Thebindingof?-arrestinstoagoNIST-occupiedGPCRstriggerstheassemblyofaMAPkinaseactivationcomplexusing?-arrestinasascaffold,withsubsequentactivationofa?-arrestin-boundpoolofERK1/2.Thereceptor—?-arrestin—ERKcomplexesarelocalizedtoendosomalvesicles,andtheirformationdoesnotresultinnucleartranslocationofactivatedERK1/2orstimulationofcellproliferation.Thefunctionof?-arrestin-boundERK1/2ispresentlyunknown.ActivationofERK1/2by?-arrestinscaffoldsmayfavorthephosphorylationofplasmamembrane,cytosolic,orcytoskeletalERK1/2substrates,oritmayleadtotranscriptionalactivationthroughtheERK-dependentactivationofotherkinases.Themodeldepicts?-arrestinscaffoldingoftheERK1/2MAPkinasecascade,basedupondataobtainedwiththeprotease-activatedPAR2andangiotensinAT1areceptors.AsimilarmechanismhasbeenproposedforregulationoftheJNK3MAPkinasecascadebyAT1areceptors.

Contributor:KosiGramatikoff,PhD

REFERENCES:AndrewJetal.PhysiologicalRegulationofGProtein-LinkedSignalingPhysiolRev,Oct1999;79:1373-1430.K.Palczewski.StructureandfunctionsofarrestinsProteinSci.,Sep1994;3:1355-1361.KLPierceandRJLefkowitz.Classicalandnewrolesofbeta-arrestinsintheregulationofG-protein-coupledreceptors.NatRevNeurosci,Oct2001;2(10):727-33.MoritzBünemannandM.MarleneHosey.G-proteincoupledreceptorkinasesasmodulatorsofG-proteinsignalingJ.Physiol.,May1999;517:5-23.RobertJ.Lefkowitz.GProtein-coupledReceptors.III.Newrolesforreceptorkinasesand-arrestinsinreceptorsignalinganddesensitization.J.Biol.Chem.,Jul1998;273:18677-18680.