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Insulin receptor substrate 1 (IRS-1)

 IRS1_HUMAN              Reviewed;        1242 AA.
P35568;
01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
01-JUN-1994, sequence version 1.
12-SEP-2018, entry version 203.
RecName: Full=Insulin receptor substrate 1;
Short=IRS-1;
Name=IRS1;
Homo sapiens (Human).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
Catarrhini; Hominidae; Homo.
NCBI_TaxID=9606;
[1]
NUCLEOTIDE SEQUENCE [MRNA].
TISSUE=Skeletal muscle;
PubMed=8513971; DOI=10.2337/diab.42.7.1041;
Araki E., Sun X.J., Haag B.L. III, Chuang L.M., Zhang Y.,
Yang-Feng T.L., White M.F., Kahn C.R.;
"Human skeletal muscle insulin receptor substrate-1. Characterization
of the cDNA, gene, and chromosomal localization.";
Diabetes 42:1041-1054(1993).
[2]
NUCLEOTIDE SEQUENCE [MRNA].
PubMed=1311924; DOI=10.1016/0006-291X(92)91640-C;
Nishiyama M., Wands J.R.;
"Cloning and increased expression of an insulin receptor substrate-1-
like gene in human hepatocellular carcinoma.";
Biochem. Biophys. Res. Commun. 183:280-285(1992).
[3]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
TISSUE=Eye;
PubMed=15489334; DOI=10.1101/gr.2596504;
The MGC Project Team;
"The status, quality, and expansion of the NIH full-length cDNA
project: the Mammalian Gene Collection (MGC).";
Genome Res. 14:2121-2127(2004).
[4]
TURNOVER.
PubMed=8240352; DOI=10.1006/bbrc.1993.2315;
Smith L.K., Bradshaw M., Croall D.E., Garner C.W.;
"The insulin receptor substrate (IRS-1) is a PEST protein that is
susceptible to calpain degradation in vitro.";
Biochem. Biophys. Res. Commun. 196:767-772(1993).
[5]
INTERACTION WITH IGF1R.
PubMed=7541045; DOI=10.1074/jbc.270.26.15639;
Craparo A., O'Neill T.J., Gustafson T.A.;
"Non-SH2 domains within insulin receptor substrate-1 and SHC mediate
their phosphotyrosine-dependent interaction with the NPEY motif of the
insulin-like growth factor I receptor.";
J. Biol. Chem. 270:15639-15643(1995).
[6]
INTERACTION WITH INSR.
PubMed=7559478; DOI=10.1074/jbc.270.40.23258;
He W., O'Neill T.J., Gustafson T.A.;
"Distinct modes of interaction of SHC and insulin receptor substrate-1
with the insulin receptor NPEY region via non-SH2 domains.";
J. Biol. Chem. 270:23258-23262(1995).
[7]
INTERACTION WITH INSR.
PubMed=7537849; DOI=10.1128/MCB.15.5.2500;
Gustafson T.A., He W., Craparo A., Schaub C.D., O'Neill T.J.;
"Phosphotyrosine-dependent interaction of SHC and insulin receptor
substrate 1 with the NPEY motif of the insulin receptor via a novel
non-SH2 domain.";
Mol. Cell. Biol. 15:2500-2508(1995).
[8]
MUTAGENESIS OF SER-794, AND PHOSPHORYLATION AT SER-794.
PubMed=12624099; DOI=10.1074/jbc.M211770200;
Horike N., Takemori H., Katoh Y., Doi J., Min L., Asano T., Sun X.J.,
Yamamoto H., Kasayama S., Muraoka M., Nonaka Y., Okamoto M.;
"Adipose-specific expression, phosphorylation of Ser794 in insulin
receptor substrate-1, and activation in diabetic animals of salt-
inducible kinase-2.";
J. Biol. Chem. 278:18440-18447(2003).
[9]
PHOSPHORYLATION AT SER-1101.
PubMed=15364919; DOI=10.1074/jbc.C400186200;
Li Y., Soos T.J., Li X., Wu J., Degennaro M., Sun X., Littman D.R.,
Birnbaum M.J., Polakiewicz R.D.;
"Protein kinase C Theta inhibits insulin signaling by phosphorylating
IRS1 at Ser(1101).";
J. Biol. Chem. 279:45304-45307(2004).
[10]
PHOSPHORYLATION BY ALK, AND INTERACTION WITH ALK.
PubMed=15226403; DOI=10.1242/jcs.01183;
Motegi A., Fujimoto J., Kotani M., Sakuraba H., Yamamoto T.;
"ALK receptor tyrosine kinase promotes cell growth and neurite
outgrowth.";
J. Cell Sci. 117:3319-3329(2004).
[11]
INTERACTION WITH SOCS7.
PubMed=16127460; DOI=10.1172/JCI23853;
Banks A.S., Li J., McKeag L., Hribal M.L., Kashiwada M., Accili D.,
Rothman P.B.;
"Deletion of SOCS7 leads to enhanced insulin action and enlarged
islets of Langerhans.";
J. Clin. Invest. 115:2462-2471(2005).
[12]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-662, AND IDENTIFICATION
BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
PubMed=15592455; DOI=10.1038/nbt1046;
Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H.,
Zha X.-M., Polakiewicz R.D., Comb M.J.;
"Immunoaffinity profiling of tyrosine phosphorylation in cancer
cells.";
Nat. Biotechnol. 23:94-101(2005).
[13]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-629 AND SER-636, 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).
[14]
INTERACTION WITH ALK, AND FUNCTION.
PubMed=16878150; DOI=10.1038/sj.onc.1209840;
Kuo A.H., Stoica G.E., Riegel A.T., Wellstein A.;
"Recruitment of insulin receptor substrate-1 and activation of NF-
kappaB essential for midkine growth signaling through anaplastic
lymphoma kinase.";
Oncogene 26:859-869(2007).
[15]
PHOSPHORYLATION AT SER-270; SER-307; SER-636 AND SER-1101.
PubMed=18952604; DOI=10.1074/jbc.M806480200;
Zhang J., Gao Z., Yin J., Quon M.J., Ye J.;
"S6K directly phosphorylates IRS-1 on Ser-270 to promote insulin
resistance in response to TNF-(alpha) signaling through IKK2.";
J. Biol. Chem. 283:35375-35382(2008).
[16]
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).
[17]
UBIQUITINATION, PHOSPHORYLATION AT SER-307; SER-312; SER-527 AND
SER-636, AND MUTAGENESIS OF SER-307; SER-312; SER-527; SER-636 AND
SER-639.
PubMed=18498745; DOI=10.1016/j.molcel.2008.03.009;
Xu X., Sarikas A., Dias-Santagata D.C., Dolios G., Lafontant P.J.,
Tsai S.C., Zhu W., Nakajima H., Nakajima H.O., Field L.J., Wang R.,
Pan Z.Q.;
"The CUL7 E3 ubiquitin ligase targets insulin receptor substrate 1 for
ubiquitin-dependent degradation.";
Mol. Cell 30:403-414(2008).
[18]
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).
[19]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-348, AND IDENTIFICATION
BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Leukemic T-cell;
PubMed=19690332; DOI=10.1126/scisignal.2000007;
Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
Rodionov V., Han D.K.;
"Quantitative phosphoproteomic analysis of T cell receptor signaling
reveals system-wide modulation of protein-protein interactions.";
Sci. Signal. 2:RA46-RA46(2009).
[20]
PHOSPHORYLATION AT SER-312 AND TYR-941.
PubMed=20685959; DOI=10.1091/mbc.E10-06-0481;
Yang X., Nath A., Opperman M.J., Chan C.;
"The double-stranded RNA-dependent protein kinase differentially
regulates insulin receptor substrates 1 and 2 in HepG2 cells.";
Mol. Biol. Cell 21:3449-3458(2010).
[21]
PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-323; THR-453; SER-527
AND SER-629, 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).
[22]
STRUCTURE BY NMR OF 157-267.
PubMed=8599766; DOI=10.1038/nsb0496-388;
Zhou M.-M., Huang B., Olejniczak E.T., Meadows R.P., Shuker S.B.,
Miyazaki M., Trueb T., Shoelson S.E., Fesik S.W.;
"Structural basis for IL-4 receptor phosphopeptide recognition by the
IRS-1 PTB domain.";
Nat. Struct. Biol. 3:388-393(1996).
[23]
X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 4-267.
PubMed=10411883; DOI=10.1073/pnas.96.15.8378;
Dhe-Paganon S., Ottinger E.A., Nolte R.T., Eck M.J., Shoelson S.E.;
"Crystal structure of the pleckstrin homology-phosphotyrosine binding
(PH-PTB) targeting region of insulin receptor substrate 1.";
Proc. Natl. Acad. Sci. U.S.A. 96:8378-8383(1999).
[24]
X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 889-902 IN COMPLEX WITH
IGF1R.
PubMed=11694888; DOI=10.1038/nsb721;
Favelyukis S., Till J.H., Hubbard S.R., Miller W.T.;
"Structure and autoregulation of the insulin-like growth factor 1
receptor kinase.";
Nat. Struct. Biol. 8:1058-1063(2001).
[25]
VARIANTS PRO-512 AND ARG-971.
PubMed=8104271; DOI=10.1016/0140-6736(93)92694-O;
Almind K., Bjoerbaek C., Vestergaard H., Hansen T., Echwald S.,
Pedersen O.;
"Aminoacid polymorphisms of insulin receptor substrate-1 in non-
insulin-dependent diabetes mellitus.";
Lancet 342:828-832(1993).
[26]
VARIANT NIDDM GLY-723 DEL.
PubMed=8723689;
DOI=10.1002/(SICI)1098-1004(1996)7:4<364::AID-HUMU13>3.3.CO;2-#;
Esposito D.L., Mammarella S., Ranieri A., della Loggia F., Capani F.,
Consoli A., Mariani-Costantini R., Caramia F.G., Cama A., Battista P.;
"Deletion of Gly723 in the insulin receptor substrate-1 of a patient
with noninsulin-dependent diabetes mellitus.";
Hum. Mutat. 7:364-366(1996).
[27]
VARIANTS NIDDM TYR-1043 AND TYR-1095.
PubMed=10206679;
DOI=10.1002/(SICI)1098-1004(1998)11:5<411::AID-HUMU12>3.0.CO;2-#;
Mammarella S., Creati B., Esposito D.L., Arcuri P., della Loggia F.,
Capani F., Mariani-Costantini R., Caramia F.G., Battista P., Cama A.;
"Novel allele of the insulin receptor substrate-1 bearing two non-
conservative amino acid substitutions in a patient with noninsulin-
dependent diabetes mellitus.";
Hum. Mutat. 11:411-411(1998).
[28]
CHARACTERIZATION OF VARIANT ARG-971.
PubMed=10843189; DOI=10.1210/jcem.85.5.6608;
Hribal M.L., Federici M., Porzio O., Lauro D., Borboni P., Accili D.,
Lauro R., Sesti G.;
"The Gly-->Arg(972) amino acid polymorphism in insulin receptor
substrate-1 affects glucose metabolism in skeletal muscle cells.";
J. Clin. Endocrinol. Metab. 85:2004-2013(2000).
[29]
ASSOCIATION OF VARIANT ARG-971 WITH NIDDM.
PubMed=12843189; DOI=10.1210/jc.2002-021716;
Marini M.A., Frontoni S., Mineo D., Bracaglia D., Cardellini M.,
De Nicolais P., Baroni A., D'Alfonso R., Perna M., Lauro D.,
Federici M., Gambardella S., Lauro R., Sesti G.;
"The Arg(972) variant in insulin receptor substrate-1 is associated
with an atherogenic profile in offspring of type 2 diabetic
patients.";
J. Clin. Endocrinol. Metab. 88:3368-3371(2003).
[30]
VARIANT ARG-971.
PubMed=14671192; DOI=10.1210/jc.2003-030453;
Abate N., Carulli L., Cabo-Chan A. Jr., Chandalia M., Snell P.G.,
Grundy S.M.;
"Genetic polymorphism PC-1 K121Q and ethnic susceptibility to insulin
resistance.";
J. Clin. Endocrinol. Metab. 88:5927-5934(2003).
[31]
VARIANT ARG-608, AND CHARACTERIZATION OF VARIANT ARG-608.
PubMed=12679424; DOI=10.1210/jc.2002-020933;
Esposito D.L., Li Y., Vanni C., Mammarella S., Veschi S.,
Della Loggia F., Mariani-Costantini R., Battista P., Quon M.J.,
Cama A.;
"A novel T608R missense mutation in insulin receptor substrate-1
identified in a subject with type 2 diabetes impairs metabolic insulin
signaling.";
J. Clin. Endocrinol. Metab. 88:1468-1475(2003).
[32]
VARIANT ARG-971, ASSOCIATION WITH ENDOTHELIAL DYSFUNCTION, AND
CARDIOVASCULAR DISEASE.
PubMed=14707024; DOI=10.1161/01.CIR.0000109498.77895.6F;
Federici M., Pandolfi A., De Filippis E.A., Pellegrini G.,
Menghini R., Lauro D., Cardellini M., Romano M., Sesti G., Lauro R.,
Consoli A.;
"G972R IRS-1 variant impairs insulin regulation of endothelial nitric
oxide synthase in cultured human endothelial cells.";
Circulation 109:399-405(2004).
[33]
VARIANT ARG-971, AND MOLECULAR MECHANISM OF LINKAGE TO NIDDM.
PubMed=15590636; DOI=10.1074/jbc.M412300200;
McGettrick A.J., Feener E.P., Kahn C.R.;
"Human insulin receptor substrate-1 (IRS-1) polymorphism G972R causes
IRS-1 to associate with the insulin receptor and inhibit receptor
autophosphorylation.";
J. Biol. Chem. 280:6441-6446(2005).
-!- FUNCTION: May mediate the control of various cellular processes by
insulin. When phosphorylated by the insulin receptor binds
specifically to various cellular proteins containing SH2 domains
such as phosphatidylinositol 3-kinase p85 subunit or GRB2.
Activates phosphatidylinositol 3-kinase when bound to the
regulatory p85 subunit (By similarity). {ECO:0000250,
ECO:0000269|PubMed:16878150}.
-!- SUBUNIT: Interacts with UBTF and PIK3CA (By similarity). Interacts
(via phosphorylated YXXM motifs) with PIK3R1 (By similarity).
Interacts with ROCK1 and FER (By similarity). Interacts (via PH
domain) with PHIP (By similarity). Interacts with GRB2 (By
similarity). Interacts with SOCS7. Interacts (via IRS-type PTB
domain) with IGF1R and INSR (via the tyrosine-phosphorylated NPXY
motif). Interacts with ALK. Interacts with EIF2AK2/PKR (By
similarity). {ECO:0000250}.
-!- INTERACTION:
P03070:- (xeno); NbExp=2; IntAct=EBI-517592, EBI-617698;
O75815:BCAR3; NbExp=3; IntAct=EBI-517592, EBI-702336;
P04626:ERBB2; NbExp=2; IntAct=EBI-517592, EBI-641062;
P06213:INSR; NbExp=3; IntAct=EBI-517592, EBI-475899;
P03495:NS (xeno); NbExp=2; IntAct=EBI-517592, EBI-2548993;
P11940:PABPC1; NbExp=2; IntAct=EBI-517592, EBI-81531;
P42336:PIK3CA; NbExp=20; IntAct=EBI-517592, EBI-2116585;
P27986:PIK3R1; NbExp=12; IntAct=EBI-517592, EBI-79464;
P27986-2:PIK3R1; NbExp=3; IntAct=EBI-517592, EBI-9090282;
Q92569:PIK3R3; NbExp=4; IntAct=EBI-517592, EBI-79893;
Q06124:PTPN11; NbExp=3; IntAct=EBI-517592, EBI-297779;
-!- PTM: Serine phosphorylation of IRS1 is a mechanism for insulin
resistance. Ser-312 phosphorylation inhibits insulin action
through disruption of IRS1 interaction with the insulin receptor
(By similarity). Phosphorylation of Tyr-896 is required for GRB2-
binding (By similarity). Phosphorylated by ALK. Phosphorylated at
Ser-270, Ser-307, Ser-636 and Ser-1101 by RPS6KB1; phosphorylation
induces accelerated degradation of IRS1. {ECO:0000250,
ECO:0000269|PubMed:15364919, ECO:0000269|PubMed:18498745,
ECO:0000269|PubMed:18952604, ECO:0000269|PubMed:20685959}.
-!- PTM: Ubiquitinated by the Cul7-RING(FBXW8) complex in a mTOR-
dependent manner, leading to its degradation: the Cul7-RING(FBXW8)
complex recognizes and binds IRS1 previously phosphorylated by S6
kinase (RPS6KB1 or RPS6KB2). {ECO:0000269|PubMed:18498745}.
-!- POLYMORPHISM: The Arg-971 polymorphism impairs the ability of
insulin to stimulate glucose transport, glucose transporter
translocation, and glycogen synthesis by affecting the
PI3K/AKT1/GSK3 signaling pathway. The polymorphism at Arg-971 may
contribute to the in vivo insulin resistance observed in carriers
of this variant. Arg-971 could contribute to the risk for
atherosclerotic cardiovascular diseases associated with non-
insulin-dependent diabetes mellitus (NIDDM) by producing a cluster
of insulin resistance-related metabolic abnormalities. In insulin-
stimulated human endothelial cells from carriers of the Arg-971
polymorphism, genetic impairment of the IRS1/PI3K/PDPK1/AKT1
insulin signaling cascade results in impaired insulin-stimulated
nitric oxide (NO) release and suggested that this may be a
mechanism through which the Arg-971 polymorphism contributes to
the genetic predisposition to develop endothelial dysfunction and
cardiovascular disease. The Arg-971 polymorphism not only reduces
phosphorylation of the substrate but allows IRS1 to act as an
inhibitor of PI3K, producing global insulin resistance.
-!- DISEASE: Diabetes mellitus, non-insulin-dependent (NIDDM)
[MIM:125853]: A multifactorial disorder of glucose homeostasis
caused by a lack of sensitivity to the body's own insulin.
Affected individuals usually have an obese body habitus and
manifestations of a metabolic syndrome characterized by diabetes,
insulin resistance, hypertension and hypertriglyceridemia. The
disease results in long-term complications that affect the eyes,
kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:10206679,
ECO:0000269|PubMed:12843189, ECO:0000269|PubMed:8723689}. Note=The
gene represented in this entry may be involved in disease
pathogenesis.
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EMBL; S85963; AAB21608.1; -; Genomic_DNA.
EMBL; S62539; AAB27175.1; -; mRNA.
EMBL; BC053895; AAH53895.1; -; mRNA.
CCDS; CCDS2463.1; -.
PIR; I53160; JS0670.
RefSeq; NP_005535.1; NM_005544.2.
UniGene; Hs.471508; -.
PDB; 1IRS; NMR; -; A=157-267.
PDB; 1K3A; X-ray; 2.10 A; B=891-902.
PDB; 1QQG; X-ray; 2.30 A; A/B=4-267.
PDB; 2Z8C; X-ray; 3.25 A; B=731-736.
PDB; 5U1M; X-ray; 1.80 A; A=161-265.
PDBsum; 1IRS; -.
PDBsum; 1K3A; -.
PDBsum; 1QQG; -.
PDBsum; 2Z8C; -.
PDBsum; 5U1M; -.
ProteinModelPortal; P35568; -.
SMR; P35568; -.
BioGrid; 109874; 63.
CORUM; P35568; -.
DIP; DIP-523N; -.
ELM; P35568; -.
IntAct; P35568; 29.
MINT; P35568; -.
STRING; 9606.ENSP00000304895; -.
DrugBank; DB08513; [4-({5-(AMINOCARBONYL)-4-[(3-METHYLPHENYL)AMINO]PYRIMIDIN-2-YL}AMINO)PHENYL]ACETIC ACID.
iPTMnet; P35568; -.
PhosphoSitePlus; P35568; -.
BioMuta; IRS1; -.
DMDM; 547738; -.
EPD; P35568; -.
MaxQB; P35568; -.
PaxDb; P35568; -.
PeptideAtlas; P35568; -.
PRIDE; P35568; -.
ProteomicsDB; 55088; -.
DNASU; 3667; -.
Ensembl; ENST00000305123; ENSP00000304895; ENSG00000169047.
GeneID; 3667; -.
KEGG; hsa:3667; -.
UCSC; uc002voh.5; human.
CTD; 3667; -.
DisGeNET; 3667; -.
EuPathDB; HostDB:ENSG00000169047.5; -.
GeneCards; IRS1; -.
HGNC; HGNC:6125; IRS1.
HPA; CAB005261; -.
HPA; HPA046433; -.
MalaCards; IRS1; -.
MIM; 125853; phenotype.
MIM; 147545; gene.
neXtProt; NX_P35568; -.
OpenTargets; ENSG00000169047; -.
PharmGKB; PA203; -.
eggNOG; ENOG410IXEK; Eukaryota.
eggNOG; ENOG410Z9EP; LUCA.
GeneTree; ENSGT00530000063420; -.
HOGENOM; HOG000113103; -.
HOVERGEN; HBG000542; -.
InParanoid; P35568; -.
KO; K16172; -.
OMA; NGYMMMS; -.
OrthoDB; EOG091G02EF; -.
PhylomeDB; P35568; -.
TreeFam; TF325994; -.
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-9603381; Activated NTRK3 signals through PI3K.
Reactome; R-HSA-982772; Growth hormone receptor signaling.
SignaLink; P35568; -.
SIGNOR; P35568; -.
ChiTaRS; IRS1; human.
EvolutionaryTrace; P35568; -.
GeneWiki; IRS1; -.
GenomeRNAi; 3667; -.
PMAP-CutDB; P35568; -.
PRO; PR:P35568; -.
Proteomes; UP000005640; Chromosome 2.
Bgee; ENSG00000169047; Expressed in 237 organ(s), highest expression level in endometrium.
CleanEx; HS_IRS1; -.
ExpressionAtlas; P35568; baseline and differential.
Genevisible; P35568; HS.
GO; GO:0005901; C:caveola; IDA:BHF-UCL.
GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
GO; GO:0005829; C:cytosol; IDA:HPA.
GO; GO:0005899; C:insulin receptor complex; ISS:BHF-UCL.
GO; GO:0043231; C:intracellular membrane-bounded organelle; ISS:UniProtKB.
GO; GO:0005634; C:nucleus; IDA:HPA.
GO; GO:0005886; C:plasma membrane; IDA:HPA.
GO; GO:0016303; F:1-phosphatidylinositol-3-kinase activity; TAS:Reactome.
GO; GO:0005158; F:insulin receptor binding; IPI:UniProtKB.
GO; GO:0005159; F:insulin-like growth factor receptor binding; IPI:UniProtKB.
GO; GO:0043548; F:phosphatidylinositol 3-kinase binding; IPI:UniProtKB.
GO; GO:0046934; F:phosphatidylinositol-4,5-bisphosphate 3-kinase activity; TAS:Reactome.
GO; GO:0001784; F:phosphotyrosine residue binding; IPI:CAFA.
GO; GO:0005080; F:protein kinase C binding; ISS:BHF-UCL.
GO; GO:0005088; F:Ras guanyl-nucleotide exchange factor activity; TAS:Reactome.
GO; GO:0042169; F:SH2 domain binding; ISS:UniProtKB.
GO; GO:0005068; F:transmembrane receptor protein tyrosine kinase adaptor activity; ISS:BHF-UCL.
GO; GO:0032869; P:cellular response to insulin stimulus; IMP:BHF-UCL.
GO; GO:0042593; P:glucose homeostasis; TAS:BHF-UCL.
GO; GO:0008286; P:insulin receptor signaling pathway; IDA:BHF-UCL.
GO; GO:0048009; P:insulin-like growth factor receptor signaling pathway; IPI:UniProtKB.
GO; GO:0038111; P:interleukin-7-mediated signaling pathway; TAS:Reactome.
GO; GO:0000165; P:MAPK cascade; TAS:Reactome.
GO; GO:0046627; P:negative regulation of insulin receptor signaling pathway; ISS:BHF-UCL.
GO; GO:0046676; P:negative regulation of insulin secretion; IDA:BHF-UCL.
GO; GO:0014065; P:phosphatidylinositol 3-kinase signaling; IDA:BHF-UCL.
GO; GO:0048015; P:phosphatidylinositol-mediated signaling; TAS:Reactome.
GO; GO:0008284; P:positive regulation of cell 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:2001275; P:positive regulation of glucose import in response to insulin stimulus; IDA: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:0046628; P:positive regulation of insulin receptor signaling pathway; ISS:BHF-UCL.
GO; GO:0043552; P:positive regulation of phosphatidylinositol 3-kinase activity; ISS:BHF-UCL.
GO; GO:0051897; P:positive regulation of protein kinase B signaling; TAS:Reactome.
GO; GO:0032868; P:response to insulin; IDA:BHF-UCL.
GO; GO:0043434; P:response to peptide hormone; 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; Complete proteome; Diabetes mellitus; Disease mutation;
Phosphoprotein; Polymorphism; Reference proteome; Repeat; Transducer;
Ubl conjugation.
CHAIN 1 1242 Insulin receptor substrate 1.
/FTId=PRO_0000084236.
DOMAIN 12 115 PH. {ECO:0000255|PROSITE-
ProRule:PRU00145}.
DOMAIN 160 264 IRS-type PTB. {ECO:0000255|PROSITE-
ProRule:PRU00389}.
REGION 3 137 Mediates interaction with PHIP.
{ECO:0000250}.
REGION 896 898 GRB2-binding. {ECO:0000250}.
MOTIF 465 468 YXXM motif 1.
MOTIF 551 554 YXXM motif 2.
MOTIF 612 615 YXXM motif 3.
MOTIF 632 635 YXXM motif 4.
MOTIF 662 665 YXXM motif 5.
MOTIF 732 735 YXXM motif 6.
MOTIF 941 944 YXXM motif 7.
MOTIF 989 992 YXXM motif 8.
MOTIF 1012 1015 YXXM motif 9.
COMPBIAS 128 134 Poly-Gly.
COMPBIAS 268 444 Ser-rich.
COMPBIAS 680 686 Poly-Ser.
COMPBIAS 807 815 Poly-Ser.
COMPBIAS 877 882 Poly-Gln.
COMPBIAS 1192 1210 Pro-rich.
MOD_RES 3 3 Phosphoserine.
{ECO:0000250|UniProtKB:P35570}.
MOD_RES 99 99 Phosphoserine; by CK2.
{ECO:0000250|UniProtKB:P35570}.
MOD_RES 270 270 Phosphoserine; by RPS6KB1.
{ECO:0000269|PubMed:18952604}.
MOD_RES 307 307 Phosphoserine; by RPS6KB1.
{ECO:0000269|PubMed:18498745,
ECO:0000269|PubMed:18952604}.
MOD_RES 312 312 Phosphoserine; by IKKB, MAPK8 and
RPS6KB1. {ECO:0000269|PubMed:18498745,
ECO:0000269|PubMed:20685959}.
MOD_RES 323 323 Phosphoserine.
{ECO:0000244|PubMed:24275569}.
MOD_RES 330 330 Phosphoserine.
{ECO:0000250|UniProtKB:P35569}.
MOD_RES 345 345 Phosphoserine.
{ECO:0000250|UniProtKB:P35569}.
MOD_RES 348 348 Phosphoserine.
{ECO:0000244|PubMed:19690332}.
MOD_RES 419 419 Phosphoserine.
{ECO:0000250|UniProtKB:P35569}.
MOD_RES 446 446 Phosphothreonine.
{ECO:0000250|UniProtKB:P35570}.
MOD_RES 453 453 Phosphothreonine.
{ECO:0000244|PubMed:24275569}.
MOD_RES 465 465 Phosphotyrosine; by INSR.
{ECO:0000250|UniProtKB:P35570}.
MOD_RES 527 527 Phosphoserine; by RPS6KB1.
{ECO:0000244|PubMed:24275569,
ECO:0000269|PubMed:18498745}.
MOD_RES 612 612 Phosphotyrosine; by INSR.
{ECO:0000250|UniProtKB:P35570}.
MOD_RES 629 629 Phosphoserine.
{ECO:0000244|PubMed:17081983,
ECO:0000244|PubMed:24275569}.
MOD_RES 632 632 Phosphotyrosine; by INSR.
{ECO:0000250|UniProtKB:P35570}.
MOD_RES 636 636 Phosphoserine; by RPS6KB1.
{ECO:0000244|PubMed:17081983,
ECO:0000269|PubMed:18498745,
ECO:0000269|PubMed:18952604}.
MOD_RES 662 662 Phosphotyrosine.
{ECO:0000244|PubMed:15592455}.
MOD_RES 794 794 Phosphoserine; by AMPK and SIK2.
{ECO:0000269|PubMed:12624099}.
MOD_RES 892 892 Phosphoserine.
{ECO:0000250|UniProtKB:P35569}.
MOD_RES 896 896 Phosphotyrosine; by INSR.
{ECO:0000250|UniProtKB:P35570}.
MOD_RES 941 941 Phosphotyrosine; by INSR.
{ECO:0000269|PubMed:20685959}.
MOD_RES 989 989 Phosphotyrosine; by INSR.
{ECO:0000250|UniProtKB:P35570}.
MOD_RES 1100 1100 Phosphoserine.
{ECO:0000250|UniProtKB:P35569}.
MOD_RES 1101 1101 Phosphoserine; by RPS6KB1 and PKC/PRKCQ.
{ECO:0000269|PubMed:15364919,
ECO:0000269|PubMed:18952604}.
MOD_RES 1179 1179 Phosphotyrosine; by INSR.
{ECO:0000250|UniProtKB:P35570}.
MOD_RES 1229 1229 Phosphotyrosine; by INSR.
{ECO:0000250|UniProtKB:P35570}.
VARIANT 158 158 P -> R (in dbSNP:rs1801108).
/FTId=VAR_014853.
VARIANT 209 209 M -> T (in dbSNP:rs1801118).
/FTId=VAR_014854.
VARIANT 512 512 A -> P (in dbSNP:rs1801276).
{ECO:0000269|PubMed:8104271}.
/FTId=VAR_005299.
VARIANT 608 608 T -> R (may contribute to insulin
resistance by impairing metabolic
signaling through PI3K-dependent
pathways; dbSNP:rs104893642).
{ECO:0000269|PubMed:12679424}.
/FTId=VAR_025320.
VARIANT 723 723 Missing (in NIDDM).
{ECO:0000269|PubMed:8723689}.
/FTId=VAR_005301.
VARIANT 809 809 S -> F (in dbSNP:rs1801120).
/FTId=VAR_014855.
VARIANT 892 892 S -> G (in dbSNP:rs1801277).
/FTId=VAR_014856.
VARIANT 971 971 G -> R (in dbSNP:rs1801278).
{ECO:0000269|PubMed:10843189,
ECO:0000269|PubMed:14671192,
ECO:0000269|PubMed:14707024,
ECO:0000269|PubMed:15590636,
ECO:0000269|PubMed:8104271}.
/FTId=VAR_005300.
VARIANT 1043 1043 S -> Y (in NIDDM).
{ECO:0000269|PubMed:10206679}.
/FTId=VAR_005302.
VARIANT 1095 1095 C -> Y (in NIDDM).
{ECO:0000269|PubMed:10206679}.
/FTId=VAR_005303.
VARIANT 1137 1137 D -> N (in dbSNP:rs3731594).
/FTId=VAR_021837.
MUTAGEN 307 307 S->A: Impaired degradation by the Cul7-
RING(FBXW8) complex; when associated with
A-312; A-527; A-636 and A-639.
{ECO:0000269|PubMed:18498745}.
MUTAGEN 312 312 S->A: Impaired degradation by the Cul7-
RING(FBXW8) complex; when associated with
A-307; A-527; A-636 and A-639.
{ECO:0000269|PubMed:18498745}.
MUTAGEN 527 527 S->A: Impaired degradation by the Cul7-
RING(FBXW8) complex; when associated with
A-307; A-312; A-636 and A-639.
{ECO:0000269|PubMed:18498745}.
MUTAGEN 636 636 S->A: Impaired degradation by the Cul7-
RING(FBXW8) complex; when associated with
A-307; A-312; A-527 and A-639.
{ECO:0000269|PubMed:18498745}.
MUTAGEN 639 639 S->A: Impaired degradation by the Cul7-
RING(FBXW8) complex; when associated with
A-307; A-312; A-527 and A-636.
{ECO:0000269|PubMed:18498745}.
MUTAGEN 794 794 S->A: Loss of phosphorylation by SIK2.
{ECO:0000269|PubMed:12624099}.
CONFLICT 134 134 G -> GG (in Ref. 2; AAB21608).
{ECO:0000305}.
CONFLICT 362 362 S -> R (in Ref. 2; AAB21608).
{ECO:0000305}.
CONFLICT 384 384 P -> R (in Ref. 2; AAB21608).
{ECO:0000305}.
STRAND 13 20 {ECO:0000244|PDB:1QQG}.
TURN 22 24 {ECO:0000244|PDB:1QQG}.
STRAND 27 33 {ECO:0000244|PDB:1QQG}.
TURN 37 39 {ECO:0000244|PDB:1QQG}.
STRAND 40 49 {ECO:0000244|PDB:1QQG}.
HELIX 50 54 {ECO:0000244|PDB:1QQG}.
STRAND 61 65 {ECO:0000244|PDB:1QQG}.
HELIX 66 68 {ECO:0000244|PDB:1QQG}.
STRAND 69 75 {ECO:0000244|PDB:1QQG}.
STRAND 81 90 {ECO:0000244|PDB:1QQG}.
STRAND 92 96 {ECO:0000244|PDB:1QQG}.
HELIX 100 113 {ECO:0000244|PDB:1QQG}.
STRAND 162 172 {ECO:0000244|PDB:5U1M}.
HELIX 173 176 {ECO:0000244|PDB:5U1M}.
STRAND 181 187 {ECO:0000244|PDB:5U1M}.
STRAND 189 196 {ECO:0000244|PDB:5U1M}.
STRAND 203 207 {ECO:0000244|PDB:5U1M}.
HELIX 208 210 {ECO:0000244|PDB:5U1M}.
STRAND 211 217 {ECO:0000244|PDB:5U1M}.
STRAND 220 225 {ECO:0000244|PDB:5U1M}.
STRAND 233 239 {ECO:0000244|PDB:5U1M}.
HELIX 243 262 {ECO:0000244|PDB:5U1M}.
STRAND 897 901 {ECO:0000244|PDB:1K3A}.
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


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