Signal -3-临床五年制2014课件

1、 Chapter 19The Molecular Mechanism of Cellular Signal TransductionFengtian HeDepartment of Biochemistry and Molecular BiologyCollege of Basic Medical Sciences Third Military Medical UniversityTel：752255(O)OutlineThe overview of signal transduction Sigal molecules Receptor Signal transduction pathway

2、Signal transduction and medical scienceQuestions: 1. Please describe the cycle of heterotrimeric G protein 2. How are about the binding properties of ligand and receptor? 3. Please describe the ion channel-linked receptor-mediated pathway and cAMP dependent PKA pathway Terms: 1. G protein 2. Small G

3、 protein 3. Intracellular receptor 4. PKAReview for the last class Section 4Signal Transduction Pathways (信号转导通路) Signal transduction pathways mediated by membrane receptors1.1 Ion channel-linked receptor-mediated pathway1.2 cAMP dependent-protein kinase A(PKA) pathway 1.3 cGMP dependent PKG pathway

4、 1.4 Ca2+ dependent protein kinase (PK) pathway 1.4.1 Ca2+ -DAG -dependent PKC pathway 1.4.2 Ca2-CaM dependent PK pathway1.5 Tyrosine protein Kinase(TPK) pathway 1.5.1 Receptor TPKRasMAPK pathway 1.5.2 JAKsSTAT pathway1.6 TGF- pathway1.7 NF-B pathwayNO，COGCPKG Phosphorylation of Es or functional pro

5、teinsGTPcGMPANPRCell membraneANP: atrial natriuretic peptides (心钠素) , secrected by cardiac atrium cells(心房细胞）GCBiological effects(Vascular dilatation)1.3 cGMP-dependent PKG pathwayNOGCPKG Phosphorylation of Es or functional proteinsGTPcGMPVascular smooth muscle cell membranerelaxation of vascular sm

6、ooth muscle and vascular dilatationNitroglycerin NOClinical tipsWhy nitroglycerin (硝酸甘油)can induce relaxation of vascular smooth muscle and vascular dilatation?（硝酸甘油为何能松弛血管平滑肌和扩张血管？）PIP2IP3DAGPKCPKC1.4.1 Ca2+ -DAG -dependent PKC pathwayPIP2: phosphatidylinosital 4,5-biphosphate(磷脂酰肌醇4,5二磷酸)IP3: inos

7、itol 1, 4, 5 triphosphate(三磷酸肌醇)DAG: diacylglycerol(甘油二脂)(1) Generation of DAG and IP3PIP2PLCDAG + IPPIP2IP3DAGPKCPKC(1) Generation of DAG and IP3Ca 2+i 0.01-1 mol/L（10-7 mol/L ）Ca 2+o 2.5mmol/L（10-3 mol/L ） 500010000（3）Function of PKC Regulation of metabolism PKC Ser/Thr-P of R, enzymes, Proteins.

8、Regulations of Gene expression Late response:Trans-acting factor-PThird messengerImmediate early genesThird messenger-PActivates genesCell proliferationPKCPKC Early response:Regulations of Gene expressionSRF:serum response factorClinical tipsWhy phorbol ester(佛波酯) can result in a lasting cell prolif

9、eration and carcinomatous change (癌变)？Early responseLate responsecell proliferation and carcinogenesisphorbol ester PKC1.4.2 Ca2-CaM dependent PK pathway HRG proteinPLCIP3Ca2+CaMCaMKBiological effectsPhosphorylation of Es or functional proteinsCaM: Calmodulin(钙调蛋白) Direct Effects（1）4 Ca2+ + CaM 4Ca2

10、+- CaM （2） Function of Ca2+- CaM complex A. Directly regulating the activities of some Es and proteins Activates both AC and PDE regulating cAMP Activates myoglobulin kinase Phosphorylation of myoglobulin Muscle contraction Activates TPK activity of insulin receptor B. Activates CaM-dependent kinase

11、(CaM-K) Ser/Thr-P of target proteins and Es, such as pyruvate kinase (如丙酮酸激酶), glycogen synthase（糖原合成酶）, phosphorylase kinase（磷酸化酶激酶) Calmodulin (CaM):Ca2 binding proteinQuestion: Why CaM can play multiple functions?TPK is related to proliferation(增殖）, differentiation(分化), dissociation（分裂）, carcinog

12、enesis（致癌）。Receptor TPK：membrane.Non receptor TPK：cytosolTPKTPK Receptor or receptor tyrosine kinase (RTK) 1.5.1 Receptor TPKRasMAPK pathway Receptor TPKGRB2: growth factor receptor binding protein 2SOS: son of sevenlessSmall G protein: RasMAPK: mitogen-activated protein kinase(丝裂原激活的蛋白激酶)：MAPK、MAPK

13、K、MAPKKK(Raf) EGF, PDGFreceptor TPKRasGTPSOSPGRB2PRafPMAPKKPMAPKPtrans-acting factorexpressionnucleusP Receptor TPKRasMAPK pathwayDo you know ？Whether epidermal growth factor(EGF) has facial function (表皮生长因子是否有美容作用）? EGFR-mediated Ras-MAPK pathwayERK: extracellular signal-regulated kinase(MAPK)MEK:

14、MAPK/ERK kinase(MAPKK)MAPKKPEGF is involved in multiple signal pathways1.5.2 TPK-associated receptor JAKsSTAT pathway TPK-associated receptor JAKs: just another kinases, Janus protein tyrosine kinases STAT: signal transducers and activators of transcription(信号传导及 转录激活因子 )TPK-associated receptor JAKs

15、STAT pathway ligandTPK-associated receptorJAKsSTAT gene expressionPPNuclear translocation of STATTPK-associated receptor JAKsSTAT pathwayHow to regulate cell proliferation for IFN and erythropoietin(EPO, 促红细胞生成素)？Do you know ？ EPO is a forbidden excitant (兴奋剂) for athlete TR-TR-1.6 TGF- pathway TGF-

16、（transforming growth factor ) receptorSreine/threonine protein kinase1.6 TGF- pathwayTGF-receptor SMAD: Named from two genes: Drosophila Mother against dpp (Mad) and C elegans (Sma). Classification of SMAD (At least 9 SMADs have been identified) receptor-regulated-SMAD (R-SMADs,受体调节的 SMADs): e.g. SM

17、AD1,2,3,5,8 common-partner-SMAD(Co-SMADs, 共同的偶配体 SMADs ): e.g. SMAD4 inhibitory-SMAD(I-SMADs, 抑制性SMADs )： e.g. SMAD 6,7TGF-通路的基本过程TGF-先识别并结合TR，使TR二聚化并自身磷酸化，随后，TR以二聚体形式加入，形成异源四聚体。TR通过转磷酸化作用使TR的 GS区内的丝/苏氨酸残基磷酸化，从而使TR被激活。活化的TR与胞质中R-SMADs (SMAD2,3)结合，并使SMAD2/3磷酸化。磷酸化的SMAD2/3因构象改变而从受体上解离下来，形成同源或异源二聚体，进而与

18、Co-SMAD（SMAD4）形成三聚体。三聚体可进入胞核，结合于DNA的顺式作用元件，参与调节基因转录。由于不同的TGF-通路最终可活化不同类型的SMAD，因此，其最终生物学效应也有差别。TGF- pathwayProliferation Differentiation MigrationApoptosisMembers of TGF family are involved in regulation of cell proliferation, differentiation, migration and apoptosis1.7 Nuclear factor-B (NF-kB) pathw

19、ay NF- B is a universal transcriptional factor It was found when studying immunoglobulin gene NF- B : including NF-B1, NF-B2 and some oncogene-encoded proteins（such as Rel） Involved in defence reaction, tissue damage and inflammation, stress, cell differentiation and apoptosisActivation of NF-BNF-B

20、signaling pathwayWhat are the mechanisms of inflammation (even system inflammation syndrom）after operation or trauma? (手术或创伤后并发的全身性炎症反应的机制何在？)Do you know ？Activation of NF-B pathway is one of the most important mechanisms Signal transduction pathways mediated by membrane receptors1.1 Ion channel-lin

21、ked receptor-mediated pathway1.2 cAMP dependent-protein kinase A(PKA) pathway 1.3 cGMP dependent PKG pathway 1.4 Ca2+ dependent protein kinase (PK) pathway 1.4.1 Ca2+ -DAG -dependent PKC pathway 1.4.2 Ca2-CaM dependent PK pathway1.5 Tyrosine protein Kinase(TPK) pathway 1.5.1 Receptor TPKRasMAPK path

22、way 1.5.2 JAKsSTAT pathway1.6 TGF- pathway1.7 NF-B pathwaySummaryNO，COGCPKG Phosphorylation of Es or functional proteinsGTPcGMPANPRCell membraneANP: atrial natriuretic peptides (心钠素) , secrected by cardiac atrium cells(心房细胞）GCBiological effects(Vascular dilatation)1.3 cGMP-dependent PKG pathwaySummary1.4 Ca2+ dependent protein kinase (PK) pathway Ca2+-DAG -dependent PKC pathway Ca2+-CaM dependent PK pathway1.5 Tyrosine protein Kinase(TPK) pathway 1.5