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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