Asp Ser Leu Asp Lys Cys Asp Met 2485 2490 2495 Gln Ile Leu Glu Glu Arg Gln Leu Ser Gly Ser Thr Pro Ser Leu Asn 2500 2505 2510 Lys Met His His Glu Asp Ser Asp Glu Ser Ser Glu Glu Glu Asp Leu 2515 2520 2525 Thr Ala Ser Gln Ile Leu Glu His Ser Asp Leu Ile Met Thr Leu Ser 2530 2535 2540 Pro Ser Glu Glu Thr Asn Pro Met Glu Leu Leu Thr Thr Ala Cys Asp 2545 2550 2555 2560 Ser Thr Pro Ala Glu Pro His Ser Phe Asn Thr Arg Met Ser Ser Phe 2565 2570 2575 Asp Ala Ser Leu Pro Asp Met Asn Asn Leu Gln Ile Ser Glu Gly Ser 2580 2585 2590 Lys Ala Glu Ala Val Arg Glu Glu Glu Asp Thr Thr Val His Glu Asp 2595 2600 2605 Asp Leu Ser Ser Ser Ile Asn Glu Leu Pro Ala Ala Phe Glu Cys Ser 2610 2615 2620 Asp Ser Phe Ser Leu Asp Met Thr Glu Gly Glu Glu Lys Gly Asn Arg 2625 2630 2635 2640 Ala Leu Asp Gln Phe Thr Leu Ala Ser Phe Gly Glu Gly Asp Arg Gly 2645 2650 2655 Val Ser Pro Pro Pro Ser Pro Phe Phe Ser Ala Ile Leu Ala Ala Phe 2660 2665 2670 Gln Pro Ala Ala Cys Asp Asp Ala Glu Glu Ala Trp Arg Ser His Ile 2675 2680 2685 Asn Gln Leu Met Cys Asp Ser Asp Gly Ser Cys Ala Val Tyr Thr Phe 2690 2695 2700 His Val Phe Ser Ser Leu Phe Lys Asn Ile Gln Lys Arg Phe Cys Phe 2705 2710 2715 2720 Leu Thr Cys Asp Ala Ala Ser Tyr Leu Gly Asp Asn Leu Arg Gly Ile 2725 2730 2735 Gly Ser Lys Phe Val Ser Ser Ser Gln Met Leu Thr Ser Cys Ser Glu 2740 2745 2750 Cys Pro Thr Leu Phe Val Asp Ala Glu Thr Leu Leu Ser Cys Gly Leu 2755 2760 2765 Leu Asp Lys Leu Lys Phe Ser Val Leu Glu Leu Gln Glu Tyr Leu Asp 2770 2775 2780 Thr Tyr Asn Asn Arg Lys Glu Ala Thr Leu Ser Trp Leu Ala Asn Cys 2785 2790 2795 2800 Lys Ala Thr Phe Ala Gly Gly Ser Arg Asp Gly Val Ile Thr Cys Gln 2805 2810 2815 Pro Gly Asp Ser Glu Glu Lys Gln Leu Glu Leu Cys Gln Arg Leu Tyr 2820 2825 2830 Lys Leu His Phe Gln Leu Leu Leu Leu Phe Gln Ser Tyr Cys Lys Leu 2835 2840 2845 Ile Gly Gln Val His Glu Val Ser Ser Met Pro Glu Leu Leu Asn Met 2850 2855 2860 Ser Arg Glu Leu Ser Asp Leu Lys Lys His Leu Lys Glu Ala Ser Ala 2865 2870 2875 2880 Val Ile Ala Ala Asp Pro Leu Tyr Ser Asp Gly Ala Trp Ser Glu Pro 2885 2890 2895 Thr Phe Thr Ser Thr Glu Ala Ala Ile Gln Ser Met Leu Glu Cys Leu 2900 2905 2910 Lys Asn Asn Glu Leu Gly Lys Ala Leu Arg Gln Ile Arg Glu Cys Arg 2915 2920 2925 Ser Leu Trp Pro Asn Asp Ile Phe Gly Ser Ser Ser Asp Asp Glu Val 2930 2935 2940 Gln Thr Leu Leu Asn Ile Tyr Phe Arg His Gln Thr Leu Gly Gln Thr 2945 2950 2955 2960 Gly Thr Tyr Ala Leu Val Gly Ser Asn Gln Ser Leu Thr Glu Ile Cys 2965 2970 2975 Thr Lys Leu Met Glu Leu Asn Met Glu Ile Arg Asp Met Ile Arg Arg 2980 2985 2990 Ala Gln Ser Tyr Arg Val Leu Thr Thr Phe Leu Pro Asp Ser Ser Val 2995 3000 3005 Ser Gly Thr Ser Leu 3010 <210> 7 <211> 877 <212> PRT <213> Homo sapiens <400> 7 Met Ala Arg Pro Arg Arg Ala Arg Glu Pro Leu Leu Val Ala Leu Leu 1 5 10 15 Pro Leu Ala Trp Leu Ala Gln Ala Gly Leu Ala Arg Ala Ala Gly Ser 20 25 30 Val Arg Leu Ala Gly Gly Leu Thr Leu Gly Gly Leu Phe Pro Val His 35 40 45 Ala Arg Gly Ala Ala Gly Arg Ala Cys Gly Gln Leu Lys Lys Glu Gln 50 55 60 Gly Val His Arg Leu Glu Ala Met Leu Tyr Ala Leu Asp Arg Val Asn 65 70 75 80 Ala Asp Pro Glu Leu Leu Pro Gly Val Arg Leu Gly Ala Arg Leu Leu 85 90 95 Asp Thr Cys Ser Arg Asp Thr Tyr Ala Leu Glu Gln Ala Leu Ser Phe 100 105 110 Val Gln Ala Leu Ile Arg Gly Arg Gly Asp Gly Asp Glu Val Gly Val 115 120 125 Arg Cys Pro Gly Gly Val Pro Leu Arg Pro Ala Pro Pro Glu Arg 130 135 140 Val Val Ala Val Val Gly Ala Ser Ala Ser Ser Val Ser Ile Met Val 145 150 155 160 Ala Asn Val Leu Arg Leu Phe Ala Ile Pro Gln Ile Ser Tyr Ala Ser 165 170 175 Thr Ala Pro Glu Leu Ser Asp Ser Thr Arg Tyr Asp Phe Phe Ser Arg 180 185 190 Val Val Pro Pro Asp Ser Tyr Gln Ala Gln Ala Met Val Asp Ile Val 195 200 205 Arg Ala Leu Gly Trp Asn Tyr Val Ser Thr Leu Ala Ser Glu Gly Asn 210 215 220 Tyr Gly Glu Ser Gly Val Glu Ala Phe Val Gln Ile Ser Arg Glu Ala 225 230 235 240 Gly Gly Val Cys Ile Ala Gln Ser Ile Lys Ile Pro Arg Glu Pro Lys 245 250 255 Pro Gly Glu Phe Ser Lys Val Ile Arg Arg Leu Met Glu Thr Pro Asn 260 265 270 Ala Arg Gly Ile Ile Ile Ile Phe Ala Asn Glu Asp Asp Ile Arg Arg Val 275 280 285 Leu Glu Ala Ala Arg Gln Ala Asn Leu Thr Gly His Phe Leu Trp Val 290 295 300 Gly Ser Asp Ser Trp Gly Ala Lys Thr Ser Pro Ile Leu Ser Leu Glu 305 310 315 320 Asp Val Ala Val Gly Ala Ile Thr Ile Leu Pro Lys Arg Ala Ser Ile 325 330 335 Asp Gly Phe Asp Gln Tyr Phe Met Thr Arg Ser Leu Glu Asn Asn Arg 340 345 350 Arg Asn Ile Trp Phe Ala Glu Phe Trp Glu Glu Asn Phe Asn Cys Lys 355 360 365 Leu Thr Ser Ser Gly Thr Gln Ser Asp Asp Ser Thr Arg Lys Cys Thr 370 375 380 Gly Glu Glu Arg Ile Gly Arg Asp Ser Thr Tyr Glu Gln Glu Gly Lys 385 390 395 400 Val Gln Phe Val Ile Asp Ala Val Tyr Ala Ile Ala His Ala Leu His 405 410 415 Ser Met His Gln Ala Leu Cys Pro Gly His Thr Gly Leu Cys Pro Ala 420 425 430 Met Glu Pro Thr Asp Gly Arg Met Leu Leu Gln Tyr Ile Arg Ala Val 435 440 445 Arg Phe Asn Gly Ser Ala Gly Thr Pro Val Met Phe Asn Glu Asn Gly 450 455 460 Asp Ala Pro Gly Arg Tyr Asp Ile Phe Gln Tyr Gln Ala Thr Asn Gly 465 470 475 480 Ser Ala Ser Ser Gly Gly Tyr Gln Ala Val Gly Gln Trp Ala Glu Thr 485 490 495 Leu Arg Leu Asp Val Glu Ala Leu Gln Trp Ser Gly Asp Pro His Glu 500 505 510 Val Pro Ser Ser Leu Cys Ser Leu Pro Cys Gly Pro Gly Glu Arg Lys 515 520 525 Lys Met Val Lys Gly Val Pro Cys Cys Trp His Cys Glu Ala Cys Asp 530 535 540 Gly Tyr Arg Phe Gln Val Asp Glu Phe Thr Cys Glu Ala Cys Pro Gly 545 550 555 560 Asp Met Arg Pro Thr Pro Asn His Thr Gly Cys Arg Pro Thr Pro Val 565 570 575 Val Arg Leu Ser Trp Ser Ser Pro Trp Ala Ala Pro Pro Leu Leu Leu 580 585 590 Ala Val Leu Gly Ile Val Ala Thr Thr Thr Val Val Ala Thr Phe Val 595 600 605 Arg Tyr Asn Asn Thr Pro Ile Val Arg Ala Ser Gly Arg Glu Leu Ser 610 615 620 Tyr Val Leu Leu Thr Gly Ile Phe Leu Ile Tyr Ala Ile Thr Phe Leu 625 630 635 640 Met Val Ala Glu Pro Gly Ala Ala Val Cys Ala Ala Arg Arg Leu Phe 645 650 655 Leu Gly Leu Gly Thr Thr Leu Ser Tyr Ser Ala Leu Leu Thr Lys Thr 660 665 670 Asn Arg Ile Tyr Arg Ile Phe Glu Gln Gly Lys Arg Ser Val Thr Pro 675 680 685 Pro Pro Phe Ile Ser Pro Thr Ser Gln Leu Val Ile Thr Phe Ser Leu 690 695 700 Thr Ser Leu Gln Val Val Gly Met Ile Ala Trp Leu Gly Ala Arg Pro 705 710 715 720 Pro His Ser Val Ile Asp Tyr Glu Glu Gln Arg Thr Val Asp Pro Glu 725 730 735 Gln Ala Arg Gly Val Leu Lys Cys Asp Met Ser Asp Leu Ser Leu Ile 740 745 750 Gly Cys Leu Gly Tyr Ser Leu Leu Leu Met Val Thr Cys Thr Val Tyr 755 760 765 Ala Ile Lys Ala Arg Gly Val Pro Glu Thr Phe Asn Glu Ala Lys Pro 770 775 780 Ile Gly Phe Thr Met Tyr Thr Thr Cys Ile Ile Trp Leu Ala Phe Val 785 790 795 800 Pro Ile Phe Phe Gly Thr Ala Gln Ser Ala Glu Lys Ile Tyr Ile Gln 805 810 815 Thr Thr Thr Leu Thr Val Ser Leu Ser Leu Ser Ala Ser Val Ser Leu 820 825 830 Gly Met Leu Tyr Val Pro Lys Thr Tyr Val Ile Leu Phe His Pro Glu 835 840 845 Gln Asn Val Gln Lys Arg Lys Arg Ser Leu Lys Ala Thr Ser Thr Val 850 855 860 Ala Ala Pro Lys Gly Glu Asp Ala Glu Ala His Lys 865 870 875 <210> 8 <211> 1232 <212> PRT <213> Homo sapiens <400> 8 Met Lys Glu Glu Val Lys Gly Ile Pro Val Arg Val Ala Leu Arg Cys 188 192 197 202 Arg Pro Leu Val Pro Lys Glu Ile Ser Glu Gly Cys Gln Met Cys Leu 207 212 217 Ser Phe Val Pro Gly Glu Pro Gln Val Val Val Gly Thr Asp Lys Ser 222 227 232 Phe Thr Tyr Asp Phe Val Phe Asp Pro Ser Thr Glu Gln Glu Glu Val 237 242 247 Phe Asn Thr Ala Val Ala Pro Leu Ile Lys Gly Val Phe Lys Gly Tyr 252 257 262 267 Asn Ala Thr Val Leu Ala Tyr Gly Gln Thr Gly Ser Gly Lys Thr Tyr 272 277 282 Ser Met Gly Gly Ala Tyr Thr Ala Glu Gln Glu Asn Glu Pro Thr Val 287 292 297 Gly Val Ile Pro Arg Val Ile Gln Leu Leu Phe Lys Glu Ile Asp Lys 302 307 312 Lys Ser Asp Phe Glu Phe Thr Leu Lys Val Ser Tyr Leu Glu Ile Tyr 317 322 327 Asn Glu Glu Ile Leu Asp Leu Leu Cys Pro Ser Arg Glu Lys Ala Gln 332 337 342 347 Ile Asn Ile Arg Glu Asp Pro Lys Glu Gly Ile Lys Ile Val Gly Leu 352 357 362 Thr Glu Lys Thr Val Leu Val Ala Leu Asp Thr Val Ser Cys Leu Glu 367 372 377 Gln Gly Asn Asn Ser Arg Thr Val Ala Ser Thr Ala Met Asn Ser Gln 382 387 392 Ser Ser Arg Ser His Ala Ile Phe Thr Ile Ser Leu Glu Gln Arg Lys 397 402 407 Lys Ser Asp Lys Asn Ser Ser Phe Arg Ser Lys Leu His Leu Val Asp 412 417 422 427 Leu Ala Gly Ser Glu Arg Gln Lys Lys Thr Lys Ala Glu Gly Asp Arg 432 437 442 Leu Lys Glu Gly Ile Asn Ile Asn Arg Gly Leu Leu Cys Leu Gly Asn 447 452 457 Val Ile Ser Ala Leu Gly Asp Asp Lys Lys Gly Gly Phe Val Pro Tyr 462 467 472 Arg Asp Ser Lys Leu Thr Arg Leu Leu Gln Asp Ser Leu Gly Gly Asn 477 482 487 Ser His Thr Leu Met Ile Ala Cys Val Ser Pro Ala Asp Ser Asn Leu 492 497 502 507 Glu Glu Thr Leu Asn Thr Leu Arg Tyr Ala Asp Arg Ala Arg Lys Ile 512 517 522 Lys Asn Lys Pro Ile Val Asn Ile Asp Pro Gln Thr Ala Glu Leu Asn 527 532 537 His Leu Lys Gln Gln Val Gln Gln Leu Gln Val Leu Leu Leu Gln Ala 542 547 552 His Gly Gly Thr Leu Pro Gly Ser Ile Thr Val Glu Pro Ser Glu Asn 557 562 567 Leu Gln Ser Leu Met Glu Lys Asn Gln Ser Leu Val Glu Glu Asn Glu 572 577 582 587 Lys Leu Ser Arg Gly Leu Ser Glu Ala Ala Gly Gln Thr Ala Gln Met 592 597 602 Leu Glu Arg Ile Ile Leu Thr Glu Gln Ala Asn Glu Lys Met Asn Ala 607 612 617 Lys Leu Glu Glu Leu Arg Gln His Ala Ala Cys Lys Leu Asp Leu Gln 622 627 632 Lys Leu Val Glu Thr Leu Glu Asp Gin Glu Leu Lys Glu Asn Val Glu 637 642 647 Ile Ile Cys Asn Leu Gln Gln Leu Ile Thr Gln Leu Ser Asp Glu Thr 652 657 662 667 Val Ala Cys Met Ala Ala Ala Ile Asp Thr Ala Val Glu Gln Glu Ala 672 677 682 Gln Val Glu Thr Ser Pro Glu Thr Ser Arg Ser Ser Asp Ala Phe Thr 687 692 697 Thr Gln His Ala Leu Arg Gln Ala Gln Met Ser Lys Glu Leu Val Glu 702 707 712 Leu Asn Lys Ala Leu Ala Leu Lys Glu Ala Leu Ala Arg Lys Met Thr 717 722 727 Gln Asn Asp Ser Gln Leu Gln Pro Ile Gln Tyr Gln Tyr Gln Asp Asn 732 737 742 747 Ile Lys Glu Leu Glu Leu Glu Val Ile Asn Leu Gln Lys Glu Lys Glu 752 757 762 Glu Leu Val Leu Glu Leu Gln Thr Ala Lys Lys Asp Ala Asn Gln Ala 767 772 777 Lys Leu Ser Glu Arg Arg Arg Lys Arg Leu Gln Glu Leu Glu Gly Gln 782 787 792 Ile Ala Asp Leu Lys Lys Lys Leu Asn Glu Gln Ser Lys Leu Leu Lys 797 802 807 Leu Lys Glu Ser Thr Glu Arg Thr Val Ser Lys Leu Asn Gln Glu Ile 812 817 822 827 Arg Met Met Lys Asn Gln Arg Val Gln Leu Met Arg Gln Met Lys Glu 832 837 842 Asp Ala Glu Lys Phe Arg Gln Trp Lys Gln Lys Lys Asp Lys Glu Val 847 852 857 Ile Gln Leu Lys Glu Arg Asp Arg Lys Arg Gln Tyr Glu Leu Leu Lys 862 867 872 Leu Glu Arg Asn Phe Gln Lys Gln Ser Asn Val Leu Arg Arg Lys Thr 877 882 887 Glu Glu Ala Ala Ala Ala Asn Lys Arg Leu Lys Asp Ala Leu Gln Lys 892 897 902 907 Gln Arg Glu Val Ala Asp Lys Arg Lys Glu Thr Gln Ser Arg Gly Met 912 917 922 Glu Gly Thr Ala Ala Arg Val Lys Asn Trp Leu Gly Asn Glu Ile Glu 927 932 937 Val Met Val Ser Thr Glu Glu Ala Lys Arg His Leu Asn Asp Leu Leu 942 947 952 Glu Asp Arg Lys Ile Leu Ala Gln Asp Val Ala Gln Leu Lys Glu Lys 957 962 967 Lys Glu Ser Gly Glu Asn Pro Pro Lys Leu Arg Arg Arg Thr Phe 972 977 982 987 Ser Leu Thr Glu Val Arg Gly Gin Val Ser Glu Ser Glu Asp Ser Ile 992 997 1002 Thr Lys Gln Ile Glu Ser Leu Glu Thr Glu Met Glu Phe Arg Ser Ala 1007 1012 1017 Gln Ile Ala Asp Leu Gln Gln Lys Leu Leu Asp Ala Glu Ser Glu Asp 1022 1027 1032 Arg Pro Lys Gln Arg Trp Glu Asn Ile Ala Thr Ile Leu Glu Ala Lys 1037 1042 1047 Cys Ala Leu Lys Tyr Leu Ile Gly Glu Leu Val Ser Ser Lys Ile Gln 1052 1057 1062 1067 Val Ser Lys Leu Glu Ser Ser Leu Lys Gln Ser Lys Thr Ser Cys Ala 1072 1077 1082 Asp Met Gln Lys Met Leu Phe Glu Glu Arg Asn His Phe Ala Glu Ile 1087 1092 1097 Glu Thr Glu Leu Gln Ala Glu Leu Val Arg Met Glu Gln Gln His Gln 1102 1107 1112 Glu Lys Val Leu Tyr Leu Leu Ser Gln Leu Gln Gln Ser Gln Met Ala 1117 1122 1127 Glu Lys Gln Leu Glu Glu Ser Val Ser Glu Lys Glu Gln Gln Leu Leu 1132 1137 1142 1147 Ser Thr Leu Lys Cys Gln Asp Glu Glu Leu Glu Lys Met Arg Glu Val 1152 1157 1162 Cys Glu Gln Asn Gln Gln Leu Leu Arg Glu Asn Glu Ile Ile Lys Gln 1167 1172 1177 Lys Leu Thr Leu Leu Gln Val Ala Ser Arg Gln Lys His Leu Pro Lys 1182 1187 1192 Asp Thr Leu Leu Ser Pro Asp Ser Ser Phe Glu Tyr Val Pro Pro Lys 1197 1202 1207 Pro Lys Pro Ser Arg Val Lys Glu Lys Phe Leu Glu Gln Ser Met Asp 1212 1217 1222 1227 Ile Glu Asp Leu Lys Tyr Cys Ser Glu His Ser Val Asn Glu His Glu 1232 1237 1242 Asp Gly Asp Gly Asp Asp Asp Glu Gly Asp Asp Glu Glu Trp Lys Pro 1247 1252 1257 Thr Lys Leu Val Lys Val Ser Arg Lys Asn Ile Gln Gly Cys Ser Cys 1262 1267 1272 Lys Gly Trp Cys Gly Asn Lys Gln Cys Gly Cys Arg Lys Gln Lys Ser 1277 1282 1287 Asp Cys Gly Val Asp Cys Cys Cys Asp Pro Thr Lys Cys Arg Asn Arg 1292 1297 1302 1307 Gln Gln Gly Lys Asp Ser Leu Gly Thr Val Glu Arg Thr Gln Asp Ser 1312 1317 1322 Glu Gly Ser Phe Lys Leu Glu Asp Pro Thr Glu Val Thr Pro Gly Leu 1327 1332 1337 Ser Phe Phe Asn Pro Val Cys Ala Thr Pro Asn Ser Lys Ile Leu Lys 1342 1347 1352 Glu Met Cys Asp Val Glu Gln Val Leu Ser Lys Lys Thr Pro Pro Ala 1357 1362 1367 Pro Ser Pro Phe Asp Leu Pro Glu Leu Lys His Val Ala Thr Glu Tyr 1372 1377 1382 1387 Gln Glu Asn Lys Ala Pro Gly Lys Lys Lys Lys Arg Ala Leu Ala Ser 1392 1397 1402 Asn Thr Ser Phe Phe Ser Gly Cys Ser Pro Ile Glu Glu Glu Ala His 1407 1412 1417 <210> 9 <211> 616 <212> PRT <213> Homo sapiens <400> 9 Met Met Glu Gly Ser Arg Gln Thr Arg Val Ser Arg Pro Tyr Lys Ile 1 5 10 15 Ser Glu Ser Ser Lys Val Tyr Arg Trp Ala Asp His Ser Ser Thr Val 20 25 30 Leu Gln Arg Leu Asn Glu Gln Arg Leu Arg Gly Leu Phe Cys Asp Val 35 40 45 Val Leu Val Ala Asp Glu Gln Arg Val Pro Ala His Arg Asn Leu Leu 50 55 60 Ala Val Cys Ser Asp Tyr Phe Asn Ser Met Phe Thr Ile Gly Met Arg 65 70 75 80 Glu Ala Phe Gln Lys Glu Val Glu Leu Ile Gly Ala Ser Tyr Ile Gly 85 90 95 Leu Lys Ala Val Val Asp Phe Leu Tyr Gly Gly Glu Leu Val Leu Asp 100 105 110 Gly Gly Asn Ile Asp Tyr Val Leu Glu Thr Ala His Leu Leu Gln Ile 115 120 125 Trp Thr Val Val Asp Phe Cys Cys Glu Tyr Leu Glu Gln Glu Val Ser 130 135 140 Glu Asp Asn Tyr Leu Tyr Leu Gln Glu Leu Ala Ser Ile Tyr Ser Leu 145 150 155 160 Lys Arg Leu Asp Ala Phe Ile Asp Gly Phe Ile Leu Asn His Phe Gly 165 170 175 Thr Leu Ser Phe Thr Pro Asp Phe Leu Gln Asn Val Ser Met Gln Lys 180 185 190 Leu Cys Val Tyr Leu Ser Ser Ser Glu Val Gln Arg Glu Cys Glu His 195 200 205 Asp Leu Leu Gln Ala Ala Leu Gln Trp Leu Thr Gln Gln Pro Glu Arg 210 215 220 Glu Ala His Ala Arg Gln Val Leu Glu Asn Ile His Phe Pro Leu Ile 225 230 235 240 Pro Lys Asn Asp Leu Leu His Arg Val Lys Pro Ala Val Cys Ser Leu 245 250 255 Leu Pro Lys Glu Ala Asn Cys Glu Gly Phe Ile Glu Glu Ala Val Arg 260 265 270 Tyr His Asn Asn Leu Ala Ala Gln Pro Val Met Gln Thr Lys Arg Thr 275 280 285 Ala Leu Arg Thr Asn Gln Glu Arg Leu Leu Phe Val Gly Gly Glu Val 290 295 300 Ser Glu Arg Cys Leu Glu Leu Ser Asp Asp Thr Cys Tyr Leu Asp Ala 305 310 315 320 Lys Ser Glu Gln Trp Val Lys Glu Thr Pro Leu Pro Ala Arg Arg Ser 325 330 335 His His Cys Val Ala Val Leu Gly Gly Phe Ile Phe Ile Ala Gly Gly 340 345 350 Ser Phe Ser Arg Asp Asn Gly Gly Asp Ala Ala Ser Asn Leu Leu Tyr 355 360 365 Arg Tyr Asp Pro Arg Cys Lys Gln Trp Ile Lys Val Ala Ser Met Asn 370 375 380 Gln Arg Arg Val Asp Phe Tyr Leu Ala Ser Ile Glu Asp Met Leu Val 385 390 395 400 Ala Ile Gly Gly Arg Asn Glu Asn Gly Ala Leu Ser Ser Val Glu Thr 405 410 415 Tyr Ser Pro Lys Thr Asp Ser Trp Ser Tyr Val Ala Gly Leu Pro Arg 420 425 430 Phe Thr Tyr Gly His Ala Gly Thr Ile Tyr Lys Asp Phe Val Tyr Ile 435 440 445 Ser Gly Gly His Asp Tyr Gln Ile Gly Pro Tyr Arg Lys Asn Leu Leu 450 455 460 Cys Tyr Asp His Arg Thr Asp Val Trp Glu Glu Arg Arg Pro Met Thr 465 470 475 480 Thr Ala Arg Gly Trp His Ser Met Cys Ser Leu Gly Asp Ser Ile Tyr 485 490 495 Ser Ile Gly Gly Ser Asp Asp Asn Ile Glu Ser Met Glu Arg Phe Asp 500 505 510 Val Leu Gly Val Glu Ala Tyr Ser Pro Gln Cys Asn Gln Trp Thr Arg 515 520 525 Val Ala Pro Leu Leu His Ala Asn Ser Glu Ser Gly Val Ala Val Trp 530 535 540 Glu Gly Arg Ile Tyr Ile Leu Gly Gly Tyr Ser Trp Glu Asn Thr Ala 545 550 555 560 Phe Ser Lys Thr Val Gln Val Tyr Asp Arg Glu Ala Asp Lys Trp Ser 565 570 575 Arg Gly Val Asp Leu Pro Lys Ala Ile Ala Gly Gly Ser Ala Cys Val 580 585 590 Cys Ala Leu Glu Pro Arg Pro Glu Asp Lys Lys Lys Lys Gly Lys Gly 595 600 605 Lys Arg His Gln Asp Arg Gly Gln 610 615 <210> 10 <211> 1766 <212> PRT <213> Homo sapiens <400> 10 Met Gly Gly Lys Asn Lys Gln Arg Thr Lys Gly Asn Leu Arg Pro Ser 1 5 10 15 Asn Ser Gly Arg Ala Ala Glu Leu Leu Ala Lys Glu Gln Gly Thr Val 20 25 30 Pro Gly Phe Ile Gly Phe Gly Thr Ser Gln Ser Asp Leu Gly Tyr Val 35 40 45 Pro Ala Ile Gln Gly Ala Glu Glu Ile Asp Ser Leu Val Asp Ser Asp 50 55 60 Phe Arg Met Val Leu Arg Lys Leu Ser Lys Lys Asp Val Thr Thr Lys 65 70 75 80 Leu Lys Ala Met Gin Glu Phe Gly Thr Met Cys Thr Glu Arg Asp Thr 85 90 95 Glu Thr Val Lys Gly Val Leu Pro Tyr Trp Pro Arg Ile Phe Cys Lys 100 105 110 Ile Ser Leu Asp His Asp Arg Arg Val Arg Glu Ala Thr Gln Gln Ala 115 120 125 Phe Glu Lys Leu Ile Leu Lys Val Lys Lys Gln Leu Ala Pro Tyr Leu 130 135 140 Lys Ser Leu Met Gly Tyr Trp Leu Met Ala Gln Cys Asp Thr Tyr Thr 145 150 155 160 Pro Ala Ala Phe Ala Ala Lys Asp Ala Phe Glu Ala Ala Phe Pro Pro 165 170 175 Ser Lys Gln Pro Glu Ala Ile Ala Phe Cys Lys Asp Glu Ile Thr Ser 180 185 190 Val Leu Gln Asp His Leu Ile Lys Glu Thr Pro Asp Thr Leu Ser Asp 195 200 205 Pro Gln Thr Val Pro Glu Glu Glu Arg Glu Ala Lys Phe Tyr Arg Val 210 215 220 Val Thr Cys Ser Leu Leu Ala Leu Lys Arg Leu Leu Cys Leu Leu Pro 225 230 235 240 Asp Asn Glu Leu Asp Ser Leu Glu Glu Lys Phe Lys Ser Leu Leu Ser 245 250 255 Gln Asn Lys Phe Trp Lys Tyr Gly Lys His Ser Val Pro Gln Ile Arg 260 265 270 Ser Ala Tyr Phe Glu Leu Val Ser Ala Leu Cys Gln Arg Ile Pro Gln 275 280 285 Leu Met Lys Glu Glu Ala Ser Lys Val Ser Pro Ser Val Leu Leu Ser 290 295 300 Ile Asp Asp Ser Asp Pro Ile Val Cys Pro Ala Leu Trp Glu Ala Val 305 310 315 320 Leu Tyr Thr Leu Thr Thr Ile Glu Asp Cys Trp Leu His Val Asn Ala 325 330 335 Lys Lys Ser Val Phe Pro Lys Leu Ser Thr Val Ile Arg Glu Gly Gly 340 345 350 Arg Gly Leu Ala Thr Val Ile Tyr Pro Tyr Leu Leu Pro Phe Ile Ser 355 360 365 Lys Leu Pro Gln Ser Ile Thr Asn Pro Lys Leu Asp Phe Phe Lys Asn 370 375 380 Phe Leu Thr Ser Leu Val Ala Gly Leu Ser Thr Glu Arg Thr Lys Thr 385 390 395 400 Ser Ser Leu Glu Ser Ser Ala Val Ile Ser Ala Phe Phe Glu Cys Leu 405 410 415 Arg Phe Ile Met Gln Gln Asn Leu Gly Glu Glu Glu Ile Glu Gln Met 420 425 430 Leu Val Asn Asp Gln Leu Ile Pro Phe Ile Asp Ala Val Leu Lys Asp 435 440 445 Pro Gly Leu Gln His Gly Gln Leu Phe Asn His Leu Ala Glu Thr Leu 450 455 460 Ser Ser Trp Glu Ala Lys Ala Asp Thr Glu Lys Asp Glu Lys Thr Ala 465 470 475 480 His Asn Leu Glu Asn Val Leu Ile His Phe Trp Glu Arg Leu Ser Glu 485 490 495 Ile Cys Val Ala Lys Ile Ser Glu Pro Glu Ala Asp Val Glu Ser Val 500 505 510 Leu Gly Val Ser Asn Leu Leu Gln Val Leu Gln Lys Pro Lys Ser Ser 515 520 525 Leu Lys Ser Ser Lys Lys Lys Asn Gly Lys Val Arg Phe Ala Asp Glu 530 535 540 Ile Leu Glu Ser Asn Lys Glu Asn Glu Lys Cys Val Ser Ser Glu Gly 545 550 555 560 Glu Lys Ile Glu Gly Trp Glu Leu Thr Thr Glu Pro Ser Leu Thr His 565 570 575 Asn Ser Ser Gly Leu Leu Ser Pro Leu Arg Lys Lys Pro Leu Glu Asp 580 585 590 Leu Val Cys Lys Leu Ala Asp Ile Ser Ile Asn Tyr Val Asn Glu Arg 595 600 605 Lys Ser Glu Gln His Leu Arg Phe Leu Ser Thr Leu Leu Asp Ser Phe 610 615 620 Ser Ser Ser Arg Val Phe Lys Met Leu Leu Gly Asp Glu Lys Gln Ser 625 630 635 640 Ile Val Gln Ala Lys Pro Leu Glu Ile Ala Lys Leu Val Gln Lys Asn 645 650 655 Pro Ala Val Gln Phe Leu Tyr Gln Lys Leu Ile Gly Trp Leu Asn Glu 660 665 670 Asp Gln Arg Lys Asp Phe Gly Phe Leu Val Asp Ile Leu Tyr Ser Ala 675 680 685 Leu Arg Cys Cys Asp Asn Asp Met Glu Arg Lys Lys Val Leu Asp Asp 690 695 700 Leu Thr Lys Val Asp Leu Lys Trp Asn Ser Leu Leu Lys Ile Ile Glu 705 710 715 720 Lys Ala Cys Pro Ser Ser Asp Lys His Ala Leu Val Thr Pro Trp Leu 725 730 735 Lys Gly Asp Ile Leu Gly Glu Lys Leu Val Asn Leu Ala Asp Cys Leu 740 745 750 Cys Asn Glu Asp Leu Glu Ser Arg Val Ser Ser Glu Ser His Phe Ser 755 760 765 Glu Arg Trp Thr Leu Leu Ser Leu Val Leu Ser Gln His Val Lys Asn 770 775 780 Asp Tyr Leu Ile Gly Asp Val Tyr Val Glu Arg Ile Ile Val Arg Leu 785 790 795 800 His Glu Thr Leu Phe Lys Thr Lys Lys Leu Ser Glu Ala Glu Ser Ser 805 810 815 Asp Ser Ser Val Ser Phe Ile Cys Asp Val Ala Tyr Asn Tyr Phe Ser 820 825 830 Ser Ala Lys Gly Cys Leu Leu Met Pro Ser Ser Glu Asp Leu Leu Leu 835 840 845 Thr Leu Phe Gln Leu Cys Ala Gln Ser Lys Glu Lys Thr His Leu Pro 850 855 860 Asp Phe Leu Ile Cys Lys Leu Lys Asn Thr Trp Leu Ser Gly Val Asn 865 870 875 880 Leu Leu Val His Gln Thr Asp Ser Ser Tyr Lys Glu Ser Thr Phe Leu 885 890 895 His Leu Ser Ala Leu Trp Leu Lys Asn Gln Val Gln Ala Ser Ser Leu 900 905 910 Asp Ile Asn Ser Leu Gln Val Leu Leu Ser Ala Val Asp Asp Leu Leu 915 920 925 Asn Thr Leu Leu Glu Ser Glu Asp Ser Tyr Leu Met Gly Val Tyr Ile 930 935 940 Gly Ser Val Met Pro Asn Asp Ser Glu Trp Glu Lys Met Arg Gln Ser 945 950 955 960 Leu Pro Met Gln Trp Leu His Arg Pro Leu Leu Glu Gly Arg Leu Ser 965 970 975 Leu Asn Tyr Glu Cys Phe Lys Thr Asp Phe Lys Glu Gln Asp Ile Lys 980 985 990 Thr Leu Pro Ser His Leu Cys Thr Ser Ala Leu Leu Ser Lys Met Val 995 1000 1005 Leu Ile Ala Leu Arg Lys Glu Thr Val Leu Glu Asn Asn Glu Leu Glu 1010 1015 1020 Lys Ile Ile Ala Glu Leu Leu Tyr Ser Leu Gln Trp Cys Glu Glu Leu 1025 1030 1035 1040 Asp Asn Pro Pro Ile Phe Leu Ile Gly Phe Cys Glu Ile Leu Gln Lys 1045 1050 1055 Met Asn Ile Thr Tyr Asp Asn Leu Arg Val Leu Gly Asn Thr Ser Gly 1060 1065 1070 Leu Leu Gln Leu Leu Phe Asn Arg Ser Arg Glu His Gly Thr Leu Trp 1075 1080 1085 Ser Leu Ile Ile Ala Lys Leu Ile Leu Ser Arg Ser Ile Ser Ser Asp 1090 1095 1100 Glu Val Lys Pro His Tyr Lys Arg Lys Glu Ser Phe Phe Pro Leu Thr 1105 1110 1115 1120 Glu Gly Asn Leu His Thr Ile Gln Ser Leu Cys Pro Phe Leu Ser Lys 1125 1130 1135 Glu Glu Lys Lys Glu Phe Ser Ala Gln Cys Ile Pro Ala Leu Leu Gly 1140 1145 1150 Trp Thr Lys Lys Asp Leu Cys Ser Thr Asn Gly Gly Phe Gly His Leu 1155 1160 1165 Ala Ile Phe Asn Ser Cys Leu Gln Thr Lys Ser Ile Asp Asp Gly Glu 1170 1175 1180 Leu Leu His Gly Ile Leu Lys Ile Ile Ile Ser Trp Lys Lys Glu His 1185 1190 1195 1200 Glu Asp Ile Phe Leu Phe Ser Cys Asn Leu Ser Glu Ala Ser Pro Glu 1205 1210 1215 Val Leu Gly Val Asn Ile Glu Ile Ile Arg Phe Leu Ser Leu Phe Leu 1220 1225 1230 Lys Tyr Cys Ser Ser Pro Leu Ala Glu Ser Glu Trp Asp Phe Ile Met 1235 1240 1245 Cys Ser Met Leu Ala Trp Leu Glu Thr Thr Ser Glu Asn Gln Ala Leu 1250 1255 1260 Tyr Ser Ile Pro Leu Val Gln Leu Phe Ala Cys Val Ser Cys Asp Leu 1265 1270 1275 1280 Ala Cys Asp Leu Ser Ala Phe Phe Asp Ser Thr Thr Leu Asp Thr Ile 1285 1290 1295 Gly Asn Leu Pro Val Asn Leu Ile Ser Glu Trp Lys Glu Phe Phe Ser 1300 1305 1310 Gln Gly Ile His Ser Leu Leu Leu Pro Ile Leu Val Thr Val Thr Gly 1315 1320 1325 Glu Asn Lys Asp Val Ser Glu Thr Ser Phe Gln Asn Ala Met Leu Lys 1330 1335 1340 Pro Met Cys Glu Thr Leu Thr Tyr Ile Ser Lys Glu Gln Leu Leu Ser 1345 1350 1355 1360 His Lys Leu Pro Ala Arg Leu Val Ala Asp Gln Lys Thr Asn Leu Pro 1365 1370 1375 Glu Tyr Leu Gln Thr Leu Leu Asn Thr Leu Ala Pro Leu Leu Leu Phe 1380 1385 1390 Arg Ala Arg Pro Val Gln Ile Ala Val Tyr His Met Leu Tyr Lys Leu 1395 1400 1405 Met Pro Glu Leu Pro Gln Tyr Asp Gln Asp Asn Leu Lys Ser Tyr Gly 1410 1415 1420 Asp Glu Glu Glu Glu Pro Ala Leu Ser Pro Pro Ala Ala Leu Met Ser 1425 1430 1435 1440 Leu Leu Ser Ile Gln Glu Asp Leu Leu Glu Asn Val Leu Gly Cys Ile 1445 1450 1455 Pro Val Gly Gln Ile Val Thr Ile Lys Pro Leu Ser Glu Asp Phe Cys 1460 1465 1470 Tyr Val Leu Gly Tyr Leu Leu Thr Trp Lys Leu Ile Leu Thr Phe Phe 1475 1480 1485 Lys Ala Ala Ser Ser Gln Leu Arg Ala Leu Tyr Ser Met Tyr Leu Arg 1490 1495 1500 Lys Thr Lys Ser Leu Asn Lys Leu Leu Tyr His Leu Phe Arg Leu Met 1505 1510 1515 1520 Pro Glu Asn Pro Thr Tyr Ala Glu Thr Ala Val Glu Val Pro Asn Lys 1525 1530 1535 Asp Pro Lys Thr Phe Phe Thr Glu Glu Leu Gln Leu Ser Ile Arg Glu 1540 1545 1550 Thr Thr Met Leu Pro Tyr His Ile Pro His Leu Ala Cys Ser Val Tyr 1555 1560 1565 His Met Thr Leu Lys Asp Leu Pro Ala Met Val Arg Leu Trp Trp Asn 1570 1575 1580 Ser Ser Glu Lys Arg Val Phe Asn Ile Val Asp Arg Phe Thr Ser Lys 1585 1590 1595 1600 Tyr Val Ser Ser Val Leu Ser Phe Gln Glu Ile Ser Ser Val Gln Thr 1605 1610 1615 Ser Thr Gln Leu Phe Asn Gly Met Thr Val Lys Ala Arg Ala Thr Thr 1620 1625 1630 Arg Glu Val Met Ala Thr Tyr Thr Ile Glu Asp Ile Val Ile Glu Leu 1635 1640 1645 Ile Ile Gln Leu Pro Ser Asn Tyr Pro Leu Gly Ser Ile Ile Val Glu 1650 1655 1660 Ser Gly Lys Arg Val Gly Val Ala Val Gln Gln Trp Arg Asn Trp Met 1665 1670 1675 1680 Leu Gln Leu Ser Thr Tyr Leu Thr His Gln Asn Gly Ser Ile Met Glu 1685 1690 1695 Gly Leu Ala Leu Trp Lys Asn Asn Val Asp Lys Arg Phe Glu Gly Val 1700 1705 1710 Glu Asp Cys Met Ile Cys Phe Ser Val Ile His Gly Phe Asn Tyr Ser 1715 1720 1725 Leu Pro Lys Lys Ala Cys Arg Thr Cys Lys Lys Lys Phe His Ser Ala 1730 1735 1740 Cys Leu Tyr Lys Trp Phe Thr Ser Ser Asn Lys Ser Thr Cys Pro Leu 1745 1750 1755 1760 Cys Arg Glu Thr Phe Phe 1765 <210> 11 <211> 1374 <212> PRT <213> Homo sapiens <400> 11 Met Ser Thr Glu Ala Asp Glu Gly Ile Thr Phe Ser Val Pro Phe 1 5 10 15 Ala Pro Ser Gly Phe Cys Thr Ile Pro Glu Gly Gly Ile Cys Arg Arg 20 25 30 Gly Gly Ala Ala Ala Val Gly Glu Gly Glu Glu His Gln Leu Pro Pro 35 40 45 Pro Pro Pro Gly Ser Phe Trp Asn Val Glu Ser Ala Ala Ala Pro Gly 50 55 60 Ile Gly Cys Pro Ala Ala Thr Ser Ser Ser Ser Ala Thr Arg Gly Arg 65 70 75 80 Gly Ser Ser Val Gly Gly Gly Ser Arg Arg Thr Thr Val Ala Tyr Val 85 90 95 Ile Asn Glu Ala Ser Gln Gly Gln Leu Val Val Ala Glu Ser Glu Ala 100 105 110 Leu Gln Ser Leu Arg Glu Ala Cys Glu Thr Val Gly Ala Thr Leu Glu 115 120 125 Thr Leu His Phe Gly Lys Leu Asp Phe Gly Glu Thr Thr Val Leu Asp 130 135 140 Arg Phe Tyr Asn Ala Asp Ile Ala Val Val Glu Met Ser Asp Ala Phe 145 150 155 160 Arg Gln Pro Ser Leu Phe Tyr His Leu Gly Val Arg Glu Ser Phe Ser 165 170 175 Met Ala Asn Asn Ile Ile Leu Tyr Cys Asp Thr Asn Ser Asp Ser Leu 180 185 190 Gln Ser Leu Lys Glu Ile Ile Cys Gln Lys Asn Thr Met Cys Thr Gly 195 200 205 Asn Tyr Thr Phe Val Pro Tyr Met Ile Thr Pro His Asn Lys Val Tyr 210 215 220 Cys Cys Asp Ser Ser Phe Met Lys Gly Leu Thr Glu Leu Met Gln Pro 225 230 235 240 Asn Phe Glu Leu Leu Leu Gly Pro Ile Cys Leu Pro Leu Val Asp Arg 245 250 255 Phe Ile Gln Leu Leu Lys Val Ala Gln Ala Ser Ser Ser Gln Tyr Phe 260 265 270 Arg Glu Ser Ile Leu Asn Asp Ile Arg Lys Ala Arg Asn Leu Tyr Thr 275 280 285 Gly Lys Glu Leu Ala Ala Glu Leu Ala Arg Ile Arg Gln Arg Val Asp 290 295 300 Asn Ile Glu Val Leu Thr Ala Asp Ile Val Ile Asn Leu Leu Leu Ser 305 310 315 320 Tyr Arg Asp Ile Gln Asp Tyr Asp Ser Ile Val Lys Leu Val Glu Thr 325 330 335 Leu Glu Lys Leu Pro Thr Phe Asp Leu Ala Ser His His His Val Lys 340 345 350 Phe His Tyr Ala Phe Ala Leu Asn Arg Arg Asn Leu Pro Gly Asp Arg 355 360 365 Ala Lys Ala Leu Asp Ile Met Ile Pro Met Val Gln Ser Glu Gly Gln 370 375 380 Val Ala Ser Asp Met Tyr Cys Leu Val Gly Arg Ile Tyr Lys Asp Met 385 390 395 400 Phe Leu Asp Ser Asn Phe Thr Asp Thr Glu Ser Arg Asp His Gly Ala 405 410 415 Ser Trp Phe Lys Lys Ala Phe Glu Ser Glu Pro Thr Leu Gln Ser Gly 420 425 430 Ile Asn Tyr Ala Val Leu Leu Leu Ala Ala Gly His Gln Phe Glu Ser 435 440 445 Ser Phe Glu Leu Arg Lys Val Gly Val Lys Leu Ser Ser Leu Leu Gly 450 455 460 Lys Lys Gly Asn Leu Glu Lys Leu Gln Ser Tyr Trp Glu Val Gly Phe 465 470 475 480 Phe Leu Gly Ala Ser Val Leu Ala Asn Asp His Met Arg Val Ile Gln 485 490 495 Ala Ser Glu Lys Leu Phe Lys Leu Lys Thr Pro Ala Trp Tyr Leu Lys 500 505 510 Ser Ile Val Glu Thr Ile Leu Ile Tyr Lys His Phe Val Lys Leu Thr 515 520 525 Thr Glu Gln Pro Val Ala Lys Gln Glu Leu Val Asp Phe Trp Met Asp 530 535 540 Phe Leu Val Glu Ala Thr Lys Thr Asp Val Thr Val Val Arg Phe Pro 545 550 555 560 Val Leu Ile Leu Glu Pro Thr Lys Ile Tyr Gln Pro Ser Tyr Leu Ser 565 570 575 Ile Asn Asn Glu Val Glu Glu Lys Thr Ile Ser Ile Trp His Val Leu 580 585 590 Pro Asp Asp Lys Lys Gly Ile His Glu Trp Asn Phe Ser Ala Ser Ser 595 600 605 Val Arg Gly Val Ser Ile Ser Lys Phe Glu Glu Arg Cys Cys Phe Leu 610 615 620 Tyr Val Leu His Asn Ser Asp Asp Phe Gln Ile Tyr Phe Cys Thr Glu 625 630 635 640 Leu His Cys Lys Lys Phe Phe Glu Met Val Asn Thr Ile Thr Glu Glu 645 650 655 Lys Gly Arg Ser Thr Glu Glu Gly Asp Cys Glu Ser Asp Leu Leu Glu 660 665 670 Tyr Asp Tyr Glu Tyr Asp Glu Asn Gly Asp Arg Val Val Leu Gly Lys 675 680 685 Gly Thr Tyr Gly Ile Val Tyr Ala Gly Arg Asp Leu Ser Asn Gln Val 690 695 700 Arg Ile Ala Ile Lys Glu Ile Pro Glu Arg Asp Ser Arg Tyr Ser Gln 705 710 715 720 Pro Leu His Glu Glu Ile Ala Leu His Lys His Leu Lys His Lys Asn 725 730 735 Ile Val Gln Tyr Leu Gly Ser Phe Ser Glu Asn Gly Phe Ile Lys Ile 740 745 750 Phe Met Glu Gln Val Pro Gly Gly Ser Leu Ser Ala Leu Leu Arg Ser 755 760 765 Lys Trp Gly Pro Leu Lys Asp Asn Glu Gln Thr Ile Gly Phe Tyr Thr 770 775 780 Lys Gln Ile Leu Glu Gly Leu Lys Tyr Leu His Asp Asn Gln Ile Val 785 790 795 800 His Arg Asp Ile Lys Gly Asp Asn Val Leu Ile Asn Thr Tyr Ser Gly 805 810 815 Val Leu Lys Ile Ser Asp Phe Gly Thr Ser Lys Arg Leu Ala Gly Ile 820 825 830 Asn Pro Cys Thr Glu Thr Phe Thr Gly Thr Leu Gln Tyr Met Ala Pro 835 840 845 Glu Ile Ile Asp Lys Gly Pro Arg Gly Tyr Gly Lys Ala Ala Asp Ile 850 855 860 Trp Ser Leu Gly Cys Thr Ile Ile Glu Met Ala Thr Gly Lys Pro Pro 865 870 875 880 Phe Tyr Glu Leu Gly Glu Pro Gln Ala Ala Met Phe Lys Val Gly Met 885 890 895 Phe Lys Val His Pro Glu Ile Pro Glu Ser Met Ser Ala Glu Ala Lys 900 905 910 Ala Phe Ile Leu Lys Cys Phe Glu Pro Asp Pro Asp Lys Arg Ala Cys 915 920 925 Ala Asn Asp Leu Leu Val Asp Glu Phe Leu Lys Val Ser Ser Lys Lys 930 935 940 Lys Lys Thr Gln Pro Lys Leu Ser Ala Leu Ser Ala Gly Ser Asn Glu 945 950 955 960 Tyr Leu Arg Ser Ile Ser Leu Pro Val Pro Val Leu Val Glu Asp Thr 965 970 975 Ser Ser Ser Ser Glu Tyr Gly Ser Val Ser Pro Asp Thr Glu Leu Lys 980 985 990 Val Asp Pro Phe Ser Phe Lys Thr Arg Ala Lys Ser Cys Gly Glu Arg 995 1000 1005 Asp Val Lys Gly Ile Arg Thr Leu Phe Leu Gly Ile Pro Asp Glu Asn 1010 1015 1020 Phe Glu Asp His Ser Ala Pro Pro Ser Pro Glu Glu Lys Asp Ser Gly 1025 1030 1035 1040 Phe Phe Met Leu Arg Lys Asp Ser Glu Arg Arg Ala Thr Leu His Arg 1045 1050 1055 Ile Leu Thr Glu Asp Gln Asp Lys Ile Val Arg Asn Leu Met Glu Ser 1060 1065 1070 Leu Ala Gln Gly Ala Glu Glu Pro Lys Leu Lys Trp Glu His Ile Thr 1075 1080 1085 Thr Leu Ile Ala Ser Leu Arg Glu Phe Val Arg Ser Thr Asp Arg Lys 1090 1095 1100 Ile Ile Ala Thr Thr Leu Ser Lys Leu Lys Leu Glu Leu Asp Phe Asp 1105 1110 1115 1120 Ser His Gly Ile Ser Gln Val Gln Val Val Leu Phe Gly Phe Gln Asp 1125 1130 1135 Ala Val Asn Lys Val Leu Arg Asn His Asn Ile Lys Pro His Trp Met 1140 1145 1150 Phe Ala Leu Asp Ser Ile Ile Arg Lys Ala Val Gln Thr Ala Ile Thr 1155 1160 1165 Ile Leu Val Pro Glu Leu Arg Pro His Phe Ser Leu Ala Ser Glu Ser 1170 1175 1180 Asp Thr Ala Asp Gln Glu Asp Leu Asp Val Glu Asp Asp His Glu Glu 1185 1190 1195 1200 Gln Pro Ser Asn Gln Thr Val Arg Arg Pro Gln Ala Val Ile Glu Asp 1205 1210 1215 Ala Val Ala Thr Ser Gly Val Ser Thr Leu Ser Ser Ser Thr Val Ser His 1220 1225 1230 Asp Ser Gln Ser Ala His Arg Ser Leu Asn Val Gln Leu Gly Arg Met 1235 1240 1245 Lys Ile Glu Thr Asn Arg Leu Leu Glu Glu Leu Val Arg Lys Glu Lys 1250 1255 1260 Glu Leu Gln Ala Leu Leu His Arg Ala Ile Glu Glu Lys Asp Gln Glu 1265 1270 1275 1280 Ile Lys His Leu Lys Leu Lys Ser Gln Pro Ile Glu Ile Pro Glu Leu 1285 1290 1295 Pro Val Phe His Leu Asn Ser Ser Gly Thr Asn Thr Glu Asp Ser Glu 1300 1305 1310 Leu Thr Asp Trp Leu Arg Val Asn Gly Ala Asp Glu Asp Thr Ile Ser 1315 1320 1325 Arg Phe Leu Ala Glu Asp Tyr Thr Leu Leu Asp Val Leu Tyr Tyr Val 1330 1335 1340 Thr Arg Asp Asp Leu Lys Cys Leu Arg Leu Arg Gly Gly Met Leu Cys 1345 1350 1355 1360 Thr Leu Trp Lys Ala Ile Ile Asp Phe Arg Asn Lys Gln Thr 1365 1370 <210> 12 <211> 1581 <212> PRT <213> Homo sapiens <400> 12 Met Lys Ala Gln Gly Glu Thr Glu Glu Ser Glu Lys Leu Ser Lys Met 1 5 10 15 Ser Ser Leu Leu Glu Arg Leu His Ala Lys Phe Asn Gln Asn Arg Pro 20 25 30 Trp Ser Glu Thr Ile Lys Leu Val Arg Gln Val Met Glu Lys Arg Val 35 40 45 Val Met Ser Ser Gly Gly His Gln His Leu Val Ser Cys Leu Glu Thr 50 55 60 Leu Gln Lys Ala Leu Lys Val Thr Ser Leu Pro Ala Met Thr Asp Arg 65 70 75 80 Leu Glu Ser Ile Ala Arg Gln Asn Gly Leu Gly Ser His Leu Ser Ala 85 90 95 Ser Gly Thr Glu Cys Tyr Ile Thr Ser Asp Met Phe Tyr Val Glu Val 100 105 110 Gln Leu Asp Pro Ala Gly Gln Leu Cys Asp Val Lys Val Ala His His 115 120 125 Gly Glu Asn Pro Val Ser Cys Pro Glu Leu Val Gln Gln Leu Arg Glu 130 135 140 Lys Asn Phe Asp Glu Phe Ser Lys His Leu Lys Gly Leu Val Asn Leu 145 150 155 160 Tyr Asn Leu Pro Gly Asp Asn Lys Leu Lys Thr Lys Met Tyr Leu Ala 165 170 175 Leu Gln Ser Leu Glu Gln Asp Leu Ser Lys Met Ala Ile Met Tyr Trp 180 185 190 Lys Ala Thr Asn Ala Gly Pro Leu Asp Lys Ile Leu His Gly Ser Val 195 200 205 Gly Tyr Leu Thr Pro Arg Ser Gly Gly His Leu Met Asn Leu Lys Tyr 210 215 220 Tyr Val Ser Pro Ser Asp Leu Leu Asp Asp Lys Thr Ala Ser Pro Ile 225 230 235 240 Ile Leu His Glu Asn Asn Val Ser Arg Ser Leu Gly Met Asn Ala Ser 245 250 255 Val Thr Ile Glu Gly Thr Ser Ala Val Tyr Lys Leu Pro Ile Ala Pro 260 265 270 Leu Ile Met Gly Ser His Pro Val Asp Asn Lys Trp Thr Pro Ser Phe 275 280 285 Ser Ser Ile Thr Ser Ala Asn Ser Val Asp Leu Pro Ala Cys Phe Phe 290 295 300 Leu Lys Phe Pro Gln Pro Ile Pro Val Ser Arg Ala Phe Val Gln Lys 305 310 315 320 Leu Gln Asn Cys Thr Gly Ile Pro Leu Phe Glu Thr Gln Pro Thr Tyr 325 330 335 Ala Pro Leu Tyr Glu Leu Ile Thr Gln Phe Glu Leu Ser Lys Asp Pro 340 345 350 Asp Pro Ile Pro Leu Asn His Asn Met Arg Phe Tyr Ala Ala Leu Pro 355 360 365 Gly Gln Gln His Cys Tyr Phe Leu Asn Lys Asp Ala Pro Leu Pro Asp 370 375 380 Gly Arg Ser Leu Gln Gly Thr Leu Val Ser Lys Ile Thr Phe Gln His 385 390 395 400 Pro Gly Arg Val Pro Leu Ile Leu Asn Leu Ile Arg His Gln Val Ala 405 410 415 Tyr Asn Thr Leu Ile Gly Ser Cys Val Lys Arg Thr Ile Leu Lys Glu 420 425 430 Asp Ser Pro Gly Leu Leu Gln Phe Glu Val Cys Pro Leu Ser Glu Ser 435 440 445 Arg Phe Ser Val Ser Phe Gln His Pro Val Asn Asp Ser Leu Val Cys 450 455 460 Val Val Met Asp Val Gln Asp Ser Thr His Val Ser Cys Lys Leu Tyr 465 470 475 480 Lys Gly Leu Ser Asp Ala Leu Ile Cys Thr Asp Asp Phe Ile Ala Lys 485 490 495 Val Val Gln Arg Cys Met Ser Ile Pro Val Thr Met Arg Ala Ile Arg 500 505 510 Arg Lys Ala Glu Thr Ile Gln Ala Asp Thr Pro Ala Leu Ser Leu Ile 515 520 525 Ala Glu Thr Val Glu Asp Met Val Lys Lys Asn Leu Pro Ala Ser 530 535 540 Ser Pro Gly Tyr Gly Met Thr Thr Gly Asn Asn Pro Met Ser Gly Thr 545 550 555 560 Thr Thr Pro Thr Asn Thr Phe Pro Gly Gly Pro Ile Thr Thr Leu Phe 565 570 575 Asn Met Ser Met Ser Ile Lys Asp Arg His Glu Ser Val Gly His Gly 580 585 590 Glu Asp Phe Ser Lys Val Ser Gln Asn Pro Ile Leu Thr Ser Leu Leu 595 600 605 Gln Ile Thr Gly Asn Gly Gly Ser Thr Ile Gly Ser Ser Pro Thr Pro 610 615 620 Pro His His Thr Pro Pro Pro Val Ser Ser Met Ala Gly Asn Thr Lys 625 630 635 640 Asn His Pro Met Leu Met Asn Leu Leu Lys Asp Asn Pro Ala Gln Asp 645 650 655 Phe Ser Thr Leu Tyr Gly Ser Ser Pro Leu Glu Arg Gln Asn Ser Ser 660 665 670 Ser Gly Ser Pro Arg Met Glu Ile Cys Ser Gly Ser Asn Lys Thr Lys 675 680 685 Lys Lys Lys Ser Ser Arg Leu Pro Pro Glu Lys Pro Lys His Gln Thr 690 695 700 Glu Asp Asp Phe Gln Arg Glu Leu Phe Ser Met Asp Val Asp Ser Gln 705 710 715 720 Asn Pro Ile Phe Asp Val Asn Met Thr Ala Asp Thr Leu Asp Thr Pro 725 730 735 His Ile Thr Pro Ala Pro Ser Gln Cys Ser Thr Pro Pro Thr Thr Tyr 740 745 750 Pro Gln Pro Val Pro His Pro Gln Pro Ser Ile Gln Arg Met Val Arg 755 760 765 Leu Ser Ser Ser Asp Ser Ile Gly Pro Asp Val Thr Asp Ile Leu Ser 770 775 780 Asp Ile Ala Glu Glu Ala Ser Lys Leu Pro Ser Thr Ser Asp Asp Cys 785 790 795 800 Pro Ala Ile Gly Thr Pro Leu Arg Asp Ser Ser Ser Ser Gly His Ser 805 810 815 Gln Ser Thr Leu Phe Asp Ser Asp Val Phe Gln Thr Asn Asn Asn Glu 820 825 830 Asn Pro Tyr Thr Asp Pro Ala Asp Leu Ile Ala Asp Ala Ala Gly Ser 835 840 845 Pro Ser Ser Asp Ser Pro Thr Asn His Phe Phe His Asp Gly Val Asp 850 855 860 Phe Asn Pro Asp Leu Leu Asn Ser Gln Ser Gln Ser Gly Phe Gly Glu 865 870 875 880 Glu Tyr Phe Asp Glu Ser Ser Gln Ser Gly Asp Asn Asp Asp Phe Lys 885 890 895 Gly Phe Ala Ser Gln Ala Leu Asn Thr Leu Gly Val Pro Met Leu Gly 900 905 910 Gly Asp Asn Gly Glu Thr Lys Phe Lys Gly Asn Asn Gln Ala Asp Thr 915 920 925 Val Asp Phe Ser Ile Ile Ser Val Ala Gly Lys Ala Leu Ala Pro Ala 930 935 940 Asp Leu Met Glu His His Ser Gly Ser Gln Gly Pro Leu Leu Thr Thr 945 950 955 960 Gly Asp Leu Gly Lys Glu Lys Thr Gln Lys Arg Val Lys Glu Gly Asn 965 970 975 Gly Thr Ser Asn Ser Thr Leu Ser Gly Pro Gly Leu Asp Ser Lys Pro 980 985 990 Gly Lys Arg Ser Arg Thr Pro Ser Asn Asp Gly Lys Ser Lys Asp Lys 995 1000 1005 Pro Pro Lys Arg Lys Lys Ala Asp Thr Glu Gly Lys Ser Pro Ser His 1010 1015 1020 Ser Ser Ser Asn Arg Pro Phe Thr Pro Pro Thr Ser Thr Gly Gly Ser 1025 1030 1035 1040 Lys Ser Pro Gly Ser Ala Gly Arg Ser Gln Thr Pro Pro Gly Val Ala 1045 1050 1055 Thr Pro Pro Ile Pro Lys Ile Thr Ile Gln Ile Pro Lys Gly Thr Val 1060 1065 1070 Met Val Gly Lys Pro Ser Ser His Ser Gln Tyr Thr Ser Ser Ser Gly Ser 1075 1080 1085 Val Ser Ser Ser Gly Ser Lys Ser His His Ser His Ser Ser Ser Ser 1090 1095 1100 Ser Ser Ser Ala Ser Thr Ser Gly Lys Met Lys Ser Ser Lys Ser Glu 1105 1110 1115 1120 Gly Ser Ser Ser Ser Lys Leu Ser Ser Ser Met Tyr Ser Ser Gln Gly 1125 1130 1135 Ser Ser Gly Ser Ser Gln Ser Lys Asn Ser Ser Gln Ser Gly Gly Lys 1140 1145 1150 Pro Gly Ser Ser Pro Ile Thr Lys His Gly Leu Ser Ser Gly Ser Ser 1155 1160 1165 Ser Thr Lys Met Lys Pro Gln Gly Lys Pro Ser Ser Leu Met Asn Pro 1170 1175 1180 Ser Leu Ser Lys Pro Asn Ile Ser Pro Ser His Ser Arg Pro Pro Gly 1185 1190 1195 1200 Gly Ser Asp Lys Leu Ala Ser Pro Met Lys Pro Val Pro Gly Thr Pro 1205 1210 1215 Pro Ser Ser Lys Ala Lys Ser Pro Ile Ser Ser Gly Ser Gly Gly Ser 1220 1225 1230 His Met Ser Gly Thr Ser Ser Ser Ser Gly Met Lys Ser Ser Ser Gly 1235 1240 1245 Leu Gly Ser Ser Gly Ser Leu Ser Gln Lys Thr Pro Pro Ser Ser Asn 1250 1255 1260 Ser Cys Thr Ala Ser Ser Ser Ser Phe Ser Ser Ser Gly Ser Ser Met 1265 1270 1275 1280 Ser Ser Ser Gln Asn Gln His Gly Ser Ser Lys Gly Lys Ser Pro Ser 1285 1290 1295 Arg Asn Lys Lys Pro Ser Leu Thr Ala Val Ile Asp Lys Leu Lys His 1300 1305 1310 Gly Val Val Thr Ser Gly Pro Gly Gly Glu Asp Pro Leu Asp Gly Gln 1315 1320 1325 Met Gly Val Ser Thr Asn Ser Ser Ser His Pro Met Ser Ser Lys His 1330 1335 1340 Asn Met Ser Gly Gly Glu Phe Gln Gly Lys Arg Glu Lys Ser Asp Lys 1345 1350 1355 1360 Asp Lys Ser Lys Val Ser Thr Ser Gly Ser Ser Val Asp Ser Ser Lys 1365 1370 1375 Lys Thr Ser Glu Ser Lys Asn Val Gly Ser Thr Gly Val Ala Lys Ile 1380 1385 1390 Ile Ile Ser Lys His Asp Gly Gly Ser Pro Ser Ile Lys Ala Lys Val 1395 1400 1405 Thr Leu Gln Lys Pro Gly Glu Ser Ser Gly Glu Gly Leu Arg Pro Gln 1410 1415 1420 Met Ala Ser Ser Lys Asn Tyr Gly Ser Pro Leu Ile Ser Gly Ser Thr 1425 1430 1435 1440 Pro Lys His Glu Arg Gly Ser Pro Ser His Ser Lys Ser Pro Ala Tyr 1445 1450 1455 Thr Pro Gln Asn Leu Asp Ser Glu Ser Glu Ser Gly Ser Ser Ile Ala 1460 1465 1470 Glu Lys Ser Tyr Gln Asn Ser Pro Ser Ser Asp Asp Gly Ile Arg Pro 1475 1480 1485 Leu Pro Glu Tyr Ser Thr Glu Lys His Lys Lys His Lys Lys Glu Lys 1490 1495 1500 Lys Lys Val Lys Asp Lys Asp Arg Asp Arg Asp Arg Asp Lys Asp Arg 1505 1510 1515 1520 Asp Lys Lys Lys Ser His Ser Ile Lys Pro Glu Ser Trp Ser Lys Ser 1525 1530 1535 Pro Ile Ser Ser Asp Gln Ser Leu Ser Met Thr Ser Asn Thr Ile Leu 1540 1545 1550 Ser Ala Asp Arg Pro Ser Arg Leu Ser Pro Asp Phe Met Ile Gly Glu 1555 1560 1565 Glu Asp Asp Asp Leu Met Asp Val Ala Leu Ile Gly Asn 1570 1575 1580 <210> 13 <211> 2385 <212> PRT <213> Homo sapiens <400> 13 Met Pro Val Leu Gly Val Ala Ser Lys Leu Arg Gln Pro Ala Val Gly 1 5 10 15 Ser Lys Pro Val His Thr Ala Leu Pro Ile Pro Asn Leu Gly Thr Thr 20 25 30 Gly Ser Gln His Cys Ser Ser Arg Pro Leu Glu Leu Thr Glu Thr Glu 35 40 45 Ser Ser Met Leu Ser Cys Gln Leu Ala Leu Lys Ser Thr Cys Glu Phe 50 55 60 Gly Glu Lys Lys Pro Leu Gln Gly Lys Ala Lys Glu Lys Glu Asp Ser 65 70 75 80 Lys Ile Tyr Thr Asp Trp Ala Asn His Tyr Leu Ala Lys Ser Gly His 85 90 95 Lys Arg Leu Ile Lys Asp Leu Gln Gln Asp Ile Ala Asp Gly Val Leu 100 105 110 Leu Ala Glu Ile Ile Gln Ile Ile Ala Asn Glu Lys Val Glu Asp Ile 115 120 125 Asn Gly Cys Pro Arg Ser Gln Ser Gln Met Ile Glu Asn Val Asp Val 130 135 140 Cys Leu Ser Phe Leu Ala Ala Arg Gly Val Asn Val Gln Gly Leu Ser 145 150 155 160 Ala Glu Glu Ile Arg Asn Gly Asn Leu Lys Ala Ile Leu Gly Leu Phe 165 170 175 Phe Ser Leu Ser Arg Tyr Lys Gln Gln Gln His His Gln Gln Gln Tyr 180 185 190 Tyr Gln Ser Leu Val Glu Leu Gln Gln Arg Val Thr His Ala Ser Pro 195 200 205 Pro Ser Glu Ala Ser Gln Ala Lys Thr Gln Gln Asp Met Gln Ser Ser 210 215 220 Leu Ala Ala Arg Tyr Ala Thr Gln Ser Asn His Ser Gly Ile Ala Thr 225 230 235 240 Ser Gln Lys Lys Pro Thr Arg Leu Pro Gly Pro Ser Arg Val Pro Ala 245 250 255 Ala Gly Ser Ser Ser Lys Val Gln Gly Ala Ser Asn Leu Asn Arg Arg 260 265 270 Ser Gln Ser Phe Asn Ser Ile Asp Lys Asn Lys Pro Pro Asn Tyr Ala 275 280 285 Asn Gly Asn Glu Lys Asp Ser Ser Lys Gly Pro Gln Ser Ser Ser Gly 290 295 300 Val Asn Gly Asn Val Gln Pro Pro Ser Thr Ala Gly Gln Pro Pro Ala 305 310 315 320 Ser Ala Ile Pro Ser Pro Ser Ala Ser Lys Pro Trp Arg Ser Lys Ser 325 330 335 Met Asn Val Lys His Ser Ala Thr Ser Thr Met Leu Thr Val Lys Gln 340 345 350 Ser Ser Thr Ala Thr Ser Pro Thr Pro Ser Ser Asp Arg Leu Lys Pro 355 360 365 Pro Val Ser Glu Gly Val Lys Thr Ala Pro Ser Gly Gln Lys Ser Met 370 375 380 Leu Glu Lys Phe Lys Leu Val Asn Ala Arg Thr Ala Leu Arg Pro Pro 385 390 395 400 Gln Pro Pro Ser Ser Gly Pro Ser Asp Gly Gly Lys Asp Asp Asp Ala 405 410 415 Phe Ser Glu Ser Gly Glu Met Glu Gly Phe Asn Ser Gly Leu Asn Ser 420 425 430 Gly Gly Ser Thr Asn Ser Ser Pro Lys Val Ser Pro Lys Leu Ala Pro 435 440 445 Pro Lys Ala Gly Ser Lys Asn Leu Ser Asn Lys Lys Ser Leu Leu Gln 450 455 460 Pro Lys Glu Lys Glu Glu Lys Asn Arg Asp Lys Asn Lys Val Cys Thr 465 470 475 480 Glu Lys Pro Val Lys Glu Glu Lys Asp Gln Val Thr Glu Met Ala Pro 485 490 495 Lys Lys Thr Ser Lys Ile Ala Ser Leu Ile Pro Lys Gly Ser Lys Thr 500 505 510 Thr Ala Ala Lys Lys Glu Ser Leu Ile Pro Ser Ser Ser Gly Ile Pro 515 520 525 Lys Pro Gly Ser Lys Val Pro Thr Val Lys Gln Thr Ile Ser Pro Gly 530 535 540 Ser Thr Ala Ser Lys Glu Ser Glu Lys Phe Arg Thr Thr Lys Gly Ser 545 550 555 560 Pro Ser Gln Ser Leu Ser Lys Pro Ile Thr Met Glu Lys Ala Ser Ala 565 570 575 Ser Ser Cys Pro Ala Pro Leu Glu Gly Arg Glu Ala Gly Gly Gln Ala Ser 580 585 590 Pro Ser Gly Ser Cys Thr Met Thr Val Ala Gln Ser Ser Gly Gln Ser 595 600 605 Thr Gly Asn Gly Ala Val Gln Leu Pro Gln Gln Gln Gln His Ser His 610 615 620 Pro Asn Thr Ala Thr Val Ala Pro Phe Ile Tyr Arg Ala His Ser Glu 625 630 635 640 Asn Glu Gly Thr Ala Leu Pro Ser Ala Asp Ser Cys Thr Ser Pro Thr 645 650 655 Lys Met Asp Leu Ser Tyr Ser Lys Thr Ala Lys Gln Cys Leu Glu Glu 660 665 670 Ile Ser Gly Glu Asp Pro Glu Thr Arg Arg Met Arg Thr Val Lys Asn 675 680 685 Ile Ala Asp Leu Arg Gln Asn Leu Glu Glu Thr Met Ser Ser Leu Arg 690 695 700 Gly Thr Gln Ile Ser His Ser Thr Leu Glu Thr Thr Phe Asp Ser Thr 705 710 715 720 Val Thr Thr Glu Val Asn Gly Arg Thr Ile Pro Asn Leu Thr Ser Arg 725 730 735 Pro Thr Pro Met Thr Trp Arg Leu Gly Gln Ala Cys Pro Arg Leu Gln 740 745 750 Ala Gly Asp Ala Pro Ser Leu Gly Ala Gly Tyr Pro Arg Ser Gly Thr 755 760 765 Ser Arg Phe Ile His Thr Asp Pro Ser Arg Phe Met Tyr Thr Thr Pro 770 775 780 Leu Arg Arg Ala Ala Val Ser Arg Leu Gly Asn Met Ser Gln Ile Asp 785 790 795 800 Met Ser Glu Lys Ala Ser Ser Asp Leu Asp Met Ser Ser Glu Val Asp 805 810 815 Val Gly Gly Tyr Met Ser Asp Gly Asp Ile Leu Gly Lys Ser Leu Arg 820 825 830 Thr Asp Asp Ile Asn Ser Gly Tyr Met Thr Asp Gly Gly Leu Asn Leu 835 840 845 Tyr Thr Arg Ser Leu Asn Arg Ile Pro Asp Thr Ala Thr Ser Arg Asp 850 855 860 Ile Ile Gln Arg Gly Val His Asp Val Thr Val Asp Ala Asp Ser Trp 865 870 875 880 Asp Asp Ser Ser Ser Val Ser Ser Gly Leu Ser Asp Thr Leu Asp Asn 885 890 895 Ile Ser Thr Asp Asp Leu Asn Thr Thr Ser Ser Val Ser Ser Tyr Ser 900 905 910 Asn Ile Thr Val Pro Ser Arg Lys Asn Thr Gln Leu Arg Thr Asp Ser 915 920 925 Glu Lys Arg Ser Thr Thr Asp Glu Thr Trp Asp Ser Pro Glu Glu Leu 930 935 940 Lys Lys Pro Glu Glu Asp Phe Asp Ser His Gly Asp Ala Gly Gly Lys 945 950 955 960 Trp Lys Thr Val Ser Ser Gly Leu Pro Glu Asp Pro Glu Lys Ala Gly 965 970 975 Gln Lys Ala Ser Leu Ser Val Ser Gln Thr Gly Ser Trp Arg Arg Gly 980 985 990 Met Ser Ala Gln Gly Gly Ala Pro Ser Arg Gln Lys Ala Gly Thr Ser 995 1000 1005 Ala Leu Lys Thr Pro Gly Lys Thr Asp Asp Ala Lys Ala Ser Glu Lys 1010 1015 1020 Gly Lys Ala Pro Leu Lys Gly Ser Ser Leu Gln Arg Ser Pro Ser Asp 1025 1030 1035 1040 Ala Gly Lys Ser Ser Gly Asp Glu Gly Lys Lys Pro Pro Ser Gly Ile 1045 1050 1055 Gly Arg Ser Thr Ala Thr Ser Ser Phe Gly Phe Lys Lys Pro Ser Gly 1060 1065 1070 Val Gly Ser Ser Ala Met Ile Thr Ser Ser Gly Ala Thr Ile Thr Ser 1075 1080 1085 Gly Ser Ala Thr Leu Gly Lys Ile Pro Lys Ser Ala Ala Ile Gly Gly 1090 1095 1100 Lys Ser Asn Ala Gly Arg Lys Thr Ser Leu Asp Gly Ser Gln Asn Gln 1105 1110 1115 1120 Asp Asp Val Val Leu His Val Ser Ser Lys Thr Thr Leu Gln Tyr Arg 1125 1130 1135 Ser Leu Pro Arg Pro Ser Lys Ser Ser Thr Ser Gly Ile Pro Gly Arg 1140 1145 1150 Gly Gly His Arg Ser Ser Thr Ser Ser Ile Asp Ser Asn Val Ser Ser 1155 1160 1165 Lys Ser Ala Gly Ala Thr Thr Ser Lys Leu Arg Glu Pro Thr Lys Ile 1170 1175 1180 Gly Ser Gly Arg Ser Ser Pro Val Thr Val Asn Gln Thr Asp Lys Glu 1185 1190 1195 1200 Lys Glu Lys Val Ala Val Ser Asp Ser Glu Ser Val Ser Leu Ser Gly 1205 1210 1215 Ser Pro Lys Ser Ser Pro Thr Ser Ala Ser Ala Cys Gly Ala Gln Gly 1220 1225 1230 Leu Arg Gln Pro Gly Ser Lys Tyr Pro Asp Ile Ala Ser Pro Thr Phe 1235 1240 1245 Arg Arg Leu Phe Gly Ala Lys Ala Gly Gly Lys Ser Ala Ser Ala Pro 1250 1255 1260 Asn Thr Glu Gly Val Lys Ser Ser Ser Val Met Pro Ser Pro Ser Thr 1265 1270 1275 1280 Thr Leu Ala Arg Gln Gly Ser Leu Glu Ser Pro Ser Ser Gly Thr Gly 1285 1290 1295 Ser Met Gly Ser Ala Gly Gly Leu Ser Gly Ser Ser Ser Pro Leu Phe 1300 1305 1310 Asn Lys Pro Ser Asp Leu Thr Thr Asp Val Ile Ser Leu Ser His Ser 1315 1320 1325 Leu Ala Ser Ser Pro Ala Ser Val His Ser Phe Thr Ser Gly Gly Leu 1330 1335 1340 Val Trp Ala Ala Asn Met Ser Ser Ser Ser Ala Gly Ser Lys Asp Thr 1345 1350 1355 1360 Pro Ser Tyr Gln Ser Met Thr Ser Leu His Thr Ser Ser Glu Ser Ile 1365 1370 1375 Asp Leu Pro Leu Ser His His Gly Ser Leu Ser Gly Leu Thr Thr Gly 1380 1385 1390 Thr His Glu Val Gln Ser Leu Leu Met Arg Thr Gly Ser Val Arg Ser 1395 1400 1405 Thr Leu Ser Glu Ser Met Gln Leu Asp Arg Asn Thr Leu Pro Lys Lys 1410 1415 1420 Gly Leu Arg Tyr Thr Pro Ser Ser Arg Gln Ala Asn Gln Glu Glu Gly 1425 1430 1435 1440 Lys Glu Trp Leu Arg Ser His Ser Thr Gly Gly Leu Gln Asp Thr Gly 1445 1450 1455 Asn Gln Ser Pro Leu Val Ser Pro Ser Ala Met Ser Ser Ser Ala Ala 1460 1465 1470 Gly Lys Tyr His Phe Ser Asn Leu Val Ser Pro Thr Asn Leu Ser Gln 1475 1480 1485 Phe Asn Leu Pro Gly Pro Ser Met Met Arg Ser Asn Ser Ile Pro Ala 1490 1495 1500 Gln Asp Ser Ser Phe Asp Leu Tyr Asp Asp Ser Gln Leu Cys Gly Ser 1505 1510 1515 1520 Ala Thr Ser Leu Glu Glu Arg Pro Arg Ala Ile Ser His Ser Gly Ser 1525 1530 1535 Phe Arg Asp Ser Met Glu Glu Val His Gly Ser Ser Leu Ser Leu Val 1540 1545 1550 Ser Ser Thr Ser Ser Leu Tyr Ser Thr Ala Glu Glu Lys Ala His Ser 1555 1560 1565 Glu Gln Ile His Lys Leu Arg Arg Glu Leu Val Ala Ser Gln Glu Lys 1570 1575 1580 Val Ala Thr Leu Thr Ser Gln Leu Ser Ala Asn Ala His Leu Val Ala 1585 1590 1595 1600 Ala Phe Glu Lys Ser Leu Gly Asn Met Thr Gly Arg Leu Gln Ser Leu 1605 1610 1615 Thr Met Thr Ala Glu Gln Lys Glu Ser Glu Leu Ile Glu Leu Arg Glu 1620 1625 1630 Thr Ile Glu Met Leu Lys Ala Gln Asn Ser Ala Ala Gln Ala Ala Ile 1635 1640 1645 Gln Gly Ala Leu Asn Gly Pro Asp His Pro Pro Lys Asp Leu Arg Ile 1650 1655 1660 Arg Arg Gln His Ser Ser Glu Ser Val Ser Ser Ile Asn Ser Ala Thr 1665 1670 1675 1680 Ser His Ser Ser Ile Gly Ser Gly Asn Asp Ala Asp Ser Lys Lys Lys 1685 1690 1695 Lys Lys Lys Asn Trp Val Asn Ser Arg Gly Ser Glu Leu Arg Ser Ser 1700 1705 1710 Phe Lys Gln Ala Phe Gly Lys Lys Lys Ser Thr Lys Pro Pro Ser Ser 1715 1720 1725 His Ser Asp Ile Glu Glu Leu Thr Asp Ser Ser Leu Pro Ala Ser Pro 1730 1735 1740 Lys Leu Pro His Asn Ala Gly Asp Cys Gly Ser Ala Ser Met Lys Pro 1745 1750 1755 1760 Ser Gln Ser Ala Ser Ala Ser Pro Leu Val Trp Pro Pro Lys Lys Arg 1765 1770 1775 Gln Asn Gly Pro Val Ile Tyr Lys His Arg Ser Arg Ile Cys Glu Cys 1780 1785 1790 Thr Glu Ala Glu Ala Glu Ile Ile Leu Gln Leu Lys Ser Glu Leu Arg 1795 1800 1805 Glu Lys Glu Leu Lys Leu Thr Asp Ile Arg Leu Glu Ala Leu Ser Ser 1810 1815 1820 Ala His His Leu Asp Gln Ile Arg Glu Ala Met Asn Arg Met Gln Asn 1825 1830 1835 1840 Glu Ile Glu Ile Leu Lys Ala Glu Asn Asp Arg Leu Lys Ala Glu Thr 1845 1850 1855 Gly Asn Thr Ala Lys Pro Thr Arg Pro Pro Ser Glu Ser Ser Ser Ser Ser 1860 1865 1870 Thr Ser Ser Ser Ser Ser Arg Gln Ser Leu Gly Leu Ser Leu Asn Asn 1875 1880 1885 Leu Asn Ile Thr Glu Ala Val Ser Ser Asp Ile Leu Leu Asp Asp Ala 1890 1895 1900 Gly Asp Ala Thr Gly His Lys Asp Gly Arg Ser Val Lys Ile Ile Val 1905 1910 1915 1920 Ser Ile Ser Lys Gly Tyr Gly Arg Ala Lys Asp Gln Lys Ser Gln Ala 1925 1930 1935 Tyr Leu Ile Gly Ser Ile Gly Val Ser Gly Lys Thr Lys Trp Asp Val 1940 1945 1950 Leu Asp Gly Val Ile Arg Arg Leu Phe Lys Glu Tyr Val Phe Arg Ile 1955 1960 1965 Asp Thr Ser Thr Ser Leu Gly Leu Ser Ser Asp Cys Ile Ala Ser Tyr 1970 1975 1980 Cys Ile Gly Asp Leu Ile Arg Ser His Asn Leu Glu Val Pro Glu Leu 1985 1990 1995 2000 Leu Pro Cys Gly Tyr Leu Val Gly Asp Asn Asn Ile Ile Thr Val Asn 2005 2010 2015 Leu Lys Gly Val Glu Glu Asn Ser Leu Asp Ser Phe Val Phe Asp Thr 2020 2025 2030 Leu Ile Pro Lys Pro Ile Thr Gln Arg Tyr Phe Asn Leu Leu Met Glu 2035 2040 2045 His His Arg Ile Ile Leu Ser Gly Pro Ser Gly Thr Gly Lys Thr Tyr 2050 2055 2060 Leu Ala Asn Lys Leu Ala Glu Tyr Val Ile Thr Lys Ser Gly Arg Lys 2065 2070 2075 2080 Lys Thr Glu Asp Ala Ile Ala Thr Phe Asn Val Asp His Lys Ser Ser 2085 2090 2095 Lys Glu Leu Gln Gln Tyr Leu Ala Asn Leu Ala Glu Gln Cys Ser Ala 2100 2105 2110 Asp Asn Asn Gly Val Glu Leu Pro Val Val Ile Ile Leu Asp Asn Leu 2115 2120 2125 His His Val Gly Ser Leu Ser Asp Ile Phe Asn Gly Phe Leu Asn Cys 2130 2135 2140 Lys Tyr Asn Lys Cys Pro Tyr Ile Ile Gly Thr Met Asn Gln Gly Val 2145 2150 2155 2160 Ser Ser Ser Pro Asn Leu Glu Leu His His Asn Phe Arg Trp Val Leu 2165 2170 2175 Cys Ala Asn His Thr Glu Pro Val Lys Gly Phe Leu Gly Arg Tyr Leu 2180 2185 2190 Arg Arg Lys Leu Ile Glu Ile Glu Ile Glu Arg Asn Ile Arg Asn Asn 2195 2200 2205 Asp Leu Val Lys Ile Ile Asp Trp Ile Pro Lys Thr Trp His His Leu 2210 2215 2220 Asn Ser Phe Leu Glu Thr His Ser Ser Ser Asp Val Thr Ile Gly Pro 2225 2230 2235 2240 Arg Leu Phe Leu Pro Cys Pro Met Asp Val Glu Gly Ser Arg Val Trp 2245 2250 2255 Phe Met Asp Leu Trp Asn Tyr Ser Leu Val Pro Tyr Ile Leu Glu Ala 2260 2265 2270 Val Arg Glu Gly Leu Gln Met Tyr Gly Lys Arg Thr Pro Trp Glu Asp 2275 2280 2285 Pro Ser Lys Trp Val Leu Asp Thr Tyr Pro Trp Ser Ser Ala Thr Leu 2290 2295 2300 Pro Gln Glu Ser Pro Ala Leu Leu Gln Leu Arg Pro Glu Asp Val Gly 2305 2310 2315 2320 Tyr Glu Ser Cys Thr Ser Thr Lys Glu Ala Thr Thr Ser Lys His Ile 2325 2330 2335 Pro Gln Thr Asp Thr Glu Gly Asp Pro Leu Met Asn Met Leu Met Lys 2340 2345 2350 Leu Gln Glu Ala Ala Asn Tyr Ser Ser Thr Gln Ser Cys Asp Ser Glu 2355 2360 2365 Ser Thr Ser His His Glu Asp Ile Leu Asp Ser Ser Leu Glu Ser Thr 2370 2375 2380 Leu 238 <210> 14 <211> 568 <212> PRT <213> Homo sapiens <400> 14 Met Val Leu Leu His Trp Cys Leu Leu Trp Leu Leu Phe Pro Leu Ser 1 5 10 15 Ser Arg Thr Gln Lys Leu Pro Thr Arg Asp Glu Glu Leu Phe Gln Met 20 25 30 Gln Ile Arg Asp Lys Ala Phe Phe His Asp Ser Ser Val Ile Pro Asp 35 40 45 Gly Ala Glu Ile Ser Ser Tyr Leu Phe Arg Asp Thr Pro Lys Arg Tyr 50 55 60 Phe Phe Val Val Glu Glu Asp Asn Thr Pro Leu Ser Val Thr Val Thr 65 70 75 80 Pro Cys Asp Ala Pro Leu Glu Trp Lys Leu Ser Leu Gln Glu Leu Pro 85 90 95 Glu Asp Arg Ser Gly Glu Gly Ser Gly Asp Leu Glu Pro Leu Glu Gln 100 105 110 Gln Lys Gln Gln Ile Ile Asn Glu Glu Gly Thr Glu Leu Phe Ser Tyr 115 120 125 Lys Gly Asn Asp Val Glu Tyr Phe Ile Ser Ser Ser Ser Ser Pro Ser Gly 130 135 140 Leu Tyr Gln Leu Asp Leu Leu Ser Thr Glu Lys Asp Thr His Phe Lys 145 150 155 160 Val Tyr Ala Thr Thr Thr Pro Glu Ser Asp Gln Pro Tyr Pro Glu Leu 165 170 175 Pro Tyr Asp Pro Arg Val Asp Val Thr Ser Leu Gly Arg Thr Thr Val 180 185 190 Thr Leu Ala Trp Lys Pro Ser Pro Thr Ala Ser Leu Leu Lys Gln Pro 195 200 205 Ile Gln Tyr Cys Val Val Ile Asn Lys Glu His Asn Phe Lys Ser Leu 210 215 220 Cys Ala Val Glu Ala Lys Leu Ser Ala Asp Asp Ala Phe Met Met Ala 225 230 235 240 Pro Lys Pro Gly Leu Asp Phe Ser Pro Phe Asp Phe Ala His Phe Gly 245 250 255 Phe Pro Ser Asp Asn Ser Gly Lys Glu Arg Ser Phe Gln Ala Lys Pro 260 265 270 Ser Pro Lys Leu Gly Arg His Val Tyr Ser Arg Pro Lys Val Asp Ile 275 280 285 Gln Lys Ile Cys Ile Gly Asn Lys Asn Ile Phe Thr Val Ser Asp Leu 290 295 300 Lys Pro Asp Thr Gln Tyr Tyr Phe Asp Val Phe Val Val Asn Ile Asn 305 310 315 320 Ser Asn Met Ser Thr Ala Tyr Val Gly Thr Phe Ala Arg Thr Lys Glu 325 330 335 Glu Ala Lys Gln Lys Thr Val Glu Leu Lys Asp Gly Lys Ile Thr Asp 340 345 350 Val Phe Val Lys Arg Lys Gly Ala Lys Phe Leu Arg Phe Ala Pro Val 355 360 365 Ser Ser His Gln Lys Val Thr Phe Phe Ile His Ser Cys Leu Asp Ala 370 375 380 Val Gln Ile Gln Val Arg Arg Asp Gly Lys Leu Leu Leu Ser Gln Asn 385 390 395 400 Val Glu Gly Ile Gln Gln Phe Gln Leu Arg Gly Lys Pro Lys Ala Lys 405 410 415 Tyr Leu Val Arg Leu Lys Gly Asn Lys Lys Gly Ala Ser Met Leu Lys 420 425 430 Ile Leu Ala Thr Thr Arg Pro Thr Lys Gln Ser Phe Pro Ser Leu Pro 435 440 445 Glu Asp Thr Arg Ile Lys Ala Phe Asp Lys Leu Arg Thr Cys Ser Ser 450 455 460 Ala Thr Val Ala Trp Leu Gly Thr Gln Glu Arg Asn Lys Phe Cys Ile 465 470 475 480 Tyr Lys Lys Glu Val Asp Asp Asn Tyr Asn Glu Asp Gln Lys Lys Arg 485 490 495 Glu Gln Asn Gln Cys Leu Gly Pro Asp Ile Arg Lys Lys Ser Glu Lys 500 505 510 Val Leu Cys Lys Tyr Phe His Ser Gln Asn Leu Gln Lys Ala Val Thr 515 520 525 Thr Glu Thr Ile Lys Gly Leu Gln Pro Gly Lys Ser Tyr Leu Leu Asp 530 535 540 Val Tyr Val Ile Gly His Gly Gly His Ser Val Lys Tyr Gln Ser Lys 545 550 555 560 Val Val Lys Thr Arg Lys Phe Cys 565 <210> 15 <211> 784 <212> PRT <213> Homo sapiens <400> 15 Met Ala Gly Gly Arg Leu Leu Leu Gly Gly Asp Phe Leu Ser Pro Pro 1151 1155 1160 1165 Pro Leu Pro Pro Leu Pro Pro Pro Pro Leu Pro Pro Leu Pro Pro Pro 1170 1175 1180 Pro Pro Glu Pro Val Leu Glu Gln Trp Arg Tyr Ser His Glu Ser Asp 1185 1190 1195 Trp Gln Trp Ala Leu Arg Arg Ser Phe Ile Cys Arg His Leu His Ser 1200 1205 1210 Tyr Pro Gly Ala Ala Leu Asp Gln Leu Leu Ala Leu Ser Ala Ala Trp 1215 1220 1225 1230 Thr Asn His Val Phe Leu Gly Cys Arg Tyr Ser Pro Arg Leu Met Glu 1235 1240 1245 Lys Ile Leu Gln Met Ala Glu Gly Ile Asp Ile Gly Glu Met Pro Ser 1250 1255 1260 Tyr Asp Leu Val Leu Ser Lys Pro Ser Lys Gly Gln Lys Arg His Leu 1265 1270 1275 Ser Thr Cys Asp Gly Gln Asn Pro Lys Lys Gln Ala Gly Ser Lys 1280 1285 1290 Phe His Ala Arg Pro Arg Phe Glu Pro Val His Phe Val Ala Ser Ser 1295 1300 1305 1310 Ser Lys Asp Glu Arg Gln Glu Asp Pro Tyr Gly Pro Gln Thr Lys Glu 1315 1320 1325 Val Asn Glu Gln Thr His Phe Ala Ser Met Pro Arg Asp Ile Tyr Gln 1330 1335 1340 Asp Tyr Thr Gln Asp Ser Phe Ser Ile Gln Asp Gly Asn Ser Gln Tyr 1345 1350 1355 Cys Asp Ser Ser Gly Phe Ile Leu Thr Lys Asp Gln Pro Val Thr Ala 1360 1365 1370 Asn Met Tyr Phe Asp Ser Gly Asn Pro Ala Pro Ser Thr Thr Ser Gln 1375 1380 1385 1390 Gln Ala Asn Ser Gln Ser Thr Pro Glu Pro Ser Pro Ser Gln Thr Phe 1395 1400 1405 Pro Glu Ser Val Val Ala Glu Lys Gln Tyr Phe Ile Glu Lys Leu Thr 1410 1415 1420 Ala Thr Ile Trp Lys Asn Leu Ser Asn Pro Glu Met Thr Ser Gly Ser 1425 1430 1435 Asp Lys Ile Asn Tyr Thr Tyr Met Leu Thr Arg Cys Ile Gln Ala Cys 1440 1445 1450 Lys Thr Asn Pro Glu Tyr Ile Tyr Ala Pro Leu Lys Glu Ile Pro Pro 1455 1460 1465 1470 Ala Asp Ile Pro Lys Asn Lys Lys Leu Leu Thr Asp Gly Tyr Ala Cys 1475 1480 1485 Glu Val Arg Cys Gln Asn Ile Tyr Leu Thr Thr Gly Tyr Ala Gly Ser 1490 1495 1500 Lys Asn Gly Ser Arg Asp Arg Ala Thr Glu Leu Ala Val Lys Leu Leu 1505 1510 1515 Gln Lys Arg Ile Glu Val Arg Val Val Arg Arg Lys Phe Lys His Thr 1520 1525 1530 Phe Gly Glu Asp Leu Val Val Cys Gln Ile Gly Met Ser Ser Tyr Glu 1535 1540 1545 1550 Phe Pro Pro Ala Leu Lys Pro Pro Glu Asp Leu Val Val Leu Gly Lys 1555 1560 1565 Asp Ala Ser Gly Gln Pro Ile Phe Asn Ala Ser Ala Lys His Trp Thr 1570 1575 1580 Asn Phe Val Ile Thr Glu Asn Ala Asn Asp Ala Ile Gly Ile Leu Asn 1585 1590 1595 Asn Ser Ala Ser Phe Asn Lys Met Ser Ile Glu Tyr Lys Tyr Glu Met 1600 1605 1610 Met Pro Asn Arg Thr Trp Arg Cys Arg Val Phe Leu Gln Asp His Cys 1615 1620 1625 1630 Leu Ala Glu Gly Tyr Gly Thr Lys Lys Thr Ser Lys His Ala Ala Ala 1635 1640 1645 Asp Glu Ala Leu Lys Ile Leu Gln Lys Thr Gln Pro Thr Tyr Pro Ser 1650 1655 1660 Val Lys Ser Ser Gln Cys His Thr Gly Ser Ser Pro Arg Gly Ser Gly 1665 1670 1675 Lys Lys Lys Asp Ile Lys Asp Leu Val Val Tyr Glu Asn Ser Ser Asn 1680 1685 1690 Pro Val Cys Thr Leu Asn Asp Thr Ala Gln Phe Asn Arg Met Thr Val 1695 1700 1705 1710 Glu Tyr Val Tyr Glu Arg Met Thr Gly Leu Arg Trp Lys Cys Lys Val 1715 1720 1725 Ile Leu Glu Ser Glu Val Ile Ala Glu Ala Val Gly Val Lys Lys Thr 1730 1735 1740 Val Lys Tyr Glu Ala Ala Gly Glu Ala Val Lys Thr Leu Lys Lys Thr 1745 1750 1755 Gln Pro Thr Val Ile Asn Asn Leu Lys Lys Gly Ala Val Glu Asp Val 1760 1765 1770 Ile Ser Arg Asn Glu Ile Gln Gly Arg Ser Ala Glu Glu Ala Tyr Lys 1775 1780 1785 1790 Gln Gln Ile Lys Glu Asp Asn Ile Gly Asn Gln Leu Leu Arg Lys Met 1795 1800 1805 Gly Trp Thr Gly Gly Gly Leu Gly Lys Ser Gly Glu Gly Ile Arg Glu 1810 1815 1820 Pro Ile Ser Val Lys Glu Gln His Lys Arg Glu Gly Leu Gly Leu Asp 1825 1830 1835 Val Glu Arg Val Asn Lys Ile Ala Lys Arg Asp Ile Glu Gln Ile Ile 1840 1845 1850 Arg Asn Tyr Ala Arg Ser Glu Ser His Thr Asp Leu Thr Phe Ser Arg 1855 1860 1865 1870 Glu Leu Thr Asn Asp Glu Arg Lys Gln Ile His Gln Ile Ala Gln Lys 1875 1880 1885 Tyr Gly Leu Lys Ser Lys Ser His Gly Val Gly His Asp Arg Tyr Leu 1890 1895 1900 Val Val Gly Arg Lys Arg Arg Lys Glu Asp Leu Leu Asp Gln Leu Lys 1905 1910 1915 Gln Glu Gly Gln Val Gly His Tyr Glu Leu Val Met Pro Gln Ala Asn 1920 1925 1930 <210> 16 <211> 510 <212> PRT <213> Homo sapiens <400> 16 Met Arg Pro Gly Leu Ser Phe Leu Leu Ala Leu Leu Phe Phe Leu Gly 1 5 10 15 Gln Ala Ala Gly Asp Leu Gly Asp Val Gly Pro Pro Ile Pro Ser Pro 20 25 30 Gly Phe Ser Ser Phe Pro Gly Val Asp Ser Ser Ser Ser Phe Ser Ser 35 40 45 Ser Ser Arg Ser Gly Ser Ser Ser Ser Arg Ser Leu Gly Ser Gly Gly 50 55 60 Ser Val Ser Gln Leu Phe Ser Asn Phe Thr Gly Ser Val Asp Asp Arg 65 70 75 80 Gly Thr Cys Gln Cys Ser Val Ser Leu Pro Asp Thr Thr Phe Pro Val 85 90 95 Asp Arg Val Glu Arg Leu Glu Phe Thr Ala His Val Leu Ser Gln Lys 100 105 110 Phe Glu Lys Glu Leu Ser Lys Val Arg Glu Tyr Val Gln Leu Ile Ser 115 120 125 Val Tyr Glu Lys Lys Leu Leu Asn Leu Thr Val Arg Ile Asp Ile Met 130 135 140 Glu Lys Asp Thr Ile Ser Tyr Thr Glu Leu Asp Phe Glu Leu Ile Lys 145 150 155 160 Val Glu Val Lys Glu Met Glu Lys Leu Val Ile Gln Leu Lys Glu Ser 165 170 175 Phe Gly Gly Ser Ser Glu Ile Val Asp Gln Leu Glu Val Glu Ile Arg 180 185 190 Asn Met Thr Leu Leu Val Glu Lys Leu Glu Thr Leu Asp Lys Asn Asn 195 200 205 Val Leu Ala Ile Arg Arg Glu Ile Val Ala Leu Lys Thr Lys Leu Lys 210 215 220 Glu Cys Glu Ala Ser Lys Asp Gln Asn Thr Pro Val Val His Pro Pro 225 230 235 240 Pro Thr Pro Gly Ser Cys Gly His Gly Gly Val Val Asn Ile Ser Lys 245 250 255 Pro Ser Val Val Gln Leu Asn Trp Arg Gly Phe Ser Tyr Leu Tyr Gly 260 265 270 Ala Trp Gly Arg Asp Tyr Ser Pro Gln His Pro Asn Lys Gly Leu Tyr 275 280 285 Trp Val Ala Pro Leu Asn Thr Asp Gly Arg Leu Leu Glu Tyr Tyr Arg 290 295 300 Leu Tyr Asn Thr Leu Asp Asp Leu Leu Leu Tyr Ile Asn Ala Arg Glu 305 310 315 320 Leu Arg Ile Thr Tyr Gly Gln Gly Ser Gly Thr Ala Val Tyr Asn Asn 325 330 335 Asn Met Tyr Val Asn Met Tyr Asn Thr Gly Asn Ile Ala Arg Val Asn 340 345 350 Leu Thr Thr Asn Thr Ile Ala Val Thr Gln Thr Leu Pro Asn Ala Ala 355 360 365 Tyr Asn Asn Arg Phe Ser Tyr Ala Asn Val Ala Trp Gln Asp Ile Asp 370 375 380 Phe Ala Val Asp Glu Asn Gly Leu Trp Val Ile Tyr Ser Thr Glu Ala 385 390 395 400 Ser Thr Gly Asn Met Val Ile Ser Lys Leu Asn Asp Thr Thr Leu Gln 405 410 415 Val Leu Asn Thr Trp Tyr Thr Lys Gln Tyr Lys Pro Ser Ala Ser Asn 420 425 430 Ala Phe Met Val Cys Gly Val Leu Tyr Ala Thr Arg Thr Met Asn Thr 435 440 445 Arg Thr Glu Glu Ile Phe Tyr Tyr Tyr Asp Thr Asn Thr Gly Lys Glu 450 455 460 Gly Lys Leu Asp Ile Val Met His Lys Met Gln Glu Lys Val Gln Ser 465 470 475 480 Ile Asn Tyr Asn Pro Phe Asp Gln Lys Leu Tyr Val Tyr Asn Asp Gly 485 490 495 Tyr Leu Leu Asn Tyr Asp Leu Ser Val Leu Gln Lys Pro Gln 500 505 510 <210> 17 <211> 347 <212> PRT <213> Homo sapiens <400> 17 Met Ile Val Gln Leu Ile Cys Thr Val Cys Phe Leu Ala Val Asn Thr 1 5 10 15 Phe His Val Arg Ser Ser Phe Asp Phe Leu Lys Ala Asp Asp Met Gly 20 25 30 Glu Ile Asn Gln Thr Leu Val Ser Glu Phe Leu Leu Leu Gly Leu Ser 35 40 45 Gly Tyr Pro Lys Ile Glu Ile Val Tyr Phe Ala Leu Ile Leu Val Met 50 55 60 Tyr Leu Val Ile Leu Ile Gly Asn Gly Val Leu Ile Ile Ala Ser Ile 65 70 75 80 Phe Asp Ser His Phe His Thr Pro Met Tyr Phe Phe Leu Gly Asn Leu 85 90 95 Ser Phe Leu Asp Ile Cys Tyr Thr Ser Ser Ser Val Pro Ser Thr Leu 100 105 110 Val Ser Leu Ile Ser Lys Lys Arg Asn Ile Ser Phe Ser Gly Cys Ala 115 120 125 Val Gln Met Phe Phe Gly Phe Ala Met Gly Ser Thr Glu Cys Leu Leu 130 135 140 Leu Gly Met Met Ala Phe Asp Arg Tyr Val Ala Ile Cys Asn Pro Leu 145 150 155 160 Arg Tyr Pro Ile Ile Leu Ser Lys Val Ala Tyr Val Leu Met Ala Ser 165 170 175 Val Ser Trp Leu Ser Gly Gly Ile Asn Ser Ala Val Gln Thr Leu Leu 180 185 190 Ala Met Arg Leu Pro Phe Cys Gly Asn Asn Ile Ile Asn His Phe Ala 195 200 205 Cys Glu Ile Leu Ala Val Leu Lys Leu Ala Cys Ala Asp Ile Ser Leu 210 215 220 Asn Ile Ile Thr Met Val Ile Ser Asn Met Ala Phe Leu Val Leu Pro 225 230 235 240 Leu Met Val Ile Phe Phe Ser Tyr Met Phe Ile Leu Tyr Thr Ile Leu 245 250 255 Gln Met Asn Ser Ala Thr Gly Arg Arg Lys Ala Phe Ser Thr Cys Ser 260 265 270 Ala His Leu Thr Val Val Ile Ile Phe Tyr Gly Thr Ile Phe Phe Met 275 280 285 Tyr Ala Lys Pro Lys Ser Gln Asp Leu Ile Gly Glu Glu Lys Leu Gln 290 295 300 Ala Leu Asp Lys Leu Ile Ser Leu Phe Tyr Gly Val Val Thr Pro Met 305 310 315 320 Leu Asn Pro Ile Leu Tyr Ser Leu Arg Asn Lys Asp Val Lys Ala Ala 325 330 335 Val Lys Tyr Leu Leu Asn Lys Lys Pro Ile His 340 345 <210> 18 <211> 4684 <212> PRT <213> Homo sapiens <400> 18 Met Val Ala Gly Met Leu Met Pro Arg Asp Gln Leu Arg Ala Ile Tyr 1 5 10 15 Glu Val Leu Phe Arg Glu Gly Val Met Val Ala Lys Lys Asp Arg Arg 20 25 30 Pro Arg Ser Leu His Pro His Val Pro Gly Val Thr Asn Leu Gln Val 35 40 45 Met Arg Ala Met Ala Ser Leu Arg Ala Arg Gly Leu Val Arg Glu Thr 50 55 60 Phe Ala Trp Cys His Phe Tyr Trp Tyr Leu Thr Asn Glu Gly Ile Ala 65 70 75 80 His Leu Arg Gln Tyr Leu His Leu Pro Pro Glu Ile Val Pro Ala Ser 85 90 95 Leu Gln Arg Val Arg Arg Pro Val Ala Met Val Met Pro Ala Arg Arg 100 105 110 Thr Pro His Val Gln Ala Val Gln Gly Pro Leu Gly Ser Pro Pro Lys 115 120 125 Arg Gly Pro Leu Pro Thr Glu Glu Gln Arg Val Tyr Arg Arg Lys Glu 130 135 140 Leu Glu Glu Val Ser Pro Glu Thr Pro Val Val Pro Ala Thr Thr Gln 145 150 155 160 Arg Thr Leu Ala Arg Pro Gly Pro Glu Pro Ala Pro Ala Thr Asp Glu 165 170 175 Arg Asp Arg Val Gln Lys Lys Thr Phe Thr Lys Trp Val Asn Lys His 180 185 190 Leu Ile Lys Ala Gln Arg His Ile Ser Asp Leu Tyr Glu Asp Leu Arg 195 200 205 Asp Gly His Asn Leu Ile Ser Leu Leu Glu Val Leu Ser Gly Asp Ser 210 215 220 Leu Pro Arg Glu Lys Gly Arg Met Arg Phe His Lys Leu Gln Asn Val 225 230 235 240 Gln Ile Ala Leu Asp Tyr Leu Arg His Arg Gln Val Lys Leu Val Asn 245 250 255 Ile Arg Asn Asp Asp Ile Ala Asp Gly Asn Pro Lys Leu Thr Leu Gly 260 265 270 Leu Ile Trp Thr Ile Ile Leu His Phe Gln Ile Ser Asp Ile Gln Val 275 280 285 Ser Gly Gln Ser Glu Asp Met Thr Ala Lys Glu Lys Leu Leu Leu Trp 290 295 300 Ser Gln Arg Met Val Glu Gly Tyr Gln Gly Leu Arg Cys Asp Asn Phe 305 310 315 320 Thr Ser Ser Trp Arg Asp Gly Arg Leu Phe Asn Ala Ile Ile His Arg 325 330 335 His Lys Pro Leu Leu Ile Asp Met Asn Lys Val Tyr Arg Gln Thr Asn 340 345 350 Leu Glu Asn Leu Asp Gln Ala Phe Ser Val Ala Glu Arg Asp Leu Gly 355 360 365 Val Thr Arg Leu Leu Asp Pro Glu Asp Val Asp Val Pro Gln Pro Asp 370 375 380 Glu Lys Ser Ile Ile Thr Tyr Val Ser Ser Leu Tyr Asp Ala Met Pro 385 390 395 400 Arg Val Pro Asp Val Gln Asp Gly Val Arg Ala Asn Glu Leu Gln Leu 405 410 415 Arg Trp Gln Glu Tyr Arg Glu Leu Val Leu Leu Leu Leu Leu Gln Trp Met 420 425 430 Arg His His Thr Ala Ala Phe Glu Glu Arg Arg Phe Pro Ser Ser Phe 435 440 445 Glu Glu Ile Glu Ile Leu Trp Ser Gln Phe Leu Lys Phe Lys Glu Met 450 455 460 Glu Leu Pro Ala Lys Glu Ala Asp Lys Asn Arg Ser Lys Gly Ile Tyr 465 470 475 480 Gln Ser Leu Glu Gly Ala Val Gln Ala Gly Gln Leu Lys Val Pro Pro 485 490 495 Gly Tyr His Pro Leu Asp Val Glu Lys Glu Trp Gly Lys Leu His Val 500 505 510 Ala Ile Leu Glu Arg Glu Lys Gln Leu Arg Ser Glu Phe Glu Arg Leu 515 520 525 Glu Cys Leu Gln Arg Ile Val Thr Lys Leu Gln Met Glu Ala Gly Leu 530 535 540 Cys Glu Glu Gln Leu Asn Gln Ala Asp Ala Leu Leu Gln Ser Asp Val 545 550 555 560 Arg Leu Leu Ala Ala Gly Lys Val Pro Gln Arg Ala Gly Glu Val Glu 565 570 575 Arg Asp Leu Asp Lys Ala Asp Ser Met Ile Arg Leu Leu Phe Asn Asp 580 585 590 Val Gln Thr Leu Lys Asp Gly Arg His Pro Gln Gly Glu Gln Met Tyr 595 600 605 Arg Arg Val Tyr Arg Leu His Glu Arg Leu Val Ala Ile Arg Thr Glu 610 615 620 Tyr Asn Leu Arg Leu Lys Ala Gly Val Ala Ala Pro Ala Thr Gln Val 625 630 635 640 Ala Gln Val Thr Leu Gln Ser Val Gln Arg Arg Pro Glu Leu Glu Asp 645 650 655 Ser Thr Leu Arg Tyr Leu Gln Asp Leu Leu Ala Trp Val Glu Glu Asn 660 665 670 Gln His Arg Val Asp Gly Ala Glu Trp Gly Val Asp Leu Pro Ser Val 675 680 685 Glu Ala Gln Leu Gly Ser His Arg Gly Leu His Gln Ser Ile Glu Glu 690 695 700 Phe Arg Ala Lys Ile Glu Arg Ala Arg Ser Asp Glu Gly Gln Leu Ser 705 710 715 720 Pro Ala Thr Arg Gly Ala Tyr Arg Asp Cys Leu Gly Arg Leu Asp Leu 725 730 735 Gln Tyr Ala Lys Leu Leu Asn Ser Ser Lys Ala Arg Leu Arg Ser Leu 740 745 750 Glu Ser Leu His Ser Phe Val Ala Ala Ala Thr Lys Glu Leu Met Trp 755 760 765 Leu Asn Glu Lys Glu Glu Glu Glu Val Gly Phe Asp Trp Ser Asp Arg 770 775 780 Asn Thr Asn Met Thr Ala Lys Lys Glu Ser Tyr Ser Ala Leu Met Arg 785 790 795 800 Glu Leu Glu Leu Lys Glu Lys Lys Ile Lys Glu Leu Gln Asn Ala Gly 805 810 815 Asp Arg Leu Leu Arg Glu Asp His Pro Ala Arg Pro Thr Val Glu Ser 820 825 830 Phe Gln Ala Ala Leu Gln Thr Gln Trp Ser Trp Met Leu Gln Leu Cys 835 840 845 Cys Cys Ile Glu Ala His Leu Lys Glu Asn Ala Ala Tyr Phe Gln Phe 850 855 860 Phe Ser Asp Val Arg Glu Ala Glu Gly Gln Leu Gln Lys Leu Gln Glu 865 870 875 880 Ala Leu Arg Arg Lys Tyr Ser Cys Asp Arg Ser Ala Thr Val Thr Arg 885 890 895 Leu Glu Asp Leu Leu Gln Asp Ala Gln Asp Glu Lys Glu Gln Leu Asn 900 905 910 Glu Tyr Lys Gly His Leu Ser Gly Leu Ala Lys Arg Ala Lys Ala Val 915 920 925 Val Gln Leu Lys Pro Arg His Pro Ala His Pro Met Arg Gly Arg Leu 930 935 940 Pro Leu Leu Ala Val Cys Asp Tyr Lys Gln Val Glu Val Thr Val His 945 950 955 960 Lys Gly Asp Glu Cys Gln Leu Val Gly Pro Ala Gln Pro Ser His Trp 965 970 975 Lys Val Leu Ser Ser Ser Ser Gly Ser Glu Ala Ala Val Pro Ser Val Cys 980 985 990 Phe Leu Val Pro Pro Asn Gln Glu Ala Gln Glu Ala Val Thr Arg 995 1000 1005 Leu Glu Ala Gln His Gln Ala Leu Val Thr Leu Trp His Gln Leu His 1010 1015 1020 Val Asp Met Lys Ser Leu Leu Ala Trp Gln Ser Leu Arg Arg Asp Val 1025 1030 1035 1040 Gln Leu Ile Arg Ser Trp Ser Leu Ala Thr Phe Arg Thr Leu Lys Pro 1045 1050 1055 Glu Glu Gln Arg Gln Ala Leu His Ser Leu Glu Leu His Tyr Gln Ala 1060 1065 1070 Phe Leu Arg Asp Ser Gln Asp Ala Gly Gly Phe Gly Pro Glu Asp Arg 1075 1080 1085 Leu Met Ala Glu Arg Glu Tyr Gly Ser Cys Ser His His Tyr Gln Gln 1090 1095 1100 Leu Leu Gln Ser Leu Glu Gln Gly Ala Gln Glu Glu Ser Arg Cys Gln 1105 1110 1115 1120 Arg Cys Ile Ser Glu Leu Lys Asp Ile Arg Leu Gln Leu Glu Ala Cys 1125 1130 1135 Glu Thr Arg Thr Val His Arg Leu Arg Leu Pro Leu Asp Lys Glu Pro 1140 1145 1150 Ala Arg Glu Cys Ala Gln Arg Ile Ala Glu Gln Gln Lys Ala Gln Ala 1155 1160 1165 Glu Val Glu Gly Leu Gly Lys Gly Val Ala Arg Leu Ser Ala Glu Ala 1170 1175 1180 Glu Lys Val Leu Ala Leu Pro Glu Pro Ser Pro Ala Ala Pro Thr Leu 1185 1190 1195 1200 Arg Ser Glu Leu Glu Leu Thr Leu Gly Lys Leu Glu Gln Val Arg Ser 1205 1210 1215 Leu Ser Ala Ile Tyr Leu Glu Lys Leu Lys Thr Ile Ser Leu Val Ile 1220 1225 1230 Arg Gly Thr Gln Gly Ala Glu Glu Val Leu Arg Ala His Glu Glu Gln 1235 1240 1245 Leu Lys Glu Ala Gln Ala Val Pro Ala Thr Leu Pro Glu Leu Glu Ala 1250 1255 1260 Thr Lys Ala Ser Leu Lys Lys Leu Arg Ala Gln Ala Glu Ala Gln Gln 1265 1270 1275 1280 Pro Thr Phe Asp Ala Leu Arg Asp Glu Leu Arg Gly Ala Gln Glu Val 1285 1290 1295 Gly Glu Arg Leu Gln Gln Arg His Gly Glu Arg Asp Val Glu Val Glu 1300 1305 1310 Arg Trp Arg Glu Arg Val Ala Gln Leu Leu Glu Arg Trp Gln Ala Val 1315 1320 1325 Leu Ala Gln Thr Asp Val Arg Gln Arg Glu Leu Glu Gln Leu Gly Arg 1330 1335 1340 Gln Leu Arg Tyr Tyr Arg Glu Ser Ala Asp Pro Leu Gly Ala Trp Leu 1345 1350 1355 1360 Gln Asp Ala Arg Arg Arg Gln Glu Gln Ile Gln Ala Met Pro Leu Ala 1365 1370 1375 Asp Ser Gln Ala Val Arg Glu Gln Leu Arg Gln Glu Gln Ala Leu Leu 1380 1385 1390 Glu Glu Ile Glu Arg His Gly Glu Lys Val Glu Glu Cys Gln Arg Phe 1395 1400 1405 Ala Lys Gln Tyr Ile Asn Ala Ile Lys Asp Tyr Glu Leu Gln Leu Val 1410 1415 1420 Thr Tyr Lys Ala Gln Leu Glu Pro Val Ala Ser Pro Ala Lys Lys Pro 1425 1430 1435 1440 Lys Val Gln Ser Gly Ser Glu Ser Val Ile Gln Glu Tyr Val Asp Leu 1445 1450 1455 Arg Thr His Tyr Ser Glu Leu Thr Thr Leu Thr Ser Gln Tyr Ile Lys 1460 1465 1470 Phe Ile Ser Glu Thr Leu Arg Arg Met Glu Glu Glu Glu Arg Leu Ala 1475 1480 1485 Glu Gln Gln Arg Ala Glu Glu Arg Glu Arg Leu Ala Glu Val Glu Ala 1490 1495 1500 Ala Leu Glu Lys Gln Arg Gln Leu Ala Glu Ala His Ala Gln Ala Lys 1505 1510 1515 1520 Ala Gln Ala Glu Arg Glu Ala Lys Glu Leu Gln Gln Arg Met Gln Glu 1525 1530 1535 Glu Val Val Arg Arg Glu Glu Ala Ala Val Asp Ala Gln Gln Gln Lys 1540 1545 1550 Arg Ser Ile Gln Glu Glu Leu Gln Gln Leu Arg Gln Ser Ser Glu Ala 1555 1560 1565 Glu Ile Gln Ala Lys Ala Arg Gln Ala Glu Ala Ala Glu Arg Ser Arg 1570 1575 1580 Leu Arg Ile Glu Glu Glu Ile Arg Val Val Arg Leu Gln Leu Glu Ala 1585 1590 1595 1600 Thr Glu Arg Gln Arg Gly Gly Ala Glu Gly Glu Leu Gln Ala Leu Arg 1605 1610 1615 Ala Arg Ala Glu Glu Ala Glu Ala Gln Lys Arg Gln Ala Gln Glu Glu 1620 1625 1630 Ala Glu Arg Leu Arg Arg Gln Val Gln Asp Glu Ser Gln Arg Lys Arg 1635 1640 1645 Gln Ala Glu Val Glu Leu Ala Ser Arg Val Lys Ala Glu Ala Glu Ala 1650 1655 1660 Ala Arg Glu Lys Gln Arg Ala Leu Gln Ala Leu Glu Glu Leu Arg Leu 1665 1670 1675 1680 Gln Ala Glu Glu Ala Glu Arg Arg Leu Arg Gln Ala Glu Val Glu Arg 1685 1690 1695 Ala Arg Gln Val Gln Val Ala Leu Glu Thr Ala Gln Arg Ser Ala Glu 1700 1705 1710 Ala Glu Leu Gln Ser Lys Arg Ala Ser Phe Ala Glu Lys Thr Ala Gln 1715 1720 1725 Leu Glu Arg Ser Leu Gln Glu Glu His Val Ala Val Ala Gln Leu Arg 1730 1735 1740 Glu Glu Ala Glu Arg Arg Ala Gln Gln Gln Ala Glu Ala Glu Arg Ala 1745 1750 1755 1760 Arg Glu Glu Ala Glu Arg Glu Leu Glu Arg Trp Gln Leu Lys Ala Asn 1765 1770 1775 Glu Ala Leu Arg Leu Arg Leu Gln Ala Glu Glu Val Ala Gln Gln Lys 1780 1785 1790 Ser Leu Ala Gln Ala Glu Ala Glu Lys Gln Lys Glu Glu Ala Glu Arg 1795 1800 1805 Glu Ala Arg Arg Arg Gly Lys Ala Glu Glu Gln Ala Val Arg Gln Arg 1810 1815 1820 Glu Leu Ala Glu Gln Glu Leu Glu Lys Gln Arg Gln Leu Ala Glu Gly 1825 1830 1835 1840 Thr Ala Gln Gln Arg Leu Ala Ala Glu Gln Glu Leu Ile Arg Leu Arg 1845 1850 1855 Ala Glu Thr Glu Gln Gly Glu Gln Gln Arg Gln Leu Leu Glu Glu Glu 1860 1865 1870 Leu Ala Arg Leu Gln Arg Glu Ala Ala Ala Ala Thr Gln Lys Arg Gln 1875 1880 1885 Glu Leu Glu Ala Glu Leu Ala Lys Val Arg Ala Glu Met Glu Val Leu 1890 1895 1900 Leu Ala Ser Lys Ala Arg Ala Glu Glu Glu Ser Arg Ser Thr Ser Glu 1905 1910 1915 1920 Lys Ser Lys Gln Arg Leu Glu Ala Glu Ala Gly Arg Phe Arg Glu Leu 1925 1930 1935 Ala Glu Glu Ala Ala Arg Leu Arg Ala Leu Ala Glu Glu Ala Lys Arg 1940 1945 1950 Gln Arg Gln Leu Ala Glu Glu Asp Ala Ala Arg Gln Arg Ala Glu Ala 1955 1960 1965 Glu Arg Val Leu Ala Glu Lys Leu Ala Ala Ile Gly Glu Ala Thr Arg 1970 1975 1980 Leu Lys Thr Glu Ala Glu Ile Ala Leu Lys Glu Lys Glu Ala Glu Asn 1985 1990 1995 2000 Glu Arg Leu Arg Arg Leu Ala Glu Asp Glu Ala Phe Gln Arg Arg Arg 2005 2010 2015 Leu Glu Glu Gln Ala Ala Gln His Lys Ala Asp Ile Glu Glu Arg Leu 2020 2025 2030 Ala Gln Leu Arg Lys Ala Ser Asp Ser Glu Leu Glu Arg Gln Lys Gly 2035 2040 2045 Leu Val Glu Asp Thr Leu Arg Gln Arg Arg Gln Val Glu Glu Glu Ile 2050 2055 2060 Leu Ala Leu Lys Ala Ser Phe Glu Lys Ala Ala Ala Gly Lys Ala Glu 2065 2070 2075 2080 Leu Glu Leu Glu Leu Gly Arg Ile Arg Ser Asn Ala Glu Asp Thr Leu 2085 2090 2095 Arg Ser Lys Glu Gln Ala Glu Leu Glu Ala Ala Arg Gln Arg Gln Leu 2100 2105 2110 Ala Ala Glu Glu Glu Arg Arg Arg Arg Glu Ala Glu Glu Arg Val Gln 2115 2120 2125 Lys Ser Leu Ala Ala Glu Glu Glu Ala Ala Arg Gln Arg Lys Ala Ala 2130 2135 2140 Leu Glu Glu Val Glu Arg Leu Lys Ala Lys Val Glu Glu Ala Arg Arg 2145 2150 2155 2160 Leu Arg Glu Arg Ala Glu Gln Glu Ser Ala Arg Gln Leu Gln Leu Ala 2165 2170 2175 Gln Glu Ala Ala Gln Lys Arg Leu Gln Ala Glu Glu Lys Ala His Ala 2180 2185 2190 Phe Ala Val Gln Gln Lys Glu Gln Glu Leu Gln Gln Thr Leu Gln Gln 2195 2200 2205 Glu Gln Ser Val Leu Asp Gln Leu Arg Gly Glu Ala Glu Ala Ala Arg 2210 2215 2220 Arg Ala Ala Glu Glu Ala Glu Glu Ala Arg Val Gln Ala Glu Arg Glu 2225 2230 2235 2240 Ala Ala Gln Ser Arg Arg Gln Val Glu Glu Ala Glu Arg Leu Lys Gln 2245 2250 2255 Ser Ala Glu Glu Gln Ala Gln Ala Arg Ala Gln Ala Gln Ala Ala Ala 2260 2265 2270 Glu Lys Leu Arg Lys Glu Ala Glu Gln Glu Ala Ala Arg Arg Ala Gln 2275 2280 2285 Ala Glu Gln Ala Ala Leu Arg Gln Lys Gln Ala Ala Asp Ala Glu Met 2290 2295 2300 Glu Lys His Lys Lys Phe Ala Glu Gln Thr Leu Arg Gln Lys Ala Gln 2305 2310 2315 2320 Val Glu Gln Glu Leu Thr Thr Leu Arg Leu Gln Leu Glu Glu Thr Asp 2325 2330 2335 His Gln Lys Asn Leu Leu Asp Glu Glu Leu Gln Arg Leu Lys Ala Glu 2340 2345 2350 Ala Thr Glu Ala Ala Arg Gln Arg Ser Gln Val Glu Glu Glu Leu Phe 2355 2360 2365 Ser Val Arg Val Gln Met Glu Glu Leu Ser Lys Leu Lys Ala Arg Ile 2370 2375 2380 Glu Ala Glu Asn Arg Ala Leu Ile Leu Arg Asp Lys Asp Asn Thr Gln 2385 2390 2395 2400 Arg Phe Leu Gln Glu Glu Ala Glu Lys Met Lys Gln Val Ala Glu Glu 2405 2410 2415 Ala Ala Arg Leu Ser Val Ala Ala Gln Glu Ala Ala Arg Leu Arg Gln 2420 2425 2430 Leu Ala Glu Glu Asp Leu Ala Gln Gln Arg Ala Leu Ala Glu Lys Met 2435 2440 2445 Leu Lys Glu Lys Met Gln Ala Val Gln Glu Ala Thr Arg Leu Lys Ala 2450 2455 2460 Glu Ala Glu Leu Leu Gln Gln Gln Lys Glu Leu Ala Gln Glu Gln Ala 2465 2470 2475 2480 Arg Arg Leu Gln Glu Asp Lys Glu Gln Met Ala Gln Gln Leu Ala Glu 2485 2490 2495 Glu Thr Gln Gly Phe Gln Arg Thr Leu Glu Ala Glu Arg Gln Arg Gln 2500 2505 2510 Leu Glu Met Ser Ala Glu Ala Glu Arg Leu Lys Leu Arg Val Ala Glu 2515 2520 2525 Met Ser Arg Ala Gln Ala Arg Ala Glu Glu Asp Ala Gln Arg Phe Arg 2530 2535 2540 Lys Gln Ala Glu Glu Ile Gly Glu Lys Leu His Arg Thr Glu Leu Ala 2545 2550 2555 2560 Thr Gln Glu Lys Val Thr Leu Val Gln Thr Leu Glu Ile Gln Arg Gln 2565 2570 2575 Gln Ser Asp His Asp Ala Glu Arg Leu Arg Glu Ala Ile Ala Glu Leu 2580 2585 2590 Glu Arg Glu Lys Glu Lys Leu Gln Gln Glu Ala Lys Leu Leu Gln Leu 2595 2600 2605 Lys Ser Glu Glu Met Gln Thr Val Gln Gln Glu Gln Leu Leu Gln Glu 2610 2615 2620 Thr Gln Ala Leu Gln Gln Ser Phe Leu Ser Glu Lys Asp Ser Leu Leu 2625 2630 2635 2640 Gln Arg Glu Arg Phe Ile Glu Gln Glu Lys Ala Lys Leu Glu Gln Leu 2645 2650 2655 Phe Gln Asp Glu Val Ala Lys Ala Gln Gln Leu Arg Glu Glu Gln Gln 2660 2665 2670 Arg Gln Gln Gln Gln Met Glu Gln Glu Arg Gln Arg Leu Val Ala Ser 2675 2680 2685 Met Glu Glu Ala Arg Arg Arg Gln His Glu Ala Glu Glu Gly Val Arg 2690 2695 2700 Arg Lys Gln Glu Glu Leu Gln Gln Leu Glu Gln Gln Arg Arg Gln Gln 2705 2710 2715 2720 Glu Glu Leu Leu Ala Glu Glu Asn Gln Arg Leu Arg Glu Gln Leu Gln 2725 2730 2735 Leu Leu Glu Glu Gln His Arg Ala Ala Leu Ala His Ser Glu Glu Val 2740 2745 2750 Thr Ala Ser Gln Val Ala Ala Thr Lys Thr Leu Pro Asn Gly Arg Asp 2755 2760 2765 Ala Leu Asp Gly Pro Ala Ala Glu Ala Glu Pro Glu His Ser Phe Asp 2770 2775 2780 Gly Leu Arg Arg Lys Val Ser Ala Gln Arg Leu Gln Glu Ala Gly Ile 2785 2790 2795 2800 Leu Ser Ala Glu Glu Leu Gln Arg Leu Ala Gln Gly His Thr Thr Val 2805 2810 2815 Asp Glu Leu Ala Arg Arg Glu Asp Val Arg His Tyr Leu Gln Gly Arg 2820 2825 2830 Ser Ser Ile Ala Gly Leu Leu Leu Lys Ala Thr Asn Glu Lys Leu Ser 2835 2840 2845 Val Tyr Ala Ala Leu Gln Arg Gln Leu Leu Ser Pro Gly Thr Ala Leu 2850 2855 2860 Ile Leu Leu Glu Ala Gln Ala Ala Ser Gly Phe Leu Leu Asp Pro Val 2865 2870 2875 2880 Arg Asn Arg Arg Leu Thr Val Asn Glu Ala Val Lys Glu Gly Val Val 2885 2890 2895 Gly Pro Glu Leu His His Lys Leu Leu Ser Ala Glu Arg Ala Val Thr 2900 2905 2910 Gly Tyr Lys Asp Pro Tyr Thr Gly Gln Gln Ile Ser Leu Phe Gln Ala 2915 2920 2925 Met Gln Lys Gly Leu Ile Val Arg Glu His Gly Ile Arg Leu Leu Glu 2930 2935 2940 Ala Gln Ile Ala Thr Gly Gly Val Ile Asp Pro Val His Ser His Arg 2945 2950 2955 2960 Val Pro Val Asp Val Ala Tyr Arg Arg Gly Tyr Phe Asp Glu Glu Met 2965 2970 2975 Asn Arg Val Leu Ala Asp Pro Ser Asp Asp Thr Lys Gly Phe Phe Asp 2980 2985 2990 Pro Asn Thr His Glu Asn Leu Thr Tyr Leu Gln Leu Leu Glu Arg Cys 2995 3000 3005 Val Glu Asp Pro Glu Thr Gly Leu Cys Leu Leu Pro Leu Thr Asp Lys 3010 3015 3020 Ala Ala Lys Gly Gly Glu Leu Val Tyr Thr Asp Ser Glu Ala Arg Asp 3025 3030 3035 3040 Val Phe Glu Lys Ala Thr Val Ser Ala Pro Phe Gly Lys Phe Gln Gly 3045 3050 3055 Lys Thr Val Thr Ile Trp Glu Ile Ile Asn Ser Glu Tyr Phe Thr Ala 3060 3065 3070 Glu Gln Arg Arg Asp Leu Leu Arg Gln Phe Arg Thr Gly Arg Ile Thr 3075 3080 3085 Val Glu Lys Ile Ile Lys Ile Ile Ile Thr Val Val Glu Glu Gln Glu 3090 3095 3100 Gln Lys Gly Arg Leu Cys Phe Glu Gly Leu Arg Ser Leu Val Pro Ala 3105 3110 3115 3120 Ala Glu Leu Leu Glu Ser Arg Val Ile Asp Arg Glu Leu Tyr Gln Gln 3125 3130 3135 Leu Gln Arg Gly Glu Arg Ser Val Arg Asp Val Ala Glu Val Asp Thr 3140 3145 3150 Val Arg Arg Ala Leu Arg Gly Ala Asn Val Ile Ala Gly Val Trp Leu 3155 3160 3165 Glu Glu Ala Gly Gln Lys Leu Ser Ile Tyr Asn Ala Leu Lys Lys Asp 3170 3175 3180 Leu Leu Pro Ser Asp Met Ala Val Ala Leu Leu Glu Ala Gln Ala Gly 3185 3190 3195 3200 Thr Gly His Ile Ile Asp Pro Ala Thr Ser Ala Arg Leu Thr Val Asp 3205 3210 3215 Glu Ala Val Arg Ala Gly Leu Val Gly Pro Glu Phe His Glu Lys Leu 3220 3225 3230 Leu Ser Ala Glu Lys Ala Val Thr Gly Tyr Arg Asp Pro Tyr Thr Gly 3235 3240 3245 Gln Ser Val Ser Leu Phe Gln Ala Leu Lys Lys Gly Leu Ile Pro Arg 3250 3255 3260 Glu Gln Gly Leu Arg Leu Leu Asp Ala Gln Leu Ser Thr Gly Gly Ile 3265 3270 3275 3280 Val Asp Pro Ser Lys Ser His Arg Val Pro Leu Asp Val Ala Cys Ala 3285 3290 3295 Arg Gly Cys Leu Asp Glu Glu Thr Ser Arg Ala Leu Ser Ala Pro Arg 3300 3305 3310 Ala Asp Ala Lys Ala Tyr Ser Asp Pro Ser Thr Gly Glu Pro Ala Thr 3315 3320 3325 Tyr Gly Glu Leu Gln Gln Arg Cys Arg Pro Asp Gln Leu Thr Gly Leu 3330 3335 3340 Ser Leu Leu Pro Leu Ser Glu Lys Ala Ala Arg Ala Arg Gln Glu Glu 3345 3350 3355 3360 Leu Tyr Ser Glu Leu Gln Ala Arg Glu Thr Phe Glu Lys Thr Pro Val 3365 3370 3375 Glu Val Pro Val Gly Gly Phe Lys Gly Arg Thr Val Thr Val Trp Glu 3380 3385 3390 Leu Ile Ser Ser Glu Tyr Phe Thr Ala Glu Gln Arg Gln Glu Leu Leu 3395 3400 3405 Arg Gln Phe Arg Thr Gly Lys Val Thr Val Glu Lys Val Ile Lys Ile 3410 3415 3420 Leu Ile Thr Ile Val Glu Glu Val Glu Thr Leu Arg Gln Glu Arg Leu 3425 3430 3435 3440 Ser Phe Ser Gly Leu Arg Ala Pro Val Pro Ala Ser Glu Leu Leu Ala 3445 3450 3455 Ser Gly Val Leu Ser Arg Ala Gln Phe Glu Gln Leu Lys Asp Gly Lys 3460 3465 3470 Thr Thr Val Lys Asp Leu Ser Glu Leu Gly Ser Val Arg Thr Leu Leu 3475 3480 3485 Gln Gly Ser Gly Cys Leu Ala Gly Ile Tyr Leu Glu Asp Thr Lys Glu 3490 3495 3500 Lys Val Ser Ile Tyr Glu Ala Met Arg Arg Gly Leu Leu Arg Ala Thr 3505 3510 3515 3520 Thr Ala Ala Leu Leu Leu Glu Ala Gln Ala Ala Thr Gly Phe Leu Val 3525 3530 3535 Asp Pro Val Arg Asn Gln Arg Leu Tyr Val His Glu Ala Val Lys Ala 3540 3545 3550 Gly Val Val Gly Pro Glu Leu His Glu Gln Leu Leu Ser Ala Glu Lys 3555 3560 3565 Ala Val Thr Gly Tyr Arg Asp Pro Tyr Ser Gly Ser Thr Ile Ser Leu 3570 3575 3580 Phe Gln Ala Met Gln Lys Gly Leu Val Leu Arg Gln His Gly Ile Arg 3585 3590 3595 3600 Leu Leu Glu Ala Gln Ile Ala Thr Gly Gly Ile Ile Asp Pro Val His 3605 3610 3615 Ser His Arg Val Pro Val Asp Val Ala Tyr Gln Arg Gly Tyr Phe Ser 3620 3625 3630 Glu Glu Met Asn Arg Val Leu Ala Asp Pro Ser Asp Asp Thr Lys Gly 3635 3640 3645 Phe Phe Asp Pro Asn Thr His Glu Asn Leu Thr Tyr Arg Gln Leu Leu 3650 3655 3660 Glu Arg Cys Val Glu Asp Pro Glu Thr Gly Leu Arg Leu Leu Pro Leu 3665 3670 3675 3680 Lys Gly Ala Glu Lys Ala Glu Val Val Glu Thr Thr Gln Val Tyr Thr 3685 3690 3695 Glu Glu Glu Thr Arg Arg Ala Phe Glu Glu Thr Gln Ile Asp Ile Pro 3700 3705 3710 Gly Gly Gly Ser His Gly Gly Ser Thr Met Ser Leu Trp Glu Val Met 3715 3720 3725 Gln Ser Asp Leu Ile Pro Glu Glu Gln Arg Ala Gln Leu Met Ala Asp 3730 3735 3740 Phe Gln Ala Gly Arg Val Thr Lys Glu Arg Met Ile Ile Ile Ile Ile 3745 3750 3755 3760 Glu Ile Ile Glu Lys Thr Glu Ile Ile Arg Gln Gln Gly Leu Ala Ser 3765 3770 3775 Tyr Asp Tyr Val Arg Arg Arg Leu Thr Ala Glu Asp Leu Phe Glu Ala 3780 3785 3790 Arg Ile Ile Ser Leu Glu Thr Tyr Asn Leu Leu Arg Glu Gly Thr Arg 3795 3800 3805 Ser Leu Arg Glu Ala Leu Glu Ala Glu Ser Ala Trp Cys Tyr Leu Tyr 3810 3815 3820 Gly Thr Gly Ser Val Ala Gly Val Tyr Leu Pro Gly Ser Arg Gln Thr 3825 3830 3835 3840 Leu Ser Ile Tyr Gln Ala Leu Lys Lys Gly Leu Leu Ser Ala Glu Val 3845 3850 3855 Ala Arg Leu Leu Leu Leu Glu Ala Gln Ala Ala Thr Gly Phe Leu Leu Asp 3860 3865 3870 Pro Val Lys Gly Glu Arg Leu Thr Val Asp Glu Ala Val Arg Lys Gly 3875 3880 3885 Leu Val Gly Pro Glu Leu His Asp Arg Leu Leu Ser Ala Glu Arg Ala 3890 3895 3900 Val Thr Gly Tyr Arg Asp Pro Tyr Thr Glu Gln Thr Ile Ser Leu Phe 3905 3910 3915 3920 Gln Ala Met Lys Lys Glu Leu Ile Pro Thr Glu Glu Ala Leu Arg Leu 3925 3930 3935 Leu Asp Ala Gln Leu Ala Thr Gly Gly Ile Val Asp Pro Arg Leu Gly 3940 3945 3950 Phe His Leu Pro Leu Glu Val Ala Tyr Gln Arg Gly Tyr Leu Asn Lys 3955 3960 3965 Asp Thr His Asp Gln Leu Ser Glu Pro Ser Glu Val Arg Ser Tyr Val 3970 3975 3980 Asp Pro Ser Thr Asp Glu Arg Leu Ser Tyr Thr Gln Leu Leu Arg Arg 3985 3990 3995 4000 Cys Arg Arg Asp Asp Gly Thr Gly Gln Leu Leu Leu Pro Leu Ser Asp 4005 4010 4015 Ala Arg Lys Leu Thr Phe Arg Gly Leu Arg Lys Gln Ile Thr Met Glu 4020 4025 4030 Glu Leu Val Arg Ser Gln Val Met Asp Glu Ala Thr Ala Leu Gln Leu 4035 4040 4045 Arg Glu Gly Leu Thr Ser Ile Glu Glu Val Thr Lys Asn Leu Gln Lys 4050 4055 4060 Phe Leu Glu Gly Thr Ser Cys Ile Ala Gly Val Phe Val Asp Ala Thr 4065 4070 4075 4080 Lys Glu Arg Leu Ser Val Tyr Gln Ala Met Lys Lys Gly Ile Ile Arg 4085 4090 4095 Pro Gly Thr Ala Phe Glu Leu Leu Glu Ala Gln Ala Ala Thr Gly Tyr 4100 4105 4110 Val Ile Asp Pro Ile Lys Gly Leu Lys Leu Thr Val Glu Glu Ala Val 4115 4120 4125 Arg Met Gly Ile Val Gly Pro Glu Phe Lys Asp Lys Leu Leu Ser Ala 4130 4135 4140 Glu Arg Ala Val Thr Gly Tyr Lys Asp Pro Tyr Ser Gly Lys Leu Ile 4145 4150 4155 4160 Ser Leu Phe Gln Ala Met Lys Lys Gly Leu Ile Leu Lys Asp His Gly 4165 4170 4175 Ile Arg Leu Leu Glu Ala Gln Ile Ala Thr Gly Gly Ile Ile Asp Pro 4180 4185 4190 Glu Glu Ser His Arg Leu Pro Val Glu Val Ala Tyr Lys Arg Gly Leu 4195 4200 4205 Phe Asp Glu Glu Met Asn Glu Ile Leu Thr Asp Pro Ser Asp Asp Thr 4210 4215 4220 Lys Gly Phe Phe Asp Pro Asn Thr Glu Glu Asn Leu Thr Tyr Leu Gln 4225 4230 4235 4240 Leu Met Glu Arg Cys Ile Thr Asp Pro Gln Thr Gly Leu Cys Leu Leu 4245 4250 4255 Pro Leu Lys Glu Lys Lys Arg Glu Arg Lys Thr Ser Ser Lys Ser Ser 4260 4265 4270 Val Arg Lys Arg Arg Val Val Ile Val Asp Pro Glu Thr Gly Lys Glu 4275 4280 4285 Met Ser Val Tyr Glu Ala Tyr Arg Lys Gly Leu Ile Asp His Gln Thr 4290 4295 4300 Tyr Leu Glu Leu Ser Glu Gln Glu Cys Glu Trp Glu Glu Ile Thr Ile 4305 4310 4315 4320 Ser Ser Ser Asp Gly Val Val Lys Ser Met Ile Ile Asp Arg Arg Ser 4325 4330 4335 Gly Arg Gln Tyr Asp Ile Asp Asp Ala Ile Ala Lys Asn Leu Ile Asp 4340 4345 4350 Arg Ser Ala Leu Asp Gln Tyr Arg Ala Gly Thr Leu Ser Ile Thr Glu 4355 4360 4365 Phe Ala Asp Met Leu Ser Gly Asn Ala Gly Gly Phe Arg Ser Arg Ser 4370 4375 4380 Ser Ser Val Gly Ser Ser Ser Ser Ser Tyr Pro Ile Ser Pro Ala Val Ser 4385 4390 4395 4400 Arg Thr Gln Leu Ala Ser Trp Ser Asp Pro Thr Glu Glu Thr Gly Pro 4405 4410 4415 Val Ala Gly Ile Leu Asp Thr Glu Thr Leu Glu Lys Val Ser Ile Thr 4420 4425 4430 Glu Ala Met His Arg Asn Leu Val Asp Asn Ile Thr Gly Gln Arg Leu 4435 4440 4445 Leu Glu Ala Gln Ala Cys Thr Gly Gly Ile Ile Asp Pro Ser Thr Gly 4450 4455 4460 Glu Arg Phe Pro Val Thr Asp Ala Val Asn Lys Gly Leu Val Asp Lys 4465 4470 4475 4480 Ile Met Val Asp Arg Ile Asn Leu Ala Gln Lys Ala Phe Cys Gly Phe 4485 4490 4495 Glu Asp Pro Arg Thr Lys Thr Lys Met Ser Ala Ala Gln Ala Leu Lys 4500 4505 4510 Lys Gly Trp Leu Tyr Tyr Glu Ala Gly Gln Arg Phe Leu Glu Val Gln 4515 4520 4525 Tyr Leu Thr Gly Gly Leu Ile Glu Pro Asp Thr Pro Gly Arg Val Pro 4530 4535 4540 Leu Asp Glu Ala Leu Gln Arg Gly Thr Val Asp Ala Arg Thr Ala Gln 4545 4550 4555 4560 Lys Leu Arg Asp Val Gly Ala Tyr Ser Lys Tyr Leu Thr Cys Pro Lys 4565 4570 4575 Thr Lys Leu Lys Ile Ser Tyr Lys Asp Ala Leu Asp Arg Ser Met Val 4580 4585 4590 Glu Glu Gly Thr Gly Leu Arg Leu Leu Glu Ala Ala Ala Gln Ser Thr 4595 4600 4605 Lys Gly Tyr Tyr Ser Pro Tyr Ser Val Ser Gly Ser Gly Ser Thr Ala 4610 4615 4620 Gly Ser Arg Thr Gly Ser Arg Thr Gly Ser Arg Ala Gly Ser Arg Arg 4625 4630 4635 4640 Gly Ser Phe Asp Ala Thr Gly Ser Gly Phe Ser Met Thr Phe Ser Ser 4645 4650 4655 Ser Ser Tyr Ser Ser Ser Ser Gly Tyr Gly Arg Arg Tyr Ala Ser Gly Ser 4660 4665 4670 Ser Ala Ser Leu Gly Gly Pro Glu Ser Ala Val Ala 4675 4680 <210> 19 <211> 1075 <212> PRT <213> Homo sapiens <400> 19 Met Phe Tyr Gly Thr His Phe Ile Met Ser Pro Pro Thr Lys Ser Lys 1 5 10 15 Leu Lys Arg Gln Ser Gln Leu Leu Ser Ser Met Leu Ser Arg Thr Leu 20 25 30 Ser Tyr Lys Tyr Arg Asp Leu Asp Ser Thr Phe Ser Ser Leu Gly Ala 35 40 45 Ser Asp Asp Pro Ala Glu Leu Ser Thr Gln Leu Ser Ala Pro Gly Val 50 55 60 Leu Lys Val Phe Gly Asp Ser Val Cys Thr Gly Thr His Tyr Lys Ser 65 70 75 80 Val Leu Ala Thr Gly Thr Ser Ser Ala Arg Glu Leu Val Lys Glu Ala 85 90 95 Leu Glu Arg Tyr Ala Leu Asp Pro Arg Gln Ala Gly Gln Tyr Val Leu 100 105 110 Cys Asp Val Val Gly Gln Ala Gly Asp Ala Gly Gln Arg Trp Gln Ala 115 120 125 Arg Cys Phe Arg Val Phe Gly Asp Ser Glu Lys Pro Leu Leu Ile Gln 130 135 140 Glu Leu Trp Lys Pro Arg Glu Gly Leu Ser Arg Arg Phe Glu Leu Arg 145 150 155 160 Lys Arg Ser Asp Val Glu Glu Leu Ala Ala Lys Glu Val Asp Thr Ile 165 170 175 Thr Ala Gly Ile Asn Ala Gln Ala Arg Arg Leu Gln Arg Ser Arg Ala 180 185 190 Lys Gly Thr Pro Thr Pro Ala Leu Gly Asp Ala Arg Ser Ser Pro Pro 195 200 205 Pro Arg Leu Arg Arg Thr Val Ser Glu Thr Ser Leu Ser Pro Val Asn 210 215 220 Ala Leu Pro Ala Ala Ala Gln Gly Pro Glu Glu Pro Gly Pro Asp Ala 225 230 235 240 Met Arg Tyr Ser Leu Tyr Gln Ser Pro His Leu Leu Leu Leu Leu Gln Gly 245 250 255 Tyr Ser Gln Gln His Asp Ser Leu Val Tyr Val Leu Asn Arg Asp Arg 260 265 270 His Thr Val Gly Gln Arg Thr Pro Ser Ser Lys Pro Ser Ile Ser Leu 275 280 285 Ser Ala Pro Asp Ile Leu Pro Leu His Cys Thr Ile Arg Arg Gln Pro 290 295 300 Leu Pro Asp Ser Gly Gln Ala Ala Gly Arg Leu Val Leu Glu Pro Ile 305 310 315 320 Pro Gly Ala His Ile Ser Val Asn Phe Ser Glu Val Gly His Arg Thr 325 330 335 Val Val Leu His His Gly Asp Leu Leu Ser Leu Gly Leu Tyr Tyr Leu 340 345 350 Leu Leu Phe Lys Asp Pro Ala Gln Ala Gln Pro Leu Pro Ala Arg Ala 355 360 365 Leu Ala Arg Leu Arg Ala Val Pro Gln Ser Cys Arg Leu Cys Gly Ala 370 375 380 Ala Leu Gly Ala Arg Gly Ala Ala Ser Pro Thr Gln Ala Ala Leu Pro 385 390 395 400 Arg Arg Gln Gln Leu Leu Leu Glu Phe Glu Pro His Leu Glu Asp Thr 405 410 415 Leu Leu Gln Arg Ile Met Thr Leu Ile Glu Pro Gly Gly Asp Asp His 420 425 430 Lys Leu Thr Pro Ala Phe Leu Leu Cys Leu Cys Ile Gln His Ser Ala 435 440 445 Thr His Phe Gln Pro Gly Thr Phe Gly Gln Leu Leu Leu Lys Ile Ala 450 455 460 Arg Leu Ile Arg Glu Thr Val Trp Glu Lys Thr Lys Glu Leu Ala Glu 465 470 475 480 Lys Gln Ala Gln Leu Gln Glu Pro Ile Ser Leu Ala Ser Cys Ala Met 485 490 495 Ala Asp Leu Val Pro Asp Leu Gln Pro Ile Leu Phe Trp Met Ser Asn 500 505 510 Ser Ile Glu Leu Leu Tyr Phe Ile Gln Gln Lys Cys Pro Leu Tyr Met 515 520 525 Gln Ser Met Glu Glu Gln Leu Asp Ile Thr Gly Ser Lys Glu Ser Leu 530 535 540 Phe Ser Cys Thr Leu Thr Ala Ser Glu Glu Ala Met Ala Val Leu Glu 545 550 555 560 Glu Val Val Leu Tyr Ala Phe Gln Gln Cys Val Tyr Tyr Val Ser Lys 565 570 575 Ser Leu Tyr Ile Cys Leu Pro Ala Leu Leu Glu Cys Pro Pro Phe Gln 580 585 590 Thr Glu Arg Arg Glu Ser Trp Ser Ser Ala Pro Glu Leu Pro Glu Glu 595 600 605 Leu Arg Arg Val Val Ser Val Tyr Gln Ala Ala Leu Asp Leu Leu Arg 610 615 620 Gln Leu Gln Val His Pro Glu Val Ala Ser Gln Met Leu Ala Tyr Leu 625 630 635 640 Phe Phe Phe Ser Gly Thr Leu Leu Leu Asn Gln Leu Leu Asp Arg Gly 645 650 655 Pro Ser Leu Ser Cys Phe His Trp Pro Arg Gly Val Gln Ala Cys Ala 660 665 670 Arg Leu Gln Gln Leu Leu Glu Trp Met Arg Ser Ala Gly Phe Gly Ala 675 680 685 Ala Gly Glu His Phe Phe Gln Lys Leu Ser Cys Thr Leu Asn Leu Leu 690 695 700 Ala Thr Pro Arg Ala Gln Leu Ile Gln Met Ser Trp Thr Ala Leu Arg 705 710 715 720 Ala Ala Phe Pro Ala Leu Ser Pro Ala Gln Leu His Arg Leu Leu Thr 725 730 735 His Tyr Gln Leu Ala Ser Ala Met Gly Pro Met Ser Thr Trp Glu Pro 740 745 750 Gly Ala Gln Asp Ser Pro Glu Ala Phe Arg Ser Glu Asp Val Leu Glu 755 760 765 Ser Tyr Glu Asn Pro Pro Pro Ile Val Leu Pro Ser Asp Gly Phe Gln 770 775 780 Val Asp Leu Glu Ala Asn Cys Leu Asp Asp Ser Ile Tyr Gln His Leu 785 790 795 800 Leu Tyr Val Arg His Phe Leu Trp Gly Leu Arg Ser Arg Ala Ser Pro 805 810 815 Gly Ser Pro Gly Arg Pro Gly Ser Gly Ala Ser Gln Pro Val Cys Pro 820 825 830 Glu Gly Met His His Val Val Leu Asp Gly His Leu Glu Ala Pro Ser 835 840 845 Cys Pro Leu Ala Pro Arg Asp Pro Gly Pro Ala Ala Arg Glu Val Ala 850 855 860 Pro Glu Arg Thr Leu Pro Leu Arg Gly Ala Pro Trp Ala Gln Ala Pro 865 870 875 880 Pro Gly Arg Gln Pro Ser Arg Gly Gly Ser Gln Ala Gly Pro Pro His 885 890 895 Thr Asp Ser Ser Cys Leu Leu Thr Pro Pro Ser Thr Pro Leu Gly Pro 900 905 910 Glu Pro Gly Asp Pro Asp Trp Pro Glu Ser Gly Gly Pro Cys Gly Lys 915 920 925 Ala Leu Pro Glu Arg Gln Arg Asn Gly Leu Ser Gly Leu Arg Gly Ala 930 935 940 Ala Pro Glu Gly Asp Ser Ala Ala Leu Ala Glu Glu Ser Pro Pro Ala 945 950 955 960 Pro Ser Ser Arg Ser Ser Ser Thr Glu Asp Phe Cys Tyr Val Phe Thr 965 970 975 Val Glu Leu Glu Arg Gly Pro Ser Gly Leu Gly Met Gly Leu Ile Asp 980 985 990 Gly Met His Thr His Leu Gly Ala Pro Gly Leu Tyr Ile Gln Thr Leu 995 1000 1005 Leu Pro Gly Ser Pro Ala Ala Ala Asp Gly Arg Leu Ser Leu Gly Asp 1010 1015 1020 Arg Ile Leu Glu Val Asn Gly Ser Ser Leu Leu Gly Leu Gly Tyr Leu 1025 1030 1035 1040 Arg Ala Val Asp Leu Ile Arg His Gly Gly Lys Lys Met Arg Phe Leu 1045 1050 1055 Val Ala Lys Ser Asp Val Glu Thr Ala Lys Lys Ile His Phe Arg Thr 1060 1065 1070 Pro Pro Leu 1075 <210> 20 <211> 3460 <212> PRT <213> Homo sapiens <400> 20 Met Glu Arg Ser Gly Trp Ala Arg Gln Thr Phe Leu Leu Ala Leu Leu 1 5 10 15 Leu Gly Ala Thr Leu Arg Ala Arg Ala Ala Ala Gly Tyr Tyr Pro Arg 20 25 30 Phe Ser Pro Phe Phe Phe Leu Cys Thr His His Gly Glu Leu Glu Gly 35 40 45 Asp Gly Glu Gln Gly Glu Val Leu Ile Ser Leu His Ile Ala Gly Asn 50 55 60 Pro Thr Tyr Tyr Val Pro Gly Gin Glu Tyr His Val Thr Ile Ser Thr 65 70 75 80 Ser Thr Phe Phe Asp Gly Leu Leu Val Thr Gly Leu Tyr Thr Ser Thr 85 90 95 Ser Val Gln Ala Ser Gln Ser Ile Gly Gly Ser Ser Ala Phe Gly Phe 100 105 110 Gly Ile Met Ser Asp His Gln Phe Gly Asn Gln Phe Met Cys Ser Val 115 120 125 Val Ala Ser His Val Ser His Leu Pro Thr Thr Asn Leu Ser Phe Ile 130 135 140 Trp Ile Ala Pro Pro Ala Gly Thr Gly Cys Val Asn Phe Met Ala Thr 145 150 155 160 Ala Thr His Arg Gly Gln Val Ile Phe Lys Asp Ala Leu Ala Gln Gln 165 170 175 Leu Cys Glu Gln Gly Ala Pro Thr Asp Val Thr Val His Pro His Leu 180 185 190 Ala Glu Ile His Ser Asp Ser Ile Ile Leu Arg Asp Asp Phe Asp Ser 195 200 205 Tyr His Gln Leu Gln Leu Asn Pro Asn Ile Trp Val Glu Cys Asn Asn 210 215 220 Cys Glu Thr Gly Glu Gln Cys Gly Ala Ile Met His Gly Asn Ala Val 225 230 235 240 Thr Phe Cys Glu Pro Tyr Gly Pro Arg Glu Leu Ile Thr Thr Gly Leu 245 250 255 Asn Thr Thr Thr Ala Ser Val Leu Gln Phe Ser Ile Gly Ser Gly Ser 260 265 270 Cys Arg Phe Ser Tyr Ser Asp Pro Ser Ile Ile Val Leu Tyr Ala Lys 275 280 285 Asn Asn Ser Ala Asp Trp Ile Gln Leu Glu Lys Ile Arg Ala Pro Ser 290 295 300 Asn Val Ser Thr Ile Ile His Ile Leu Tyr Leu Pro Glu Asp Ala Lys 305 310 315 320 Gly Glu Asn Val Gln Phe Gln Trp Lys Gln Glu Asn Leu Arg Val Gly 325 330 335 Glu Val Tyr Glu Ala Cys Trp Ala Leu Asp Asn Ile Leu Ile Ile Asn 340 345 350 Ser Ala His Arg Gln Val Val Leu Glu Asp Ser Leu Asp Pro Val Asp 355 360 365 Thr Gly Asn Trp Leu Phe Phe Pro Gly Ala Thr Val Lys His Ser Cys 370 375 380 Gln Ser Asp Gly Asn Ser Ile Tyr Phe His Gly Asn Glu Gly Ser Glu 385 390 395 400 Phe Asn Phe Ala Thr Thr Arg Asp Val Asp Leu Ser Thr Glu Asp Ile 405 410 415 Gln Glu Gln Trp Ser Glu Glu Phe Glu Ser Gln Pro Thr Gly Trp Asp 420 425 430 Val Leu Gly Ala Val Ile Gly Thr Glu Cys Gly Thr Ile Glu Ser Gly 435 440 445 Leu Ser Met Val Phe Leu Lys Asp Gly Glu Arg Lys Leu Cys Thr Pro 450 455 460 Ser Met Asp Thr Thr Gly Tyr Gly Asn Leu Arg Phe Tyr Phe Val Met 465 470 475 480 Gly Gly Ile Cys Asp Pro Gly Asn Ser His Glu Asn Asp Ile Ile Leu 485 490 495 Tyr Ala Lys Ile Glu Gly Arg Lys Glu His Ile Thr Leu Asp Thr Leu 500 505 510 Ser Tyr Ser Ser Tyr Lys Val Pro Ser Leu Val Ser Val Val Ile Asn 515 520 525 Pro Glu Leu Gln Thr Pro Ala Thr Lys Phe Cys Leu Arg Gln Lys Asn 530 535 540 His Gln Gly His Asn Arg Asn Val Trp Ala Val Asp Phe Phe His Val 545 550 555 560 Leu Pro Val Leu Pro Ser Thr Met Ser His Met Ile Gln Phe Ser Ile 565 570 575 Asn Leu Gly Cys Gly Thr His Gln Pro Gly Asn Ser Val Ser Leu Glu 580 585 590 Phe Ser Thr Asn His Gly Arg Ser Trp Ser Leu Leu His Thr Glu Cys 595 600 605 Leu Pro Glu Ile Cys Ala Gly Pro His Leu Pro His Ser Thr Val Tyr 610 615 620 Ser Ser Glu Asn Tyr Ser Gly Trp Asn Arg Ile Thr Ile Pro Leu Pro 625 630 635 640 Asn Ala Ala Leu Thr Arg Asn Thr Arg Ile Arg Trp Arg Gln Thr Gly 645 650 655 Pro Ile Leu Gly Asn Met Trp Ala Ile Asp Asn Val Tyr Ile Gly Pro 660 665 670 Ser Cys Leu Lys Phe Cys Ser Gly Arg Gly Gln Cys Thr Arg His Gly 675 680 685 Cys Lys Cys Asp Pro Gly Phe Ser Gly Pro Ala Cys Glu Met Ala Ser 690 695 700 Gln Thr Phe Pro Met Phe Ile Ser Glu Ser Phe Gly Ser Ser Arg Leu 705 710 715 720 Ser Ser Tyr His Asn Phe Tyr Ser Ile Arg Gly Ala Glu Val Ser Phe 725 730 735 Gly Cys Gly Val Leu Ala Ser Gly Lys Ala Leu Val Phe Asn Lys Asp 740 745 750 Gly Arg Arg Gln Leu Ile Thr Ser Phe Leu Asp Ser Ser Gln Ser Arg 755 760 765 Phe Leu Gln Phe Thr Leu Arg Leu Gly Ser Lys Ser Val Leu Ser Thr 770 775 780 Cys Arg Ala Pro Asp Gln Pro Gly Glu Gly Val Leu Leu His Tyr Ser 785 790 795 800 Tyr Asp Asn Gly Ile Thr Trp Lys Leu Leu Glu His Tyr Ser Tyr Leu 805 810 815 Ser Tyr His Glu Pro Arg Ile Ile Ser Val Glu Leu Pro Gly Asp Ala 820 825 830 Lys Gln Phe Gly Ile Gln Phe Arg Trp Trp Gln Pro Tyr His Ser Ser 835 840 845 Gln Arg Glu Asp Val Trp Ala Ile Asp Glu Ile Ile Met Thr Ser Val 850 855 860 Leu Phe Asn Ser Ile Ser Leu Asp Phe Thr Asn Leu Val Glu Val Thr 865 870 875 880 Gln Ser Leu Gly Phe Tyr Leu Gly Asn Val Gln Pro Tyr Cys Gly His 885 890 895 Asp Trp Thr Leu Cys Phe Thr Gly Asp Ser Lys Leu Ala Ser Ser Met 900 905 910 Arg Tyr Val Glu Thr Gln Ser Met Gln Ile Gly Ala Ser Tyr Met Ile 915 920 925 Gln Phe Ser Leu Val Met Gly Cys Gly Gln Lys Tyr Thr Pro His Met 930 935 940 Asp Asn Gln Val Lys Leu Glu Tyr Ser Thr Asn His Gly Leu Thr Trp 945 950 955 960 His Leu Val Gln Glu Glu Cys Leu Pro Ser Met Pro Ser Cys Gln Glu 965 970 975 Phe Thr Ser Ala Ser Ile Tyr His Ala Ser Glu Phe Thr Gln Trp Arg 980 985 990 Arg Val Ile Val Leu Leu Pro Gln Lys Thr Trp Ser Ser Ala Thr Arg 995 1000 1005 Phe Arg Trp Ser Gln Ser Tyr Tyr Thr Ala Gln Asp Glu Trp Ala Leu 1010 1015 1020 Asp Ser Ile Tyr Ile Gly Gln Gln Cys Pro Asn Met Cys Ser Gly His 1025 1030 1035 1040 Gly Ser Cys Asp His Gly Ile Cys Arg Cys Asp Gln Gly Tyr Gln Gly 1045 1050 1055 Thr Glu Cys His Pro Glu Ala Ala Leu Pro Ser Thr Ile Met Ser Asp 1060 1065 1070 Phe Glu Asn Gln Asn Gly Trp Glu Ser Asp Trp Gln Glu Val Ile Gly 1075 1080 1085 Gly Glu Ile Val Lys Pro Glu Gln Gly Cys Gly Val Ile Ser Ser Gly 1090 1095 1100 Ser Ser Leu Tyr Phe Ser Lys Ala Gly Lys Arg Gln Leu Val Ser Trp 1105 1110 1115 1120 Asp Leu Asp Thr Ser Trp Val Asp Phe Val Gln Phe Tyr Ile Gln Ile 1125 1130 1135 Gly Gly Glu Ser Ala Ser Cys Asn Lys Pro Asp Ser Arg Glu Glu Gly 1140 1145 1150 Val Leu Leu Gln Tyr Ser Asn Asn Gly Gly Ile Gln Trp His Leu Leu 1155 1160 1165 Ala Glu Met Tyr Phe Ser Asp Phe Ser Lys Pro Arg Phe Val Tyr Leu 1170 1175 1180 Glu Leu Pro Ala Ala Ala Lys Thr Pro Cys Thr Arg Phe Arg Trp Trp 1185 1190 1195 1200 Gln Pro Val Phe Ser Gly Glu Asp Tyr Asp Gln Trp Ala Val Asp Asp 1205 1210 1215 Ile Ile Ile Leu Ser Glu Lys Gln Lys Gln Ile Ile Pro Val Ile Asn 1220 1225 1230 Pro Thr Leu Pro Gln Asn Phe Tyr Glu Lys Pro Ala Phe Asp Tyr Pro 1235 1240 1245 Met Asn Gln Met Ser Val Trp Leu Met Leu Ala Asn Glu Gly Met Val 1250 1255 1260 Lys Asn Glu Thr Phe Cys Ala Ala Thr Pro Ser Ala Met Ile Phe Gly 1265 1270 1275 1280 Lys Ser Asp Gly Asp Arg Phe Ala Val Thr Arg Asp Leu Thr Leu Lys 1285 1290 1295 Pro Gly Tyr Val Leu Gln Phe Lys Leu Asn Ile Gly Cys Ala Asn Gln 1300 1305 1310 Phe Ser Ser Thr Ala Pro Val Leu Leu Gln Tyr Ser His Asp Ala Gly 1315 1320 1325 Met Ser Trp Phe Leu Val Lys Glu Gly Cys Tyr Pro Ala Ser Ala Gly 1330 1335 1340 Lys Gly Cys Glu Gly Asn Ser Arg Glu Leu Ser Glu Pro Thr Met Tyr 1345 1350 1355 1360 His Thr Gly Asp Phe Glu Glu Trp Thr Arg Ile Thr Ile Val Ile Pro 1365 1370 1375 Arg Ser Leu Ala Ser Ser Lys Thr Arg Phe Arg Trp Ile Gln Glu Ser 1380 1385 1390 Ser Ser Gln Lys Asn Val Pro Pro Phe Gly Leu Asp Gly Val Tyr Ile 1395 1400 1405 Ser Glu Pro Cys Pro Ser Tyr Cys Ser Gly His Gly Asp Cys Ile Ser 1410 1415 1420 Gly Val Cys Phe Cys Asp Leu Gly Tyr Thr Ala Ala Gln Gly Thr Cys 1425 1430 1435 1440 Val Ser Asn Val Pro Asn His Asn Glu Met Phe Asp Arg Phe Glu Gly 1445 1450 1455 Lys Leu Ser Pro Leu Trp Tyr Lys Ile Thr Gly Ala Gln Val Gly Thr 1460 1465 1470 Gly Cys Gly Thr Leu Asn Asp Gly Lys Ser Leu Tyr Phe Asn Gly Pro 1475 1480 1485 Gly Lys Arg Glu Ala Arg Thr Val Pro Leu Asp Thr Arg Asn Ile Arg 1490 1495 1500 Leu Val Gln Phe Tyr Ile Gln Ile Gly Ser Lys Thr Ser Gly Ile Thr 1505 1510 1515 1520 Cys Ile Lys Pro Arg Thr Arg Asn Glu Gly Leu Ile Val Gln Tyr Ser 1525 1530 1535 Asn Asp Asn Gly Ile Leu Trp His Leu Leu Arg Glu Leu Asp Phe Met 1540 1545 1550 Ser Phe Leu Glu Pro Gln Ile Ile Ser Ile Asp Leu Pro Gln Asp Ala 1555 1560 1565 Lys Thr Pro Ala Thr Ala Phe Arg Trp Trp Gln Pro Gln His Gly Lys 1570 1575 1580 His Ser Ala Gln Trp Ala Leu Asp Asp Val Leu Ile Gly Met Asn Asp 1585 1590 1595 1600 Ser Ser Gln Thr Gly Phe Gln Asp Lys Phe Asp Gly Ser Ile Asp Leu 1605 1610 1615 Gln Ala Asn Trp Tyr Arg Ile Gln Gly Gly Gln Val Asp Ile Asp Cys 1620 1625 1630 Leu Ser Met Asp Thr Ala Leu Ile Phe Thr Glu Asn Ile Gly Lys Pro 1635 1640 1645 Arg Tyr Ala Glu Thr Trp Asp Phe His Val Ser Ala Ser Thr Phe Leu 1650 1655 1660 Gln Phe Glu Met Ser Met Gly Cys Ser Lys Pro Phe Ser Asn Ser His 1665 1670 1675 1680 Ser Val Gln Leu Gln Tyr Ser Leu Asn Asn Gly Lys Asp Trp His Leu 1685 1690 1695 Val Thr Glu Glu Cys Val Pro Pro Thr Ile Gly Cys Leu His Tyr Thr 1700 1705 1710 Glu Ser Ser Ile Tyr Thr Ser Glu Arg Phe Gln Asn Trp Lys Arg Ile 1715 1720 1725 Thr Val Tyr Leu Pro Leu Ser Thr Ile Ser Pro Arg Thr Arg Phe Arg 1730 1735 1740 Trp Ile Gln Ala Asn Tyr Thr Val Gly Ala Asp Ser Trp Ala Ile Asp 1745 1750 1755 1760 Asn Val Val Leu Ala Ser Gly Cys Pro Trp Met Cys Ser Gly Arg Gly 1765 1770 1775 Ile Cys Asp Ala Gly Arg Cys Val Cys Asp Arg Gly Phe Gly Gly Pro 1780 1785 1790 Tyr Cys Val Pro Val Val Pro Leu Pro Ser Ile Leu Lys Asp Asp Phe 1795 1800 1805 Asn Gly Asn Leu His Pro Asp Leu Trp Pro Glu Val Tyr Gly Ala Glu 1810 1815 1820 Arg Gly Asn Leu Asn Gly Glu Thr Ile Lys Ser Gly Thr Ser Leu Ile 1825 1830 1835 1840 Phe Lys Gly Glu Gly Leu Arg Met Leu Ile Ser Arg Asp Leu Asp Cys 1845 1850 1855 Thr Asn Thr Met Tyr Val Gln Phe Ser Leu Arg Phe Ile Ala Lys Ser 1860 1865 1870 Thr Pro Glu Arg Ser His Ser Ile Leu Leu Gln Phe Ser Ile Ser Gly 1875 1880 1885 Gly Ile Thr Trp His Leu Met Asp Glu Phe Tyr Phe Pro Gln Thr Thr 1890 1895 1900 Asn Ile Leu Phe Ile Asn Val Pro Leu Pro Tyr Thr Ala Gln Thr Asn 1905 1910 1915 1920 Ala Thr Arg Phe Arg Leu Trp Gln Pro Tyr Asn Asn Gly Lys Lys Glu 1925 1930 1935 Glu Ile Trp Ile Val Asp Asp Phe Ile Ile Asp Gly Asn Asn Val Asn 1940 1945 1950 Asn Pro Val Met Leu Leu Asp Thr Phe Asp Phe Gly Pro Arg Glu Asp 1955 1960 1965 Asn Trp Phe Phe Tyr Pro Gly Gly Asn Ile Gly Leu Tyr Cys Pro Tyr 1970 1975 1980 Ser Ser Lys Gly Ala Pro Glu Glu Asp Ser Ala Met Val Phe Val Ser 1985 1990 1995 2000 Asn Glu Val Gly Glu His Ser Ile Thr Thr Arg Asp Leu Asn Val Asn 2005 2010 2015 Glu Asn Thr Ile Ile Gln Phe Glu Ile Asn Val Gly Cys Ser Thr Asp 2020 2025 2030 Ser Ser Ser Ala Asp Pro Val Arg Leu Glu Phe Ser Arg Asp Phe Gly 2035 2040 2045 Ala Thr Trp His Leu Leu Leu Pro Leu Cys Tyr His Ser Ser Ser His 2050 2055 2060 Val Ser Ser Leu Cys Ser Thr Glu His His Pro Ser Ser Thr Tyr Tyr 2065 2070 2075 2080 Ala Gly Thr Met Gln Gly Trp Arg Arg Glu Val Val His Phe Gly Lys 2085 2090 2095 Leu His Leu Cys Gly Ser Val Arg Phe Arg Trp Tyr Gln Gly Phe Tyr 2100 2105 2110 Pro Ala Gly Ser Gln Pro Val Thr Trp Ala Ile Asp Asn Val Tyr Ile 2115 2120 2125 Gly Pro Gln Cys Glu Glu Met Cys Asn Gly Gln Gly Ser Cys Ile Asn 2130 2135 2140 Gly Thr Lys Cys Ile Cys Asp Pro Gly Tyr Ser Gly Pro Thr Cys Lys 2145 2150 2155 2160 Ile Ser Thr Lys Asn Pro Asp Phe Leu Lys Asp Asp Phe Glu Gly Gln 2165 2170 2175 Leu Glu Ser Asp Arg Phe Leu Leu Met Ser Gly Gly Lys Pro Ser Arg 2180 2185 2190 Lys Cys Gly Ile Leu Ser Ser Gly Asn Asn Leu Phe Phe Asn Glu Asp 2195 2200 2205 Gly Leu Arg Met Leu Met Thr Arg Asp Leu Asp Leu Ser His Ala Arg 2210 2215 2220 Phe Val Gln Phe Phe Met Arg Leu Gly Cys Gly Lys Gly Val Pro Asp 2225 2230 2235 2240 Pro Arg Ser Gln Pro Val Leu Leu Gln Tyr Ser Leu Asn Gly Gly Leu 2245 2250 2255 Ser Trp Ser Leu Leu Gln Glu Phe Leu Phe Ser Asn Ser Ser Asn Val 2260 2265 2270 Gly Arg Tyr Ile Ala Leu Glu Ile Pro Leu Lys Ala Arg Ser Gly Ser 2275 2280 2285 Thr Arg Leu Arg Trp Trp Gln Pro Ser Glu Asn Gly His Phe Tyr Ser 2290 2295 2300 Pro Trp Val Ile Asp Gln Ile Leu Ile Gly Gly Asn Ile Ser Gly Asn 2305 2310 2315 2320 Thr Val Leu Glu Asp Asp Phe Thr Thr Leu Asp Ser Arg Lys Trp Leu 2325 2330 2335 Leu His Pro Gly Gly Thr Lys Met Pro Val Cys Gly Ser Thr Gly Asp 2340 2345 2350 Ala Leu Val Phe Ile Glu Lys Ala Ser Thr Arg Tyr Val Val Ser Thr 2355 2360 2365 Asp Val Ala Val Asn Glu Asp Ser Phe Leu Gln Ile Asp Phe Ala Ala 2370 2375 2380 Ser Cys Ser Val Thr Asp Ser Cys Tyr Ala Ile Glu Leu Glu Tyr Ser 2385 2390 2395 2400 Val Asp Leu Gly Leu Ser Trp His Pro Leu Val Arg Asp Cys Leu Pro 2405 2410 2415 Thr Asn Val Glu Cys Ser Arg Tyr His Leu Gln Arg Ile Leu Val Ser 2420 2425 2430 Asp Thr Phe Asn Lys Trp Thr Arg Ile Thr Leu Pro Leu Pro Pro Tyr 2435 2440 2445 Thr Arg Ser Gln Ala Thr Arg Phe Arg Trp His Gln Pro Ala Pro Phe 2450 2455 2460 Asp Lys Gln Gln Thr Trp Ala Ile Asp Asn Val Tyr Ile Gly Asp Gly 2465 2470 2475 2480 Cys Ile Asp Met Cys Ser Gly His Gly Arg Cys Ile Gln Gly Asn Cys 2485 2490 2495 Val Cys Asp Glu Gln Trp Gly Gly Leu Tyr Cys Asp Asp Pro Glu Thr 2500 2505 2510 Ser Leu Pro Thr Gln Leu Lys Asp Asn Phe Asn Arg Ala Pro Ser Ser 2515 2520 2525 Gln Asn Trp Leu Thr Val Asn Gly Gly Lys Leu Ser Thr Val Cys Gly 2530 2535 2540 Ala Val Ala Ser Gly Met Ala Leu His Phe Ser Gly Gly Cys Ser Arg 2545 2550 2555 2560 Leu Leu Val Thr Val Asp Leu Asn Leu Thr Asn Ala Glu Phe Ile Gln 2565 2570 2575 Phe Tyr Phe Met Tyr Gly Cys Leu Ile Thr Pro Asn Asn Arg Asn Gln 2580 2585 2590 Gly Val Leu Leu Glu Tyr Ser Val Asn Gly Gly Ile Thr Trp Asn Leu 2595 2600 2605 Leu Met Glu Ile Phe Tyr Asp Gln Tyr Ser Lys Pro Gly Phe Val Asn 2610 2615 2620 Ile Leu Leu Pro Pro Asp Ala Lys Glu Ile Ala Thr Arg Phe Arg Trp 2625 2630 2635 2640 Trp Gln Pro Arg His Asp Gly Leu Asp Gln Asn Asp Trp Ala Ile Asp 2645 2650 2655 Asn Val Leu Ile Ser Gly Ser Ala Asp Gln Arg Thr Val Met Leu Asp 2660 2665 2670 Thr Phe Ser Ser Ala Pro Val Pro Gln His Glu Arg Ser Pro Ala Asp 2675 2680 2685 Ala Gly Pro Val Gly Arg Ile Ala Phe Asp Met Phe Met Glu Asp Lys 2690 2695 2700 Thr Ser Val Asn Glu His Trp Leu Phe His Asp Asp Cys Thr Val Glu 2705 2710 2715 2720 Arg Phe Cys Asp Ser Pro Asp Gly Val Met Leu Cys Gly Ser His Asp 2725 2730 2735 Gly Arg Glu Val Tyr Ala Val Thr His Asp Leu Thr Pro Thr Glu Gly 2740 2745 2750 Trp Ile Met Gln Phe Lys Ile Ser Val Gly Cys Lys Val Ser Glu Lys 2755 2760 2765 Ile Ala Gln Asn Gln Ile His Val Gln Tyr Ser Thr Asp Phe Gly Val 2770 2775 2780 Ser Trp Asn Tyr Leu Val Pro Gln Cys Leu Pro Ala Asp Pro Lys Cys 2785 2790 2795 2800 Ser Gly Ser Val Ser Gln Pro Ser Val Phe Phe Pro Thr Lys Gly Trp 2805 2810 2815 Lys Arg Ile Thr Tyr Pro Leu Pro Glu Ser Leu Val Gly Asn Pro Val 2820 2825 2830 Arg Phe Arg Phe Tyr Gln Lys Tyr Ser Asp Met Gln Trp Ala Ile Asp 2835 2840 2845 Asn Phe Tyr Leu Gly Pro Gly Cys Leu Asp Asn Cys Arg Gly His Gly 2850 2855 2860 Asp Cys Leu Arg Glu Gln Cys Ile Cys Asp Pro Gly Tyr Ser Gly Pro 2865 2870 2875 2880 Asn Cys Tyr Leu Thr His Thr Leu Lys Thr Phe Leu Lys Glu Arg Phe 2885 2890 2895 Asp Ser Glu Glu Ile Lys Pro Asp Leu Trp Met Ser Leu Glu Gly Gly 2900 2905 2910 Ser Thr Cys Thr Glu Cys Gly Ile Leu Ala Glu Asp Thr Ala Leu Tyr 2915 2920 2925 Phe Gly Gly Ser Thr Val Arg Gln Ala Val Thr Gln Asp Leu Asp Leu 2930 2935 2940 Arg Gly Ala Lys Phe Leu Gln Tyr Trp Gly Arg Ile Gly Ser Glu Asn 2945 2950 2955 2960 Asn Met Thr Ser Cys His Arg Pro Ile Cys Arg Lys Glu Gly Val Leu 2965 2970 2975 Leu Asp Tyr Ser Thr Asp Gly Gly Ile Thr Trp Thr Leu Leu His Glu 2980 2985 2990 Met Asp Tyr Gln Lys Tyr Ile Ser Val Arg His Asp Tyr Ile Leu Leu 2995 3000 3005 Pro Glu Asp Ala Leu Thr Asn Thr Thr Arg Leu Arg Trp Trp Gln Pro 3010 3015 3020 Phe Val Ile Ser Asn Gly Ile Val Val Ser Gly Val Glu Arg Ala Gln 3025 3030 3035 3040 Trp Ala Leu Asp Asn Ile Leu Ile Gly Gly Ala Glu Ile Asn Pro Ser 3045 3050 3055 Gln Leu Val Asp Thr Phe Asp Asp Glu Gly Thr Ser His Glu Glu Asn 3060 3065 3070 Trp Ser Phe Tyr Pro Asn Ala Val Arg Thr Ala Gly Phe Cys Gly Asn 3075 3080 3085 Pro Ser Phe His Leu Tyr Trp Pro Asn Lys Lys Lys Asp Lys Thr His 3090 3095 3100 Asn Ala Leu Ser Ser Arg Glu Leu Ile Ile Gln Pro Gly Tyr Met Met 3105 3110 3115 3120 Gln Phe Lys Ile Val Val Gly Cys Glu Ala Thr Ser Cys Gly Asp Leu 3125 3130 3135 His Ser Val Met Leu Glu Tyr Thr Lys Asp Ala Arg Ser Asp Ser Trp 3140 3145 3150 Gln Leu Val Gln Thr Gln Cys Leu Pro Ser Ser Ser Asn Ser Ile Gly 3155 3160 3165 Cys Ser Pro Phe Gln Phe His Glu Ala Thr Ile Tyr Asn Ser Val Asn 3170 3175 3180 Ser Ser Ser Trp Lys Arg Ile Thr Ile Gln Leu Pro Asp His Val Ser 3185 3190 3195 3200 Ser Ser Ala Thr Gln Phe Arg Trp Ile Gln Lys Gly Glu Glu Thr Glu 3205 3210 3215 Lys Gln Ser Trp Ala Ile Asp His Val Tyr Ile Gly Glu Ala Cys Pro 3220 3225 3230 Lys Leu Cys Ser Gly His Gly Tyr Cys Thr Thr Gly Ala Ile Cys Ile 3235 3240 3245 Cys Asp Glu Ser Phe Gln Gly Asp Asp Cys Ser Val Phe Ser His Asp 3250 3255 3260 Leu Pro Ser Tyr Ile Lys Asp Asn Phe Glu Ser Ala Arg Val Thr Glu 3265 3270 3275 3280 Ala Asn Trp Glu Thr Ile Gln Gly Gly Val Ile Gly Ser Gly Cys Gly 3285 3290 3295 Gln Leu Ala Pro Tyr Ala His Gly Asp Ser Leu Tyr Phe Asn Gly Cys 3300 3305 3310 Gln Ile Arg Gln Ala Ala Thr Lys Pro Leu Asp Leu Thr Arg Ala Ser 3315 3320 3325 Lys Ile Met Phe Val Leu Gln Ile Gly Ser Met Ser Gln Thr Asp Ser 3330 3335 3340 Cys Asn Ser Asp Leu Ser Gly Pro His Ala Val Asp Lys Ala Val Leu 3345 3350 3355 3360 Leu Gln Tyr Ser Val Asn Asn Gly Ile Thr Trp His Val Ile Ala Gln 3365 3370 3375 His Gln Pro Lys Asp Phe Thr Gln Ala Gln Arg Val Ser Tyr Asn Val 3380 3385 3390 Pro Leu Glu Ala Arg Met Lys Gly Val Leu Leu Arg Trp Trp Gln Pro 3395 3400 3405 Arg His Asn Gly Thr Gly His Asp Gln Trp Ala Leu Asp His Val Glu 3410 3415 3420 Val Val Leu Val Ser Thr Arg Lys Gln Asn Tyr Met Met Asn Phe Ser 3425 3430 3435 3440 Arg Gln His Gly Leu Arg His Phe Tyr Asn Arg Arg Arg Arg Ser Leu 3445 3450 3455 Arg Arg Tyr Pro 3460 <210> 21 <211> 671 <212> PRT <213> Homo sapiens <400> 21 Met Gln Pro Asp Met Ser Leu Asn Val Ile Lys Met Lys Ser Ser Asp 1 5 10 15 Phe Leu Glu Ser Ala Glu Leu Asp Ser Gly Gly Phe Gly Lys Val Ser 20 25 30 Leu Cys Phe His Arg Thr Gln Gly Leu Met Ile Met Lys Thr Val Tyr 35 40 45 Lys Gly Pro Asn Cys Ile Glu His Asn Glu Ala Leu Leu Glu Glu Ala 50 55 60 Lys Met Met Asn Arg Leu Arg His Ser Arg Val Val Lys Leu Leu Gly 65 70 75 80 Val Ile Ile Glu Glu Gly Lys Tyr Ser Leu Val Met Glu Tyr Met Glu 85 90 95 Lys Gly Asn Leu Met His Val Leu Lys Ala Glu Met Ser Thr Pro Leu 100 105 110 Ser Val Lys Gly Arg Ile Ile Leu Glu Ile Ile Ile Glu Gly Met Cys Tyr 115 120 125 Leu His Gly Lys Gly Val Ile His Lys Asp Leu Lys Pro Glu Asn Ile 130 135 140 Leu Val Asp Asn Asp Phe His Ile Lys Ile Ala Asp Leu Gly Leu Ala 145 150 155 160 Ser Phe Lys Met Trp Ser Lys Leu Asn Asn Glu Glu His Asn Glu Leu 165 170 175 Arg Glu Val Asp Gly Thr Ala Lys Lys Asn Gly Gly Thr Leu Tyr Tyr 180 185 190 Met Ala Pro Glu His Leu Asn Asp Val Asn Ala Lys Pro Thr Glu Lys 195 200 205 Ser Asp Val Tyr Ser Phe Ala Val Val Leu Trp Ala Ile Phe Ala Asn 210 215 220 Lys Glu Pro Tyr Glu Asn Ala Ile Cys Glu Gln Gln Leu Ile Met Cys 225 230 235 240 Ile Lys Ser Gly Asn Arg Pro Asp Val Asp Asp Ile Thr Glu Tyr Cys 245 250 255 Pro Arg Glu Ile Ile Ser Leu Met Lys Leu Cys Trp Glu Ala Asn Pro 260 265 270 Glu Ala Arg Pro Thr Phe Pro Gly Ile Glu Glu Lys Phe Arg Pro Phe 275 280 285 Tyr Leu Ser Gln Leu Glu Glu Ser Val Glu Glu Asp Val Lys Ser Leu 290 295 300 Lys Lys Glu Tyr Ser Asn Glu Asn Ala Val Val Lys Arg Met Gln Ser 305 310 315 320 Leu Gln Leu Asp Cys Val Ala Val Pro Ser Ser Arg Ser Asn Ser Ala 325 330 335 Thr Glu Gln Pro Gly Ser Leu His Ser Ser Gln Gly Leu Gly Met Gly 340 345 350 Pro Val Glu Glu Ser Trp Phe Ala Pro Ser Leu Glu His Pro Gln Glu 355 360 365 Glu Asn Glu Pro Ser Leu Gln Ser Lys Leu Gln Asp Glu Ala Asn Tyr 370 375 380 His Leu Tyr Gly Ser Arg Met Asp Arg Gln Thr Lys Gln Gln Pro Arg 385 390 395 400 Gln Asn Val Ala Tyr Asn Arg Glu Glu Glu Arg Arg Arg Arg Val Ser 405 410 415 His Asp Pro Phe Ala Gln Gln Arg Pro Tyr Glu Asn Phe Gln Asn Thr 420 425 430 Glu Gly Lys Gly Thr Ala Tyr Ser Ser Ala Ala Ser His Gly Asn Ala 435 440 445 Val His Gln Pro Ser Gly Leu Thr Ser Gln Pro Gln Val Leu Tyr Gln 450 455 460 Asn Asn Gly Leu Tyr Ser Ser His Gly Phe Gly Thr Arg Pro Leu Asp 465 470 475 480 Pro Gly Thr Ala Gly Pro Arg Val Trp Tyr Arg Pro Ile Pro Ser His 485 490 495 Met Pro Ser Leu His Asn Ile Pro Val Pro Glu Thr Asn Tyr Leu Gly 500 505 510 Asn Thr Pro Thr Met Pro Phe Ser Ser Leu Pro Pro Thr Asp Glu Ser 515 520 525 Ile Lys Tyr Thr Ile Tyr Asn Ser Thr Gly Ile Gln Ile Gly Ala Tyr 530 535 540 Asn Tyr Met Glu Ile Gly Gly Thr Ser Ser Ser Leu Leu Asp Ser Thr 545 550 555 560 Asn Thr Asn Phe Lys Glu Glu Pro Ala Ala Lys Tyr Gln Ala Ile Phe 565 570 575 Asp Asn Thr Thr Ser Leu Thr Asp Lys His Leu Asp Pro Ile Arg Glu 580 585 590 Asn Leu Gly Lys His Trp Lys Asn Cys Ala Arg Lys Leu Gly Phe Thr 595 600 605 Gln Ser Gln Ile Asp Glu Ile Asp His Asp Tyr Glu Arg Asp Gly Leu 610 615 620 Lys Glu Lys Val Tyr Gln Met Leu Gln Lys Trp Val Met Arg Glu Gly 625 630 635 640 Ile Lys Gly Ala Thr Val Gly Lys Leu Ala Gln Ala Leu His Gln Cys 645 650 655 Ser Arg Ile Asp Leu Leu Ser Ser Leu Ile Tyr Val Ser Gln Asn 660 665 670 <210> 22 <211> 1314 <212> PRT <213> Homo sapiens <400> 22 Met Ala Ser Lys Gly Ala Gly Met Ser Phe Ser Arg Lys Ser Tyr Arg 1 5 10 15 Leu Thr Ser Asp Ala Glu Lys Ser Arg Val Thr Gly Ile Val Gln Glu 20 25 30 Lys Leu Leu Asn Asp Tyr Leu Asn Arg Ile Phe Ser Ser Ser Ser Glu His 35 40 45 Ala Pro Pro Ala Ala Thr Ser Arg Lys Pro Leu Asn Phe Gln Asn Leu 50 55 60 Pro Glu His Leu Asp Gln Leu Leu Gln Val Asp Asn Glu Glu Glu Glu 65 70 75 80 Ser Gln Gly Gln Val Glu Gly Arg Leu Gly Pro Ser Thr Val Val Leu 85 90 95 Asp His Thr Gly Gly Phe Glu Gly Leu Leu Leu Val Asp Asp Asp Leu 100 105 110 Leu Gly Val Ile Gly His Ser Asn Phe Gly Thr Ile Arg Ser Thr Thr 115 120 125 Cys Val Tyr Lys Gly Lys Trp Leu Tyr Glu Val Leu Ile Ser Ser Ser Gln 130 135 140 Gly Leu Met Gln Ile Gly Trp Cys Thr Ile Ser Cys Arg Phe Asn Gln 145 150 155 160 Glu Glu Gly Val Gly Asp Thr His Asn Ser Tyr Ala Tyr Asp Gly Asn 165 170 175 Arg Val Arg Lys Trp Asn Val Thr Thr Thr Asn Tyr Gly Lys Ala Trp 180 185 190 Ala Ala Gly Asp Ile Val Ser Cys Leu Ile Asp Leu Asp Asp Gly Thr 195 200 205 Leu Ser Phe Cys Leu Asn Gly Val Ser Leu Gly Thr Ala Phe Glu Asn 210 215 220 Leu Ser Arg Gly Leu Gly Met Ala Tyr Phe Pro Ala Ile Ser Leu Ser 225 230 235 240 Phe Lys Glu Ser Val Ala Phe Asn Phe Gly Ser Arg Pro Leu Arg Tyr 245 250 255 Pro Val Ala Gly Tyr Arg Pro Leu Gln Asp Pro Ser Ala Asp Leu 260 265 270 Val Arg Ala Gln Arg Leu Leu Gly Cys Phe Arg Ala Val Leu Ser Val 275 280 285 Glu Leu Asp Pro Val Glu Gly Arg Leu Leu Asp Lys Glu Ser Ser Lys 290 295 300 Trp Arg Leu Arg Gly Gln Pro Thr Val Leu Leu Thr Leu Ala His Ile 305 310 315 320 Phe His His Phe Ala Pro Leu Leu Arg Lys Val Tyr Leu Val Glu Ala 325 330 335 Val Leu Met Ser Phe Leu Leu Gly Ile Val Glu Lys Gly Thr Pro Thr 340 345 350 Gln Ala Gln Ser Val Val His Gln Val Leu Asp Leu Leu Trp Leu Phe 355 360 365 Met Glu Asp Tyr Glu Val Gln Asp Cys Leu Lys Gln Leu Met Met Ser 370 375 380 Leu Leu Arg Leu Tyr Arg Phe Ser Pro Ile Val Pro Asp Leu Gly Leu 385 390 395 400 Gln Ile His Tyr Leu Arg Leu Thr Ile Ala Ile Leu Arg His Glu Lys 405 410 415 Ser Arg Lys Phe Leu Leu Ser Asn Val Leu Phe Asp Val Leu Arg Ser 420 425 430 Val Val Phe Phe Tyr Ile Lys Ser Pro Leu Arg Val Glu Glu Ala Gly 435 440 445 Leu Gln Glu Leu Ile Pro Thr Thr Trp Trp Pro His Cys Ser Ser Arg 450 455 460 Glu Gly Lys Glu Ser Thr Glu Met Lys Glu Glu Thr Ala Glu Glu Arg 465 470 475 480 Leu Arg Arg Arg Ala Tyr Glu Arg Gly Cys Gln Arg Leu Arg Lys Arg 485 490 495 Ile Glu Val Val Glu Glu Leu Gln Val Gln Ile Leu Lys Leu Leu Leu 500 505 510 Asp Asn Lys Asp Asp Asn Gly Gly Glu Ala Ser Arg Tyr Ile Phe Leu 515 520 525 Thr Lys Phe Arg Lys Phe Leu Gln Glu Asn Ala Ser Gly Arg Gly Asn 530 535 540 Met Pro Met Leu Cys Pro Pro Glu Tyr Met Val Cys Phe Leu His Arg 545 550 555 560 Leu Ile Ser Ala Leu Arg Tyr Tyr Trp Asp Glu Tyr Lys Ala Ser Asn 565 570 575 Pro His Ala Ser Phe Ser Glu Glu Ala Tyr Ile Pro Gln Val Phe 580 585 590 Tyr Asn Gly Lys Val Asp Tyr Phe Asp Leu Gln Arg Leu Gly Gly Leu 595 600 605 Leu Ser His Leu Arg Lys Thr Leu Lys Asp Asp Leu Ala Ser Lys Ala 610 615 620 Asn Ile Val Ile Asp Pro Leu Glu Leu Gln Ser Thr Ala Met Asp Asp 625 630 635 640 Leu Asp Glu Asp Glu Glu Pro Ala Pro Ala Met Ala Gln Arg Pro Met 645 650 655 Gln Ala Leu Ala Val Gly Gly Pro Leu Pro Leu Pro Arg Pro Gly Trp 660 665 670 Leu Ser Ser Pro Thr Leu Gly Arg Ala Asn Arg Phe Leu Ser Thr Ala 675 680 685 Ala Val Ser Leu Met Thr Pro Arg Arg Pro Leu Ser Thr Ser Glu Lys 690 695 700 Val Lys Val Arg Thr Leu Ser Val Glu Gln Arg Thr Arg Glu Asp Ile 705 710 715 720 Glu Gly Ser His Trp Asn Glu Gly Leu Leu Leu Gly Arg Pro Pro Glu 725 730 735 Glu Pro Glu Gln Pro Leu Thr Glu Asn Ser Leu Leu Glu Val Leu Asp 740 745 750 Gly Ala Val Met Met Tyr Asn Leu Ser Val His Gln Gln Leu Gly Lys 755 760 765 Met Val Gly Val Ser Asp Asp Val Asn Glu Tyr Ala Met Ala Leu Arg 770 775 780 Asp Thr Glu Asp Lys Leu Arg Arg Cys Pro Lys Arg Arg Lys Asp Ile 785 790 795 800 Leu Ala Glu Leu Thr Lys Ser Gln Lys Val Phe Ser Glu Lys Leu Asp 805 810 815 His Leu Ser Arg Arg Leu Ala Trp Val His Ala Thr Val Tyr Ser Gln 820 825 830 Glu Lys Met Leu Asp Ile Tyr Trp Leu Leu Arg Val Cys Leu Arg Thr 835 840 845 Ile Glu His Gly Asp Arg Thr Gly Ser Leu Phe Ala Phe Met Pro Glu 850 855 860 Phe Tyr Leu Ser Val Ala Ile Asn Ser Tyr Ser Ala Leu Lys Asn Tyr 865 870 875 880 Phe Gly Pro Val His Ser Met Glu Glu Leu Pro Gly Tyr Glu Glu Thr 885 890 895 Leu Thr Arg Leu Ala Ala Ile Leu Ala Lys His Phe Ala Asp Ala Arg 900 905 910 Ile Val Gly Thr Asp Ile Arg Asp Ser Leu Met Gln Ala Leu Ala Ser 915 920 925 Tyr Val Cys Tyr Pro His Ser Leu Arg Ala Val Glu Arg Ile Pro Glu 930 935 940 Glu Gln Arg Ile Ala Met Val Arg Asn Leu Leu Ala Pro Tyr Glu Gln 945 950 955 960 Arg Pro Trp Ala Gln Thr Asn Trp Ile Leu Val Arg Leu Trp Arg Gly 965 970 975 Cys Gly Phe Gly Tyr Arg Tyr Thr Arg Leu Pro His Leu Leu Lys Thr 980 985 990 Lys Leu Glu Asp Ala Asn Leu Pro Ser Leu Gln Lys Pro Cys Pro Ser 995 1000 1005 Thr Leu Leu Gln Gln His Met Ala Asp Leu Leu Gln Gln Gly Pro Asp 1010 1015 1020 Val Ala Pro Ser Phe Leu Asn Ser Val Leu Asn Gln Leu Asn Trp Ala 1025 1030 1035 1040 Phe Ser Glu Phe Ile Gly Met Ile Gln Glu Ile Gln Gln Ala Ala Glu 1045 1050 1055 Arg Leu Glu Arg Asn Phe Val Asp Ser Arg Gln Leu Lys Val Cys Ala 1060 1065 1070 Thr Cys Phe Asp Leu Ser Val Ser Leu Leu Arg Val Leu Glu Met Thr 1075 1080 1085 Ile Thr Leu Val Pro Glu Ile Phe Leu Asp Trp Thr Arg Pro Thr Ser 1090 1095 1100 Glu Met Leu Leu Arg Arg Leu Ala Gln Leu Leu Asn Gln Val Leu Asn 1105 1110 1115 1120 Arg Val Thr Ala Glu Arg Asn Leu Phe Asp Arg Val Val Thr Leu Arg 1125 1130 1135 Leu Pro Gly Leu Glu Ser Val Asp His Tyr Pro Ile Leu Val Ala Val 1140 1145 1150 Thr Gly Ile Leu Val Gln Leu Leu Val Arg Gly Pro Ala Ser Glu Arg 1155 1160 1165 Glu Gln Ala Thr Ser Val Leu Leu Ala Asp Pro Cys Phe Gln Leu Arg 1170 1175 1180 Ser Ile Cys Tyr Leu Leu Gly Gln Pro Glu Pro Pro Ala Pro Gly Thr 1185 1190 1195 1200 Ala Leu Pro Ala Pro Asp Arg Lys Arg Phe Ser Leu Gln Ser Tyr Ala 1205 1210 1215 Asp Tyr Ile Ser Ala Asp Glu Leu Ala Gln Val Glu Gln Met Leu Ala 1220 1225 1230 His Leu Thr Ser Ala Ser Ala Gln Ala Ala Ala Ala Ser Leu Pro Thr 1235 1240 1245 Ser Glu Glu Asp Leu Cys Pro Ile Cys Tyr Ala His Pro Ile Ser Ala 1250 1255 1260 Val Phe Gln Pro Cys Gly His Lys Ser Cys Lys Ala Cys Ile Asn Gln 1265 1270 1275 1280 His Leu Met Asn Asn Lys Asp Cys Phe Phe Cys Lys Thr Thr Ile Val 1285 1290 1295 Ser Val Glu Asp Trp Glu Lys Gly Ala Asn Thr Ser Thr Thr Ser Ser 1300 1305 1310 Ala Ala <210> 23 <211> 377 <212> PRT <213> Homo sapiens <400> 23 Met Gly Pro Ala Ala Arg Pro Ala Leu Arg Ser Pro Pro Pro Pro Pro 1 5 10 15 Pro Pro Pro Pro Ser Pro Leu Leu Leu Leu Leu Leu Pro Leu Leu Pro Leu 20 25 30 Trp Leu Gly Leu Ala Gly Pro Gly Ala Ala Ala Asp Gly Ser Glu Pro 35 40 45 Ala Ala Gly Ala Gly Arg Gly Gly Ala Arg Ala Val Arg Val Asp Val 50 55 60 Arg Leu Pro Arg Gln Asp Ala Leu Val Leu Glu Gly Val Arg Ile Gly 65 70 75 80 Ser Glu Ala Asp Pro Ala Pro Leu Leu Gly Gly Arg Leu Leu Leu Met 85 90 95 Asp Ile Val Asp Ala Glu Gln Glu Ala Pro Val Glu Gly Trp Ile Ala 100 105 110 Val Ala Tyr Val Gly Lys Glu Gln Ala Ala Gln Phe His Gln Glu Asn 115 120 125 Lys Gly Ser Gly Pro Gln Ala Tyr Pro Lys Ala Leu Val Gln Gln Met 130 135 140 Arg Arg Ala Leu Phe Leu Gly Ala Ser Ala Leu Leu Leu Leu Leu Ile Leu 145 150 155 160 Asn His Asn Val Val Arg Glu Leu Asp Ile Ser Gln Leu Leu Leu Arg 165 170 175 Pro Val Ile Val Leu His Tyr Ser Ser Asn Val Thr Lys Leu Leu Asp 180 185 190 Ala Leu Leu Gln Arg Thr Gln Ala Thr Ala Glu Ile Thr Ser Gly Glu 195 200 205 Ser Leu Ser Ala Asn Ile Glu Trp Lys Leu Thr Leu Trp Thr Thr Cys 210 215 220 Gly Leu Ser Lys Asp Gly Tyr Gly Gly Trp Gln Asp Leu Val Cys Leu 225 230 235 240 Gly Gly Ser Arg Ala Gln Glu Gln Lys Pro Leu Gln Gln Leu Trp Asn 245 250 255 Ala Ile Leu Leu Val Ala Met Leu Leu Cys Thr Gly Leu Val Val Gln 260 265 270 Ala Gln Arg Gln Ala Ser Arg Gln Ser Gln Arg Glu Leu Gly Gly Gln 275 280 285 Val Asp Leu Phe Lys Arg Arg Val Val Arg Arg Leu Ala Ser Leu Lys 290 295 300 Thr Arg Arg Cys Arg Leu Ser Arg Ala Ala Gln Gly Leu Pro Asp Pro 305 310 315 320 Gly Ala Glu Thr Cys Ala Val Cys Leu Asp Tyr Phe Cys Asn Lys Gln 325 330 335 Trp Leu Arg Val Leu Pro Cys Lys His Glu Phe His Arg Asp Cys Val 340 345 350 Asp Pro Trp Leu Met Leu Gln Gln Thr Cys Pro Leu Cys Lys Phe Asn 355 360 365 Val Leu Gly Asn Arg Tyr Ser Asp Asp 370 375 <210> 24 <211> 434 <212> PRT <213> Homo sapiens <400> 24 Met Ala Ala Ser Asp Thr Glu Arg Asp Gly Leu Ala Pro Glu Lys Thr 1 5 10 15 Ser Pro Asp Arg Asp Lys Lys Lys Glu Gln Ser Glu Val Ser Val Ser 20 25 30 Pro Arg Ala Ser Lys His His Tyr Ser Arg Ser Arg Ser Arg Ser Arg 35 40 45 Glu Arg Lys Arg Lys Ser Asp Asn Glu Gly Arg Lys His Arg Ser Arg 50 55 60 Ser Arg Ser Lys Glu Gly Arg Arg His Glu Ser Lys Asp Lys Ser Ser 65 70 75 80 Lys Lys His Lys Ser Glu Glu His Asn Asp Lys Glu His Ser Ser Asp 85 90 95 Lys Gly Arg Glu Arg Leu Asn Ser Ser Glu Asn Gly Glu Asp Arg His 100 105 110 Lys Arg Lys Glu Arg Lys Ser Ser Arg Gly Arg Ser His Ser Arg Ser 115 120 125 Arg Ser Arg Glu Arg Arg His Arg Ser Arg Ser Arg Glu Arg Lys Lys 130 135 140 Ser Arg Ser Arg Ser Arg Glu Arg Lys Lys Ser Arg Ser Arg Ser Arg 145 150 155 160 Glu Arg Lys Lys Ser Arg Ser Arg Ser Arg Glu Arg Lys Arg Arg Ile 165 170 175 Arg Ser Arg Ser Arg Ser Arg Ser Arg His Arg His Arg Thr Arg Ser 180 185 190 Arg Ser Arg Thr Arg Ser Arg Ser Arg Asp Arg Lys Lys Arg Ile Glu 195 200 205 Lys Pro Arg Arg Phe Ser Arg Ser Leu Ser Arg Thr Pro Ser Pro Pro 210 215 220 Pro Phe Arg Gly Arg Asn Thr Ala Met Asp Ala Gln Glu Ala Leu Ala 225 230 235 240 Arg Arg Leu Glu Arg Ala Lys Lys Leu Gln Glu Gln Arg Glu Lys Glu 245 250 255 Met Val Glu Lys Gln Lys Gln Gln Glu Ile Ala Ala Ala Ala Ala Thr 260 265 270 Gly Gly Ser Val Leu Asn Val Ala Ala Leu Leu Ala Ser Gly Thr Gln 275 280 285 Val Thr Pro Gln Ile Ala Met Ala Ala Gln Met Ala Ala Leu Gln Ala 290 295 300 Lys Ala Leu Ala Glu Thr Gly Ile Ala Val Pro Ser Tyr Tyr Asn Pro 305 310 315 320 Ala Ala Val Asn Pro Met Lys Phe Ala Glu Gln Glu Lys Lys Arg Lys 325 330 335 Met Leu Trp Gln Gly Lys Lys Glu Gly Asp Lys Ser Gln Ser Ala Glu 340 345 350 Ile Trp Glu Lys Leu Asn Phe Gly Asn Lys Asp Gln Asn Val Lys Phe 355 360 365 Arg Lys Leu Met Gly Ile Lys Ser Glu Asp Glu Ala Gly Cys Ser Ser 370 375 380 Val Asp Glu Glu Ser Tyr Lys Thr Leu Lys Gln Gln Glu Glu Val Phe 385 390 395 400 Arg Asn Leu Asp Ala Gln Tyr Glu Met Ala Arg Ser Gln Thr His Thr 405 410 415 Gln Arg Gly Met Gly Leu Gly Phe Thr Ser Ser Met Arg Gly Met Asp 420 425 430 Ala Val <210> 25 <211> 1273 <212> PRT <213> Homo sapiens <400> 25 Met Lys Arg Arg Leu Asp Asp Gln Glu Ser Pro Val Tyr Ala Ala Gln 1 5 10 15 Gln Arg Arg Ile Pro Gly Ser Thr Glu Ala Phe Pro His Gln His Arg 20 25 30 Val Leu Ala Pro Ala Pro Pro Val Tyr Glu Ala Val Ser Glu Thr Met 35 40 45 Gln Ser Ala Thr Gly Ile Gln Tyr Ser Val Thr Pro Ser Tyr Gln Val 50 55 60 Ser Ala Met Pro Gln Ser Ser Gly Ser His Gly Pro Ala Ile Ala Ala 65 70 75 80 Val His Ser Ser His His His Pro Thr Ala Val Gln Pro His Gly Gly 85 90 95 Gln Val Val Gln Ser His Ala His Pro Ala Pro Pro Val Ala Pro Val 100 105 110 Gln Gly Gln Gln Gln Phe Gln Arg Leu Lys Val Glu Asp Ala Leu Ser 115 120 125 Tyr Leu Asp Gln Val Lys Leu Gln Phe Gly Ser Gln Pro Gln Val Tyr 130 135 140 Asn Asp Phe Leu Asp Ile Met Lys Glu Phe Lys Ser Gln Ser Ile Asp 145 150 155 160 Thr Pro Gly Val Ile Ser Arg Val Ser Gln Leu Phe Lys Gly His Pro 165 170 175 Asp Leu Ile Met Gly Phe Asn Thr Phe Leu Pro Pro Gly Tyr Lys Ile 180 185 190 Glu Val Gln Thr Asn Asp Met Val Asn Val Thr Thr Pro Gly Gln Val 195 200 205 His Gln Ile Pro Thr His Gly Ile Gln Pro Gln Pro Gln Pro Pro Pro 210 215 220 Gln His Pro Ser Gln Pro Ser Ala Gln Ser Ala Pro Ala Pro Ala Gln 225 230 235 240 Pro Ala Pro Gln Pro Pro Pro Ala Lys Val Ser Lys Pro Ser Gln Leu 245 250 255 Gln Ala His Thr Pro Ala Ser Gln Gln Thr Pro Pro Leu Pro Pro Tyr 260 265 270 Ala Ser Pro Arg Ser Pro Pro Val Gln Pro His Thr Pro Val Thr Ile 275 280 285 Ser Leu Gly Thr Ala Pro Ser Leu Gln Asn Asn Gln Pro Val Glu Phe 290 295 300 Asn His Ala Ile Asn Tyr Val Asn Lys Ile Lys Asn Arg Phe Gln Gly 305 310 315 320 Gln Pro Asp Ile Tyr Lys Ala Phe Leu Glu Ile Leu His Thr Tyr Gln 325 330 335 Lys Glu Gln Arg Asn Ala Lys Glu Ala Gly Gly Asn Tyr Thr Pro Ala 340 345 350 Leu Thr Glu Gln Glu Val Tyr Ala Gln Val Ala Arg Leu Phe Lys Asn 355 360 365 Gln Glu Asp Leu Leu Ser Glu Phe Gly Gln Phe Leu Pro Asp Ala Asn 370 375 380 Ser Ser Val Leu Leu Ser Lys Thr Thr Ala Glu Lys Val Asp Ser Val 385 390 395 400 Arg Asn Asp His Gly Gly Thr Val Lys Lys Pro Gln Leu Asn Asn Lys 405 410 415 Pro Gln Arg Pro Ser Gln Asn Gly Cys Gln Ile Arg Arg His Pro Thr 420 425 430 Gly Thr Thr Pro Pro Val Lys Lys Lys Lys Pro Lys Leu Leu Asn Leu Lys 435 440 445 Asp Ser Ser Met Ala Asp Ala Ser Lys His Gly Gly Gly Thr Glu Ser 450 455 460 Leu Phe Phe Asp Lys Val Arg Lys Ala Leu Arg Ser Ala Glu Ala Tyr 465 470 475 480 Glu Asn Phe Leu Arg Cys Leu Val Ile Phe Asn Gln Glu Val Ile Ser 485 490 495 Arg Ala Glu Leu Val Gln Leu Val Ser Pro Phe Leu Gly Lys Phe Pro 500 505 510 Glu Leu Phe Asn Trp Phe Lys Asn Phe Leu Gly Tyr Lys Glu Ser Val 515 520 525 His Leu Glu Thr Tyr Pro Lys Glu Arg Ala Thr Glu Gly Ile Ala Met 530 535 540 Glu Ile Asp Tyr Ala Ser Cys Lys Arg Leu Gly Ser Ser Tyr Arg Ala 545 550 555 560 Leu Pro Lys Ser Tyr Gln Gln Pro Lys Cys Thr Gly Arg Thr Pro Leu 565 570 575 Cys Lys Glu Val Leu Asn Asp Thr Trp Val Ser Phe Pro Ser Trp Ser 580 585 590 Glu Asp Ser Thr Phe Val Ser Ser Lys Lys Thr Gln Tyr Glu Glu His 595 600 605 Ile Tyr Arg Cys Glu Asp Glu Arg Phe Glu Leu Asp Val Val Leu Glu 610 615 620 Thr Asn Leu Ala Thr Ile Arg Val Leu Glu Ala Ile Gln Lys Lys Leu 625 630 635 640 Ser Arg Leu Ser Ala Glu Glu Gln Ala Lys Phe Arg Leu Asp Asn Thr 645 650 655 Leu Gly Gly Thr Ser Glu Val Ile His Arg Lys Ala Leu Gln Arg Ile 660 665 670 Tyr Ala Asp Lys Ala Ala Asp Ile Ile Asp Gly Leu Arg Lys Asn Pro 675 680 685 Ser Ile Ala Val Pro Ile Val Leu Lys Arg Leu Lys Met Lys Glu Glu 690 695 700 Glu Trp Arg Glu Ala Gln Arg Gly Phe Asn Lys Val Trp Arg Glu Gln 705 710 715 720 Asn Glu Lys Tyr Tyr Leu Lys Ser Leu Asp His Gln Gly Ile Asn Phe 725 730 735 Lys Gln Asn Asp Thr Lys Val Leu Arg Ser Lys Ser Leu Leu Asn Glu 740 745 750 Ile Glu Ser Ile Tyr Asp Glu Arg Gln Glu Gln Ala Thr Glu Glu Asn 755 760 765 Ala Gly Val Pro Val Gly Pro His Leu Ser Leu Ala Tyr Glu Asp Lys 770 775 780 Gln Ile Leu Glu Asp Ala Ala Ala Leu Ile Ile His His Val Lys Arg 785 790 795 800 Gln Thr Gly Ile Gln Lys Glu Asp Lys Tyr Lys Ile Lys Gln Ile Met 805 810 815 His His Phe Ile Pro Asp Leu Leu Phe Ala Gln Arg Gly Asp Leu Ser 820 825 830 Asp Val Glu Glu Glu Glu Glu Glu Glu Met Asp Val Asp Glu Ala Thr 835 840 845 Gly Ala Val Lys Lys His Asn Gly Val Gly Gly Ser Pro Lys Ser 850 855 860 Lys Leu Leu Phe Ser Asn Thr Ala Ala Gln Lys Leu Arg Gly Met Asp 865 870 875 880 Glu Val Tyr Asn Leu Phe Tyr Val Asn Asn Asn Trp Tyr Ile Phe Met 885 890 895 Arg Leu His Gln Ile Leu Cys Leu Arg Leu Leu Arg Ile Cys Ser Gln 900 905 910 Ala Glu Arg Gln Ile Glu Glu Glu Asn Arg Glu Arg Glu Trp Glu Arg 915 920 925 Glu Val Leu Gly Ile Lys Arg Asp Lys Ser Asp Ser Pro Ala Ile Gln 930 935 940 Leu Arg Leu Lys Glu Pro Met Asp Val Asp Val Glu Asp Tyr Tyr Pro 945 950 955 960 Ala Phe Leu Asp Met Val Arg Ser Leu Leu Asp Gly Asn Ile Asp Ser 965 970 975 Ser Gln Tyr Glu Asp Ser Leu Arg Glu Met Phe Thr Ile His Ala Tyr 980 985 990 Ile Ala Phe Thr Met Asp Lys Leu Ile Gln Ser Ile Val Arg Gln Leu 995 1000 1005 Gln His Ile Val Ser Asp Glu Ile Cys Val Gln Val Thr Asp Leu Tyr 1010 1015 1020 Leu Ala Glu Asn Asn Asn Gly Ala Thr Gly Gly Gln Leu Asn Thr Gln 1025 1030 1035 1040 Asn Ser Arg Ser Leu Leu Glu Ser Thr Tyr Gln Arg Lys Ala Glu Gln 1045 1050 1055 Leu Met Ser Asp Glu Asn Cys Phe Lys Leu Met Phe Ile Gln Ser Gln 1060 1065 1070 Gly Gln Val Gln Leu Thr Ile Glu Leu Leu Asp Thr Glu Glu Glu Asn 1075 1080 1085 Ser Asp Asp Pro Val Glu Ala Glu Arg Trp Ser Asp Tyr Val Glu Arg 1090 1095 1100 Tyr Met Asn Ser Asp Thr Thr Ser Pro Glu Leu Arg Glu His Leu Ala 1105 1110 1115 1120 Gln Lys Pro Val Phe Leu Pro Arg Asn Leu Arg Arg Ile Arg Lys Cys 1125 1130 1135 Gln Arg Gly Arg Glu Gln Gln Glu Lys Glu Gly Lys Glu Gly Asn Ser 1140 1145 1150 Lys Lys Thr Met Glu Asn Val Asp Ser Leu Asp Lys Leu Glu Cys Arg 1155 1160 1165 Phe Lys Leu Asn Ser Tyr Lys Met Val Tyr Val Ile Lys Ser Glu Asp 1170 1175 1180 Tyr Met Tyr Arg Arg Thr Ala Leu Leu Arg Ala His Gln Ser His Glu 1185 1190 1195 1200 Arg Val Ser Lys Arg Leu His Gln Arg Phe Gln Ala Trp Val Asp Lys 1205 1210 1215 Trp Thr Lys Glu His Val Pro Arg Glu Met Ala Ala Glu Thr Ser Lys 1220 1225 1230 Trp Leu Met Gly Glu Gly Leu Glu Gly Leu Val Pro Cys Thr Thr Thr 1235 1240 1245 Cys Asp Thr Glu Thr Leu His Phe Val Ser Ile Asn Lys Tyr Arg Val 1250 1255 1260 Lys Tyr Gly Thr Val Phe Lys Ala Pro 1265 1270 <210> 26 <211> 610 <212> PRT <213> Homo sapiens <400> 26 Met Ser Arg Ser Pro Leu Asn Pro Ser Gln Leu Arg Ser Val Gly Ser 1 5 10 15 Gln Asp Ala Leu Ala Pro Leu Pro Pro Pro Ala Pro Gln Asn Pro Ser 20 25 30 Thr His Ser Trp Asp Pro Leu Cys Gly Ser Leu Pro Trp Gly Leu Ser 35 40 45 Cys Leu Leu Ala Leu Gln His Val Leu Val Met Ala Ser Leu Leu Cys 50 55 60 Val Ser His Leu Leu Leu Leu Cys Ser Leu Ser Pro Gly Gly Leu Ser 65 70 75 80 Tyr Ser Pro Ser Gln Leu Leu Ala Ser Ser Phe Phe Ser Cys Gly Met 85 90 95 Ser Thr Ile Leu Gln Thr Trp Met Gly Ser Arg Leu Pro Leu Val Gln 100 105 110 Ala Pro Ser Leu Glu Phe Leu Ile Pro Ala Leu Val Leu Thr Ser Gln 115 120 125 Lys Leu Pro Arg Ala Ile Gln Thr Pro Gly Asn Ser Ser Leu Met Leu 130 135 140 His Leu Cys Arg Gly Pro Ser Cys His Gly Leu Gly His Trp Asn Thr 145 150 155 160 Ser Leu Gln Glu Val Ser Gly Ala Val Val Val Ser Gly Leu Leu Gln 165 170 175 Gly Met Met Gly Leu Leu Gly Ser Pro Gly His Val Phe Pro His Cys 180 185 190 Gly Pro Leu Val Leu Ala Pro Ser Leu Val Val Ala Gly Leu Ser Ala 195 200 205 His Arg Glu Val Ala Gln Phe Cys Phe Thr His Trp Gly Leu Ala Leu 210 215 220 Leu Val Ile Leu Leu Met Val Val Cys Ser Gln His Leu Gly Ser Cys 225 230 235 240 Gln Phe His Val Cys Pro Trp Arg Arg Ala Ser Thr Ser Ser Ser Thr His 245 250 255 Thr Pro Leu Pro Val Phe Arg Leu Leu Ser Val Leu Ile Pro Val Ala 260 265 270 Cys Val Trp Ile Val Ser Ala Phe Val Gly Phe Ser Val Ile Pro Gln 275 280 285 Glu Leu Ser Ala Pro Thr Lys Ala Pro Trp Ile Trp Leu Pro His Pro 290 295 300 Gly Glu Trp Asn Trp Pro Leu Leu Thr Pro Arg Ala Leu Ala Ala Gly 305 310 315 320 Ile Ser Met Ala Leu Ala Ala Ser Thr Ser Ser Leu Gly Cys Tyr Ala 325 330 335 Leu Cys Gly Arg Leu Leu His Leu Pro Pro Pro Pro Pro His Ala Cys 340 345 350 Ser Arg Gly Leu Ser Leu Glu Gly Leu Gly Ser Val Leu Ala Gly Leu 355 360 365 Leu Gly Ser Pro Met Gly Thr Ala Ser Ser Phe Pro Asn Val Gly Lys 370 375 380 Val Gly Leu Ile Gln Ala Gly Ser Gln Gln Val Ala His Leu Val Gly 385 390 395 400 Leu Leu Cys Val Gly Leu Gly Leu Ser Pro Arg Leu Ala Gln Leu Leu 405 410 415 Thr Thr Ile Pro Leu Pro Val Val Gly Gly Val Leu Gly Val Thr Gln 420 425 430 Ala Val Val Leu Ser Ala Gly Phe Ser Ser Phe Tyr Leu Ala Asp Ile 435 440 445 Asp Ser Gly Arg Asn Ile Phe Ile Val Gly Phe Ser Ile Phe Met Ala 450 455 460 Leu Leu Leu Pro Arg Trp Phe Arg Glu Ala Pro Val Leu Phe Ser Thr 465 470 475 480 Gly Trp Ser Pro Leu Asp Val Leu Leu His Ser Leu Leu Thr Gln Pro 485 490 495 Ile Phe Leu Ala Gly Leu Ser Gly Phe Leu Leu Glu Asn Thr Ile Pro 500 505 510 Gly Thr Gln Leu Glu Arg Gly Leu Gly Gly Gly Leu Pro Ser Pro Phe 515 520 525 Thr Ala Gln Glu Ala Arg Met Pro Gln Lys Pro Arg Glu Lys Ala Ala 530 535 540 Gln Val Tyr Arg Leu Pro Phe Pro Ile Gln Asn Leu Cys Pro Cys Ile 545 550 555 560 Pro Gln Pro Leu His Cys Leu Cys Pro Leu Pro Glu Asp Pro Gly Asp 565 570 575 Glu Glu Gly Gly Ser Ser Glu Pro Glu Glu Met Ala Asp Leu Leu Pro 580 585 590 Gly Ser Gly Glu Pro Cys Pro Glu Ser Ser Arg Glu Gly Phe Arg Ser 595 600 605 Gln Lys 610 <210> 27 <211> 540 <212> PRT <213> Homo sapiens <400> 27 Met Pro Leu Phe Ala Thr Asn Pro Phe Asp Gln Asp Val Glu Lys Ala 1 5 10 15 Thr Ser Glu Met Asn Thr Ala Glu Asp Trp Gly Leu Ile Leu Asp Ile 20 25 30 Cys Asp Lys Val Gly Gln Ser Arg Thr Gly Pro Lys Asp Cys Leu Arg 35 40 45 Ser Ile Met Arg Arg Val Asn His Lys Asp Pro His Val Ala Met Gln 50 55 60 Ala Leu Thr Leu Leu Gly Ala Cys Val Ser Asn Cys Gly Lys Ile Phe 65 70 75 80 His Leu Glu Val Cys Ser Arg Asp Phe Ala Ser Glu Val Ser Asn Val 85 90 95 Leu Asn Lys Gly His Pro Lys Val Cys Glu Lys Leu Lys Ala Leu Met 100 105 110 Val Glu Trp Thr Asp Glu Phe Lys Asn Asp Pro Gln Leu Ser Leu Ile 115 120 125 Ser Ala Met Ile Lys Asn Leu Lys Glu Gln Gly Val Thr Phe Pro Ala 130 135 140 Ile Gly Ser Gln Ala Ala Glu Gln Ala Lys Ala Ser Pro Ala Leu Val 145 150 155 160 Ala Lys Asp Pro Gly Thr Val Ala Asn Lys Lys Glu Glu Glu Asp Leu 165 170 175 Ala Lys Ala Ile Glu Leu Ser Leu Lys Glu Gln Arg Gln Gln Ser Thr 180 185 190 Thr Leu Ser Thr Leu Tyr Pro Ser Thr Ser Ser Leu Leu Thr Asn His 195 200 205 Gln His Glu Gly Arg Lys Val Arg Ala Ile Tyr Asp Phe Glu Ala Ala 210 215 220 Glu Asp Asn Glu Leu Thr Phe Lys Ala Gly Glu Ile Ile Thr Val Leu 225 230 235 240 Asp Asp Ser Asp Pro Asn Trp Trp Lys Gly Glu Thr His Gln Gly Ile 245 250 255 Gly Leu Phe Pro Ser Asn Phe Val Thr Ala Asp Leu Thr Ala Glu Pro 260 265 270 Glu Met Ile Lys Thr Glu Lys Lys Thr Val Gln Phe Ser Asp Asp Val 275 280 285 Gln Val Glu Thr Ile Glu Pro Glu Pro Glu Pro Ala Phe Ile Asp Glu 290 295 300 Asp Lys Met Asp Gln Leu Leu Gln Met Leu Gln Ser Thr Asp Pro Ser 305 310 315 320 Asp Asp Gln Pro Asp Leu Pro Glu Leu Leu His Leu Glu Ala Met Cys 325 330 335 His Gln Met Gly Pro Leu Ile Asp Glu Lys Leu Glu Asp Ile Asp Arg 340 345 350 Lys His Ser Glu Leu Ser Glu Leu Asn Val Lys Val Met Glu Ala Leu 355 360 365 Ser Leu Tyr Thr Lys Leu Met Asn Glu Asp Pro Met Tyr Ser Met Tyr 370 375 380 Ala Lys Leu Gln Asn Gln Pro Tyr Tyr Met Gln Ser Ser Gly Val Ser 385 390 395 400 Gly Ser Gln Val Tyr Ala Gly Pro Pro Ser Gly Ala Tyr Leu Val 405 410 415 Ala Gly Asn Ala Gln Met Ser His Leu Gln Ser Tyr Ser Leu Pro Pro 420 425 430 Glu Gln Leu Ser Ser Leu Ser Gln Ala Val Val Pro Ser Ala Asn 435 440 445 Pro Ala Leu Pro Ser Gln Gln Thr Gln Ala Ala Tyr Pro Asn Thr Met 450 455 460 Val Ser Ser Val Gln Gly Asn Thr Tyr Pro Ser Gln Ala Pro Val Tyr 465 470 475 480 Ser Pro Pro Pro Ala Ala Thr Ala Ala Ala Ala Thr Ala Asp Val Thr 485 490 495 Leu Tyr Gln Asn Ala Gly Pro Asn Met Pro Gln Val Pro Asn Tyr Asn 500 505 510 Leu Thr Ser Ser Thr Leu Pro Gln Pro Gly Gly Ser Gln Gln Pro Pro 515 520 525 Gln Pro Gln Gln Pro Tyr Ser Gln Lys Ala Leu Leu 530 535 540 <210> 28 <211> 403 <212> PRT <213> Homo sapiens <400> 28 Met His Asn Phe Glu Glu Glu Leu Thr Cys Pro Ile Cys Tyr Ser Ile 1 5 10 15 Phe Glu Asp Pro Arg Val Leu Pro Cys Ser His Thr Phe Cys Arg Asn 20 25 30 Cys Leu Glu Asn Ile Leu Gln Ala Ser Gly Asn Phe Tyr Ile Trp Arg 35 40 45 Pro Leu Arg Ile Pro Leu Lys Cys Pro Asn Cys Arg Ser Ile Thr Glu 50 55 60 Ile Ala Pro Thr Gly Ile Glu Ser Leu Pro Val Asn Phe Ala Leu Arg 65 70 75 80 Ala Ile Ile Glu Lys Tyr Gln Gln Glu Asp His Pro Asp Ile Val Thr 85 90 95 Cys Pro Glu His Tyr Arg Gln Pro Leu Asn Val Tyr Cys Leu Leu Asp 100 105 110 Lys Lys Leu Val Cys Gly His Cys Leu Thr Ile Gly Gln His His Gly 115 120 125 His Pro Ile Asp Asp Leu Gln Ser Ala Tyr Leu Lys Glu Lys Asp Thr 130 135 140 Pro Gln Lys Leu Leu Glu Gln Leu Thr Asp Thr His Trp Thr Asp Leu 145 150 155 160 Thr His Leu Ile Glu Lys Leu Lys Glu Gln Lys Ser His Ser Glu Lys 165 170 175 Met Ile Gln Gly Asp Lys Glu Ala Val Leu Gln Tyr Phe Lys Glu Leu 180 185 190 Asn Asp Thr Leu Glu Gln Lys Lys Lys Ser Phe Leu Thr Ala Leu Cys 195 200 205 Asp Val Gly Asn Leu Ile Asn Gln Glu Tyr Thr Pro Gln Ile Glu Arg 210 215 220 Met Lys Glu Ile Arg Glu Gln Gln Leu Glu Leu Met Ala Leu Thr Ile 225 230 235 240 Ser Leu Gln Glu Glu Ser Pro Leu Lys Phe Leu Glu Lys Val Asp Asp 245 250 255 Val Arg Gln His Val Gln Ile Leu Lys Gln Arg Pro Leu Pro Glu Val 260 265 270 Gln Pro Val Glu Ile Tyr Pro Arg Val Ser Lys Ile Leu Lys Glu Glu 275 280 285 Trp Ser Arg Thr Glu Ile Gly Gln Ile Lys Asn Val Leu Ile Pro Lys 290 295 300 Met Lys Ile Ser Pro Lys Arg Met Ser Cys Ser Trp Pro Gly Lys Asp 305 310 315 320 Glu Lys Glu Val Glu Phe Leu Lys Ile Leu Asn Ile Val Val Val Thr 325 330 335 Leu Ile Ser Val Ile Leu Met Ser Ile Leu Phe Phe Asn Gln His Ile 340 345 350 Ile Thr Phe Leu Ser Glu Ile Thr Leu Ile Trp Phe Ser Glu Ala Ser 355 360 365 Leu Ser Val Tyr Gln Ser Leu Ser Asn Ser Leu His Lys Val Lys Asn 370 375 380 Ile Leu Cys His Ile Phe Tyr Leu Leu Lys Glu Phe Val Trp Lys Ile 385 390 395 400 Val Ser His <210> 29 <211> 1092 <212> PRT <213> Homo sapiens <400> 29 Met Met Asp Ser Pro Lys Ile Gly Asn Gly Leu Pro Val Ile Gly Pro 1 5 10 15 Gly Thr Asp Ile Gly Ile Ser Ser Leu His Met Val Gly Tyr Leu Gly 20 25 30 Lys Asn Phe Asp Ser Ala Lys Val Pro Ser Asp Glu Tyr Cys Pro Ala 35 40 45 Cys Arg Glu Lys Gly Lys Leu Lys Ala Leu Lys Thr Tyr Arg Ile Ser 50 55 60 Phe Gln Glu Ser Ile Phe Leu Cys Glu Asp Leu Gln Cys Ile Tyr Pro 65 70 75 80 Leu Gly Ser Lys Ser Leu Asn Asn Leu Ile Ser Pro Asp Leu Glu Glu 85 90 95 Cys His Thr Pro His Lys Pro Gln Lys Arg Lys Ser Leu Glu Ser Ser 100 105 110 Tyr Lys Asp Ser Leu Leu Leu Ala Asn Ser Lys Lys Thr Arg Asn Tyr 115 120 125 Ile Ala Ile Asp Gly Gly Lys Val Leu Asn Ser Lys His Asn Gly Glu 130 135 140 Val Tyr Asp Glu Thr Ser Ser Asn Leu Pro Asp Ser Ser Gly Gly Gln 145 150 155 160 Asn Pro Ile Arg Thr Ala Asp Ser Leu Glu Arg Asn Glu Ile Leu Glu 165 170 175 Ala Asp Thr Val Asp Met Ala Thr Thr Lys Asp Pro Ala Thr Val Asp 180 185 190 Val Ser Gly Thr Gly Arg Pro Ser Pro Gln Asn Glu Gly Cys Thr Ser 195 200 205 Lys Leu Glu Met Pro Leu Glu Ser Lys Cys Thr Ser Phe Pro Gln Ala 210 215 220 Leu Cys Val Gln Trp Lys Asn Ala Tyr Ala Leu Cys Trp Leu Asp Cys 225 230 235 240 Ile Leu Ser Ala Leu Val His Ser Glu Glu Leu Lys Asn Thr Val Thr 245 250 255 Gly Leu Cys Ser Lys Glu Glu Ser Ile Phe Trp Arg Leu Leu Thr Lys 260 265 270 Tyr Asn Gln Ala Asn Thr Leu Leu Tyr Thr Ser Gln Leu Ser Gly Val 275 280 285 Lys Asp Gly Asp Cys Lys Lys Leu Thr Ser Glu Ile Phe Ala Glu Ile 290 295 300 Glu Thr Cys Leu Asn Glu Val Arg Asp Glu Ile Phe Ile Ser Leu Gln 305 310 315 320 Pro Gln Leu Arg Cys Thr Leu Gly Asp Met Glu Ser Pro Val Phe Ala 325 330 335 Phe Pro Leu Leu Leu Lys Leu Glu Thr His Ile Glu Lys Leu Phe Leu 340 345 350 Tyr Ser Phe Ser Trp Asp Phe Glu Cys Ser Gln Cys Gly His Gln Tyr 355 360 365 Gln Asn Arg His Met Lys Ser Leu Val Thr Phe Thr Asn Val Ile Pro 370 375 380 Glu Trp His Pro Leu Asn Ala Ala His Phe Gly Pro Cys Asn Asn Cys 385 390 395 400 Asn Ser Lys Ser Gln Ile Arg Lys Met Val Leu Glu Lys Val Ser Pro 405 410 415 Ile Phe Met Leu His Phe Val Glu Gly Leu Pro Gln Asn Asp Leu Gln 420 425 430 His Tyr Ala Phe His Phe Glu Gly Cys Leu Tyr Gln Ile Thr Ser Val 435 440 445 Ile Gln Tyr Arg Ala Asn Asn His Phe Ile Thr Trp Ile Leu Asp Ala 450 455 460 Asp Gly Ser Trp Leu Glu Cys Asp Asp Leu Lys Gly Pro Cys Ser Glu 465 470 475 480 Arg His Lys Lys Phe Glu Val Pro Ala Ser Glu Ile His Ile Val Ile 485 490 495 Trp Glu Arg Lys Ile Ser Gln Val Thr Asp Lys Glu Ala Ala Cys Leu 500 505 510 Pro Leu Lys Lys Thr Asn Asp Gln His Ala Leu Ser Asn Glu Lys Pro 515 520 525 Val Ser Leu Thr Ser Cys Ser Val Gly Asp Ala Ala Ser Ala Glu Thr 530 535 540 Ala Ser Val Thr His Pro Lys Asp Ile Ser Val Ala Pro Arg Thr Leu 545 550 555 560 Ser Gln Asp Thr Ala Val Thr His Gly Asp His Leu Leu Ser Gly Pro 565 570 575 Lys Gly Leu Val Asp Asn Ile Leu Pro Leu Thr Leu Glu Glu Thr Ile 580 585 590 Gln Lys Thr Ala Ser Val Ser Gln Leu Asn Ser Glu Ala Phe Leu Leu 595 600 605 Glu Asn Lys Pro Val Ala Glu Asn Thr Gly Ile Leu Lys Thr Asn Thr 610 615 620 Leu Leu Ser Gln Glu Ser Leu Met Ala Ser Ser Val Ser Ala Pro Cys 625 630 635 640 Asn Glu Lys Leu Ile Gln Asp Gln Phe Val Asp Ile Ser Phe Pro Ser 645 650 655 Gln Val Val Asn Thr Asn Met Gln Ser Val Gln Leu Asn Thr Glu Asp 660 665 670 Thr Val Asn Thr Lys Ser Val Asn Asn Thr Asp Ala Thr Gly Leu Ile 675 680 685 Gln Gly Val Lys Ser Val Glu Ile Glu Lys Asp Ala Gln Leu Lys Gln 690 695 700 Phe Leu Thr Pro Lys Thr Glu Gln Leu Lys Pro Glu Arg Val Thr Ser 705 710 715 720 Gln Val Ser Asn Leu Lys Lys Lys Glu Thr Thr Ala Asp Ser Gln Thr 725 730 735 Thr Thr Ser Lys Ser Leu Gln Asn Gln Ser Leu Lys Glu Asn Gln Lys 740 745 750 Lys Pro Phe Val Gly Ser Trp Val Lys Gly Leu Ile Ser Arg Gly Ala 755 760 765 Ser Phe Met Pro Leu Cys Val Ser Ala His Asn Arg Asn Thr Ile Thr 770 775 780 Asp Leu Gln Pro Ser Val Lys Gly Val Asn Asn Phe Gly Gly Phe Lys 785 790 795 800 Thr Lys Gly Ile Asn Gln Lys Ala Ser His Val Ser Lys Lys Ala Arg 805 810 815 Lys Ser Ala Ser Lys Pro Pro Pro Ile Ser Lys Pro Pro Ala Gly Pro 820 825 830 Pro Ser Ser Asn Gly Thr Ala Ala His Pro His Ala His Ala Ala Ser 835 840 845 Glu Val Leu Glu Lys Ser Gly Ser Thr Ser Cys Gly Ala Gln Leu Asn 850 855 860 His Ser Ser Tyr Gly Asn Gly Ile Ser Ser Ala Asn His Glu Asp Leu 865 870 875 880 Val Glu Gly Gln Ile His Lys Leu Arg Leu Lys Leu Arg Lys Lys Leu 885 890 895 Lys Ala Glu Lys Lys Lys Leu Ala Ala Leu Met Ser Ser Pro Gln Ser 900 905 910 Arg Thr Val Arg Ser Glu Asn Leu Glu Gln Val Pro Gln Asp Gly Ser 915 920 925 Pro Asn Asp Cys Glu Ser Ile Glu Asp Leu Leu Asn Glu Leu Pro Tyr 930 935 940 Pro Ile Asp Ile Ala Ser Glu Ser Ala Cys Thr Thr Val Pro Gly Val 945 950 955 960 Ser Leu Tyr Ser Ser Gln Thr His Glu Glu Ile Leu Ala Glu Leu Leu 965 970 975 Ser Pro Thr Pro Val Ser Thr Glu Leu Ser Glu Asn Gly Glu Gly Asp 980 985 990 Phe Arg Tyr Leu Gly Met Gly Asp Ser His Ile Pro Pro Val Pro 995 1000 1005 Ser Glu Phe Asn Asp Val Ser Gln Asn Thr His Leu Arg Gln Asp His 1010 1015 1020 Asn Tyr Cys Ser Pro Thr Lys Lys Asn Pro Cys Glu Val Gln Pro Asp 1025 1030 1035 1040 Ser Leu Thr Asn Asn Ala Cys Val Arg Thr Leu Asn Leu Glu Ser Pro 1045 1050 1055 Met Lys Thr Asp Ile Phe Asp Glu Phe Phe Ser Ser Ser Ala Leu Asn 1060 1065 1070 Ala Leu Ala Asn Asp Thr Leu Asp Leu Pro His Phe Asp Glu Tyr Leu 1075 1080 1085 Phe Glu Asn Tyr 1090 <210> 30 <211> 2382 <212> PRT <213> Homo sapiens <400> 30 Met Ser Gly Gly Ala Ala Glu Lys Gln Ser Ser Thr Pro Gly Ser Leu 1 5 10 15 Phe Leu Ser Pro Pro Ala Pro Ala Pro Lys Asn Gly Ser Ser Ser Asp 20 25 30 Ser Ser Val Gly Glu Lys Leu Gly Ala Ala Ala Ala Asp Ala Val Thr 35 40 45 Gly Arg Thr Glu Glu Tyr Arg Arg Arg Arg His Thr Met Asp Lys Asp 50 55 60 Ser Arg Gly Ala Ala Ala Thr Thr Thr Thr Thr Glu His Arg Phe Phe 65 70 75 80 Arg Arg Ser Val Ile Cys Asp Ser Asn Ala Thr Ala Leu Glu Leu Pro 85 90 95 Gly Leu Pro Leu Ser Leu Pro Gln Pro Ser Ile Pro Ala Ala Val Pro 100 105 110 Gln Ser Ala Pro Pro Glu Pro His Arg Glu Glu Thr Val Thr Ala Thr 115 120 125 Ala Thr Ser Gln Val Ala Gln Gln Pro Pro Ala Ala Ala Ala Pro Gly 130 135 140 Glu Gln Ala Val Ala Gly Pro Ala Pro Ser Thr Val Pro Ser Ser Thr 145 150 155 160 Ser Lys Asp Arg Pro Val Ser Gln Pro Ser Leu Val Gly Ser Lys Glu 165 170 175 Glu Pro Pro Pro Ala Arg Ser Gly Ser Gly Gly Gly Ser Ala Lys Glu 180 185 190 Pro Gln Glu Glu Arg Ser Gln Gln Gln Asp Asp Ile Glu Glu Leu Glu 195 200 205 Thr Lys Ala Val Gly Met Ser Asn Asp Gly Arg Phe Leu Lys Phe Asp 210 215 220 Ile Glu Ile Gly Arg Gly Ser Phe Lys Thr Val Tyr Lys Gly Leu Asp 225 230 235 240 Thr Glu Thr Thr Val Glu Val Ala Trp Cys Glu Leu Gln Asp Arg Lys 245 250 255 Leu Thr Lys Ser Glu Arg Gln Arg Phe Lys Glu Glu Ala Glu Met Leu 260 265 270 Lys Gly Leu Gln His Pro Asn Ile Val Arg Phe Tyr Asp Ser Trp Glu 275 280 285 Ser Thr Val Lys Gly Lys Lys Cys Ile Val Leu Val Thr Glu Leu Met 290 295 300 Thr Ser Gly Thr Leu Lys Thr Tyr Leu Lys Arg Phe Lys Val Met Lys 305 310 315 320 Ile Lys Val Leu Arg Ser Trp Cys Arg Gln Ile Leu Lys Gly Leu Gln 325 330 335 Phe Leu His Thr Arg Thr Pro Pro Ile Ile His Arg Asp Leu Lys Cys 340 345 350 Asp Asn Ile Phe Ile Thr Gly Pro Thr Gly Ser Val Lys Ile Gly Asp 355 360 365 Leu Gly Leu Ala Thr Leu Lys Arg Ala Ser Phe Ala Lys Ser Val Ile 370 375 380 Gly Thr Pro Glu Phe Met Ala Pro Glu Met Tyr Glu Glu Lys Tyr Asp 385 390 395 400 Glu Ser Val Asp Val Tyr Ala Phe Gly Met Cys Met Leu Glu Met Ala 405 410 415 Thr Ser Glu Tyr Pro Tyr Ser Glu Cys Gln Asn Ala Ala Gln Ile Tyr 420 425 430 Arg Arg Val Thr Ser Gly Val Lys Pro Ala Ser Phe Asp Lys Val Ala 435 440 445 Ile Pro Glu Val Lys Glu Ile Ile Ile Glu Gly Cys Ile Arg Gln Asn Lys 450 455 460 Asp Glu Arg Tyr Ser Ile Lys Asp Leu Leu Asn His Ala Phe Phe Gln 465 470 475 480 Glu Glu Thr Gly Val Arg Val Glu Leu Ala Glu Glu Asp Asp Gly Glu 485 490 495 Lys Ile Ala Ile Lys Leu Trp Leu Arg Ile Glu Asp Ile Lys Lys Leu 500 505 510 Lys Gly Lys Tyr Lys Asp Asn Glu Ala Ile Glu Phe Ser Phe Asp Leu 515 520 525 Glu Arg Asp Val Pro Glu Asp Val Ala Gln Glu Met Val Glu Ser Gly 530 535 540 Tyr Val Cys Glu Gly Asp His Lys Thr Met Ala Lys Ala Ile Lys Asp 545 550 555 560 Arg Val Ser Leu Ile Lys Arg Lys Arg Glu Gln Arg Gln Leu Val Arg 565 570 575 Glu Glu Gln Glu Lys Lys Lys Gln Glu Glu Ser Ser Leu Lys Gln Gln 580 585 590 Val Glu Gln Ser Ser Ala Ser Gln Thr Gly Ile Lys Gln Leu Pro Ser 595 600 605 Ala Ser Thr Gly Ile Pro Thr Ala Ser Thr Thr Ser Ala Ser Val Ser 610 615 620 Thr Gln Val Glu Pro Glu Glu Pro Glu Ala Asp Gln His Gln Gln Leu 625 630 635 640 Gln Tyr Gln Gln Pro Ser Ile Ser Val Leu Ser Asp Gly Thr Val Asp 645 650 655 Ser Gly Gln Gly Ser Ser Val Phe Thr Glu Ser Arg Val Ser Ser Gln 660 665 670 Gln Thr Val Ser Tyr Gly Ser Gln His Glu Gln Ala His Ser Thr Gly 675 680 685 Thr Val Pro Gly His Ile Pro Ser Thr Val Gln Ala Gln Ser Gln Pro 690 695 700 His Gly Val Tyr Pro Pro Ser Ser Val Ala Gln Gly Gln Ser Gln Gly 705 710 715 720 Gln Pro Ser Ser Ser Ser Leu Thr Gly Val Ser Ser Ser Gln Pro Ile 725 730 735 Gln His Pro Gln Gln Gln Gln Gly Ile Gln Gln Thr Ala Pro Pro Gln 740 745 750 Gln Thr Val Gln Tyr Ser Leu Ser Gln Thr Ser Thr Ser Ser Glu Ala 755 760 765 Thr Thr Ala Gln Pro Val Ser Gln Pro Gln Ala Pro Gln Val Leu Pro 770 775 780 Gln Val Ser Ala Gly Lys Gln Leu Pro Val Ser Gln Pro Val Pro Thr 785 790 795 800 Ile Gln Gly Glu Pro Gln Ile Pro Val Ala Thr Gln Pro Ser Val Val 805 810 815 Pro Val His Ser Gly Ala His Phe Leu Pro Val Gly Gln Pro Leu Pro 820 825 830 Thr Pro Leu Leu Pro Gln Tyr Pro Val Ser Gln Ile Pro Ile Ser Thr 835 840 845 Pro His Val Ser Thr Ala Gln Thr Gly Phe Ser Ser Leu Pro Ile Thr 850 855 860 Met Ala Ala Gly Ile Thr Gln Pro Leu Leu Thr Leu Ala Ser Ser Ala 865 870 875 880 Thr Thr Ala Ala Ile Pro Gly Val Ser Thr Val Val Pro Ser Gln Leu 885 890 895 Pro Thr Leu Leu Gln Pro Val Thr Gln Leu Pro Ser Gln Val His Pro 900 905 910 Gln Leu Leu Gln Pro Ala Val Gln Ser Met Gly Ile Pro Ala Asn Leu 915 920 925 Gly Gln Ala Ala Glu Val Pro Leu Ser Ser Gly Asp Val Leu Tyr Gln 930 935 940 Gly Phe Pro Pro Arg Leu Pro Pro Gln Tyr Pro Gly Asp Ser Asn Ile 945 950 955 960 Ala Pro Ser Ser Asn Val Ala Ser Val Cys Ile His Ser Thr Val Leu 965 970 975 Ser Pro Pro Met Pro Thr Glu Val Leu Ala Thr Pro Gly Tyr Phe Pro 980 985 990 Thr Val Val Gln Pro Tyr Val Glu Ser Asn Leu Leu Val Pro Met Gly 995 1000 1005 Gly Val Gly Gly Gln Val Gln Val Ser Gln Pro Gly Gly Ser Leu Ala 1010 1015 1020 Gln Ala Pro Thr Thr Ser Ser Gln Gln Ala Val Leu Glu Ser Thr Gln 1025 1030 1035 1040 Gly Val Ser Gln Val Ala Pro Ala Glu Pro Val Ala Val Ala Gln Thr 1045 1050 1055 Gln Ala Thr Gln Pro Thr Thr Leu Ala Ser Ser Val Asp Ser Ala His 1060 1065 1070 Ser Asp Val Ala Ser Gly Met Ser Asp Gly Asn Glu Asn Val Pro Ser 1075 1080 1085 Ser Ser Gly Arg His Glu Gly Arg Thr Thr Lys Arg His Tyr Arg Lys 1090 1095 1100 Ser Val Arg Ser Arg Ser Arg His Glu Lys Thr Ser Arg Pro Lys Leu 1105 1110 1115 1120 Arg Ile Leu Asn Val Ser Asn Lys Gly Asp Arg Val Val Glu Cys Gln 1125 1130 1135 Leu Glu Thr His Asn Arg Lys Met Val Thr Phe Lys Phe Asp Leu Asp 1140 1145 1150 Gly Asp Asn Pro Glu Glu Ile Ala Thr Ile Met Val Asn Asn Asp Phe 1155 1160 1165 Ile Leu Ala Ile Glu Arg Glu Ser Phe Val Asp Gln Val Arg Glu Ile 1170 1175 1180 Ile Glu Lys Ala Asp Glu Met Leu Ser Glu Asp Val Ser Val Glu Pro 1185 1190 1195 1200 Glu Gly Asp Gln Gly Leu Glu Ser Leu Gln Gly Lys Asp Asp Tyr Gly 1205 1210 1215 Phe Ser Gly Ser Gln Lys Leu Glu Gly Glu Phe Lys Gln Pro Ile Pro 1220 1225 1230 Ala Ser Ser Met Pro Gln Gln Ile Gly Ile Pro Thr Ser Ser Leu Thr 1235 1240 1245 Gln Val Val His Ser Ala Gly Arg Arg Phe Ile Val Ser Pro Val Pro 1250 1255 1260 Glu Ser Arg Leu Arg Glu Ser Lys Val Phe Pro Ser Glu Ile Thr Asp 1265 1270 1275 1280 Thr Val Ala Ala Ser Thr Ala Gln Ser Pro Gly Met Asn Leu Ser His 1285 1290 1295 Ser Ala Ser Ser Leu Ser Leu Gln Gln Ala Phe Ser Glu Leu Arg Arg 1300 1305 1310 Ala Gln Met Thr Glu Gly Pro Asn Thr Ala Pro Pro Asn Phe Ser His 1315 1320 1325 Thr Gly Pro Thr Phe Pro Val Val Pro Phe Leu Ser Ser Ile Ala 1330 1335 1340 Gly Val Pro Thr Thr Ala Ala Ala Thr Ala Pro Val Pro Ala Thr Ser 1345 1350 1355 1360 Ser Pro Pro Asn Asp Ile Ser Thr Ser Val Ile Gln Ser Glu Val Thr 1365 1370 1375 Val Pro Thr Glu Glu Gly Ile Ala Gly Val Ala Thr Ser Thr Gly Val 1380 1385 1390 Val Thr Ser Gly Gly Leu Pro Ile Pro Val Ser Glu Ser Pro Val 1395 1400 1405 Leu Ser Ser Val Val Ser Ser Ile Thr Ile Pro Ala Val Val Ser Ile 1410 1415 1420 Ser Thr Thr Ser Pro Ser Leu Gln Val Pro Thr Ser Thr Ser Glu Ile 1425 1430 1435 1440 Val Val Ser Ser Thr Ala Leu Tyr Pro Ser Val Thr Val Ser Ala Thr 1445 1450 1455 Ser Ala Ser Ala Gly Gly Ser Thr Ala Thr Pro Gly Pro Lys Pro Pro 1460 1465 1470 Ala Val Val Ser Gln Gln Ala Ala Gly Ser Thr Thr Val Gly Ala Thr 1475 1480 1485 Leu Thr Ser Val Ser Thr Thr Thr Ser Phe Pro Ser Thr Ala Ser Gln 1490 1495 1500 Leu Cys Ile Gln Leu Ser Ser Ser Thr Ser Thr Pro Thr Leu Ala Glu 1505 1510 1515 1520 Thr Val Val Val Ser Ala His Ser Leu Asp Lys Thr Ser His Ser Ser 1525 1530 1535 Thr Thr Gly Leu Ala Phe Ser Leu Ser Ala Pro Ser Ser Ser Ser Ser Ser 1540 1545 1550 Pro Gly Ala Gly Val Ser Ser Tyr Ile Ser Gln Pro Gly Gly Leu His 1555 1560 1565 Pro Leu Val Ile Pro Ser Val Ile Ala Ser Thr Pro Ile Leu Pro Gln 1570 1575 1580 Ala Ala Gly Pro Thr Ser Thr Pro Leu Leu Pro Gln Val Pro Ser Ile 1585 1590 1595 1600 Pro Pro Leu Val Gln Pro Val Ala Asn Val Pro Ala Val Gln Gln Thr 1605 1610 1615 Leu Ile His Ser Gln Pro Gln Pro Ala Leu Leu Pro Asn Gln Pro His 1620 1625 1630 Thr His Cys Pro Glu Val Asp Ser Asp Thr Gln Pro Lys Ala Pro Gly 1635 1640 1645 Ile Asp Asp Ile Lys Thr Leu Glu Glu Lys Leu Arg Ser Leu Phe Ser 1650 1655 1660 Glu His Ser Ser Ser Gly Ala Gln His Ala Ser Val Ser Leu Glu Thr 1665 1670 1675 1680 Ser Leu Val Ile Glu Ser Thr Val Thr Pro Gly Ile Pro Thr Thr Ala 1685 1690 1695 Val Ala Pro Ser Lys Leu Leu Thr Ser Thr Thr Ser Thr Cys Leu Pro 1700 1705 1710 Pro Thr Asn Leu Pro Leu Gly Thr Val Ala Leu Pro Val Thr Pro Val 1715 1720 1725 Val Thr Pro Gly Gin Val Ser Thr Pro Val Ser Thr Thr Thr Ser Gly 1730 1735 1740 Val Lys Pro Gly Thr Ala Pro Ser Lys Pro Pro Leu Thr Lys Ala Pro 1745 1750 1755 1760 Val Leu Pro Val Gly Thr Glu Leu Pro Ala Gly Thr Leu Pro Ser Glu 1765 1770 1775 Gln Leu Pro Pro Phe Pro Gly Pro Ser Leu Thr Gln Ser Gln Gln Pro 1780 1785 1790 Leu Glu Asp Leu Asp Ala Gln Leu Arg Arg Thr Leu Ser Pro Glu Met 1795 1800 1805 Ile Thr Val Thr Ser Ala Val Gly Pro Val Ser Met Ala Ala Pro Thr 1810 1815 1820 Ala Ile Thr Glu Ala Gly Thr Gln Pro Gln Lys Gly Val Ser Gln Val 1825 1830 1835 1840 Lys Glu Gly Pro Val Leu Ala Thr Ser Ser Gly Ala Gly Val Phe Lys 1845 1850 1855 Met Gly Arg Phe Gln Val Ser Val Ala Ala Asp Gly Ala Gln Lys Glu 1860 1865 1870 Gly Lys Asn Lys Ser Glu Asp Ala Lys Ser Val His Phe Glu Ser Ser 1875 1880 1885 Thr Ser Glu Ser Ser Val Leu Ser Ser Ser Ser Pro Glu Ser Thr Leu 1890 1895 1900 Val Lys Pro Glu Pro Asn Gly Ile Thr Ile Pro Gly Ile Ser Ser Asp 1905 1910 1915 1920 Val Pro Glu Ser Ala His Lys Thr Thr Ala Ser Glu Ala Lys Ser Asp 1925 1930 1935 Thr Gly Gln Pro Thr Lys Val Gly Arg Phe Gln Val Thr Thr Thr Ala 1940 1945 1950 Asn Lys Val Gly Arg Phe Ser Val Ser Lys Thr Glu Asp Lys Ile Thr 1955 1960 1965 Asp Thr Lys Lys Glu Gly Pro Val Ala Ser Pro Pro Phe Met Asp Leu 1970 1975 1980 Glu Gln Ala Val Leu Pro Ala Val Ile Pro Lys Lys Glu Lys Pro Glu 1985 1990 1995 2000 Leu Ser Glu Pro Ser His Leu Asn Gly Pro Ser Ser Asp Pro Glu Ala 2005 2010 2015 Ala Phe Leu Ser Arg Asp Val Asp Asp Gly Ser Gly Ser Pro His Ser 2020 2025 2030 Pro His Gln Leu Ser Ser Lys Ser Leu Pro Ser Gln Asn Leu Ser Gln 2035 2040 2045 Ser Leu Ser Asn Ser Phe Asn Ser Ser Tyr Met Ser Ser Asp Asn Glu 2050 2055 2060 Ser Asp Ile Glu Asp Glu Asp Leu Lys Leu Glu Leu Arg Arg Leu Arg 2065 2070 2075 2080 Asp Lys His Leu Lys Glu Ile Gln Asp Leu Gln Ser Arg Gln Lys His 2085 2090 2095 Glu Ile Glu Ser Leu Tyr Thr Lys Leu Gly Lys Val Pro Ala Val 2100 2105 2110 Ile Ile Pro Pro Ala Ala Pro Leu Ser Gly Arg Arg Arg Arg Pro Thr 2115 2120 2125 Lys Ser Lys Gly Ser Lys Ser Ser Arg Ser Ser Ser Leu Gly Asn Lys 2130 2135 2140 Ser Pro Gln Leu Ser Gly Asn Leu Ser Gly Gln Ser Ala Ala Ser Val 2145 2150 2155 2160 Leu His Pro Gln Gln Thr Leu His Pro Pro Gly Asn Ile Pro Glu Ser 2165 2170 2175 Gly Gln Asn Gln Leu Leu Gln Pro Leu Lys Pro Ser Pro Ser Ser Asp 2180 2185 2190 Asn Leu Tyr Ser Ala Phe Thr Ser Asp Gly Ala Ile Ser Val Pro Ser 2195 2200 2205 Leu Ser Ala Pro Gly Gin Gly Thr Ser Ser Thr Asn Thr Val Gly Ala 2210 2215 2220 Thr Val Asn Ser Gln Ala Ala Gln Ala Gln Pro Pro Ala Met Thr Ser 2225 2230 2235 2240 Ser Arg Lys Gly Thr Phe Thr Asp Asp Leu His Lys Leu Val Asp Asn 2245 2250 2255 Trp Ala Arg Asp Ala Met Asn Leu Ser Gly Arg Arg Gly Ser Lys Gly 2260 2265 2270 His Met Asn Tyr Glu Gly Pro Gly Met Ala Arg Lys Phe Ser Ala Pro 2275 2280 2285 Gly Gln Leu Cys Ile Ser Met Thr Ser Asn Leu Gly Gly Ser Ala Pro 2290 2295 2300 Ile Ser Ala Ala Ser Ala Thr Ser Leu Gly His Phe Thr Lys Ser Met 2305 2310 2315 2320 Cys Pro Pro Gln Gln Tyr Gly Phe Pro Ala Thr Pro Phe Gly Ala Gln 2325 2330 2335 Trp Ser Gly Thr Gly Gly Pro Ala Pro Gln Pro Leu Gly Gln Phe Gln 2340 2345 2350 Pro Val Gly Thr Ala Ser Leu Gln Asn Phe Asn Ile Ser Asn Leu Gln 2355 2360 2365 Lys Ser Ile Ser Asn Pro Gly Ser Asn Leu Arg Thr Thr 2370 2375 2380 <210> 31 <211> 441 <212> PRT <213> Homo sapiens <400> 31 Met Ala Pro Arg Ala Gln Ile Gln Gly Pro Leu Thr Phe Gly Asp Val 1 5 10 15 Ala Val Ala Phe Thr Arg Ile Glu Trp Arg His Leu Asp Ala Ala Gln 20 25 30 Arg Ala Leu Tyr Arg Asp Val Met Leu Glu Asn Tyr Gly Asn Leu Val 35 40 45 Ser Val Gly Leu Leu Ser Ser Lys Pro Lys Leu Ile Thr Gln Leu Glu 50 55 60 Gln Gly Ala Glu Pro Trp Thr Glu Val Arg Glu Ala Pro Ser Gly Thr 65 70 75 80 His Ala Val Glu Asp Tyr Trp Phe Glu Thr Lys Met Ser Ala Leu Lys 85 90 95 Gln Ser Thr Ser Glu Ala Ser Val Leu Gly Glu Arg Thr Lys Ser Val 100 105 110 Met Met Glu Lys Gly Leu Asp Trp Glu Gly Arg Ser Ser Thr Glu Lys 115 120 125 Asn Tyr Lys Cys Lys Glu Cys Gly Lys Val Phe Lys Tyr Asn Ser Ser 130 135 140 Phe Ile Ser His Gln Arg Asn His Thr Ser Glu Lys Pro His Lys Cys 145 150 155 160 Lys Glu Cys Gly Ile Ala Phe Met Asn Ser Ser Ser Leu Leu Asn His 165 170 175 His Lys Val His Ala Gly Lys Gln Pro Tyr Arg Cys Ile Glu Cys Gly 180 185 190 Lys Phe Leu Lys Lys His Ser Thr Phe Ile Asn His Gln Arg Ile His 195 200 205 Ser Arg Glu Lys Pro His Lys Cys Ile Glu Cys Gly Lys Thr Phe Arg 210 215 220 Lys Asn Ser Ile Leu Leu Ser His Gln Arg Ile His Thr Gly Gln Lys 225 230 235 240 Pro Tyr Lys Cys Asn Asp Cys Gly Lys Ala Phe Ala Gln Asn Ala Ala 245 250 255 Leu Thr Arg His Glu Arg Ile His Ser Gly Glu Lys Pro Phe Lys Cys 260 265 270 Asn Lys Cys Gly Arg Ala Phe Arg Asp Asn Ser Thr Val Leu Glu His 275 280 285 Gln Lys Ile His Thr Gly Glu Lys Pro Tyr Gln Cys Asn Glu Cys Gly 290 295 300 Lys Ala Phe Arg Lys Ser Ser Thr Leu Ile Ser His Gln Arg Met His 305 310 315 320 Thr Gly Glu Lys Pro Tyr His Cys Ser Lys Cys Gly Lys Ser Phe Arg 325 330 335 Tyr Ser Ser Ser Phe Ala Gly His Gln Lys Thr His Ser Gly Asn Lys 340 345 350 Pro Tyr Gln Cys Arg Asp Cys Gly Lys Ala Phe Thr Lys Ser Ser Thr 355 360 365 Leu Thr Gly His Gln Arg Ile His Thr Gly Glu Lys Pro Tyr His Cys 370 375 380 Lys Lys Cys Gly Lys Ala Phe Arg His Ser Ser Gly Leu Val Glu His 385 390 395 400 Gln Arg Leu His Thr Gly Glu Lys Pro Tyr Lys Cys Asn Glu Cys Gly 405 410 415 Lys Ala Phe Pro Arg Ser Ser Ala Leu Lys Gln His Lys Lys Ile His 420 425 430 Asn Lys Glu Arg Ala Met Lys Cys Ser 435 440 <210> 32 <211> 1158 <212> PRT <213> Homo sapiens <400> 32 Met Ala Ala Val Arg Gly Ala Pro Leu Leu Ser Cys Leu Leu Ala Leu 1 5 10 15 Leu Ala Leu Cys Pro Gly Gly Arg Pro Gln Thr Val Leu Thr Asp Asp 20 25 30 Glu Ile Glu Glu Phe Leu Glu Gly Phe Leu Ser Glu Leu Glu Pro Glu 35 40 45 Pro Arg Glu Asp Asp Val Glu Ala Pro Pro Pro Glu Pro Thr Pro 50 55 60 Arg Val Arg Lys Ala Gln Ala Gly Gly Lys Pro Gly Lys Arg Pro Gly 65 70 75 80 Thr Ala Ala Glu Val Pro Pro Glu Lys Thr Lys Asp Lys Gly Lys Lys 85 90 95 Gly Lys Lys Asp Lys Gly Pro Lys Val Pro Lys Glu Ser Leu Glu Gly 100 105 110 Ser Pro Arg Pro Pro Lys Lys Gly Lys Glu Lys Pro Pro Lys Ala Thr 115 120 125 Lys Lys Pro Lys Glu Lys Pro Pro Lys Ala Thr Lys Lys Pro Lys Glu 130 135 140 Lys Pro Pro Lys Ala Thr Lys Lys Pro Lys Glu Lys Pro Pro Lys Ala 145 150 155 160 Thr Lys Lys Pro Pro Ser Gly Lys Arg Pro Pro Ile Leu Ala Pro Ser 165 170 175 Glu Thr Leu Glu Trp Pro Leu Pro Pro Pro Pro Ser Pro Gly Pro Glu 180 185 190 Glu Leu Pro Gln Glu Gly Gly Ala Pro Leu Ser Asn Asn Trp Gln Asn 195 200 205 Pro Gly Glu Glu Thr His Val Glu Ala Arg Glu His Gln Pro Glu Pro 210 215 220 Glu Glu Glu Thr Glu Gln Pro Thr Leu Asp Tyr Asn Asp Gln Ile Glu 225 230 235 240 Arg Glu Asp Tyr Glu Asp Phe Glu Tyr Ile Arg Arg Gln Lys Gln Pro 245 250 255 Arg Pro Pro Pro Ser Arg Arg Arg Arg Pro Glu Arg Val Trp Pro Glu 260 265 270 Pro Pro Glu Glu Lys Ala Pro Ala Pro Ala Pro Glu Glu Arg Ile Glu 275 280 285 Pro Pro Val Lys Pro Leu Leu Pro Pro Leu Pro Pro Asp Tyr Gly Asp 290 295 300 Gly Tyr Val Ile Pro Asn Tyr Asp Asp Met Asp Tyr Tyr Phe Gly Pro 305 310 315 320 Pro Pro Pro Gln Lys Pro Asp Ala Glu Arg Gln Thr Asp Glu Glu Lys 325 330 335 Glu Glu Leu Lys Lys Pro Lys Lys Glu Asp Ser Ser Pro Lys Glu Glu 340 345 350 Thr Asp Lys Trp Ala Val Glu Lys Gly Lys Asp His Lys Glu Pro Arg 355 360 365 Lys Gly Glu Glu Leu Glu Glu Glu Trp Thr Pro Thr Glu Lys Val Lys 370 375 380 Cys Pro Pro Ile Gly Met Glu Ser His Arg Ile Glu Asp Asn Gln Ile 385 390 395 400 Arg Ala Ser Ser Met Leu Arg His Gly Leu Gly Ala Gln Arg Gly Arg 405 410 415 Leu Asn Met Gln Thr Gly Ala Thr Glu Asp Asp Tyr Tyr Asp Gly Ala 420 425 430 Trp Cys Ala Glu Asp Asp Ala Arg Thr Gln Trp Ile Glu Val Asp Thr 435 440 445 Arg Arg Thr Thr Arg Phe Thr Gly Val Ile Thr Gln Gly Arg Asp Ser 450 455 460 Ser Ile His Asp Asp Phe Val Thr Thr Phe Phe Val Gly Phe Ser Asn 465 470 475 480 Asp Ser Gln Thr Trp Val Met Tyr Thr Asn Gly Tyr Glu Glu Met Thr 485 490 495 Phe His Gly Asn Val Asp Lys Asp Thr Pro Val Leu Ser Glu Leu Pro 500 505 510 Glu Pro Val Val Ala Arg Phe Ile Arg Ile Tyr Pro Leu Thr Trp Asn 515 520 525 Gly Ser Leu Cys Met Arg Leu Glu Val Leu Gly Cys Ser Val Ala Pro 530 535 540 Val Tyr Ser Tyr Tyr Ala Gln Asn Glu Val Val Ala Thr Asp Asp Leu 545 550 555 560 Asp Phe Arg His His Ser Tyr Lys Asp Met Arg Gln Leu Met Lys Val 565 570 575 Val Asn Glu Glu Cys Pro Thr Ile Thr Arg Thr Tyr Ser Leu Gly Lys 580 585 590 Ser Ser Arg Gly Leu Lys Ile Tyr Ala Met Glu Ile Ser Asp Asn Pro 595 600 605 Gly Glu His Glu Leu Gly Glu Pro Glu Phe Arg Tyr Thr Ala Gly Ile 610 615 620 His Gly Asn Glu Val Leu Gly Arg Glu Leu Leu Leu Leu Leu Leu Met Gln 625 630 635 640 Tyr Leu Cys Arg Glu Tyr Arg Asp Gly Asn Pro Arg Val Arg Ser Leu 645 650 655 Val Gln Asp Thr Arg Ile His Leu Val Pro Ser Leu Asn Pro Asp Gly 660 665 670 Tyr Glu Val Ala Ala Gln Met Gly Ser Glu Phe Gly Asn Trp Ala Leu 675 680 685 Gly Leu Trp Thr Glu Glu Gly Phe Asp Ile Phe Glu Asp Phe Pro Asp 690 695 700 Leu Asn Ser Val Leu Trp Gly Ala Glu Glu Arg Lys Trp Val Pro Tyr 705 710 715 720 Arg Val Pro Asn Asn Asn Leu Pro Ile Pro Glu Arg Tyr Leu Ser Pro 725 730 735 Asp Ala Thr Val Ser Thr Glu Val Arg Ala Ile Ile Ala Trp Met Glu 740 745 750 Lys Asn Pro Phe Val Leu Gly Ala Asn Leu Asn Gly Gly Glu Arg Leu 755 760 765 Val Ser Tyr Pro Tyr Asp Met Ala Arg Thr Pro Thr Gln Glu Gln Leu 770 775 780 Leu Ala Ala Ala Met Ala Ala Ala Arg Gly Glu Asp Glu Asp Glu Val 785 790 795 800 Ser Glu Ala Gln Glu Thr Pro Asp His Ala Ile Phe Arg Trp Leu Ala 805 810 815 Ile Ser Phe Ala Ser Ala His Leu Thr Leu Thr Glu Pro Tyr Arg Gly 820 825 830 Gly Cys Gln Ala Gln Asp Tyr Thr Gly Gly Met Gly Ile Val Asn Gly 835 840 845 Ala Lys Trp Asn Pro Arg Thr Gly Thr Ile Asn Asp Phe Ser Tyr Leu 850 855 860 His Thr Asn Cys Leu Glu Leu Ser Phe Tyr Leu Gly Cys Asp Lys Phe 865 870 875 880 Pro His Glu Ser Glu Leu Pro Arg Glu Trp Glu Asn Asn Lys Glu Ala 885 890 895 Leu Leu Thr Phe Met Glu Gln Val His Arg Gly Ile Lys Gly Val Val 900 905 910 Thr Asp Glu Gln Gly Ile Pro Ile Ala Asn Ala Thr Ile Ser Val Ser 915 920 925 Gly Ile Asn His Gly Val Lys Thr Ala Ser Gly Gly Asp Tyr Trp Arg 930 935 940 Ile Leu Asn Pro Gly Glu Tyr Arg Val Thr Ala His Ala Glu Gly Tyr 945 950 955 960 Thr Pro Ser Ala Lys Thr Cys Asn Val Asp Tyr Asp Ile Gly Ala Thr 965 970 975 Gln Cys Asn Phe Ile Leu Ala Arg Ser Asn Trp Lys Arg Ile Arg Glu 980 985 990 Ile Met Ala Met Asn Gly Asn Arg Pro Ile Pro His Ile Asp Pro Ser 995 1000 1005 Arg Pro Met Thr Pro Gln Gln Arg Arg Leu Gln Gln Arg Arg Leu Gln 1010 1015 1020 His Arg Leu Arg Leu Arg Ala Gln Met Arg Leu Arg Arg Leu Asn Ala 1025 1030 1035 1040 Thr Thr Thr Leu Gly Pro His Thr Val Pro Pro Thr Leu Pro Pro Ala 1045 1050 1055 Pro Ala Thr Thr Leu Ser Thr Thr Ile Glu Pro Trp Gly Leu Ile Pro 1060 1065 1070 Pro Thr Thr Ala Gly Trp Glu Glu Ser Glu Thr Glu Thr Tyr Thr Glu 1075 1080 1085 Val Val Thr Glu Phe Gly Thr Glu Val Glu Pro Glu Phe Gly Thr Lys 1090 1095 1100 Val Glu Pro Glu Phe Glu Thr Gln Leu Glu Pro Glu Phe Glu Thr Gln 1105 1110 1115 1120 Leu Glu Pro Glu Phe Glu Glu Glu Glu Glu Glu Glu Lys Glu Glu Glu 1125 1130 1135 Ile Ala Thr Gly Gln Ala Phe Pro Phe Thr Thr Val Glu Thr Tyr Thr 1140 1145 1150 Val Asn Phe Gly Asp Phe 1155 <210> 33 <211> 534 <212> PRT <213> Homo sapiens <400> 33 Met Arg Leu Arg Gly Cys Gly Pro Arg Ala Ala Pro Ala Ser Ser Ala 133 137 142 147 Gly Ala Ser Asp Ala Arg Leu Leu Ala Pro Pro Gly Arg Asn Pro Phe 152 157 162 Val His Glu Leu Arg Leu Ser Ala Leu Gln Lys Ala Gln Val Ala Leu 167 172 177 Met Thr Leu Thr Leu Phe Pro Val Arg Leu Leu Val Ala Ala Ala Met 182 187 192 Met Leu Leu Ala Trp Pro Leu Ala Leu Val Ala Ser Leu Gly Ser Ala 197 202 207 212 Glu Lys Glu Pro Glu Gln Pro Pro Ala Leu Trp Arg Lys Val Val Asp 217 222 227 Phe Leu Leu Lys Ala Ile Met Arg Thr Met Trp Phe Ala Gly Gly Phe 232 237 242 His Arg Val Ala Val Lys Gly Arg Gln Ala Leu Pro Thr Glu Ala Ala 247 252 257 Ile Leu Thr Leu Ala Pro His Ser Ser Tyr Phe Asp Ala Ile Pro Val 262 267 272 Thr Met Thr Met Ser Ser Ile Val Met Lys Ala Glu Ser Arg Asp Ile 277 282 287 292 Pro Ile Trp Gly Thr Leu Ile Gln Tyr Ile Arg Pro Val Phe Val Ser 297 302 307 Arg Ser Asp Gln Asp Ser Arg Arg Lys Thr Val Glu Glu Ile Lys Arg 312 317 322 Arg Ala Gln Ser Asn Gly Lys Trp Pro Gln Ile Met Ile Phe Pro Glu 327 332 337 Gly Thr Cys Thr Asn Arg Thr Cys Leu Ile Thr Phe Lys Pro Gly Ala 342 347 352 Phe Ile Pro Gly Ala Pro Val Gln Pro Val Val Leu Arg Tyr Pro Asn 357 362 367 372 Lys Leu Asp Thr Ile Thr Trp Thr Trp Gln Gly Pro Gly Ala Leu Glu 377 382 387 Ile Leu Trp Leu Thr Leu Cys Gln Phe His Asn Gln Val Glu Ile Glu 392 397 402 Phe Leu Pro Val Tyr Ser Pro Ser Glu Glu Glu Lys Arg Asn Pro Ala 407 412 417 Leu Tyr Ala Ser Asn Val Arg Arg Val Met Ala Glu Ala Leu Gly Val 422 427 432 Ser Val Thr Asp Tyr Thr Phe Glu Asp Cys Gln Leu Ala Leu Ala Glu 437 442 447 452 Gly Gln Leu Arg Leu Pro Ala Asp Thr Cys Leu Leu Glu Phe Ala Arg 457 462 467 Leu Val Arg Gly Leu Gly Leu Lys Pro Glu Lys Leu Glu Lys Asp Leu 472 477 482 Asp Arg Tyr Ser Glu Arg Ala Arg Met Lys Gly Gly Glu Lys Ile Gly 487 492 497 Ile Ala Glu Phe Ala Ala Ser Leu Glu Val Pro Val Ser Asp Leu Leu 502 507 512 Glu Asp Met Phe Ser Leu Phe Asp Glu Ser Gly Ser Gly Glu Val Asp 517 522 527 532 Leu Arg Glu Cys Val Val Ala Leu Ser Val Val Cys Arg Pro Ala Arg 537 542 547 Thr Leu Asp Thr Ile Gln Leu Ala Phe Lys Met Tyr Gly Ala Gln Glu 552 557 562 Asp Gly Ser Val Gly Glu Gly Asp Leu Ser Cys Ile Leu Lys Thr Ala 567 572 577 Leu Gly Val Ala Glu Leu Thr Val Thr Asp Leu Phe Arg Ala Ile Asp 582 587 592 Gln Glu Glu Lys Gly Lys Ile Thr Phe Ala Asp Phe His Arg Phe Ala 597 602 607 612 Glu Met Tyr Pro Ala Phe Ala Glu Glu Tyr Leu Tyr Pro Asp Gln Thr 617 622 627 His Phe Glu Ser Cys Ala Glu Thr Ser Pro Ala Pro Ile Pro Asn Gly 632 637 642 Phe Cys Ala Asp Phe Ser Pro Glu Asn Ser Asp Ala Gly Arg Lys Pro 647 652 657 Val Arg Lys Lys Leu Asp 662 <210> 34 <211> 923 <212> PRT <213> Homo sapiens <400> 34 Met Ser Gln Phe Lys Arg Gln Arg Ile Asn Pro Leu Pro Gly Gly Arg 1 5 10 15 Asn Phe Ser Gly Thr Ala Ser Thr Ser Leu Leu Gly Pro Pro Pro Gly 20 25 30 Leu Leu Thr Pro Pro Val Ala Thr Glu Leu Ser Gln Asn Ala Arg His 35 40 45 Leu Gln Gly Gly Glu Lys Gln Arg Val Phe Thr Gly Ile Val Thr Ser 50 55 60 Leu His Asp Tyr Phe Gly Val Val Asp Glu Glu Val Phe Phe Gln Leu 65 70 75 80 Ser Val Val Lys Gly Arg Leu Pro Gln Leu Gly Glu Lys Val Leu Val 85 90 95 Lys Ala Ala Tyr Asn Pro Gly Gln Ala Val Pro Trp Asn Ala Val Lys 100 105 110 Val Gln Thr Leu Ser Asn Gln Pro Leu Leu Lys Ser Pro Ala Pro Pro 115 120 125 Leu Leu His Val Ala Ala Leu Gly Gln Lys Gln Gly Ile Leu Gly Ala 130 135 140 Gln Pro Gln Leu Ile Phe Gln Pro His Arg Ile Pro Pro Leu Phe Pro 145 150 155 160 Gln Lys Pro Leu Ser Leu Phe Gln Thr Ser His Thr Leu His Leu Ser 165 170 175 His Leu Asn Arg Phe Pro Ala Arg Gly Pro His Gly Arg Leu Asp Gln 180 185 190 Gly Arg Ser Asp Asp Tyr Asp Ser Lys Lys Arg Lys Gln Arg Ala Gly 195 200 205 Gly Glu Pro Trp Gly Ala Lys Lys Pro Arg His Asp Leu Pro Pro Tyr 210 215 220 Arg Val His Leu Thr Pro Tyr Thr Val Asp Ser Pro Ile Cys Asp Phe 225 230 235 240 Leu Glu Leu Gln Arg Arg Tyr Arg Ser Leu Leu Val Pro Ser Asp Phe 245 250 255 Leu Ser Val His Leu Ser Trp Leu Ser Ala Phe Pro Leu Ser Gln Pro 260 265 270 Phe Ser Leu His His Pro Ser Arg Ile Gln Val Ser Ser Glu Lys Glu 275 280 285 Ala Ala Pro Asp Ala Gly Ala Glu Pro Ile Thr Ala Asp Ser Asp Pro 290 295 300 Ala Tyr Ser Ser Lys Val Leu Leu Leu Ser Ser Ser Pro Gly Leu Glu Glu 305 310 315 320 Leu Tyr Arg Cys Cys Met Leu Phe Val Asp Asp Met Ala Glu Pro Arg 325 330 335 Glu Thr Pro Glu His Pro Leu Lys Gln Ile Lys Phe Leu Leu Gly Arg 340 345 350 Lys Glu Glu Glu Ala Val Leu Val Gly Gly Glu Trp Ser Pro Ser Leu 355 360 365 Asp Gly Leu Asp Pro Gln Ala Asp Pro Gln Val Leu Val Arg Thr Ala 370 375 380 Ile Arg Cys Ala Gln Ala Gln Thr Gly Ile Asp Leu Ser Gly Cys Thr 385 390 395 400 Lys Trp Trp Arg Phe Ala Glu Phe Gln Tyr Leu Gln Pro Gly Pro Pro 405 410 415 Arg Arg Leu Gln Thr Val Val Val Tyr Leu Pro Asp Val Trp Thr Ile 420 425 430 Met Pro Thr Leu Glu Glu Trp Glu Ala Leu Cys Gln Gln Lys Ala Ala 435 440 445 Glu Ala Ala Pro Thr Gln Glu Ala Gln Gly Glu Thr Glu Pro Thr 450 455 460 Glu Gln Ala Pro Asp Ala Leu Glu Gln Ala Ala Asp Thr Ser Arg Arg 465 470 475 480 Asn Ala Glu Thr Pro Glu Ala Thr Thr Gln Gln Glu Thr Asp Thr Asp 485 490 495 Leu Pro Glu Ala Pro Pro Pro Pro Leu Glu Pro Ala Val Ile Ala Arg 500 505 510 Pro Gly Cys Val Asn Leu Ser Leu His Gly Ile Val Glu Asp Arg Arg 515 520 525 Pro Lys Glu Arg Ile Ser Phe Glu Val Met Val Leu Ala Glu Leu Phe 530 535 540 Leu Glu Met Leu Gln Arg Asp Phe Gly Tyr Arg Val Tyr Lys Met Leu 545 550 555 560 Leu Ser Leu Pro Glu Lys Val Val Ser Pro Pro Glu Pro Glu Lys Glu 565 570 575 Glu Ala Ala Lys Glu Glu Ala Thr Lys Glu Glu Glu Ala Ile Lys Glu 580 585 590 Glu Val Val Lys Glu Pro Lys Asp Glu Ala Gln Asn Glu Gly Pro Ala 595 600 605 Thr Glu Ser Glu Ala Pro Leu Lys Glu Asp Gly Leu Leu Pro Lys Pro 610 615 620 Leu Ser Ser Gly Gly Glu Glu Glu Glu Lys Pro Arg Gly Glu Ala Ser 625 630 635 640 Glu Asp Leu Cys Glu Met Ala Leu Asp Pro Glu Leu Leu Leu Leu Arg 645 650 655 Asp Asp Gly Glu Glu Glu Phe Ala Gly Ala Lys Leu Glu Asp Ser Glu 660 665 670 Val Arg Ser Val Ala Ser Asn Gln Ser Glu Met Glu Phe Ser Ser Leu 675 680 685 Gln Asp Met Pro Lys Glu Leu Asp Pro Ser Ala Val Leu Pro Leu Asp 690 695 700 Cys Leu Leu Ala Phe Val Phe Phe Asp Ala Asn Trp Cys Gly Tyr Leu 705 710 715 720 His Arg Arg Asp Leu Glu Arg Ile Leu Leu Thr Leu Gly Ile Arg Leu 725 730 735 Ser Ala Glu Gln Ala Lys Gln Leu Val Ser Arg Val Val Thr Gln Asn 740 745 750 Ile Cys Gln Tyr Arg Ser Leu Gln Tyr Ser Arg Gln Glu Gly Leu Asp 755 760 765 Gly Gly Leu Pro Glu Glu Val Leu Phe Gly Asn Leu Asp Leu Leu Pro 770 775 780 Pro Pro Gly Lys Ser Thr Lys Pro Gly Ala Ala Pro Thr Glu His Lys 785 790 795 800 Ala Leu Val Ser His Asn Gly Ser Leu Ile Asn Val Gly Ser Leu Leu 805 810 815 Gln Arg Ala Glu Gln Gln Asp Ser Gly Arg Leu Tyr Leu Glu Asn Lys 820 825 830 Ile His Thr Leu Glu Leu Lys Leu Glu Glu Ser His Asn Arg Phe Ser 835 840 845 Ala Thr Glu Val Thr Asn Lys Thr Leu Ala Ala Glu Met Gln Glu Leu 850 855 860 Arg Val Arg Leu Ala Glu Ala Glu Glu Thr Ala Arg Thr Ala Glu Arg 865 870 875 880 Gln Lys Ser Gln Leu Gln Arg Leu Leu Gln Glu Leu Arg Arg Arg Leu 885 890 895 Thr Pro Leu Gln Leu Glu Ile Gln Arg Val Val Glu Lys Ala Asp Ser 900 905 910 Trp Val Glu Lys Glu Glu Pro Ala Pro Ser Asn 915 920 <210> 35 <211> 258 <212> PRT <213> Homo sapiens <400> 35 Met Leu Val Leu Tyr Gly His Ser Thr Gln Asp Leu Pro Glu Thr Asn 1 5 10 15 Ala Arg Val Val Gly Gly Thr Glu Ala Gly Arg Asn Ser Trp Pro Ser 20 25 30 Gln Ile Ser Leu Gln Tyr Arg Ser Gly Gly Ser Arg Tyr His Thr Cys 35 40 45 Gly Gly Thr Leu Ile Arg Gln Asn Trp Val Met Thr Ala Ala His Cys 50 55 60 Val Asp Tyr Gln Lys Thr Phe Arg Val Val Ala Gly Asp His Asn Leu 65 70 75 80 Ser Gln Asn Asp Gly Thr Glu Gln Tyr Val Ser Val Gln Lys Ile Val 85 90 95 Val His Pro Tyr Trp Asn Ser Asp Asn Val Ala Ala Gly Tyr Asp Ile 100 105 110 Ala Leu Leu Arg Leu Ala Gln Ser Val Thr Leu Asn Ser Tyr Val Gln 115 120 125 Leu Gly Val Leu Pro Gln Glu Gly Ala Ile Leu Ala Asn Asn Ser Pro 130 135 140 Cys Tyr Ile Thr Gly Trp Gly Lys Thr Lys Thr Asn Gly Gln Leu Ala 145 150 155 160 Gln Thr Leu Gln Gln Ala Tyr Leu Pro Ser Val Asp Tyr Ala Ile Cys 165 170 175 Ser Ser Ser Ser Tyr Trp Gly Ser Thr Val Lys Asn Thr Met Val Cys 180 185 190 Ala Gly Gly Asp Gly Val Arg Ser Gly Cys Gln Gly Asp Ser Gly Gly 195 200 205 Pro Leu His Cys Leu Val Asn Gly Lys Tyr Ser Val His Gly Val Thr 210 215 220 Ser Phe Val Ser Ser Arg Gly Cys Asn Val Ser Arg Lys Pro Thr Val 225 230 235 240 Phe Thr Gln Val Ser Ala Tyr Ile Ser Trp Ile Asn Asn Val Ile Ala 245 250 255 Ser Asn <210> 36 <211> 698 <212> PRT <213> Homo sapiens <400> 36 Met Gln Asp Asp Leu Leu Met Asp Lys Ser Lys Thr Gln Pro Gln Pro 1 5 10 15 Gln Gln Gln Gln Arg Gln Gln Gln Gln Pro Gln Pro Glu Ser Ser Val 20 25 30 Ser Glu Ala Pro Ser Thr Pro Leu Ser Ser Glu Thr Pro Lys Pro Glu 35 40 45 Glu Asn Ser Ala Val Pro Ala Leu Ser Pro Ala Ala Ala Pro Ala 50 55 60 Pro Asn Gly Pro Asp Lys Met Gln Met Glu Ser Pro Leu Leu Pro Gly 65 70 75 80 Leu Ser Phe His Gln Pro Pro Gln Gln Pro Pro Pro Pro Gln Glu Pro 85 90 95 Ala Ala Pro Gly Ala Ser Leu Ser Pro Ser Phe Gly Ser Thr Trp Ser 100 105 110 Thr Gly Thr Thr Asn Ala Val Glu Asp Ser Phe Phe Gln Gly Ile Thr 115 120 125 Pro Val Asn Gly Thr Met Leu Phe Gln Asn Phe Pro His His Val Asn 130 135 140 Pro Val Phe Gly Gly Thr Phe Ser Pro Gln Ile Gly Leu Ala Gln Thr 145 150 155 160 Gln His His Gln Gln Pro Pro Pro Pro Ala Pro Ala Pro Gln Pro Ala 165 170 175 Gln Pro Ala Gln Pro Pro Gln Ala Gln Pro Pro Gln Gln Arg Arg Ser 180 185 190 Pro Ala Ser Pro Ser Gln Ala Pro Tyr Ala Gln Arg Ser Ala Ala Ala 195 200 205 Ala Tyr Gly His Gln Pro Ile Met Thr Ser Lys Pro Ser Ser Ser Ser 210 215 220 Ala Val Ala Ala Ala Ala Ala Ala Ala Ala Ala Ser Ser Ala Ser Ser 225 230 235 240 Ser Trp Asn Thr His Gln Ser Val Asn Ala Ala Trp Ser Ala Pro Ser 245 250 255 Asn Pro Trp Gly Gly Leu Gln Ala Gly Arg Asp Pro Arg Arg Ala Val 260 265 270 Gly Val Gly Val Gly Val Gly Val Gly Val Pro Ser Pro Leu Asn Pro 275 280 285 Ile Ser Pro Leu Lys Lys Pro Phe Ser Ser Asn Val Ile Ala Pro Pro 290 295 300 Lys Phe Pro Arg Ala Ala Pro Leu Thr Ser Lys Ser Trp Met Glu Asp 305 310 315 320 Asn Ala Phe Arg Thr Asp Asn Gly Asn Asn Leu Leu Pro Phe Gln Asp 325 330 335 Arg Ser Arg Pro Tyr Asp Thr Phe Asn Leu His Ser Leu Glu Asn Ser 340 345 350 Leu Met Asp Met Ile Arg Thr Asp His Glu Pro Leu Lys Gly Lys His 355 360 365 Tyr Pro Pro Ser Gly Pro Pro Met Ser Phe Ala Asp Ile Met Trp Arg 370 375 380 Asn His Phe Ala Gly Arg Met Gly Ile Asn Phe His His Pro Gly Thr 385 390 395 400 Asp Asn Ile Met Ala Leu Asn Asn Ala Phe Leu Asp Asp Ser His Gly 405 410 415 Asp Gln Ala Leu Ser Ser Gly Leu Ser Ser Pro Thr Arg Cys Gln Asn 420 425 430 Gly Glu Arg Val Glu Arg Tyr Ser Arg Lys Val Phe Val Gly Gly Leu 435 440 445 Pro Pro Asp Ile Asp Glu Asp Glu Ile Thr Ala Ser Phe Arg Arg Phe 450 455 460 Gly Pro Leu Val Val Asp Trp Pro His Lys Ala Glu Ser Lys Ser Tyr 465 470 475 480 Phe Pro Pro Lys Gly Tyr Ala Phe Leu Leu Phe Gln Glu Glu Ser Ser 485 490 495 Val Gln Ala Leu Ile Asp Ala Cys Leu Glu Glu Asp Gly Lys Leu Tyr 500 505 510 Leu Cys Val Ser Ser Pro Thr Ile Lys Asp Lys Pro Val Gln Ile Arg 515 520 525 Pro Trp Asn Leu Ser Asp Ser Asp Phe Val Met Asp Gly Ser Gln Pro 530 535 540 Leu Asp Pro Arg Lys Thr Ile Phe Val Gly Gly Val Pro Arg Pro Leu 545 550 555 560 Arg Ala Val Glu Leu Ala Met Ile Met Asp Arg Leu Tyr Gly Gly Val 565 570 575 Cys Tyr Ala Gly Ile Asp Thr Asp Pro Glu Leu Lys Tyr Pro Lys Gly 580 585 590 Ala Gly Arg Val Ala Phe Ser Asn Gln Gln Ser Tyr Ile Ala Ala Ile 595 600 605 Ser Ala Arg Phe Val Gln Leu Gln His Asn Asp Ile Asp Lys Arg Val 610 615 620 Glu Val Lys Pro Tyr Val Leu Asp Asp Gln Met Cys Asp Glu Cys Gln 625 630 635 640 Gly Thr Arg Cys Gly Gly Lys Phe Ala Pro Phe Phe Cys Ala Asn Val 645 650 655 Thr Cys Leu Gln Tyr Tyr Cys Glu Tyr Cys Trp Ala Ser Ile His Ser 660 665 670 Arg Ala Gly Arg Glu Phe His Lys Pro Leu Val Lys Glu Gly Gly Asp 675 680 685 Arg Pro Arg His Val Pro Phe Arg Trp Ser 690 695 <210> 37 <211> 419 <212> PRT <213> Homo sapiens <400> 37 Met Pro Leu Ser Arg Trp Leu Arg Ser Val Gly Val Phe Leu Leu Pro 1 5 10 15 Ala Pro Tyr Trp Ala Pro Arg Glu Arg Trp Leu Gly Ser Leu Arg Arg 20 25 30 Pro Ser Leu Val His Gly Tyr Pro Val Leu Ala Trp His Ser Ala Arg 35 40 45 Cys Trp Cys Gln Ala Trp Thr Glu Glu Pro Arg Ala Leu Cys Ser Ser 50 55 60 Leu Arg Met Asn Gly Asp Gln Asn Ser Asp Val Tyr Ala Gln Glu Lys 65 70 75 80 Gln Asp Phe Val Gln His Phe Ser Gln Ile Val Arg Val Leu Thr Glu 85 90 95 Asp Glu Met Gly His Pro Glu Ile Gly Asp Ala Ile Ala Arg Leu Lys 100 105 110 Glu Val Leu Glu Tyr Asn Ala Ile Gly Gly Lys Tyr Asn Arg Gly Leu 115 120 125 Thr Val Val Val Ala Phe Arg Glu Leu Val Glu Pro Arg Lys Gln Asp 130 135 140 Ala Asp Ser Leu Gln Arg Ala Trp Thr Val Gly Trp Cys Val Glu Leu 145 150 155 160 Leu Gln Ala Phe Phe Leu Val Ala Asp Asp Ile Met Asp Ser Ser Leu 165 170 175 Thr Arg Arg Gly Gln Ile Cys Trp Tyr Gln Lys Pro Gly Val Gly Leu 180 185 190 Asp Ala Ile Asn Asp Ala Asn Leu Leu Glu Ala Cys Ile Tyr Arg Leu 195 200 205 Leu Lys Leu Tyr Cys Arg Glu Gln Pro Tyr Tyr Leu Asn Leu Ile Glu 210 215 220 Leu Phe Leu Gln Ser Ser Tyr Gln Thr Glu Ile Gly Gln Thr Leu Asp 225 230 235 240 Leu Leu Thr Ala Pro Gln Gly Asn Val Asp Leu Val Arg Phe Thr Glu 245 250 255 Lys Arg Tyr Lys Ser Ile Val Lys Tyr Lys Thr Ala Phe Tyr Ser Phe 260 265 270 Tyr Leu Pro Ile Ala Ala Ala Met Tyr Met Ala Gly Ile Asp Gly Glu 275 280 285 Lys Glu His Ala Asn Ala Lys Lys Ile Leu Leu Glu Met Gly Glu Phe 290 295 300 Phe Gln Ile Gln Asp Asp Tyr Leu Asp Leu Phe Gly Asp Pro Ser Val 305 310 315 320 Thr Gly Lys Ile Gly Thr Asp Ile Gln Asp Asn Lys Cys Ser Trp Leu 325 330 335 Val Val Gln Cys Leu Gln Arg Ala Thr Pro Glu Gln Tyr Gln Ile Leu 340 345 350 Lys Glu Asn Tyr Gly Gln Lys Glu Ala Glu Lys Val Ala Arg Val Lys 355 360 365 Ala Leu Tyr Glu Glu Leu Asp Leu Pro Ala Val Phe Leu Gln Tyr Glu 370 375 380 Glu Asp Ser Tyr Ser His Ile Met Ala Leu Ile Glu Gln Tyr Ala Ala 385 390 395 400 Pro Leu Pro Pro Ala Val Phe Leu Gly Leu Ala Arg Lys Ile Tyr Lys 405 410 415 Arg Arg Lys <210> 38 <211> 558 <212> PRT <213> Homo sapiens <400> 38 Met Ala Ala Leu Thr Arg Asp Pro Gln Phe Gln Lys Leu Gln Gln Trp 1 5 10 15 Tyr Arg Glu His Arg Ser Glu Leu Asn Leu Arg Arg Leu Phe Asp Ala 20 25 30 Asn Lys Asp Arg Phe Asn His Phe Ser Leu Thr Leu Asn Thr Asn His 35 40 45 Gly His Ile Leu Val Asp Tyr Ser Lys Asn Leu Val Thr Glu Asp Val 50 55 60 Met Arg Met Leu Val Asp Leu Ala Lys Ser Arg Gly Val Glu Ala Ala 65 70 75 80 Arg Glu Arg Met Phe Asn Gly Glu Lys Ile Asn Tyr Thr Glu Gly Arg 85 90 95 Ala Val Leu His Val Ala Leu Arg Asn Arg Ser Asn Thr Pro Ile Leu 100 105 110 Val Asp Gly Lys Asp Val Met Pro Glu Val Asn Lys Val Leu Asp Lys 115 120 125 Met Lys Ser Phe Cys Gln Arg Val Arg Ser Gly Asp Trp Lys Gly Tyr 130 135 140 Thr Gly Lys Thr Ile Thr Asp Val Ile Asn Ile Gly Ile Gly Gly Ser 145 150 155 160 Asp Leu Gly Pro Leu Met Val Thr Glu Ala Leu Lys Pro Tyr Ser Ser 165 170 175 Gly Gly Pro Arg Val Trp Tyr Val Ser Asn Ile Asp Gly Thr His Ile 180 185 190 Ala Lys Thr Leu Ala Gln Leu Asn Pro Glu Ser Ser Leu Phe Ile Ile 195 200 205 Ala Ser Lys Thr Phe Thr Thr Gln Glu Thr Ile Thr Asn Ala Glu Thr 210 215 220 Ala Lys Glu Trp Phe Leu Gln Ala Ala Lys Asp Pro Ser Ala Val Ala 225 230 235 240 Lys His Phe Val Ala Leu Ser Thr Asn Thr Thr Lys Val Lys Glu Phe 245 250 255 Gly Ile Asp Pro Gln Asn Met Phe Glu Phe Trp Asp Trp Val Gly Gly 260 265 270 Arg Tyr Ser Leu Trp Ser Ala Ile Gly Leu Ser Ile Ala Leu His Val 275 280 285 Gly Phe Asp Asn Phe Glu Gln Leu Leu Ser Gly Ala His Trp Met Asp 290 295 300 Gln His Phe Arg Thr Thr Pro Leu Glu Lys Asn Ala Pro Val Leu Leu 305 310 315 320 Ala Leu Leu Gly Ile Trp Tyr Ile Asn Cys Phe Gly Cys Glu Thr His 325 330 335 Ala Met Leu Pro Tyr Asp Gln Tyr Leu His Arg Phe Ala Ala Tyr Phe 340 345 350 Gln Gln Gly Asp Met Glu Ser Asn Gly Lys Tyr Ile Thr Lys Ser Gly 355 360 365 Thr Arg Val Asp His Gln Thr Gly Pro Ile Val Trp Gly Glu Pro Gly 370 375 380 Thr Asn Gly Gln His Ala Phe Tyr Gln Leu Ile His Gln Gly Thr Lys 385 390 395 400 Met Ile Pro Cys Asp Phe Leu Ile Pro Val Gln Thr Gln His Pro Ile 405 410 415 Arg Lys Gly Leu His His Lys Ile Leu Leu Ala Asn Phe Leu Ala Gln 420 425 430 Thr Glu Ala Leu Met Arg Gly Lys Ser Thr Glu Glu Ala Arg Lys Glu 435 440 445 Leu Gln Ala Ala Gly Lys Ser Pro Glu Asp Leu Glu Arg Leu Leu Pro 450 455 460 His Lys Val Phe Glu Gly Asn Arg Pro Thr Asn Ser Ile Val Phe Thr 465 470 475 480 Lys Leu Thr Pro Phe Met Leu Gly Ala Leu Val Ala Met Tyr Glu His 485 490 495 Lys Ile Phe Val Gln Gly Ile Ile Trp Asp Ile Asn Ser Phe Asp Gln 500 505 510 Trp Gly Val Glu Leu Gly Lys Gln Leu Ala Lys Lys Ile Glu Pro Glu 515 520 525 Leu Asp Gly Ser Ala Gln Val Thr Ser His Asp Ala Ser Thr Asn Gly 530 535 540 Leu Ile Asn Phe Ile Lys Gln Gln Arg Glu Ala Arg Val Gln 545 550 555 <210> 39 <211> 932 <212> PRT <213> Homo sapiens <400> 39 Met Lys Gln Leu Pro Ala Ala Thr Val Arg Leu Leu Ser Ser Ser Ser Gln 1 5 10 15 Ile Ile Thr Ser Val Val Ser Val Val Lys Glu Leu Ile Glu Asn Ser 20 25 30 Leu Asp Ala Gly Ala Thr Ser Val Asp Val Lys Leu Glu Asn Tyr Gly 35 40 45 Phe Asp Lys Ile Glu Val Arg Asp Asn Gly Glu Gly Ile Lys Ala Val 50 55 60 Asp Ala Pro Val Met Ala Met Lys Tyr Tyr Thr Ser Lys Ile Asn Ser 65 70 75 80 His Glu Asp Leu Glu Asn Leu Thr Thr Tyr Gly Phe Arg Gly Glu Ala 85 90 95 Leu Gly Ser Ile Cys Cys Ile Ala Glu Val Leu Ile Thr Thr Arg Thr 100 105 110 Ala Ala Asp Asn Phe Ser Thr Gln Tyr Val Leu Asp Gly Ser Gly His 115 120 125 Ile Leu Ser Gln Lys Pro Ser His Leu Gly Gin Gly Thr Thr Val Thr 130 135 140 Ala Leu Arg Leu Phe Lys Asn Leu Pro Val Arg Lys Gln Phe Tyr Ser 145 150 155 160 Thr Ala Lys Lys Cys Lys Asp Glu Ile Lys Lys Ile Gln Asp Leu Leu 165 170 175 Met Ser Phe Gly Ile Leu Lys Pro Asp Leu Arg Ile Val Phe Val His 180 185 190 Asn Lys Ala Val Ile Trp Gln Lys Ser Arg Val Ser Asp His Lys Met 195 200 205 Ala Leu Met Ser Val Leu Gly Thr Ala Val Met Asn Asn Met Glu Ser 210 215 220 Phe Gln Tyr His Ser Glu Glu Ser Gln Ile Tyr Leu Ser Gly Phe Leu 225 230 235 240 Pro Lys Cys Asp Ala Asp His Ser Phe Thr Ser Leu Ser Thr Pro Glu 245 250 255 Arg Ser Phe Ile Phe Ile Asn Ser Arg Pro Val His Gln Lys Asp Ile 260 265 270 Leu Lys Leu Ile Arg His His Tyr Asn Leu Lys Cys Leu Lys Glu Ser 275 280 285 Thr Arg Leu Tyr Pro Val Phe Phe Leu Lys Ile Asp Val Pro Thr Ala 290 295 300 Asp Val Asp Val Asn Leu Thr Pro Asp Lys Ser Gln Val Leu Leu Gln 305 310 315 320 Asn Lys Glu Ser Val Leu Ile Ala Leu Glu Asn Leu Met Thr Thr Cys 325 330 335 Tyr Gly Pro Leu Pro Ser Thr Asn Ser Tyr Glu Asn Asn Lys Thr Asp 340 345 350 Val Ser Ala Ala Asp Ile Val Leu Ser Lys Thr Ala Glu Thr Asp Val 355 360 365 Leu Phe Asn Lys Val Glu Ser Ser Gly Lys Asn Tyr Ser Asn Val Asp 370 375 380 Thr Ser Val Ile Pro Phe Gln Asn Asp Met His Asn Asp Glu Ser Gly 385 390 395 400 Lys Asn Thr Asp Asp Cys Leu Asn His Gln Ile Ser Ile Gly Asp Phe 405 410 415 Gly Tyr Gly His Cys Ser Ser Glu Ile Ser Asn Ile Asp Lys Asn Thr 420 425 430 Lys Asn Ala Phe Gln Asp Ile Ser Met Ser Asn Val Ser Trp Glu Asn 435 440 445 Ser Gln Thr Glu Tyr Ser Lys Thr Cys Phe Ile Ser Ser Val Lys His 450 455 460 Thr Gln Ser Glu Asn Gly Asn Lys Asp His Ile Asp Glu Ser Gly Glu 465 470 475 480 Asn Glu Glu Glu Ala Gly Leu Glu Asn Ser Ser Glu Ile Ser Ala Asp 485 490 495 Glu Trp Ser Arg Gly Asn Ile Leu Lys Asn Ser Val Gly Glu Asn Ile 500 505 510 Glu Pro Val Lys Ile Leu Val Pro Glu Lys Ser Leu Pro Cys Lys Val 515 520 525 Ser Asn Asn Asn Tyr Pro Ile Pro Glu Gln Met Asn Leu Asn Glu Asp 530 535 540 Ser Cys Asn Lys Lys Ser Asn Val Ile Asp Asn Lys Ser Gly Lys Val 545 550 555 560 Thr Ala Tyr Asp Leu Leu Ser Asn Arg Val Ile Lys Lys Pro Met Ser 565 570 575 Ala Ser Ala Leu Phe Val Gln Asp His Arg Pro Gln Phe Leu Ile Glu 580 585 590 Asn Pro Lys Thr Ser Leu Glu Asp Ala Thr Leu Gln Ile Glu Glu Leu 595 600 605 Trp Lys Thr Leu Ser Glu Glu Glu Lys Leu Lys Tyr Glu Glu Lys Ala 610 615 620 Thr Lys Asp Leu Glu Arg Tyr Asn Ser Gln Met Lys Arg Ala Ile Glu 625 630 635 640 Gln Glu Ser Gln Met Ser Leu Lys Asp Gly Arg Lys Lys Ile Lys Pro 645 650 655 Thr Ser Ala Trp Asn Leu Ala Gln Lys His Lys Leu Lys Thr Ser Leu 660 665 670 Ser Asn Gln Pro Lys Leu Asp Glu Leu Leu Gln Ser Gln Ile Glu Lys 675 680 685 Arg Arg Ser Gln Asn Ile Lys Met Val Gln Ile Pro Phe Ser Met Lys 690 695 700 Asn Leu Lys Ile Asn Phe Lys Lys Gln Asn Lys Val Asp Leu Glu Glu 705 710 715 720 Lys Asp Glu Pro Cys Leu Ile His Asn Leu Arg Phe Pro Asp Ala Trp 725 730 735 Leu Met Thr Ser Lys Thr Glu Val Met Leu Leu Asn Pro Tyr Arg Val 740 745 750 Glu Glu Ala Leu Leu Phe Lys Arg Leu Leu Glu Asn His Lys Leu Pro 755 760 765 Ala Glu Pro Leu Glu Lys Pro Ile Met Leu Thr Glu Ser Leu Phe Asn 770 775 780 Gly Ser His Tyr Leu Asp Val Leu Tyr Lys Met Thr Ala Asp Asp Gln 785 790 795 800 Arg Tyr Ser Gly Ser Thr Tyr Leu Ser Asp Pro Arg Leu Thr Ala Asn 805 810 815 Gly Phe Lys Ile Lys Leu Ile Pro Gly Val Ser Ile Thr Glu Asn Tyr 820 825 830 Leu Glu Ile Glu Gly Met Ala Asn Cys Leu Pro Phe Tyr Gly Val Ala 835 840 845 Asp Leu Lys Glu Ile Leu Asn Ala Ile Leu Asn Arg Asn Ala Lys Glu 850 855 860 Val Tyr Glu Cys Arg Pro Arg Lys Val Ile Ser Tyr Leu Glu Gly Glu 865 870 875 880 Ala Val Arg Leu Ser Arg Gln Leu Pro Met Tyr Leu Ser Lys Glu Asp 885 890 895 Ile Gln Asp Ile Ile Tyr Arg Met Lys His Gln Phe Gly Asn Glu Ile 900 905 910 Lys Glu Cys Val His Gly Arg Pro Phe Phe His His Leu Thr Tyr Leu 915 920 925 Pro Glu Thr Thr 930 <210> 40 <211> 505 <212> PRT <213> Homo sapiens <400> 40 Met Leu Asn Arg Val Arg Ser Ala Val Ala His Leu Val Ser Ser Gly 1 5 10 15 Gly Ala Pro Pro Arg Pro Lys Ser Pro Asp Leu Pro Asn Ala Ala 20 25 30 Ser Ala Pro Pro Ala Ala Ala Pro Glu Ala Pro Arg Ser Pro Pro Ala 35 40 45 Lys Ala Gly Ser Gly Ser Ala Thr Pro Ala Lys Ala Val Glu Ala Arg 50 55 60 Ala Ser Phe Ser Arg Pro Thr Phe Leu Gln Leu Ser Pro Gly Gly Leu 65 70 75 80 Arg Arg Ala Asp Asp His Ala Gly Arg Ala Val Gln Ser Pro Pro Asp 85 90 95 Thr Gly Arg Arg Leu Pro Trp Ser Thr Gly Tyr Ala Glu Val Ile Asn 100 105 110 Ala Gly Lys Ser Arg His Asn Glu Asp Gln Ala Cys Cys Glu Val Val 115 120 125 Tyr Val Glu Gly Arg Arg Ser Val Thr Gly Val Pro Arg Glu Pro Ser 130 135 140 Arg Gly Gln Gly Leu Cys Phe Tyr Tyr Trp Gly Leu Phe Asp Gly His 145 150 155 160 Ala Gly Gly Gly Ala Ala Glu Met Ala Ser Arg Leu Leu His Arg His 165 170 175 Ile Arg Glu Gln Leu Lys Asp Leu Val Glu Ile Leu Gln Asp Pro Ser 180 185 190 Pro Pro Pro Leu Cys Leu Pro Thr Thr Pro Gly Thr Pro Asp Ser Ser 195 200 205 Asp Pro Ser His Leu Leu Gly Pro Gln Ser Cys Trp Ser Ser Gln Lys 210 215 220 Glu Val Ser His Glu Ser Leu Val Val Gly Ala Val Glu Asn Ala Phe 225 230 235 240 Gln Leu Met Asp Glu Gln Met Ala Arg Glu Arg Arg Gly His Gln Val 245 250 255 Glu Gly Gly Cys Cys Ala Leu Val Val Ile Tyr Leu Leu Gly Lys Val 260 265 270 Tyr Val Ala Asn Ala Gly Asp Ser Arg Ala Ile Ile Val Arg Asn Gly 275 280 285 Glu Ile Ile Pro Met Ser Arg Glu Phe Thr Pro Glu Thr Glu Arg Gln 290 295 300 Arg Leu Gln Leu Leu Gly Phe Leu Lys Pro Glu Leu Leu Gly Ser Glu 305 310 315 320 Phe Thr His Leu Glu Phe Pro Arg Arg Val Leu Pro Lys Glu Leu Gly 325 330 335 Gln Arg Met Leu Tyr Arg Asp Gln Asn Met Thr Gly Trp Ala Tyr Lys 340 345 350 Lys Ile Glu Leu Glu Asp Leu Arg Phe Pro Leu Val Cys Gly Glu Gly 355 360 365 Lys Lys Ala Arg Val Met Ala Thr Ile Gly Val Thr Arg Gly Leu Gly 370 375 380 Asp His Ser Leu Lys Val Cys Ser Ser Thr Leu Pro Ile Lys Pro Phe 385 390 395 400 Leu Ser Cys Phe Pro Glu Val Arg Val Tyr Asp Leu Thr Gln Tyr Glu 405 410 415 His Cys Pro Asp Asp Val Leu Val Leu Gly Thr Asp Gly Leu Trp Asp 420 425 430 Val Thr Thr Asp Cys Glu Val Ala Ala Thr Val Asp Arg Val Leu Ser 435 440 445 Ala Tyr Glu Pro Asn Asp His Ser Arg Tyr Thr Ala Leu Ala Gln Ala 450 455 460 Leu Val Leu Gly Ala Arg Gly Thr Pro Arg Asp Arg Gly Trp Arg Leu 465 470 475 480 Pro Asn Asn Lys Leu Gly Ser Gly Asp Asp Ile Ser Val Phe Val Ile 485 490 495 Pro Leu Gly Gly Pro Gly Ser Tyr Ser 500 505 <210> 41 <211> 2752 <212> PRT <213> Homo sapiens <400> 41 Met Tyr Asn Gly Ile Gly Leu Pro Thr Pro Arg Gly Ser Gly Thr Asn 1 5 10 15 Gly Tyr Val Gln Arg Asn Leu Ser Leu Val Arg Gly Arg Arg Gly Glu 20 25 30 Arg Pro Asp Tyr Lys Gly Glu Glu Glu Leu Arg Arg Leu Glu Ala Ala 35 40 45 Leu Val Lys Arg Pro Asn Pro Asp Ile Leu Asp His Glu Arg Lys Arg 50 55 60 Arg Val Glu Leu Arg Cys Leu Glu Leu Glu Glu Met Met Glu Glu Gln 65 70 75 80 Gly Tyr Glu Glu Gln Gln Ile Gln Glu Lys Val Ala Thr Phe Arg Leu 85 90 95 Met Leu Leu Glu Lys Asp Val Asn Pro Gly Gly Lys Glu Glu Thr Pro 100 105 110 Gly Gln Arg Pro Ala Val Thr Glu Thr His Gln Leu Ala Glu Leu Asn 115 120 125 Glu Lys Lys Asn Glu Arg Leu Arg Ala Ala Phe Gly Ile Ser Asp Ser 130 135 140 Tyr Val Asp Gly Ser Ser Phe Asp Pro Gln Arg Arg Ala Arg Glu Ala 145 150 155 160 Lys Gln Pro Ala Pro Glu Pro Lys Pro Tyr Ser Leu Val Arg Glu 165 170 175 Ser Ser Ser Ser Arg Ser Pro Thr Pro Lys Gln Lys Lys Lys Lys Lys 180 185 190 Lys Lys Asp Arg Gly Arg Arg Ser Glu Ser Ser Ser Pro Arg Arg Glu 195 200 205 Arg Lys Lys Ser Ser Lys Lys Lys Lys His Arg Ser Glu Ser Glu Ser 210 215 220 Lys Lys Arg Lys His Arg Ser Pro Thr Pro Lys Ser Lys Arg Lys Ser 225 230 235 240 Lys Asp Lys Lys Arg Lys Arg Ser Arg Ser Thr Thr Pro Ala Pro Lys 245 250 255 Ser Arg Arg Ala His Arg Ser Thr Ser Ala Asp Ser Ala Ser Ser Ser Ser 260 265 270 Asp Thr Ser Arg Ser Arg Ser Arg Ser Ala Ala Ala Lys Thr His Thr 275 280 285 Thr Ala Leu Ala Gly Arg Ser Pro Ser Pro Ala Ser Gly Arg Arg Gly 290 295 300 Glu Gly Asp Ala Pro Phe Ser Glu Pro Gly Thr Thr Ser Thr Gln Arg 305 310 315 320 Pro Ser Ser Pro Glu Thr Ala Thr Lys Gln Pro Ser Ser Pro Tyr Glu 325 330 335 Asp Lys Asp Lys Asp Lys Lys Glu Lys Ser Ala Thr Arg Pro Ser Pro 340 345 350 Ser Pro Glu Arg Ser Ser Thr Gly Pro Glu Pro Pro Ala Pro Thr Pro 355 360 365 Leu Leu Ala Glu Arg His Gly Gly Ser Pro Gln Pro Leu Ala Thr Thr 370 375 380 Pro Leu Ser Gln Glu Pro Val Asn Pro Pro Ser Glu Ala Ser Pro Thr 385 390 395 400 Arg Asp Arg Ser Pro Pro Lys Ser Pro Glu Lys Leu Pro Gln Ser Ser 405 410 415 Ser Ser Glu Ser Ser Pro Pro Ser Pro Gln Pro Thr Lys Val Ser Arg 420 425 430 His Ala Ser Ser Ser Pro Glu Ser Pro Lys Pro Ala Pro Ala Pro Gly 435 440 445 Ser His Arg Glu Ile Ser Ser Ser Pro Thr Ser Lys Asn Arg Ser His 450 455 460 Gly Arg Ala Lys Arg Asp Lys Ser His Ser His Thr Pro Ser Arg Arg 465 470 475 480 Met Gly Arg Ser Arg Ser Pro Ala Thr Ala Lys Arg Gly Arg Ser Arg 485 490 495 Ser Arg Thr Pro Thr Lys Arg Gly His Ser Arg Ser Arg Ser Pro Gln 500 505 510 Trp Arg Arg Ser Arg Ser Ala Gln Arg Trp Gly Arg Ser Arg Ser Pro 515 520 525 Gln Arg Arg Gly Arg Ser Arg Ser Pro Gln Arg Pro Gly Trp Ser Arg 530 535 540 Ser Arg Asn Thr Gln Arg Arg Gly Arg Ser Arg Ser Ala Arg Arg Gly 545 550 555 560 Arg Ser His Ser Arg Ser Pro Ala Thr Arg Gly Arg Ser Arg Ser Arg 565 570 575 Thr Pro Ala Arg Arg Gly Arg Ser Arg Ser Arg Thr Pro Ala Arg Arg 580 585 590 Arg Ser Arg Ser Arg Thr Pro Thr Arg Arg Arg Ser Arg Ser Arg Thr 595 600 605 Pro Ala Arg Arg Gly Arg Ser Arg Ser Arg Thr Pro Ala Arg Arg Arg 610 615 620 Ser Arg Thr Arg Ser Pro Val Arg Arg Arg Ser Arg Ser Arg Ser Pro 625 630 635 640 Ala Arg Arg Ser Gly Arg Ser Arg Ser Arg Thr Pro Ala Arg Arg Gly 645 650 655 Arg Ser Arg Ser Arg Thr Pro Ala Arg Arg Gly Arg Ser Arg Ser Arg 660 665 670 Thr Pro Ala Arg Arg Ser Gly Arg Ser Arg Ser Arg Thr Pro Ala Arg 675 680 685 Arg Gly Arg Ser Arg Ser Arg Thr Pro Arg Arg Gly Arg Ser Arg Ser 690 695 700 Arg Ser Leu Val Arg Arg Gly Arg Ser His Ser Arg Thr Pro Gln Arg 705 710 715 720 Arg Gly Arg Ser Gly Ser Ser Ser Glu Arg Lys Asn Lys Ser Arg Thr 725 730 735 Ser Gln Arg Arg Ser Arg Ser Asn Ser Ser Pro Glu Met Lys Lys Ser 740 745 750 Arg Ile Ser Ser Arg Arg Ser Arg Ser Leu Ser Ser Pro Arg Ser Lys 755 760 765 Ala Lys Ser Arg Leu Ser Leu Arg Arg Ser Leu Ser Gly Ser Ser Pro 770 775 780 Cys Pro Lys Gln Lys Ser Gln Thr Pro Pro Arg Arg Ser Arg Ser Gly 785 790 795 800 Ser Ser Gln Pro Lys Ala Lys Ser Arg Thr Pro Pro Arg Arg Ser Arg 805 810 815 Ser Ser Ser Ser Pro Pro Pro Lys Gln Lys Ser Lys Thr Pro Ser Arg 820 825 830 Gln Ser His Ser Ser Ser Ser Ser Pro His Pro Lys Val Lys Ser Gly Thr 835 840 845 Pro Pro Arg Gln Gly Ser Ile Thr Ser Pro Gln Ala Asn Glu Gln Ser 850 855 860 Val Thr Pro Gln Arg Arg Ser Cys Phe Glu Ser Ser Pro Asp Pro Glu 865 870 875 880 Leu Lys Ser Arg Thr Pro Ser Arg His Ser Cys Ser Gly Ser Ser Pro 885 890 895 Pro Arg Val Lys Ser Ser Thr Pro Pro Arg Gln Ser Pro Ser Arg Ser 900 905 910 Ser Ser Pro Gln Pro Lys Val Lys Ala Ile Ile Ser Pro Arg Gln Arg 915 920 925 Ser His Ser Gly Ser Ser Ser Pro Ser Pro Ser Arg Val Thr Ser Arg 930 935 940 Thr Thr Pro Arg Arg Ser Arg Ser Val Ser Pro Cys Ser Asn Val Glu 945 950 955 960 Ser Arg Leu Leu Pro Arg Tyr Ser His Ser Gly Ser Ser Ser Pro Asp 965 970 975 Thr Lys Val Lys Pro Glu Thr Pro Pro Arg Gln Ser His Ser Gly Ser 980 985 990 Ile Ser Pro Tyr Pro Lys Val Lys Ala Gln Thr Pro Pro Gly Pro Ser 995 1000 1005 Leu Ser Gly Ser Lys Ser Pro Cys Pro Gln Glu Lys Ser Lys Asp Ser 1010 1015 1020 Leu Val Gln Ser Cys Pro Gly Ser Leu Ser Leu Cys Ala Gly Val Lys 1025 1030 1035 1040 Ser Ser Thr Pro Pro Gly Glu Ser Tyr Phe Gly Val Ser Ser Leu Gln 1045 1050 1055 Leu Lys Gly Gln Ser Gln Thr Ser Pro Asp His Arg Ser Asp Thr Ser 1060 1065 1070 Ser Pro Glu Val Arg Gln Ser His Ser Glu Ser Pro Ser Leu Gln Ser 1075 1080 1085 Lys Ser Gln Thr Ser Pro Lys Gly Gly Arg Ser Arg Ser Ser Ser Pro 1090 1095 1100 Val Thr Glu Leu Ala Ser Arg Ser Pro Ile Arg Gln Asp Arg Gly Glu 1105 1110 1115 1120 Phe Ser Ala Ser Pro Met Leu Lys Ser Gly Met Ser Pro Glu Gln Ser 1125 1130 1135 Arg Phe Gln Ser Asp Ser Ser Ser Ser Tyr Pro Thr Val Asp Ser Asn Ser 1140 1145 1150 Leu Leu Gly Gln Ser Arg Leu Glu Thr Ala Glu Ser Lys Glu Lys Met 1155 1160 1165 Ala Leu Pro Pro Gln Glu Asp Ala Thr Ala Ser Pro Pro Arg Gln Lys 1170 1175 1180 Asp Lys Phe Ser Pro Phe Pro Val Gln Asp Arg Pro Glu Ser Ser Leu 1185 1190 1195 1200 Val Phe Lys Asp Thr Leu Arg Thr Pro Pro Arg Glu Arg Ser Gly Ala 1205 1210 1215 Gly Ser Ser Pro Glu Thr Lys Glu Gln Asn Ser Ala Leu Pro Thr Ser 1220 1225 1230 Ser Gln Asp Glu Glu Leu Met Glu Val Val Glu Lys Ser Glu Glu Pro 1235 1240 1245 Ala Gly Gln Ile Leu Ser His Leu Ser Ser Glu Leu Lys Glu Met Ser 1250 1255 1260 Thr Ser Asn Phe Glu Ser Ser Pro Glu Val Glu Glu Arg Pro Ala Val 1265 1270 1275 1280 Ser Leu Thr Leu Asp Gln Ser Gln Ser Gln Ala Ser Leu Glu Ala Val 1285 1290 1295 Glu Val Pro Ser Met Ala Ser Ser Trp Gly Gly Pro His Phe Ser Pro 1300 1305 1310 Glu His Lys Glu Leu Ser Asn Ser Pro Leu Arg Glu Asn Ser Phe Gly 1315 1320 1325 Ser Pro Leu Glu Phe Arg Asn Ser Gly Pro Leu Gly Thr Glu Met Asn 1330 1335 1340 Thr Gly Phe Ser Ser Glu Val Lys Glu Asp Leu Asn Gly Pro Phe Leu 1345 1350 1355 1360 Asn Gln Leu Glu Thr Asp Pro Ser Leu Asp Met Lys Glu Gln Ser Thr 1365 1370 1375 Arg Ser Ser Gly His Ser Ser Ser Glu Leu Ser Pro Asp Ala Val Glu 1380 1385 1390 Lys Ala Gly Met Ser Ser Asn Gln Ser Ile Ser Ser Pro Val Leu Asp 1395 1400 1405 Ala Val Pro Arg Thr Pro Ser Arg Glu Arg Ser Ser Ser Ala Ser Ser 1410 1415 1420 Pro Glu Met Lys Asp Gly Leu Pro Arg Thr Pro Ser Arg Arg Ser Arg 1425 1430 1435 1440 Ser Gly Ser Ser Pro Gly Leu Arg Asp Gly Ser Gly Thr Pro Ser Arg 1445 1450 1455 His Ser Leu Ser Gly Ser Ser Pro Gly Met Lys Asp Ile Pro Arg Thr 1460 1465 1470 Pro Ser Arg Gly Arg Ser Glu Cys Asp Ser Ser Pro Glu Pro Lys Ala 1475 1480 1485 Leu Pro Gln Thr Pro Arg Pro Arg Ser Arg Ser Pro Ser Ser Pro Glu 1490 1495 1500 Leu Asn Asn Lys Cys Leu Thr Pro Gln Arg Glu Arg Ser Gly Ser Glu 1505 1510 1515 1520 Ser Ser Val Asp Gln Lys Thr Val Ala Arg Thr Pro Leu Gly Gln Arg 1525 1530 1535 Ser Arg Ser Gly Ser Ser Gln Glu Leu Asp Val Lys Pro Ser Ala Ser 1540 1545 1550 Pro Gln Glu Arg Ser Glu Ser Asp Ser Ser Pro Asp Ser Lys Ala Lys 1555 1560 1565 Thr Arg Thr Pro Leu Arg Gln Arg Ser Arg Ser Gly Ser Ser Pro Glu 1570 1575 1580 Val Asp Ser Lys Ser Arg Leu Ser Pro Arg Arg Ser Arg Ser Gly Ser 1585 1590 1595 1600 Ser Pro Glu Val Lys Asp Lys Pro Arg Ala Ala Pro Arg Ala Gln Ser 1605 1610 1615 Gly Ser Asp Ser Ser Pro Glu Pro Lys Ala Pro Ala Pro Arg Ala Leu 1620 1625 1630 Pro Arg Arg Ser Arg Ser Gly Ser Ser Ser Lys Gly Arg Gly Pro Ser 1635 1640 1645 Pro Glu Gly Ser Ser Ser Thr Glu Ser Ser Pro Glu His Pro Pro Lys 1650 1655 1660 Ser Arg Thr Ala Arg Arg Gly Ser Arg Ser Ser Pro Glu Pro Lys Thr 1665 1670 1675 1680 Lys Ser Arg Thr Pro Pro Arg Arg Arg Ser Ser Arg Ser Ser Pro Glu 1685 1690 1695 Leu Thr Arg Lys Ala Arg Leu Ser Arg Arg Ser Arg Ser Ala Ser Ser 1700 1705 1710 Ser Pro Glu Thr Arg Ser Arg Thr Pro Pro Arg His Arg Arg Ser Pro 1715 1720 1725 Ser Val Ser Ser Pro Glu Pro Ala Glu Lys Ser Arg Ser Ser Arg Arg 1730 1735 1740 Arg Arg Ser Ala Ser Ser Pro Arg Thr Lys Thr Thr Ser Arg Arg Gly 1745 1750 1755 1760 Arg Ser Pro Ser Pro Lys Pro Arg Gly Leu Gln Arg Ser Arg Ser Arg 1765 1770 1775 Ser Arg Arg Glu Lys Thr Arg Thr Thr Arg Arg Arg Asp Arg Ser Gly 1780 1785 1790 Ser Ser Gln Ser Thr Ser Arg Arg Arg Gln Arg Ser Arg Ser Arg Ser 1795 1800 1805 Arg Val Thr Arg Arg Arg Arg Gly Gly Ser Gly Tyr His Ser Arg Ser 1810 1815 1820 Pro Ala Arg Gln Glu Ser Ser Arg Thr Ser Ser Arg Arg Arg Arg Gly 1825 1830 1835 1840 Arg Ser Arg Thr Pro Pro Thr Ser Arg Lys Arg Ser Arg Ser Arg Thr 1845 1850 1855 Ser Pro Ala Pro Trp Lys Arg Ser Arg Ser Arg Ala Ser Pro Ala Thr 1860 1865 1870 His Arg Arg Ser Arg Ser Arg Thr Pro Leu Ile Ser Arg Arg Arg Ser 1875 1880 1885 Arg Ser Arg Thr Ser Pro Val Ser Arg Arg Arg Ser Arg Ser Arg Thr 1890 1895 1900 Ser Val Thr Arg Arg Arg Ser Arg Ser Arg Ala Ser Pro Val Ser Arg 1905 1910 1915 1920 Arg Arg Ser Arg Ser Arg Thr Pro Val Thr Arg Arg Arg Ser Arg 1925 1930 1935 Ser Arg Thr Pro Thr Thr Arg Arg Arg Ser Arg Ser Arg Thr Pro Pro 1940 1945 1950 Val Thr Arg Arg Arg Ser Arg Ser Arg Thr Pro Pro Val Thr Arg Arg 1955 1960 1965 Arg Ser Arg Ser Arg Thr Ser Pro Ile Thr Arg Arg Arg Ser Arg Ser 1970 1975 1980 Arg Thr Ser Pro Val Thr Arg Arg Arg Ser Arg Ser Arg Thr Ser Pro 1985 1990 1995 2000 Val Thr Arg Arg Arg Ser Arg Ser Arg Thr Ser Pro Val Thr Arg Arg 2005 2010 2015 Arg Ser Arg Ser Arg Thr Pro Pro Ala Ile Arg Arg Arg Arg Ser Arg Ser 2020 2025 2030 Arg Thr Pro Leu Leu Pro Arg Lys Arg Ser Arg Ser Arg Ser Pro Leu 2035 2040 2045 Ala Ile Arg Arg Arg Ser Arg Ser Arg Thr Pro Arg Thr Ala Arg Gly 2050 2055 2060 Lys Arg Ser Leu Thr Arg Ser Pro Pro Ala Ile Arg Arg Arg Ser Ala 2065 2070 2075 2080 Ser Gly Ser Ser Ser Asp Arg Ser Arg Ser Ala Thr Pro Pro Ala Thr 2085 2090 2095 Arg Asn His Ser Gly Ser Arg Thr Pro Pro Val Ala Leu Asn Ser Ser 2100 2105 2110 Arg Met Ser Cys Phe Ser Arg Pro Ser Met Ser Pro Thr Pro Leu Asp 2115 2120 2125 Arg Cys Arg Ser Pro Gly Met Leu Glu Pro Leu Gly Ser Ser Arg Thr 2130 2135 2140 Pro Met Ser Val Leu Gln Gln Ala Gly Gly Ser Met Met Asp Gly Pro 2145 2150 2155 2160 Gly Pro Arg Ile Pro Asp His Gln Arg Thr Ser Val Pro Glu Asn His 2165 2170 2175 Ala Gln Ser Arg Ile Ala Leu Ala Leu Thr Ala Ile Ser Leu Gly Thr 2180 2185 2190 Ala Arg Pro Pro Ser Met Ser Ala Ala Gly Leu Ala Ala Arg Met 2195 2200 2205 Ser Gln Val Pro Ala Pro Val Pro Leu Met Ser Leu Arg Thr Ala Pro 2210 2215 2220 Ala Ala Asn Leu Ala Ser Arg Ile Pro Ala Ala Ser Ala Ala Ala Met 2225 2230 2235 2240 Asn Leu Ala Ser Ala Arg Thr Pro Ala Ile Pro Thr Ala Val Asn Leu 2245 2250 2255 Ala Asp Ser Arg Thr Pro Ala Ala Ala Ala Ala Met Asn Leu Ala Ser 2260 2265 2270 Pro Arg Thr Ala Val Ala Pro Ser Ala Val Asn Leu Ala Asp Pro Arg 2275 2280 2285 Thr Pro Thr Ala Pro Ala Val Asn Leu Ala Gly Ala Arg Thr Pro Ala 2290 2295 2300 Ala Leu Ala Ala Leu Ser Leu Thr Gly Ser Gly Thr Pro Pro Thr Ala 2305 2310 2315 2320 Ala Asn Tyr Pro Ser Ser Ser Arg Thr Pro Gln Ala Pro Ala Ser Ala 2325 2330 2335 Asn Leu Val Gly Pro Arg Ser Ala His Ala Thr Ala Pro Val Asn Ile 2340 2345 2350 Ala Gly Ser Arg Thr Ala Ala Ala Leu Ala Pro Ala Ser Leu Thr Ser 2355 2360 2365 Ala Arg Met Ala Pro Ala Leu Ser Gly Ala Asn Leu Thr Ser Pro Arg 2370 2375 2380 Val Pro Leu Ser Ala Tyr Glu Arg Val Ser Gly Arg Thr Ser Pro Pro 2385 2390 2395 2400 Leu Leu Asp Arg Ala Arg Ser Arg Thr Pro Pro Ser Ala Pro Ser Gln 2405 2410 2415 Ser Arg Met Thr Ser Glu Arg Ala Pro Ser Pro Ser Ser Arg Met Gly 2420 2425 2430 Gln Ala Pro Ser Gln Ser Leu Leu Pro Pro Ala Gln Asp Gln Pro Arg 2435 2440 2445 Ser Pro Val Pro Ser Ala Phe Ser Asp Gln Ser Arg Cys Leu Ile Ala 2450 2455 2460 Gln Thr Thr Pro Val Ala Gly Ser Gln Ser Leu Ser Ser Gly Ala Val 2465 2470 2475 2480 Ala Thr Thr Thr Ser Ser Ala Gly Asp His Asn Gly Met Leu Ser Val 2485 2490 2495 Pro Ala Pro Gly Val Pro His Ser Asp Val Gly Glu Pro Pro Ala Ser 2500 2505 2510 Thr Gly Ala Gln Gln Pro Ser Ala Leu Ala Ala Leu Gln Pro Ala Lys 2515 2520 2525 Glu Arg Arg Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser 2530 2535 2540 Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Gly Ser Ser Ser Ser 2545 2550 2555 2560 Ser Asp Ser Glu Gly Ser Ser Leu Pro Val Gln Pro Glu Val Ala Leu 2565 2570 2575 Lys Arg Val Pro Ser Pro Thr Pro Ala Pro Lys Glu Ala Val Arg Glu 2580 2585 2590 Gly Arg Pro Pro Glu Pro Thr Pro Ala Lys Arg Lys Arg Arg Ser Ser 2595 2600 2605 Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser 2610 2615 2620 Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser Ser 2625 2630 2635 2640 Ser Ser Ser Ser Ser Ser Ser Ser Ser Pro Ser Pro Ala Lys Pro Gly Pro 2645 2650 2655 Gln Ala Leu Pro Lys Pro Ala Ser Pro Lys Lys Pro Pro Pro Gly Glu 2660 2665 2670 Arg Arg Ser Arg Ser Pro Arg Lys Pro Ile Asp Ser Leu Arg Asp Ser 2675 2680 2685 Arg Ser Leu Ser Tyr Ser Pro Val Glu Arg Arg Arg Pro Ser Pro Gln 2690 2695 2700 Pro Ser Pro Arg Asp Gln Gln Ser Ser Ser Ser Glu Arg Gly Ser Arg 2705 2710 2715 2720 Arg Gly Gln Arg Gly Asp Ser Arg Ser Pro Ser His Lys Arg Arg Arg 2725 2730 2735 Glu Thr Pro Ser Pro Arg Pro Met Arg His Arg Ser Ser Arg Ser Pro 2740 2745 2750 <210> 42 <211> 422 <212> PRT <213> Homo sapiens <400> 42 Met Val Ser Glu Ser His His Glu Ala Leu Ala Ala Pro Val Thr 1 5 10 15 Thr Val Ala Thr Val Leu Pro Ser Asn Ala Thr Glu Pro Ala Ser Pro 20 25 30 Gly Glu Gly Lys Glu Asp Ala Phe Ser Lys Leu Lys Glu Lys Phe Met 35 40 45 Asn Glu Leu His Lys Ile Pro Leu Pro Pro Trp Ala Leu Ile Ala Ile 50 55 60 Ala Ile Val Ala Val Leu Leu Val Leu Thr Cys Cys Phe Cys Ile Cys 65 70 75 80 Lys Lys Cys Leu Phe Lys Lys Lys Asn Lys Lys Lys Gly Lys Glu Lys 85 90 95 Gly Gly Lys Asn Ala Ile Asn Met Lys Asp Val Lys Asp Leu Gly Lys 100 105 110 Thr Met Lys Asp Gln Ala Leu Lys Asp Asp Asp Ala Glu Thr Gly Leu 115 120 125 Thr Asp Gly Glu Glu Lys Glu Glu Pro Lys Glu Glu Glu Lys Leu Gly 130 135 140 Lys Leu Gln Tyr Ser Leu Asp Tyr Asp Phe Gln Asn Asn Gln Leu Leu 145 150 155 160 Val Gly Ile Ile Gln Ala Ala Glu Leu Pro Ala Leu Asp Met Gly Gly 165 170 175 Thr Ser Asp Pro Tyr Val Lys Val Phe Leu Leu Pro Asp Lys Lys Lys 180 185 190 Lys Phe Glu Thr Lys Val His Arg Lys Thr Leu Asn Pro Val Phe Asn 195 200 205 Glu Gln Phe Thr Phe Lys Val Pro Tyr Ser Glu Leu Gly Gly Lys Thr 210 215 220 Leu Val Met Ala Val Tyr Asp Phe Asp Arg Phe Ser Lys His Asp Ile 225 230 235 240 Ile Gly Glu Phe Lys Val Pro Met Asn Thr Val Asp Phe Gly His Val 245 250 255 Thr Glu Glu Trp Arg Asp Leu Gln Ser Ala Glu Lys Glu Glu Gln Glu 260 265 270 Lys Leu Gly Asp Ile Cys Phe Ser Leu Arg Tyr Val Pro Thr Ala Gly 275 280 285 Lys Leu Thr Val Val Ile Leu Glu Ala Lys Asn Leu Lys Lys Met Asp 290 295 300 Val Gly Gly Leu Ser Asp Pro Tyr Val Lys Ile His Leu Met Gln Asn 305 310 315 320 Gly Lys Arg Leu Lys Lys Lys Lys Thr Thr Ile Lys Lys Asn Thr Leu 325 330 335 Asn Pro Tyr Tyr Asn Glu Ser Phe Ser Phe Glu Val Pro Phe Glu Gln 340 345 350 Ile Gln Lys Val Gln Val Val Val Thr Val Leu Asp Tyr Asp Lys Ile 355 360 365 Gly Lys Asn Asp Ala Ile Gly Lys Val Phe Val Gly Tyr Asn Ser Thr 370 375 380 Gly Ala Glu Leu Arg His Trp Ser Asp Met Leu Ala Asn Pro Arg Arg 385 390 395 400 Pro Ile Ala Gln Trp His Thr Leu Gln Val Glu Glu Glu Val Asp Ala 405 410 415 Met Leu Ala Val Lys Lys 420 <210> 43 <211> 500 <212> PRT <213> Homo sapiens <400> 43 Met Ser Gly Pro Gly Pro Arg Glu Pro Pro Pro Glu Ala Gly Ala Ala 1 5 10 15 Gly Gly Glu Ala Ala Val Glu Gly Ala Gly Gly Gly Asp Ala Ala Leu 20 25 30 Gly Glu Pro Gly Leu Ser Phe Thr Thr Thr Asp Leu Ser Leu Val Glu 35 40 45 Met Thr Glu Val Glu Tyr Thr Gln Leu Gln His Ile Leu Cys Ser His 50 55 60 Met Glu Ala Ala Ala Asp Gly Glu Leu Glu Thr Arg Leu Asn Ser Ala 65 70 75 80 Leu Leu Ala Ala Ala Gly Pro Gly Ala Gly Ala Gly Gly Phe Ala Ala 85 90 95 Gly Gly Gln Gly Gly Ala Ala Pro Val Tyr Pro Val Leu Cys Pro Ser 100 105 110 Ala Leu Ala Ala Asp Ala Pro Cys Leu Gly His Ile Asp Phe Gln Glu 115 120 125 Leu Arg Met Met Leu Leu Ser Glu Ala Gly Ala Ala Glu Lys Thr Ser 130 135 140 Gly Gly Gly Asp Gly Ala Arg Ala Arg Ala Asp Gly Ala Ala Lys Glu 145 150 155 160 Gly Ala Gly Ala Ala Ala Ala Ala Ala Gly Pro Asp Gly Ala Pro Glu 165 170 175 Ala Arg Ala Lys Pro Ala Val Arg Val Arg Leu Glu Asp Arg Phe Asn 180 185 190 Ser Ile Pro Ala Glu Pro Pro Pro Ala Pro Arg Gly Pro Glu Pro Pro 195 200 205 Glu Pro Gly Gly Ala Leu Asn Asn Leu Val Thr Leu Ile Arg His Pro 210 215 220 Ser Glu Leu Met Asn Val Pro Leu Gln Gln Gln Asn Lys Cys Thr Ala 225 230 235 240 Leu Val Lys Asn Lys Thr Ala Ala Thr Thr Thr Ala Leu Gln Phe Thr 245 250 255 Tyr Pro Leu Phe Thr Thr Asn Ala Cys Ser Thr Ser Gly Asn Ser Asn 260 265 270 Leu Ser Gln Thr Gln Ser Ser Ser Asn Ser Cys Ser Val Leu Glu Ala 275 280 285 Ala Lys His Gln Asp Ile Gly Leu Pro Arg Ala Phe Ser Phe Cys Tyr 290 295 300 Gln Gln Glu Ile Glu Ser Thr Lys Gln Thr Leu Gly Ser Arg Asn Lys 305 310 315 320 Val Leu Pro Glu Gln Val Trp Ile Lys Val Gly Glu Ala Ala Leu Cys 325 330 335 Lys Gln Ala Leu Lys Arg Asn Arg Ser Arg Met Arg Gln Leu Asp Thr 340 345 350 Asn Val Glu Arg Arg Ala Leu Gly Glu Ile Gln Asn Val Gly Glu Gly 355 360 365 Ala Thr Ala Thr Gln Gly Ala Trp Gln Ser Ser Glu Ser Ser Gln Ala 370 375 380 Asn Leu Gly Glu Gln Ala Gln Ser Gly Pro Gln Gly Gly Arg Ser Gln 385 390 395 400 Arg Arg Glu Arg His Asn Arg Met Glu Arg Asp Arg Arg Arg Arg Ile 405 410 415 Arg Ile Cys Cys Asp Glu Leu Asn Leu Leu Val Pro Phe Cys Asn Ala 420 425 430 Glu Thr Asp Lys Ala Thr Thr Leu Gln Trp Thr Thr Ala Phe Leu Lys 435 440 445 Tyr Ile Gln Glu Arg His Gly Asp Ser Leu Lys Lys Glu Phe Glu Ser 450 455 460 Val Phe Cys Gly Lys Thr Gly Arg Arg Leu Lys Leu Thr Arg Pro Asp 465 470 475 480 Ser Leu Val Thr Cys Pro Ala Gln Gly Ser Leu Gln Ser Ser Pro Ser 485 490 495 Met Glu Ile Lys 500 <210> 44 <211> 1050 <212> PRT <213> Homo sapiens <400> 44 Met Glu Val Ala Val Glu Lys Ala Val Ala Ala Ala Ala Ala Ala Ser 1 5 10 15 Ala Ala Ala Ser Gly Gly Pro Ser Ala Ala Pro Ser Gly Glu Asn Glu 20 25 30 Ala Glu Ser Arg Gln Gly Pro Asp Ser Glu Arg Gly Gly Glu Ala Ala 35 40 45 Arg Leu Asn Leu Leu Asp Thr Cys Ala Val Cys His Gln Asn Ile Gln 50 55 60 Ser Arg Ala Pro Lys Leu Leu Pro Cys Leu His Ser Phe Cys Gln Arg 65 70 75 80 Cys Leu Pro Ala Pro Gln Arg Tyr Leu Met Leu Pro Ala Pro Met Leu 85 90 95 Gly Ser Ala Glu Thr Pro Pro Val Pro Ala Pro Gly Ser Pro Val 100 105 110 Ser Gly Ser Ser Pro Phe Ala Thr Gln Val Gly Val Ile Arg Cys Pro 115 120 125 Val Cys Ser Gln Glu Cys Ala Glu Arg His Ile Ile Asp Asn Phe Phe 130 135 140 Val Lys Asp Thr Thr Glu Val Pro Ser Ser Thr Val Glu Lys Ser Asn 145 150 155 160 Gln Val Cys Thr Ser Cys Glu Asp Asn Ala Glu Ala Asn Gly Phe Cys 165 170 175 Val Glu Cys Val Glu Trp Leu Cys Lys Thr Cys Ile Arg Ala His Gln 180 185 190 Arg Val Lys Phe Thr Lys Asp His Thr Val Arg Gln Lys Glu Glu Val 195 200 205 Ser Pro Glu Ala Val Gly Val Thr Ser Gln Arg Pro Val Phe Cys Pro 210 215 220 Phe His Lys Lys Glu Gln Leu Lys Leu Tyr Cys Glu Thr Cys Asp Lys 225 230 235 240 Leu Thr Cys Arg Asp Cys Gln Leu Leu Glu His Lys Glu His Arg Tyr 245 250 255 Gln Phe Ile Glu Glu Ala Phe Gln Asn Gln Lys Val Ile Ile Asp Thr 260 265 270 Leu Ile Thr Lys Leu Met Glu Lys Thr Lys Tyr Ile Lys Phe Thr Gly 275 280 285 Asn Gln Ile Gln Asn Arg Ile Ile Glu Val Asn Gln Asn Gln Lys Gln 290 295 300 Val Glu Gln Asp Ile Lys Val Ala Ile Phe Thr Leu Met Val Glu Ile 305 310 315 320 Asn Lys Lys Gly Lys Ala Leu Leu His Gln Leu Glu Ser Leu Ala Lys 325 330 335 Asp His Arg Met Lys Leu Met Gln Gln Gln Gln Glu Val Ala Gly Leu 340 345 350 Ser Lys Gln Leu Glu His Val Met His Phe Ser Lys Trp Ala Val Ser 355 360 365 Ser Gly Ser Ser Thr Ala Leu Leu Tyr Ser Lys Arg Leu Ile Thr Tyr 370 375 380 Arg Leu Arg His Leu Leu Arg Ala Arg Cys Asp Ala Ser Pro Val Thr 385 390 395 400 Asn Asn Thr Ile Gln Phe His Cys Asp Pro Ser Phe Trp Ala Gln Asn 405 410 415 Ile Ile Asn Leu Gly Ser Leu Val Ile Glu Asp Lys Glu Ser Gln Pro 420 425 430 Gln Met Pro Lys Gln Asn Pro Val Val Glu Gln Asn Ser Gln Pro Pro 435 440 445 Ser Gly Leu Ser Ser Asn Gln Leu Ser Lys Phe Pro Thr Gln Ile Ser 450 455 460 Leu Ala Gln Leu Arg Leu Gln His Met Gln Gln Gln Val Met Ala Gln 465 470 475 480 Arg Gln Gln Val Gln Arg Arg Pro Ala Pro Val Gly Leu Pro Asn Pro 485 490 495 Arg Met Gln Gly Pro Ile Gln Gln Pro Ser Ile Ser His Gln Gln Pro 500 505 510 Pro Pro Arg Leu Ile Asn Phe Gln Asn His Ser Pro Lys Pro Asn Gly 515 520 525 Pro Val Leu Pro Pro His Pro Gln Gln Leu Arg Tyr Pro Pro Asn Gln 530 535 540 Asn Ile Pro Arg Gln Ala Ile Lys Pro Asn Pro Leu Gln Met Ala Phe 545 550 555 560 Leu Ala Gln Gln Ala Ile Lys Gln Trp Gln Ile Ser Ser Gly Gln Gly 565 570 575 Thr Pro Ser Thr Thr Asn Ser Thr Ser Ser Thr Pro Ser Ser Pro Thr 580 585 590 Ile Thr Ser Ala Ala Gly Tyr Asp Gly Lys Ala Phe Gly Ser Pro Met 595 600 605 Ile Asp Leu Ser Ser Pro Val Gly Gly Ser Tyr Asn Leu Pro Ser Leu 610 615 620 Pro Asp Ile Asp Cys Ser Ser Thr Ile Met Leu Asp Asn Ile Val Arg 625 630 635 640 Lys Asp Thr Asn Ile Asp His Gly Gln Pro Arg Pro Pro Ser Asn Arg 645 650 655 Thr Val Gln Ser Pro Asn Ser Ser Val Pro Ser Pro Gly Leu Ala Gly 660 665 670 Pro Val Thr Met Thr Ser Val His Pro Pro Ile Arg Ser Pro Ser Ala 675 680 685 Ser Ser Val Gly Ser Arg Gly Ser Ser Gly Ser Ser Ser Lys Pro Ala 690 695 700 Gly Ala Asp Ser Thr His Lys Val Pro Val Val Met Leu Glu Pro Ile 705 710 715 720 Arg Ile Lys Gln Glu Asn Ser Gly Pro Pro Glu Asn Tyr Asp Phe Pro 725 730 735 Val Val Ile Val Lys Gln Glu Ser Asp Glu Glu Ser Arg Pro Gln Asn 740 745 750 Ala Asn Tyr Pro Arg Ser Ile Leu Thr Ser Leu Leu Leu Asn Ser Ser 755 760 765 Gln Ser Ser Thr Ser Glu Glu Thr Val Leu Arg Ser Asp Ala Pro Asp 770 775 780 Ser Thr Gly Asp Gln Pro Gly Leu His Gln Asp Asn Ser Ser Asn Gly 785 790 795 800 Lys Ser Glu Trp Leu Asp Pro Ser Gln Lys Ser Pro Leu His Val Gly 805 810 815 Glu Thr Arg Lys Glu Asp Asp Pro Asn Glu Asp Trp Cys Ala Val Cys 820 825 830 Gln Asn Gly Gly Glu Leu Leu Cys Cys Glu Lys Cys Pro Lys Val Phe 835 840 845 His Leu Ser Cys His Val Pro Thr Leu Thr Asn Phe Pro Ser Gly Glu 850 855 860 Trp Ile Cys Thr Phe Cys Arg Asp Leu Ser Lys Pro Glu Val Glu Tyr 865 870 875 880 Asp Cys Asp Ala Pro Ser His Asn Ser Glu Lys Lys Lys Thr Glu Gly 885 890 895 Leu Val Lys Leu Thr Pro Ile Asp Lys Arg Lys Cys Glu Arg Leu Leu 900 905 910 Leu Phe Leu Tyr Cys His Glu Met Ser Leu Ala Phe Gln Asp Pro Val 915 920 925 Pro Leu Thr Val Pro Asp Tyr Tyr Lys Ile Ile Lys Asn Pro Met Asp 930 935 940 Leu Ser Thr Ile Lys Lys Arg Leu Gln Glu Asp Tyr Ser Met Tyr Ser 945 950 955 960 Lys Pro Glu Asp Phe Val Ala Asp Phe Arg Leu Ile Phe Gln Asn Cys 965 970 975 Ala Glu Phe Asn Glu Pro Asp Ser Glu Val Ala Asn Ala Gly Ile Lys 980 985 990 Leu Glu Asn Tyr Phe Glu Glu Leu Leu Lys Asn Leu Tyr Pro Glu Lys 995 1000 1005 Arg Phe Pro Lys Pro Glu Phe Arg Asn Glu Ser Glu Asp Asn Lys Phe 1010 1015 1020 Ser Asp Asp Ser Asp Asp Asp Asp Phe Val Gln Pro Arg Lys Lys Arg Leu 1025 1030 1035 1040 Lys Ser Ile Glu Glu Arg Gln Leu Leu Lys 1045 1050

Claims (10)

AKAP9 gene mutation, BPIFB6 gene mutation, CHD4 gene mutation, DNMT3A gene mutation, DPM1 gene mutation, FRY gene mutation, GRM6 gene mutation, KIF4A gene mutation, KLHL36 gene mutation, LTN1 gene mutation, MAP3K5 gene mutation, MED1 gene mutation, NAV3 gene mutation, NDNF gene mutation, NKRF gene mutation, OLFM4 gene mutation, OR13C3 gene mutation, PLEC gene mutation, RADIL gene mutation, RELN gene mutation, mutation in the RIPK1 gene, mutation in the RNF123 gene, mutation in the RNF215 gene, mutation in the RSRC2 gene, mutation in the SIN3A gene, mutation in the SLC23A3 gene, mutation in the STAM gene, mutation in the TRIM59 gene, mutation in the USPL1 gene, mutation in the WNK1 gene and A composition for prognostic diagnosis of bladder cancer according to a pathological stage, comprising a reagent capable of detecting a pathological stage-specific marker of a bladder cancer patient comprising at least one selected from the group consisting of a mutation of the ZNF485 gene. The method according to claim 1,
The reagent is a composition comprising one or more selected from the group consisting of primers, probes, aptamers and antibodies. The method according to claim 1,
The pathological stage-specific marker is AEBP1 gene mutation, LPCAT1 gene mutation, CCAR2 gene mutation, CELA1 gene mutation, CPEB3 gene mutation, FDPS gene mutation, GPI gene mutation, PMS1 gene mutation, PPM1J gene A composition further comprising at least one selected from the group consisting of a mutation of the SRRM2 gene, a mutation of the SYT1 gene, a mutation of the TCFL5 gene, and a mutation of the TRIM24 gene. AKAP9 gene mutation, BPIFB6 gene mutation, CHD4 gene mutation, DNMT3A gene mutation, DPM1 gene mutation, FRY gene mutation, GRM6 gene mutation, KIF4A gene mutation, KLHL36 gene mutation, LTN1 gene mutation, MAP3K5 gene mutation, MED1 gene mutation, NAV3 gene mutation, NDNF gene mutation, NKRF gene mutation, OLFM4 gene mutation, OR13C3 gene mutation, PLEC gene mutation, RADIL gene mutation, RELN gene mutation, mutation in the RIPK1 gene, mutation in the RNF123 gene, mutation in the RNF215 gene, mutation in the RSRC2 gene, mutation in the SIN3A gene, mutation in the SLC23A3 gene, mutation in the STAM gene, mutation in the TRIM59 gene, mutation in the USPL1 gene, mutation in the WNK1 gene and A kit for prognostic diagnosis of bladder cancer according to a pathological stage, comprising a reagent capable of detecting a pathological stage-specific marker of a bladder cancer patient comprising at least one selected from the group consisting of a mutation of the ZNF485 gene. 5. The method according to claim 4,
The reagent is a kit comprising at least one selected from the group consisting of primers, probes, aptamers and antibodies. 5. The method according to claim 4,
The pathological stage-specific marker is AEBP1 gene mutation, LPCAT1 gene mutation, CCAR2 gene mutation, CELA1 gene mutation, CPEB3 gene mutation, FDPS gene mutation, GPI gene mutation, PMS1 gene mutation, PPM1J gene A kit further comprising at least one selected from the group consisting of a mutation of the SRRM2 gene, a mutation of the SYT1 gene, a mutation of the TCFL5 gene, and a mutation of the TRIM24 gene. preparing sample DNA from a sample of a bladder cancer patient;
Using the composition for prognostic diagnosis of any one of claims 1 to 3 or the kit for prognostic diagnosis of bladder cancer of any one of claims 4 to 6 with respect to the sample DNA, confirming the presence or absence of a pathological stage-specific marker; A method of providing information necessary for prognostic diagnosis of bladder cancer patients comprising a. 8. The method of claim 7,
The method further comprising the step of amplifying the sample DNA prepared from the bladder cancer patient sample. 8. The method of claim 7,
Among the pathological stage-specific markers, mutation of DPM1 gene, mutation of GRM6 gene, mutation of KIF4A gene, mutation of KLHL36 gene, mutation of NDNF gene, mutation of NKRF gene, mutation of RADIL gene, mutation of RIPK1 gene, RNF215 gene When at least one is identified from the group consisting of a mutation, a mutation of the STAM gene, a mutation of the TRIM59 gene, and a mutation of the ZNF485 gene, the survival rate is lower or the recurrence rate is higher than that of a person for which the pathological stage-specific marker is not identified. A method further comprising a step; 8. The method of claim 7,
Among the pathological stage-specific markers, mutation in AKAP9 gene, mutation in BPIFB6 gene, mutation in CHD4 gene, mutation in DNMT3A gene, mutation in FRY gene, mutation in LTN1 gene, mutation in MAP3K5 gene, mutation in MED1 gene, NAV3 gene mutation in OLFM4 gene, mutation in OR13C3 gene, mutation in PLEC gene, mutation in RELN gene, mutation in RNF123 gene, mutation in RSRC2 gene, mutation in SIN3A gene, mutation in SLC23A3 gene, mutation in USPL1 gene, mutation in WNK1 gene. When at least one selected from the group consisting of mutations of the mutation is confirmed, determining that the survival rate is higher or the recurrence rate is lower than that of a person for which the pathological stage-specific marker is not identified.