Thehepatocytegrowthfactorreceptor,alsocalledc-Met,isactivatedbyHGFandstimulatesproliferationofhepatocytesandothercelltypes.MutatedformsoftheHGFreceptorareassociatedwithoncogenesisandmetastasis,makingtheHGFreceptorapotentialtherapeutictargetforcancerdrugs.Changesincellmotility,cellshape,adhesion,resistancetoapoptosis,andanchorageindependentgrowthallcontributetotheroleofc-Metincancer.TheHGFreceptorisaheterodimerwithtyrosinekinaseactivityandassociateswithamultiproteincomplexinvolvedindownstreamsignaltransduction.TheHGFreceptorcanassociatewithseveraldifferentsignalingsystems,includingsrc,Grb2/SOS,PI3kinaseandGab1.OneofthemajorsubstratesoftheactivatedHGFreceptortyrosinekinaseistheadaptorproteinGab1.Gab1interactswithCrkandCrkL,twoproteinswithSH2andSH3proteininteractiondomainsthatcoupletosignalingfurtherdownstream.TheactionsofHGFonpaxillin,DOCK180andRap1mediatedthroughGAB1andothermembersofthiscomplexaltercellmotility.RegulationofRho,Rac1andCDC42pathwaysinresponsetoHGFallcontributetochangesincellularmotility.AnothertargetoftheHGFreceptorkinaseisthefocaladhesionkinase,FAK.TheactivationofFAKinducestheformationoffocaladhesions,apreliminarysteptoincreasedcellmotilityandtissueinvasionbytransformedcells,andpaxillinphosphorylationmayalsoaltercelladhesionofMettransformedcells.Srcandp130casarerequiredfortheroleofFAKinHGFinducedcellulartransformation.HGFalsoblocksanoikis,theinductionofapoptosisthroughsUSPensionofcells,byactingonErkandAKTkinases.ThisactivitymaycontributetoanchorageindependentgrowthofMettransformedcells.SignalingbyintegrinsalsoplaysakeyroleintheactivationoftissueinvasivegrowthbyHGF.Thealpha6beta4integrinactsasacofactoralongwithMetatoparticipateincellgrowthandproliferation.Inadditiontoalteringcelladhesion,proliferationandcellmotility,HGFalterscellulartranscriptionthroughactivationofSTAT3.STAT3activationbyHGFisindependentofPI3kinaseormapkinasesandaltersgeneexpressionleADIngtochangesincellularshape.AlthoughHGFisassociatedwithcellularproliferationandsurvival,inratliverepithelialcellsHGFinducesapoptosisandinhibitscellgrowth.

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