（五） Cell Signaling and Transduction

细胞信号传导
Cell Signaling = Cell Communication

 There are 3.72×1013 cells in the

human body. How do the cells talk to each
other?

Telephone game
Signaling affects every aspect of cell structure & function
 Activation of enzyme activity--metabolism, survival, apoptosis, immunity, cell cycle...
 Change in cytoskeletal organization--movement, immunity, transportation…
 Change in ion permeability--neural transmission, immunity, transportation…
 Initiation of DNA synthesis--cell cycle, cell growth, reproduction, differentiation…
 Change in gene expression--cell differentiation, development, stress, immunity…

Importance of Signal Transduction

Development
Apoptosis
Signal
Transduction

Cell Growth Immunology

Metabolism

4
一、生物是物质、能量与信息的整合系统---
分层次、严格有序、可调控的结构体系。
个体之间 组织器官之间 细胞之间

二、协调人体内部的生物信息调控---
神经、激素协同作用控制个体内稳态。

三、细胞信号转导---生物体生命活动基础。

当前生命科学基础与应用研究中的核心问题
 激素，生长因子，NO ,声，光 等
配基（Ligand）：
（信号分子） 神经递质

组成个体的细胞的所有生命活动，包括增殖，分化，
凋亡，衰老，免疫等，以及神经信号传递，肌细胞收
缩等等
 个体内信号的来源

气体分子（扩散）
分泌的各种因子

神经传递递质 内分泌激素
大脑皮层功能分区
 大脑皮质各区的主要功能

•额叶，高级认知功能，比如语言、决策、学习、计
划、 、情感等，自主运动的控制,。
顶叶，躯体感觉，响应疼痛、触 摸、品尝、温度、压
力的感觉，该区域也与数学和逻辑相关。
颞叶，听觉， 也与记忆和情感有关。
枕叶，负责处理视觉信息。

大脑皮层是神经系统的最高级中枢，各种分析器中枢都
在大脑皮层中，如皮肤、听觉、视觉、嗅觉、味觉、内
脏、平衡、运动、语言等中枢。
信息在大脑皮质中加工整合与反应

高崇明等 主编 生物学导论
大脑皮质感觉区和运动区与身体各部的关系

每一身体部位在
皮质中占据的面
积与身体表面积
无关，而与敏感
度密切相关！

注意感觉区脸部
占据的区域

高崇明等 主编 生物学导论
皮质

下丘脑
垂体
 神奇的大脑

美国得克萨斯州阿莱多市, 6岁的
杰西·霍尔,患慢性局灶性脑炎,呈现
中风、癫痫、智力下降、反应迟
钝等症状,如果不加以控制，最终
必然全身瘫痪！
2006年6月,大脑半球切除手术
2008年8月,半脑女孩 得以康复，
原因不知.可能是因为她的左脑在
术后“接管”了通常由右脑控制
的工作，并正常发挥其功能。
内分泌系统在信息传递中的作用

人体内分泌系统的组成

激素特征：

来源——由内分泌腺分泌

传输——无特定管道，随血流传布

作用——特定靶细胞

效应——低浓度、强效应
神经激素配合作用控制个体内稳态

下丘脑－脑下垂体（垂体）－内分泌系统
形成人 体调控通路

激素的分泌受着神经系统的调控

下丘脑：既能传导 垂体 ：内分泌系
神经冲动、又有分 统的中心， 分泌
泌激素的功能。在 多种激素，都是蛋
内分泌系统中居于 白质分子
最高的统治地位，
 血糖水平调控的复杂网络
胰岛β-细胞 血糖上升

胰岛素 血糖上升 恢复正常 肝糖原分解

细胞吸收葡萄糖 正常血糖水平90mg/100ml
及在肝中合成糖 胰高血糖素
原贮藏
恢复正常 血糖下降

血糖下降 胰岛α-细胞

血糖水平的激素调节
 多细胞生物的生命活动是通过细胞间复
杂有序的通讯而整合的

细胞通讯的基本原理

信号细胞与靶细胞

细胞通讯的基本类型
近距离和远距离的分泌型细胞通讯
 多细胞生物通讯方式

细胞通讯目前已知几百种信号分子所介导。这些信号分子的化
学性质为蛋白质，小肽，氨基酸，核酸，激素， 脂肪酸衍生物
等，甚至是气体 NO和 CO.

1) Contact-dependent signaling: 接触通讯

2) Gap Junctions: 细胞间隙连接,允许临近细胞交流信息

3) Secreted signal-dependent signaling: 分泌信号通讯，胞吐作

用释放出大多数的信号分子来启动信号转导
 细胞通讯的基本类型
Secreted signal-dependent signaling

Contact-dependent signaling Gap Junctions

1) Secreted signals-dependent signaling

(d)
(a) Endocrine signaling: cells secrete signal molecules, called
hormones, into the bloodstream, which carries the molecules far and wide,
allowing them to act on target cells that may lie anywhere in the body.
 Contact-dependent signaling

Many signal molecules remain bound to the surface of the signaling cell and influence
only cells that contact it. Such contact-dependent signaling is especially important
during development and in immune responses.

Contact-dependent signaling during development can sometimes operate over relatively

large distances, where the communicating cells extend long processes to make contact
with one another.
Contact-dependent cell killing
粒酶（Granzyme B）
T淋巴细胞和自然杀伤细胞

感染细胞或癌细胞
胞吐作用释放粒酶颗粒，诱导凋亡
Contact-dependent cell killing
 Effector cytotoxic T cells killing target cells in culture

(A) Electron micrograph showing an effector cytotoxic T cell binding to a target cell.

(A) Electron micrograph showing a cytotoxic T cell and a tumor cell that the T cell has killed.
 Gap junction-dependent signaling

Gap junctions are narrow water-filled channels that directly connect the cytoplasms
of adjacent epithelial cells, & some other cell types. The channels allow the exchange
of inorganic ions and other small water soluble molecules, but not of macromolecules
such as proteins or nucleic acids.

Thus, cells connected by gap junctions can communicate with each other directly. In
this way, gap junctions provide for the most intimate cell communication.
 General principles of cell signaling
(1) Each cell is programmed to respond to specific
combinations of extracellular signal molecules
The cell integrates different information and mounts an appropriate and
comprehensive response.

Signal molecules work in

combinations to regulate
the behavior of the cell.

An individual cell often requires multiple signals to

survive (blue arrows) and additional signals to grow
and divide (red arrow) or differentiate (green arrows).
If deprived of appropriate survival signals, a cell will
undergo a form of cell suicide known as apoptosis. The
actual situation is even more complex.
 Signal-integration is mediated by important molecules

Signals A and B activate different signaling pathways, each leads to the phosphorylation of protein Y at
different sites. Protein Y is activated only when both sites are phosphorylated, and therefore becomes active
only when A and B are simultaneously present.
(2) Different cells respond differently to the same molecule

Muscle relaxation

Various responses induced by neurotransmitter acetylcholine

(3) Four features of cell signaling
(4) molecular switches
 Two molecular switches for signaling

Phosphorylation and dephosphorylation GTP binding protein is induced to

via protein kinases and phosphatases. exchange its bound GDP for GTP,
Thereby stimulating or inhibiting the which activates the protein; the
activities. protein then inactivates itself by
hydrolyzing its bound GTP to GDP.
Two molecular switches for signaling
1) Signaling by phosphorylation

The alterations in the

conformation of signaling
proteins are usually
accomplished by protein
kinases and protein
phosphatases

The human genome

encodes as many as 518
different protein kinases
and 150 different protein
phosphatases.
 Two molecular switches for signaling
2) Signaling by GTP-binding

The Nobel Prize in Physiology

or Medicine 1994

(NIH.1970s)

“For their discoveries of G-proteins

and the role of these proteins in signal
transduction in cells”
 Accessory proteins for cycling of G-proteins
Guanine nucleotide-exchange factors (GEFs): An inactive G
protein is converted to the active form when the bound GDP is
replaced with a GTP. GEFs are proteins that bind to an inactive
G protein and stimulate dissociation of the bound GDP.
Thereby GEFs activates G-protein
Guanine nucleotide-dissociation inhibitors (GDIs): GDIs are
proteins that inhibit the release of GDP from a G-protein, thus
maintaining G-protein in the inactive, GDP-bound state.
GTPase-activating proteins (GAPs): Most G proteins possess
some capability to hydrolyze a GTP, but this capability is
greatly accelerated by interaction with specific GAPs. Thereby
GAPs inactivate G-protein by stimulating it to hydrolyze its
bound GTP.
Two molecular switches for signaling
2) Signaling by GTP-binding
Secreted signal-dependent signaling
分泌信号通讯
Signal transduction mediated by the
receptors within cells or on surface
受体作用的特点
受体存在于细胞膜、胞浆或细胞核内
•高度专一性：受体选择性与特定配体结合。
•高亲和力
•可逆性:属非共价结合
•可饱和性：反应服从质量作用定律，结合曲线呈可
饱和状态
•特定的作用模式
•一般为蛋白质（糖蛋白、脂蛋白或糖脂蛋白）
•受体与配体之间的结合不通过共价键介导，主要靠
离子键、氢键、范德华力和疏水作用而相互结合。
 两种类型的受体

细胞内受体——亲脂性激素受体

受体 离子通道耦联受体:分布神经肌肉细胞

细胞表面受体 G蛋白耦联受体:产生第二信使

与酶连接的受体:各种生长因子受体
Receptors include two classes:
The receptors within cells

1. The Nuclear Receptors

2. The signaling triggered by

gases (NO, CO)

3. The Cytosolic Receptors

 细胞内受体：1. 核受体 Nuclear Receptors
Nuclear receptors are all structurally related, being part of the very large nuclear receptor
superfamily.

Many family members have been identified by DNA sequencing only, and their ligand is not
yet known; these proteins are therefore referred to as orphan nuclear receptors.

More than half of the 48 nuclear receptor family encoded in the human genome are orphans.

类视黄醇、类固醇激素、甲状腺素、 维生素A、维生素D
 细胞内受体蛋白家族和作用模型
类固醇激素受体、非类固醇激素受体和孤核受体

皮质醇

雌激素

黄体酮

维生素

甲状腺素

视黄酸
Ligands for nuclear receptors are small and hydrophobic
1. Steroid hormones—Cholesterol
2. Vitamin D—Secosteroids
(Cholesterol-like)
3. Retinoids —Vitamin A
4. Thyroid hormone- tyrosine-based
皮质醇 雌二醇 睾酮

Steroid hormones
Five types according to the receptors:
甲状腺素 1) Glucocorticoids（糖（肾上腺）皮质激素）
2) Mineralocorticoids (矿皮质激素类) ；3) Androgens（雄激素）
4) Estrogens（雌激素）；5) Progestogens (sex steroids孕激素类)
固
醇
类 细
激 胞
素 内
信 受
号 体
途
径
 HRE
hormone
response
element

激素反应元件
细胞内受体：2. NO
The action of Nitric oxide on blood vessels

c-GMP PDE(cGMP二脂酶）

GMP
细胞内受体：3. Cytosolic Receptors
The 膜受体细胞的信号转导过程
receptors on cell surface
 The receptors
Extracellular signals are initiated by receptors
Receptor proteins are present in target cells.

Binding of extracellular signaling molecules to cell-surface receptors

triggers a conformational change in the receptor, which in turn leads to
intracellular signal-transduction pathways that ultimately modulate
cellular metabolism, function, or gene expression.
细胞通讯与生物学效应
 细胞间信息物质影响细胞功能的途径

种类 信息物质 受体 引起细胞内的变化
神经 乙酰胆碱、谷氨酸、 质膜 影响离子通道关闭
递质  –氨基丁酸 受体
类胰岛素样生长因 -1、质膜 引起酶蛋白和功能蛋白的
生长
表皮生长因子、 血 受体 磷酸化和去磷酸化，改变
因子
小板衍生生长因子 细胞的代谢和基因表达
蛋白质、多肽及氨基 质膜 同上
激素 酸衍生物类激素 受体
类固醇激素、甲状腺 胞内 调节转录
素 皮质激素 受体
维生 维生素A、维生素D 胞内 同上
素 （维生素E 维生素K？？） 受体
 受体激活细胞内信号蛋白复合体的策略（1）

A receptor and some of the intracellular signaling proteins it activates in

sequence are preassembled into a signaling complex on the inactive receptor by
a large scaffold protein.
 受体激活细胞内信号蛋白复合体的策略（2）

The signaling complex assembles on a receptor only after the binding of an extracellular
signal molecule. Here the activated receptor phosphorylates itself at multiple sites,
which then act as docking sites for intracellular signaling proteins
 受体激活细胞内信号蛋白复合体的策略（3）

Activation of a receptor leads to the increased phosphorylation of specific phospholipids in

the adjacent plasma membrane, which then serve as docking sites for specific intracellular
signaling proteins, which can now interact with each other.
信号传递中的分子开关：1,磷酸化与去磷酸化
2,G蛋白与GTP或GDP的两种状态
 三、多细胞生物的生命活动是通过细
胞间复杂有序的通讯而整合的

细胞通讯的基本原理

信号细胞与靶细胞

细胞通讯的基本类型
膜受体细胞的信号转导过程
膜受体信号转导过程
以及细胞应答反应
膜受体的信号转导主要通路

1) The ion-linked receptors

2) G protein-linked receptors

3) Receptor tyrosine kinase (RTK)

4) Jak-STAT

5) TGFβ-SMAD

6) Notch

7) Wnt/β-catenin

8) Hedgehog

9) NF-κB
细胞表面受体

1，离子通道偶联
受体

2，G蛋白偶联受体

3，酶联受体
 受
体
1 分
子
离
的
子主
通要
道类
受型
体之
一
：

如:突触信号传导
 The ion-channel-coupled receptors
 Involved in synaptic signaling between nerve cells, or nerve
cells and other electrically excitable target cells such as muscle cells.

 Mediated by both voltage-gated and ligand-gated ion channel

receptors.
 Electrical Voltage-gated
Nerve impulse signal Potassium channel
Voltage-gated
sodium channel

Voltage-gated Ion
(Ca2+, Na+, K+)
channel receptors
Electrical signal stimulates the
Voltage-gated ion receptors
to release neurotransmitters

Ligand-gated ion
channel receptors
Neurotransmitters bind to the
Ligand-gated ion receptors on the
postsynaptic cell to relay the signal
Three states of the acetylcholine receptor
麻
醉
剂
 2. Signaling mediated by GPCRs
G protein-coupled receptors
G蛋白偶联受体信号通路

 GPCR superfamily: form the largest family of receptor.

C. elegans genome encodes about 1000 different GPCRs out of 19,000 genes.

About 1000 GPCRs in humans, >1300 in mice.

 GPCRs mediate most responses to signals from the external world (light, smell and taste) ,
as well as signals from other cells, including hormones, neurotransmitters, and local
mediators.

 Ligands: photons, odorants, tastants and hormones, neurotransmitters, chemoattractants.

external world
 The structure of GPCRs
Ligand-
binding site

 Seven transmembrane domains; C-terminal: S/T-rich, sites of

phosphorylation allow for the desensitization of GPCRs.
 Ligands bind to the extracellular portion of the receptor.
G蛋白偶联受体激活G蛋白
Activation of G protein by an activated GPCR

In the unstimulated state, the α subunit has

GDP----G protein is inactive.

Binding of an extracellular signal to a GPCR

changes the conformation of the receptor,
which in turn alters the conformation of the
G protein.

The alteration of the  subunit of the G

protein allows it to exchange its GDP for
GTP, activating both the α subunit and the
β/γ complex, both regulate the activity of
target proteins in the plasma membrane.

The activated GPCR acts as a guanine

nucleotide exchange factor (GEF).
 The G proteins
G proteins are important signal transducing molecules
Heterotrimeric G proteins, "large" G proteins, are made up of α, β, and
γ subunits, activated by G protein-coupled receptors.

Monomeric G proteins, “small" G proteins, homologous to α subunit in

heterotrimers, belong to the Ras superfamily of small GTPases.

α and γ have covalently attached lipid molecules that help bind them to PM
 Two types of GPCR: stimulating or inhibiting
（前列腺素E1）
(肾上腺素)

促肾上腺皮质激素）

Stimulatory Ligands/Receptor---Stimulatory G protein (Gs) to activate adenylyl cyclase

Inhibitory Ligands/Receptor --- Inhibitory G protein (Gi) to inhibit adenylyl cyclase

 Four Major Families of G Proteins

嗅觉神经

Families are determined by amino acid sequence relatedness of the a subunits.

20  subunits, 6 β subunits and 11  subunits have been described in humans.

 Monomeric small G proteins: homologous to α subunit in
heterotrimers, belong to the Ras superfamily of small GTPases

 Ras superfamily consists of various monomeric GTPases

 only Ras and Rho relay signals from cell-surface receptors
 信号传导途径的关键成分：第二信使

第二信使之一
cAMP:环腺苷酸
cAMP的产生
 G 蛋白耦联
受体的cAMP信
号传递通路。

活化PKA

Alfred G. Gilman Martin Rodbell

（1941－ ） （1925－1998）

The Nobel Prize in Physiology

or Medicine 1994
"for their discovery of G-
proteins and the role of these
proteins in signal transduction
in cells"
 （促肾上腺皮质激素）

(肾上腺素)
(卵泡刺激素 )

（黄体激素）

（血液中的复合胺）
（生长激素抑制素）
The response by a liver to glucagon or epinephrine
胰高血糖素 肾上腺素

① To regulate gene expression

②To inhibit glycogen synthesis Glucose

③To enhance glycogen degradation

味觉，嗅觉和视觉的产生
基于G蛋白信号转导
 味
觉
信
号
转
导

高崇明等 主编 生物学导论
嗅
觉
信
号
转
导

cAMP门控阳离子通道
视
觉
信
号
转
导

PDE:cGMP磷酸二脂酶

高崇明等 主编 生物学导论
 第二信使
磷酯酰肌醇
Phosphatidylinositol (PIP2)

二酰基甘油
三磷酸肌醇

Ca2+
 IP3 is water-soluble
molecule. It leaves
the plasma membrane
and diffuses rapidly
二酰甘油 through the cytosol.
When it reaches the
ER, it binds to and
opens IP3-gated Ca2+-
release channels (also
called IP3 receptors)
in the ER membrane.
Ca2+ is released
through the open
channels, quickly
raising the Ca2+
concentration in the
磷脂酰肌醇-4,5二磷酸 三磷酸肌醇 cytosol

PLCβ acts on PIP2 present in the inner half of the plasma membrane, cleaves PIP2 to
generate two products: IP3 and DAG, thus splits the signal into two branches.
  The pathway through phospholipase C results in a rise
in intracellular Ca+

SignalsGPLR GP PLC IP3 and DAG (twin signals).

IP3 IP3 receptor(Ca2+ channel, located at the surface of sER)  Elevation of cytosolic Ca2+;
DAG activates PKC to phosphorylate Ser and Thr on target proteins.
Calcium binds to calcium-binding proteins(CaM) which affects other proteins.
PKC
G-protein-linked receptor desensitization depends on
receptor phosphorylation by PKA, PKC, CaMK2 or G-
protein-linked receptor kinases (GRKs)
受体分子主要类型3. 酶联受体
Receptor tyrosine kinase (RTK) and RTK-Ras signaling pathway

RTK are the second major type of cell-surface receptors

over 50 kinds have been identified, involved primarily in the control of cell growth
and differentiation rather than metabolism.

 Six classes of enzyme-linked receptors  Ligands of RTKs:

have thus far been identified:
1.Nerve growth factor (NGF)
Receptor tyrosine kinase (RTK);
2.Platelet-derived growth factor (PDGF)
Tyrosine-kinase-associated receptor;
3.Fibroblast growth factor (FGF)
Receptor like tyrosine phosphatases;
4.Epidermal growth factor (EGF)
Receptor serine/threonine kinase;
5.insulin and insulin-like GF (IGF-1)
Receptor guanylyl cyclases;
6.Ephrins (Eph): critical in embryo
Histidine-kinase-associated receptor development & tumorogenesisVascular endothelial
factor

7. (VEGF)
多种生长
因子，胰
酪
岛素 以 氨
及胰岛素 酸
样生长因 激
子 酶
受
体
一 . RAS-MAK激酶信号通路
 Steps in activation of Ras by RTKs
Phosphotyrosines of RTK act as
binding sites for a specific SH2
protein called GRB2 (Growth factor
receptor binding protein in mammalian).
GRB2 is not a protein with
catalytic activity, but one that
functions solely as an adapter
molecule that links other proteins
into a complex.
Sos (son of sevenless) is a guanine
nucleotide exchange factor (GEF) for
Ras.
When a ligand binds to the RTK
and recruits the Grb2-Sos to the inner
surface of the membrane, the Sos
protein binds to Ras causing GDP/GTP
exchange, thus activating Ras.
 GTP-GDP cycling of Ras protein

(Sos)

Ras gene mutations is found in

30% of all human tumors.
(Sos)
Ras (21Kda ) consists of a single
small subunit. Ras has a very
weak GTPase activity and would
remain in the active, GTP-bound
(Ras-GAP1)
state for 30mins. In the cell, Ras
activity is regulated by GAP that
stimulate the Ras GTPase about
105-fold.
 Ras-activated MAP-kinase serine/threonine

Raf是一种MAPKKK。
(Raf)

14 MAPKKKs, 7 MAPKKs,
MEK
and 13 MAPKs have been
identified in mammals.
Functions of MAP kinase
ERK cascade
•yeastmating pheromones;
•Fruit flies differentiation of the
photoreceptors;
•Flowering plants defense
against pathogens.
•mammals cell proliferation.

MAP kinase=mitogen-activated protein kinase; MAP-KKK=Raf (Ser/Thr-PK)

二 . PI3K-PKB（AKT）信号通路
当接受来自酪氨酸激酶和G蛋白偶联受体的信号后，PI3K的p85
调节亚基即被募集到临近质膜的部位，p110亚基通过与p85亚基
结合把底物Ptd Ins(4，5)P2(PIP2，磷脂酰肌醇2磷酸)转化为Ptd
Ins(3，4，5)P3(PIP3，磷脂酰肌醇3磷酸)。PI(3，4，5)P3可以
和蛋白激酶B(PKB，Akt)的N端PH结构域结合。使Akt从细胞质转
移到细胞膜上．并在3一磷酸肌醇依赖性蛋白激酶1(PDKI)和3一
磷酸肌醇依赖性蛋白激酶2(PDK2)的辅助下，分别使Akt蛋白上的
苏氨酸磷酸化位点(Thr308)和丝氨酸磷酸化位点(Ser473)磷酸化
而使其激活。激活后的Akt通过直接和间接两种途径激活其底物
雷帕霉素靶体蛋白(mTOR)：
 RTK-Ras two signaling pathway

Ligand-RTK, recruits Grb2-Sos, the Sos binds to Ras, functions as a guanine

nucleotide exchange factor (GEF), causing GDP/GTP exchange, thus activates Ras.
 Insulin receptor

Insulin receptor utilizes IRS,

instead of Grb2, to transmit the
signal.
IRSs: insulin receptor substrates
IRS
Phosphorylated IRS acts as a “docking
station” that binds proteins possessing
SH2 domains.
Insulin suppresses blood glucose by promoting
glycogen synthesis

②①

Glucose
协助扩散的葡糖糖转运体
 Regulation of blood glucose level

Glucose

Glucose

促进糖原合成 促进糖原分解
三 . TGF β-Smad信号通路
 TGFβ-SMAD signaling pathway

The transforming growth factor-β (TGFβ) consists of (30–40 in humans)

structurally related, secreted, dimeric proteins.

During development, they regulate pattern formation and influence

various cell behaviors, including proliferation, specification and
differentiation, extracellular matrix production, and cell
death. In adults, they are involved in tissue repair and in immune
regulation, as well as in many other processes.
TGF-β-Smad 信号通路
（受体丝氨酸/苏氨酸蛋白激酶）
 Senescent Signals
TGF-β

TβRI
TβRII
P
Smad
2/3

Smad P
2/3

Smad 4
P
Epigenetic Smad
Smad 4
Modifiers 2/3

Smad P TFs
Smad 4
2/3

Cellular Senescence
细胞的信号转导

细胞内受体与细胞表面受体

信号转导的第二信使

细胞信号转导的主要通路和级联反应
 通过第二信使，
推动后续多步反
应，并使激素信
号放大。

第二信使分子：
cAMP 、 cGMP ,三磷
酸肌醇（IP3),
二酰基甘油(DAG)
和Ca 2+

第三信使？ Ca 2+
第二信使之三：Ca2+
 细胞信号转导网络与交叉对话

（cross talking）

信号转导的网络整合系统

信号转导的交叉对话
 每一条信号转导途径都是由许多蛋白质组
成，如受体、G蛋白、酶、蛋白激酶、效应
蛋白质、调节蛋白等。所有这些蛋白质不仅
结构、功能各异，在各组织表达不同，而且
在细胞内定位也不同。然而细胞内各条信号
传递途径之间不是各自为政，相互孤立的，
而是相互联系，形成网络。
1. 一条信息途径的成员，可参与激活或
抑制另一条信息途径。
2. 两种不同的信息途径可共同作用于同
一效应蛋白或同一基因调控区而协同
发挥作用。
3. 一种信息分子可作用几条信息传递途
径。
5. Convergence, divergence, and crosstalk
among different signaling pathway

A. Convergence:
Signals from a
variety of unrelated
receptors can lead to
the formation of p-Y
docking sites for the
SH2 domain of the
adaptor protein
(converge to activate
a common effector)
B. Divergence: Signals from the same ligand can
diverge to activate a variety of different effectors.
C. Crosstalk: Signals can be passed back and
forth between different pathways
6. In actual fact, signaling pathways in the
cell are much more complicated
 细
胞
信
号
调
控
网
络

生存依赖于精巧调控的细胞间、细胞内
分子通讯网络：内环境恒稳态
细胞信号转导大事记
1955年，Sutherland，cAMP第二信使学说，获
1971年诺贝尔生理和医学奖
1963年， cGMP作为胞内信使的发现
1978年，Rasmussen，Ca2+第二信使学说
1983年，IP3和DG作为胞内信使的发现
80年代，Gilman和Rodbell，G蛋白的研究，获
1994年诺贝尔生理和医学奖
80-90年代，酪氨酸蛋白激酶与信号转导的研究
 The Nobel Prize in Physiology or Medicine
"for their discovery of1994
G-proteins and the role of
these proteins in signal transduction in cells"

Alfred G. Gilman Martin Rodbell

National Institute of Environmental
University of Texas, Southwestern Health Sciences Research Triangle
Medical Center Dallas, TX, USA Park, NC, USA
1941 - 1925 - 1998
 The Nobel Prize in Physiology or Medicine
"for their discoveries1998
concerning nitric oxide as a
signalling molecule in the cardiovascular
system"

Robert F. Furchgott Louis J. Ignarro Ferid

SUNY Health Science UCLA School of
Muradof Texas,
University
Center, Brooklyn, NY, USA Medicine, Los Angeles, Health Science Center,
CA, USA Dallas, TX, USA
1916 - 1941 - 1936-
 The Nobel Prize in Physiology or Medicine
"for their discoveries
1986of growth factors"

Stanley Cohen Rita Levi-Montalcini

Vanderbilt University School of Institute of Cell Biology
Medicine，Nashville, TN, USA
of the C.N.R，Rome, Italy
1922 - 1909-
 The Nobel Prize in Physiology or Medicine
"for their discovery 1989
of the cellular origin of
retroviral oncogenes"

J. Michael Bishop Harold E. Varmus

University of California, School of Medicine ，
San Francisco, CA, USA
1936 - 1939-
哈哈，

下
课
了