Ras-Raf-MAPK--mTOR-PI3K-AKT信号通路详解

SignalTransductionPathways&theClinicalImplicationsLixinKAN,PhDProfessorAnhuiMedicalUniversity,ChinaDistinguishedprofessorBengbuMedicalCollege,ChinaAdjunctprofessorNorthwesternUniversity,[e-mail]:Concept,components,commonfeaturesofcellsignaltransductionpathways2.Ras-Raf-MAPKpathway3.PI3K/AKT/mTORpathway4.Jak-STATpathway5.NF-kBpathway6.Notchpathway7.AbnormalCellsignalinganddiseasesCONTENTOVERVIEWSignaltransductionreferstotheprocessthattheextracellularstimuliregulatethebiologicalfunctions,throughmembranousorintracellularreceptorsmediatedsignalcascade.DefinitionProliferationDifferentiationMotilityDeathTransformationSignalsBiochemicalprocessesGrowthfactorsCytokinesExtracellularmatrixproteinsCellstressesSchematicviewofCellsignalingCellsignalingaffectsvirtuallyEVERYASPECTofcellstructuresandfunctions.1.Extracellularsignalmolecules:Ligand/Agonist.2.Receptor–arespecificproteins,whichareabletorecognizeandbindtocorrespondingligands.Bindingisspecific,butnotalwaysin1-1fashion.3.Transducers–carriesthemessagefromthereceptortotheeffector.Transducerscouldbeenzymes,adaptor,orothers.Transductionisamulti-stepprocess.4.Effectorproteins–producesa2ndmessengersuchascAMP.COMPONENTSBindtomembranereceptorsBindtointracellular--receptorsExtracellularmoleculesChemicalSignalProteinsandpeptides:Hormones,cytokinesAminoacidderivatives:CatecholamineFattyacidderivatives:ProstaglandinsSteroidhormones,Thyroxine,VD3PhysicalSignallight,wave,voice,pressure&temperatureSignalmoleculesLigand/Agonist1.Extracellularsignalmolecules:Ligand/Agonistarenormallyreleasedbysignal-producingcells,reachandbindtothereceptorproteinoftargetcells.Typesofsignalmolecules—Lipid-solublemoleculesWater-solublemoleculesGaseousmolecules(NO)Propertiesofsignalmolecules—Specificity,highlyefficient,competitiveDosage-dependent,saturableReversible,canbedeactivated2.Receptorproteins–arespecificproteins,whichareabletorecognizeandbindtocorrespondingligands,andtransducesignaltonextsignalingmoleculesinsideofthecell.1.actascell’s‘letterboxes’,andreceivemessages2.Transmitamessageintothecell,whichnormallyleadstoaspecificcellulareffect3.Eachcellhasmultiplespecificreceptors,makingitresponsivetodifferentchemicals.Distribution:•Cellsurfacereceptors•IntracellularreceptorsDomainsofcellsurfacereceptors:•Theextracellularsegment---bindingsite•Thehydrophobicmembranespanningsegment---Trans-membrane（highlyconserved）•Thecytoplasmicsegment---enzymedomain（highlyconserved），transferringaphosphategroupfromATPtotyrosineorserine/threonineonasubstrateprotein.ReceptorsProperties:•Specificity•Saturability•Highaffinity•ReversibilityLigand-Receptorbindingisanreversibleequilibriumprocess,obeyingthelawofmassDifferentKindsofintracellularproteinsservedifferentpurposes1.Relayproteins2.Messengerproteins3.Adaptorproteins4.Amplifierproteins5.Transducerproteins6.Bifurcationproteins7.Integratorproteins8.LatentgeneregulatoryproteinsIntracellularproteinsEffectorprotein–producesamobilesecondmessengersuchascAMP.InthecaseofcAMP,theeffectorproteinisadenylatecyclase(alsocalledadenylylcyclase).Effectorprotein1.Receptorscouldeitherbecellmembraneornuclearreceptors.2.arelativelysmallnumberofmechanismshavebeenemployed.3.conservedintracellularproteinsplaykeyrolesindifferentsignalingpathways.4.differentsignalingpathwaysarere-usedindifferentcontexts.5.Amplificationofexternalsignalsisoftennecessary.6.Convergence,divergence,andcrosstalkamongdifferentsignalingpathways.7.Desensitizationofreceptors.8.Externalsignalsinducetwodirectcellularresponses:(1)changestheactivityofpre-existedproteins(2)changesingeneexpression.commonfeaturesofcellsignalingcellmembranereceptorsmostwater-solublemolecules/factorsbindtocellmembranereceptorsandactivatethesignalingtransductionpathway.Testosterone,andotherlipidsolublefactors,suchasRA,travelsthroughthebloodandenterscellsthroughoutthebody.Inthecytoplasm,theybindandactivatereceptorproteins.Theseactivatedproteinsenterthenucleusandturnontargetgenes.1Thesteroidhormonetestosteronepassesthroughtheplasmamembrane.TheboundproteinstimulatesthetranscriptionofthegeneintomRNA.4ThemRNAistranslatedintoaspecificprotein.5Testosteronebindstoareceptorproteininthecytoplasm,activatingit.2Thehormone-receptorcomplexentersthenucleusandbindstospecificgenes.3SignalingpathwayvianuclearreceptorOtherfeatures:SignalFlowisnotalwaysin1-1fashionSignalReceptorTransducerTargetsResponseEachcellisprogrammedtorespondtoaspecificcombinationsofextracellularsignalmolecules,butthefinalread-outsarecontext-dependentSIGNALSMAYHAVECONTEXT-DEPENDENTEFFECTSHCell-surfaceReceptorsBelongtoDifferentClassesRas-Raf-MAPK,mTOR-PI3K-AKT,Jak-STAT,NF-kBNotch•RTK-Ras-Raf-MAPKsignalingpathwayOverviewofRTK-Ras-Raf-MAPKsignalingpathwayRTK-inducedRasactivationRas-MAPkinasecascadeMAPKphosphorylatestranscriptionfactorsorotherproteinsThesignalstartswhenasignalingmoleculebindstothereceptoronthecellsurfaceandendswhentheDNAinthenucleusexpressesaproteinandproducessomechangeinthecell,suchascelldivision.Thepathwayincludesmanyproteins,includingMAPK(mitogen-