ActivationoftheMAPKkinasepathwayhasbeenidentifiedasamechanismthatintegrinsusetoregulategeneexpressionleADIngtocellshapechangesduringcellspreadingormigrationEpithelialcellsrespondtoextracellularmatrix(ECM)causeintegrin-mediatedFAKphosphorylationthatinturnphosphorylatesthesurroundingproteins(paxillin,Fyn/shc,andsrc)andleadstosignalamplification.FAKalsobindsPI-3kinaseandisupstreamoftheMAPkinasepathway.WhenMAPkinaseorPI-3kinasewasinhibited,actinreorganizationwasblocked.Srcphosphorylatesp190RhoGAP,inactivatingitsGAPfunctionthatmayallowRhoGTPtostayactivelonger,promotingfurthersignalamplification.ActivatedRhoGTPbindstodownstreamkinasessuchasRho-associatedcoiledcoil-containingproteinkinase(p160ROCK)andp140diaphanous(p140Dia)toincreaseactinpolymerizationandcontraction.Actinreorganizationassistsintegrinclustering,allowingmoreECMbindingthatincreaseFAKphosphorylationandothersignaltransductionevents.

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REFERENCES:ChiaLinChu,WendeR.Reenstra,DanielL.OrLow,andKathyKayHartfordSvoboa.ErkandPI-3Kinasearenecessaryforcollagenbindingandactinreorganizationincornelepithelia.InvestigativeOphthalmology&VisualScience,October2000vol.41,No.11.P3374