BackgroundInformation | FAK(FocalAdhesionKinase)isanon-receptortyrosinekinasewhichlocalizestofocaladhesionsandplaysakeyroleinintegrin-mediatedsignalingpathwaysregulatingcellmigration.Itautophosphorylatesontyrosine397duringadhesionandspreADIng,andisthoughttobeacriticaltransducerofadhesion-dependentgrowthandsurvival.FAKanditphosphorylationstateshavebeenimplicatedincancermetastasisandtumorcellsurvivalandadhesion-independentgrowth.Additionally,recentevidenceindicatesthatelevationofFAKactivityinhumancarcinomacellsisassociatedwithincreasedinvasivepotential.AcentralroleintumorformationandprogressionsuggestthatFAKisanattractivetargetfortherapeuticintervention.Cellsurfaceintegrinswhenengagedwiththeirligandsleadtotherecruitmentofanumberofintracellularproteinstospecializedsitesofthecytoplasmicfaceintofocaladhesions.Thesefocaladhesionplaquesarecomposedofmanyproteinsthatincludekinases,phosphatases,scaffoldingproteins,andG-proteins.Theactivationofintegrinsleadstothetyrosinephosphorylationofseveralcytoplasmicproteinscriticaltothebiochemicalprocess,includingFAK,Src,paxillin,tensin,andp130Cas.Thisclusteringandactivationofproteinsatthemembraneleadstotheactivationofmanydivergingsignalingpathwaysthatresultincytoskeletalre-organization.ThisstartswitheithertherecruitmentofSrcandFAKtotheplasmamembranefollowingintegrinorPI3Kinaseactivation.Thenon-receptorprotein-tyrosinekinases(PTKs)FAKandSrcarekeymembersofthefocaladhesioncomplex.ThesePTKsco-Localizeandassociatewiththetransmembraneintegrinsandvariousdownstreamtargetsofcertaingrowthfactorreceptors.TheoutcomeofSrcbindingtoFAKisthephosphorylationofseveraltyrosineresiduesinFAKanditsrelatedproteins,includingtheFAKautophosphorylationsiteTyr397.ThisautophosphorylationoccursimmediatelyafterintegrinclusteringandallowsfortheassociationofFAKwithvarioussignalingproteinssuchasPI3kinase,Grb2-Sos,p130Cas,andpaxillin.ThephosphorylationofFAKTyr397iscrucialformanyoftheestablishedBIOLOGicalrolesofFAK,includingcellmigration,cellcycleprogression,andpreventionofanoikis,aformofdetachment-inducedapoptosisandiscorrelatedwiththeinvasivenessoftumorsandisthoughttobeapivotalplayerbymodulatingtheturnoveroffocaladhesionstoregulatecellmigration.Phosphoinositide3-Kinase(PI3kinaseorPI3K)alsoplaysaroleincellmigrationviaitsbindingtotheautophosphorylationsite(Tyr397)ofFAKthroughoneorbothofitsSH2domainsinthep85subunitofPI3K.ThisisthesamesiteinFAKthatisboundbySrc.Intheory,thebindingofPI3kinasetoFAKmaybeinvolvedinactivitieslikecellproliferation,apoptosis,andmigrationthatarerelatedtothephosphorylationofTyr397.ThisissubstantiatedbytheobservationthatAKTisdownstreamofPI3kinaseandisamediatorinpreventingapoptosis.ThereforeitispossIBLethatFAK/PI3kinaseassociationmayhelpregulateapoptosis. |