Roles of the Raf MEK ERK pathway in cell growth, m

ReviewRolesoftheRaf/MEK/ERKpathwayincellgrowth,malignanttransformationanddrugresistanceJamesA.McCubreya,b,⁎,LindaS.Steelmana,WilliamH.Chappella,StephenL.Abramsa,EllisW.T.Wonga,FuminChanga,BrianLehmannc,DavidM.Terrianb,c,MicheleMilellad,AgostinoTafurie,FrancaStivalaf,MassimoLibraf,JorgBaseckeg,CamillaEvangelistih,AlbertoM.Martellih,RichardA.Franklina,baDepartmentofMicrobiologyandImmunology,BrodySchoolofMedicineatEastCarolinaUniversity,Greenville,NC27858,USAbLeoJenkinsCancerCenter,BrodySchoolofMedicineatEastCarolinaUniversity,Greenville,NC27858,USAcDepartmentofAnatomyandCellBiology,BrodySchoolofMedicineatEastCarolinaUniversity,Greenville,NC27858,USAdReginaElenaCancerCenter,Rome,ItalyeDepartmentofHematology-Oncology,LaSapienza,UniversityofRome,Rome,ItalyfDepartmentofBiomedicalSciences,UniversityofCatania,Catania,ItalygDivisionofHematologyandOncology,DepartmentofMedicine,UniversityofGöttingen,Göttingen,GermanyhDepartmentofHumanAnatomicalSciences,UniversityofBologna,Bologna,ItalyReceived5September2006;receivedinrevisedform2October2006;accepted3October2006Availableonline7October2006AbstractGrowthfactorsandmitogensusetheRas/Raf/MEK/ERKsignalingcascadetotransmitsignalsfromtheirreceptorstoregulategeneexpressionandpreventapoptosis.Somecomponentsofthesepathwaysaremutatedoraberrantlyexpressedinhumancancer(e.g.,Ras,B-Raf).Mutationsalsooccuratgenesencodingupstreamreceptors(e.g.,EGFRandFlt-3)andchimericchromosomaltranslocations(e.g.,BCR-ABL)whichtransmittheirsignalsthroughthesecascades.Evenintheabsenceofobviousgeneticmutations,thispathwayhasbeenreportedtobeactivatedinover50%ofacutemyelogenousleukemiaandacutelymphocyticleukemiaandisalsofrequentlyactivatedinothercancertypes(e.g.,breastandprostatecancers).Importantly,thisincreasedexpressionisassociatedwithapoorprognosis.TheRas/Raf/MEK/ERKandRas/PI3K/PTEN/Aktpathwaysinteractwitheachothertoregulategrowthandinsomecasestumorigenesis.Forexample,insomecells,PTENmutationmaycontributetosuppressionoftheRaf/MEK/ERKcascadeduetotheabilityofactivatedAkttophosphorylateandinactivatedifferentRafs.Althoughbothofthesepathwaysarecommonlythoughttohaveanti-apoptoticanddrugresistanceeffectsoncells,theydisplaydifferentcelllineagespecificeffects.Forexample,Raf/MEK/ERKisusuallyassociatedwithproliferationanddrugresistanceofhematopoieticcells,whileactivationoftheRaf/MEK/ERKcascadeissuppressedinsomeprostatecancercelllineswhichhavemutationsatPTENandexpresshighlevelsofactivatedAkt.FurthermoretheRas/Raf/MEK/ERKandRas/PI3K/PTEN/Aktpathwaysalsointeractwiththep53pathway.SomeoftheseinteractionscanresultincontrollingtheactivityandsubcellularlocalizationofBim,Bak,Bax,PumaandNoxa.Raf/MEK/ERKmaypromotecellcyclearrestinprostatecellsandthismayberegulatedbyp53asrestorationofwild-typep53inp53deficientprostatecancercellsresultsintheirenhancedsensitivitytochemotherapeuticdrugsandincreasedexpressionofRaf/MEK/ERKpathway.Thusinadvancedprostatecancer,itmaybeadvantageoustoinduceRaf/MEK/ERKexpressiontopromotecellcyclearrest,whileinhematopoieticcancersitmaybebeneficialtoinhibitRaf/MEK/ERKinducedproliferationanddrugresistance.ThustheRaf/MEK/ERKpathwayhasdifferenteffectsongrowth,preventionofapoptosis,cellcyclearrestandinductionofdrugresistanceincellsofvariouslineageswhichmaybeduetothepresenceoffunctionalp53andPTENandtheexpressionoflineagespecificfactors.©2006ElsevierB.V.Allrightsreserved.Keywords:Raf/MEK/ERK;Signaling;Apoptosis;Drugresistance;PI3K/Akt;CancertherapyBiochimicaetBiophysicaActa1773(2007)1263–1284⁎Correspondingauthor.DepartmentofMicrobiologyandImmunology,BrodySchoolofMedicineatEastCarolinaUniversity,Greenville,NC27834,USA.Tel.:[phone];fax:[phone].E-mailaddress:[e-mail](J.A.McCubrey).0167-4889/$-seefrontmatter©2006ElsevierB.V.Allrightsreserved.doi:10.1016/j.bbamcr.2006.10.0011.Introduction1.1.OverviewoftheRas/Raf/MEK/ERKsignalingTheRas/Raf/MEK/ERKcascadecouplessignalsfromcellsurfacereceptorstotranscriptionfactors,whichregulategeneexpression.Furthermore,thiscascadealsoregulatestheactivityofmanyproteinsinvolvedinapoptosis.AdiagrammaticoverviewoftheRas/Raf/MEK/ERKpathwayispresentedinFig.1.ThispathwayisoftenactivatedincertaintumorsbychromosomaltranslocationssuchasBCR-ABL,mutationsincytokinereceptorssuchasFlt-3,Kit,Fmsoroverexpressionofwildtypeormutatedreceptors,e.g.,EGFR.TheRaf/MEK/ERKpathwayalsohasprofoundeffectsontheregulationofapoptosisbythepost-translationalphosphorylationofapoptoticregula-torymoleculesincludingBad,Bim,Mcl-1,caspase9andmorecontroversiallyBcl-2.Thispathwayhasdiverseeffectswhichcanregulatecellcycleprogression,apoptosisordifferentiation[1].Asurveyoftheliteraturedocumentsthedailyincreaseinthecomplexityofthispathway,astherearemultiplemembersofthekinase,transcriptionfactor,apoptoticregulatorandcaspaseexecutionerfamilies,whichcanbeactivatedorinactivatedbyproteinphosphorylation.Furthermore,thispathwaycaninducethetranscriptionofcertaingenes.Raf,eitherthroughdownstreamMEKandERK,orindependentlyofMEKandERK,caninducethephosphorylationofproteins,whichcontrolapoptosi