Theeverevolvingmitogen-activatedproteinkinase(MAPkinase)pathwaysconsistoffourmajorgroupingsandnumerousrelatedproteinswhichconstituteinterrelatedsignaltransductioncascadesactivatedbystimulisuchasgrowthfactors,stress,cytokinesandinflammation.ThefourmajorgroupingsaretheErk(red),JNKorSAPK(blue),p38(green)andtheBigMAPKorERK5(lightblue)cascades.SignalsfromcellsurfacereceptorssuchasGPCRsandgrowthfactorreceptorsaretransduced,directlyorviasmallGproteinssuchasrasandrac,tomultipletiersofproteinkinasesthatamplifythesesignalsand/orregulateeachother.Thediagramisorganizedtoillustratethecascadesbythebackgroundcolorsandalsothetiersofkinasesasindicateddownthelefthandsideandseparatedbythehorizontaldashedlines.InsomecascadesthefirstactivationtierinvolvestheMAPKKKKs,MAPkinasekinasekinasekinasesorMAP4Kproteins.Thenexttieraretheserine/threonineMAPKKKs,MAPkinasekinasekinaseorMAP3KssuchasRAF,TAK,ASK,andMEKK1.Thislevelhasthegreatestamountofcross-communicationcurentlyknown.Theserine/threonine/tyrosineMAPKKs,MAPKinasekinasesorMAP2Ks,suchastheMKKandMEKkinases,areonestepupfromtheMAPkinasecascade,phosphorylatingandactivatingthesekinases.Thefocaltier,theMAPKsorMAPkinasesincludesJNK1,p38,andERKs,andarethekinasesthatgiveeachcascadeitsnameBR>Theendpointsofthesecascades,showninthebottomtier,includestheMAPKactivatedproteinkinases(MAPKAPK)andsomeofthenumeroustranscriptionfactorsthatregulategenesinvolvedinapoptosis,inflammation,cellgrowthanddifferentiationNOTES:-Thesharedcolorandtheboldarrowsshowthemajorflowofeachcascade.-Thesmallerarrowsindicatecrosscommunicationbetweencascades.Inmanycasesthisisrestrictedtocertaincelltypesorrequiresadditionalfactors.-KinasesthathavebeenidentifiedasMAPkinasesbasedonsequenceorstructuralhomolgiesbuthavenotyetbeenassignedtoacascadehavebeenplacedoutsidethegroupingbackrgounds.-ThePAKs(p21associatedkinases)arenotMAPKsbutparticipateinthetransductiontotheJNKcascadeareincludedforthisreason.)-MEK4appearstofunctioninboththeJNKandp38cascadesandsohasamixedcolor.MEK4signalismuchstrongerintheJNKthanthep38cascadeandsotheboldarrowtowardstheJNKandthedashedarrowtowardsthep38cascadeindicatetherelativestrengthsofsignaling.-ForspaceandreadABIlityconcernsnotallinteractionsandstimuliareindicatedandthescaffoldandphosphataseproteinsarenotshown.

Contributor:GlennCroston,PhD,RogerAnderson,PhD

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