SonicHedgehog(Shh)isoneofafamilyofthreesecretedproteins,includingIndianHedgehog(Ihh)andDesertHedgehog(Dhh),thatplaydistinctandcrucialrolesindevelopment.ThemorphogenicsignalShhprovidesinthedevelopingCNSinducesproliferationofneuronalprecursorcellsinthedevelopingcerebellumandothertissues.ProliferativesignalingbyShhisinvolvedinthedevelopmentofcancer,includingspecificbrainandskincancerssuchasbasalcellcarcinomas,whileactivationofShhsignalinginneuronsmayalsoprovideameanstoinduceneuronalregeneration.MitogenicShhsignalingdoesnotappeartoinvolveMapkinasepathways,butmayinvolveinductionofCyclinD1expressiontomaintainRbinthehyperphosphorylatedstateandallowprogressionthroughtheG1phaseofthecellcycle.ActivationofmycmaybeonemechanismbywhichShhinducescellcycleprogression.ActivationofShhproliferativesignalingoccursthroughbindingtoareceptorcomplexincludingPatched(Ptc-1)andSmoothened,aG-proteincoupledreceptor.PatchedisanintegralmembraneproteinwithtwelvetransmembranedomainsthatactsasaninhibitorofSmoothenedactivation.PatchedhasbeenclassifiedasatumorsuppressorduetoitsinhibitionofSmoothenedandthepresenceofinactivatedPtc-1mutationsinsomecancers.OnepossibilityisthatPtc-1,whichresemblestransmembranechannels,maynotdirectlyassociatewithSmoothenedbutmayrepressSmoothenedsignalingbytransportinganendogenousSmoothenedinhibitoracrosstheplasmamembraneintothecytoplasm.Smallnon-peptidicagoNISTsandantagonistsoftheShhpathwayhavebeenidentifiedandappeartoactattheleveloftheSmoothenedreceptor,providingpharmacologicaltoolstostudyShhsignaling.ThepathwaydownstreamoftheSmoothenedreceptorhasremainedsomewhatunclear,butinvolvestheGlifamilyoftranscriptionalactivators,includingGli-1,Gli-2,andGli-3,homologsofthedrosophilagenecubitisinterruptis.KinasesincludingGSK-3andPKAopposeactivationoftheShhpathway,perhapsbyregulatingthestABIlityofShhpathwayintermediatesignalingfactorstranscriptionfactors.SupressorofFused(SUFU)interactsdirectlywithGliproteins,repressingShhsignalingwhileDyrk1isakinasethatactsbyadistinctpathwaytostimulateGli1activationoftranscription.ThemultiplicityoffactorsinvolvedinShhsignalingcreatesmanyopportunitiesfortherapeuticinterventioninthetreatmentofcancerandpossIBLyneurodegenerativediseases.

Contributor:GlennCroston,PhD

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