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MGP001656

UniProt Annotations

Entry Information
Gene Nameinsulin receptor substrate 1
Protein EntryIRS1_HUMAN
UniProt IDP35568
SpeciesHuman
Comments
Comment typeDescription
DiseaseDiabetes 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.
FunctionMay 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}.
InteractionP03070:- (xeno); NbExp=2; IntAct=EBI-517592, EBI-617698; 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; Q06124:PTPN11; NbExp=3; IntAct=EBI-517592, EBI-297779;
PolymorphismThe 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.
PtmSerine 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:17081983, ECO:0000269|PubMed:18498745, ECO:0000269|PubMed:18952604, ECO:0000269|PubMed:20685959}.
PtmUbiquitinated 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}.
SimilarityContains 1 IRS-type PTB domain. {ECO:0000255|PROSITE- ProRule:PRU00389}.
SimilarityContains 1 PH domain. {ECO:0000255|PROSITE- ProRule:PRU00145}.
SubunitInteracts 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}.
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