SnapShot:RasSignalingMeganCullyandJulianDownwardCancerResearchUKLondonResearchInstitute,LondonWC2A3PX,UKSeeonlineversionforlegendandreferences.1292Cell133,June27,2008©2008ElsevierInc.DOI10.1016/j.cell.2008.06.0201292.e1Cell133,June27,2008©2008ElsevierInc.DOI10.1016/j.cell.2008.06.020SnapShot:RasSignalingMeganCullyandJulianDownwardCancerResearchUKLondonResearchInstitute,LondonWC2A3PX,UKRasisamonomericmembrane-associatedGTP-bindingproteinthatregulatescellproliferationandsurvivalinresponsetoextracellularstimuli,suchasactivationofepi-dermalgrowthfactorreceptor(EGFR)orTcellreceptor(TCR).Originallyidentifiedasanoncogeneinmurinesarcomaviruses,activatingmutationsinRashavebeenfoundinabout30%ofhumantumors.DysregulationoftheRassignalingpathwayplaysakeyroleintheprogressionofcancer.WhenboundtoGTP,Rasisactiveandstimulatesseveraldownstreamtargetsbydirectinteractions.RashasintrinsicGTPaseactivity,whichcanbeactivatedbyGTPase-activatingproteins(GAPs)suchastheNF1tumorsuppressorgeneproductandp120GAP.ActivationofRasoccurslargelythroughguaninenucleotideexchangefactors(GEFs)suchasSosandRasGRP1,whichcatalyzetheexchangeofRas-boundGDPwithfreeGTP.MultipledownstreameffectorpathwaysmediateRassignaling,includingtheRaf/MEK/ERKkinasecascade,thePI3-kinase/Akt/mTorpathway,andtheRalGTPasepathway.Raf/MEK/ERKistheprototypicalmitogen-activatedproteinkinase(MAPK)cascade,whereineachkinasephosphorylatesandactivatesitsdownstreamtarget,culminatingintheactivationofmultipletargetsincludingseveraltranscriptionfactors.MuchoftherecentworkontheMAPKcascadehasfocusedonnegativefeedbackloops,suchasthephosphorylationofRafandSosbyERK,aswellasthetranscriptionofnegativeregulatorssuchasSproutyandSpred.ThesecondofthemajordownstreamRastargets,thePI3-kinase/Akt/mTorpathway,contributestocellgrowth,proliferation,andsurvivaldownstreamofRas.PI3-kinaseisalipidkinasethatphosphorylatesphosphatidylinositol(4,5)bisphosphate(PIP2)togeneratethesecondmessengerphosphatidylinositol(3,4,5)trisphosphate(PIP3).PIP3activatesAkt(PKB)andals...
