Classification of phosphatase according to the Amino acid sequence in active centerSer/Thr phosphatase Ser/Thr phosphatase Tyr phosphataseTyr phosphataseDual specificity Dual specificity.G protein/small G protein guanine nucleotide binding protein，G protein（鸟苷酸结合蛋白）亦称GTP结合蛋白 a signal molecule in various pathways,functioning differently in different cellsTwo forms of G protein G protein binding with GTP:its active form GTP hydrolysed to GDP:inactive form 2 types of G protein：Hetero-trimer G protein:（G）,(G)binding with receptor with 7 transmembrane dormains，Small G protein(21kD）1.Hetero-trimer G protein mediated receptor signal directlyGGMultiple Sites subunit with GTPase act.Binding site with receptorBingding site withsubunitsGDP/GTP binding siteBinding with dwonstream moleculesformed a complex with G,localized in regulate targeted protein directlyin mammalian The activation/deactivation cycle for hormonally stimulated adenylate cyclaseG protein-coupled receptors，GPCRs Ligand-GPCRs G protein-（AC,PLC)-cell function The role of PIP2 in intracellular signaling2.Ras surperfamily:important signal moleculesSmall G protein（21kD），functioning as switch Ras is a first discoved G protein Ras family:each contains a GTPase domain Factors control small G protein act.Factor increasing act.：guanine nucleotide exchange factor(GEF)guanine nucleotide release protein(GNRP)Factor decreasing act.：guanine nucleotide dissociation inhibitor(GDI)GTPase activation protein(GAP)Ras activation and its regulatorsGTPGDPRasRasSOS GAPonoffSummary of Section 31.Proteins are the main components of signaling pathways 2.Proetin kinases and phosphotases are the switch in signaling pathways.3.G protein and small G protein are function as their binding with GTP/GDPSection 4The Structural Basis of Signal Transduction Network细胞信号转导网络的结构基础.Signaling Complex and its characterProteins wont separated each other in cells but aggregated Protein complex-functioning in life1.Signaling complex ensures the efficiency,precision,variety Priority:directly contact directly contact，efficency,precisionefficency,precision amplification amplification collaboration,variety collaboration,variety complex,multiple complex,multiple 2.Signaling complex exists at membrane and cytoskeleton structureProtein complex existed in membrane structure or cell skeleton compartmentation。
Advantage 由于已经有相对固定的分子作为集合目标由于已经有相对固定的分子作为集合目标存在，有利于信号转导分子存在，有利于信号转导分子很快找到结合很快找到结合伴侣，伴侣，因此复合体转导效率要高于一个完因此复合体转导效率要高于一个完全自由扩散的系统；全自由扩散的系统；在形成信号转导复合体时，转导分子将以在形成信号转导复合体时，转导分子将以有序的方式依次进入复合体，有序的方式依次进入复合体，因此信号转因此信号转导的导的准确性准确性会高于自由扩散系统会高于自由扩散系统3.Components of complex changes depended on exogenous signalsDynamic state:the components and formation of signal complexdepended on exogenous signals Significance:withdrew ligand-stop signaing immediately reutilization of signal molecules,save energy.Domain is substantial basis of protein-protein interactionprotein interaction domain1.prot-prot interaction mediated by domains Character of protein interaction domain(PID)one molecule contains two PID same domain existed in various proteins,but sequence are not exactly same binding specificity PID doesnt have enzyme activity,just binding Distribution and role of protein interaction domainProtein kinaseBtkPHTHSH3SH2催化区催化区Adaptor Grb2SH3SH2SH3TF statDNA 结合区结合区SH2TACytoskeleton tensin/SH2PTBPIDSrc homology 2 Src homology 3 pleckstrin homologyProtein tyrosine binding WW SH2SH3PHPTBWWrecognized motifTyr-PiPro rich Phospholipid derivation Tyr-PiPro richDomain and its recognized motif2.Src homology 2(SH2)domainSrc homology 2 domain:SH2 domianFunction:the recognized motif is phosphorylated tyrosine and neighboring amino acids Different protein contains different SH2 -selectivity 3.SH3 DomainSrc homology 2 domain:SH3 domianFunction:the recognized motif is proline-rich(9-10 Pro)sequence4.PH Domain recognizes the phospholipids PH domain in pleckstrin in platelet，so called pleckstrin homologyPH binding with membrane PL derivative，make its localization to membrane,enzyme activity increasePH is a basic structure of prot-prot,prot-lipid interaction.adaptor proteins and scaffolding proteinsadaptor protein a kind of mediator protein,Link one,upstream prot.,to another,downstream role：recruit and organize the complex Most adaptor proteins contain two domains,no other special domain 1.adaptor proteinAdaptor protein Adaptor protein NckNckSH2CNSH3SH3SH3HGFR,VEGFR,BCR-AblPDGFR,EphB1 SLP-76,HPK1,p130casIRS-1,p62doc CKIg g2,WASP,IRS-1,DOCK180,NIKIRS-1,DOCK180,Sos,NIK,Pak1,Pak3,NAP4,WIP,dynamin,synaptojanin、Abl,c-CblAbl,c-Cbl,NAP1,Sam682.Scaffolding proteins ensures the efficiency and specificityScaffolding proteins:large MW,binding with many signal molecules in same pathwaySignificance keep the related molecules gather together,keep specificity,not across to with other pathway Scaffolding proteins increase or decrease the activity of signaling create the complex and variety in signaling pathwaySumaary of Section 41.Signaling complex exists at membrane and cytoskeleton structure.Within complex the special domain in a protein is a base of interacting with others.1.Adaptor proteins and scaffolding proteins are the linker molecules in signaling and network.Section 5General Signal Pathways Mediated by Membrane Receptors 膜受体介导的基本信号转导通路 3 types of membrane bound receptor：Ion channel receptor (ICR)G-protein coupling receptor (GPCR)Single transmembrane receptor (STMR)内源性配体结构跨膜区段数目功能细胞应答ICR神经递质寡聚体形成的孔道4个离子通道去极化与超极化GPCR神经递质、激素、趋化因子、外源刺激（味，光）单体7个激活G蛋白去极化与超极化调节蛋白质功能和表达水平STMR生长因子细胞因子具有或不具有催化活性的单体1个激活蛋白酪氨酸激酶调节蛋白质的功能和表达水平，调节细胞分化和增殖Characters of 3 types receptors.Ion Channel Receptor structurally a channel,open or close pass through ion,ligand-gated receptor channel Ligand:neurotransmitter mainly Acetyl choline receptorAcetylcholine Binding SiteIon channeloverlook side look The role of AcetylcholinIon channel memb.electric potential change chemical signal formation cell functionIon channel Cation channel:Acetyl Choline,Glutamic acid,5-Hydroxytrypotamine Anion channel:Glycine，-aminobutylic acid .G-protein coupling receptor second messenger-target moleculesGPCR:binding G protein with tri-subunit activate G proteinGPCR a serpentine receptor,7 transmembraneG G蛋白偶联区蛋白偶联区1.G-protein activation initiates signalingModel of transduction via G-protein：ligand receptor binding receptor activates G-protein G-protein act.or inh.target prtoein change second messenger level or distribution,second messenger affects its target molecule conformational change G-protein cycle2.Activated G-protein alters activity of target mole.活化的G蛋白的亚基主要作用于生成或水解细胞内第二信使的酶，如AC、PLC等效应分子（effector），改变它们的活性，从而改变细胞内第二信使的浓度。
可以激活AC的G蛋白的亚基称为s（s 代表stimulate）；反之，称为i（i代表inhibit）GasaiaqatEffective mole.AC AC PLC cGMP-PDE Messenge in cyto.cAMPcAMPCa2+、IP3、DAGcGMPTarget mole.PKA PKA PKC Na+Chan.Ga subunit and its effect 3.Glucagon receptor-AC-cAMP-PKA pathways Adrenocorticotrophin(ACTH)Corticoliberin(CRH)Dopamine AdrenalineGlucagon Histamine（H2 receptor）Lutropin(LH)Melanotrophin (MSH)Olfaction moleculeParathyrin Prostaglandin E1,E25-HT（1a）、5-HT（2）Somatostadin Taste molecule Signals acts by AC-cAMP-PKA pathways 4.Angiotensin II receptor-PLC-IP3/DAG-PKC Angiotensin II receptor is a GCPR q PLC-IP3/DAG-PKC pathwayAcetyl Choline M1ATP Adrenergic agonistlight(fruit fly)Gastrin releasing peptideGlutaminegonadotrophin releasaing hormone(GRH)5-HT（1c）Thyrotropin releasing hormone(TRH)vasopressin-antidiuretic hormonehistamine H1 receptorSignals acts by PLC-IP3/DG-PKC此外，由于G蛋白亚型的不同，形成多种其他通路和效应，如PDE-cGMP-Na+通道信号转导通路、PLC-IP3-Ca2+/CaM-PK信号转导通路等。
Enzyme coupling receptor-protein kinase kinase protein kinase target mole酶偶联受体指那些自身具有酶活性，或者自身没有酶活性，但与酶分子结合存在的一类受体这些受体大多为只有1个跨膜区段的糖蛋白，亦称为单跨膜受体酶偶联受体种类繁多，但是以具有PTK活性和与PTK偶联的受体居多常见的酶偶联受体：受体型蛋白酪氨酸激酶（受体型蛋白酪氨酸激酶（receptors tyrosine kinases，RTKs）蛋白酪氨酸激酶偶联受体（蛋白酪氨酸激酶偶联受体（tyrosine kinase-coupled receptors，TKCRs）受体型蛋白酪氨酸磷酸酶（受体型蛋白酪氨酸磷酸酶（receptors tyrosine phosphatases，RTPs）受体型蛋白丝受体型蛋白丝/苏氨酸激酶（苏氨酸激酶（receptors serine/threonine kinase，RSTK）受体型鸟苷酸环化酶（受体型鸟苷酸环化酶（receptors guanylate cyclases，RGCs）酶偶联受体大部分是生长因子和细胞因子的受体，它们所介导的信号转导通路主要是那些调节蛋白质的功能和表达水平、调节细胞增殖和分化。
1.PTK coupling receptor:similar model PTK coupling receptor主要通过蛋白质相互作用激活自身或细胞内其他的PTK或丝/苏氨酸激酶来转导信号PTK偶联受体介导的信号转导途径的基本模式：结合配体结合配体后受体形成二聚体或寡聚体；后受体形成二聚体或寡聚体；第一个蛋白激酶被激活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，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-蛋白质相互作蛋白质相互作用激活与它紧密偶联的蛋白激酶；用激活与它紧密偶联的蛋白激酶；通过蛋白质通过蛋白质-蛋白质相互作用或蛋白激酶的磷酸化修饰蛋白质相互作用或蛋白激酶的磷酸化修饰激活下游激活下游信号转导分子信号转导分子，通常是继续活化下游的一些蛋白激酶；，通常是继续活化下游的一些蛋白激酶；蛋白激酶通过磷酸化修饰蛋白激酶通过磷酸化修饰激活代谢途径中的关键酶、反式作用激活代谢途径中的关键酶、反式作用因子因子等，影响代谢途径、基因表达、细胞运动、细胞增殖等。
等，影响代谢途径、基因表达、细胞运动、细胞增殖等表皮生长因子受体作用机制：表皮生长因子受体作用机制：2.EGFR signaling pathway:RasMAPK表皮生长因子受体（epidermal growth factor receptor,EGFR）是一个典型的受体型PTKRasMAPK途径是EGFR的主要信号通路之一EGFR介导的信号转导过程3.Others pathways than enzyme couping receptorT细胞抗原受体、B细胞抗原受体、肥大细胞表面的IgE受体 属于酶偶联受体，它们自身不具备蛋白酪氨酸激属于酶偶联受体，它们自身不具备蛋白酪氨酸激酶活性；酶活性；非受体型的非受体型的Src家族蛋白酪氨酸激酶和家族蛋白酪氨酸激酶和ZAP70家族家族蛋白酪氨酸激酶是这一类受体的直接信号转导分蛋白酪氨酸激酶是这一类受体的直接信号转导分子下游分子包括下游分子包括PLC、MAPK家族的活化，并有家族的活化，并有多种衔接蛋白参与多种衔接蛋白参与大部分白细胞介素（interlukin,IL）受体属于酶偶联受体通过通过JAK（Janus Kinase）-STAT（signal transducer and activator of transcription）通路转导信号。
通路转导信号细胞内有数种细胞内有数种JAK和数种和数种STAT的亚型存在，分别转的亚型存在，分别转导不同的白细胞介素的信号导不同的白细胞介素的信号白介素介导的信号转导途径白介素介导的信号转导途径转化生长因子（transform growth factor,TGF）受体属于单次跨膜受体，自身具有蛋白丝氨酸激属于单次跨膜受体，自身具有蛋白丝氨酸激酶催化结构域酶催化结构域受体活化后通过信号分子受体活化后通过信号分子Smad介导的途径介导的途径调节靶基因转录，影响细胞的分化调节靶基因转录，影响细胞的分化细胞内有数种细胞内有数种Smad存在，参与存在，参与TGF家族不家族不同成员（如骨形成蛋白等）的信号转导同成员（如骨形成蛋白等）的信号转导R-SMADR-SMADR-SMADSARACO-SMADCO-SMADR-SMADTGF消信号转导示意图消信号转导示意图在细胞信号转导过程中，信号迅速发生并迅速终止，反应过程具有级联放大效应细胞内的信号转导系统具有通用性；细胞内一些信号转导分子和信号转导通路需要为不同的受体所共用，但是各种细胞又有其特殊的方式严格控制信号转导的特异性流向影响细胞可以对外源信息做出特异性反应的因素包括：细胞间信息分子的浓度、相应受体的分布与含量、细胞内信号转导分子的种类和含量等。
不同组织可以以不同的方式使用同一信号转导分子，但是相互作用的分子可以不同，蛋白激酶的底物也可能不一样，从而导致输出信号的差别Summary of section 51.Ion Channel Receptor 2.G-protein coupling receptor is a serpentine receptor and following as second messenger-target molecules3.Cascade of Enzyme coupling receptor:Enzyme coupling receptor-protein kinase kinase protein kinase target moleHuman beta-adrenoreceptorIntegrins are not monomers.They mediate their biological function through heterodimer formation and ligand binding.Solely overexpressed 1 subunit might induce the expression of certain subunit before it could have growth-inhibitory effect.。