生理化学教学课件：ch22 Coupling of Gene Expression with Cell Signaling

Chapter22CouplingofGeneExpressionwithCellSignaling

ContentofthischapterThegeneralMechanismofcellSignalTransductionSmallChemicalsasSecondMessengers ProteinsasSignalTransducers2.SignalTransductionNetworkControlingGeneExpression3.NuclearReceptorMediated-GeneExpressionControlsignaling4.GeneralSignalPathwaysMediatedbyMembraneReceptorsSection1GeneralMechanismofCellSignalTransductionⅠ.SiganlTransductionisa complicatednetworkSynthesisofsignalmoleculesincellReleasefromcellTraffictotargetcellRecognitionbyreceptorincellsurfaceInitiationofsignalingintargetcellChangeofmetabolismandfunctionsSignaleliminationandterminationofcellresponseSignaltransductionnetworkSignaltransducerSignaltransductionpathway在细胞内介导信号传递的所有分子

信号转导过程信号转导分子的排列方式信号转导通路交叉联系形成的调控系统信号转导通路的生物学功能BiologicalroleofsignalingSecondmessenger介导信号在细胞内传递的小分子物质TFranscriptionfactorChromatinrelatedprotienRNAprocessingproteinRNAtransferproteinCellcyclinSkeletoneNH2AAAAAm7GTranslationSignalingnetworkSignalReceptSignalTransductionRespondsProfileofcellsignalingⅡ.Signaloutsideinbyspecificrecepters

DefinitionofReceptor:

onekindofmoleculesacceptingthesignal

chemicalproperty:proteinorglycoproteinRoleofreceptersRecogniseitsligandSwitchthesignaloutsidein,thentransferitsinformationtofollowingmoles,resultincellresponsefinally

Thecharactersofreceptor-ligandbinding

HighspecificityHighaffinitySaturationReversion配体-受体结合曲线3typesofcellsurfacememb.receptor

Ligand-gatedreceptor

配体门控受体（属于膜离子通道）

Gprotein-coupledreceptor，GPCR

G-蛋白偶联受体（七跨膜受体）

Enzyme-linkedreceptor

酶（蛋白）偶联受体（单跨膜受体）

Receptorsdistribution

Cytosolreceptorsligands:Lipid-soluble,Steroidhormone,Thyroxin,RetinoidCellsurfacememb.receptorsligands:Watersoluble,Growthfactor,Cytokine,Water-solublehormone,Celladhesionmolecule

Howtodefinethesecondmessenger?

Criteriaforsecondmessenger1.Smallmolecules,Conc.changeimmediatelyincellafteractionofexogenoussignal2.

messengeranalogcanmimictheexogenoussignal3.responddisappearedafterblockmessengerchange4.confirmedtargetmoleculeexistedincell

5.asanallostericeffector

6.notinvolvedinenergymetabolism

ⅢSecondmessengeranditsroleHowdosethesecondmessengerwork?ChangeofitsConc.anddistribution

resultinginsignalingact.orinact.GenerationordegradationofsecondmessengerbyenzymeregulationEnzymes(generatedordegradedsecondmessenger),areregulatedbysignalingmoleculesinmembrane-boundreceptormediatedpathwayHowtoregulatetheConc.ofsecondmessenger?Cyclicnucleotidesareimpt.secondmessenger

Cyclicnucleotideassecondmessenger cAMP

andcGMPSpecialenzymescatalyzetheformationand hydralizationofsecondmessenger鸟(1)StructureoftwonucleotidecyclaseAdenylatecyclase，ACMammaryAC

8

isozymsACisregulatedbyG

prot.

MembraneboundglycoproteinMW.120kDGuanylatecyclase，GCReceptortypeofGC

3types:GC-A,GC-B,GC-C，

GC-AandGC-BarereceptorsofAtrialNatriureticpeptide(ANP)心钠素CytosolGCContainsHemeandactivatedbyNOanditsrelatedcompounds(2)Phosphodiesterase(PDE)PDE:HydrolyzethecAMP

andcGMPPDE(likePDE2)

hasrelativespecificitytocAMP

andcGMPPDE3,PDE4arespecificforcAMP,notcGMP(3).Lipidsassecondmessengerdiacylglycerol，DAG(二脂酰甘油）arachidonicacid，AA（花生四烯酸）phosphatidicacid，PA （磷脂酸）lysophosphatidicacid，LPA（溶血磷脂酸）PI-4-phosphate，PIP （4-磷酸磷脂酰肌醇）phosphatidylinositol-4,5-diphosphate，PIP2

(磷脂酰肌醇-4,5-二磷酸)Inositol-1,4,5-triphosphate，IP3（肌醇-1,4,5-三磷酸）

ThesearemetabolitesoflipidmetabolismSynthesisofLipidsecondmessenger

(4)RoleofNOisrelatedtocGMPnitricoxide(NO)

synthasecatalyzestheformationofNONO合酶CitrullineArginineNHH2NNH2+H2N+COO-NHH2NOH2N+COO-NO＋EffectsofNOinPhys.andpathphysiologyEffectEnzymesandproteinsAct.Inh.Act./Inh.ADP-核糖转移酶，可溶性鸟苷酸环化酶,环氧化酶细胞色素，顺乌头酸酶，质子ATP酶，运铁蛋白，核糖核苷酸还原酶，脂加氧酶氨基的亚硝基化，巯基的亚硝基化NOactivatesandinhibitstheenzymesandproteins

CaMisamainregulartorfor

NOS，3typesofNOShavebindingsitetoCaMSignalsinvolvedinCa2+increase,canaffectNOSⅣMolecularswitchcontrolssignaling

Proteinkinaseandphosphtaseswitch2.GproteinswitchProteinphosphorylationordephosphorylationdrivenbyproteinkinaseorproteinphosphatase,isamajorwaytoregulateactivityofsignalingmoleculesProteinphosphorylationordephosphorylationincreaseordecreaseenzyme’sactivity,whichdependsontheconformationalchange

Molecularswitch:ProteinPhosphorylationanddephosphorylation

kinaseAccepterofPi蛋白丝氨酸/苏氨酸激酶蛋白酪氨酸激酶蛋白组/赖/精氨酸激酶蛋白半胱氨酸激酶蛋白天冬氨酸/谷氨酸激酶丝氨酸/苏氨酸羟基酪氨酸的酚羟基咪唑环、胍基、ε-氨基巯基酰基ProteinkinaseProteinkinasetransfersthe

-PiofATPtoaminoacidoftargetproteinProteinphosphatase蛋白丝氨酸/苏氨酸磷酸酶蛋白酪氨酸磷酸酶个别的蛋白磷酸酶具有双重作用，即可同时作用于酪氨酸和丝/苏氨酸残基蛋白磷酸酶衰减蛋白激酶信号PTKPTK无活性活化P自我磷酸化PTPPTPSSP无活性活化SrcfamilyPTK无活性SrcfamilyPTKPTPPPTK活化活化信号抑制信号Molecularswitch:

G

protein/smallGproteinandtheirrole

鸟苷酸结合蛋白（guaninenucleotidebindingprotein，Gprotein）简称G蛋白，具有GTP酶活性，亦称GTP结合蛋白，是一类信号转导分子。G蛋白结合GTP时为活化形式，作用于下游分子使相应信号途径开放；当结合的GTP水解为GDP时则回到非活化状态，使信号途径关闭。2typesofG

protein异源三聚体G

protein：

α

subunit（Gα）,β、γsubunit(Gβγ)

存在于细胞质膜内侧

SmallGprotein（21kD）ⅤProteincomplex

insignalingSignalingmoleculesdosenotexistseparately,gathertogetheroraggregatedeachothersequentiallyBecomeaproteincomplexperformingroles

Signalingcomplex

highefficient,accurate,diversity生物利用蛋白质复合物系统完成信号转导功能的优势是：①复合体中信号转导分子之间直接接触，可有效、迅速传递信号；②多个蛋白质形成的复合物可产生放大效应；③可以根据细胞外信号强弱形成有差别的信号复合体，输出多种信号，产生多方面的协同效果；④信号转导复合体增加了信号转导反应的复杂性、多样性和调控层次，使调节更精细、更准确。DynamicschangeofcomponentsofproteincomplexwithsignalingComponentsortheirformationofproteincomplexarechangeddynamicallywithvarioussignalsSignificance：1.association/disassociationofproteincomplex,

resultingeitherstartorendthesignaling

2.Componentsreused

efficientlyInstantandamplification

Signalingstartsorendsimmediatelywith

amplificationduringtheprocess

Universality:1.varioussignalings(receptors)sharesomemolecules2.Differentcellhasitsownspecificpathwayandtargeting

ⅥCharactersofcellsignalingFactorsinfluencespecificresponsebycell

1.Conc.ofextra-cellularmole.,2.Receptoramountanddistribution

3.CellularmolesamountandvarietyDifferenttissueemploysamesignaling,butthetypeofmolesandkinasesubstratemaydifferent,resultingindifferentresponsesorbiologicalroles

SummaryofSection1Cellsignalingworksinnetworkwhichconsistsofanumberofpathways.Ligand-receptorbindingisalwaysthefirststepintheactionofanextracellularmessengermoleculeinitstargetcells.Chemicalmodification,protein-proteininteractionarethemajorwaystochangetheconformationofproteinsignals,resultinginthesignaltransduction.

Section2SignalTransductionNetworkControllingGeneExpressionⅠGeneexpressionregulatedbycelltoadaptenvironmentThechangeofGeneexpressionprofileisdominanteffectofsignaling

Solublesignals(extra-orin-cellular)andreceptors(membrane-bound)areproteins,regulatedbygeneexpression

Physical，chemical,biologicalsignalsacceptedbylivingbody,thenbeconvertedtochemicalsignalingChemicalsignalmoles:watersolubleormembrane-boundmoles.Signalinginmulticellular

organisms

Cell-cellcontactdirectlyHormonebybloodstreamtodistantcellsHormoneandcytokine-mediatedsignalinguauallyfunctioningbysignalingnetwork

Onecellstimuletsothercells,beregulatedbyothershormoneorcytokinesalsoⅡGeneexpressionregulatedbysignalingnetwork2.Geneexpressionregulatedat

post-transcriptionlevelbysignalingGeneexpressionregulatedat

transcriptionlevelbysignalingDNAregulationsequence,chromotinstructure,Transcriptionfactors(TF)andco-factors

mRNAstability,RNAbindingprotein,miRNA、proteinandcomplexintranslationprocess

TF

inducedby

cellular

signaling细胞内众多的组织特异性或可调控的转录因子接受受体传递的信号，依据细胞分工和功能的需求实现基因表达的时空特异性

p300,aTF,influencedbysignalings

ⅢSignalingbasedonmoleculeswitchsTwokindsofmoleculeswitchsmainly

Proteinserinekinase/tyrosinekinasePhosphorylationordephosphorylation2.G

protein/smallGprotein

bindingwithGTPorGDP

SecondmessengeSer/ThrkinaseTFsgeneexpressionSer/ThrkinasetargetedbysecondmessengeAllostericregulationbycAMPandcGMP

cAMPandcGMPtargetingproteinkinasedirectlycAMPandcGMP–allostericregulationofproteinconformation–changeofproteinactivitycAMPtargetsProteinKinaseA

cAMP

targetingcAMP-dependentproteinkinase(cAPK）proteinkinaseA，(PKA）cAMPPKA

activationSer/ThephosphorylationofproteinsbustracteschangeofproteinactivityBiologicalfunction蛋白激酶的逐级磷酸化是细胞信号通路的重要特征MAPK的逐级磷酸化是将膜受体接受的信号转导至核内基因表达控制的重要环节，是细胞生长、分化和应激反应的共同信号通路MAP种类转录因子蛋白激酶ERKElk-1、c-Fos、c-JunRsk2、P70S6KJNKc-Jun、SP-1、ATF-2P38c-Myc、CREB、SP-1、ATF-2PRAK、MSK部分MAPK底物举例ProteinTyrosinekinase

ProteinTyrosinekinase(PTK)ReceptorPTK：Non-receptorPTK：NucleiPTKReceptorPTKEGFRMETIGFRPTKdomainNon-receptorPTK

SrcfamilySH3SH1SH2MyrPSH3SH1SH2SH3SH1SH2PHSH1likeSH1ZAP70familyTecfamilyJAKSrc

family:Src、Fyn、Lck、Lynetc.bindingwithmembranereceptorZAP70family:ZAP70,Syk

etcTecfamily:Btk、Itk、Tec

etc.involvedindevelopmentandcellactivation

JAK

family:JAK1、JAK2、JAK3etc.

involvedincytokinesignaling异源三聚体G蛋白直接介导受体信号转换α亚基（Gα）β、γ亚基(Gβγ)具有多个功能位点α亚基具有GTP酶活性与受体结合并受其活化调节的部位βγ亚基结合部位GDP/GTP结合部位与下游效应分子相互作用部位主要作用是与α亚基形成复合体并定位于质膜内侧；在哺乳细胞，βγ亚基也可直接调节某些效应蛋白。G

proteinanditscycleSmallGproteinRas超家族成员是重要的信号转导分子SmallGprotein（21kD），它们在多种细胞信号转导途径中亦具有开关作用。Ras是第一个被发现的小G蛋白，因此这类蛋白质被称为Ras家族，因为它们均由一个GTP酶结构域构成，故又称Ras样GTP酶。G蛋白的活化启动信号转导信号转导途径的基本模式：①配体与受体结合；②受体活化G蛋白；③G蛋白激活或抑制效应分子；④效应分子改变第二信使的含量与分布；⑤第二信使作用于相应的靶分子，使之构象改变，从而改变细胞的代谢过程及基因表达等。GPCR受体信号转导的第一步反应都是活化G蛋白。ⅣProteininteractioninthesignalingnetworkSignalrecognizingandbindingothermolecule

—protein-proteininteraction

dependsonproteininteractiondomain

ProteininteractiondomainProteinkinaseBtkPHTHSH3SH2CatalyticAdaptorprot.Grb2SH3SH2SH3TFstatDNA结合区SH2TACytoskeletonprot.tensin//SH2PTBCharactersofproteininteractiondomaincontains≧2domains,binding≧2proteinsatmeanwhile2.Sameproteininteractiondomainexistedinvariousproteins,butprimarysequenceisslightlydifferent,makingspecifityofeachprotein3.proteininteractiondomainisnotcatalyticdomainDomainsMotifrecognizedSrchomology2SH2含磷酸化酪氨酸模体Srchomology3SH3富含脯氨酸模体pleckstrinhomologyPH磷脂衍生物ProteintyrosinebindingPTB含磷酸化酪氨酸模体WWWW富含脯氨酸模体Domainandmotifmediatedtheprotein-protieninteraction

Adaptorandscaffoldproteininsignalingadaptorproteinisalinkproteinbetweenup-streamanddown-streamprotein

FunctionslikeinteractiondomaininproteinRole:recruitproteinstoformproteincomplexMostadaptorproteincontain

≧2bindingdomains,nootherfunctionaldomains

AdaptorlinkthesignaltransducersSH2CNSH3SH3SH3HGFR,VEGFR,BCR-AblPDGFR,EphB1SLP-76,HPK1,p130casIRS-1,p62doc

CKIg2,WASP,IRS-1,DOCK180,NIKIRS-1,DOCK180,Sos,NIK,Pak1,Pak3,NAP4,WIP,dynamin,synaptojanin、Abl,c-CblAbl,c-Cbl,NAP1,Sam68StructureofNck,anadaptorproteinScaffoldproteinleadinghighspecificityandeffeciencyscaffoldingproteins,largeMW,bindingmoresignaltransducersatonesignalpathwayatmeanwhileSignificance:1.separatedfromotherpathways,keepsignalmolesstableandaccuracy2.functionsasactivatororinhibitortosignalmoles3.resultingmuchmorecomplexinthesignalregulationSummaryofSection2Signalsmediatedbyreceptors,transducer,secondmessenger,regulatinggeneexpressionGproteinandproteinkinasearemainmoleculeswitchesSignaltransducersformedpathways,thensignalingnetworkSignalingcomplexformedbyProtein-proteininteraction,resultingthesignalinginhighspecificityandeffeciencySection3NuclearReceptorMediated-SignalingRegulatingGeneExpressionNuclearreceptors（NR）:1.Locatedincytosolandnucleus2.BindingDNA

sequence,with

TFactivity3.RegulatedgeneexpressionⅠNuclearReceptorSuperfamily

StructureofNuclearReceptor

ⅡNRClassificationdependsonitsligandTypeReceptorsTypeI(SteriodHrR）glucocorticoidreceptor（GR）糖皮质激素受体mineralcorticoidreceptor（MR）盐皮质激素受体estronereceptor（ER）雌激素受体progestogenreceptor（PR）孕激素受体androgenreceptor（AR）雄激素受体Type

II（non-steriodHrR）thyroidhormonereceptor（TR）甲状腺激素受体retinoidXreceptor，（RAR）视黄酸受体retinoidXreceptor（RXR）视黄醇X受体vitaminD3receptor（VDR）维生素D3受体peroxisomeproliferator-activatorreceptor(PPAR)过氧化物酶体增殖活化受体TypeIII（orphanR）nervegrowthfactor-inducedreceptor（NGFI-B)神经生长因子诱导受体testisreceptors2（TR2)睾丸受体2X-linkedorphanreceptor-1X染色体连锁孤儿受体Nomenclature

ofNuclearReceptor原则：根据DNA结合结构域（C结构域）和配体结合结构域（E结构域）在不同核受体间的同源性进行命名

目前共计分为6个亚家族，28个组别人的甲状腺素受体（TR）属于第1亚家族A组中的第一个成员，因此被称为NR1A1NRxyz核受体核受体的亚家族亚家族中的组别组别中的成员ⅢNuclearReceptorregulatedtargetgeneexpressiondirectlyHormoneresponseelement(HRE)ⅣCofactorparticipatedinNuclearReceptorRegulatinggeneexpression

3.SMATSilencingmediatorforretinoidandthyroidhormonereceptor

Steroidhormonereceptorsuperfamilycoactivator,SRC-1类固醇激素共激活因子-12.Nuclearreceptorcorepresser共抑制因子N-CoRCofactor:coactivatororcorepressorCofactordon’tbindwithDNAdirectlyCofactordon’tparticipateinRNAPolII2.Cofactordobindnuclearreceptor,influencethestructureofchromatinlocaly

Howdosecofactorwork?

SRCfamilycanbind6–10proteinsstably,ormanyotherproteinsloosely,toformacofactorcomplex2.Cofactorcomplexmodifiedbyacetylation,methylationandubiquitination,influencingtheabilityofnuclearreceptorinregulationofgeneexpressionCofactorcomplex结合在糖皮质激素反应元件GRE而产生激活转录通过蛋白相互作用影响其他转录因子活性而抑制转录结合于GRE，募集N-CoR等共抑制因子而抑制转录其他核受体形成二聚体，结合于其他激素反应元件，影响转录DiversityofNuclearReceptorregulatinggeneexpression糖皮质激素（GR）——受体复合物Section4MembraneReceptorMediated-SignalingRegulatingGeneExpressionⅠMembraneReceptorMediated-Signaling

coupledwithgeneexpressionLigand-gatedreceptorGprotein-coupledreceptor，GPCREnzyme-linkedreceptor

特性离子通道受体

G-蛋白偶联受体单次跨膜受体内源性配体神经递质神经递质、激素、趋化因子、外源刺激（味，光）生长因子细胞因子结构寡聚体形成的孔道单体具有或不具有催化活性的单体跨膜区段数目4个7个1个功能离子通道激活G蛋白激活蛋白酪氨酸激酶细胞应答去极化与超极化去极化与超极化调节蛋白质功能和表达水平调节蛋白质的功能和表达水平，调节细胞分化和增殖Charactersof3typesmembr.receptor1.GproteincoupledreceptormediatedsignalingregulatinggeneexpressionG蛋白偶联区GPCR（serpantinereceptor）2.Enzymelinkedreceptormedicatedsignalingregulatinggeneexpression

Enzymelinkedreceptorhaskinaseactivity,orcoupledwithPTKSomehaveself-catalyzationHaveonetrans-membranedomain

receptorstyrosinekinases，RTKs 受体型蛋白酪氨酸激酶

tyrosinekinase-coupledreceptors，TKCRs 蛋白酪氨酸激酶偶联受体receptorstyrosinephosphatases,RTPs 受体型蛋白酪氨酸磷酸酶receptorsserine/threoninekinase，RSTK

受体型蛋白丝/苏氨酸激酶receptorsguanylatecyclases，RGCs

受体型鸟苷酸环化酶

CommonEnzymelinkedreceptorTheligandsofmostenzymelinkedreceptorsaregrowthfactorandcytokine,regulatingthegeneexpression,resultingincellproliferationanddifferentiationⅡSpecialsignalingcoupledwithgeneexpression

①结合配体后受体形成二聚体或寡聚体；②第一个蛋白激酶被激活。对于具有蛋白激酶活性的受体来说，此步骤是激活受体胞内结构域的蛋白激酶活性；对于没有蛋白激酶活性的受体来说，此步骤是受体通过蛋白质-蛋白质相互作用激活与它紧密偶联的蛋白激酶；③通过蛋白质-蛋白质相互作用或蛋白激酶的磷酸化修饰激活下游信号转导分子，通常是继续活化下游的一些蛋白激酶；④蛋白激酶通过磷酸化修饰激活代谢途径中的关键酶、反式作用因子等，影响代谢途径、基因表达、细胞运动、细胞增殖等。PTK偶联受体介导的信号转导途径的基本模式1.EGFR

mediatedRas-MAPKsignalingEpidermalgrowthfactorreceptor,EGFR

isaclassic

receptorPTKThroughRas→MAPKpathwayEGFR

mediatedRas-MAPK

signalingregulatinggeneexpressionEGFR

mediatedsignaling

Transformgrowthfactorβ,（TGFβ）receptor2.TGFβRactivatedSmads,TFs3.TNFR

mediatedsignalingandactivatedNF-

B,aTF4.Interlukinreceptormediatedsignaling

HappyNewYeartoyouall

YearDiscorvaryNobelwinner1923Insulin(proteinsignal)FrederickGrantBantingJohnJamesRichardMacleod1936ChemicaltransmittionofNerveImpulseHenryHallettDaleOttoLoewi1950Corticosteroid(steriod)EdwardCalvinKendallPhilipShowalterHenchTadeusReichstein1970Synthesis,releaseandinactivationofNeurotransmitterSirBernardKatzUlfvonEulerJuliusAxelrod1971MechanismofHormonebySecondMessenger(smallmolecules)EarlWilberSutherland1982ProstaglandinandassociatedactivecompoundSuneK.BergströmBengtI.SamuelssonJohnR.Vane1986GrowthfactorStanleyCohenRitaLevi-Montalciniyear

discoveryNobelprizewinner1992Proteinphosphorylation(modificatin)EdmondH.FischerEdwinG.Krebs1994GproteinanditsroleinsignalingAlfredGilman，MartinRodbell1998NO,asignalmoleculeincardiovascularsystemRobertF.Furchgott，LouisJ.Ignarro，FeridMurad2000Siganlinginneuro-systemArvidCarlsson，PaulGreengard，EricR.Kandel2001KeyregulatorincellcycleLelandH.HartwellR.TimothyHuntPaulM.Nurse2003MechanismofionchannelincellsurfacePeterAgreRoderickMacKinnon2004SmellreceptoranditsmechanismRichardAxel，LindaB.Buck2004ProteindegradationmediatedbyUbiquitinAaronCiechanover，AvramHershko，IrwinRose2.CyclicnucleotideregulatetheproteinactivitybyallostericeffectcAMP

andcGMP-secondmessenger,stimulatesthedownsteamproteins,allostericalteration,thenactivitychangeProt.kinaseisonekindofimportanttargetsofcyclicnucleotide(1)ProteinkinaseA

(PKA)isatargetofcAMPcAMP

affectscAMP-dependentproteinkinase

A，PKAThesubstratesofPKAwerephosphorylatedattheirserineorthreoninresidues,resultinginthekinaseactivationorinact.SubstratesPathwaysGlucogensynthaseglucogenesisGlycogenphosphorylase

bkinaseglycogenolysisPyruvatedehydrolasePyruvate→AcetylCoAHormone-sensitivelipaseTGhydrolysisandFFAoxidationTyrosinehydroxylaseSynthesisofDopamine,adrenalinandnoradenalinHintoneH1,H2BDNAaggragationProteinphosphotase1inhibitor1ProteindephosphorylationTranscriptfactor-CREBTranscriptionregulationThelistofPKAsubstrates(2)ProteinkinseG,PKG,isthetargetofcGMPcGMP

affectscGMP-dependentproteinkinase，PKGcGMP

stimulatesPKG1.PhospholypaseandphosphatidylinositolkinasesTwotypesofenzymescatalyzesthegenerationoflipidsecondmessenger(1)Phospholipase

(PL):phospholipaseA,B,C，(2)

phosphatidylinositolkinases(PIKs):phosphorylatesphosphatidylinositol(PI）toformPIPorPIP2orPIP3PhospholypaseCcatalyzestheformationofDAG,IP3PhosphatidylinositolspecificphospholypaseC（PI-PLCorPLC）PIP2DAG+Inositoltriphosphate（IP3）PI-PLCPI-PLCdistributedwidelyintissues,includingsubtypesofPLC

、PLC

、PLC

、PLC

andPLC

PLCisactivatedbycouplingtoGproteinPLCγisactivatedbyreceptortyrosinekinasePI-3KcatalyzesthephophorylatioenofvariousPIPIPIPPIP2

PI-3-PPI-3,4-P2PI-3,4,5-P3

PI-3K

Catalyticsubunit（P110）Regulatingsubunit（P85）PI-3KPhosphatidylinositol3-kinase磷脂酰肌醇-3激酶OthertypesofPLCandPIKareimportantinthesignalingtogeneratethesecondmessengers

Ganglioside(神经节苷脂)isalsotheresourseofsecondmessenger,suchasceramide（神经酰胺）asignalfunctioninginapoptosis

2.LipidsecondmessengerregulatesthetargetmoleculesbyallostericeffectTargetmolecules,conformationalalterationDifferentsecondmessenger,differenttargetsanddifferenteffects(1)Calciumchannel

istargetofIP3IP3watersoluable,formedatcellsurface,transfertocytosol,bindingwithitsreceptorinERIP3＋IP3

receptorCalciumchannelopen，CareleasefromERCaConc.increaseincytosolLymphocytesand

olfactorycellsIP3＋IP3

receptors

Calciumchannelopen,CareleasefromER

CaConc.increaseincytosol(2)

PKCistargetofDAG

andCalciumproteinkinaseC，PKC:

Ser/ThrProteinKinase,Functioningwidely

SubstrateofPKC:membranereceptor,membraneprotein,enzymes,TFIsozymeofPKC:

12,differentCharacters,tissuedistribution,cellularlocalization,activators,etal催化结构域Ca2+DAG磷脂酰丝氨酸调节结构域催化结构域底物Ca2+DAG磷脂酰丝氨酸调节结构域假底物结合区MechanismofDAC

activatingPKC3.PKBisthetargetofPIP3proteinkinaseB，PKB

Ser/ThrProteinKinase

Kinasedomain

homologousto

PKA（68％）,PKC（73％）PKB,anothernameAktT-lymphoma:

reversetranscritionalviruscontainedaoncogene-aktprotein-Akt，homologoustoPKB

PKB

substrateGlycogensynthase3,ribosomalproteinS6kinase、someTF,translationalinhibitor4E-B