单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,细胞信号转导与肿瘤,中山大学2005级分子医学博士生课程第四讲,2005年9月27日,黎孟枫,医学博士,中山大学基础医学院微生物学教研室mengli,细胞信号转导与肿瘤中山大学2005级分子医学博士生,1,引言：细胞信号转导与生命过程问题的提出和理论的产生,细胞信号转导理论概述,信号转导研究中的重大理论问题及热点领域,信号转导的研究方法与工具,信号转导理论研究及应用举例：在肿瘤发生发展中的信号转导的意义,信号转导与肿瘤临床：诊断和治疗,细胞信号转导经典文献举例,引言：细胞信号转导与生命过程问题的提出和理论的产生,2,引言,信号转导与生命过程,问题的提出和理论的产生,引言信号转导与生命过程,3,细胞信号转导理论建立以前的细胞生物学,细胞的显微结构（胞膜、胞浆、胞核）,细胞的生理功能（生存、“活性”、分裂增殖、胞间连接、吞饮、分泌、迁移、死亡),细胞组分的生物化学（脂、糖、核酸、蛋白）,细胞的超微结构和亚细胞结构（脂质双层膜结构、细胞器),细胞信号转导理论建立以前的细胞生物学细胞的显微结构（胞膜、胞,4,组织生长需要,细胞分裂增殖,细胞,生长因子,细胞周期,蛋白表达,病原体侵入,抗感染状态,细胞,抗原,细胞因子,表达分泌,细胞过度生长,细胞死亡,细胞,死亡因子,胞内致死,分子表达,组织生长需要细胞分裂增殖细胞生长因子细胞周期病原体侵入抗感染,5,细胞骨架蛋,白表达、激活,牵动细胞移动,(Cell movement),趋化因子,细胞粘附,细胞存活,(Survival),抗凋亡因子,表达、激活,胞外信号,信号作用,于细胞,基因表,达改变,细胞表,型改变,细胞骨架蛋牵动细胞移动趋化因子细胞粘附细胞存活抗凋亡因子胞外,6,信号通路和肿瘤ppt课件,7,信号通路和肿瘤ppt课件,8,细胞信号转导理论概述,细胞信号转导理论概述,9,信号通路和肿瘤ppt课件,10,胞外信号分子(可溶性分子、细胞表面分子、组织基质分子),靶细胞跨膜分子(狭义受体如EGFR或广义受体如Integrin),靶细胞受体（胞内段）化学变化（如磷酸化、二聚体形成）,靶细胞内信号转导分子化学变化与激活,（如磷酸化、去磷酸化、聚体形成）,激活的信号转导分子进入胞核,进入胞核的转导分子作用于基因转录调控区,基因表达改变,胞外信号分子(可溶性分子、细胞表面分子、组织基质分子)靶细胞,11,Extracellular Signal Molecules,Growth Factors,PDGF(Platelet-Derived Growth Factor),EGF(Epidermal Growth Factor),TGF-,(Transforming Growth Factor-,),EPO(Erythropoietin),NGF(Nerve Growth Factor),IGF(Insulin-like Growth Factor),TPO(Thrombopoietin),2.Cytokines,IFN-,(Interferon-,),IFN-,(Interferon-,),TNF(Tumor Necrosis Factor),Interleukins(1,2,3,4),3.Death molecules,Fas,4.,Adhesion molecules,Cadherins,Adhesin,5.Hormone,Insulin,6.Stress,Extracellular Signal Molecules,12,Signal Transducing Receptors,Transmembrane,receptors that have intrinsic enzymatic activity.,A,utophosphorylation,P,hosphorylation of other substrates,A)Tyrosine kinases:PDGF-R,insulin-R,EGFR and FGF-R,B)Tyrosine phosphatases:e.g.CD45,C)Guanylate cyclases:e.g.natriuretic peptide receptors),D)Serine/Threonine kinases:activin and TGF-,b,receptors,Signal Transducing ReceptorsTr,13,2.Receptors that are coupled,inside the cell,to GTP-binding and hydrolyzing proteins(G-proteins).,e.g.,adrenergic receptors,odorant receptors,and certain hormone receptors(e.g.glucagon,angiotensin,vasopressin and bradykinin).,3.Receptors that are found intracellularly and upon ligand binding migrate to the nucleus where the ligand-receptor complex directly affects gene transcription,e.g.,STAT1,3,4,5,6(Signal transducer and activator of transcription),4.Simple receptors:,e.g.,ion-channels that lead to changes in membrane electric potential,2.Receptors that are coupled,14,信号转导过程中的生物化学,磷酸化反应（酪氨酸激酶、丝/苏氨酸激酶）,蛋白质构象改变,去磷酸化反应（磷酸酶）,受体或其他信号转导分子的聚体化,信号转导过程中的生物化学磷酸化反应（酪氨酸激酶、丝/苏氨酸激,15,Signal Transducers,Receptor Tyrosine Kinases(RTKs),contains:,An extracellular ligand binding domain.,An intracellular tyrosine kinase domain.,An intracellular regulatory domain.,A transmembrane domain.,Tyrosine phosphorylation,Interact with and phosphorylate,Src homology domain 2,(SH2)-containing proteins,(e.g.,PLC-,Ras,PI-3K,etc),Phosphorylate other kinases,phosphorylate proteins,which,upon phosphorylated,can enter,the nuclear and bind,DNA regulatory,regions.,Signal TransducersReceptor Tyr,16,Class,Examples,Structural Features of Class,I,EGF receptor,NEU/HER2,HER3,cysteine-rich sequences,II,insulin receptor,IGF-1 receptor,cysteine-rich sequences;characterized by disulfide-linked heterotetramers,III,PDGF receptors,c-Kit,contain 5 immunoglobulin-like domains;contain the kinase insert,IV,FGF receptors,contain 3 immunoglobulin-like domains as well as the kinase insert;acidic domain,V,vascular endothelial growth factor(VEGF)receptor,contain 7 immunoglobulin-like domains as well as the kinase insert domain,VI,hepatocyte growth factor(HGF)and scatter factor(SC)receptors,heterodimeric like the class II receptors except that one of the two protein subunits is completely extracellular.The HGF receptor is a proto-oncogene that was originally identified as the Met oncogene,VII,neurotrophin receptor family(trkA,trkB,trkC)and NGF receptor,contain no or few cysteine-rich domains;NGFR has leucine rich domain,Characteristics of the Common Classes of RTKs,ClassExamplesStructural Featur,17,Non-Receptor Protein Tyrosine Kinases(PTKs),Two non-receptor PTK families:,1)The archetypapl PTK familty:Src-related proteins,2)Janus kinase(Jak)family,Most non-receptor PTKs couple to cellular receptors that lack enzymatic activity themselves(e.g.,CD4,CD8,TCR and all cytokine receptors such as IL-2R,Non-Receptor Protein Tyrosine,18,信号通路和肿瘤ppt课件,19,信号通路和肿瘤ppt课件,20,信号通路和肿瘤ppt课件,21,Receptor Serine/Threonine Kinases(RSTKs),Typical example:Receptors for the TGF-,superfamily of ligands,The TGF-,superfamily include 30 multifunctional proteins,e.g.,activins,inhibins and the bone morphogenetic proteins(BMPs).,17 RSTKs isolated are in 2 subfamilies:type I and type II receptors.,Nuclear proteins responding to TGF-,activation include c-Myc and Smad,Ligands bind,to the type,II receptors,Complexed,with type I,receptors,Type II R,phosphorylates,type I receptor,Initiation of,signaling,cascade,Receptor Serine/Threonine Kina,22,信号通路和肿瘤ppt课件,23,No