Migrationofcellsisinvolvedinessentialfunctionssuchasdevelopment,invasivenessofcancercells,leukocytemovementtowardchemotacticsignals,andfibroblastresponsetoinjury.CellscanmigrateinaspecificdirectioninresponsetoextracellularsignalsthroughpathwaysthattriggerchangesintheCytoskeleton,particularlyactinfilaments,increasinglamellipodiaandfilopodiaformationanddecreasingfocaladhesions.FactorslikePDGFactivatePI3kinaseandmultiplepathwaysdownstreamtostimulatecellmigration.Onepathwayregulatingmigrationthroughthep85regulatorysubunitofPI3kinasedoesnotrequirePI3-kinaseactivity.Inthispathway,p85ofPI3-kinaseactivatescdc42,whichactivatesN-Wasp(Wiskott-AldrichSyndromeProtein)toregulateARP-2/3.ARP-2/3isacomplexofproteinslocalizedattheleADIngedgeofmovingcellsthatnucleatestheformationofnewactinfibersandinteractswithWasptostimulatemigration.Thecdc42pathwayalsoregulatesp21-activatekinase1(PAK1).AnotherpathwaybywhichPI3kinaseregulatesmigrationisthroughthesmallGTPaseRac.PAK1isadownstreamtargetofRacaswellascdc42.DownstreamofRacandPAK1,Myosinlightchainkinase(MLCK)phosphorylatesmyosinlightchaintoincreasecellmigration.Theregulationofthelocalizationandactivityofsignalingfactorscreatescoordinatedpathwayslinkingextracellularsignalsandcellularmigration.

Contributor:GlennCroston,PhD

REFERENCES:JimenezCetal.JCellBiol2000Oct16;151(2):249-62.RoleofthePI3Kregulatorysubunitinthecontrolofactinorganizationandcellmigration.JonesGE.JLeukocBiol2000Nov;68(5):593-602.Cellularsignalinginmacrophagemigrationandchemotaxis.KlemkeRL.JCellBiol1997Apr21;137(2):481-92.Regulationofcellmotilitybymitogen-activatedproteinkinase.SellsMAetal.CurrBiol1997Mar1;7(3):202-10.Humanp21-activatedkinase(Pak1)regulatesactinorganizationinmammaliancells.

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