1286Cell127,December15,2006©2006ElsevierInc.DOI10.1016/j.cell.2006.12.005Seeonlineversionforlegendandreferences.SnapShot:NF-kBSignalingPathwaysMatthewS.Hayden,A.PhillipWest,andSankarGhoshDepartmentsofImmunobiologyandMolecularBiophysicsandBiochemistry,YaleUniversitySchoolofMedicine,NewHaven,CT06519,USA1286.e1Cell127,December15,2006©2006ElsevierInc.DOI10.1016/j.cell.2006.12.005SnapShot:NF-kBSignalingPathwaysMatthewS.Hayden,A.PhillipWest,andSankarGhoshDepartmentsofImmunobiologyandMolecularBiophysicsandBiochemistry,YaleUniversitySchoolofMedicine,NewHaven,CT06519,USAFigureLegend(A)Toll-likereceptorsignaling.AToll-likereceptor(TLR)boundtoligandrecruitsTIR-containingadaptormolecules,MyD88and/orTRIF,whichbindtodownstreamef-fectorsIRAK1-4andRIP1,respectively.ActiveIRAKsbindtoTRAF6andTAK1,whichsubsequentlyactivatetheIKKcomplex.UbiquitinationofTRAFandtheregulatorysubunitoftheIKKcomplex,NEMO,facilitatesactivationofthecatalyticIKKβsubunit.ThisresultsinthephosphorylationandproteasomaldegradationofIkBandthereleaseofheterodimersofthemastertranscriptionfactorNF-kB.(B)TNFreceptorsignaling.SignalingviamembersoftheTNFreceptorsuperfamily,suchasTNFR1,leadstorecruitmentoftheadaptorproteinsFADDandTRADD,severalTRAFfamilymembers(TRAF2,5,and6),andthekinaseRIP1.TheTRAF/RIPcomplexrecruitsandactivatesTAK1,whichinducesactivationoftheIKKcomplexanddownstreamsignalingviatheNF-kBpathway.Whenstimulated,asubsetofTNFRsuperfamilymembersthatbindtoTRAF3(CD40,LTβR,BAFFR)induceTRAF3degradationresultinginaccumulationofthekinaseNIK,whichundergoesconstitutivedegradationintheabsenceofstimulation.AccumulatedNIKphosphorylatesandactivatesIKKα.IKKα,inturn,inducesprocessingoftheNF-kBfamilymemberp100intop52and,thus,activationofp52-containingNF-kBcomplexes(prototypicallyRelB:p52).(C)Antigenreceptorsignaling.SignalingviatheTcellreceptor(TCR),oranalogouslythroughtheBcellreceptor(BCR),recruitstheSrcfamilytyrosinekinases,ZAP70andSyk,leadingtoproductionofinositide-3-phosphate(IP3)anddiacylglycerol(DAG).Activationof...
