insulin receptor substrate 1; IRS-1 (IRS1)
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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
- GRB2
- activates phosphatidylinositol 3-kinase when bound to the regulatory p85 subunit (putative)
- insulin & IL-4 stimulate IRS-1 phosphorylation
- insulin induces association of IRS-1 with the integrin alpha-5/beta-3 receptor[5]
- Ser phosphorylation of IRS1 is a mechanism for insulin resistance
- Ser-312 phosphorylation inhibits insulin action via disruption of IRS1 interaction with the insulin receptor
- phosphorylation of Tyr-896 is required for GRB2-binding
- interacts with the NPXY motif of Tyr-phosphorylated IGF1R & INSR via the PTB domain
- binds to phosphatidylinositol 3-kinase p85 subunit via phosphorylated YXXM motifs
- binds ROCK1
- binds to UBTF & PIK3CA in nuclear extracts
- interacts with SOCS7
Structure
- contains 1 IRS-type PTB domain
- contains 1 PH domain
Pathology
- polymorphisms in IRS1 may be involved in the etiology of non-insulin-dependent diabetes mellitus (NIDDM)
Polymorphism
- the Arg-971 polymorphism impairs the ability of insulin to stimulate glucose transport, glucose transporter translocation, & glycogen synthesis by affecting the PI3K/AKT1/GSK3 signaling pathway; Arg-971 may contribute to the in vivo insulin resistance observed in carriers of this variant; Arg-971 could contribute to the risk for atherosclerosis 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 Arg-971, genetic impairment of the IRS1/PI3K/PDPK1/AKT1 insulin signaling cascade results in impaired insulin-stimulated nitric oxide (NO) release & suggested that this may be a mechanism through which the Arg-971 polymorphism contributes to the genetic predisposition to develop endothelial dysfunction & cardiovascular disease; Arg-971 not only reduces phosphorylation of the substrate but allows IRS1 to act as an inhibitor of PI3K, producing global insulin resistance
More general terms
References
- ↑ Baltensperger K, Kozma LM, Cherniack AD, Klarlund JK, Chawla A, Banerjee U, Czech MP. Binding of the Ras activator son of sevenless to insulin receptor substrate-1 signaling complexes. Science. 1993 Jun 25;260(5116):1950-2. PMID: https://www.ncbi.nlm.nih.gov/pubmed/8391166
- ↑ Saltiel AR. The paradoxical regulation of protein phosphorylation in insulin action. FASEB J. 1994 Oct;8(13):1034-40. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/7926368
- ↑ White MF The IRS-1 signaling system. Curr Opin Genet Dev 4:47 1994 PMID: https://www.ncbi.nlm.nih.gov/pubmed/8193539
- ↑ Pawson T. Protein modules and signalling networks. Nature. 1995 Feb 16;373(6515):573-80. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/7531822
- ↑ 5.0 5.1 Clark EA & Brugge JS Integrins and signal transduction pathways: the road taken. Science 268:233 1995 PMID: https://www.ncbi.nlm.nih.gov/pubmed/7716514
- ↑ UniProt http://www.uniprot.org/uniprot/P35568.html