Overview:

IRS1isthesubstratefortheinsulintyrosinekinasereceptoranditisexpressedinavarietyofinsulin-responsivetissues.IRS1isadockingproteinwithnointrinsicenzymaticactivity.ViaitsSH2domains,IRS1facilitatesinteractionsbetweenkeyplayersininsulinsignalingsuchastheinsulinreceptor.14-3-3competitivelybindswithIRS1againsttheinsulinreceptor(1).Thiscompetitionhasimplicationstowardstheregulationofinsulinsensitivity.IRS1hasbeenlinkedtocolorectalcanceranddietviatheregulationofplasmainsulinlevels.Thus,variationofIRS1functionmayhaveimplicationsincolorectalcancer(2).IRS1hasseveralSer/ThrphosphorylationsitesincludingSer312,whichissensitivetoTNF-alphaorcalyculinAtreatment(3)andSer636/639,whichisassociatedwithS6KandmTORactivation(4).

References:

1.Ogihara,T.etal:14-3-3proteinbindstoinsulinreceptorsubstrate-1,oneofthebindingsitesofwhichisinthephosphotyrosinebindingdomain.J.Biol.Chem.272:25267-25274,1997.2.Slattery,ML.etal:GeneticvariationinIGF1,IGFBP3,IRS1,IRS2andriskofbreastcancerinwomenlivinginsouthwesternUnitedStates.BreastCancerResTreat.2007.3.Gao,Z.etal:Serinephosphorylationofinsulinreceptorsubstrate1byinhibitorkappaBkinasecomplex.JBiolChem.2002Dec13;277(50):48115-21.4.Khamzina,L.etal:Increasedactivationofthemammaliantargetofrapamycinpathwayinliverandskeletalmuscleofobeserats:possIBLeinvolvementinobesity-linkedinsulinresistance.Endocrinology.2005Mar;146(3):1473-81.