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Chapter 16
Cellular signal transduction
A general introduction
When outer environment changes：
Unicellular organism ——
Directly responds to
extraneous signals.
Multicellular ——
transmits the information by the
intercellular complicated signal
transduction system, and regulates the
activity of body.
Intercellular signal transduction
can be transduced by：
* directly contact between adjacent cells.
* Regulation of metabolism and function of itself
and other cells by means of secreting chemical
substances by cells.
chemical substances which regulate
the life activity of cells ——signaling
substance
General manner of intercellular signal
transduction :
stimulation
secretive
cell
target cell
target cell
signal
substance
(first messenger)
receptor
second
messengers
effector
protein
effector
protein
section 1
signaling substances
Ⅰ、 Intercellular signaling
substance
*
Definition
A general designation of chemical
substances which are secreted by the cells in
order to regulate the life activity of the target
cells.
*
Chemical character
protein, peptide, amino acid derivatives,
steroid hormone, fatty acid derivatives,
NO and so on
* Classification
1、Local chemical medium
Paracrine signal
characteristics ：
 Paracrine signal molecules are
secreted by common cells in vivo ；
 Paracrine signal molecule do not
enter blood circulation, but arrive
nearby target cells by diffusion.
 The effective time is usually short.
For instance:
growth factor, NO, prostaglandins and so on.
2、Hormones
Endocrine signal
Characteristics：
 endocrine signal molecule are
secreted by endocrine cells which are
specially differentiated;
 arrive the target cells through the
blood circulation;
 effective time of most of them is longer.
For instance:
Insulin, thyroxine, adrenalin and so on.
3. Neural transmitter
Characteristic ：
 synapse-secreted signal;
 secreted by nerve cell;
 arrive to the target cell
through the synaptic cleft ；
 effective time is short.
e.g.
acetylcholine、noradrenaline and so on .
Others ：
Some intercellular signaling substances can
act on the same cell or on the secreting cells
themselves. They are called autocrine signal.
Some intercellular signaling substances can
transmit information in different bodies, e.g.
Insect sex hormone.
the pathways of intercellular signaling
substances affect the cellular functions
Type
Signal substance
Receptor
Changes in the cells
membrane
receptor
Effect on the on-off of ion
channel
insulin-linked growth
membrane
receptor
factor-1 、epidermal
growth factor 、
platelet-derived growth
factor.
resulting in
phosphorylation and
dephosphorylation of
enzyme protein and
function protein, change
the metabolism of cell and
gene expression.
Neural
acetylcholine、
transmitter glutamic acid、Υ–
amido-butyric acid.
Growth
factor
Hormone
protein、polypeptide
and amino acid
ramification and so on
hormone、steroid
hormone、thyroxine.
Membrane
receptor
intracellular
receptor
Ditto.
Effect the transcription of
genes.
Ⅱ、Intracellular signaling substance
* Definition
Chemical substance which is transmiting
cell regulation signals within the cells .
* Chemical property:
Inorganic ions： Ca2+
Derivative of lipid ：DAG、Cer
Derivative of saccharide: IP3
nucleotide：cAMP、cGMP
signal protein molecule
※
Secondary messenger
Small molecules which are used to
transduce information within the cells.
For instances：
Ca2+、DAG、IP3、Cer、cAMP、
cGMP and so on .
Section 2
receptor
※ Receptor
Receptors are proteins, anchored in
cell membrane or in the cells, which
can recognize and bind with specific
biological active molecules, and result
in biological effect.
※ Ligand
biological active molecules which can
bind with receptor are named as ligand.
Intracellular receptor
The receptors located in the cytosol
and nucleus are all DNA binding
proteins.
Membrane receptor
Large number of the receptors located
on the plasma membrane are enchasing
glycoprotein 。
Ⅰ.Classification, structure and
function of receptors
1. Membrane receptor
A. circular receptor——the ion channel
dependent on the ligand
Acetylcholine
receptor
B. -helix receptor with seven
transmembrane fragments
—serpentine receptor
G protein
couple region
※ GTP/GDP binding protein
（G protein）
G protein, which is combined with GTP
or GDP, is a kind of peripheric protein
which is located on the cytosolic face of the
plasma membrane. It is composed of three
subunits: 、、.
G protein has two conformations ：
inactive state; active state.
Inactive
Active
G protein cycle
Signal transduction mediated by this
receptor can be reduced to：
hormone
receptor
G protein
enzyme
second messenger
Protein kinase
Enzyme or other
functional protein
biological effect
G proteins in the process of
the signal transduction
Type of G protein
Gs
-subunit
Function
s
S timulating AC
Ｇi
Ｇq
ｉ
q
Ｇo*
o
Transportor
Ｔa
AC: adenylate cyclase
PLC: phospholipase C
Inhibiting AC
PLC stimulating specifically
phosphoinositol
In brain the main G protein
which can regulate the ion
channel
Stimulating vision
C． -helix receptor with single
transmembrane fragment：
IgG-linked
sequence
membrane
TPK
EGF-R
IgG: immunoglobulins
Tyrosine protein kinase-linked receptor：
Receptor has the activity of tyrosine protein
kinase after binding with ligand. For instance:
insulin receptor IGF-R epithelium growth
factor EGF-R）
Receptor not linked with tyrosine protein kinase：
Receptor is linked with tyrosine protein kinase
after binding with ligand so to produce the
activity of TPK. For instance: growth hormone
receptor, interferon receptor.
Autophosphorylation：
Some receptors with a single transmembrane
fragment have the activity of catalysis. When
they bind with ligand, they will form a
receptor-dimer. The TPK in each monomer
will be activated, and phosphorylate their
counterpart in dimer. This process is known
as autophosphorylatoin.
Acting mechanism of EGF:
2. Intracellular receptor
A． Structure of receptor
ＮＨ2
COOH
Highly DNA
variable binding
domain domain
hormone
binding site
B. Correlated ligand ——
Steroid hormone, thyroxine and
retinoic acid and so on
C. Function ——
Most of intracellular receptors are
trans-acting factors. After binding to
the corresponding ligands, they can
bind with DNA cis-acting elements to
regulate gene transcription.
Ⅱ 、acting characteristic of receptor
• High specificity
• High affinity
• Saturability
• Reversibility
• Specifically
acting mode
Ⅲ、Regulation of the activity of
receptor
•Influence of phosphorylation and dephosphorylation
•Influence of metabolism of membrane lipid
• enzymatic hydrolysis
•Regulation of Ｇprotein
section 3
The pathway of signal
transduction
Signal transduction mediaed intracellular receptor：
Signal transduction mediaed membrane receptor：
1. Signal transduction mediated
by membrane receptor：
– The pathway of cAMP-protein kinase
– The pathway of cGMP-protein kinase
– The pathway of Ca2+-dependent protein
kinase
– the pathway of tyrosine protein kinase
– the pathway of nuclear factor  
A. The pathway of signal transduction
mediated by cAMP-protein kinase A
a、constituents：
Extracellular signaling molecules
（mainly are glucagon、adrenalin
and adrenotrophin）.
Receptor，G protein，AC，cAMP ,
PKA
b． Synthesis and degradation of cAMP ：
ATP
ＡＣ
phosphodiesterase
cAMP
5`-AMP
Mg2+
Mg2+
PPi
H2O
NH2
N
O
O
O
HO P O P O P O CH2
OH
OH
N
N
(Adenylate cyclase, AC)
N
O
OH
NH2
N
N
OH OH
ATP
O
NH2
N
N
O
HO P O CH2
N
O
O
CH2
P
O
N
O
N
OH
OH
cAMP
N
OH
AMP
OH OH
(Phosphodiesterase, PDE)
C．Acting mechanism of cAMP：
cAMP
C
R
C
R
＋ 4cAMP
C
C
R
cAMP
R
cAMP
＋
cAMP
•Activates of cAMP protein kinase
Ｃ：catalytic subunit
Ｒ： regulation subunit
（cAMP-dependent protein kinase，PKA）
Serine/threonine protein kinases family
R：regulation subunit
C：catalytic subunit
D．Effect of PKA ：
（a） regulation on metabolism
realize the regulation by
phosphorylating the effector proteins.
UDP
glycogen
n+1
Pi
glycogen
synthase
UDPG
phosphorylase
PPi
UTP
G-1-P
G-6-P
Glu
adrenalin＋receptor
ATP
adrenalin · receptor
complex
PPi
phosphoprotein
phosphatase
PKA
⊕
Activating
Ｇ-protein
ATP
phosphorlatase
kinase a
phosphorylase ｂ
Activating AC
ATP
phosphorlatase
kinase b
PPi
cAMP
phosphorylase ａ
H2 O
phosphoprotein
phosphatase

⊕
inhibitorＩb
PKA
Effection of Adrenalin on the
metabolism of glycogen
ATP
phosphoprotein
phosphatase
inhibitorＩa
PPi

Phosphorylation of substrate protein by PKA
substrate
histone
ribosome
Protein
results of
phosphorylation
lose repression
on transcription
promote
translation
physilologocal
significance
promote transcription
and synthesis of protein
promote the synthesis
of protein
membrane
protein
change of conformation
and function of membrane
change of permeability
ion channel
tubulin
change of conformation
and function
influence the secretion
function of cells
myogen of
cardiac muscle
eacy to bind with Ca2+
enhance the contraction
cardiac muscle
（b）Regulation effect on gene
expression
In transcription regulatory region of the genes
regulated by cAMP, there is a consensus sequenc
（TGACGTCA）which is known as cAMP
response element (CRE).
cAMP response element binding protein (CREB)
can interact with CRE to regulate the transcription
of the gene.
cell membrane
nucleus
membrane
（二）the pathway of Ca2+-dependent
protein kinase
1. The pathway of Ca2+－phospholipid
dependent protein kinase
(1) Second messenger： DAG，IP3
*
The production of
PIP2
PLC
DAG，IP3:
DAG + IP３
lecithin
phosphatidic acid
phosphatidic acid
hydrolase
Regulation of
metabolism
Gene expression
Ca2+-DAG-PKC pathway
* Function of DAG，IP3 ：
DAG：
DAG, phosphatidylserine and Ca2+ cooperate
to activate PKC by allosteric effect.
IP3 ：
bind to the receptor on endoplasmic reticulum
so to promote the release of Ca2+.
(2) Structure and function of PKC
Structure and typing:
There are four conservative regions of
amino acid sequence (C1, C2, C3, C4 ) and
variable regions（Ｖ），dividing into
regulation region and catalytic region.
C1： Cys-rich
regulation
region
catalytic
region
DAG binding site and
TPA binding site
C2： Ca2+ binding site
C3： ATP binding site
C4： substrate binding,
site of transfer of phosphate
group
Ca2+-dependent type：，，
classificati
on
Ca2+ non-dependent type： 、、、、
C1
C2
C3
regulatory
region
C1
C3
C4
C4
catalytic
region
，，
、、、
C1
C3
C4

* The function of physiology of PKC
① Regulating metabolism
The activated PKC cause a series of
phosphorylation of Ser, Thr residues of
target proteins.
Target proteins include：
Membrane receptors,
Membrane proteins and various enzymes.
② Regulation on gene expression：
The activation of genes by PKC
include early response and late
response.
c-fos Early
activation
PKC
signal
receptor
AP1 / c-jun
mRNAs
Pi
Pi
Late
activation
Pi
C-fos
Pi
5’TGACTCA3’
AP1/C-jun
nucleus
TRE
Cell membrane
Early activation and late activation of genes by PKC
DNA
2. The pathway of Ca2+-CaM-dependent
protein kinase
(the pathway of Ca2+-CaM kinase )
(1) constituents：
receptor, G protein, PLC, IP3, Ca2+,
calmodulin, CaM-kinase
calmodulin (CaM)
CaM has four Ca2+-binding sites. CaM and Ca2+
work together to activate CaM-kinase, and
phosphorylate many proteins (Ser/Thr residues).
三、The pathway of cGMP-protein kinase
1. constituents：
Receptor，Guanylate cyclase (GC ) ，
cGMP, PKG
2、Synthesis and degradation of cGMP
GTP
GＣ
Mg2+
PPi
phosphodiesterase
cGMP
H2 O
Ca2+ or Mg2+
5′- GMP
3、function of PKG
Phosphorylate Ser/Thr residues of proteins or
enzymes
hormone
R
G protein
Cell membrane
GC
GC
GTP
NO
cGMP
PKG
phosphorylation
of proteins
四、The pathway of tyrosine protein kinase
（ tyrosine – protein kinase , TPK ）
Classificatoin:
Receptor-TPK（on cell membrane）
for instance: insulin receptor, growth facter receptor, and
receptors coded by proto-oncogenes (erb-B, kit, fins etc.)
Non-receptor-TPK（in cytosol）
such as JAK and TPK coded by proto-oncogenes（src, yes,
bcr-abl）
1. Receptor-TPK-ras-MAPK pathway
1、constituents:
catalytic receptor, Grb2, SOS , Ras protein, Raf protein,
MAPK system
Grb2 (growth factor receptor bound protein 2)
SH2
SH3
SH2 domain ( src homology domain 2) ：
SH2 is the consensus amino acid sequence in some linking
proteins in cells. SH2 domain is homologous to tyrosineprotein kinase region coded by proto-oncogene src. This
region can recognize and bind the phosphorylated tyrosine
residue.
Ras：product of proto-oncogene，similar to G
subunit of G protein
SOS（son of sevenless)：
Proline-rich，can bind to SH3, and promote the
conversion of GDP in Ras to GTP.
Raf protein：has the activity of Ser/Thr protein
kinase.
MAPK system（mitogen-activated protein kinase)：
Include MAPK, MAPK kinase (MAPKK), MAPKK
kinase (MAPKKK)，a group of proteins which are
both enzymes and substrates.
extracellular signal
EGF、PDF and so on.
PTK-linked active receptor
dimer
Ras-GTP
GRB2 SOS
Cell
membrane
Raf P
MAPKK
nucleus
trans-acting factor
P
MAPK
P
P
Regulation of gene expression
Regulation of other proteins activated
unactivated receptor
unactivated Ras
activation of receptor
activation of Ras
Other enzyme effector
kinases system
The activation of Ras protein and its action in signal transduction
outside
of cell
inside of
cell
dimerization
Cell
membrane
cytosol
Activation of PDGF receptor and signal transduction
2. The pathway of JAKs-STAT
form：noncatalytic receptor；JAKs;
signal transducer and transcription
activator （STAT）
（ 五）The pathway of
nuclear factor Ｂ
nuclear factor-  B (NF- B) :
TNF
Cer etc. kinase system
Infection by virus,
lipidsaccharide, active
oxygen intermediates
and so on
Activation of NF- B
• Sketch map of activation
pathway of NF- B
the pathway mainly involves the signal
transduction in the process of body defence
response, tissue damage and stress,
differentiation and apoptosis, and inhibitation on
the growth of tumor.
Ⅱ、Signal transduction mediated
by intracellular receptor
• Intracellular receptor：
nuclear receptor
cytosolic receptor
• ligand：
steroid hormone
thyroxine
section 4
crosstalking of signal
transduction
• Member of one signal pathway can join to
activate or inhibit another signal pathway.
• Two different signal pathway can together
effect on same effectic proteins or same
regulatory region of gene to bring into play
effection.
• A kind of signal molecule can effect on
several pathways of signal transduction.
section 5
signal transduction and disease
* Familial hypercholesterolemia：deficiency of
LDL receptor
* insulin-independent diabetes mellitus：
decrease of insulin receptor or deficiency of
function
* others:
For instance: cholera and pertussis are related to the
abnormality of G protein.
summary
•
Basic concepts
Signaling substances：classification，concept
receptor： concept， types，
characteristics of interaction with ligand
Second messengers
•
Important signal transduction pathway