信号通路与肿瘤

Class
Examples
Structural Features of Class
I
EGF receptor,
NEU/HER2, HER3
cysteine-rich sequences
II insulin receptor, IGF-1 cysteine-rich sequences; characterized by disulfide-linked
• 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
信号转导与生命过程
V
vascular endothelial growth factor (VEGF)
receptor
contain 7 immunoglobulin-like domains as well as the kinase insert domain
VI
hepatocyte growth factor heterodimeric like the class II receptors except that one of the two (HGF) and scatter factor protein subunits is completely extracellular. The HGF receptor is a
(SC) receptors
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
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
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.
基因表 达改变
细胞表 型改变
细胞信号转导理论概述
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
receptor
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
B) Tyrosine phosphatases: e.g. CD45
C) Guanylate cyclases: e.g. natriuretic peptide receptors)
D) Serine/Threonine kinases: activin and TGF- receptors
2. Receptors that are coupled, inside the cell, to GTPbinding and hydrolyzing proteins (G-proteins).
Complexed with type I receptors
Type II R phosphorylates type I receptor
Initiation of signaling cascade
• Non-Receptor Serine/Threonine Kinases
1) cAMP-dependent protein kinase (PKA) 2) Protein kinase C (PKC) 3) Mitogen activated protein kinases (MAPK or ERK)
——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……)
• >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
Phosphorylate other kinases
phosphorylate proteins, which upon phosphorylated, can enter
the nuclear and bind DNA regulatory regions.
Characteristics of the Common Classes of RTKs
NGF (Nerve Growth Factor), IGF (Insulin-like Growth Factor), TPO
(Thrombopoietin)
3. 2. Cytokines
4.
IFN- (Inteeron- ), TNF (Tumor Necrosis
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
细胞周期 蛋白表达
细胞分裂增殖
细胞因子 表达分泌
抗感染状态
胞内致死 分子表达
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
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).
• Intracellular Hormone Receptors
1. Residing within the cytoplasm. 2. The steroid/thyroid hormone receptor superfamily (e.g. glucocorticoid, vitamin D, retinoic acid and thyroid hormone receptors): bind steroid/thyroid hormone, translocate to nuclear and bind specific DNA sequences hormone response elements (HREs).
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
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
Factor), Interleukins (1, 2, 3, 4…)
5. 3. Death molecules
6.
Fas
7. 4. Adhesion molecules
8.
Cadherins, Adhesin…
9. 5. Hormone
10. Insulin
11.6. Stress
Signal Transducing Receptors
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
Extracellular Signal Molecules
1. Growth Factors
2.
PDGF (Platelet-Derived Growth Factor), EGF (Epidermal Growth
Factor), TGF- (Transforming Growth Factor-), EPO (Erythropoietin),
1. Transmembrane receptors that have intrinsic enzymatic activity.
2. 3. ——Autophosphorylation 4. ——Phosphorylation of other substrates
A) Tyrosine kinases: PDGF-R, insulin-R, EGFR and FGF-R
produce cAMP 2) GPCRs that activate PLC-g leading to hydrolysis of
polyphosphoinositides: angiotensin, bradykinin and vasopressin receptors. 3) Photoreceptor
•An intracellular tyrosine kinase domain. Tyrosine phosphorylation
•An intracellular regulatory domain.
•A transmembrane domain.
Interact with and phosphorylate Src homology domain 2 (SH2)-containing proteins (e.g., PLC-, Ras, PI-3K, etc)
(requiring phosphorylation of both tyrosine and threonine)
• 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