Progressionthroughthecellcycleisaccompaniedbyactivationoftheproto-oncogenec-Src,aproteintyrosinekinase.OverexpressionofSrcleadstotyrosinephosphorylationofmultipleproteinsubstratesandcellulartransformation.DuringinterphasetheSrcproteinfoldsbackuponitselftostayintheinactivestate,withaphophotyrosineresidueinonedomainatTyrosine529boundbyanSH2domaininthesameprotein.Activationofc-Srcinvolvesprotein-tyrosinephosphatasealpha(PTP-alpha,orRPTP-alpha),atransmembraneproteinwithacytoplasmicphosphatasedomain.AvarietyofevidencehasindicatedthatPTP-alphadephosphorylatesc-SrcatTyr529,allowingSrctoopenupandbecomeactivated,andthatthisactivationoccursinassociationwithmitosis.ToactivateSrc,PTP-alphamustfirstopenupthefoldedSrcthroughbindingitselftothephosphorylatedSrcdomain,aprocessblockedbybindingofGrb-2toPTP-alphaatphosphorylatedTyr789.PTP-alphaphosphorylatedatTyr789alsobindstotheSrcSH2domain,causingtheSrcstructuretoopenatSrcTyr529tobecomeavailablefordephosphorylation.DuringmitosisthemitotickinaseCdc-2phosphorylatesSrc,alongwithothercellularsubstrates,andinsodoingmakesSrcmorepronePTP-alphadephosphorylationandactivation.TheactivityofPTP-alphatowardSrcisalsoregulatedbyphosphorylationofPTP-alphabyproteinkinaseCatserines180and204,releasingtheinhibitionofPTP-alphabyGrb-2.Inthenormalcellcycle,Srcactivityisdown-regulatedaftercelldivisionthroughdephosphorylationbyproteinphosphatasesandphosphorylationbyCsk(C-terminalsrckinase)andPTP-alphadephoshorylationreturnsthecycletoitsinterphasecondition.TheregulationofSrcactivityduringmitosisdemonstrateshowproteinphosphorylationcanshiftsthedelicateequilibriumofmolecularinteractionsandcellularresponses.

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REFERENCES:TomasMustelinandTonyHunter.MeetingatMitosis:CellCycle-SpecificRegulationofc-SrcbyRPTPa.Sciencesstkejan15,2002.Xin-MinZhengandDavidShalloway.TwomechanismsactivatePTPaduringmitosis.TheEMBOJournalVol.20No.21pp.6037-49,2001.