The-Interaction-Between-Signal-Regulatory-Protein-

IY32CH02-BarclayARI29October201315:59REVIEWSINADVANCETheInteractionBetweenSignalRegulatoryProteinAlpha(SIRPα)andCD47:Structure,Function,andTherapeuticTargetA.NeilBarclay1andTimoK.vandenBerg21SirWilliamDunnSchoolofPathology,UniversityofOxford,OxfordOX13RE,UK;email:[e-mail]2SanquinResearchandLandsteinerLaboratory,AcademicMedicalCenter,UniversityofAmsterdam,1066CXAmsterdam,TheNetherlands;email:[e-mail].2014.32:25–50TheAnnualReviewofImmunologyisonlineatimmunol.annualreviews.orgThisarticle’sdoi:10.1146/annurev-immunol-032713-120142Copyrightc2014byAnnualReviews.AllrightsreservedKeywordspairedreceptor,CD47,SIRPα,phagocytosis,cancer,inflammationAbstractCD47isabroadlyexpressedmembraneproteinthatinteractswiththemyeloidinhibitoryimmunoreceptorSIRPα(alsotermedCD172aorSHPS-1).SIRPαistheprototypicmemberoftheSIRPpairedreceptorfamilyofcloselyrelatedSIRPproteins.EngagementofSIRPαbyCD47providesadownregulatorysignalthatinhibitshostcellphagocytosis,andCD47thereforefunctionsasa“don’t-eat-me”signal.Here,wediscussre-centstructuralanalysisofCD47-SIRPαinteractionsandimplicationsofthisforthefunctionandevolutionofSIRPαandpairedreceptorsingeneral.Furthermore,wereviewtheproposedrolesofCD47-SIRPαinteractionsinphagocytosis,(auto)immunity,andhostdefense,aswellasitspotentialsignificanceasatherapeutictargetincancerandinflammationandforim-provinggraftsurvivalinxenotransplantation.25ReviewinAdvancefirstpostedonlineonNovember6,2013.(Changesmaystilloccurbeforefinalpublicationonlineandinprint.)ChangesmaystilloccurbeforefinalpublicationonlineandinprintAnnu.Rev.Immunol.2014.32.Downloadedfrom(PUMC)on11/20/13.Forpersonaluseonly.IY32CH02-BarclayARI29October201315:59SIRPα:signalregulatoryproteinalphaSHPS-1,CD172a,BIT,p84,MYD-1,PTPNS1:allacronymsfortheproteinmorecommonlytermedSIRPαPairedreceptor:termforafamilyofcloselyrelatedmembranereceptorsthatcontainatleastonememberwithinhibitoryandonewithactivatingpotentialsINTRODUCTIONSignalregulatoryproteinalpha,orSIRPα(alsoknownasCD172a),wasfirstidentifiedasamembraneproteinpresentmainlyonmacrophagesandmyeloidcellsthatwasassociatedwiththeSrchomologyregion2(SH2)domain–containingphosphatases—SHP-1andSHP-2;initiallyitwasalsotermedSHPS-1(1).SIRPαcontainsthreeIg-likedomains,asingletransmembraneregion,andacytoplasmicregionthatcontainsfourTyrresidues(1)withITIMmotifs(seesidebaronImmunoreceptorTyrosine-BasedInhibitoryMotif),astructurethatisconsistentwithSIRPα’sroleasaninhibitoryreceptor.TheligandwasidentifiedindependentlyasCD47inmouse(2),human(3),andrat(4);itwasalsoknownasintegrin-associatedprotein(IAP)becauseitisassociatedwithintegrinssuchasαvβ3.CD47isexpressedathighlevelsoncancercells,fromwhichitwasfirstcloned(5).CD47isanunusualproteininthatitcontainsfivetransmembraneregionstogetherwithasingleIg-likedomainthatinteractswiththeNH2-terminaldomainofSIRPα.Theinteractionplaysaroleincontrollingphagocytosis,andCD47isoftentermeda“don’t-eat-me”signalthroughitseffectonSIRPα(6,7).ThisreviewfocusesontheinteractionofCD47andSIRPαintheimmunesystem.Wediscussstructuralaspectsoftheinteraction,theSIRPpairedreceptorfamily,andtheimplicationsfortheevolutionofpairedreceptors.Wealsodiscussfunctionalanalysisoftheoutcomeoftheinteractionandstrongrecentinterestindevelopingtherapeuticstotargetthisinteractionincancerandxenotransplantation.BothSIRPαandCD47arealsopresentinthenervoussystem,butthisisdiscussedelsewhere(see,e.g.,2,8,9).MOLECULARANALYSISOFCD47ANDTHESIRPFAMILYTheSIRPPairedReceptorFamilyTheSIRPfamilyconsistsofaninhibitoryreceptor,SIRPα(SHPS-1orCD172a);anactivat-ingreceptor,SIRPβ1(CD172b);andanonsignalingreceptor,SIRPγ(CD172g)(Figure1)(6,10–13).1TherearealsosomemoredistantlyrelatedproteinssuchasSIRPδandSIRPβ2thathavenotyetbeencharacterized(Figure1).ThereisconsiderablevariabilityintherepertoireofSIRPgenesindifferentspecies,althoughSIRPαandSIRPβ1arepresentinmammalsandchickens(10,15).IMMUNORECEPTORTYROSINE-BASEDINHIBITORYMOTIFITIMisatandemarrangementoftwotyrosine-centeredpeptidemotifsinthecytoplasmictailofinhibitoryreceptors.Uponphosphorylationofthetyrosineresidues,theITIMmediatestherecruitmentandactivationofSH2domain–containingtyrosinephosphatases,suchasSHP-1andSHP-2,whichmayacttodephosphorylatephosphoproteinsubstratesandtherebyaffectintracellularsignalingpathways,mostofteninanegativefashion.Thespacingofthetyrosineresidues,whichislargerinITIMthaninITAM(immunotyrosinetyrosine-basedactivatingmotif),isamajordeterminantofspecificity(147).TheITIMsinsomereceptors,suchastheinhibitoryFcγRIIb,alsohavethecapacitytobindandactivatetheinositolphosphatasesSHIP-1andSHIP-2.1SIRPγwasoriginallycalledSIRPβ2,butisnowcalledSIRPγbecauseSIRPβisreservedforactivatinggenes(14).Thus,herein,SIRPγreferstotheoldtermSIRPβ2andSIRPβ1referstotheoldtermSIRPβ.26Barclay·vandenBergChangesmaystilloccurbeforefinalpublicationonlineandinprintAnnu.Rev.Immunol.2014.32.Downloadedfrom(PUMC)on11/20/13.Forpersonaluseonly.IY32CH02-BarclayARI29October201315