Seeonlineversionforlegend,abbreviations,andreferences.1018Cell131,November30,2007©2007ElsevierInc.DOI10.1016/j.cell.2007.11.013SnapShot:EGFRSignalingPathwayYosefYardenandBen-ZionShiloTheWeizmannInstituteofScience,Rehovot76100,Israel1018.e1Cell131,November30,2007©2007ElsevierInc.DOI10.1016/j.cell.2007.11.013SnapShot:EGFRSignalingPathwayYosefYardenandBen-ZionShiloTheWeizmannInstituteofScience,Rehovot76100,IsraelTheepidermalgrowthfactorreceptor(EGFR/ErbB)pathwayplayspivotalrolesincell-cellcommunicationinbothvertebrateandinvertebrates.InDrosophilaandC.eleganstheEGFRpathwayparticipatesinthedeterminationofnumerouscellfates,includingthedevelopmentofthecompoundeyeandthevulva.ThefourEGFRorthologsinvertebratesformalayeredsignalingnetworkthatparticipatesinspecificationofcellfateandcoordinatescellproliferation.Mutationsincomponentsofthepathwayarecommonlyinvolvedinhumancancer.(1)Ligandprocessing:Differentmechanismsareemployedinvertebratesandinvertebratesforprocessingtheligandinthesignal-producingcelltogeneratethesecret-ed,activeform.InDrosophila,theligandprecursorforSpi,Grk,orKrnisretainedintheER.ItassociateswiththechaperoneStarandistraffickedtoalatecompartmentwheretheintramembraneproteaseRhomboidresides,cleavingtheligandtogeneratethesecretedform.RhomboidalsocleavesthechaperoneStar,thusattenuatingthelevelofligandthatistrafficked.Invertebrates,theligandprecursorsaretraffickedtotheplasmamembrane,wheretheyarecleavedbyADAMmetalloproteases.(2)Receptormaturation:ThenascentformsofEGFRanditssibling,HER2,associateintheERwithacomplexcomprisingtheHSP90chaperoneandthekinase-ded-icatedadaptor,CDC37.Uponglycosylationanddeliverytotheplasmamembrane,onlythematureformofHER2,aswellassomenaturallyoccurringEGFRmutants,remainassociatedwiththechaperone.InpolarizedtissuesthePDZdomainproteinsLIN-2,-7,and-10associatewithandstabilizethereceptorinthebasolateralsurface.(3)Receptordimerization:Intheabsenceofaligand,EGFRexistsinaconformationthatsuppresseskinaseactivityandrestrainsformationofreceptordimer...
