细胞信号转导和肿瘤专家讲座.pptx

第五章细胞信号转导与肿瘤历史回顾基本组成主要传导通路信号传导与肿瘤问题与展望一、历史回顾1951RitaLevi-Montalcini发觉第一个生长因子NGF1960StanleyCohen在纯化NFG时发觉EGF生长因子发觉使StanleyCohen和RitaLevi-Montalcini获1986年NobelPrizeKrebs像Gilman像1978v-Src蛋白产物被证实是酪氨酸蛋白激酶1983Sis癌基因蛋白产物被发觉是PDGFB链1983第一个人癌基因H-ras克隆，是一个G蛋白1989第一个抑癌基因Rb克隆，在细胞周期调控中具主要作用1989重新认识P53二、Asimpleintracellularsignalingpathwayactivatedbyanextracellularsignalmolecule1.Extracellularsignalmolecule2.Receptorprotein（1）IntracellularreceptorproteinsStructure:DNA-bindingdomain，DBDligand-bindingdomain，LBD与肿瘤发生关系①配体量增加②受体构象改变③激活转录与细胞增殖相关因子（2）Cell-surfacereceptorproteins①、酪氨酸激酶受体②、G蛋白偶联受体③、细胞因子受体④、黏附因子受体⑤、蛋白酪氨酸激酶联络受体⑥、其它受体ser/thr激酶受体酪氨酸磷酸酯酶受体鸟嘌呤核苷酸环化酶离子通道受体电压门控离子通道受体3.IntracellularsignalingproteinsadaptorscaffoldproteinsG蛋白第二信使胞内激酶4、Targetproteins三、主要信号通路（二）、SignalingthroughG-protein-linkedcell-surfacereceptors癌基因gsp和gip2（三）、Signalingthroughenzyme-linkedcell-surfacereceptors1、ReceptortyrosinekinasereceptortyrosinekinaseadaptorRTK-raspathway与肿瘤发生关系生长因子类癌基因受体酪氨酸激酶类癌基因激活机制原癌基因产物N-端配体结合区缺失受体膜外区或跨膜区突变受体过分表示激酶催化区部分氨基酸缺失，亦能增加受体酪氨酸激酶活性癌基因rasH-ras(HarveyrasorHa-ras)K-ras(KierstenrasorKi-ras)N-rasRTK-PI3K-PKB(Akt)pathway—leadingcelltogrowthPTENPTENgene(geneofphosphateandtensionhomologydeletedonchromosometen)Specificinositolphospholipidphosphatases：removephosphatefrom3positionoftheinositolringMutationsthatinactiveonesuchphosphatase,andtherebyprolongsignalingbyPI3-K,promotethedevelopmentofcancer,andtheyarefoundinmanyhumancancerspathwayTumorPI3K（oncogene）：p85mutationAktb：overexpressionPTENmutation2、Jak-STATpathwaySignalligandcytokinereceptorsCytoplasmictyrosinekinaseJaks(Januskinases):Jak1,Jak2,Jak3,Tyk2STATs(signaltransducersandactivatorsoftranscription)TherearesevenknownSTATsEachwithanSH2domainFunctions:MediatesthebindingoftheSTATproteintoaphosphotyrosinedockingsiteonanactivetedcytokinereceptor(orreceptortyrosinekinase).Oncebound,theTaksphosphorylatetheSTATontyrosines,causingittodissociatefromthereceptorTheSH2domainonthereleasedSTATnowmediatesitsbindingtoaphosphotyrosineonanotherSTATmolecu