Insulin Receptor Substrate 1 (IRS1)

HIRS1

SPN	U303
HGNC	6125
MGI	99454
PubMed	20074531
RGD	2922
UniProt	P35568
Wiki	IRS1

Insulin receptor substrate 1 plays a key role in transmitting signals from the IGF-1 receptors to intracellular pathways PI3K / Akt and Erk MAP kinase pathways. Tyrosine phosphorylation of the insulin receptors or IGF-1 receptors, upon extracellular ligand binding, induces the cytoplasmic binding of IRS-1 to these receptors, through its SH2 domains.

IRS-1 plays important biological function for both metabolic and mitogenic (growth promoting) pathways: mice deficent of IRS1 have only a mild diabetic phenotype, but a pronounced growth impairment, i.e. IRS-1 knockout mice only reach 50% of the weight of normal mice. IRS-1 may also play a role in cancer, as it has been shown that transgenic mice overexpressing IRS-1 develop breast cancer.

Reference

"Human skeletal muscle insulin receptor substrate-1. Characterization of the cDNA, gene, and chromosomal localization."
Diabetes 42:1041-1054(1993) [PubMed] [Europe PMC] [Abstract]

"Cloning and increased expression of an insulin receptor substrate-1-like gene in human hepatocellular carcinoma."
Biochem. Biophys. Res. Commun. 183:280-285(1992) [PubMed] [Europe PMC] [Abstract]

"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]

"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) [PubMed] [Europe PMC] [Abstract]

"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) [PubMed] [Europe PMC] [Abstract]

"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) [PubMed] [Europe PMC] [Abstract]

"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) [PubMed] [Europe PMC] [Abstract]

"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) [PubMed] [Europe PMC] [Abstract]

"Protein kinase C Theta inhibits insulin signaling by phosphorylating IRS1 at Ser(1101)."
J. Biol. Chem. 279:45304-45307(2004) [PubMed] [Europe PMC] [Abstract]

"ALK receptor tyrosine kinase promotes cell growth and neurite outgrowth."
J. Cell Sci. 117:3319-3329(2004) [PubMed] [Europe PMC] [Abstract]

"Deletion of SOCS7 leads to enhanced insulin action and enlarged islets of Langerhans."
J. Clin. Invest. 115:2462-2471(2005) [PubMed] [Europe PMC] [Abstract]

"Immunoaffinity profiling of tyrosine phosphorylation in cancer cells."
Nat. Biotechnol. 23:94-101(2005) [PubMed] [Europe PMC] [Abstract]

"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks."
Cell 127:635-648(2006) [PubMed] [Europe PMC] [Abstract]

"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) [PubMed] [Europe PMC] [Abstract]

"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) [PubMed] [Europe PMC] [Abstract]

"Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient phosphoproteomic analysis."
J. Proteome Res. 7:1346-1351(2008) [PubMed] [Europe PMC] [Abstract]

"The CUL7 E3 ubiquitin ligase targets insulin receptor substrate 1 for ubiquitin-dependent degradation."
Mol. Cell 30:403-414(2008) [PubMed] [Europe PMC] [Abstract]

"Large-scale proteomics analysis of the human kinome."
Mol. Cell. Proteomics 8:1751-1764(2009) [PubMed] [Europe PMC] [Abstract]

"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions."
Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract]

"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) [PubMed] [Europe PMC] [Abstract]

"An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome."
J. Proteomics 96:253-262(2014) [PubMed] [Europe PMC] [Abstract]

"Structural basis for IL-4 receptor phosphopeptide recognition by the IRS-1 PTB domain."
Nat. Struct. Biol. 3:388-393(1996) [PubMed] [Europe PMC] [Abstract]

"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) [PubMed] [Europe PMC] [Abstract]

"Structure and autoregulation of the insulin-like growth factor 1 receptor kinase."
Nat. Struct. Biol. 8:1058-1063(2001) [PubMed] [Europe PMC] [Abstract]

"Aminoacid polymorphisms of insulin receptor substrate-1 in non-insulin-dependent diabetes mellitus."
Lancet 342:828-832(1993) [PubMed] [Europe PMC] [Abstract]

"Deletion of Gly723 in the insulin receptor substrate-1 of a patient with noninsulin-dependent diabetes mellitus."
Hum. Mutat. 7:364-366(1996) [PubMed] [Europe PMC] [Abstract]

"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) [PubMed] [Europe PMC] [Abstract]

"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) [PubMed] [Europe PMC] [Abstract]

"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) [PubMed] [Europe PMC] [Abstract]

"Genetic polymorphism PC-1 K121Q and ethnic susceptibility to insulin resistance."
J. Clin. Endocrinol. Metab. 88:5927-5934(2003) [PubMed] [Europe PMC] [Abstract]

"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) [PubMed] [Europe PMC] [Abstract]

"G972R IRS-1 variant impairs insulin regulation of endothelial nitric oxide synthase in cultured human endothelial cells."
Circulation 109:399-405(2004) [PubMed] [Europe PMC] [Abstract]

"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) [PubMed] [Europe PMC] [Abstract]