Transcript signal pathway

Multicellular Organisms have BIG Communication Problems
Oi! We need
some glucose!
Hey You – divide
now!!!
?
Will you
PLEASE stop
dividing!
Come in #7,
your time is up!
Chapter 6
Signal Transduction
Cell communication
Cell communication
Cell recognition
and cell recognition
Cell signal….
Signal
Transduct
ion
Cell receptor….
Signal pathway
intercellular receptor
signal pathway
cell surface receptor
signal pathway…..
Integrin protein pathway
Network signal and signal characteristi
Nobel prizes awarded for research
in signal transduction
Year
Recipient
Prize
Area of Research
2000
A. Carlsson, P. Greengard, E. Kandel
M&P
Signal transduction in the nervous system
1999
G. Blobel
M&P
Signal hypothesis of protein translocation
1998
R. Furchgott, L. Ignarro, F. Murad
M&P
Role of NO as cellular messenger
1994
A. Gilman, M. Rodbell
M&P
Structure and function of GTP-binding(G)
proteins
1992
E. Fischer, E. Krebs
M&P
Alteration of enzyme activity
phosphorylation/dephosphorylation
1971
E.W. Sutherland
M&P
Mechanism of hormone action and cyclic
AMP
2001
L. H. Hartwell, R. T. Hunt, P. M. Nurse
M&P
key regulators of the cell cycle
2002
S. Brenner, H. R. Horvitz, J. E. Sulston
M&P
Apoptosis
by
6.1 cell communication and cell recognition
6.1.1 Cell communication
a Secret chemical signal
b Contact-depend signal( 接触性依赖的通讯）
c Gap junction signal
The Secret chemical Signal
Endocrine signaling – signaling molecules act on
target cells distant from their site of synthesis by
cells of endocrine organs
Paracrine signaling – signaling molecules released by
a cell only affect target cells in close proximity
Autocrine signaling – cells respond to substances that
they themselves release, same cell type
chemical snaptic Neuronal signaling
？


6.1.2 cell recognition
细胞通过其表面受体与胞内信号物质选择性结合，
导致胞内一系列生理生化变化，最终表现为细胞整
体的生物学效应
Cells selectively bind with intercellular signal by cell
surface receptor,trigger a series of physiological and
biochemical changes , result in integrated cell effect
Signal transduction
An extracellular signal can produce a change in
the intracellular state of the cell without the
initial signal crossing the membrane.
6.1.3 Cell signal
Classify by chemical characteristic


Hydrophobic signal （菑类激素；甲状腺
素)can transport through cell membrane ,bind
with receptor in cytoplasm and nucleus to
form complex
Hydrophilic signal, cannot transport through
cell membrane,bind with cell surface receptor
and produce second signal ,this process called
signal transduction
Gaseous signal :Nitric Oxide
In response to a signal from nerve cells, endothelial内皮细胞
cells that line blood vessels make and release nitric oxide.
Nitric oxide enters muscle cells in the vessel wall causing them
to relax and dilate (扩大的)
Blood flow increases and more oxygen can reach organs such as
the heart.
The 1998 Nobel prize was awarded to two U.S. scientists for
discovering this mechanism.
Nitric Oxide and Carbon Monoxide
◆The nitric oxide (NO) is a major paracrine
signaling molecule in the nervous, immune, and
circulatory systems. NO is able to diffuse directly
across the plasma membrane of its target cells. The
molecular basis of NO action, however, is distinct
from that of steroid action; rather than binding to
a receptor that regulates transcription, NO alters
the activity of intracellular target enzymes.
◆一氧化氮是可溶性的气体，产自精氨酸，在一
些组织中作为局部介质起作用。NO能够引起血
管壁的平滑肌细胞松弛
NO
classify by signal location

Extracellular
• Receptors which have N
terminal face outwards
and C terminal inside the
cell.
• When bound to a signal
molecule, changes its
conformation
• Signal molecules are
specific to their receptors

Intercellular
• Mostly triggered by the extracellular signal
• Which converts the extracellular into an
intracellular signal
• Eg. - G protein, GTPase, cAMP, Ca++,
Kinases, phosphatases and many more
• Also called as second messengers
6.1.4 Second messenger and molecular switch
Second messenger:
Primitive signal bind with receptor and then
trigger second messenger （ cAMP,IP3,DG,)
第二信息至少有两个特征:

是第一信息同其膜受体结合后最早在细胞膜内侧
或胞浆中出现，仅在细胞内部起作用的信息分子

能启动或调节细胞内稍晚出现的反应。

目前公认的第二信息有cAMP、DG、IP3、cGMP和
Ca2+
Molecule switch protein
Protein kinase phosphorylation let it open ，
Dephosphorylation let it close
Protein+GTP=active
Protein+GDP=INactive
Communication by extracellular signals
steps :
1)Synthesis and release of signaling molecules
by the signaling cell
2) Transport of the signal to the target cell
3) detection of the signal by a specific
receptor protein
4) And change in cellular metabolism or gene
expression triggered by the receptorsignaling molecule complex
5) Removal of the signal, often terminating
the cellular response
6.2 Cell receptor
Receptor: recognition and selectively bind with
ligand signal, extracellular siganl change into
intercellular physical or chemical signal，triggered
a series of process，result in biological effect
Cell
receptor
Membrane Receptor
intracellular receptor
cell surface receptor
Nucleus receptor
Receptors
Signal molecules
that do not enter the
cell bind to cellsurface receptors.

Signal molecules
that enter the cell
bind to intracellular
receptors.

intracellular receptor

Transmembrane receptors
That span the thickness of
the plasma membrane
Intracellular domain and
extracellular domain
Signal
trasduction/through small
molecules (Ca++) – Ion
Channels
intracellular receptor
Three classes of cell-surface
receptors

Ion-channel-linked receptors open an ion
channel in response to the signal molecule.

G-protein-linked receptors activate an
intracellular G-protein that in turn activates
intracellular enzymes.

Enzyme-linked receptors directly activate a
membrane bound enzyme.

Nuclear receptors
Soluble proteins localised within the
cytoplasm or the nuceloplasm
Ligand activated trascription activators
Hormone regulation
Steroid receptors (located within cytosol
Defining a Receptor
Specificity – a receptor must be able to
distinguish between often closely-related signals
High affinity – signals are often present in low
concentrations – effective receptors can often
detect nM to pM concentrations
Saturability – a cell has a finite number of
receptors and, thus there is a limit to the number
of ligand molecules a cell can bind
Reversibility – ligand-receptor association is
not covalent – as the ligand concentration
drops the complex can dissociate
Coupling – the receptor transfers a signal
from ligand to cell
Coping with Multiple Signals – Receptor ‘Crosstalk’
Suppose a cell receives two signals. Signal A inhibits
proliferation, whilst signal B stimulates proliferation…
A
Signal A activates
a kinase…
B
kinase
…which phosphorylates
and inactivates the
receptor for signal B result – no proliferation


If ‘crosstalk’ only works in one direction (A
to B) then signal A will be dominant
If ‘crosstalk’ works in both directions, the
outcome will depend on several factors e.g.
Timing of signal perception
Relative receptor density
Relative signal concentration


6.3 intercellular receptor signal
pathway
亲脂小分子与细胞内受体结合
细胞内受体的本质是激素激活的基因调控蛋
白，构成细胞内受体超家族
steroid hormone(甾类激素)signal pathway
primary response
secondary response
6.4 cell surface signal pathway
A Ion-channel-linked receptors
open an ion channel in response to the signal
molecule.
B G-protein-linked receptors
activate an intracellular G-protein that in
turn activates intracellular enzymes.
C Enzyme-linked receptors
directly activate a membrane bound enzyme.
A (ion-channel-linked receptor)
Types of ion channel
B G protein -linked signal pathway

1994 Nobel prize. Discovery of G-protein
coupled receptors and their role in signal
transduction

43,409 articles in Medline that mention G
proteins.

G  ＋GTP激活态（open ）
 G  ＋GDP失活态（close

G-protein sructure

G-protein-coupled receptors

C-AMP

G-protein-linked signal pathway
G-protein sructure （G-protein subunits）


4 subtypes
 binds GTP






activation of 2nd mess.
less variability
 also activates 2nd mess.

G-protein subtypes
Gi/o


Gs


Gq


G12/13


 inhibition
of cAMPsynthesis
production
 mediates
signalling between GPCR
 increased
of
cAMP
activation of
PLC
leading
to
and
RhoA
(GTPase)
2+
 inhibition
of Ca of
channels
2+ and K+ channels
activation
Ca
activation of
PKC (DAG)

function
under investigation
+
activation of GIRK K channels
intracellular Ca2+ release (IP3)

1. Basic facts about G proteins
• Each G-protein consists of 3 sub-units, sub-units
can be together or separated.
• Each G-protein has a binding site that can be
occupied by either GDP or GTP.
• A G-protein is said to be inactive when it is
bound to GDP.
• A G-protein is said to be active when it is bound
to GTP.
Small GTP-binding proteins
 Ras (growth factor signal cascades).
 Rab (vesicle targeting and fusion).
 ARF (forming vesicle coatomer coats).
 Ran (transport of proteins into & out of the
nucleus).
 Rho (regulation of actin cytoskeleton)
G-proteins
exterior
L
G
cytosol


Effector
Signal
G-protein-coupled receptors
与配体结合
Extracellular
-NH2
-S-S-
e1
TM1
TM2
e3
e2
TM3
TM4
TM5
D
R
Y
C2
C1
Cytoplasmic
C3
G蛋白作用部位
COOH-
TM6
TM7
cAMP
ATP  cAMP + PPi
NH2
cAMP
Cyclic AMP
N
N
H2
5' C
O
P
O

N
N
4'
O
H
H 3'
O
H
1'
2' H
OH
O-
Cyclic-AMP is suited to be a transient signal.
Synthesis & degradation of cAMP are both
spontaneous, but enzymes are required to
synthesize these reactions.

Enzymes that synthesize and degrade cAMP
are regulated.

G-protein-linked signal pathway


C-1 CAMP signal pathway
C-2 磷脂酰肌醇信号通路(Double
messenger pathway)
Subunit of cAMP
Rs and Ri
GS and Gi
CAMP enzyme
PKA
GENE
EXPRESXSION
cAMP activate cAMP-depend PKA
protein kinase A
transcription factor CREB
(CRE-binding protein)
expression of cAMPinducible genes.
CAMP途径的信号解除和抑制
信号解除
●通过磷酸二酯酶将cAMP降解,形成5'-AMP；
信号抑制
●通过抑制型的信号作用于Ri, 然后通过Gi起作
用
PIP2-DG pathway
PKC




是Ca²⁺依赖性的，有两个功能区：
一个是亲水的催化活性中心，
另一个是疏水的膜结合区。
在未受到刺激的细胞中，PKC以非活性形式分布
于细胞溶质中，当细胞接受外界信号时，PIP₂水
解，细胞内Ca²⁺浓度的升高，引起从胞质转移到
细胞膜上而成待活状态，质膜上DG瞬间积累，使
PKC 与Ca²⁺的亲和力增加，而处于活化状态。
?
信号的终止
DAG信号的解除
DAG只是由PIP2 水解得到的暂时性产物,
寿命只有几秒钟, 靠两种方式进行降解:
◆被DAG磷酸激酶磷酸化,生成磷脂酸(PA),PA
被转化为CMP-磷脂酸,再与肌醇作用合成磷
脂肌醇(PI)。
◆DAG 被DAG 酯酶水解生成单脂酰甘油, 再
进一步水解成自由的多不饱和脂肪酸和花
生四烯酸甘油。
 Removal of IP3
◆IP3 hydrolyzation
在5’磷酸酶的作用下, 水解为I(1,4)P2, 并进
一步水解成肌醇。5’磷酸酶是一种膜结合的酶。
◆在胞浆的肌醇磷酸脂3-激酶的作用下 IP3 被
磷酸化成I(1,3,4,5)P4。
Ca2+信号解除
?
●IP4 参与打开细胞质膜上的Ca2+ 通道, 使细胞质
中的Ca2+较为持久地增高。
● 胞 内 Ca2+ 浓 度 持 久 地 升 高 , 可 激 活 Ca2+-ATP 酶
（质膜、内质网膜的钙泵），从而降低胞质中的
Ca2+ ，使胞质中的Ca2+ 迅速恢复到基态水平(10-7
M),并使活性CaM-酶复合物解离,从而酶失去活性,
细胞反应终止。
C Enzyme linked receptor
RTK-RAS pathway
Other enzyme –linked receptor
GRF
RAS+GDP
RAS+GTP
GAP
MAP : 有丝分
裂原活化 蛋白
MAPKKK: MAP
激酶的激酶的
激酶
MAPKK: MAP
激酶的激酶
MAPK: MAP激酶
Ras 蛋白信息传递途径
◆Ras是原癌基因的表达产物；
◆介导：
细胞外信号→受体→Ras→Rafl→MAPKKK
→MAPKK (MEK)→MAPK，转录因子→激活
靶基因→细胞应答和效应。
◆该通路与EGF受体有关，并且有一中介蛋白
参与
Ras switch

SUMMARY
Receptor tyrosine kinases (RTKs), which bind to
peptide/protein hormones, may exist as dimers or
dimerize during binding to ligands.
Ligand binding leads to activation of the kinase
activity of the receptor and autophosphorylation of
tyrosine residues in its cytosolic domain. The activated
receptor also can phosphorylate other protein
substrates.
Ras is an intracellular GTPase switch protein that
acts downstream from most RTKs.
RTKs are linked indirectly to Ras via two proteins,
GRB2 and Sos

The SH2 domain in GRB2, an adapter protein,
binds to specific phosphotyrosines in activated
RTKs. The two SH3 domains in GRB2 then
bind Sos, a guaninenucleotide exchange factor,
thereby bringing Sos close to membrane-bound
Ras ·

Binding of Sos to inactive Ras causes a large
conformational change that permits release of
GDP and binding of GTP.

Normally, Ras activation and the subsequent
cellular response is induced by ligand binding
to an RTK.



6.5 Integrin protein pathway
整联蛋白是细胞表面的跨膜蛋白包括纤连蛋
白，胶原，和蛋白聚糖
粘着斑功能：机械结构功能；信号传递功能
细胞表面到细胞核的信号通路
细胞表面到细胞质核糖体的信号通路
6.6 Network signal and signal
characteristics
A Basic points of signal transduction
 多途径多层次，具备收敛和发散特点
 既有专一性又具备作用机制的相似性
 信号可以有控制的适度放大
具备进行适应的特点
逐渐降低表面受体的数目
快速钝化受体

B
蛋白激酶的网络整合信息
interaction of Signal pathway
Signal transduction
across the plasma
membrane can cause a
cascade of events
that amplify the signal
and distribute it to
influence several cell
processes in parallel.
Why do cells communicate?
During development, cells differentiate to
adopt specialized roles.
Cells need to know whether to live, die, or
divide.
Neurotransmission.
Regulation of metabolism.
Contraction-expansion.
Secondary sexual characteristics.
Cell Communication
Why do cells communicate?
How are signals transmitted between
cells?