NFkB Signaling Pathway

NuclearfactorkB(NF-kB)isanucleartranscriptionfactorthatregulatesexpressionofalargenumberofgenesthatarecriticalfortheregulationofapoptosis,viralreplication,tumorigenesis,inflammation,andvariousautoimmunediseases.TheactivationofNF-kBisthoughttobepartofastressresponseasitisactivatedbyavarietyofstimulithatincludegrowthfactors,cytokines,lymphokines,UV,pharmacologicalagents,andstress.Initsinactiveform,NF-kBissequesteredinthecytoplasm,boundbymembersoftheIkBfamilyofinhibitorproteins,whichincludeIkBa,IkBb,IkBg,andIkBe.ThevariousstimulithatactivateNF-kBcausephosphorylationofIkB,whichisfollowedbyitsubiquitinationandsubsequentdegradation.Thisresultsintheexposureofthenuclearlocalizationsignals(NLS)onNF-kBsubunitsandthesubsequenttranslocationofthemoleculetothenucleus.Inthenucleus,NF-kBbindswithaconsensussequence(5GGGACTTTCC-3)ofvariousgenesandthusactivatestheirtranscription.IkBproteinsarephosphorylatedbyIkBkinasecomplexconsistingofatleastthreeproteins;IKK1/IKKa,IKK2/IKKb,andIKK3/IKKg.TheseenzymesphosphorylateIkBleadingtoitsubiquitinationanddegradation.Tumornecrosisfactor(TNF)whichisthebest-studiedactivatorbindstoitsreceptorandrecruitsaproteincalledTNFreceptordeathdomain(TRADD).TRADDbindstotheTNFreceptor-associatedfactor2(TRAF-2)thatrecruitsNF-kB-induciblekinase(NIK).BothIKK1andIKK2havecanonicalsequencesthatcanbephosphorylatedbytheMAPkinaseNIK/MEKK1andbothkinasescanindependentlyphosphorylateIkBaorIkBb.TRAF-2alsointeractswithA20,azincfingerproteinwhoseexpressionisinducedbyagentsthatactivateNF-kB.A20functionstoblockTRAF2-mediatedNF-kBactivation.A20alsoinhibitsTNFandIL-1inducedactivationofNF-kBsuggestingthatitmayactasageneralinhibitorofNF-kBactivation.

Contributor:ChunWu,PhD,UshaPonnappan,PhD.UofArkansas

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