信号通路和肿瘤

Characteristics of the Common Classes of RTKs
Class Examples Structural Features of Class
I
EGF receptor, NEU/HER2, HER3
cysteine-rich sequences cysteine-rich sequences; characterized by disulfide-linked heterotetramers contain 5 immunoglobulin-like domains; contain the kinase insert contain 3 immunoglobulin-like domains as well as the kinase insert; acidic domain
•
G-Protein Coupled Receptors
1. >1000 GPCRs, most of which are orphan receptors) 2. Three different classes of GPCR: 1) GPCRs that modulate adenylate cyclase activity and produce cAMP 2) GPCRs that activate PLC-g leading to hydrolysis of polyphosphoinositides: angiotensin, bradykinin and vasopressin receptors. 3) Photoreceptor
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@gzsums.edu.cn
• 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
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
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
Extracellular Signal Molecules
1. 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)
胞外信号分子(可溶性分子、细胞表面分子、组织基质分子)
Байду номын сангаас
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
VI
VII
Non-Receptor Protein Tyrosine Kinases (PTKs) Two non-receptor PTK families:
1) The archetypapl PTK familty: Src-related proteins
2) Janus kinase (Jak) family
V
contain 7 immunoglobulin-like domains as well as the kinase insert domain
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 contain no or few cysteine-rich domains; NGFR has leucine rich domain
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
组织生长需要
病原体侵入
细胞过度生长
生长因子
抗原
死亡因子
细胞
细胞
细胞
细胞分裂增殖
抗感染状态
细胞死亡
趋化因子
细胞骨架蛋 白表达、激活
牵动细胞移动 (Cell movement)
细胞粘附
抗凋亡因子 表达、激活
细胞存活 (Survival)
胞外信号
信号作用 于细胞
基因表 达改变
细胞表 型改变
细胞信号转导理论概述
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.
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
•
Non-Receptor Serine/Threonine Kinases
1) cAMP-dependent protein kinase (PKA) 2) Protein kinase C (PKC) 3) Mitogen activated protein kinases (MAPK or ERK) (requiring phosphorylation of both tyrosine and threonine)
D) Serine/Threonine kinases: activin and TGF- receptors
2. Receptors that are coupled, inside the cell, to GTPbinding and hydrolyzing proteins (G-proteins).
II
insulin receptor, IGF-1 receptor
PDGF receptors, c-Kit
III
IV
FGF receptors vascular endothelial growth factor (VEGF) receptor hepatocyte growth factor (HGF) and scatter factor (SC) receptors neurotrophin receptor family (trkA, trkB, trkC) and NGF receptor
引言
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……)
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
Signal Transducers
• Receptor Tyrosine Kinases (RTKs) contains: •An extracellular ligand binding domain. •An intracellular tyrosine kinase domain. Tyrosine phosphorylation •An intracellular regulatory domain. •A transmembrane domain.
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
Signal Transducing Receptors
1. Transmembrane receptors that have intrinsic enzymatic activity.
——Autophosphorylation ——Phosphorylation 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)