Seeonlineversionforlegendandreferences.246Cell128,March23,2007©2007ElsevierInc.DOI10.1016/j.cell.2007.03.011SnapShot:NotchSignalingPathwayMa.XeniaG.IlaganandRaphaelKopanDepartmentofMolecularBiologyandPharmacology,WashingtonUniversitySchoolofMedicine,St.Louis,MO630,USASnapShot:NotchSignalingPathwayMa.XeniaG.IlaganandRaphaelKopanDepartmentofMolecularBiologyandPharmacology,WashingtonUniversitySchoolofMedicine,St.Louis,MO630,USA246.eCell128,March23,2007©2007ElsevierInc.DOI10.1016/j.cell.2007.03.011TheNotchsignalingpathwayisashort-rangecommunicationtransducerthatisinvolvedinregulatingmanycellularprocesses(proliferation,stemcellandstemcellnichemaintenance,cellfatespecification,differentiation,andcelldeath)duringdevelopmentandrenewalofadulttissues.Notchsignalingismediatedbyproteolysisanddoesnotappeartoinvolveanysecondarymessengers.However,dependingoncellularcontext,theamplitudeandtimingofNotchactivitycanberegulatedbyposttranslationalmodificationstoligandsandreceptorsandtheirtrafficking.(1)ReceptorMaturationNotchreceptorsarelargesinglepasstypeItransmembraneproteins.Upontranslation,theNotchproteinisfucosylatedbythechaperoneO-fut,amodificationes-sentialfortheproductionofafunctionalreceptor.IncellsexpressingFringe,thefucoseisextendedbytheglycosyltransferaseactivityofFringe,alteringtheabilityofspecificligandstoactivateNotch(seebelow).Thematurereceptorundergoesproteolyticcleavagebyproteinconvertases(PC5;Furin)atsite1(S1)andthenistargetedtothecellsurfaceasaheterodimerheldtogetherbynoncovalentinteractions.(2)EndosomalSortingSeveralmechanismscontrolthesteady-statelevelsoftheNotchreceptoratthecellsurfaceandthereforeregulateitsavailabilityforbindingofligand.Forexample,Numb,incooperationwiththeAP2componentα-adaptinandAP2-orNumb-associatedkinase(NAK),canpromoteNotchendocytosisanddegradation.SeveralE3ubiquitinligases—Deltex,Nedd4,Su(Dx)/Itch,Cbl—targetNotch,shiftingreceptortraffickingtowarddegradationorrecycling.Otherproteinspreventinappropriatereceptoractivationintheabsenceofli...
