细胞信号转导英文版

Chapter15CellularSignalTransductionThebiochemistryandmolecularbiologydepartmentofCMUWhenenvironmentchanges:

Monad——respondsdirectly.

Multicellularorganisms——signalthroughelaboratesystemofintercellularorintracellularcommunication，andconsequentlyregulatefunctionsoforganisms.SignalingmoleculeReceptoroftargetcellIntracellularmoleculebiologicaleffectSignaltransduction

§1SignalingMoleculesSignalingmoleculesSignalingmolecules,whicharereleasedbysignal-producingcells,reachandtransferbiologicalsignalstotheirtargetcellstoinitiatespecificcellularresponses.

ExtracellularmoleculesIntracellularmolecules

1.

Extracellularmoleculesprotein&peptides:Hormone,cytokineAA&itsderivatives:Gly,Glu,adrenaline,thyroxineSteroid:SexHormone,glucocorticosteroidFattyacidderivatives:prostaglandin

(1)

Paracrinesignaling

(localchemicalmediators)Secretedbycommoncells.Reachneighboringtargetcellsbypassivediffusion.Timeofactionisshort. SuchasGF,PG(2)EndocrinesignalSecretedbyendocrinecells.Reachtargetcellsbybloodcirculation.Timeofactionislong. Suchasinsulin,thyroxine,adrenalin

(3)Synapticsignal(neurotransmitters)Secretedbyneuronalcells.Reachanotherneuronbysynapticgap.Timeofactionisshort. SuchasAcetylcholine(Ach),noradrenaline(4)GaseoussignalSimplestructure,halflifeisshortandactiveinchemistry.SuchasNO,CO.

GASMOLECULE

(5)AutocrinesignalActbacktotheirowncells.SuchasGF,cytokine,interferon,interleukin.

2.

IntracellularmoleculeCa2+ions

DG,ceramidelipidderivativesIP3carbohydratederivativescAMPcGMPnucleotidesRas,JAK,RafproteinsSecondmessenger:

Smallmoleculessynthesizedincellsinresponsetoanexternalsignalarethesecondmessengers,whichareresponsibleforintracellularsignaltransduction.SuchasCa2+,DG,Cer,IP3,

cAMP,cGMPThirdmessengers:

Thirdmessengersarethemoleculeswhichtransmitmessagefromoutsidetoinsideofnucleousorfrominsidetooutsideofnucleous,alsocalledDNAbindingprotein.

EffectbymembranereceptorsEffectbyintracellularreceptorsIntracellularmoleculesExtracellularmoleculesSignalmoleculescAMP,cGMP,IP3,DG,Ca2+Proteinsandpeptides:Hormones,cytokinesAminoacidderivatives:CatecholaminesFattyacidderivatives:ProstaglandinsSteroidhormones,Thyroxine,VD3

§2ReceptorReceptor

Receptorsarespecificmembraneproteins,whichareabletorecognizeandbindtocorrespondingligandmolecules,becomeactivated,andtransducesignaltonextsignalingmolecules.

GlycoproteinorLipoproteinligand

Asmallmoleculethatbindsspecificallytoalargerone;forexample,ahormoneistheligandforitsspecificproteinreceptor.

Membranereceptors

membraneGlycoproteinIntracellularreceptors

Cytosolornuclei

DNAbindingprotein

(1)Ligand-gateionchannelstype(cyclicreceptor)ligand→receptor→ionchannelopenorclose1.membranereceptors

1)7-helicestransmembranereceptor

(2)GProtein-CoupledReceptors

(serpentineR)

CytosolicsideOligosaccharideunitGproteinreferstoanyproteinwhichbindstoGDPorGTPandactassignaltransduction.Gproteinsconsistofthreedifferentsubunits(,,-subunit).-subunitcarriesGTPaseactivity,bindingandhydrolysisofGTP.2)Gprotein(Guanylatebindingprotein)

Gs→s→AC→cAMP↑Gi→i→AC→cAMP↓Gq→q→PI-PLC→IP3+DAGGo→o→ionchannelGt→t

→cGMPPDE→cGMP→Rhodopsin3)ClassesofGproteinGlucagon-adrenaline→s→AC↑ACTH

-adrenalineangiotensinⅡacetylcholine(M2M4)GFreleaseinhibitoryfactor→i→AC↓

RibosylationofArgofGG

s

-ATPGs

-ADPACcAMPCl-+

H2OCavityofintestinediarrheaHCO3-CholeratoxinATPasePertussis

toxini-ADP-ribosylationGi

AC↑

allergyofhistaminecAMP↑ACcGMPPDE(phosphodiesterase）PLCPLA2Channelprotein4)EffectproteinsofGprotein

cAMPATP

5)PathwayofGproteinlinkedreceptorHRGproteinEssecondarymessegerProteinkinasePhophorylationofEsorfunctionalproteinBiologicaleffect

(3)Singletransmembraneα-helixreceptor

TyrosineproteinkinaseReceptor(catalyticreceptor)

IGF－R,EGF－RNontyrosineproteinkinaseReceptor GrowthHormoneR,interferonRTyrosineproteinkinaseReceptororreceptortyrosinekinase(RTK)

Cys-richdomainImmunoglobulin-likedomainEGFRIGF-1RPDGFRFGFRIntracellularinsulineffectsCytosolInsulinNon-receptortyrosinekinase(NRTK)

DomainofDownstreammoleculesofTPKRSH2domain(Scrhomology2domain)SH3

domainPHdomain(pleckstrinhomologydomain)Membranereceptor–ANPSolublereceptor–

NO,CO(4)Guanylatecyclase(GC)receptor

2.Intracellularreceptor

(transcriptionregulatedreceptor)

IntracellularRistrans-actingelememtcis-actingelementgeneexpression Localizedinthecytosoland/orinthenucleus.ligand:SteroidH,VD3,Thyroxine

3.PropertiesofbindingofHandR

highlyspecificityhighlyaffinity

saturation

reversiblebinding

specialfunctionmodel

4.ControlofreceptoractivityPhosphorylationordephosphorylationofR

Phospholipidofmembrane

Enzymecatalyzedhydrolysis

Gproteinregulation(1)Recognizethespecialligand(2)Bindingtospecialligand(3)Signaltransductionbiologicaleffect5.

Functionofreceptor

§3PathwayofSignalTransduction

SignaltransductionmediatedbymembranereceptorcAMPdependent-proteinkinaseApathwaycGMPdependentPKGpathwayCa2+dependentPKpathwayTyrosineproteinKinasepathwayNF-κBpathwayTGF-βpathway1.cAMPdependent-proteinkinaseApathway

HRGproteinPhosphorylationofEsorfunctionalproteinsBiologicaleffectsPKAcAMPAC

(1)cAMPmetabolism

ACPDEAC：AdenylatecyclasePDE：Phosphodiesterase

(2)MechanismofcAMPeffect

ActivatecAMP-dependentproteinkinase(PKA).(3)PKAeffect

PhosphorylatespecificallySer/Thrresiduesinseveralproteins

（1）Regulationofmetabolism （2）Regulationofgeneexpression

CRE:cAMPresponseelement(TGACGTCA)CREB:CREbindingprotein

DNACRECREBPKAＰTranscriptionmRNACREBPKAＰCREBＰCREBＰCREBＰCREBＰCREBＰCREBＰ2.Ca2+dependentPKpathway

(1)Ca2+-DAG-dependentPKCpathwayHRPIP2GproteinPLCIP3DG

ERPKCCa2+PSBiologicaleffectsPhosphorylationofEsorfunctionalproteins[Ca2+]i0.01-1mol/L（10-7mol/L

）[Ca2+]o2.5mmol/L（10-3mol/L

）5000~10000×1）FunctionofDGandIP3

IP3+R→openofCa2＋channel→[Ca2＋]↑PS,Ca2＋DGPKC↑2）FunctionofPKC

regulationofmetabolism

PKC→Ser/Thr-PofR,enzyme,ProteinofMb.

Geneexpression

Lateresponse:Trans-actingfactor-PThirdmessengerImmediateearlygenesThirdmessenger-PActivategenesCellproliferationPKCPKCEarlyresponse:(2)Ca2＋-CaMdependentproteinkinasepathway

HRGproteinPLCIP3Ca2+CaMCaMKBiologicaleffectsPhosphorylationofEsorfunctionalproteinsCalmodulin(CaM）：

Ca2＋bindingprotein

4Ca2＋+

CaM

→Ca2＋-

CaM

↓CaMkinase↑ ↓ Ser/Thr-P ↓Ca2＋pump,AC↑GC↑Es(glycogensynthase,phosphorylasekinase)3.cGMP-dependentPKGpathway

BiologicaleffectsPhosphorylationofEsorfunctionalproteinsANPNO,COSolubleGCPKGcGMPReceptor-linkedGC(1)cGMP

(2)FunctionofPKG

Ser/Thr-PofproteinandEGCPDEGC:GuanylatecyclaseANP（atrialnatriureticpeptides）↓GCNO↓cGMP↓PKG↓Vasculardilatation4.Tyrosine-proteinkinasepathway(TPK)

TPKreceptorisrelatedtoproliferation,differentiation,dissociation,carcinomatouschange.TPK：

receptorTPK：Mb.

nonreceptorTPK：cytosol(1)ReceptorTPK－Ras－MAPKpathway

GRB2,SOS,Ra