细胞信号转导英文版.ppt

Chapter15CellularSignalTransduction ThebiochemistryandmolecularbiologydepartmentofCMU 1 Whenenvironmentchanges Monad respondsdirectly Multicellularorganisms signalthroughelaboratesystemofintercellularorintracellularcommunication andconsequentlyregulatefunctionsoforganisms 2 Signalingmolecule Receptoroftargetcell Intracellularmolecule biologicaleffect Signaltransduction 3 4 1SignalingMolecules 5 Signalingmolecules Signalingmolecules whicharereleasedbysignal producingcells reachandtransferbiologicalsignalstotheirtargetcellstoinitiatespecificcellularresponses 6 ExtracellularmoleculesIntracellularmolecules 7 1 Extracellularmolecules protein peptides Hormone cytokineAA itsderivatives Gly Glu adrenaline thyroxineSteroid SexHormone glucocorticosteroidFattyacidderivatives prostaglandin 8 1 Paracrinesignaling localchemicalmediators Secretedbycommoncells Reachneighboringtargetcellsbypassivediffusion Timeofactionisshort SuchasGF PG 9 2 Endocrinesignal Secretedbyendocrinecells Reachtargetcellsbybloodcirculation Timeofactionislong Suchasinsulin thyroxine adrenalin 10 3 Synapticsignal neurotransmitters Secretedbyneuronalcells Reachanotherneuronbysynapticgap Timeofactionisshort SuchasAcetylcholine Ach noradrenaline 11 4 Gaseoussignal Simplestructure halflifeisshortandactiveinchemistry SuchasNO CO 12 GASMOLECULE 13 5 Autocrinesignal Actbacktotheirowncells SuchasGF cytokine interferon interleukin 14 2 Intracellularmolecule Ca2 ionsDG ceramidelipidderivativesIP3carbohydratederivativescAMPcGMPnucleotidesRas JAK Rafproteins 15 Secondmessenger Smallmoleculessynthesizedincellsinresponsetoanexternalsignalarethesecondmessengers whichareresponsibleforintracellularsignaltransduction SuchasCa2 DG Cer IP3 cAMP cGMP 16 Thirdmessengers Thirdmessengersarethemoleculeswhichtransmitmessagefromoutsidetoinsideofnucleousorfrominsidetooutsideofnucleous alsocalledDNAbindingprotein 17 Effectbymembranereceptors Effectbyintracellularreceptors Intracellularmolecules Extracellularmolecules Signalmolecules cAMP cGMP IP3 DG Ca2 Proteinsandpeptides Hormones cytokines Aminoacidderivatives Catecholamines Fattyacidderivatives Prostaglandins Steroidhormones Thyroxine VD3 18 2Receptor 19 Receptor Receptorsarespecificmembraneproteins whichareabletorecognizeandbindtocorrespondingligandmolecules becomeactivated andtransducesignaltonextsignalingmolecules GlycoproteinorLipoprotein 20 ligandAsmallmoleculethatbindsspecificallytoalargerone forexample ahormoneistheligandforitsspecificproteinreceptor 21 MembranereceptorsmembraneGlycoproteinIntracellularreceptorsCytosolornucleiDNAbindingprotein 22 1 Ligand gateionchannelstype cyclicreceptor ligand receptor ionchannelopenorclose 1 membranereceptors 23 24 25 26 1 7 helicestransmembranereceptor 2 GProtein CoupledReceptors serpentineR 27 28 GproteinreferstoanyproteinwhichbindstoGDPorGTPandactassignaltransduction Gproteinsconsistofthreedifferentsubunits subunit subunitcarriesGTPaseactivity bindingandhydrolysisofGTP 2 Gprotein Guanylatebindingprotein 29 30 Gs s AC cAMP Gi i AC cAMP Gq q PI PLC IP3 DAGGo o ionchannelGt t cGMPPDE cGMP Rhodopsin 3 ClassesofGprotein 31 32 Glucagon adrenaline s AC ACTH adrenalineangiotensin acetylcholine M2M4 GFreleaseinhibitoryfactor i AC 33 34 RibosylationofArgofG G s ATP G s ADP AC cAMP Cl H2O Cavityofintestinediarrhea HCO3 Choleratoxin ATPase 35 Pertussistoxin i ADP ribosylationGiAC allergyofhistamine cAMP 36 ACcGMPPDE phosphodiesterase PLCPLA2Channelprotein 4 EffectproteinsofGprotein 37 cAMP ATP 38 39 5 PathwayofGproteinlinkedreceptor H R Gprotein Es secondarymesseger Proteinkinase PhophorylationofEsorfunctionalprotein Biologicaleffect 40 3 Singletransmembrane helixreceptor TyrosineproteinkinaseReceptor catalyticreceptor IGF R EGF RNontyrosineproteinkinaseReceptorGrowthHormoneR interferonR 41 42 TyrosineproteinkinaseReceptororreceptortyrosinekinase RTK 43 Intracellularinsulineffects Cytosol Insulin 44 Non receptortyrosinekinase NRTK 45 DomainofDownstreammoleculesofTPKR SH2domain Scrhomology2domain SH3domainPHdomain pleckstrinhomologydomain 46 47 Membranereceptor ANPSolublereceptor NO CO 4 Guanylatecyclase GC receptor 48 49 2 Intracellularreceptor transcriptionregulatedreceptor IntracellularRistrans actingelememtcis actingelementgeneexpressionLocalizedinthecytosoland orinthenucleus ligand SteroidH VD3 Thyroxine 50 51 3 PropertiesofbindingofHandR highlyspecificityhighlyaffinitysaturationreversiblebindingspecialfunctionmodel 52 4 Controlofreceptoractivity PhosphorylationordephosphorylationofRPhospholipidofmembraneEnzymecatalyzedhydrolysisGproteinregulation 53 1 Recognizethespecialligand 2 Bindingtospecialligand 3 Signaltransductionbiologicaleffect 5 Functionofreceptor 54 3PathwayofSignalTransduction 55 Signaltransductionmediatedbymembranereceptor cAMPdependent proteinkinaseApathwaycGMPdependentPKGpathwayCa2 dependentPKpathwayTyrosineproteinKinasepathwayNF BpathwayTGF pathway 56 1 cAMPdependent proteinkinaseApathway H R Gprotein PhosphorylationofEsorfunctionalproteins Biologicaleffects PKA cAMP AC 57 1 cAMPmetabolism AC PDE AC Adenylatecyclase PDE Phosphodiesterase 58 59 2 MechanismofcAMPeffect ActivatecAMP dependentproteinkinase PKA 60 61 3 PKAeffect 62 63 PhosphorylatespecificallySer Thrresiduesinseveralproteins 1 Regulationofmetabolism 2 Regulationofgeneexpression 64 65 CRE cAMPresponseelement TGACGTCA CREB CREbindingprotein 66 DNA CREB PKA Transcription mRNA CREB PKA 67 68 2 Ca2 dependentPKpathway 1 Ca2 DAG dependentPKCpathway H R PIP2 Gprotein PLC IP3 DG ER PKC Ca2 PS Biologicaleffects PhosphorylationofEsorfunctionalproteins 69 70 Ca2 i0 01 1 mol L 10 7mol L Ca2 o2 5mmol L 10 3mol L 5000 10000 71 1 FunctionofDGandIP3 IP3 R openofCa2 channel Ca2 PS Ca2 DG PKC 72 73 2 FunctionofPKC regulationofmetabolismPKC Ser Thr PofR enzyme ProteinofMb Geneexpression 74 Lateresponse Trans actingfactor P Thirdmessenger Immediateearlygenes Thirdmessenger P Activategenes Cellproliferation PKC PKC Earlyresponse 75 76 2 Ca2 CaMdependentproteinkinasepathway H R Gprotein PLC IP3 Ca2 CaM CaMK Biologicaleffects PhosphorylationofEsorfunctionalproteins 77 Calmodulin CaM Ca2 bindingprotein4Ca2 CaM Ca2 CaM CaMkinase Ser Thr P Ca2 pump AC GC Es glycogensynthase phosphorylasekinase 78 79 80 3 cGMP dependentPKGpathway Biologicaleffects PhosphorylationofEsorfunctionalproteins ANP NO CO SolubleGC PKG cGMP Receptor linkedGC 81 1 cGMP 2 FunctionofPKGSer Thr PofproteinandE GC PDE GC Guanylatecyclase 82 ANP atrialnatriureticpeptides GCNO cGMP PKG Vasculardilatation 83 84 4 Tyrosine proteinkinasepathway TPK TPKreceptorisrelatedtoproliferation differentiation dissociation carcinomatouschange TPK receptorTPK Mb nonreceptorTPK cytosol 85 1 ReceptorTPK Ras MAPKpathway GRB2 SOS Ras RafSmallGprotein RasMAPK mito