Insulin receptor substrate 2 (IRS-2)

 IRS2_HUMAN              Reviewed;        1338 AA.
 Q9Y4H2; Q96RR2; Q9BZG0; Q9Y6I5;
 30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
 29-MAR-2005, sequence version 2.
 10-FEB-2021, entry version 183.
 RecName: Full=Insulin receptor substrate 2;
          Short=IRS-2;
 Name=IRS2;
 Homo sapiens (Human).
 Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
 Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
 Homo.
 NCBI_TaxID=9606;
 [1]
 NUCLEOTIDE SEQUENCE [GENOMIC DNA].
 PubMed=9312143; DOI=10.1074/jbc.272.40.25267;
 Ogihara T., Isobe T., Ichimura T., Taoka M., Funaki M., Sakoda H.,
 Onishi Y., Inukai K., Anai M., Fukushima Y., Kikuchi M., Yazaki Y., Oka Y.,
 Asano T.;
 "14-3-3 protein binds to insulin receptor substrate-1, one of the binding
 sites of which is in the phosphotyrosine binding domain.";
 J. Biol. Chem. 272:25267-25274(1997).
 [2]
 NUCLEOTIDE SEQUENCE [MRNA].
 PubMed=10077005; DOI=10.1210/mend.13.3.0256;
 Vassen L., Wegrzyn W., Klein-Hitpass L.;
 "Human insulin receptor substrate-2 (IRS-2) is a primary progesterone
 response gene.";
 Mol. Endocrinol. 13:485-494(1999).
 [3]
 NUCLEOTIDE SEQUENCE [GENOMIC DNA].
 Heyne B.;
 "Insulin receptor substrate 2 gene sequence.";
 Submitted (NOV-2000) to the EMBL/GenBank/DDBJ databases.
 [4]
 NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
 PubMed=15057823; DOI=10.1038/nature02379;
 Dunham A., Matthews L.H., Burton J., Ashurst J.L., Howe K.L.,
 Ashcroft K.J., Beare D.M., Burford D.C., Hunt S.E., Griffiths-Jones S.,
 Jones M.C., Keenan S.J., Oliver K., Scott C.E., Ainscough R., Almeida J.P.,
 Ambrose K.D., Andrews D.T., Ashwell R.I.S., Babbage A.K., Bagguley C.L.,
 Bailey J., Bannerjee R., Barlow K.F., Bates K., Beasley H., Bird C.P.,
 Bray-Allen S., Brown A.J., Brown J.Y., Burrill W., Carder C., Carter N.P.,
 Chapman J.C., Clamp M.E., Clark S.Y., Clarke G., Clee C.M., Clegg S.C.,
 Cobley V., Collins J.E., Corby N., Coville G.J., Deloukas P., Dhami P.,
 Dunham I., Dunn M., Earthrowl M.E., Ellington A.G., Faulkner L.,
 Frankish A.G., Frankland J., French L., Garner P., Garnett J.,
 Gilbert J.G.R., Gilson C.J., Ghori J., Grafham D.V., Gribble S.M.,
 Griffiths C., Hall R.E., Hammond S., Harley J.L., Hart E.A., Heath P.D.,
 Howden P.J., Huckle E.J., Hunt P.J., Hunt A.R., Johnson C., Johnson D.,
 Kay M., Kimberley A.M., King A., Laird G.K., Langford C.J., Lawlor S.,
 Leongamornlert D.A., Lloyd D.M., Lloyd C., Loveland J.E., Lovell J.,
 Martin S., Mashreghi-Mohammadi M., McLaren S.J., McMurray A., Milne S.,
 Moore M.J.F., Nickerson T., Palmer S.A., Pearce A.V., Peck A.I., Pelan S.,
 Phillimore B., Porter K.M., Rice C.M., Searle S., Sehra H.K., Shownkeen R.,
 Skuce C.D., Smith M., Steward C.A., Sycamore N., Tester J., Thomas D.W.,
 Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P.,
 Whitehead S.L., Willey D.L., Wilming L., Wray P.W., Wright M.W., Young L.,
 Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Beck S., Bentley D.R.,
 Rogers J., Ross M.T.;
 "The DNA sequence and analysis of human chromosome 13.";
 Nature 428:522-528(2004).
 [5]
 NUCLEOTIDE SEQUENCE OF 1-1337, AND VARIANTS SER-879 AND ALA-882.
 Heyne B., Gehrisch S., Jaross W.;
 "Two missense mutations in insulin receptor substrate 2 (G879S and
 G882A).";
 Submitted (JUL-2000) to the EMBL/GenBank/DDBJ databases.
 [6]
 PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-388; SER-391 AND SER-560, AND
 IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
 TISSUE=Cervix carcinoma;
 PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
 Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.;
 "Global, in vivo, and site-specific phosphorylation dynamics in signaling
 networks.";
 Cell 127:635-648(2006).
 [7]
 PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-350 AND THR-527, AND
 IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
 TISSUE=Cervix carcinoma;
 PubMed=16964243; DOI=10.1038/nbt1240;
 Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
 "A probability-based approach for high-throughput protein phosphorylation
 analysis and site localization.";
 Nat. Biotechnol. 24:1285-1292(2006).
 [8]
 PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-915, AND IDENTIFICATION BY
 MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
 TISSUE=Cervix carcinoma;
 PubMed=18220336; DOI=10.1021/pr0705441;
 Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., Yates J.R. III;
 "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient
 phosphoproteomic analysis.";
 J. Proteome Res. 7:1346-1351(2008).
 [9]
 PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-388; SER-391 AND SER-915, AND
 IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
 TISSUE=Platelet;
 PubMed=18088087; DOI=10.1021/pr0704130;
 Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
 Schuetz C., Walter U., Gambaryan S., Sickmann A.;
 "Phosphoproteome of resting human platelets.";
 J. Proteome Res. 7:526-534(2008).
 [10]
 PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-306; SER-346; THR-350;
 SER-365; SER-384; SER-388; SER-391; SER-523; THR-527; SER-577; THR-579;
 THR-580; SER-594; SER-608; SER-620; SER-679; SER-735; SER-736; SER-770;
 THR-779; SER-828; SER-915; SER-973; SER-1100; THR-1159; SER-1162; SER-1174;
 SER-1176 AND SER-1203, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
 ANALYSIS].
 TISSUE=Cervix carcinoma;
 PubMed=18669648; DOI=10.1073/pnas.0805139105;
 Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
 Elledge S.J., Gygi S.P.;
 "A quantitative atlas of mitotic phosphorylation.";
 Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
 [11]
 IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
 PubMed=19413330; DOI=10.1021/ac9004309;
 Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
 "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
 refined SCX-based approach.";
 Anal. Chem. 81:4493-4501(2009).
 [12]
 PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-391, AND IDENTIFICATION BY
 MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
 PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200;
 Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
 Mann M., Daub H.;
 "Large-scale proteomics analysis of the human kinome.";
 Mol. Cell. Proteomics 8:1751-1764(2009).
 [13]
 PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-306; SER-388; SER-391;
 SER-560; SER-594; TYR-675; SER-736; SER-915 AND SER-1176, AND
 IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
 TISSUE=Cervix carcinoma;
 PubMed=20068231; DOI=10.1126/scisignal.2000475;
 Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
 Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
 "Quantitative phosphoproteomics reveals widespread full phosphorylation
 site occupancy during mitosis.";
 Sci. Signal. 3:RA3-RA3(2010).
 [14]
 IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
 PubMed=21269460; DOI=10.1186/1752-0509-5-17;
 Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
 Bennett K.L., Superti-Furga G., Colinge J.;
 "Initial characterization of the human central proteome.";
 BMC Syst. Biol. 5:17-17(2011).
 [15]
 PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-306; SER-560; SER-915 AND
 SER-1176, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
 PubMed=21406692; DOI=10.1126/scisignal.2001570;
 Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
 Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
 "System-wide temporal characterization of the proteome and phosphoproteome
 of human embryonic stem cell differentiation.";
 Sci. Signal. 4:RS3-RS3(2011).
 [16]
 PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-306; THR-350; THR-520;
 THR-527; SER-560; SER-577; THR-579; SER-594; TYR-675; SER-679; SER-682;
 SER-736; SER-805; SER-915; SER-973; SER-1100; SER-1174; SER-1176; SER-1186
 AND SER-1203, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
 ANALYSIS].
 TISSUE=Cervix carcinoma, and Erythroleukemia;
 PubMed=23186163; DOI=10.1021/pr300630k;
 Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
 Mohammed S.;
 "Toward a comprehensive characterization of a human cancer cell
 phosphoproteome.";
 J. Proteome Res. 12:260-271(2013).
 [17]
 PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-594; SER-915; SER-973;
 THR-1082 AND SER-1100, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE
 ANALYSIS].
 TISSUE=Liver;
 PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
 Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L.,
 Ye M., Zou H.;
 "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
 phosphoproteome.";
 J. Proteomics 96:253-262(2014).
 [18]
 METHYLATION [LARGE SCALE ANALYSIS] AT ARG-412, AND IDENTIFICATION BY MASS
 SPECTROMETRY [LARGE SCALE ANALYSIS].
 TISSUE=Colon carcinoma;
 PubMed=24129315; DOI=10.1074/mcp.o113.027870;
 Guo A., Gu H., Zhou J., Mulhern D., Wang Y., Lee K.A., Yang V., Aguiar M.,
 Kornhauser J., Jia X., Ren J., Beausoleil S.A., Silva J.C., Vemulapalli V.,
 Bedford M.T., Comb M.J.;
 "Immunoaffinity enrichment and mass spectrometry analysis of protein
 methylation.";
 Mol. Cell. Proteomics 13:372-387(2014).
 [19]
 VARIANT ASP-1057.
 PubMed=12687350; DOI=10.1007/s00439-003-0935-3;
 Lautier C., El Mkadem S.A., Renard E., Brun J.F., Gris J.-C., Bringer J.,
 Grigorescu F.;
 "Complex haplotypes of IRS2 gene are associated with severe obesity and
 reveal heterogeneity in the effect of Gly1057Asp mutation.";
 Hum. Genet. 113:34-43(2003).
 -!- FUNCTION: May mediate the control of various cellular processes by
     insulin.
 -!- SUBUNIT: Interacts with PHIP. {ECO:0000250}.
 -!- INTERACTION:
     Q9Y4H2; P27986: PIK3R1; NbExp=3; IntAct=EBI-1049582, EBI-79464;
     Q9Y4H2; Q96EB6: SIRT1; NbExp=2; IntAct=EBI-1049582, EBI-1802965;
     Q9Y4H2; P63104: YWHAZ; NbExp=3; IntAct=EBI-1049582, EBI-347088;
 -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000250}.
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 EMBL; AB000732; BAA24500.1; -; Genomic_DNA.
 EMBL; AF073310; AAD21531.1; -; mRNA.
 EMBL; AF322115; AAG50013.1; -; Genomic_DNA.
 EMBL; AF322114; AAG50013.1; JOINED; Genomic_DNA.
 EMBL; AL162497; -; NOT_ANNOTATED_CDS; Genomic_DNA.
 EMBL; AF288517; AAK83053.1; -; Genomic_DNA.
 CCDS; CCDS9510.1; -.
 RefSeq; NP_003740.2; NM_003749.2.
 PDB; 3FQW; X-ray; 1.93 A; C=1097-1105.
 PDB; 3FQX; X-ray; 1.70 A; C=1097-1105.
 PDBsum; 3FQW; -.
 PDBsum; 3FQX; -.
 SMR; Q9Y4H2; -.
 BioGRID; 114209; 55.
 ELM; Q9Y4H2; -.
 IntAct; Q9Y4H2; 19.
 MINT; Q9Y4H2; -.
 STRING; 9606.ENSP00000365016; -.
 iPTMnet; Q9Y4H2; -.
 PhosphoSitePlus; Q9Y4H2; -.
 BioMuta; IRS2; -.
 DMDM; 62298062; -.
 EPD; Q9Y4H2; -.
 jPOST; Q9Y4H2; -.
 MassIVE; Q9Y4H2; -.
 MaxQB; Q9Y4H2; -.
 PaxDb; Q9Y4H2; -.
 PeptideAtlas; Q9Y4H2; -.
 PRIDE; Q9Y4H2; -.
 ProteomicsDB; 86205; -.
 Antibodypedia; 25473; 339 antibodies.
 DNASU; 8660; -.
 Ensembl; ENST00000375856; ENSP00000365016; ENSG00000185950.
 GeneID; 8660; -.
 KEGG; hsa:8660; -.
 UCSC; uc001vqv.4; human.
 CTD; 8660; -.
 DisGeNET; 8660; -.
 GeneCards; IRS2; -.
 HGNC; HGNC:6126; IRS2.
 HPA; ENSG00000185950; Tissue enhanced (bone).
 MalaCards; IRS2; -.
 MIM; 600797; gene.
 neXtProt; NX_Q9Y4H2; -.
 OpenTargets; ENSG00000185950; -.
 PharmGKB; PA375; -.
 VEuPathDB; HostDB:ENSG00000185950.8; -.
 eggNOG; ENOG502QUNU; Eukaryota.
 GeneTree; ENSGT00940000161407; -.
 HOGENOM; CLU_004902_1_0_1; -.
 InParanoid; Q9Y4H2; -.
 OMA; YKAPYTC; -.
 OrthoDB; 298675at2759; -.
 PhylomeDB; Q9Y4H2; -.
 TreeFam; TF325994; -.
 PathwayCommons; Q9Y4H2; -.
 Reactome; R-HSA-109704; PI3K Cascade.
 Reactome; R-HSA-112399; IRS-mediated signalling.
 Reactome; R-HSA-112412; SOS-mediated signalling.
 Reactome; R-HSA-1257604; PIP3 activates AKT signaling.
 Reactome; R-HSA-1266695; Interleukin-7 signaling.
 Reactome; R-HSA-198203; PI3K/AKT activation.
 Reactome; R-HSA-2219530; Constitutive Signaling by Aberrant PI3K in Cancer.
 Reactome; R-HSA-2428928; IRS-related events triggered by IGF1R.
 Reactome; R-HSA-2586552; Signaling by Leptin.
 Reactome; R-HSA-5673001; RAF/MAP kinase cascade.
 Reactome; R-HSA-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.
 Reactome; R-HSA-74713; IRS activation.
 Reactome; R-HSA-74749; Signal attenuation.
 Reactome; R-HSA-8853659; RET signaling.
 Reactome; R-HSA-9006335; Signaling by Erythropoietin.
 Reactome; R-HSA-9027276; Erythropoietin activates Phosphoinositide-3-kinase (PI3K).
 Reactome; R-HSA-9027277; Erythropoietin activates Phospholipase C gamma (PLCG).
 Reactome; R-HSA-9027283; Erythropoietin activates STAT5.
 Reactome; R-HSA-9027284; Erythropoietin activates RAS.
 Reactome; R-HSA-982772; Growth hormone receptor signaling.
 SignaLink; Q9Y4H2; -.
 SIGNOR; Q9Y4H2; -.
 BioGRID-ORCS; 8660; 146 hits in 879 CRISPR screens.
 ChiTaRS; IRS2; human.
 EvolutionaryTrace; Q9Y4H2; -.
 GeneWiki; IRS2; -.
 GenomeRNAi; 8660; -.
 Pharos; Q9Y4H2; Tbio.
 PRO; PR:Q9Y4H2; -.
 Proteomes; UP000005640; Chromosome 13.
 RNAct; Q9Y4H2; protein.
 Bgee; ENSG00000185950; Expressed in decidua and 249 other tissues.
 Genevisible; Q9Y4H2; HS.
 GO; GO:0005829; C:cytosol; IBA:GO_Central.
 GO; GO:0005886; C:plasma membrane; IBA:GO_Central.
 GO; GO:0032991; C:protein-containing complex; IEA:Ensembl.
 GO; GO:0071889; F:14-3-3 protein binding; IEA:Ensembl.
 GO; GO:0005158; F:insulin receptor binding; IBA:GO_Central.
 GO; GO:0043548; F:phosphatidylinositol 3-kinase binding; IBA:GO_Central.
 GO; GO:0019904; F:protein domain specific binding; IEA:Ensembl.
 GO; GO:0019901; F:protein kinase binding; IEA:Ensembl.
 GO; GO:0019903; F:protein phosphatase binding; IEA:Ensembl.
 GO; GO:0007411; P:axon guidance; TAS:Reactome.
 GO; GO:0007420; P:brain development; IEA:Ensembl.
 GO; GO:0071333; P:cellular response to glucose stimulus; IEA:Ensembl.
 GO; GO:0032869; P:cellular response to insulin stimulus; IMP:BHF-UCL.
 GO; GO:0006006; P:glucose metabolic process; TAS:ProtInc.
 GO; GO:0008286; P:insulin receptor signaling pathway; ISS:BHF-UCL.
 GO; GO:0038111; P:interleukin-7-mediated signaling pathway; TAS:Reactome.
 GO; GO:0055088; P:lipid homeostasis; TAS:BHF-UCL.
 GO; GO:0030879; P:mammary gland development; IEA:Ensembl.
 GO; GO:0000165; P:MAPK cascade; TAS:Reactome.
 GO; GO:0002903; P:negative regulation of B cell apoptotic process; ISS:BHF-UCL.
 GO; GO:0033673; P:negative regulation of kinase activity; ISS:BHF-UCL.
 GO; GO:0010748; P:negative regulation of long-chain fatty acid import across plasma membrane; IMP:BHF-UCL.
 GO; GO:0048015; P:phosphatidylinositol-mediated signaling; TAS:Reactome.
 GO; GO:0030890; P:positive regulation of B cell proliferation; ISS:BHF-UCL.
 GO; GO:0030335; P:positive regulation of cell migration; IEA:Ensembl.
 GO; GO:0008284; P:positive regulation of cell population proliferation; NAS:BHF-UCL.
 GO; GO:0032000; P:positive regulation of fatty acid beta-oxidation; IMP:BHF-UCL.
 GO; GO:0046326; P:positive regulation of glucose import; IMP:BHF-UCL.
 GO; GO:0010907; P:positive regulation of glucose metabolic process; IMP:BHF-UCL.
 GO; GO:0045725; P:positive regulation of glycogen biosynthetic process; IMP:BHF-UCL.
 GO; GO:0032024; P:positive regulation of insulin secretion; ISS:BHF-UCL.
 GO; GO:0002053; P:positive regulation of mesenchymal cell proliferation; IEA:Ensembl.
 GO; GO:0014068; P:positive regulation of phosphatidylinositol 3-kinase signaling; TAS:Reactome.
 GO; GO:0051897; P:positive regulation of protein kinase B signaling; TAS:Reactome.
 GO; GO:0046579; P:positive regulation of Ras protein signal transduction; TAS:Reactome.
 GO; GO:0019216; P:regulation of lipid metabolic process; TAS:BHF-UCL.
 GO; GO:0009749; P:response to glucose; ISS:BHF-UCL.
 GO; GO:0007165; P:signal transduction; TAS:ProtInc.
 CDD; cd01204; PTB_IRS; 1.
 Gene3D; 2.30.29.30; -; 2.
 InterPro; IPR039011; IRS.
 InterPro; IPR002404; IRS_PTB.
 InterPro; IPR011993; PH-like_dom_sf.
 InterPro; IPR001849; PH_domain.
 PANTHER; PTHR10614; PTHR10614; 1.
 Pfam; PF02174; IRS; 1.
 Pfam; PF00169; PH; 1.
 PRINTS; PR00628; INSULINRSI.
 SMART; SM00233; PH; 1.
 SMART; SM00310; PTBI; 1.
 PROSITE; PS51064; IRS_PTB; 1.
 PROSITE; PS50003; PH_DOMAIN; 1.
 1: Evidence at protein level;
 3D-structure; Cytoplasm; Methylation; Phosphoprotein; Reference proteome;
 Transducer.
 CHAIN           1..1338
                 /note="Insulin receptor substrate 2"
                 /id="PRO_0000084239"
 DOMAIN          16..144
                 /note="PH"
                 /evidence="ECO:0000255|PROSITE-ProRule:PRU00145"
 DOMAIN          194..298
                 /note="IRS-type PTB"
                 /evidence="ECO:0000255|PROSITE-ProRule:PRU00389"
 MOTIF           540..543
                 /note="YXXM motif 1"
 MOTIF           598..601
                 /note="YXXM motif 2"
 MOTIF           653..656
                 /note="YXXM motif 3"
 MOTIF           675..678
                 /note="YXXM motif 4"
 MOTIF           742..745
                 /note="YXXM motif 5"
 MOTIF           823..826
                 /note="YXXM motif 6"
 MOTIF           1072..1075
                 /note="YXXM motif 7"
 COMPBIAS        19..28
                 /note="Poly-Asn"
 COMPBIAS        371..380
                 /note="Poly-Ala"
 COMPBIAS        447..452
                 /note="Poly-Ser"
 COMPBIAS        460..467
                 /note="Poly-Pro"
 COMPBIAS        533..537
                 /note="Poly-Gly"
 COMPBIAS        642..645
                 /note="Poly-Ser"
 COMPBIAS        694..701
                 /note="Poly-Ala"
 COMPBIAS        944..947
                 /note="Poly-Ser"
 COMPBIAS        1031..1038
                 /note="Poly-Pro"
 COMPBIAS        1265..1278
                 /note="Poly-Pro"
 MOD_RES         306
                 /note="Phosphoserine"
                 /evidence="ECO:0000244|PubMed:18669648,
                 ECO:0000244|PubMed:20068231, ECO:0000244|PubMed:21406692,
                 ECO:0000244|PubMed:23186163"
 MOD_RES         346
                 /note="Phosphoserine"
                 /evidence="ECO:0000244|PubMed:18669648"
 MOD_RES         350
                 /note="Phosphothreonine"
                 /evidence="ECO:0000244|PubMed:16964243,
                 ECO:0000244|PubMed:18669648, ECO:0000244|PubMed:23186163"
 MOD_RES         365
                 /note="Phosphoserine"
                 /evidence="ECO:0000244|PubMed:18669648"
 MOD_RES         384
                 /note="Phosphoserine"
                 /evidence="ECO:0000244|PubMed:18669648"
 MOD_RES         388
                 /note="Phosphoserine"
                 /evidence="ECO:0000244|PubMed:17081983,
                 ECO:0000244|PubMed:18088087, ECO:0000244|PubMed:18669648,
                 ECO:0000244|PubMed:20068231"
 MOD_RES         391
                 /note="Phosphoserine"
                 /evidence="ECO:0000244|PubMed:17081983,
                 ECO:0000244|PubMed:18088087, ECO:0000244|PubMed:18669648,
                 ECO:0000244|PubMed:19369195, ECO:0000244|PubMed:20068231"
 MOD_RES         412
                 /note="Omega-N-methylarginine"
                 /evidence="ECO:0000244|PubMed:24129315"
 MOD_RES         520
                 /note="Phosphothreonine"
                 /evidence="ECO:0000244|PubMed:23186163"
 MOD_RES         523
                 /note="Phosphoserine"
                 /evidence="ECO:0000244|PubMed:18669648"
 MOD_RES         527
                 /note="Phosphothreonine"
                 /evidence="ECO:0000244|PubMed:16964243,
                 ECO:0000244|PubMed:18669648, ECO:0000244|PubMed:23186163"
 MOD_RES         540
                 /note="Phosphotyrosine; by INSR"
                 /evidence="ECO:0000250"
 MOD_RES         560
                 /note="Phosphoserine"
                 /evidence="ECO:0000244|PubMed:17081983,
                 ECO:0000244|PubMed:20068231, ECO:0000244|PubMed:21406692,
                 ECO:0000244|PubMed:23186163"
 MOD_RES         577
                 /note="Phosphoserine"
                 /evidence="ECO:0000244|PubMed:18669648,
                 ECO:0000244|PubMed:23186163"
 MOD_RES         579
                 /note="Phosphothreonine"
                 /evidence="ECO:0000244|PubMed:18669648,
                 ECO:0000244|PubMed:23186163"
 MOD_RES         580
                 /note="Phosphothreonine"
                 /evidence="ECO:0000244|PubMed:18669648"
 MOD_RES         594
                 /note="Phosphoserine"
                 /evidence="ECO:0000244|PubMed:18669648,
                 ECO:0000244|PubMed:20068231, ECO:0000244|PubMed:23186163,
                 ECO:0000244|PubMed:24275569"
 MOD_RES         608
                 /note="Phosphoserine"
                 /evidence="ECO:0000244|PubMed:18669648"
 MOD_RES         620
                 /note="Phosphoserine"
                 /evidence="ECO:0000244|PubMed:18669648"
 MOD_RES         653
                 /note="Phosphotyrosine; by INSR"
                 /evidence="ECO:0000250|UniProtKB:P81122"
 MOD_RES         675
                 /note="Phosphotyrosine; by INSR"
                 /evidence="ECO:0000244|PubMed:20068231,
                 ECO:0000244|PubMed:23186163"
 MOD_RES         679
                 /note="Phosphoserine"
                 /evidence="ECO:0000244|PubMed:18669648,
                 ECO:0000244|PubMed:23186163"
 MOD_RES         682
                 /note="Phosphoserine"
                 /evidence="ECO:0000244|PubMed:23186163"
 MOD_RES         735
                 /note="Phosphoserine"
                 /evidence="ECO:0000244|PubMed:18669648"
 MOD_RES         736
                 /note="Phosphoserine"
                 /evidence="ECO:0000244|PubMed:18669648,
                 ECO:0000244|PubMed:20068231, ECO:0000244|PubMed:23186163"
 MOD_RES         770
                 /note="Phosphoserine"
                 /evidence="ECO:0000244|PubMed:18669648"
 MOD_RES         779
                 /note="Phosphothreonine"
                 /evidence="ECO:0000244|PubMed:18669648"
 MOD_RES         805
                 /note="Phosphoserine"
                 /evidence="ECO:0000244|PubMed:23186163"
 MOD_RES         828
                 /note="Phosphoserine"
                 /evidence="ECO:0000244|PubMed:18669648"
 MOD_RES         915
                 /note="Phosphoserine"
                 /evidence="ECO:0000244|PubMed:18088087,
                 ECO:0000244|PubMed:18220336, ECO:0000244|PubMed:18669648,
                 ECO:0000244|PubMed:20068231, ECO:0000244|PubMed:21406692,
                 ECO:0000244|PubMed:23186163, ECO:0000244|PubMed:24275569"
 MOD_RES         919
                 /note="Phosphotyrosine; by INSR"
                 /evidence="ECO:0000250"
 MOD_RES         973
                 /note="Phosphoserine"
                 /evidence="ECO:0000244|PubMed:18669648,
                 ECO:0000244|PubMed:23186163, ECO:0000244|PubMed:24275569"
 MOD_RES         978
                 /note="Phosphotyrosine; by INSR"
                 /evidence="ECO:0000250"
 MOD_RES         1082
                 /note="Phosphothreonine"
                 /evidence="ECO:0000244|PubMed:24275569"
 MOD_RES         1100
                 /note="Phosphoserine"
                 /evidence="ECO:0000244|PubMed:18669648,
                 ECO:0000244|PubMed:23186163, ECO:0000244|PubMed:24275569"
 MOD_RES         1159
                 /note="Phosphothreonine"
                 /evidence="ECO:0000244|PubMed:18669648"
 MOD_RES         1162
                 /note="Phosphoserine"
                 /evidence="ECO:0000244|PubMed:18669648"
 MOD_RES         1174
                 /note="Phosphoserine"
                 /evidence="ECO:0000244|PubMed:18669648,
                 ECO:0000244|PubMed:23186163"
 MOD_RES         1176
                 /note="Phosphoserine"
                 /evidence="ECO:0000244|PubMed:18669648,
                 ECO:0000244|PubMed:20068231, ECO:0000244|PubMed:21406692,
                 ECO:0000244|PubMed:23186163"
 MOD_RES         1186
                 /note="Phosphoserine"
                 /evidence="ECO:0000244|PubMed:23186163"
 MOD_RES         1203
                 /note="Phosphoserine"
                 /evidence="ECO:0000244|PubMed:18669648,
                 ECO:0000244|PubMed:23186163"
 MOD_RES         1253
                 /note="Phosphotyrosine; by INSR"
                 /evidence="ECO:0000250"
 VARIANT         789
                 /note="H -> Y (in dbSNP:rs35223808)"
                 /id="VAR_033992"
 VARIANT         879
                 /note="G -> S (in dbSNP:rs549588978)"
                 /evidence="ECO:0000269|Ref.5"
                 /id="VAR_021557"
 VARIANT         882
                 /note="G -> A (in dbSNP:rs201499247)"
                 /evidence="ECO:0000269|Ref.5"
                 /id="VAR_021558"
 VARIANT         999
                 /note="V -> M (in dbSNP:rs35927012)"
                 /id="VAR_033993"
 VARIANT         1057
                 /note="G -> D (in dbSNP:rs1805097)"
                 /evidence="ECO:0000269|PubMed:12687350"
                 /id="VAR_014857"
 CONFLICT        28
                 /note="N -> NN (in Ref. 2; AAD21531)"
                 /evidence="ECO:0000305"
 CONFLICT        39..41
                 /note="KQK -> NEE (in Ref. 2; AAD21531)"
                 /evidence="ECO:0000305"
 CONFLICT        59
                 /note="E -> K (in Ref. 1; BAA24500)"
                 /evidence="ECO:0000305"
 CONFLICT        81
                 /note="K -> N (in Ref. 1; BAA24500)"
                 /evidence="ECO:0000305"
 CONFLICT        107
                 /note="A -> P (in Ref. 1; BAA24500)"
                 /evidence="ECO:0000305"
 CONFLICT        171
                 /note="L -> V (in Ref. 1; BAA24500)"
                 /evidence="ECO:0000305"
 CONFLICT        371
                 /note="A -> R (in Ref. 2; AAD21531)"
                 /evidence="ECO:0000305"
 CONFLICT        379..382
                 /note="GARP -> AQRL (in Ref. 2; AAD21531)"
                 /evidence="ECO:0000305"
 CONFLICT        406
                 /note="S -> I (in Ref. 1; BAA24500)"
                 /evidence="ECO:0000305"
 CONFLICT        410..419
                 /note="GGRGSKVALL -> RAAGTKWHCF (in Ref. 1; BAA24500)"
                 /evidence="ECO:0000305"
 CONFLICT        424
                 /note="A -> G (in Ref. 1; BAA24500)"
                 /evidence="ECO:0000305"
 CONFLICT        436..438
                 /note="AHS -> EHL (in Ref. 1; BAA24500)"
                 /evidence="ECO:0000305"
 CONFLICT        453
                 /note="G -> D (in Ref. 1; BAA24500)"
                 /evidence="ECO:0000305"
 CONFLICT        456
                 /note="S -> W (in Ref. 1; BAA24500)"
                 /evidence="ECO:0000305"
 CONFLICT        468
                 /note="P -> L (in Ref. 1; BAA24500)"
                 /evidence="ECO:0000305"
 CONFLICT        662
                 /note="L -> F (in Ref. 2; AAD21531)"
                 /evidence="ECO:0000305"
 CONFLICT        704
                 /note="S -> F (in Ref. 1; BAA24500)"
                 /evidence="ECO:0000305"
 CONFLICT        714
                 /note="S -> F (in Ref. 1; BAA24500)"
                 /evidence="ECO:0000305"
 CONFLICT        848
                 /note="S -> T (in Ref. 1; BAA24500)"
                 /evidence="ECO:0000305"
 CONFLICT        872
                 /note="P -> R (in Ref. 2; AAD21531)"
                 /evidence="ECO:0000305"
 CONFLICT        875..878
                 /note="GRPE -> RRS (in Ref. 2; AAD21531)"
                 /evidence="ECO:0000305"
 CONFLICT        956
                 /note="S -> L (in Ref. 1; BAA24500)"
                 /evidence="ECO:0000305"
 CONFLICT        1252
                 /note="N -> K (in Ref. 1; BAA24500)"
                 /evidence="ECO:0000305"
 CONFLICT        1303
                 /note="G -> R (in Ref. 1; BAA24500)"
                 /evidence="ECO:0000305"
 CONFLICT        1314..1338
                 /note="LPPANTYASIDFLSHHLKEATIVKE -> PAPCPTTYAQH (in Ref. 1;
                 BAA24500)"
                 /evidence="ECO:0000305"
 SEQUENCE   1338 AA;  137334 MW;  58E569E8BDBAF3D7 CRC64;
 MASPPRHGPP GPASGDGPNL NNNNNNNNHS VRKCGYLRKQ KHGHKRFFVL RGPGAGGDEA
 TAGGGSAPQP PRLEYYESEK KWRSKAGAPK RVIALDCCLN INKRADAKHK YLIALYTKDE
 YFAVAAENEQ EQEGWYRALT DLVSEGRAAA GDAPPAAAPA ASCSASLPGA LGGSAGAAGA
 EDSYGLVAPA TAAYREVWQV NLKPKGLGQS KNLTGVYRLC LSARTIGFVK LNCEQPSVTL
 QLMNIRRCGH SDSFFFIEVG RSAVTGPGEL WMQADDSVVA QNIHETILEA MKALKELFEF
 RPRSKSQSSG SSATHPISVP GARRHHHLVN LPPSQTGLVR RSRTDSLAAT PPAAKCSSCR
 VRTASEGDGG AAAGAAAAGA RPVSVAGSPL SPGPVRAPLS RSHTLSGGCG GRGSKVALLP
 AGGALQHSRS MSMPVAHSPP AATSPGSLSS SSGHGSGSYP PPPGPHPPLP HPLHHGPGQR
 PSSGSASASG SPSDPGFMSL DEYGSSPGDL RAFCSHRSNT PESIAETPPA RDGGGGGEFY
 GYMTMDRPLS HCGRSYRRVS GDAAQDLDRG LRKRTYSLTT PARQRPVPQP SSASLDEYTL
 MRATFSGSAG RLCPSCPASS PKVAYHPYPE DYGDIEIGSH RSSSSNLGAD DGYMPMTPGA
 ALAGSGSGSC RSDDYMPMSP ASVSAPKQIL QPRAAAAAAA AVPSAGPAGP APTSAAGRTF
 PASGGGYKAS SPAESSPEDS GYMRMWCGSK LSMEHADGKL LPNGDYLNVS PSDAVTTGTP
 PDFFSAALHP GGEPLRGVPG CCYSSLPRSY KAPYTCGGDS DQYVLMSSPV GRILEEERLE
 PQATPGPSQA ASAFGAGPTQ PPHPVVPSPV RPSGGRPEGF LGQRGRAVRP TRLSLEGLPS
 LPSMHEYPLP PEPKSPGEYI NIDFGEPGAR LSPPAPPLLA SAASSSSLLS ASSPASSLGS
 GTPGTSSDSR QRSPLSDYMN LDFSSPKSPK PGAPSGHPVG SLDGLLSPEA SSPYPPLPPR
 PSASPSSSLQ PPPPPPAPGE LYRLPPASAV ATAQGPGAAS SLSSDTGDNG DYTEMAFGVA
 ATPPQPIAAP PKPEAARVAS PTSGVKRLSL MEQVSGVEAF LQASQPPDPH RGAKVIRADP
 QGGRRRHSSE TFSSTTTVTP VSPSFAHNPK RHNSASVENV SLRKSSEGGV GVGPGGGDEP
 PTSPRQLQPA PPLAPQGRPW TPGQPGGLVG CPGSGGSPMR RETSAGFQNG LNYIAIDVRE
 EPGLPPQPQP PPPPLPQPGD KSSWGRTRSL GGLISAVGVG STGGGCGGPG PGALPPANTY
 ASIDFLSHHL KEATIVKE

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