生理化學(xué)教學(xué)課件：ch22 Coupling of Gene Expression with Cell Signaling

Chapter22CouplingofGeneExpressionwithCellSignaling

ContentofthischapterThegeneralMechanismofcellSignalTransductionSmallChemicalsasSecondMessengers ProteinsasSignalTransducers2.SignalTransductionNetworkControlingGeneExpression3.NuclearReceptorMediated-GeneExpressionControlsignaling4.GeneralSignalPathwaysMediatedbyMembraneReceptorsSection1GeneralMechanismofCellSignalTransductionⅠ.SiganlTransductionisa complicatednetworkSynthesisofsignalmoleculesincellReleasefromcellTraffictotargetcellRecognitionbyreceptorincellsurfaceInitiationofsignalingintargetcellChangeofmetabolismandfunctionsSignaleliminationandterminationofcellresponseSignaltransductionnetworkSignaltransducerSignaltransductionpathway在細(xì)胞內(nèi)介導(dǎo)信號(hào)傳遞的所有分子

信號(hào)轉(zhuǎn)導(dǎo)過(guò)程信號(hào)轉(zhuǎn)導(dǎo)分子的排列方式信號(hào)轉(zhuǎn)導(dǎo)通路交叉聯(lián)系形成的調(diào)控系統(tǒng)信號(hào)轉(zhuǎn)導(dǎo)通路的生物學(xué)功能BiologicalroleofsignalingSecondmessenger介導(dǎo)信號(hào)在細(xì)胞內(nèi)傳遞的小分子物質(zhì)TFranscriptionfactorChromatinrelatedprotienRNAprocessingproteinRNAtransferproteinCellcyclinSkeletoneNH2AAAAAm7GTranslationSignalingnetworkSignalReceptSignalTransductionRespondsProfileofcellsignalingⅡ.Signaloutsideinbyspecificrecepters

DefinitionofReceptor:

onekindofmoleculesacceptingthesignal

chemicalproperty:proteinorglycoproteinRoleofreceptersRecogniseitsligandSwitchthesignaloutsidein,thentransferitsinformationtofollowingmoles,resultincellresponsefinally

Thecharactersofreceptor-ligandbinding

HighspecificityHighaffinitySaturationReversion配體-受體結(jié)合曲線(xiàn)3typesofcellsurfacememb.receptor

Ligand-gatedreceptor

配體門(mén)控受體（屬于膜離子通道）

Gprotein-coupledreceptor，GPCR

G-蛋白偶聯(lián)受體（七跨膜受體）

Enzyme-linkedreceptor

酶（蛋白）偶聯(lián)受體（單跨膜受體）

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鳥(niǎo)(1)StructureoftwonucleotidecyclaseAdenylatecyclase，ACMammaryAC

8

isozymsACisregulatedbyG

prot.

MembraneboundglycoproteinMW.120kDGuanylatecyclase，GCReceptortypeofGC

3types:GC-A,GC-B,GC-C，

GC-AandGC-BarereceptorsofAtrialNatriureticpeptide(ANP)心鈉素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-核糖轉(zhuǎn)移酶，可溶性鳥(niǎo)苷酸環(huán)化酶,環(huán)氧化酶細(xì)胞色素，順烏頭酸酶，質(zhì)子ATP酶，運(yùn)鐵蛋白，核糖核苷酸還原酶，脂加氧酶氨基的亞硝基化，巰基的亞硝基化NOactivatesandinhibitstheenzymesandproteins

CaMisamainregulartorfor

NOS，3typesofNOShavebindingsitetoCaMSignalsinvolvedinCa2+increase,canaffectNOSⅣMolecularswitchcontrolssignaling

Proteinkinaseandphosphtaseswitch2.GproteinswitchProteinphosphorylationordephosphorylationdrivenbyproteinkinaseorproteinphosphatase,isamajorwaytoregulateactivityofsignalingmoleculesProteinphosphorylationordephosphorylationincreaseordecreaseenzyme’sactivity,whichdependsontheconformationalchange

Molecularswitch:ProteinPhosphorylationanddephosphorylation

kinaseAccepterofPi蛋白絲氨酸/蘇氨酸激酶蛋白酪氨酸激酶蛋白組/賴(lài)/精氨酸激酶蛋白半胱氨酸激酶蛋白天冬氨酸/谷氨酸激酶絲氨酸/蘇氨酸羥基酪氨酸的酚羥基咪唑環(huán)、胍基、ε-氨基巰基酰基ProteinkinaseProteinkinasetransfersthe

-PiofATPtoaminoacidoftargetproteinProteinphosphatase蛋白絲氨酸/蘇氨酸磷酸酶蛋白酪氨酸磷酸酶?jìng)€(gè)別的蛋白磷酸酶具有雙重作用，即可同時(shí)作用于酪氨酸和絲/蘇氨酸殘基蛋白磷酸酶衰減蛋白激酶信號(hào)PTKPTK無(wú)活性活化P自我磷酸化PTPPTPSSP無(wú)活性活化SrcfamilyPTK無(wú)活性SrcfamilyPTKPTPPPTK活化活化信號(hào)抑制信號(hào)Molecularswitch:

G

protein/smallGproteinandtheirrole

鳥(niǎo)苷酸結(jié)合蛋白（guaninenucleotidebindingprotein，Gprotein）簡(jiǎn)稱(chēng)G蛋白，具有GTP酶活性，亦稱(chēng)GTP結(jié)合蛋白，是一類(lèi)信號(hào)轉(zhuǎn)導(dǎo)分子。G蛋白結(jié)合GTP時(shí)為活化形式，作用于下游分子使相應(yīng)信號(hào)途徑開(kāi)放；當(dāng)結(jié)合的GTP水解為GDP時(shí)則回到非活化狀態(tài)，使信號(hào)途徑關(guān)閉。2typesofG

protein異源三聚體G

protein：

α

subunit（Gα）,β、γsubunit(Gβγ)

存在于細(xì)胞質(zhì)膜內(nèi)側(cè)

SmallGprotein（21kD）ⅤProteincomplex

insignalingSignalingmoleculesdosenotexistseparately,gathertogetheroraggregatedeachothersequentiallyBecomeaproteincomplexperformingroles

Signalingcomplex

highefficient,accurate,diversity生物利用蛋白質(zhì)復(fù)合物系統(tǒng)完成信號(hào)轉(zhuǎn)導(dǎo)功能的優(yōu)勢(shì)是：①?gòu)?fù)合體中信號(hào)轉(zhuǎn)導(dǎo)分子之間直接接觸，可有效、迅速傳遞信號(hào)；②多個(gè)蛋白質(zhì)形成的復(fù)合物可產(chǎn)生放大效應(yīng)；③可以根據(jù)細(xì)胞外信號(hào)強(qiáng)弱形成有差別的信號(hào)復(fù)合體，輸出多種信號(hào)，產(chǎn)生多方面的協(xié)同效果；④信號(hào)轉(zhuǎn)導(dǎo)復(fù)合體增加了信號(hào)轉(zhuǎn)導(dǎo)反應(yīng)的復(fù)雜性、多樣性和調(diào)控層次，使調(diào)節(jié)更精細(xì)、更準(zhǔn)確。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細(xì)胞內(nèi)眾多的組織特異性或可調(diào)控的轉(zhuǎn)錄因子接受受體傳遞的信號(hào)，依據(jù)細(xì)胞分工和功能的需求實(shí)現(xiàn)基因表達(dá)的時(shí)空特異性

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蛋白激酶的逐級(jí)磷酸化是細(xì)胞信號(hào)通路的重要特征MAPK的逐級(jí)磷酸化是將膜受體接受的信號(hào)轉(zhuǎn)導(dǎo)至核內(nèi)基因表達(dá)控制的重要環(huán)節(jié)，是細(xì)胞生長(zhǎng)、分化和應(yīng)激反應(yīng)的共同信號(hào)通路MAP種類(lèi)轉(zhuǎn)錄因子蛋白激酶ERKElk-1、c-Fos、c-JunRsk2、P70S6KJNKc-Jun、SP-1、ATF-2P38c-Myc、CREB、SP-1、ATF-2PRAK、MSK部分MAPK底物舉例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異源三聚體G蛋白直接介導(dǎo)受體信號(hào)轉(zhuǎn)換α亞基（Gα）β、γ亞基(Gβγ)具有多個(gè)功能位點(diǎn)α亞基具有GTP酶活性與受體結(jié)合并受其活化調(diào)節(jié)的部位βγ亞基結(jié)合部位GDP/GTP結(jié)合部位與下游效應(yīng)分子相互作用部位主要作用是與α亞基形成復(fù)合體并定位于質(zhì)膜內(nèi)側(cè)；在哺乳細(xì)胞，βγ亞基也可直接調(diào)節(jié)某些效應(yīng)蛋白。G

proteinanditscycleSmallGproteinRas超家族成員是重要的信號(hào)轉(zhuǎn)導(dǎo)分子SmallGprotein（21kD），它們?cè)诙喾N細(xì)胞信號(hào)轉(zhuǎn)導(dǎo)途徑中亦具有開(kāi)關(guān)作用。Ras是第一個(gè)被發(fā)現(xiàn)的小G蛋白，因此這類(lèi)蛋白質(zhì)被稱(chēng)為Ras家族，因?yàn)樗鼈兙梢粋€(gè)GTP酶結(jié)構(gòu)域構(gòu)成，故又稱(chēng)Ras樣GTP酶。G蛋白的活化啟動(dòng)信號(hào)轉(zhuǎn)導(dǎo)信號(hào)轉(zhuǎn)導(dǎo)途徑的基本模式：①配體與受體結(jié)合；②受體活化G蛋白；③G蛋白激活或抑制效應(yīng)分子；④效應(yīng)分子改變第二信使的含量與分布；⑤第二信使作用于相應(yīng)的靶分子，使之構(gòu)象改變，從而改變細(xì)胞的代謝過(guò)程及基因表達(dá)等。GPCR受體信號(hào)轉(zhuǎn)導(dǎo)的第一步反應(yīng)都是活化G蛋白。ⅣProteininteractioninthesignalingnetworkSignalrecognizingandbindingothermolecule

—protein-proteininteraction

dependsonproteininteractiondomain

ProteininteractiondomainProteinkinaseBtkPHTHSH3SH2CatalyticAdaptorprot.Grb2SH3SH2SH3TFstatDNA結(jié)合區(qū)SH2TACytoskeletonprot.tensin//SH2PTBCharactersofproteininteractiondomaincontains≧2domains,binding≧2proteinsatmeanwhile2.Sameproteininteractiondomainexistedinvariousproteins,butprimarysequenceisslightlydifferent,makingspecifityofeachprotein3.proteininteractiondomainisnotcatalyticdomainDomainsMotifrecognizedSrchomology2SH2含磷酸化酪氨酸模體Srchomology3SH3富含脯氨酸模體pleckstrinhomologyPH磷脂衍生物ProteintyrosinebindingPTB含磷酸化酪氨酸模體WWWW富含脯氨酸模體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）糖皮質(zhì)激素受體mineralcorticoidreceptor（MR）鹽皮質(zhì)激素受體estronereceptor（ER）雌激素受體progestogenreceptor（PR）孕激素受體androgenreceptor（AR）雄激素受體Type

II（non-steriodHrR）thyroidhormonereceptor（TR）甲狀腺激素受體retinoidXreceptor，（RAR）視黃酸受體retinoidXreceptor（RXR）視黃醇X受體vitaminD3receptor（VDR）維生素D3受體peroxisomeproliferator-activatorreceptor(PPAR)過(guò)氧化物酶體增殖活化受體TypeIII（orphanR）nervegrowthfactor-inducedreceptor（NGFI-B)神經(jīng)生長(zhǎng)因子誘導(dǎo)受體testisreceptors2（TR2)睪丸受體2X-linkedorphanreceptor-1X染色體連鎖孤兒受體Nomenclature

ofNuclearReceptor原則：根據(jù)DNA結(jié)合結(jié)構(gòu)域（C結(jié)構(gòu)域）和配體結(jié)合結(jié)構(gòu)域（E結(jié)構(gòu)域）在不同核受體間的同源性進(jìn)行命名

目前共計(jì)分為6個(gè)亞家族，28個(gè)組別人的甲狀腺素受體（TR）屬于第1亞家族A組中的第一個(gè)成員，因此被稱(chēng)為NR1A1NRxyz核受體核受體的亞家族亞家族中的組別組別中的成員ⅢNuclearReceptorregulatedtargetgeneexpressiondirectlyHormoneresponseelement(HRE)ⅣCofactorparticipatedinNuclearReceptorRegulatinggeneexpression

3.SMATSilencingmediatorforretinoidandthyroidhormonereceptor

Steroidhormonereceptorsuperfamilycoactivator,SRC-1類(lèi)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結(jié)合在糖皮質(zhì)激素反應(yīng)元件GRE而產(chǎn)生激活轉(zhuǎn)錄通過(guò)蛋白相互作用影響其他轉(zhuǎn)錄因子活性而抑制轉(zhuǎn)錄結(jié)合于GRE，募集N-CoR等共抑制因子而抑制轉(zhuǎn)錄其他核受體形成二聚體，結(jié)合于其他激素反應(yīng)元件，影響轉(zhuǎn)錄DiversityofNuclearReceptorregulatinggeneexpression糖皮質(zhì)激素（GR）——受體復(fù)合物Section4MembraneReceptorMediated-SignalingRegulatingGeneExpressionⅠMembraneReceptorMediated-Signaling

coupledwithgeneexpressionLigand-gatedreceptorGprotein-coupledreceptor，GPCREnzyme-linkedreceptor

特性離子通道受體

G-蛋白偶聯(lián)受體單次跨膜受體內(nèi)源性配體神經(jīng)遞質(zhì)神經(jīng)遞質(zhì)、激素、趨化因子、外源刺激（味，光）生長(zhǎng)因子細(xì)胞因子結(jié)構(gòu)寡聚體形成的孔道單體具有或不具有催化活性的單體跨膜區(qū)段數(shù)目4個(gè)7個(gè)1個(gè)功能離子通道激活G蛋白激活蛋白酪氨酸激酶細(xì)胞應(yīng)答去極化與超極化去極化與超極化調(diào)節(jié)蛋白質(zhì)功能和表達(dá)水平調(diào)節(jié)蛋白質(zhì)的功能和表達(dá)水平，調(diào)節(jié)細(xì)胞分化和增殖Charactersof3typesmembr.receptor1.GproteincoupledreceptormediatedsignalingregulatinggeneexpressionG蛋白偶聯(lián)區(qū)GPCR（serpantinereceptor）2.Enzymelinkedreceptormedicatedsignalingregulatinggeneexpression

Enzymelinkedreceptorhaskinaseactivity,orcoupledwithPTKSomehaveself-catalyzationHaveonetrans-membranedomain

receptorstyrosinekinases，RTKs 受體型蛋白酪氨酸激酶

tyrosinekinase-coupledreceptors，TKCRs 蛋白酪氨酸激酶偶聯(lián)受體receptorstyrosinephosphatases,RTPs 受體型蛋白酪氨酸磷酸酶receptorsserine/threoninekinase，RSTK

受體型蛋白絲/蘇氨酸激酶receptorsguanylatecyclases，RGCs

受體型鳥(niǎo)苷酸環(huán)化酶

CommonEnzymelinkedreceptorTheligandsofmostenzymelinkedreceptorsaregrowthfactorandcytokine,regulatingthegeneexpression,resultingincellproliferationanddifferentiationⅡSpecialsignalingcoupledwithgeneexpression

①結(jié)合配體后受體形成二聚體或寡聚體；②第一個(gè)蛋白激酶被激活。對(duì)于具有蛋白激酶活性的受體來(lái)說(shuō)，此步驟是激活受體胞內(nèi)結(jié)構(gòu)域的蛋白激酶活性；對(duì)于沒(méi)有蛋白激酶活性的受體來(lái)說(shuō)，此步驟是受體通過(guò)蛋白質(zhì)-蛋白質(zhì)相互作用激活與它緊密偶聯(lián)的蛋白激酶；③通過(guò)蛋白質(zhì)-蛋白質(zhì)相互作用或蛋白激酶的磷酸化修飾激活下游信號(hào)轉(zhuǎn)導(dǎo)分子，通常是繼續(xù)活化下游的一些蛋白激酶；④蛋白激酶通過(guò)磷酸化修飾激活代謝途徑中的關(guān)鍵酶、反式作用因子等，影響代謝途徑、基因表達(dá)、細(xì)胞運(yùn)動(dòng)、細(xì)胞增殖等。PTK偶聯(lián)受體介導(dǎo)的信號(hào)轉(zhuǎn)導(dǎo)途徑的基本模式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.Bergstr?mBengtI.SamuelssonJohnR.Vane1986GrowthfactorStanleyCohenRitaLevi-Montalciniyear

discoveryNobelprizewinner1992Proteinphosphorylation(modificatin)EdmondH.FischerEdwinG.Krebs1994GproteinanditsroleinsignalingAlfredGilman，MartinRodbell1998NO,asignalmoleculeincardiovascularsystemRobertF.Furchgott，LouisJ.Ignarro，F(xiàn)eridMurad2000Siganlinginneuro-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(神經(jīng)節(jié)苷脂)isalsotheresourseofsecondmessenger,suchasceramide（神經(jīng)酰胺）asignalfunctioninginapoptosis

2.LipidsecondmessengerregulatesthetargetmoleculesbyallostericeffectTargetmolecules,conformationalalterationDifferentsecondmessenger,differenttargetsanddifferenteffects(1)Calciumchannel

istargetofIP3IP3watersoluable,formedatcellsurface,transfertocytosol,bindingwithitsreceptorinERIP3＋I(xiàn)P3

receptorCalciumchannelopen，CareleasefromERCaConc.increaseincytosolLymphocytesand

olfactorycellsIP3＋I(xiàn)P3

receptors

Calciumchannelopen,CareleasefromER

CaConc.increaseincytosol(2)

PKCistargetofDAG

andCalciumproteinkinaseC，PKC:

Ser/ThrProteinKinase,Functioningwidely

SubstrateofPKC:membranereceptor,membraneprotein,enzymes,TFIsozymeofPKC:

12,differentCharacters,tissuedistribution,cellularlocalization,activators,etal催化結(jié)構(gòu)域Ca2+DAG磷脂酰絲氨酸調(diào)節(jié)結(jié)構(gòu)域催化結(jié)構(gòu)域底物Ca2+DAG磷脂酰絲氨酸調(diào)節(jié)結(jié)構(gòu)域假底物結(jié)合區(qū)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