Seeonlineversionforlegendandreferences.612Cell131,November2,2007©2007ElsevierInc.DOI10.1016/j.cell.2007.10.033SnapShot:JAK-STATSignalingClaudiaMertensandJamesE.DarnellJr.LaboratoryofMolecularCellBiology,TheRockefellerUniversity,NewYork,NY10065,USA612.e1Cell131,November2,2007©2007ElsevierInc.DOI10.1016/j.cell.2007.10.033SnapShot:JAK-STATSignalingClaudiaMertensandJamesE.DarnellJr.LaboratoryofMolecularCellBiology,TheRockefellerUniversity,NewYork,NY10065,USATheJAK(Januskinase)-STAT(signaltransducerandactivatoroftranscription)signalingpathwayisinvolvedintransmittinginformationfromextracellularpolypeptidesignalstotargetgenepromotersinthenucleus.JAK-STATsignalingregulatesmanycellularprocessesincludinginnateandadaptiveimmunefunction,development,cellproliferation,differentiation,andapoptosis.TheprincipalplayersofthepathwayaretheSTATproteins,afamilyoflatentcytoplasmictranscriptionsfactors.AllsevenmammalianSTATproteins(STAT1,2,3,4,5A,5B,6)sharesixstructuralregions:anN-terminaldomain(ND),acoiled-coildomain(CC),aDNA-bindingdomain(DBD),alinkerdomain(L),aSrchomology2(SH2)domain,andatranscriptionactivationdomainatthecarboxy(C)terminus.Asingletyrosineresidue(Y~700)withintheCterminusisphosphorylated(reddot)whenthemoleculeisactivated.(SpecificmodificationsforindividualSTATsareindicatedwhereknown.)Priortoactivation,unphosphorylatedSTATproteinsformstabledimersinthecytoplasm,whicharestructurallydistinctfromthetyrosine-phosphorylatedSTATdimersthatformafteractivation.UnphosphorylatedSTAT1andSTAT5dimerizethroughtheirN-terminaldomainsandthroughaCC:DBDdomaininteractioninan“antiparallel”conformation(theSH2domainsofthetwomoleculesinthedimerpointinoppositedirections).STATseithermayhavetoformdimersinordertobephosphorylated(STAT4)ormaybeactivatedasmonomers.ThecanonicalJAK-STATsignalingpathwayisinitiatedbybindingofacytokineligandtoacell-surfacecytokinereceptor.TheintracellulardomainsofmanycytokinereceptorsarephysicallyassociatedwithtyrosinekinasesoftheJAKfamily.TherearefourmammalianJAKs(JAK1...
