ID IRS1_HUMAN Reviewed; 1242 AA. AC P35568; DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot. DT 01-JUN-1994, sequence version 1. DT 07-APR-2021, entry version 223. DE RecName: Full=Insulin receptor substrate 1; DE Short=IRS-1; GN Name=IRS1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Skeletal muscle; RX PubMed=8513971; DOI=10.2337/diab.42.7.1041; RA Araki E., Sun X.J., Haag B.L. III, Chuang L.M., Zhang Y., Yang-Feng T.L., RA White M.F., Kahn C.R.; RT "Human skeletal muscle insulin receptor substrate-1. Characterization of RT the cDNA, gene, and chromosomal localization."; RL Diabetes 42:1041-1054(1993). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=1311924; DOI=10.1016/0006-291x(92)91640-c; RA Nishiyama M., Wands J.R.; RT "Cloning and increased expression of an insulin receptor substrate-1-like RT gene in human hepatocellular carcinoma."; RL Biochem. Biophys. Res. Commun. 183:280-285(1992). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Eye; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [4] RP TURNOVER. RX PubMed=8240352; DOI=10.1006/bbrc.1993.2315; RA Smith L.K., Bradshaw M., Croall D.E., Garner C.W.; RT "The insulin receptor substrate (IRS-1) is a PEST protein that is RT susceptible to calpain degradation in vitro."; RL Biochem. Biophys. Res. Commun. 196:767-772(1993). RN [5] RP INTERACTION WITH IGF1R. RX PubMed=7541045; DOI=10.1074/jbc.270.26.15639; RA Craparo A., O'Neill T.J., Gustafson T.A.; RT "Non-SH2 domains within insulin receptor substrate-1 and SHC mediate their RT phosphotyrosine-dependent interaction with the NPEY motif of the insulin- RT like growth factor I receptor."; RL J. Biol. Chem. 270:15639-15643(1995). RN [6] RP INTERACTION WITH INSR. RX PubMed=7559478; DOI=10.1074/jbc.270.40.23258; RA He W., O'Neill T.J., Gustafson T.A.; RT "Distinct modes of interaction of SHC and insulin receptor substrate-1 with RT the insulin receptor NPEY region via non-SH2 domains."; RL J. Biol. Chem. 270:23258-23262(1995). RN [7] RP INTERACTION WITH INSR. RX PubMed=7537849; DOI=10.1128/mcb.15.5.2500; RA Gustafson T.A., He W., Craparo A., Schaub C.D., O'Neill T.J.; RT "Phosphotyrosine-dependent interaction of SHC and insulin receptor RT substrate 1 with the NPEY motif of the insulin receptor via a novel non-SH2 RT domain."; RL Mol. Cell. Biol. 15:2500-2508(1995). RN [8] RP MUTAGENESIS OF SER-794, AND PHOSPHORYLATION AT SER-794. RX PubMed=12624099; DOI=10.1074/jbc.m211770200; RA Horike N., Takemori H., Katoh Y., Doi J., Min L., Asano T., Sun X.J., RA Yamamoto H., Kasayama S., Muraoka M., Nonaka Y., Okamoto M.; RT "Adipose-specific expression, phosphorylation of Ser794 in insulin receptor RT substrate-1, and activation in diabetic animals of salt-inducible kinase- RT 2."; RL J. Biol. Chem. 278:18440-18447(2003). RN [9] RP PHOSPHORYLATION AT SER-1101. RX PubMed=15364919; DOI=10.1074/jbc.c400186200; RA Li Y., Soos T.J., Li X., Wu J., Degennaro M., Sun X., Littman D.R., RA Birnbaum M.J., Polakiewicz R.D.; RT "Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 RT at Ser(1101)."; RL J. Biol. Chem. 279:45304-45307(2004). RN [10] RP PHOSPHORYLATION BY ALK, AND INTERACTION WITH ALK. RX PubMed=15226403; DOI=10.1242/jcs.01183; RA Motegi A., Fujimoto J., Kotani M., Sakuraba H., Yamamoto T.; RT "ALK receptor tyrosine kinase promotes cell growth and neurite outgrowth."; RL J. Cell Sci. 117:3319-3329(2004). RN [11] RP INTERACTION WITH SOCS7. RX PubMed=16127460; DOI=10.1172/jci23853; RA Banks A.S., Li J., McKeag L., Hribal M.L., Kashiwada M., Accili D., RA Rothman P.B.; RT "Deletion of SOCS7 leads to enhanced insulin action and enlarged islets of RT Langerhans."; RL J. Clin. Invest. 115:2462-2471(2005). RN [12] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-662, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=15592455; DOI=10.1038/nbt1046; RA Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H., RA Zha X.-M., Polakiewicz R.D., Comb M.J.; RT "Immunoaffinity profiling of tyrosine phosphorylation in cancer cells."; RL Nat. Biotechnol. 23:94-101(2005). RN [13] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-629 AND SER-636, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026; RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.; RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling RT networks."; RL Cell 127:635-648(2006). RN [14] RP INTERACTION WITH ALK, AND FUNCTION. RX PubMed=16878150; DOI=10.1038/sj.onc.1209840; RA Kuo A.H., Stoica G.E., Riegel A.T., Wellstein A.; RT "Recruitment of insulin receptor substrate-1 and activation of NF-kappaB RT essential for midkine growth signaling through anaplastic lymphoma RT kinase."; RL Oncogene 26:859-869(2007). RN [15] RP PHOSPHORYLATION AT SER-270; SER-307; SER-636 AND SER-1101. RX PubMed=18952604; DOI=10.1074/jbc.m806480200; RA Zhang J., Gao Z., Yin J., Quon M.J., Ye J.; RT "S6K directly phosphorylates IRS-1 on Ser-270 to promote insulin resistance RT in response to TNF-(alpha) signaling through IKK2."; RL J. Biol. Chem. 283:35375-35382(2008). RN [16] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18220336; DOI=10.1021/pr0705441; RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., Yates J.R. III; RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient RT phosphoproteomic analysis."; RL J. Proteome Res. 7:1346-1351(2008). RN [17] RP UBIQUITINATION, PHOSPHORYLATION AT SER-307; SER-312; SER-527 AND SER-636, RP AND MUTAGENESIS OF SER-307; SER-312; SER-527; SER-636 AND SER-639. RX PubMed=18498745; DOI=10.1016/j.molcel.2008.03.009; RA Xu X., Sarikas A., Dias-Santagata D.C., Dolios G., Lafontant P.J., RA Tsai S.C., Zhu W., Nakajima H., Nakajima H.O., Field L.J., Wang R., RA Pan Z.Q.; RT "The CUL7 E3 ubiquitin ligase targets insulin receptor substrate 1 for RT ubiquitin-dependent degradation."; RL Mol. Cell 30:403-414(2008). RN [18] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200; RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., RA Mann M., Daub H.; RT "Large-scale proteomics analysis of the human kinome."; RL Mol. Cell. Proteomics 8:1751-1764(2009). RN [19] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-348, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [20] RP PHOSPHORYLATION AT SER-312 AND TYR-941. RX PubMed=20685959; DOI=10.1091/mbc.e10-06-0481; RA Yang X., Nath A., Opperman M.J., Chan C.; RT "The double-stranded RNA-dependent protein kinase differentially regulates RT insulin receptor substrates 1 and 2 in HepG2 cells."; RL Mol. Biol. Cell 21:3449-3458(2010). RN [21] RP PHOSPHORYLATION AT TYR-612; TYR-632 AND TYR-896, AND MUTAGENESIS OF TYR-612 RP AND TYR-632. RX PubMed=23401856; DOI=10.1128/mcb.01447-12; RA Koh A., Lee M.N., Yang Y.R., Jeong H., Ghim J., Noh J., Kim J., Ryu D., RA Park S., Song P., Koo S.H., Leslie N.R., Berggren P.O., Choi J.H., RA Suh P.G., Ryu S.H.; RT "C1-Ten is a protein tyrosine phosphatase of insulin receptor substrate 1 RT (IRS-1), regulating IRS-1 stability and muscle atrophy."; RL Mol. Cell. Biol. 33:1608-1620(2013). RN [22] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-323; THR-453; SER-527 AND RP SER-629, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [23] RP STRUCTURE BY NMR OF 157-267. RX PubMed=8599766; DOI=10.1038/nsb0496-388; RA Zhou M.-M., Huang B., Olejniczak E.T., Meadows R.P., Shuker S.B., RA Miyazaki M., Trueb T., Shoelson S.E., Fesik S.W.; RT "Structural basis for IL-4 receptor phosphopeptide recognition by the IRS-1 RT PTB domain."; RL Nat. Struct. Biol. 3:388-393(1996). RN [24] RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 4-267. RX PubMed=10411883; DOI=10.1073/pnas.96.15.8378; RA Dhe-Paganon S., Ottinger E.A., Nolte R.T., Eck M.J., Shoelson S.E.; RT "Crystal structure of the pleckstrin homology-phosphotyrosine binding (PH- RT PTB) targeting region of insulin receptor substrate 1."; RL Proc. Natl. Acad. Sci. U.S.A. 96:8378-8383(1999). RN [25] RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 889-902 IN COMPLEX WITH IGF1R. RX PubMed=11694888; DOI=10.1038/nsb721; RA Favelyukis S., Till J.H., Hubbard S.R., Miller W.T.; RT "Structure and autoregulation of the insulin-like growth factor 1 receptor RT kinase."; RL Nat. Struct. Biol. 8:1058-1063(2001). RN [26] RP VARIANTS PRO-512 AND ARG-971. RX PubMed=8104271; DOI=10.1016/0140-6736(93)92694-o; RA Almind K., Bjoerbaek C., Vestergaard H., Hansen T., Echwald S., RA Pedersen O.; RT "Aminoacid polymorphisms of insulin receptor substrate-1 in non-insulin- RT dependent diabetes mellitus."; RL Lancet 342:828-832(1993). RN [27] RP VARIANT NIDDM GLY-723 DEL. RX PubMed=8723689; RX DOI=10.1002/(sici)1098-1004(1996)7:4<364::aid-humu13>3.0.co;2-0; RA Esposito D.L., Mammarella S., Ranieri A., della Loggia F., Capani F., RA Consoli A., Mariani-Costantini R., Caramia F.G., Cama A., Battista P.; RT "Deletion of Gly723 in the insulin receptor substrate-1 of a patient with RT noninsulin-dependent diabetes mellitus."; RL Hum. Mutat. 7:364-366(1996). RN [28] RP VARIANTS NIDDM TYR-1043 AND TYR-1095. RX PubMed=10206679; RX DOI=10.1002/(sici)1098-1004(1998)11:5<411::aid-humu12>3.0.co;2-#; RA Mammarella S., Creati B., Esposito D.L., Arcuri P., della Loggia F., RA Capani F., Mariani-Costantini R., Caramia F.G., Battista P., Cama A.; RT "Novel allele of the insulin receptor substrate-1 bearing two non- RT conservative amino acid substitutions in a patient with noninsulin- RT dependent diabetes mellitus."; RL Hum. Mutat. 11:411-411(1998). RN [29] RP CHARACTERIZATION OF VARIANT ARG-971. RX PubMed=10843189; DOI=10.1210/jcem.85.5.6608; RA Hribal M.L., Federici M., Porzio O., Lauro D., Borboni P., Accili D., RA Lauro R., Sesti G.; RT "The Gly-->Arg(972) amino acid polymorphism in insulin receptor substrate-1 RT affects glucose metabolism in skeletal muscle cells."; RL J. Clin. Endocrinol. Metab. 85:2004-2013(2000). RN [30] RP ASSOCIATION OF VARIANT ARG-971 WITH NIDDM. RX PubMed=12843189; DOI=10.1210/jc.2002-021716; RA Marini M.A., Frontoni S., Mineo D., Bracaglia D., Cardellini M., RA De Nicolais P., Baroni A., D'Alfonso R., Perna M., Lauro D., Federici M., RA Gambardella S., Lauro R., Sesti G.; RT "The Arg(972) variant in insulin receptor substrate-1 is associated with an RT atherogenic profile in offspring of type 2 diabetic patients."; RL J. Clin. Endocrinol. Metab. 88:3368-3371(2003). RN [31] RP VARIANT ARG-971. RX PubMed=14671192; DOI=10.1210/jc.2003-030453; RA Abate N., Carulli L., Cabo-Chan A. Jr., Chandalia M., Snell P.G., RA Grundy S.M.; RT "Genetic polymorphism PC-1 K121Q and ethnic susceptibility to insulin RT resistance."; RL J. Clin. Endocrinol. Metab. 88:5927-5934(2003). RN [32] RP VARIANT ARG-608, AND CHARACTERIZATION OF VARIANT ARG-608. RX PubMed=12679424; DOI=10.1210/jc.2002-020933; RA Esposito D.L., Li Y., Vanni C., Mammarella S., Veschi S., Della Loggia F., RA Mariani-Costantini R., Battista P., Quon M.J., Cama A.; RT "A novel T608R missense mutation in insulin receptor substrate-1 identified RT in a subject with type 2 diabetes impairs metabolic insulin signaling."; RL J. Clin. Endocrinol. Metab. 88:1468-1475(2003). RN [33] RP VARIANT ARG-971, ASSOCIATION WITH ENDOTHELIAL DYSFUNCTION, AND RP CARDIOVASCULAR DISEASE. RX PubMed=14707024; DOI=10.1161/01.cir.0000109498.77895.6f; RA Federici M., Pandolfi A., De Filippis E.A., Pellegrini G., Menghini R., RA Lauro D., Cardellini M., Romano M., Sesti G., Lauro R., Consoli A.; RT "G972R IRS-1 variant impairs insulin regulation of endothelial nitric oxide RT synthase in cultured human endothelial cells."; RL Circulation 109:399-405(2004). RN [34] RP VARIANT ARG-971, AND MOLECULAR MECHANISM OF LINKAGE TO NIDDM. RX PubMed=15590636; DOI=10.1074/jbc.m412300200; RA McGettrick A.J., Feener E.P., Kahn C.R.; RT "Human insulin receptor substrate-1 (IRS-1) polymorphism G972R causes IRS-1 RT to associate with the insulin receptor and inhibit receptor RT autophosphorylation."; RL J. Biol. Chem. 280:6441-6446(2005). CC -!- FUNCTION: May mediate the control of various cellular processes by CC insulin. When phosphorylated by the insulin receptor binds specifically CC to various cellular proteins containing SH2 domains such as CC phosphatidylinositol 3-kinase p85 subunit or GRB2. Activates CC phosphatidylinositol 3-kinase when bound to the regulatory p85 subunit CC (By similarity). {ECO:0000250, ECO:0000269|PubMed:16878150}. CC -!- SUBUNIT: Interacts with UBTF and PIK3CA (By similarity). Interacts (via CC phosphorylated YXXM motifs) with PIK3R1 (By similarity). Interacts with CC ROCK1 and FER (By similarity). Interacts (via PH domain) with PHIP (By CC similarity). Interacts with GRB2 (By similarity). Interacts with SOCS7 CC (PubMed:16127460). Interacts (via IRS-type PTB domain) with IGF1R and CC INSR (via the tyrosine-phosphorylated NPXY motif) (PubMed:7541045, CC PubMed:7559478, PubMed:7537849). Interacts with ALK (PubMed:15226403, CC PubMed:16878150). Interacts with EIF2AK2/PKR (By similarity). Interacts CC with GKAP1 (By similarity). Interacts with DGKZ in the absence of CC insulin; insulin stimulation decreases this interaction (By CC similarity). Found in a ternary complex with DGKZ and PIP5K1A in the CC absence of insulin stimulation (By similarity). CC {ECO:0000250|UniProtKB:P35569, ECO:0000250|UniProtKB:P35570, CC ECO:0000269|PubMed:15226403, ECO:0000269|PubMed:16127460, CC ECO:0000269|PubMed:16878150, ECO:0000269|PubMed:7537849, CC ECO:0000269|PubMed:7541045, ECO:0000269|PubMed:7559478}. CC -!- INTERACTION: CC P35568; O75815: BCAR3; NbExp=3; IntAct=EBI-517592, EBI-702336; CC P35568; P04626: ERBB2; NbExp=2; IntAct=EBI-517592, EBI-641062; CC P35568; P06213: INSR; NbExp=3; IntAct=EBI-517592, EBI-475899; CC P35568; P11940: PABPC1; NbExp=2; IntAct=EBI-517592, EBI-81531; CC P35568; P42336: PIK3CA; NbExp=20; IntAct=EBI-517592, EBI-2116585; CC P35568; P27986: PIK3R1; NbExp=12; IntAct=EBI-517592, EBI-79464; CC P35568; P27986-2: PIK3R1; NbExp=3; IntAct=EBI-517592, EBI-9090282; CC P35568; Q92569: PIK3R3; NbExp=4; IntAct=EBI-517592, EBI-79893; CC P35568; Q06124: PTPN11; NbExp=3; IntAct=EBI-517592, EBI-297779; CC P35568; P03495: NS; Xeno; NbExp=2; IntAct=EBI-517592, EBI-2548993; CC P35568; P03070; Xeno; NbExp=2; IntAct=EBI-517592, EBI-617698; CC -!- PTM: Serine phosphorylation of IRS1 is a mechanism for insulin CC resistance. Ser-312 phosphorylation inhibits insulin action through CC disruption of IRS1 interaction with the insulin receptor (By CC similarity). Phosphorylation of Tyr-896 is required for GRB2-binding CC (By similarity). Phosphorylated by ALK. Phosphorylated at Ser-270, Ser- CC 307, Ser-636 and Ser-1101 by RPS6KB1; phosphorylation induces CC accelerated degradation of IRS1 (PubMed:18952604). Phosphorylated on CC tyrosine residues in response to insulin (PubMed:23401856). In skeletal CC muscles, dephosphorylated on Tyr-612 by TNS2 under anabolic conditions; CC dephosphorylation results in the proteasomal degradation of IRS1 CC (PubMed:23401856). {ECO:0000250|UniProtKB:P35569, CC ECO:0000250|UniProtKB:P35570, ECO:0000269|PubMed:15364919, CC ECO:0000269|PubMed:18498745, ECO:0000269|PubMed:18952604, CC ECO:0000269|PubMed:20685959, ECO:0000269|PubMed:23401856}. CC -!- PTM: Ubiquitinated by the Cul7-RING(FBXW8) complex in a mTOR-dependent CC manner, leading to its degradation: the Cul7-RING(FBXW8) complex CC recognizes and binds IRS1 previously phosphorylated by S6 kinase CC (RPS6KB1 or RPS6KB2). {ECO:0000269|PubMed:18498745}. CC -!- POLYMORPHISM: The Arg-971 polymorphism impairs the ability of insulin CC to stimulate glucose transport, glucose transporter translocation, and CC glycogen synthesis by affecting the PI3K/AKT1/GSK3 signaling pathway. CC The polymorphism at Arg-971 may contribute to the in vivo insulin CC resistance observed in carriers of this variant. Arg-971 could CC contribute to the risk for atherosclerotic cardiovascular diseases CC associated with non-insulin-dependent diabetes mellitus (NIDDM) by CC producing a cluster of insulin resistance-related metabolic CC abnormalities. In insulin-stimulated human endothelial cells from CC carriers of the Arg-971 polymorphism, genetic impairment of the CC IRS1/PI3K/PDPK1/AKT1 insulin signaling cascade results in impaired CC insulin-stimulated nitric oxide (NO) release and suggested that this CC may be a mechanism through which the Arg-971 polymorphism contributes CC to the genetic predisposition to develop endothelial dysfunction and CC cardiovascular disease. The Arg-971 polymorphism not only reduces CC phosphorylation of the substrate but allows IRS1 to act as an inhibitor CC of PI3K, producing global insulin resistance. CC -!- DISEASE: Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: CC A multifactorial disorder of glucose homeostasis caused by a lack of CC sensitivity to the body's own insulin. Affected individuals usually CC have an obese body habitus and manifestations of a metabolic syndrome CC characterized by diabetes, insulin resistance, hypertension and CC hypertriglyceridemia. The disease results in long-term complications CC that affect the eyes, kidneys, nerves, and blood vessels. CC {ECO:0000269|PubMed:10206679, ECO:0000269|PubMed:12843189, CC ECO:0000269|PubMed:8723689}. Note=The gene represented in this entry CC may be involved in disease pathogenesis. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; S85963; AAB21608.1; -; Genomic_DNA. DR EMBL; S62539; AAB27175.1; -; mRNA. DR EMBL; BC053895; AAH53895.1; -; mRNA. DR CCDS; CCDS2463.1; -. DR PIR; I53160; JS0670. DR RefSeq; NP_005535.1; NM_005544.2. DR PDB; 1IRS; NMR; -; A=157-267. DR PDB; 1K3A; X-ray; 2.10 A; B=891-902. DR PDB; 1QQG; X-ray; 2.30 A; A/B=4-267. DR PDB; 2Z8C; X-ray; 3.25 A; B=731-736. DR PDB; 5U1M; X-ray; 1.80 A; A=161-265. DR PDB; 6BNT; X-ray; 3.20 A; B=607-620. DR PDBsum; 1IRS; -. DR PDBsum; 1K3A; -. DR PDBsum; 1QQG; -. DR PDBsum; 2Z8C; -. DR PDBsum; 5U1M; -. DR PDBsum; 6BNT; -. DR BMRB; P35568; -. DR SMR; P35568; -. DR BioGRID; 109874; 98. DR CORUM; P35568; -. DR DIP; DIP-523N; -. DR ELM; P35568; -. DR IntAct; P35568; 33. DR MINT; P35568; -. DR STRING; 9606.ENSP00000304895; -. DR DrugBank; DB08513; [4-({5-(AMINOCARBONYL)-4-[(3-METHYLPHENYL)AMINO]PYRIMIDIN-2-YL}AMINO)PHENYL]ACETIC ACID. DR iPTMnet; P35568; -. DR PhosphoSitePlus; P35568; -. DR BioMuta; IRS1; -. DR DMDM; 547738; -. DR EPD; P35568; -. DR jPOST; P35568; -. DR MassIVE; P35568; -. DR MaxQB; P35568; -. DR PaxDb; P35568; -. DR PeptideAtlas; P35568; -. DR PRIDE; P35568; -. DR ProteomicsDB; 55088; -. DR Antibodypedia; 3935; 2508 antibodies. DR DNASU; 3667; -. DR Ensembl; ENST00000305123; ENSP00000304895; ENSG00000169047. DR GeneID; 3667; -. DR KEGG; hsa:3667; -. DR UCSC; uc002voh.5; human. DR CTD; 3667; -. DR DisGeNET; 3667; -. DR GeneCards; IRS1; -. DR HGNC; HGNC:6125; IRS1. DR HPA; ENSG00000169047; Low tissue specificity. DR MalaCards; IRS1; -. DR MIM; 125853; phenotype. DR MIM; 147545; gene. DR neXtProt; NX_P35568; -. DR OpenTargets; ENSG00000169047; -. DR PharmGKB; PA203; -. DR VEuPathDB; HostDB:ENSG00000169047.5; -. DR eggNOG; ENOG502QUNU; Eukaryota. DR GeneTree; ENSGT00940000161579; -. DR HOGENOM; CLU_004902_2_0_1; -. DR InParanoid; P35568; -. DR OMA; YGKLWTN; -. DR OrthoDB; 298675at2759; -. DR PhylomeDB; P35568; -. DR TreeFam; TF325994; -. DR PathwayCommons; P35568; -. DR Reactome; R-HSA-109704; PI3K Cascade. DR Reactome; R-HSA-112399; IRS-mediated signalling. DR Reactome; R-HSA-112412; SOS-mediated signalling. DR Reactome; R-HSA-1257604; PIP3 activates AKT signaling. DR Reactome; R-HSA-1266695; Interleukin-7 signaling. DR Reactome; R-HSA-198203; PI3K/AKT activation. DR Reactome; R-HSA-2219530; Constitutive Signaling by Aberrant PI3K in Cancer. DR Reactome; R-HSA-2428928; IRS-related events triggered by IGF1R. DR Reactome; R-HSA-2586552; Signaling by Leptin. DR Reactome; R-HSA-5673001; RAF/MAP kinase cascade. DR Reactome; R-HSA-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling. DR Reactome; R-HSA-74713; IRS activation. DR Reactome; R-HSA-74749; Signal attenuation. DR Reactome; R-HSA-9603381; Activated NTRK3 signals through PI3K. DR Reactome; R-HSA-982772; Growth hormone receptor signaling. DR SignaLink; P35568; -. DR SIGNOR; P35568; -. DR BioGRID-ORCS; 3667; 30 hits in 994 CRISPR screens. DR ChiTaRS; IRS1; human. DR EvolutionaryTrace; P35568; -. DR GeneWiki; IRS1; -. DR GenomeRNAi; 3667; -. DR Pharos; P35568; Tbio. DR PRO; PR:P35568; -. DR Proteomes; UP000005640; Chromosome 2. DR RNAct; P35568; protein. DR Bgee; ENSG00000169047; Expressed in endometrium and 248 other tissues. DR ExpressionAtlas; P35568; baseline and differential. DR Genevisible; P35568; HS. DR GO; GO:0005901; C:caveola; IDA:BHF-UCL. DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005899; C:insulin receptor complex; ISS:BHF-UCL. DR GO; GO:0043231; C:intracellular membrane-bounded organelle; ISS:UniProtKB. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; ISS:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IDA:HPA. DR GO; GO:0005158; F:insulin receptor binding; IPI:UniProtKB. DR GO; GO:0005159; F:insulin-like growth factor receptor binding; IPI:UniProtKB. DR GO; GO:0043548; F:phosphatidylinositol 3-kinase binding; IPI:UniProtKB. DR GO; GO:0001784; F:phosphotyrosine residue binding; IPI:CAFA. DR GO; GO:0005080; F:protein kinase C binding; ISS:BHF-UCL. DR GO; GO:0042169; F:SH2 domain binding; ISS:UniProtKB. DR GO; GO:0030159; F:signaling receptor complex adaptor activity; IDA:BHF-UCL. DR GO; GO:0005068; F:transmembrane receptor protein tyrosine kinase adaptor activity; ISS:BHF-UCL. DR GO; GO:0071398; P:cellular response to fatty acid; ISS:ARUK-UCL. DR GO; GO:0032869; P:cellular response to insulin stimulus; IMP:BHF-UCL. DR GO; GO:0042593; P:glucose homeostasis; TAS:BHF-UCL. DR GO; GO:0008286; P:insulin receptor signaling pathway; IDA:UniProtKB. DR GO; GO:0048009; P:insulin-like growth factor receptor signaling pathway; IPI:UniProtKB. DR GO; GO:0038111; P:interleukin-7-mediated signaling pathway; TAS:Reactome. DR GO; GO:0000165; P:MAPK cascade; TAS:Reactome. DR GO; GO:0046627; P:negative regulation of insulin receptor signaling pathway; ISS:BHF-UCL. DR GO; GO:0046676; P:negative regulation of insulin secretion; IDA:BHF-UCL. DR GO; GO:0014065; P:phosphatidylinositol 3-kinase signaling; IDA:BHF-UCL. DR GO; GO:0048015; P:phosphatidylinositol-mediated signaling; TAS:Reactome. DR GO; GO:0008284; P:positive regulation of cell population proliferation; NAS:BHF-UCL. DR GO; GO:0032000; P:positive regulation of fatty acid beta-oxidation; IMP:BHF-UCL. DR GO; GO:0046326; P:positive regulation of glucose import; IDA:BHF-UCL. DR GO; GO:0010907; P:positive regulation of glucose metabolic process; IMP:BHF-UCL. DR GO; GO:0045725; P:positive regulation of glycogen biosynthetic process; IMP:BHF-UCL. DR GO; GO:0046628; P:positive regulation of insulin receptor signaling pathway; IDA:BHF-UCL. DR GO; GO:0043552; P:positive regulation of phosphatidylinositol 3-kinase activity; ISS:BHF-UCL. DR GO; GO:0051897; P:positive regulation of protein kinase B signaling; TAS:Reactome. DR GO; GO:0032868; P:response to insulin; IDA:BHF-UCL. DR GO; GO:0043434; P:response to peptide hormone; ISS:BHF-UCL. DR GO; GO:0007165; P:signal transduction; TAS:ProtInc. DR CDD; cd01204; PTB_IRS; 1. DR Gene3D; 2.30.29.30; -; 2. DR IDEAL; IID00657; -. DR InterPro; IPR039011; IRS. DR InterPro; IPR002404; IRS_PTB. DR InterPro; IPR011993; PH-like_dom_sf. DR InterPro; IPR001849; PH_domain. DR PANTHER; PTHR10614; PTHR10614; 1. DR Pfam; PF02174; IRS; 1. DR Pfam; PF00169; PH; 1. DR PRINTS; PR00628; INSULINRSI. DR SMART; SM00233; PH; 1. DR SMART; SM00310; PTBI; 1. DR PROSITE; PS51064; IRS_PTB; 1. DR PROSITE; PS50003; PH_DOMAIN; 1. PE 1: Evidence at protein level; KW 3D-structure; Diabetes mellitus; Disease variant; Phosphoprotein; KW Reference proteome; Repeat; Transducer; Ubl conjugation. FT CHAIN 1..1242 FT /note="Insulin receptor substrate 1" FT /id="PRO_0000084236" FT DOMAIN 12..115 FT /note="PH" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00145" FT DOMAIN 160..264 FT /note="IRS-type PTB" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00389" FT REGION 3..137 FT /note="Mediates interaction with PHIP" FT /evidence="ECO:0000250" FT REGION 896..898 FT /note="GRB2-binding" FT /evidence="ECO:0000250" FT MOTIF 465..468 FT /note="YXXM motif 1" FT MOTIF 551..554 FT /note="YXXM motif 2" FT MOTIF 612..615 FT /note="YXXM motif 3" FT MOTIF 632..635 FT /note="YXXM motif 4" FT MOTIF 662..665 FT /note="YXXM motif 5" FT MOTIF 732..735 FT /note="YXXM motif 6" FT MOTIF 941..944 FT /note="YXXM motif 7" FT MOTIF 989..992 FT /note="YXXM motif 8" FT MOTIF 1012..1015 FT /note="YXXM motif 9" FT COMPBIAS 128..134 FT /note="Poly-Gly" FT COMPBIAS 268..444 FT /note="Ser-rich" FT COMPBIAS 680..686 FT /note="Poly-Ser" FT COMPBIAS 807..815 FT /note="Poly-Ser" FT COMPBIAS 877..882 FT /note="Poly-Gln" FT COMPBIAS 1192..1210 FT /note="Pro-rich" FT MOD_RES 3 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P35570" FT MOD_RES 99 FT /note="Phosphoserine; by CK2" FT /evidence="ECO:0000250|UniProtKB:P35570" FT MOD_RES 270 FT /note="Phosphoserine; by RPS6KB1" FT /evidence="ECO:0000269|PubMed:18952604" FT MOD_RES 307 FT /note="Phosphoserine; by RPS6KB1" FT /evidence="ECO:0000269|PubMed:18498745, FT ECO:0000269|PubMed:18952604" FT MOD_RES 312 FT /note="Phosphoserine; by IKKB, MAPK8 and RPS6KB1" FT /evidence="ECO:0000269|PubMed:18498745, FT ECO:0000269|PubMed:20685959" FT MOD_RES 323 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 330 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P35569" FT MOD_RES 345 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P35569" FT MOD_RES 348 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19690332" FT MOD_RES 419 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P35569" FT MOD_RES 446 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:P35570" FT MOD_RES 453 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 465 FT /note="Phosphotyrosine; by INSR" FT /evidence="ECO:0000250|UniProtKB:P35570" FT MOD_RES 527 FT /note="Phosphoserine; by RPS6KB1" FT /evidence="ECO:0000269|PubMed:18498745, FT ECO:0007744|PubMed:24275569" FT MOD_RES 612 FT /note="Phosphotyrosine; by INSR" FT /evidence="ECO:0000269|PubMed:23401856" FT MOD_RES 629 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:17081983, FT ECO:0007744|PubMed:24275569" FT MOD_RES 632 FT /note="Phosphotyrosine; by INSR" FT /evidence="ECO:0000269|PubMed:23401856" FT MOD_RES 636 FT /note="Phosphoserine; by RPS6KB1" FT /evidence="ECO:0000269|PubMed:18498745, FT ECO:0000269|PubMed:18952604, ECO:0007744|PubMed:17081983" FT MOD_RES 662 FT /note="Phosphotyrosine" FT /evidence="ECO:0007744|PubMed:15592455" FT MOD_RES 794 FT /note="Phosphoserine; by AMPK and SIK2" FT /evidence="ECO:0000269|PubMed:12624099" FT MOD_RES 892 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P35569" FT MOD_RES 896 FT /note="Phosphotyrosine; by INSR" FT /evidence="ECO:0000269|PubMed:23401856" FT MOD_RES 941 FT /note="Phosphotyrosine; by INSR" FT /evidence="ECO:0000269|PubMed:20685959" FT MOD_RES 989 FT /note="Phosphotyrosine; by INSR" FT /evidence="ECO:0000250|UniProtKB:P35570" FT MOD_RES 1100 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P35569" FT MOD_RES 1101 FT /note="Phosphoserine; by RPS6KB1 and PKC/PRKCQ" FT /evidence="ECO:0000269|PubMed:15364919, FT ECO:0000269|PubMed:18952604" FT MOD_RES 1179 FT /note="Phosphotyrosine; by INSR" FT /evidence="ECO:0000250|UniProtKB:P35570" FT MOD_RES 1229 FT /note="Phosphotyrosine; by INSR" FT /evidence="ECO:0000250|UniProtKB:P35570" FT VARIANT 158 FT /note="P -> R (in dbSNP:rs1801108)" FT /id="VAR_014853" FT VARIANT 209 FT /note="M -> T (in dbSNP:rs1801118)" FT /id="VAR_014854" FT VARIANT 512 FT /note="A -> P (in dbSNP:rs1801276)" FT /evidence="ECO:0000269|PubMed:8104271" FT /id="VAR_005299" FT VARIANT 608 FT /note="T -> R (may contribute to insulin resistance by FT impairing metabolic signaling through PI3K-dependent FT pathways; dbSNP:rs104893642)" FT /evidence="ECO:0000269|PubMed:12679424" FT /id="VAR_025320" FT VARIANT 723 FT /note="Missing (in NIDDM; dbSNP:rs1259467443)" FT /evidence="ECO:0000269|PubMed:8723689" FT /id="VAR_005301" FT VARIANT 809 FT /note="S -> F (in dbSNP:rs1801120)" FT /id="VAR_014855" FT VARIANT 892 FT /note="S -> G (in dbSNP:rs1801277)" FT /id="VAR_014856" FT VARIANT 971 FT /note="G -> R (in dbSNP:rs1801278)" FT /evidence="ECO:0000269|PubMed:10843189, FT ECO:0000269|PubMed:14671192, ECO:0000269|PubMed:14707024, FT ECO:0000269|PubMed:15590636, ECO:0000269|PubMed:8104271" FT /id="VAR_005300" FT VARIANT 1043 FT /note="S -> Y (in NIDDM)" FT /evidence="ECO:0000269|PubMed:10206679" FT /id="VAR_005302" FT VARIANT 1095 FT /note="C -> Y (in NIDDM)" FT /evidence="ECO:0000269|PubMed:10206679" FT /id="VAR_005303" FT VARIANT 1137 FT /note="D -> N (in dbSNP:rs3731594)" FT /id="VAR_021837" FT MUTAGEN 307 FT /note="S->A: Impaired degradation by the Cul7-RING(FBXW8) FT complex; when associated with A-312; A-527; A-636 and A- FT 639." FT /evidence="ECO:0000269|PubMed:18498745" FT MUTAGEN 312 FT /note="S->A: Impaired degradation by the Cul7-RING(FBXW8) FT complex; when associated with A-307; A-527; A-636 and A- FT 639." FT /evidence="ECO:0000269|PubMed:18498745" FT MUTAGEN 527 FT /note="S->A: Impaired degradation by the Cul7-RING(FBXW8) FT complex; when associated with A-307; A-312; A-636 and A- FT 639." FT /evidence="ECO:0000269|PubMed:18498745" FT MUTAGEN 612 FT /note="Y->F: Induces IRS1 degradation." FT /evidence="ECO:0000269|PubMed:23401856" FT MUTAGEN 632 FT /note="Y->F: Does not affect IRS1 stability." FT /evidence="ECO:0000269|PubMed:23401856" FT MUTAGEN 636 FT /note="S->A: Impaired degradation by the Cul7-RING(FBXW8) FT complex; when associated with A-307; A-312; A-527 and A- FT 639." FT /evidence="ECO:0000269|PubMed:18498745" FT MUTAGEN 639 FT /note="S->A: Impaired degradation by the Cul7-RING(FBXW8) FT complex; when associated with A-307; A-312; A-527 and A- FT 636." FT /evidence="ECO:0000269|PubMed:18498745" FT MUTAGEN 794 FT /note="S->A: Loss of phosphorylation by SIK2." FT /evidence="ECO:0000269|PubMed:12624099" FT CONFLICT 134 FT /note="G -> GG (in Ref. 2; AAB21608)" FT /evidence="ECO:0000305" FT CONFLICT 362 FT /note="S -> R (in Ref. 2; AAB21608)" FT /evidence="ECO:0000305" FT CONFLICT 384 FT /note="P -> R (in Ref. 2; AAB21608)" FT /evidence="ECO:0000305" FT STRAND 13..20 FT /evidence="ECO:0007744|PDB:1QQG" FT TURN 22..24 FT /evidence="ECO:0007744|PDB:1QQG" FT STRAND 27..33 FT /evidence="ECO:0007744|PDB:1QQG" FT TURN 37..39 FT /evidence="ECO:0007744|PDB:1QQG" FT STRAND 40..49 FT /evidence="ECO:0007744|PDB:1QQG" FT HELIX 50..54 FT /evidence="ECO:0007744|PDB:1QQG" FT STRAND 61..65 FT /evidence="ECO:0007744|PDB:1QQG" FT HELIX 66..68 FT /evidence="ECO:0007744|PDB:1QQG" FT STRAND 69..75 FT /evidence="ECO:0007744|PDB:1QQG" FT STRAND 81..90 FT /evidence="ECO:0007744|PDB:1QQG" FT STRAND 92..96 FT /evidence="ECO:0007744|PDB:1QQG" FT HELIX 100..113 FT /evidence="ECO:0007744|PDB:1QQG" FT STRAND 162..172 FT /evidence="ECO:0007744|PDB:5U1M" FT HELIX 173..176 FT /evidence="ECO:0007744|PDB:5U1M" FT STRAND 181..187 FT /evidence="ECO:0007744|PDB:5U1M" FT STRAND 189..196 FT /evidence="ECO:0007744|PDB:5U1M" FT STRAND 203..207 FT /evidence="ECO:0007744|PDB:5U1M" FT HELIX 208..210 FT /evidence="ECO:0007744|PDB:5U1M" FT STRAND 211..217 FT /evidence="ECO:0007744|PDB:5U1M" FT STRAND 220..225 FT /evidence="ECO:0007744|PDB:5U1M" FT STRAND 233..239 FT /evidence="ECO:0007744|PDB:5U1M" FT HELIX 243..262 FT /evidence="ECO:0007744|PDB:5U1M" FT STRAND 897..901 FT /evidence="ECO:0007744|PDB:1K3A" SQ SEQUENCE 1242 AA; 131591 MW; 3C0EFD9E32B3E64A CRC64; MASPPESDGF SDVRKVGYLR KPKSMHKRFF VLRAASEAGG PARLEYYENE KKWRHKSSAP KRSIPLESCF NINKRADSKN KHLVALYTRD EHFAIAADSE AEQDSWYQAL LQLHNRAKGH HDGAAALGAG GGGGSCSGSS GLGEAGEDLS YGDVPPGPAF KEVWQVILKP KGLGQTKNLI GIYRLCLTSK TISFVKLNSE AAAVVLQLMN IRRCGHSENF FFIEVGRSAV TGPGEFWMQV DDSVVAQNMH ETILEAMRAM SDEFRPRSKS QSSSNCSNPI SVPLRRHHLN NPPPSQVGLT RRSRTESITA TSPASMVGGK PGSFRVRASS DGEGTMSRPA SVDGSPVSPS TNRTHAHRHR GSARLHPPLN HSRSIPMPAS RCSPSATSPV SLSSSSTSGH GSTSDCLFPR RSSASVSGSP SDGGFISSDE YGSSPCDFRS SFRSVTPDSL GHTPPARGEE ELSNYICMGG KGPSTLTAPN GHYILSRGGN GHRCTPGTGL GTSPALAGDE AASAADLDNR FRKRTHSAGT SPTITHQKTP SQSSVASIEE YTEMMPAYPP GGGSGGRLPG HRHSAFVPTR SYPEEGLEMH PLERRGGHHR PDSSTLHTDD GYMPMSPGVA PVPSGRKGSG DYMPMSPKSV SAPQQIINPI RRHPQRVDPN GYMMMSPSGG CSPDIGGGPS SSSSSSNAVP SGTSYGKLWT NGVGGHHSHV LPHPKPPVES SGGKLLPCTG DYMNMSPVGD SNTSSPSDCY YGPEDPQHKP VLSYYSLPRS FKHTQRPGEP EEGARHQHLR LSTSSGRLLY AATADDSSSS TSSDSLGGGY CGARLEPSLP HPHHQVLQPH LPRKVDTAAQ TNSRLARPTR LSLGDPKAST LPRAREQQQQ QQPLLHPPEP KSPGEYVNIE FGSDQSGYLS GPVAFHSSPS VRCPSQLQPA PREEETGTEE YMKMDLGPGR RAAWQESTGV EMGRLGPAPP GAASICRPTR AVPSSRGDYM TMQMSCPRQS YVDTSPAAPV SYADMRTGIA AEEVSLPRAT MAAASSSSAA SASPTGPQGA AELAAHSSLL GGPQGPGGMS AFTRVNLSPN RNQSAKVIRA DPQGCRRRHS SETFSSTPSA TRVGNTVPFG AGAAVGGGGG SSSSSEDVKR HSSASFENVW LRPGELGGAP KEPAKLCGAA GGLENGLNYI DLDLVKDFKQ CPQECTPEPQ PPPPPPPHQP LGSGESSSTR RSSEDLSAYA SISFQKQPED RQ //