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3102008834ChinMedBiotechnol,August2008,Vol.3,No.4··Ras/Raf/MEK/ERKRas/Raf/MEK/ERKmitogen-activatedproteinkinaseMAPK[1]immediateearlygenesIEGIEG[2]Ras/Raf/MEK/ERKRas/Raf/MEK/ERKERKMEKMEK1/2ERKERK1/2RafMEKERKERKMEKMEKERKERKS6ribosomalproteinS6kinaseRSKcAMPresponsiveelementbindingproteinCREBIEGc-Fosc-Mycc-JunEgr1[3]ERKIEG[4]ERK2ERK/cyclin/cyclindependentkinasecyclin/CDK[5]ERKcyclinD1G1/ScyclinB/CDK1M[3]ERKcyclinD1cyclinD1p21cip1p21cip1[6]ERKERKPC12EGFERKNGFERKEGFReceptorEGFREGFERKPC12[7]ERKMEKERKRSKMEKERKRSKMEKNNESnuclearexportingsequenceCMEKERKMEKERKERKERK[8]100850Emailbigantcc@yahoo.com.cn2008-04-222008834ChinMedBiotechnol,August2008,Vol.3,No.4311ERKERKERK[9]Ras1kinasesuppressorofRasKSR1Raf-1MEKERKKSR1C[10]KSR1S392β1TGF-β-activatedkinase1c-TAK1[11]14-3-32Aproteinphosphatase2APP2AinosinemonophosphateIMP[12-13]S392KSR114-3-3KSR1MEKRaf14-3-3KSR1ERKFXFPERKRaf/MEK/ERK[14]Sef1similarexpressiontofgfgenes1ERKMEK/ERKERK[15]Sef1Ras[16]3-/BPI3K/AKTPI3K/AKTGPI3Kp85p110[17]CREBERKCREBPI3KLY294002ERKcyclinD1PI3KERK[18]PI3K/AKTAKTRaf-1S259B-RafS364S428Raf-114-3-3[19]15phosphoproteinenrichedinastrocytes15PEA15ERKERKPEA15ERKERKAKTPEA15ERK[20]ERKAKTPEA15ERKRSK2CREB[21]ERK[22][23]ERKRafA-RafB-RafRaf-13NIH-3T3A-RafRaf-1B-RafG1[14]ERKERKRaf-1Ras[24]ERK20ERKERKIIMEKPD184352PD0325901[25][1]MurphyLO,BlenisJ.MAPKsignalspecificity:therightplaceattherighttime.TrendsBiochemSci,2006,31(5):268-275.[2]MurphyLO,MacKeiganJP,BlenisJ.Anetworkofimmediateearlygeneproductspropagatessubtledifferencesinmitogen-activatedproteinkinasesignalamplitudeandduration.MolCellBiol,2004,24(1):144-153.[3]ChambardJC,LeflochR,PouysségurJ,etal.ERKimplicationincellcycleregulation.BiochimBiophysActa,2007,1773(8):1299-1310.[4]YamashitaM,ShinnakasuR,AsouH,etal.Ras-ERKMAPKcascaderegulatesGATA3stabilityandTh2differentiationthrough3122008834ChinMedBiotechnol,August2008,Vol.3,No.4ubiquitin-proteasomepathway.JBiolChem,2005,280(33):29409-29419.[5]LentsNH,KeenanSM,BelloneC,etal.StimulationoftheRaf/MEK/ERKcascadeisnecessaryandsufficientforactivationandThr-160phosphorylationofanuclear-targetedCDK2.JBiolChem,2002,277(49):47469-47475.[6]ColemanML,MarshallCJ,OlsonMF.Raspromotesp21(Waf1/Cip1)proteinstabilityviaacyclinD1-imposedblockinproteasome-mediateddegradation.EMBOJ,2003,22(9):2036-2046.[7]TraverseS,SeedorfK,PatersonH,etal.EGFtriggersneuronaldifferentiationofPC12cellsthatoverexpresstheEGFreceptor.CurrBiol,1994,4(8):694-701.[8]AdachiM,FukudaM,NishidaE.NuclearexportofMAPkinase(ERK)involvesaMAPkinasekinase(MEK)-dependentactivetransportmechanism.JCellBiol,2000,148(5):849-856.[9]MorrisonDK,DavisRJ.RegulationofMAPkinasesignalingmodulesbyscaffoldproteinsinmammals.AnnuRevCellDevBiol,2003,19:91-118.[10]KolesnickR,XingHR.InflammatoryboweldiseaserevealsthekinaseactivityofKSR1.JClinInvest,2004,114:1233-1237.[11]MüllerJ,OryS,CopelandT,etal.C-TAK1regulatesRassignalingbyphosphorylatingtheMAPKscaffold,KSR1.MolCell,2001,8(5):983-993.[12]OryS,ZhouM,ConradsTP,etal.Proteinphosphatase2ApositivelyregulatesRassignalingbydephosphorylatingKSR1andRaf-1oncritical14-3-3bindingsites.CurrBiol,2003,13(16):1356-1364.[13]MathenySA,ChenC,KortumRL,etal.RasregulatesassemblyofmitogenicsignallingcomplexesthroughtheeffectorproteinIMP.Nature,2004,427(6971):256-260.[14]ShaulYD,SegerR.TheMEK/ERKcascade:fromsignalingspecificitytodiversefunctions.BiochimBiophysActa,2007,1773(8):1213-1226.[15]ToriiS,KusakabeM,YamamotoT,etal.SefisaspatialregulatorforRas/MAPkinasesignaling.DevCell,2004,7(1):33-44.[16]RenY,ChengL,RongZ,etal.hSefco-localizesandinteractswithRasintheinhibitionofRas/MAPKsignalingpathway.BiochemBiophysResCommun,2006,347(4):988-993.[17]ChangF,LeeJT,NavolanicPM,etal.InvolvementofPI3K/Aktpathwayincellcycleprogression,apoptosis,andneoplastictransformation:atargetforcancerchemotherapy.Leukemia,2003,17(3):590-603.[18]ShengH,ShaoJ,DuboisRN.Akt/PKBactivityisrequiredforHa-Ras-mediatedtransformationofintestinalepithelialcells.JBiolChem,2001,276(17):14498-14504.[19]McCubreyJA,SteelmanLS,ChappellWH,etal.RolesoftheRaf/MEK/ERKpathwayincellgrowth,malignanttransformationanddrugresistance.BiochimBiophysActa,2007,1773(8):1263-1284.[20]WhitehurstAW,RobinsonFL,MooreMS,etal.ThedeatheffectordomainproteinPEA-15preventsnuclearentryofERK2byinhibitingrequiredinteractions.JBiolChem,2004,279(13):12840-12847.[21]VaidyanathanH,Opoku-AnsahJ,PastorinoS,etal.ERKMAPkinaseistargetedtoRSK2bythephosphoproteinPEA-15.ProcNatlAcadSciUSA,2007,104(50):19837-19842.[22]SoloagaA,ThomsonS,WigginGR,etal.MSK2andMSK1mediatethemitogen-andstress-inducedphosphorylationofhistoneH3andHMG-14.EMBOJ,2003,22(11):2788-2797.[23]StefanovskyVY,LangloisF,Bazett-JonesD,etal.ERKmodulatesDNAbendingandenhancesomestructurebyphosphorylatingHMG1-boxes1and2oftheRNApolymeraseItranscriptionfactorUBF.Biochemistry,2006,45(11):3626-3634.[24]DoughertyMK,MüllerJ,RittDA,etal.RegulationofRaf-1bydirectfeedbackphosphorylation.MolCell,2005,17(2):215-224.[25]KohnoM,PouyssegurJ.TargetingtheERKsignalingpathwayincancertherapy.AnnMed,2006,38(8):200-211.··3318220086262008627