TrkA,theproductoftheproto-oncogenetrk,isamemberoftheneurotrophictyrosinekinasereceptorfamilythathasthreemembers.TrkA,TrkBandTrkCpreferentiallybindNGF,NT-4andBDNF,andNT-3,respectively.AllTrkfamilyproteinsshareaconservedcomplexsubdomainorganizationconsistingofasignalpeptide,twocysteine-richdomains,aclusterofthreeleucine-richmotifs,andtwoimmunoglobulin-likedomainsintheextracellularregion,aswellasanintracellularregionthatcontainsthetyrosinekinasedomain.TwodistinctratTrkAisoforms(TrkA-IandTrk-A-II)thatdifferbya6-aminoacidinsertionintheirextracellulardomainhavebeenidentified.ThelongerTrkAisoformistheonlyisoformexpressedwithinneuronaltissueswhereastheshorterTrkA-Iisexpressedmainlyinnon-neuronaltissues.NGFbindstoTrkAwithlowaffinityandactivatesitscytoplasmickinase,initiatingasignalingcascadethatmediatesneuronalsurvivalanddifferentiation.HigheraffinitybindingofNGFrequiresthecoexpressionofTrkAwiththep75NGFreceptor(NGFR),amemberofthetumornecrosisfactorreceptorsuperfamily.NGFRbindsallneurotrophinswithlowaffinityandmodulatesTrkactivityaswellasaltersthespecificityofTrkreceptorsfortheirligands.NGFRcanalsomediatecelldeathwhenexpressedindependentofTrk(Esposito,D.etal.,2001,J.Biol.Chem.276:32687;Sofroniew,M.V.etal.,2001,Annu.Rev.Neurosci.24:1217).