TNFactsonseveraldifferentsignalingpathwaysthroughtwocellsurfacereceptors,TNFR1andTNFR2(SeeTNFR1andTNFR2SignalingPathways)toregulateapoptoticpathways,NF-kBactivationofinflammation,andactivatestress-activatedproteinkinases(SAPKs).InteractionofTNFR1withTRADDleadstoactivationofNF-kBandapoptosispathways,whileinteractionwithTRAF2hasgenerallybeenthoughttobeinvolvedinstresskinaseandNF-kBactivationbutisnotrequiredforTNFtoinduceapoptosis.ActivationofNF-kBismediatedbyTRAF2throughtheNIKkinaseandalsobyRIPbuttheobservationthatTNFactivatesNF-kBinmicelackingTRAF2indicatesthatTRAF-2doesnotplayanessentialroleinthisprocess.Stress-activatedproteinkinases,alsocalledJNKs,areafamilyofmapkinasesactivatedbycellularstressandinflammatorysignals.BindingofTNFtotheTNFR1receptoractivatesthegerminalcenterkinase(GCK)throughtheTNFadaptorTraf2,activatingthemapkinaseMEKK1.BothGCKandMEKK1interactwithTraf2,andGCKisrequiredforMEKK1activationbyTNF,butGCKkinaseactivitydoesnotappeartoberequiredforMEKK1activation.Instead,GCKactivatesMEKK1bycausingMEKK1oligomerizationandautophosphorylation.TankincreasestheaffinityofTraf2forGCKtoincreaseMapkinaseactivationbyTNF.Onceactivated,MEKK1standsatthetopofamapkinasepathwaysleADIngtotranscriptionalregulation,includingJNKphosphorylationofc-JuntostimulatetranscriptionalactivationbyAP-1,aheterodimerofc-junandfosorATFproteins.Theactivationofthep38MapkinasealsocontributestoAP-1activationleadingtothetranscriptionalactivationofmanystressandgrowthrelatedgenes.RIPhasbeensuggestedasacomponentofthep38pathwayinadditiontoplayingaroleinNF-kBactivation.MEKK1knockoutmicesupporttheroleofMEKK1inJNKactivationinsomecellsbutdidnotsupportMEKK1dependentactivationofNF-kB.AlternativeredundantmechanismsmayobscuretheroleofMEKK1inNF-kBmechanisms.TNFactivationofstresskinasepathwaysanddownstreamtranscriptionfactorsmayhelptomodulatetheapoptoticpathwaysalsoactivatedbyTNF.

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