UniProtSummary | FUNCTION:Serine/threoninekinasewhichactsasanessentialcomponentoftheMAPkinasesignaltransductionpathway.MAPK1/ERK2andMAPK3/ERK1arethe2MAPKswhichplayanimportantroleintheMAPK/ERKcascade.TheyparticipatealsoinasignalingcascadeinitiatedbyactivatedKITandKITLG/SCF.Dependingonthecellularcontext,theMAPK/ERKcascademediatesdiversebiologicalfunctionssuchascellgrowth,adhesion,survivalanddifferentiationthroughtheregulationoftranscription,translation,cytoskeletalrearrangements.ThetheMAPK/ERKcascadeplaysalsoaroleininitiationandregulationofmeiosis,mitosis,andpostmitoticfunctionsindifferentiatedcellsbyphosphorylatinganumberoftranscriptionfactors.About160substrateshavealreadybeendiscoveredforERKs.Manyofthesesubstratesarelocalizedinthenucleus,andseemtoparticipateintheregulationoftranscriptionuponstimulation.However,othersubstratesarefoundinthecytosolaswellasinothercellularorganelles,andthoseareresponsIBLeforprocessessuchastranslation,mitosisandapoptosis.Moreover,theMAPK/ERKcascadeisalsoinvolvedintheregulationoftheendosomaldynamics,includinglysosomeprocessingandendosomecyclingthroughtheperinuclearrecyclingcompartment(PNRC);aswellasinthefragmentationoftheGolgiapparatusduringmitosis.Thesubstratesincludetranscriptionfactors(suchasATF2,BCL6,ELK1,ERF,FOS,HSF4orSPZ1),cytoskeletalelements(suchasCANX,CTTN,GJA1,MAP2,MAPT,PXN,SORBS3orSTMN1),regulatorsofapoptosis(suchasBAD,BTG2,CASP9,DAPK1,IER3,MCL1orPPARG),regulatorsoftranslation(suchasEIF4EBP1)andavarietyofothersignaling-relatedmolecules(likeARHGEF2,FRS2orGRB10).Proteinkinases(suchasRAF1,RPS6KA1/RSK1,RPS6KA3/RSK2,RPS6KA2/RSK3,RPS6KA6/RSK4,SYK,MKNK1/MNK1,MKNK2/MNK2,RPS6KA5/MSK1,RPS6KA4/MSK2,MAPKAPK3orMAPKAPK5)andphosphatases(suchasDUSP1,DUSP4,DUSP6orDUSP16)areothersubstrateswhichenablethepropagationtheMAPK/ERKsignaltoadditionnalcytosolicandnucleartargets,therebyextendingthespecificityofthecascade. Actsasatranscriptionalrepressor.Bindstoa[GC]AAA[GC]consensussequence.Represstheexpressionofinterferongamma-inducedgenes.SeemstobindtothepromoterofCCL5,DMP1,IFIH1,IFITM1,IRF7,IRF9,LAMP3,OAS1,OAS2,OAS3andSTAT1.Transcriptionalactivityisindependentofkinaseactivity. CATALYTICACTIVITY:ATP+aprotein=ADP+aphosphoprotein. COFACTOR:MagnesiumBysimilarity. ENZYMEREGULATION:PhosphorylatedbyMAP2K1/MEK1andMAP2K2/MEK2onThr-185andTyr-187inresponsetoexternalstimulilikeinsulinorNGF.Bothphosphorylationsarerequiredforactivity.Thisphosphorylationcausesdramaticconformationalchanges,whichenablefullactivationandinteractionofMAPK1/ERK2withitssubstrates.PhosphorylationonSer-29bySGK1resultsinitsactivationbyenhancingitsinteractionwithMAP2K1/MEK1andMAP2K2/MEK2.DephospphorylatedandinactivatedbyDUSP3,DUSP6andDUSP9.Inactivatedbypyrimidylpyrroleinhibitors. SUBUNITSTRUCTURE:Bindsbothupstreamactivatorsanddownstreamsubstratesinmultimolecularcomplexes.BindstoHIV-1NefthroughitsSH3domain.Thisinteractioninhibitsitstyrosine-kinaseactivity.InteractswithADAM15,ARHGEF2,ARRB2,DAPK1(viadeathdomain),HSF4,IER3,IPO7,DUSP6,NISCH,SGK1,andisoform1ofNEK2.Interacts(phosphorylatedform)withCAV2("Tyr-19"-phosphorylatedform);theinteraction,promotedbyinsulin,leadstonuclearlocationandMAPK1activation.InteractswithMORG1,PEA15andMKNK2Bysimilarity.MKNK2isoform1bindingpreventsfromdephosphorylationandinactivationBysimilarity. SUBCELLULARLOCATION:Nucleus.Cytoplasm?Cytoskeleton?centrosome.Cytoplasm.Note:PEA15-bindingandphosphorylatedDAPK1promoteitscytoplasmicretention.PhosphorylationatSer-246andSer-248aswellasautophosphorylationatThr-190promotenuclearlocalization. DOMAIN:TheTXYmotifcontainsthethreonineandtyrosineresidueswhosephosphorylationactivatestheMAPkinases. PTM:PhosphorylateduponKITandFLT3signalingBysimilarity.DuallyphosphorylatedonThr-185andTyr-187,whichactivatestheenzyme.UndergoesregulatoryphosphorylationonadditionalresiduessuchasSer-246andSer-248inthekinaseinsertdomain(KID)Thesephosphorylations,whichareprobablymediatedbymorethanonekinase,areimportantforbindingofMAPK1/ERK2toimportin-7(IPO7)anditsnucleartranslocation.Inaddition,autophosphorylationofThr-190wasshowntoaffectthesubcellularlocalizationofMAPK1/ERK2aswell.Ligand-activatedALKinducestyrosinephosphorylation.DephosphorylatedbyPTPRJatTyr-187.PhosphorylationonSer-29bySGK1resultsinitsactivationbyenhancingitsinteractionwithMAP2K1/MEK1andMAP2K2/MEK2.DUSP3andDUSP6dephosphorylatespecificallyMAPK1/ERK2andMAPK3/ERK1whereasDUSP9dephosphorylatesabroaderrangeofMAPKs. SEQUENCESIMILARITIES:Belongstotheproteinkinasesuperfamily.CMGCSer/Thrproteinkinasefamily.MAPkinasesubfamily. Contains1proteinkinasedomain. SEQUENCECAUTION:ThesequenceCAA77753.1differsfromthatshown.Reason:Erroneousinitiation.TranslationN-terminallyextended. |