复旦细胞生物学课件08细胞信号传导

Cellsignalingcanaffectvirtuallyeveryaspectofcellstructureandfunction:Activationofenzymeactivity;Changeincytoskeletalorganization;Changeinionpermeability;InitiationofDNAsynthesis;Activationorrepressionofgeneexpression.Chapter8CellSignaling1.OverviewofintercellularsignalingGeneralschemesofintercellularsignaling(1)EachcellisprogrammedtorespondtospecificcombinationsofextracellularsignalmoleculesThecellintegratesdifferentinformationandmountsanappropriateandcomprehensiveresponse.Thesesignalmoleculesworkincombinationstoregulatethebehaviorofthecell.CellsrespondtostimuliviacellsignalingA.Someofthebasiccharacteristicsofcellsignaling(2)Signalingpathwaysconsistofaseriesofstepssignalmagnification1.Recognitionofthestimulusbyaspecificplasmamembranereceptor.2.Transferofasignalacrosstheplasmamembrane.3.Signalmagnification:Transmissionofthesignaltoeffectormoleculeswithinthecell,whichcausesachangeincellularactivities.4.Cessationofthecellularresponseduetoinactivationofthesignalmolecule.(3)Fourfeaturesofsignal-transducingsystems(4)DifferentcellscanresponddifferentlytothesameextracellularsignalmoleculeVariousresponsesinducedbyneurotramsmitteracetylcholine(5)Acellcanremembertheeffectofsomesignals,afterthesignalhasdisappeared.(Ca2+)ProteinkinaseactivitedbyCa2+tophosphorylateitselfandotherproteins,theautophosphorylationkeepsthekinaseactivelongafterCa2+levelsreturntonormal.Transientextracellularsignalsofteninducemuchlonger-termchangesincellsduringthedevelopmentofamulticellularorganism.Theyusuallydependonself-activatingmemorymechanismsthatoperatefurtherdownstreaminasignalingpathway,atthelevelofgenetranscription.B.SignalMoleculesandReceptors(1)Signalmolecules:(2)Receptorsincludetwoclasses:Thefunctionsofreceptors:Receptor-mediatedendocytosis;Signaltransduction:1.Theactivationofreceptormakeforthecascades;2.Thedesensitizationofreceptormakeforclosedownofthecascades;3.Thedown-regulationofreceptormakeforthedepressedreaction;Differentkindsofintracellularsignalingproteinsalongasignalingpathwayfromasurfacereceptortothenucleus.Relayproteinssimplypassthemessagetothenextsignalingcomponentinthechain.Messengerproteinscarrythesignalfromoneparttoanother(fromcytosoltonucleus).AdaptorproteinslinkonesignalingproteinstoanotherAmplifierproteins,(enzymesorionchannels)signalingcascade.Transducerproteinsconvertthesignalintoadfferentform.Bifurcation(分歧)proteinsspreadthesignalfromonesignalingpathwaytoanother.Integratorproteinsreceivesignalsfromtwoormoresignalingpathwaysandintegratethembeforerelayingasignalonward.Latentgeneregulatoryproteinsareactivatedatthecellsurfacebyactivatedreceptorsandthenmigratetothenucleustostimulategenetrascription.Mostactivatedcell-surfacereceptorsrelaysignalsviasmallmolecules(secondmessengers)andanetworkofintracellularsignalingproteins.Twotypesofintracellularsignalingcomplexes,enhancethespeed,efficiency,andspecificityoftheresponse.InteractionsbetweenintracellularsignalingproteinsaremediatedbymodularbindingdomainsPHdomain:Pleckstrin:血小板、白细胞C激酶底物同源域Bcellactivation(3)FourgeneraltypesofsignaltransducersC.TwotypesofintracellularsignalingproteinsthatactasMolecularSwitches.Phosphorylationanddephosphorylationviaproteinkinasesandphosphatases.TherebystimulatingorinhibitingtheactivitiesGAPsinactivateG-protein;GEFsactivatesG-protein;GDIs(guaninenucleotide-dissociationinhibitors)maintaintheG-proteininactive.GEF:guanine-nucleotide-exchangefactorGRF:guanine-nucleotidereleasefactor,GAP:GTPase-activatingproteinTheNobelPrizeinPhysiologyorMedicine1992“fortheirdiscoveriesconcerningreversibleproteinphosphorylationasabiologicalregulatorymechanism”Signaltransductionpathwaysconsistprimarilyofproteinkinasesandproteinphosphatases.ThealterationsintheconformationofsignalingprteinsareusuallyaccomplishedbyproteinkinasesandproteinphosphatasesThehumangenomeencodesasmanyas2000differentproteinkinasesandmorethan300differentproteinphosphatases.TheNobelPrizeinPhysiologyorMedicine1994“fortheirdiscoveriesofG-proteinsandtheroleoftheseproteinsinsignaltransductionincells”G-proteinactivationandinactivationcycle(NIH.1970s)TheaccessoryproteinsforcyclingofG-proteinsGTPase-activatingproteins(GAPs):MostGproteinspossesssomecapabilitytohydrolyzeaGTP,butthiscapabilityisgreatlyacceleratedbyinteractionwithspecificGAPs.TherebyGAPsinactivateG-proteinbystimulatingittohydrolyzeitsboundGTP.Guaninenucleotide-exchangefactors(GEFs):AninactiveGproteinisconvertedtotheactiveformwhentheboundGDPisreplacedwithaGTP.GEFsareproteinsthatbindtoaninactiveGproteinandstimulatedissociationoftheboundGDP.TherebyGEFsactivatesG-protein.Guaninenucleotide-dissociationinhibitors(GDIs):GDIsareproteinsthatinhibitthereleaseofaboundGDPfromaG-protein,thusmaintainingG-proteinintheinactive,GDP-boundstate.2.SignaltransdutionmediatedbythereceptorswithincellsA.Nuclearreceptorsforsteroid,retinoicacid,vitaminDandthyroidhormonesB.NitricoxidegassignalsbybindingdirectlytoanenzymeinsidethetargetcellTwodiscovers:Duringthe1980s,bacteria-killingactivityofmacrophagesincellculturedependsonthepresenceofarginineinthemed