Cell signal transduction

& diseases

Zhao Mingyao
BMC.ZZU
2006-5-27
 Cell signal transduction
& diseases

                                                                         

Zhao Mingyao
BMC.ZZU
2006-4-11
 BODYBUILDING
Mechanic
pressure
stimulation

signal
cell signal transduction
cell change
signal
Proliferation
Differentiation
Metabolism
Function
Stress
Apoptosis
oror lossdisease
 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

Structure and function of GTP-binding(G)
1994 A. Gilman, M. Rodbell M&P
proteins
Alteration of enzyme activity by
1992 E. Fischer, E. Krebs M&P
phosphorylation/dephosphorylation

Mechanism of hormone action and cyclic

1971 E.W. Sutherland M&P
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
 Studying line
1. signal constitution
2. signal transduction
3. pathophysiology of CST: related diseas
es such as tumor , inflammation , aids, Al
z
4. treatment
 part1 cell signal constitution

(1)Extracellular signal
Chemical: lipid-soluble & water-soluble
Physical: mechanical, light, electrical

(2)Intracellular signal
Enzyme, protein, ion, lipid
(3)Second messenger
cAMP
Ca2+
DAG(1,2-diacylglycerol)
NO, CO
ceramide, phosphocholine
Alteration of Ca2+ concentration in plant cell
after stimulation of red light
 (4) enzyme components

1)Phospholipase(PL) ~ : PLA2, C, D, SMase (sphingomyelinase)

2)phosphatidylinositol kinase ~: PI-3K, PI-4K, PI-5K
3) Tripolymer GP & Small GP: GP(G) = GTPase
4) Protein kinase & Protein phosphatase: PSTK & TPK or PTK
Protein kinase & Protein phosphatase

• Protein kinase: protein serine/threonine kin

ase, ( PSTK ) & tyrosine protein kinase ( T
PK or PTK )
Protein phosphatase : PSTP & PTP

P*/-P
P*/-P

e r hr
r
S T
Ty
(5) Receptors ( membrane ~ & nuclear ~)
1. ionotropic ~
2. GPCR (metabolism type R)
3. ~ tyrosine protein kinase >20 families
4. TPK-linking ~
5. PSTK ~ (protein serine/threonine kinase)
6. TNF ~ > 10 members
7. Guanylyl Cyclase ~
8. Cell adhesion molecule(CAM) >5 families
9. Nuclear ~
Receptor-mediated function
1. ionotropic ~: + neurotransmitter , ion
2. GPCR: metabolism , function modulation
3. ~ TPK: +insulin, GH
4. TPK-linking ~ : cytokine, antigen, some CAM
5. PSTK ~ : TGF-β
6. TNF ~ : apoptosis, NF-kB
7. Guanylyl Cyclase ~: vasodilation, excreting Na + urine
8. CAM : communication between cells
9. Nuclear ~: transcription regulatory factor
Part 2 signal transduction pathway
signal transduction pathway
introduced by membrane receptor

tmd
emd
imd

Recepter
Glycoprotein
introduced by membrane receptor

Up stream

Down ~

DNA
ligand

End effector
 channel
Effect protein Transporter
PL C


E 
E


GTP
GDP

Neucler receptor

DNA
Major pathway

of cellular signal transduction

GP ～ : AC~ , PLCb~
TPK ～ : RTPK~, non RTPK~,
GC (guanylyl cyclase) ～
Nuclear receptor ～
 1. signal transduction pathway
introduced by GP receptor

GP

DG-PKC
AC PLC β

IP3 、 Ca2+-CaMK
1,2-diacylglycerol
 Tripolymer GP & Small GP

GP(G) = GTPase
GTP GDP
Small GP: Ras family,Rho ~, Rab ~
GEF +
Small GP
GAP -
signal transduction pathway introduced by GP -R
β-R α2-R ， M-R α1-R ， ET-R

Gsα Gi
Gqα

+ - + +
AC  PLCβ

cAMP
PIP2 IP3

PKA DAG(DG)

Target Pro Ca2+ released

phospho Targetgene
transcription PKC
Target Pro
phospho
 2. signal transduction pathway
introduced by TPK
(1)Receptor tyrosine protein kinase~, RTPK pathway
(2) nonRTPK pathway (PTK-linking receptor ~)
(1)Receptor tyrosine protein kinase pat
hway, RTK (20 types)

TPK

Ras-MAPK
PLC-PIP2 PI3K
Proliferation
differentiation
RTPK pathway (>20 types)
Insulin, IGF
GF

>50 kinds

TPK

Grb2 PLC
PI3K
Sos
PIP2 IP3
PKB
Ras DAG

Raf PKC Ca2+ -MK

Target pro
phosphorylation MEK Transcriptional factor
phosphorylation DNA
(2)nonRTPK receptor

IL 、 IFN 、 erythropoietin （ most cytokine ）

JAK
JAK JA
K
FAK PTK in Src family
PTK phosphorylation

STAT
inducing transcription express of regulating gene

DNA response element

cellular phenotype
change
JAK-STAT Pathway
3. signal transduction pathway
introduced by GC
Vascular GC signal transduction system

cytokines
CO
Ca2+ GTP
R
sG GC
NO synthas
Ach-R C cGM
e
arg NO P PKG
Vascular ?
dilation
NO
VEC VSMC
4. ~ pathway introduced by
intracellular and nuclear receptor
Nuclear receptor located in cytoplas
ma or nuclear, as ligand-dependent tr
anscription factor

GC, Mineralo~, gonadal H;

Steroid hormon-R in cytoplasma except estrogen;
bind to HSP

T3,Vit D, Tretinoin;
Thyroxine hormon-R
Dimer; in ?
bind to pro or DNA
 检测活细胞激酶活性
Src 和 EGFR 介导着信号从膜上到细胞中心的过程
Section 2. pathophysiology of CS
T
Etiology and pathogenesis
(1) Gene mutation
(2) Abnormal function of immune
(3) Secondary abnormality
 (1) Gene mutation
signal pro
amount :↓ or↑
function : ↓, or↑
structure : domain ;deactivated;
continually activated; dominant
negative effect
(2) Abnormal function of immune

Self-antibody against Signal Pro

 (3) Secondary abnormality
• Blood pH
• ion concentration
• ATP
• hormone
receptor up-regulation or down-regulation
receptor hypersensitivity or desensitization
Section 3 dysfunction of cell
abnormal signaling in disease
 1.Aberrent first messenger ( signal
molecules) in diseases
• Ligand : drug or hormone
• Insulin: type I
• Growth factors
• TSH
• Autoantibody: hyperthyroidism and hypoth
yroidism
 2.Aberrent receptors in diseases

• Receptor up-regulation/hypersensitivity
• Receptor down-regulation/desensitization
(1)receptor gene mutation
(2)secondary receptor deficit
deficit
 3. Aberrent G-proteins
• (1)cholera
• (2)pertussis
• (3) psudohypoparathyroidism ( PHP )
• (4)acomegaly and gigantism
(1)cholera
Action of cholera toxin. A, B (cholera toxin subunits); GM1
(GM1 ganglioside receptor); Gs (G protein); AC (adenyla
te cyclase); Gi (G protein); cAMP (cyclic AMP); CFTR (cy
stic fibrosis transmembrane conductance regulator).
 Cholera toxin , CTX
Cl- 、 H2O





GTP cAMP
CTX GDP
Leads to ribosylation of Ar AC
g201 in Gsα _
Gsα+GTP ATP
(2) Pertussis (whooping cough)
 Pertussis toxin

Inhibit release and activity

Gai Catecholamine overreaction

Ribosylate a cysteine Hypersensitivity to histamine,

insulin over-secretion

? ?
 Pertussis US Age Demographic

United States (1978-

81)
Age Groups United States
(Years) (1997-2000)

<1 53.5 29.4

1-4 26.5 11.1
5-9 8.2 9.8
10-19 5.4 29.4
>15 6.5
>20 20.4

The seeming reemergence of Pertussis infection substantiates

the need to evaluate and update current efforts for keeping
worldwide whooping cough in check
 (3) pseudohypoparathyroidism (
PHP )

PHP is a genetic disorder that

resembles hypoparathyroidism
(lowered levels of parathyroid h
ormone) but is caused by a lack
of response to PTH rather than
a deficiency in the hormone itsel
f.
 PHP

Type 1A : one-gene mutation in Gsα; with

hormone resistance relate to AC
（ TSH 、 LH 、 FSH ）
Type 1B ： Gsαnor 、 only resistant to
PTH
 (4) acromegaly
and gigantism
• A chronic disease of adults marked by enl
argement of the bones of the extremities, f
ace, and jaw that is caused by overactivity
of the pituitary gland
• excessive size; usually caused by excessi
ve secretion of growth hormone from the p
ituitary gland
acromegaly Child ?
and gigantism proliferation

+ AC cAMP
GHRH Gs GH secretion

Mutation,
Arg201or Gln227
Adult?
osteoepiphysis
 4. Aberrent intracellular signaling

• Ca2+
• NO
• NF-kP
5.Mutiple signaling aberration
 (1)type 2 diabetes mellitus

• 1)insulin receptor disorders

• Gene mutation
• Autoimmune lesion
• Secondary receptor abnormality
2)disorders in post-receptor
signal transduction
(1) Insulin-resistant diabetes
abnormal receptor, deficiency behind
receptor

Glucose -carry

PTK
insulin Glycogen thynthase

Cellular proliferation
 P85/p110

mutation
(2)cancers
malignant tumor
Biological features
• hyperproliferation
• hypodifferentiation
• hypoapoptosis
• metastasis

•Cell division cycle deregulated

•Invasion and metastasis
Cellular canceration
total features
multifactors , multisteps, multigenes

Colon cancer as a model

From normal cell to cancer cell
 Cellular canceration
• Proto-oncogene: over-expression,mutation
• Tumor depressor gene:mutation, loss, low-
expression
• DNA repair gene: mutation, loss, incorrect
repair (polβ)
Signal theory about cellular canceration

positive modulating > negative modulating

positive signal > negative signal

Signal theory of canceration

+
+
+
+ +
proliferation differentiation
+
+ apoptosis
+

cell

oncogene tumor depressor gene

DNA repair gene Apop-related gene
p53
 Mechanism of Cellular canceration :
positive signal ↑↑
• 1 、 expressing GF-like substances
sis ≈ PDGFβchain
Int-2 ≈ fibroblast growth factor
2 、 expressing GF-R kind protein

erb- β encoding EGF-R ,

though without ligand binding domai
n but continually activating prolifera
tion signal of downstream
 3 、 expressing PK kin
d
Encoding nonreceptor PTK or PS/TK

Src products contain higher activity of T

PK
 4 、 expressing signal
transduction molecule kinds
• ras : 21000, small GP, ras binding to
GTP under the catalyzing of sos, activ
ating downstream
• Varied ras with GDP binding rate ↑ or
GTP enzyme activity ↓, ras activate
d continually
• colon cancer, bladder ~, breast ~, pan
creatic ~,
 GF

TPK*** Mutation ,
Activation
Grb2 PLC (up-regulation)
PI3K
Sos
PKB
Ras

Raf PKC

Pro P* MEK
TF P* DNA
 Activated
Phospholipase C
induces a chain of
phosphorylation
events and
 5. expressing internuclear protei
n kinds

• Myc, Fos, Jun located in nuclear

• transcription factor
• jun and fos binding with AP-1 site on
DNA
negative signal (Tumor suppress gene product )

keep cell in G1 phase(arrest)

or following specific program
to differentiate
to be senile
to be apoptosis
6.Relationship between stimulants
and pathological effects
• Signal pathway cross-talk
• Receptor cross-talk
(1)Epinephrine
β-R α2-R ，

Gsα Gi

+ -
AC 

cAMP

PKA

Target Pro
phospho Targetgene
transcription
 (2)Endotoxin
α1-R ， ET-R
Epinephrine
β-R

Gqα Gsα
+ +
PLCβ AC

PIP2 cAMP
IP3
PKA

DAG(DG) Ca2+
Ca2+
KCa pump
CaMK
MLCK
PKC
[Ca2+]
myosin

A-V shunt
Artery contraction
(3)Myocardial hypertrophy
Mechanic stimulation
Ang-II PDGF

integrin
Gqα
+ TPK
PLCβ Src
Grb2 PLC
PIP2 Src
Sos FAK
IP3

Ras
DAG(DG) Ca2+

Raf ERK
MEK
AP-1 SRF
PKC
Pro P*
DNA
Section 4 principles of treatment
• first signal
• receptors
• intracellular messenger & transducers
• nuclear transcription factors
 1.regulating first signal
Ach: inhibiting cholinesterase in Alzheimer
disease;
L-Dopa: Parkinson disease
HE: decrease GABA
ACEI: Pulmonary hypertension
 2. regulating the structure and
function of receptors
• Agonist & Antagonist
• Hypoxic pulmonary hypertension:
a1-R Antagonist and ET-R Antagonist
• Gene mutation: gene therapy
3.regulating the level and modifications of
intracellular messenger molecules and transducers

• Ca2+ : Ca2+ channel blocker

• cAMP: β-R antagonist,
inhibitor of phosphodiesterase
• α
4.regulating the level of nuclear
transcription factors
• NF-κB: ?

key tache of inflammation

•

This is signal of class ending

Our nerves become relaxed

due to this signal