细胞生物学：第5章细胞通讯

《细胞生物学：第5章细胞通讯》由会员分享，可在线阅读，更多相关《细胞生物学：第5章细胞通讯（93页珍藏版）》请在金锄头文库上搜索。

1、1CHAPTER5细胞通讯细胞通讯CELLCOMMUNICATION2OUTLINE5.1 BASICCHARACTERISTICSOFCELL-SIGNALINGSYSTEMS5.2 GPROTEINCOUPLEDRECEPTOR5.3 SIGNALINGVIAENZYME-LINKEDRECEPTORSANDOTHERSIGNALINGPATHWAY5.4 SIGNALCONVERGENT、DIVERGENT、CROSSTALKANDCELLADAPTATION3细胞通讯：细胞通讯：CellCommunication细胞间或细胞内通过高精细胞间或细胞内通过高精度和高效的接收信息通讯度和高效

2、的接收信息通讯机制机制并通过放大引起快速的细并通过放大引起快速的细胞生理反应胞生理反应/或引起基因活或引起基因活动，动，从而发生一系列的细胞活从而发生一系列的细胞活动来协调各组织行动，使动来协调各组织行动，使之成为统一生命整体对外之成为统一生命整体对外界环境变化作出综合应答。界环境变化作出综合应答。4CellSignal：信号的产生及传送信号的产生及传送synthesisofsignalmoleculereleasetransportCellCommunicationReactionSignalTransduction：信号的接收、转换、应答信号的接收、转换、应答signalrecogniti

3、ontransductionresponseTransductionSignalmoleculesrecognition(receptor)ReactionSIGNALINGCOMPONENTSuFour Types of Cell CommunicationuCell-Surface Receptors Fall into Three Main ClassesuThe Basic Cell Signaling Process(A) Contact-dependent: dont need secreted molecule(B) Papacrine: to nearby neighbor(C

4、) Neuronal signaling(D) Endocrine: to long distanceFrom Bruce Alberts et al., Molecular Biology of The Cell (5th edition)Signal can act over long or short range. Four Types of Cell Communication Contact-dependentsignalingcontrolsnerve-cellproduction:Eachfutureneurondeliversaninhibitorysignaltothecel

5、lsnexttoittodeterthemfromspecializingasneuronstooFrom Essential Cell Biology ( Garland Science 2010)From Essential Cell Biology ( Garland Science 2010)From Essential Cell Biology ( Garland Science 2010)105.1.1CellSignalingandSignalmolecule不依赖于细胞接触：不依赖于细胞接触：依赖于细胞接触：依赖于细胞接触：11TransductionSignalmolecul

6、esrecognition(receptor)Reaction5.1.2SignalRecognitionandReceptors受体（受体（receptorreceptor）：任何能够与信号分子结合并能：任何能够与信号分子结合并能引起细胞功能变化的生物大分子。引起细胞功能变化的生物大分子。12接收信息接收信息受体受体信号分子信号分子配体配体(ligand)(ligand) From Bruce Alberts et al., Molecular Biology of The Cell (5th edition)1.Anion-channel-coupledopensorclosesinres

7、ponsetobindingofitsextracellularsignalmolecule.Thesechannelsarealsocalledtransmitter-gatedionchannelsCellsurfacereceptorsfallintothreebasicclasses From Bruce Alberts et al., Molecular Biology of The Cell (5th edition)2.G-protein-coupledreceptor:WhenaG-coupledreceptorbindsitsextracellularsignalmolecu

8、le,thesignalispassedfirsttoaGTP-bindingprotein(Gprotein)thatisassociatedwiththereceptor.TheactivatedGproteinthenleavesthereceptorandturnonatargetenzyme(orionchannel)inthemembrane From Bruce Alberts et al., Molecular Biology of The Cell (5th edition)3.Enzyme-coupledreceptors:Anenzyme-linkedreceptorbi

9、ndsitsextracellularsignalmolecule,switchingonanenzymeactivity,eitherattheotherendoftheenzymeorotherassociatedenzyme16Cell-surfaceReceptors（受体本身就是离子通道的一部分）（受体本身就是离子通道的一部分）（GTPGTP结合的调节蛋白偶联）结合的调节蛋白偶联）（受体本身就是酶，又称催化受体）（受体本身就是酶，又称催化受体）17IntracellularReceptorsTwomotifs,twobindingsites18TransductionSignalmo

10、leculesrecognition(receptor)Reaction195.1.3SignalTransduction信号转导：信号转导：细胞表面受体通细胞表面受体通过一定机制将外过一定机制将外部信号转为内部信号转为内 部信号。部信号。Manyintracellularsignalingproteinsactasmolecularswitches:(A)Signaling by phosphorylation : signaling proteins are activated by the addition of a phosphate group by protein kinase,

11、and inactivated by removal of the phosphate by protein phosphatase. Protein kinase phosphates serine/threonine (called ser/thr kinase) or tyrosine (called tyrosine kinase)(B) Signaling by GTP-binding protein: a GTP-binding signaling protein is induced to exchange its bound GDT for GTP (i.e. adds aph

12、osphate to the protein). The hydrolysis of the bound GTP to GDP Then switches the protein offProteinkinase2isactivatedbyproteinkinase1.Onceactivated,proteinkinase2phosphorylatesproteinkinase3,activatingtheenzyme.Proteinkinase3thenphosphorylatesatranscriptionfactor,increasingitsaffinityforasiteontheD

13、NA.BindingofatranscriptionfactortotheDNAaffectsthetranscriptionofthegeneinquestion.Eachoftheseactivationstepsinthepathwayisreversedbyaphosphatase.From Gerald Karp, Cell and Molecular Biology- concepts and experiments (6th edition)Signal transduction pathway consisting of protein kinases and protein

14、phosphatases From Bruce Alberts et al., Molecular Biology of The Cell (5th edition)GTPase-activatingproteins(GAPs)inactivatetheproteinbystimulatingittohydrolyzeitsboundGTPtoGDP.Guaninenucleotideexchangefactors(GEFs)activatetheinactiveproteinbystimulatingittoreleaseitsGDP;NotethattheconcentrationofGT

15、Pincytosolis10timesgreaterthantheconcentrationofGDP,theproteinrapidlybindsGTPonceitejectsGDPandistherebyactivatedThe regulation of a monomeric GTPases. 23SecondMessenger第一信使：第一信使：细胞外部信号。细胞外部信号。第二信使：第二信使：由细胞表面受体转换而来的细胞内部信号。第一信使由细胞表面受体转换而来的细胞内部信号。第一信使同其膜受体结合后最早在胞膜内侧或胞浆中出现的仅在细胞内部同其膜受体结合后最早在胞膜内侧或胞浆中出现的仅

16、在细胞内部起作用的信号分子；能启动或调解细胞内稍晚出现的细胞应答。起作用的信号分子；能启动或调解细胞内稍晚出现的细胞应答。24SignalTransductionataGlance25TypesofReceptor-EffectorLinkage26TransductionSignalmoleculesrecognition(receptor)ReactionExtracellularsignalscanactslowlyorrapidlyFrom Essential Cell Biology ( Garland Science 2010)28SignalCascadeTwo differen

17、t types of signal transduction pathways: one in which a signaling pathway is activated by a diffusible second messenger and another in which a signaling pathway is activated by recruitment of proteins to the plasma membrane. Most signal transduction pathways involve a combination of these mechanisms

18、. signaling pathways are not typically linear tracks as depicted here, but are branched and interconnected to form a complex web. From Gerald Karp, Cell and Molecular Biology- concepts and experiments (6th edition)TheBasicCellSignalingProcess305.2GProtein-coupledReceptor 2006 Nature Review Drug Disc

19、overy 2006 Nature Review Drug Discovery GPCRGPCRTrulyuniquedrugs：1,300Smallmolecules：1,200Majordrugtargets：300Drugtargetsinhuman：2664majortypesofdrugtargets：GPCRs，nuclearreceptors，ligand-gatedorvoltage-gatedionchannelsGPCR：60GPCRGPCR最具潜力的药靶最具潜力的药靶最具潜力的药靶最具潜力的药靶20062006全球销量前全球销量前全球销量前全球销量前1010名的药物名的药

20、物名的药物名的药物排行排行排行排行药名药名药名药名20062006年年年年销售额销售额销售额销售额 (USD(USD百万百万百万百万) )公司公司公司公司疾病疾病疾病疾病主要靶点主要靶点主要靶点主要靶点批准上市日期批准上市日期批准上市日期批准上市日期1 1LipitorLipitor14,38514,385PfizerPfizer高血脂高血脂高血脂高血脂HMG-CoAHMG-CoA还原酶还原酶还原酶还原酶Dec-96Dec-962 2Advair,SeretideAdvair,Seretide6,1296,129GSKGSK哮喘哮喘哮喘哮喘糖皮质激素受体糖皮质激素受体糖皮质激素受体糖皮质激素受

21、体/ /肾上肾上肾上肾上腺素受体腺素受体腺素受体腺素受体Aug-00Aug-003 3Plavix,IscoverPlavix,Iscover6,0576,057Bristol-MyersBristol-MyersSquibb/Sanofi-Squibb/Sanofi-AventisAventis血栓血栓血栓血栓P2Y12P2Y12受体受体受体受体Nov-97Nov-974 4NexiumNexium5,1825,182AstraZenecaAstraZeneca肠胃溃疡肠胃溃疡肠胃溃疡肠胃溃疡质子泵抑制剂质子泵抑制剂质子泵抑制剂质子泵抑制剂Mar-00Mar-005 5NorvascNorv

22、asc4,8664,866PfizerPfizer高血压高血压高血压高血压钙离子通道钙离子通道钙离子通道钙离子通道Jul-92Jul-926 6RemicadeRemicade4,4284,428Johnson&Johnson,Johnson&Johnson,Schering-Plough,Schering-Plough,MitsubishiTanabeMitsubishiTanabePharmaPharma自免疫性肠炎及类自免疫性肠炎及类自免疫性肠炎及类自免疫性肠炎及类风湿性关节风湿性关节风湿性关节风湿性关节炎炎炎炎TNFTNF抗体抗体抗体抗体Aug-98Aug-987 7EnbrelEnb

23、rel4,3794,379WyethWyeth类风湿性关节炎类风湿性关节炎类风湿性关节炎类风湿性关节炎TNFTNFNov-98Nov-988 8ZyprexaZyprexa4,3644,364EliLillyandCompanyEliLillyandCompany精神病精神病精神病精神病多种多种多种多种GPCR,GPCR,包括包括包括包括D1,D2,5HT2A,D1,D2,5HT2A,5HT2C5HT2C等等等等Sep-96Sep-969 9DiovanDiovan4,2234,223NovartisNovartis高血压高血压高血压高血压血管紧张素受体血管紧张素受体血管紧张素受体血管紧张素受

24、体AT1RAT1RDec-96Dec-961010RisperdalRisperdal4,1834,183Johnson&JohnsonJohnson&Johnson精神病精神病精神病精神病多种多种多种多种GPCR,GPCR,包括包括包括包括5HT1A,5HT1,55HT1A,5HT1,5HT2A,5HT2CHT2A,5HT2C，5HT75HT7，D1,D2,D1,D2,等等等等Dec-93Dec-9333G-蛋白蛋白:组成组成:一般由三个亚基组成一般由三个亚基组成,分别叫分别叫、,、两亚基通常紧密结合在一起两亚基通常紧密结合在一起,只有在蛋白只有在蛋白变性时才分开。变性时才分开。功能功能位点

25、位点:亚基具有三个功能亚基具有三个功能位点位点：GTP结合位点结合位点;鸟苷三磷酸水解酶鸟苷三磷酸水解酶(GTPase)活性活性;ADP-核糖化位点。核糖化位点。34CyclingofGProteinGDI（鸟苷解离抑制蛋白）（鸟苷解离抑制蛋白）GEF（鸟苷交换因子）（鸟苷交换因子）GAP（GTPase激活蛋白）激活蛋白）Bindingofsignalmoleculetoreceptorcausestheconformationchangeofthisreceptor,whichinturnalterstheconformationoftheGproteinThealterationofthe

26、subunitofGproteinallowsittoexchangeitsGDPtoGTPThiscausestheGproteintobreakupintotwoactivatecomponents-subunitandacomplex,bothcanregulatetheactivityoftargetproteinsintheplasmamembraneFrom Essential Cell Biology ( Garland Science 2010)36ClassificationofGproteins37e.g.GPCRactivationtoopeningofK+channel

27、sintheplasmamembraneofheartmusclecellsactivatedbg complexbindstoandopensaK+channelinactivationoftheasubunitbyhydrolysisofitsboundGTPreturnstheGproteintoitsinactivestate,allowingtheK+channeltocloseG-protein Regulation of Ion Channels From Essential Cell Biology ( Garland Science 2010)39PKASystem40PKA

28、activationphosphorylate serine/threonine residues on their target proteins.41?PKAFunction(cytoplasm)1.phosphorylateskeytargetenzymes42DiscoveryofcAMP(第二信使第二信使)1947年医学和生理学诺贝年医学和生理学诺贝尔奖获得者尔奖获得者431971年医学和生理学诺贝年医学和生理学诺贝尔奖获得者尔奖获得者DiscoveryofcAMP(第二信使第二信使)EarlW.Sutherland44DiscoveryofcAMP(第二信使第二信使)EarlW.S

29、utherland45AlfredG.GilmanMartinRodbell1994年医学和生理学诺贝尔奖获得者年医学和生理学诺贝尔奖获得者DiscoveryofGprotein461994年医学和生理学诺贝尔奖获得者年医学和生理学诺贝尔奖获得者DiscoveryofGprotein47DiscoveryofGprotein48DiscoveryofGprotein49DiscoveryofGprotein50PKAFunction(Nuclear)2.Transcriptionregulation51cAMPcAMP途径的信号解除和抑制途径的信号解除和抑制 ? ?信号解除信号解除通过磷酸二酯

30、酶将通过磷酸二酯酶将cAMPcAMP降解降解, ,形成形成5-AMP5-AMP；信号抑制信号抑制通过抑制型的信号作用于通过抑制型的信号作用于Ri, Ri, 然后通过然后通过GiGi起作起作用。用。 52的的合合成成与与分分解解cAMP53cAMPcAMP信号的抑制（信号的抑制（GiGi）54毒素对毒素对cAMP信号途径的影响信号途径的影响霍乱毒素霍乱毒素(choleratoxin) 能把能把NAD+上的上的NAD-核糖转移到核糖转移到Gs蛋白的蛋白的亚基上，使亚基上，使G蛋白核糖化蛋白核糖化(ADP-ribosylation),这样将抑制这样将抑制亚基亚基GTPase活性活性。百日咳毒素百日咳

31、毒素(whoopingcouchtoxin)作用机理同霍乱毒素相同，但是使作用机理同霍乱毒素相同，但是使Gi蛋白进行蛋白进行ADP核糖核糖化化,阻止阻止Gi亚基活化，亚基活化，其结果也是使其结果也是使cAMP的浓度增的浓度增加。加。55磷脂肌醇信号途径磷脂肌醇信号途径(PhosphatidylinositolSignaling) G蛋白偶联受体系统的一种。该通蛋白偶联受体系统的一种。该通路路也也称称IP3、DAG、Ca2+信信号号通通路路,或或称称为为PKC(ProteinkinaseC)系统。系统。56PKCSystem57PKCActivation58PKCFunction(Nuclear

32、)59CaCa2+2+的第二信使作用的第二信使作用Calcium ions play a significant role in a remarkable variety of cellular activities, including muscle contraction, cell division, secretion, endocytosis, fertilization, synaptic transmission, metabolism, and cell movement. 钙调蛋白钙调蛋白(calmodulin) Each molecule of calmodulin con

33、tains four binding sites for calcium. Calmodulin does not have sufficient affinity for Ca2+ to bind the ion in a non-stimulated cell. If, however, the Ca2+ concentration rises in response to a stimulus, the ions bind to calmodulin, changing the conformation of the protein and increasing its affinity

34、 for a variety of effectors. ? 60Ca2+andCalmodulinCa2+/Calmodulindependentproteinkinases61(PKC)IP3/DAG/Ca2+信号的终止信号的终止DAGDAG信号的解除信号的解除 DAGDAG只只是是由由PIPPIP2 2水水解解得得到到的的暂暂时时性性产产物物, , 寿寿命只有几秒钟命只有几秒钟, , 靠两种方式进行降解靠两种方式进行降解: :被被DAGDAG磷磷酸酸激激酶酶磷磷酸酸化化, ,生生成成磷磷脂脂酸酸(PA),PA(PA),PA被被转转化化为为CMP-CMP-磷磷脂脂酸酸, ,再再与与肌肌醇醇

35、作作用用合合成成磷磷脂肌醇脂肌醇(PI)(PI)。DAG DAG 被被DAG DAG 酯酯酶酶水水解解生生成成单单脂脂酰酰甘甘油油,进进一一步步水水解解成成自自由由的的多多不不饱饱和和脂脂肪肪酸酸和和花花生生四四烯烯酸甘油。酸甘油。62IP3作用的终止作用的终止IP3的水解的水解在在5磷酸酶的作用下磷酸酶的作用下,水解为水解为I(1,4)P2,并进并进一步水解成肌醇。一步水解成肌醇。5磷酸酶是一种膜结合的酶。磷酸酶是一种膜结合的酶。在在胞胞浆浆的的肌肌醇醇磷磷酸酸脂脂3-激激酶酶的的作作用用下下IP3被被磷酸化成磷酸化成I(1,3,4,5)P4。(PKC)IP3/DAG/Ca2+信号的终止信号

36、的终止63Ca2+信号解除信号解除IP4参参与与打打开开细细胞胞质质膜膜上上的的Ca2+通通道道,使使细细胞胞质质中中的的Ca2+较为持久地增高。较为持久地增高。胞胞内内Ca2+浓浓度度持持久久地地升升高高,可可激激活活Ca2+-ATP酶酶（质质膜膜、内内质质网网膜膜的的钙钙泵泵），从从而而降降低低胞胞质质中中的的Ca2+，使使胞胞质质中中的的Ca2+迅迅速速恢恢复复到到基基态态水水平平(10-7M),并并使使活活性性CaM-酶复合物解离酶复合物解离,从而酶失去活性从而酶失去活性,细胞反应终止。细胞反应终止。(PKC)IP3/DAG/Ca2+信号的终止信号的终止645.3Enzyme-link

37、edreceptorv特点：特点：受体本身是一种具有跨膜结构的酶蛋白，其胞外域与配体结合而被激活，通过胞内侧激酶反应将胞外信号传至胞内。不不需需要要信信号号偶偶联联蛋蛋白白(G-(G-蛋蛋白白), ), 而而是是通通过过受受体体自自身身的的酪酪氨酸蛋白激酶的活性来完成信号跨膜转换；氨酸蛋白激酶的活性来完成信号跨膜转换；该该通通路路对对信信号号的的反反应应比比较较慢慢( (通通常常要要几几小小时时) )，并并且且需需要要许多细胞内的转换步骤；许多细胞内的转换步骤；通常与细胞分裂相关。通常与细胞分裂相关。65Enzyme-linkedreceptorv3个结构区，细胞外配体结合结构域，细胞内的催化

38、结构域（具有酶活性或与酶有关的结构域）；和单次跨膜结构域66Enzyme-linkedreceptorv种类酪氨酸激酶偶联受体(tyrosine kinase-linked receptors)内源酶促活性受体(receptors with intrinsic enzymatic activity )，有很多种类型： 鸟苷环化酶受体(Receptor guanylyl cyclase)；酪氨酸磷酸酶受体(Receptor of tyrosine phophatase); 酪氨酸激酶受体(Receptor tyrosine kinase)；丝氨酸/苏氨酸激酶受体(Receptor serine/

39、threonine kinase)。67Tyrosine kinase-linked receptor68receptors with intrinsic enzymatic activity 69内源酶促活性受体鸟苷环化酶受体(Receptor guanylyl cyclase)：心房钠尿肽受体本身是鸟苷环化酶结构：配体结合结构域蛋白激酶样结构域催化结构域cGMP为第二信使cGMP依赖性蛋白激酶G（PKG）70cGMP 也是GPCR信号通路中的第二信使：光受体视紫红质G蛋白：转导素cGMP特异性的磷酸二酯酶第二信使cGMP ：71PKGPKG (cGMP dependent protein

40、kinase） cGMP的靶蛋白，是依赖于cGMP的蛋白激酶G二聚体：催化亚基同cGMP结合的调节亚基作用的底物: 组蛋白(H1, H2A, H4)磷酸化酶激酶糖原合成酶丙酮酸激酶激素敏感性脂肪酶胆固醇脂水解酶等72酪氨酸激酶受体(Receptor tyrosine kinase， RTK)：受体本身是酪氨酸激酶结构：胞外配体结合结构域单次跨膜螺旋胞内RTK结构域靶蛋白酪氨酸残基磷酸化细胞生长因子受体：EGF，PDGF， M-CSF， IGF1，NGF，FGF，VEGF，HGF内源酶促活性受体73RTK激活：单体无活性受体二聚体：信号分子二聚体或构象改变形成信号传导复合物细胞内信号传导蛋白结合

41、并激活74酪氨酸激酶受体(Receptor tyrosine kinase， RTK)：四聚体激活：自磷酸化胰岛素受体底物（IRS）磷酸化 可作为一块“磁铁”同那些具有SH2结构域的蛋白结合，根据所结合蛋白的具体结构产生不同的效应。胰岛素受体75酪氨酸激酶受体(Receptor tyrosine kinase， RTK)：SH结构域：Src同源结构域SH2， SH3SH2是一种与磷酸酪氨酸基序具有高亲和性的结合位点（氨基酸序列）IRS：IRS1-PI(3)K，Shc-Grb2-Ras，IRS2-PLC-PKCIRS/SH结合特异性胰岛素受体76酪氨酸激酶受体(Receptor tyrosine

42、 kinase， RTK)：糖蛋白三个结构域:EGF结合结构域跨膜区蛋白激酶活性区域受体激活：C端有几个含酪氨酸残基的自身磷酸化部位与靶蛋白SH2结合EGF受体77酪氨酸激酶受体(Receptor tyrosine kinase， RTK)：Rat Sarcoma，是原癌基因的表达产物；介导： 细胞外信号受体RasRaflMAPKKKMAPKK(MEK)MAPK 转录因子激活靶基因细胞应答和效应。Ras78酪氨酸激酶受体(Receptor tyrosine kinase， RTK)：RasGAFGEF单体GTP结合蛋白，弱GTP酶活性激活：鸟苷交换因子-GEF释放GDP失活： GTP酶激活蛋白

43、-GAPGrb2和Sos蛋白79Enzyme-linked receptor Enzyme-linked receptor Grb2和Sos蛋白 Grb2 生长因子受体结合蛋白：SH结构域RTK效应蛋白 Sos 鸟苷酸释放蛋白：一种GEF, Ras激活蛋白Ras80Enzyme-linked receptor Enzyme-linked receptor Ras 生长因子信号经Ras的级联反应MAPKKK: MAP激酶的激酶的激酶-RafMAPKK: MAP激酶的激酶-MEKMAPK: MAP激酶MAP :促分裂原活化蛋白Ras突变与癌变From Gerald Karp, Cell and M

44、olecular Biology-concepts and experiments (6th edition)OnetargetproteinthatcanbeactivatedbyNOisguanylcyclase.TheactivatedcyclasecatalyzestheproductionofcGTPfromGTPsignaltransductionpathwaythatoperatesbymeansofNOandcyclicGMPthatleadstothedilationofbloodvesselsuFunction of focal adhesion uIntegrin sig

45、naling depends on focal adhesion kinase (FAK) uRho family regulation of the actin cytoskeletonCell signaling and the cytoskeletonThemechanical-structuralfunctionoffocaladhesion,whichiscarriedoutbyactinfilamentsandassociatedproteinsSignalingfunctionfromextracellularsurfacenucleus(wheretheystimulateth

46、etranscriptionofgenesinvolvedincellgrowthandproliferation),whichiscarriedoutbytyrosinekinase(SrcandFAK)Function of focal adhesion Focaladhesions(cellmatrixadhesions)arespecifictypesoflargemacromolecularassemblies.ItisthemechanicallinkagestotheECM.When integrins cluster at cell-matrix contacts, FAK i

47、s recruited by intracellularanchorprotinessuchastalinorpaxillinFocaladhesionsconcentrateanddirectnumeroussignalingproteinsatsitesofintegrinbindingandclustering.Signalpathwaythatleadtotheassemblyofthefibersofafocaladhesion.Rhoisinvolvedinregulatingtheorganizationofthecellsactincytoskeleton.Integrin s

48、ignaling depends on focal adhesion kinase (FAK) ModelforsignalingfromtheFAKprotein-tyrosinekinase.BindingofintegrinstotheextracellularmatrixstimulatesFAKactivity,leadingtoitsautophosphorylation.SrcthenbindstotheFAKautophosphorylationsiteandphosphorylatesFAKonadditionaltyrosineresidues.Thesephosphoty

49、rosinesserveasbindingsitesfortheGrb-2-Soscomplex,leadingtoactivationofRasandtheMAPkinasecascade,aswellasforadditionaldownstreamsignalingmolecules,includingPI3-kinase.From Geoffrey M. Cooper, The Cell A Molecular Approach (2nd edition)86SignalIntegration87信号的趋同、趋异与串话SignalIntegration 趋同(convergent ):

50、 不同的生长因子作用于不同的受体，但能整合激活一个共同的效应物，如Ras或MAP激酶；88信号的趋同、趋异与串话 趋异（divergent): 相同配体，如EGF或胰岛素能够转换激活许多不同的效应物，引起细胞的不同反应；SignalIntegration89信号的趋同、趋异与串话 串话(crosstalk):不同信号途径间的相互影响 PKA/RTK cAMP的信号通路主要是引起细胞代谢变化; cAMP也抑制一些细胞的生长，机理主要是阻断MAP激酶的级联放大。 SignalIntegration90SignalTermination 信号分子水解cAMP, IP3, DAG受体钝化Arresti

51、n 同源钝化cAMP/PKA异源钝化受体减量调节受体内吞磷酸酶作用 The desensitization of G proteinThephosphorylationofthecytoplasmicdomainoftheactivatedGPCRbyaGprotein-coupledreceptorkinase(GRK).ArrestinsbindingtothephosphorylatedGPCRspreventsthefurtheractivationofGproteins.Desensitizationisanimportantmechanismthatallowsacelltores

52、pondtochangesinitsenvironmentratherthancontinuetobeinastateofactivationendlesslyinthepresenceofanunchangingenvironment.FromGeraldKarp,CellandMolecularBiology-conceptsandexperiments(6thedition)G-protein-coupled receptor desensitization depends on receptor phosphorylation by PKA,PKC, CaMK2 or G-protein-coupled receptor kinases(GRKs) From Essential Cell Biology ( Garland Science 2010)93思考题思考题: :1 1、何谓细胞通讯？有哪些方式？、何谓细胞通讯？有哪些方式？2 2、什么是细胞信号转导？、什么是细胞信号转导？3 3、细胞膜表面受体的信号转导途径有哪些？、细胞膜表面受体的信号转导途径有哪些？4 4、细胞内信号转导系统间如何进行相互作用？、细胞内信号转导系统间如何进行相互作用？