title: Insulin receptor substrate 4 associates with the protein IRAS.
abstract: The insulin receptor substrates (IRSs) are key components in signaling from the insulin receptor, and consequently any proteins that interact with them are expected to participate in insulin signaling. In this study we have searched for proteins that interact with IRS-4 by identifying the proteins that coimmunoprecipitated with IRS-4 from human embryonic kidney 293 cells by microsequencing through mass spectrometry. A group of proteins was found. These included phosphatidylinositol 3-kinase, a protein previously identified as an IRS-4 interactor, and several proteins for which there was no previous evidence of IRS-4 association. One of these proteins, named IRAS, that had been found earlier in another context was examined in detail. The results from the overexpression of IRAS, where its amount was about the same as that of IRS-4, indicated that IRAS associated directly with IRS-4 and showed that the increased complexation of IRS-4 with IRAS did not alter the insulin-stimulated tyrosine phosphorylation of IRS-4 or the association of IRS-4 with phosphatidylinositol 3-kinase or Grb2. On the other hand, overexpression of IRAS enhanced IRS-4-dependent insulin stimulation of the extracellularly regulated kinase. The domains of IRAS and IRS-4 responsible for the association of these two proteins were identified, and it was shown that IRAS also associates with IRS-1, IRS-2, and IRS-3.
authors.affiliation: Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sano
authors.forename: Simon C H
authors.initials: SC
authors.lastname: Liu
authors.forename: William S
authors.initials: WS
authors.lastname: Lane
authors.forename: John E
authors.initials: JE
authors.lastname: Piletz
authors.forename: Gustav E
authors.initials: GE
authors.lastname: Lienhard
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism*; D002460:Cell Line; D018076:DNA, Complementary / Q000378:metabolism; D051380:GRB2 Adaptor Protein; D006801:Humans; D054755:Imidazoline Receptors; D015151:Immunoblotting; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D013058:Mass Spectrometry; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000737:chemistry* / Q000378:metabolism*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018076:DNA, Complementary; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C526292:IRS1 protein, human; C526297:IRS2 protein, human; C491585:IRS3P protein, human; C107686:IRS4 protein, human; D054755:Imidazoline Receptors; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; C491531:Irs4 protein, mouse; C458505:NISCH protein, human; D010750:Phosphoproteins; D011506:Proteins; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases