Axonsextendsignificantdistancestoinnervatetargettissues.Atthesiteofinnervation,targettissuesreleaseneurotrophinsincludingNGF,BDNFandneurotrophin-3thatstimulatethesurvivaloftheassociatedneuron.LocalsignalingbyactivatedTrkreceptorsatthesynapticterminusmediatessomepresynapticneuronalresponsestoneurotrophins.MapkinasepathwaysactivatedbyTrkreceptoractivateErk1andErk2attheterminusstimulatingaxonalgrowth,andPI3KactivatesAKTintheterminusaswell.Activationofthesekinasesdoesnotpropagateasignaltothecellbodythoughanddoesnotinduceatranscriptionalresponse.Thislocalsignalingattheterminusorlocalsignalingatthecellbodyappearsdistinctfromthesignalingpathwaythattransducesthesurvivalsignalfromthetargettissue.Retrogradeaxonaltransportplaysanessentialroleinneuronalsurvivalinducedbyneurotrophinsreleasedatthetargettissue.Failureofretrogradeneurotrophinsignalingmayplayaroleinneurodegenerativeconditions.TheneuronalsurvivalsignalisinitiatedbybindingofneurotrophinstoTrkreceptorsinthepresynapticmembrane,thentravelsbackalongtheaxontotheneuronalcellbody.Totransmitthesignalbackalongtheaxon,activatedTrkreceptorsareinternalizedthroughreceptor-mediatedendocytosisandreceptorcontainingvesiclesthenrapidlytravelbacktothecellbodyalongaxonalmicrotubules.Severalreportsindicatethatneurotrophinsremainreceptor-boundduringtheretrogradeaxonaltransporttothecellbody,butrecentlyitwasreportedthatretrogradetransportofNGFwasnotrequiredtoinduceneuronalsurvival.Onceinthecellbody,Trkreceptorsactivatemultiplepathways.AkeypathwayactivatedbyTrkafterretrogradetransportinvolvesErk5,alsocalledBMK1.TrkactivatesMek5,whichactivatesErk5,inducingphosphorylationoftheCREBandMef2transcriptionfactors.Erk5doesnotdirectlyphosphorylateCREB,buttranslocatesintothenucleusandphosphorylatesthekinaseRsk,whichphosphorylatesCREBinturn.BothCREBandMef2induceatranscriptionalprogramthatcontributestoneuronalsurvival.LocalactivationofErk5onthecellbodydoesnotappeartoinducethesamesignalingsystemorneuronalsurvival,indicatingthattheretrogradetransportisanessentialpartofthesurvivalsignalingsystem.Also,activationofErk1andErk2inthecellbodycaninduceCREBactivationandneuronalsurvival,butthesekinasesarenotactivatedbyneurotrophinsappliedtotheaxonalterminus.AnotherpathwayactivatedbyretrogradeneurotrophinsignalingthoughErk5isPI3Kinase.

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