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1、,细胞通讯与信号传递,第八章 细胞信号转导,The forms of cell communication- Different types of chemical signals can be received by cells,Gap junction,细胞信号通路的相关因子和机制,产生和运输信号分子和细胞受体 信号分子和细胞受体特异性结合 启动信号转导途径 细胞产生效应 信号解除,细胞反应停止,化学信号分子,亲脂性的信号分子 亲水性的信号分子 气体信号分子(NO、CO),信号受体,Ion-channel-linked receptor,G protein-linked recetor,E
2、nzyme-linked recetor,细胞对外界信号的反应取决于: 1、细胞受体对信号结合的特异性 2、细胞本身的固有特征,相同的信号,不同的受体,不同的效应(A和B),相同的信号,相同的受体,不同的效应(B和C),第二信使: cAMP、cGMP、IP3、DG etc.,第二信使与分子开关,分子开关: 在信号传递过程中,通过自身“开启”和“关闭”两种状态的转换,实现对下游靶蛋白活性控制的蛋白质分子。主要有两类:一类通过结合GTP和水解GTP,另一类通过磷酸化和去磷酸化,而实现蛋白活性的开启和关闭。,二、信号转导系统及其特性,(一)细胞表面受体介导的信号转导系统 1、信号与受体识别并特异性结
3、合 2、信号转导,产生第二信使或信号蛋白 3、信号传递、放大,产生生物学效应 4、细胞反应降低或终止,(二)信号途径由多种信号蛋白组成信号传递链 1、信号蛋白 2、相互作用机制:蛋白质模式结合域 (三)信号转导系统的主要特性 特异性、放大作用、信号终止、信号整合,Each cell is programmed to respond to specific combinations of exreaceluular signal molecules,每个细胞可以同时接受多种信号分子,特定的信号分子的组合可以引起特定的细胞效应,细胞内受体介导的信号传递,本质:激素激活的基因调控蛋白,Figure
4、15-13 Early primary response (A) and delayed secondary response (B) that result from the activation of an intracellular receptor protein. The response to a steroid hormone is illustrated, but the same principles apply for all ligands that activate this family of receptor proteins. Some of the primar
5、y-response proteins turn on secondary-response genes, whereas others turn off the primary-response genes. The actual number of primary- and secondary-response genes is greater than shown. As expected, drugs that inhibit protein synthesis suppress the transcription of secondary-response genes but not
6、 primary-response genes.,初级反应阶段,发生迅速,次级反应阶段,发生延迟,放大初级反应,NO信号分子及信号传递,It has been known for many years that acetylcholine dilate blood vessels by causing their smooth muscles to relax. In 1980, Furchgott concluded that blood vessels are dilated because the endothelial cells produce a signal molecule t
7、hat makes smooth muscle cells relax. In 1986 work by Furchgott and parallel work by Louis Ignarro identified NO as the signal that cause relaxation of the vascular smooth muscle. 1998, Received Nobel Prize,NO对血管的作用,第三节 G蛋白偶联受体介导的信号转导,一、. G蛋白偶联受体,G蛋白偶联受体的结构: 1、7次跨膜螺旋 2、螺旋5、6之间的胞内结构域具有G蛋白的结合位点 3、C-末端:
8、 Ser- and Thr-rich -the sites of phosphorylation make for the desensitization of GPLR.,G蛋白的结构及活化,二、G蛋白偶联受体介导的细胞信号通路,1、cAMP信号通路 2、磷脂酰肌醇信号通路 3、G蛋白耦联离子通道的信号通路,1、cAMP signaling pathway,腺苷酸环化酶,受体-配体复合物激活G蛋白,cAMP的浓度受到调节,G蛋白的类型 Gs Rs 激活腺苷酸环化酶 Gi Ri 抑制腺苷酸环化酶,细胞质效应,细胞核效应,CRE(cAMP response element,CRE):cAMP效应
9、元件,细胞质效应,细胞核效应,cAMP信号通路,R受体- 配体复合物 激活G蛋白 活化腺苷酸环化酶 产生第二信使cAMP cAMP依赖的蛋白激酶A 底物蛋白 细胞反应,信号的终止和信号的启动是同样重要的机制,Cholera is caused by a bacterium that multiplies in the intestine, where it produces a protein called cholera toxin. This enters the cells lining the intestine and modifies the subunit of G protei
10、n so that it can no longer hydrolyze its bound GTP. The altered subunit thus remains in the active state indefinitely, continuing to transmit a signal to its target proteins: Outflow of Na+ and water into the gut.,2、磷脂酰肌醇信号通路:双信使通路,IP3-Ca2+ pathway and DG-PKC pathway,Elevation of cytosolic Ca2+ via
11、the IP signaling pathway,SignalsGPLR GP PLC IP3 and DAG (twin signals). IP3 IP3 receptor(Ca2+ channel, located at the surface of sER) Elevation of cytosolic Ca2+; DAG activates PKC to phosphoralate Ser and Thr on target proteins. Calcium binds to calcium-binding proteins(CaM) which affects other pro
12、teins.,IP3信号的终止是通过去磷酸化形成IP2、或磷酸化为IP4 。 DG通过两种途径终止其信使作用: 一是被DG-激酶磷酸化成为磷脂酸,进入磷脂酰肌醇循环; 二是被DG酯酶水解成单酯酰甘油。,Figure 15-32 Two intracellular pathways by which activated C-kinase can activate the transcription of specific genes. In one (red arrows) C-kinase activates a phosphorylation cascade that leads to th
13、e phosphorylation of a pivotal protein kinase called MAP-kinase, which in turn phosphorylates and activates the gene regulatory protein Elk-1. Elk-1 is bound to a short DNA sequence in association with another DNA-binding protein. In the other pathway (green arrows) C-kinase activation leads to the
14、phosphorylation of Ik-B, which releases the gene regulatory protein NF-kB so that it can migrate into the nucleus and activate the transcription of specific genes.,磷脂酰肌醇信号通路,信号分子、G蛋白偶联的受体、G蛋白、 磷脂酶C(PLC)、4,5二磷酸磷脂酰肌醇(PIP2) 第二信使:IP3和DG。 IP3动员细胞内源Ca,使细胞质中的钙离子浓度增加;DG活化蛋白激酶C(PKC),3、G蛋白耦联受体介导的离子通道,信号G蛋白耦联受
15、体G蛋白 效应蛋白:离子通道,三、离子通道偶联受体介导的信号传递,第四节 酶连受体介导的信号转导,酶偶联的受体 既有信号分子的结合位点,又具有酶的活性或与有酶活性的分子结合,当配体与受体结合后能激活酶的活性。,酶偶联型受体的种类,受体酪氨酸激酶 受体丝氨酸/苏氨酸激酶 受体酪氨酸磷脂酶 受体鸟苷酸环化酶 酪氨酸激酶联系的受体,一、受体酪氨酸蛋白激酶及RTK-Ras蛋白信号通路,受体酪氨酸激酶RTK: 多种生长因子和胰岛素受体,Signaling ligands of RTKs: 1.Nerve growth factor (NGF) 2.Platelet-derived growth fact
16、or (PDGF) 3.Fibroblast growth factor (FGF) 4.Epidermal growth factor (EGF) 5.insulin and insulin-like GF(IGF-1) 6. vascular endothelial factor(VEGF),受体活化:受体二聚化,信号转导的启动,磷酸化的酪氨酸残基(活化的RTK)与具有SH2结构域的分子结合; SHSrc同源区(Src homolog region SH),首先在Src蛋白中发现, Src是最初在Rous肉瘤病毒中发现的一种癌基因。,活化的RTK结合的蛋白,接头蛋白:偶联活化的受体与其他信
17、号分子,参与构成信号转导复合物,但本身不具酶活性,也不传递信号。如GRB2,都具有SH2和SH3结构域,SH2与磷酸化的酪氨酸残基结合,SH3选择性结合不同的富含脯氨酸的序列的蛋白。,信号通路中有关的酶:PLC、GAP等,RTK-Ras信号通路中的分子开关蛋白Ras,Ras: rat sarcoma Ras蛋白是原癌基因c-ras的表达产物,一种小的单体GTP结合调节蛋白,具有弱的GTP酶活性,在信号传导中具有分子开关的作用。,Ras蛋白的活性调节,被GEF激活 GAP(GTP酶活化蛋白)使其失活。,RTK-Ras信号转换复合物,生长因子信号-RTK受体活化的RTK接头蛋白(GRB2)GEF(
18、Sos)激活Ras蛋白,RTK-Ras signaling pathway,MAP-kinase serine/threonine phosphorylation Pathway activated by Ras,Ras-activated phosphorylation cascade,MAP kinase=mitogen-activated protein kinase; MAP-KKK=Raf (Ser/Thr-PK),二、细胞表面其他酶联受体,(一)受体丝氨酸/苏氨酸激酶 TGF-超家族的受体 配体-受体结合,激活受体酶活性,激活转录因子调节基因表达,(二)酪氨酸激酶联系的受体 包括各
19、类细胞因子(如干扰素)的受体,受体本身不具有酶活性,但可连接胞内酪氨酸蛋白激酶(如JAK),信号途径为JAKSTAT或RAS途径。,三、由细胞表面整联蛋白介导的信号传递,由细胞表面整联蛋白介导与细胞外基质 装配形成黏着斑: 具有机械结构功能 信号传递,1.The mechanical-structural function of focal adhesion, which is carried out by actin filaments and associated proteins. 2. Signaling function from extracellular surfacenucle
20、us (where they stimulate the transcription of genes involved in cell growth and proliferation), which is carried out by tyrosine kinase (Src and FAK),第五节 信号的整合与控制,一、细胞对信号的整合 (一)细胞对信号的反应: 1、对胞外信号产生多样性反应 2、收敛性和发散性 (二)蛋白激酶的网络整合,A. 收敛: 来自非相关受体的信号产生相同的效应,信号通路的收敛和发散特征,B. 发散: 来自相同配体的信号,发散激活不同的效应器,产生多种细胞效应。
21、,C. Crosstalk: 不同的信号通路之间可以相互交叉,(二)蛋白激酶的网络整合,二、细胞对信号的控制,信号的启动 信号通路自身的调节 信号的终止,信号终止,信号分子水解 分子开关的调节 细胞对信号分子的脱敏,G-protein-linked receptor desensitization depends on receptor phosphorylation by PKA, PKC, CaMK2 or G-protein-linked receptor kinases(GRKs),G蛋白偶联受体被修饰脱敏,The target cells can become desensitized to a signal molecule by five ways.,Three general ways of the desensitization: 1. Receptor inactivation by alteration; 2. Receptor sequestration by internalization; 3. Receptor down-regulation by destroying in Ls.,Sequestration; down-regulation; inactivation; inactivation; inhibitory protein,
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