Notchisalargecell-surfacereceptorthatisactivatedbycontactwithmembrane-boundligandsonneighboringcells.TheligandsthatactivateNotchincludeDeltaandSerrate,andLag-2isaNotchligandinc.elegans.ActivationofNotchbybindingwithitsligandonthesurfaceofneighboringcellsisinvolvedinseveraldevelopmentalpathways,helpingtodeterminecellfate.MuchoftheearlyinsightintoNotchsignalingwasderivedfromgeneticstudiesinDrosophilaandC.elegansmodels.Threedifferentproteolyticstepsprocessthe300kDprecursorofmatureNotch.Oneproteaseisafurin-likeenzymethatcleavesNotchconstitutivelyadjacenttotheaminoacidsequenceRQRRintheextracellulardomain.AnotherproteolyticstepinNotchprocessingiscarriedoutbyTACE,alsoknownasADAM17.BindingofextracellularligandtoNotchalsoinducescleavageatthetransmembraneregionbyagamma-secretaseactivitythatisdependentonpresenilin-1.Theexactidentityofthepolypeptidethatcatalyzesthegamma-secretaseenzymeactivityhasbeendebated.LabelingofpresenilinwithirreversIBLegamma-secretasetransitionstateinhibitorsindicatesthatisitselfinfactthesiteofproteaseactivity(Esleretal.2000).Ithasalsobeenarguedthatthegammasecretaseisnotpresenilin-1itself,butanotherpolypeptidethatrequiresNotchforitsactivityandisdistinctfromPresenilin-1(Taniguchietal,2002).CleavageofNotchintheextracellulardomainreleasestheNotchintracellulardomain(NCID)whichmigratesintothenucleuswhereitassociateswithCSLtranscriptionfactorsandactsasatranscriptionalcoactivator.TheproteolyticprocessingofNotchresemblesinseveralwaystheproteolyticprocessingofamyloidpresursorprotein(APP)thatisimplicatedinplaqueformationinAlzheimer’sdisease,withTACEandPresenilin-1implicatedinproteolyticprocessingofbothNotchandAPP.

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REFERENCES:BartDeStrooperandWimAnnaert.Presenilinsandtheintramembraneproteolysisofproteins:factsandfiction.NatureCellBIOLOGy.3:E221-E225(2001)Esler,W.P.etal.(2000)Transition-stateanalogueinhibitorsofgamma-secretasebinddirectlytopresenilin-1.NatCellBiol2(7),428-34HaraldSteinerandChristianHaass.IntramembraneProteolysisbyPresenilins.NatureReviews.MolecularCellBiology.1:217-224(2000).Logeat,F.etal.(1998)TheNotch1receptoriscleavedconstitutivelybyafurin-likeconvertase.ProcNatlAcadSciUSA95(14),8108-12Mumm,J.S.etal.(2000)Aligand-inducedextracellularcleavageregulatesgamma-secretase-likeproteolyticactivationofNotch1.MolCell5(2),197-206Schroeter,E.H.,Kisslinger,J.A.,Kopan,R.(1998)Notch-1signallingrequiresligand-inducedproteolyticreleaseofintracellulardomain.Nature393(6683),382-6Selkoe,D.J.(2001)Presenilin,Notch,andthegenesisandtreatmentofAlzheimersdisease.ProcNatlAcadSciUSA98(20):11039-41Taniguchi,Y.etal.(2002)Notchreceptorcleavagedependsonbutisnotdirectlyexecutedbypresenilins.ProcNatlAcadSciUSA99(6),4014-9

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