Cell signal transduction

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Cell signal transduction diseases
moon rover
Zhao Mingyao BMC. ZZU
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cell signal transduction
specific response
cell
signal
Proliferation Differentiation Metabolism Function
Stress Apoptosis
? or ? or loss ? disease

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1. Signal constitution
site feature
(1)Extracellular (2)Intracellular Chemical lipid-soluble water-soluble Physical mechanical, light, electrical Enzyme, protein, ion, lipid
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• (3)Second messenger
• cAMP, cGMP
• Ca2
• DAG(1,2-diacylglycerol)
• NO, CO, ?
• ceramide, phosphocholine

allosteric agent
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(4) Enzyme components

• ?Phospholipase(PL) PLA2, C, D, SMase
  (sphingomyelinase)
• ?Phosphatidylinositol kinase PI-3K, PI-4K, PI-5K
  / PTEN
• ?GP (Tripolymer Small ) GP(G?) GTPase
• ?Protein kinase phosphatase PSTK TPK or PTK
• ?AC, GC/ cyclic nucleotide phosphodiesterase
  

phosphatase and tensin homolog deleted on
chromosome ten (PTEN)
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(5) Receptor and its function

• 1. ionotropic neurotransmitter , ion
• 2. GPCR metabolism , function modulation
• 3. TPK insulin, GH
• 4. TPK-linking cytokine, antigen, some CAM
• 5. PSTK TGF-ß
• 6. TNF apoptosis, NF-kB
• 7. Guanylyl Cyclase vasodilation, excreting
  Na urine
• 8. CAM communication between cells
• 9. Nuclear transcription regulatory factor

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2. Signal transduction pathway
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Major pathway

• of cellular signal transduction

GP
TPK
GC (guanylyl cyclase)
Nuclear
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(1) Signal transduction pathway
introduced by GP receptor
GP

DG-PKC

PLC ß
AC
IP3?Ca2-CaK
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•    ß-R a2-R,M-R
  a1-R,ET-R
• Gsa Gi
  Gqa
• AC PLCß
• cAMP PIP2
  IP3
• PKA DAG(DG)
• gene PKC

Cori, 1947
Gilman 1994

-

???
?
cGMP?
Sutherland 1971
Murad 1998
Pro
glycogenolysis
Edmond H. Fischer
Krebs 1992
GPCR signal pathway
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Mechanism of GP
GP(G?) GTPase
GDP
GTP
off
on

GEF
Small GP (G?)
-
GAP
guanine-nucleotide exchange factor
GTPase activating protein
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signal transduction pathway introduced by GP -R
ß-R a2-R,M-R
a1-R,ET-R
Gi
Gsa
Gqa



-
???
AC
PLCß

cAMP
PIP2

•     

IP3
PKA
DAG(DG)
Ca2 released
Target Pro phospho
Targetgene transcription
PKC
Target Pro phospho
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Cholera toxin, CTX
Cl-?H2O
?
?
?
GTP
cAMP
GDP
CTX leads to Gsaarg201 ADP-ribosylation
AC
ATP
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Pertussis toxin, PTX
?
?
?
Gia
PTX leads to Gia ADP-ribosylation, blocks its
activation

-
AC
PLCß
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(2) signal transduction pathway introduced
by TPK

• Receptor tyrosine protein kinase, RTK (20 types)
• PTK-linking receptor

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1)Receptor tyrosine protein kinase, RTK (20 types)
TPK
Ras-MAPK
PLC?-PIP2
PI3K

Proliferation differentiation
20
GF
gt50 kinds
TPK
Grb2
PLC?

• PI3K

Sos
PIP2
IP3
PKB
DAG
Ras
Ca2
Raf
PKC
Target pro phosphorylation
MEK
Transcriptional factor phosphorylation
DNA

ERK
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Receptor Tyrosine Kinases

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2)PTK-linking receptor

• 
  
• 
  
  
• 
  
  
• 
  
  

IL?IFN?erythropoietin(most cytokine)

JAK
JAK
PTK in Src family
FAK
PTK
phosphorylation
STAT
inducing transcription
regulating express gene
DNA response element
cellular phenotype change
JAK-STAT Pathway
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(3) Signal transduction pathway
introduced by GC
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Furchgott
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cytokines
Furchgott found
CO
Ca2
GTP
R
GC

sGC
NO synthase
Ach-R
cGMP
arg
PKG
NO
Vascular dilation
?
VEC
VSMC
NO
Vascular GC signal transduction system
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(4) Signal transduction pathway introduced
by nuclear receptor

GC, Mineralo, gonadal H
Steroid hormon-R
in cytoplasma except estrogen R
bind to HSP

Thyroxine hormon-R
T3,Vit D, Tretinoin
Dimer in ?
bind to pro or DNA
? -R
as ligand-dependent transcription factor
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Crosstalk

• one or more components of one signal
  transduction pathway affect another

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3. Pathophysiology of CST

• Etiology and pathogenesis
• Structure and expression change of gene
• (2) Abnormal function of immune
• (3) Secondary abnormality

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(1) Structure and expression change of gene

• signal pro ( p53 )
• amount ?or?
• function ? or?
• structure(mutation) domain deactivated
• continually activated
• dominant negative effect

GF-GFR acromegaly and gigantism
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Hormone resistance syndrome
A disease caused by target cell reducing or
losing its response to the hormone, but the
hormone synthesis and secretion in normal
level
Nephrogenic diabetes insipidus
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Constitutive activation

• Receptor hyperactivation out of control
  due to gene mutation, also known as the receptor
  gaining functional mutation

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(2) Abnormal function of immune

• Self-antibody against Signal Pro

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• Stimulating Ab to the receptor for
  thyroid-stimulating hormone (TSH)
  Hyperthyroidism, proptosis (protrusion of the
  eyes globes),

Graves disease

• Blocking Ab to the TSHR
• Hypothyroidism, myxedema

Hashimotos thyroiditis
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(3) Secondary abnormality

• Blood pH
• Ion concentration
• ATP

Pulling on single molecules Nature ...
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• Receptor up-regulation or down-regulation

Receptor hypersensitivity or desensitization
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4.Abnormal signal transduction and disease
One or multiple pathways One or multiple steps
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(1) Insulin-resistant diabetes (type II)

• abnormal receptor, deficiency behind receptor

Glucose -carry
PTK
Glycogen thynthase
insulin
Cellular proliferation
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(2)Malignant tumor

• Biological features
• hyperproliferation
• hypodifferentiation
• hypoapoptosis
• metastasis

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Cellular canceration

• Proto-oncogene over-expression,mutation
• Tumor depressor genemutation, loss,
  low-expression
• DNA repair gene mutation, loss, incorrect repair
  (polß)

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Cellular canceration total features

• multifactors , multisteps, multigenes

Colon cancer as a model
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keep cell in G1 phase following specific
program to differentiate to be senile to be
apoptosis
Tumor suppress gene
negative signal
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(3) Autoimmune receptor disease

• 1) Ab against receptor structure change
• same
  antigen
• 2) Ab against specificity
• Stimulating Ab TSHR --- Graves disease
• Blocking Ab TSHR --- Hashimoto disease
• Blocking Ab nAchR --- Myasthenia gravis

chronic thyroiditis
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(4) Inflammation

• More cells, factors , complicated net
• LPS-R
• TNF-R
• IL-1R

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TNFa
R
SM
sphingomyelinase
SMase
PK
ceramide

?
I ? B
NF- ? B
NF- ? B
I ? B
P65
P50
Gene transcription
Cytokine, IM
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Immune in stress
Activation of NF-?B
inhibit
ß2-adr-R
ß-arrestin2
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(5) Cardiovascular disease
Myocardial hypertrophy
Myocardial Remodeling
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Mechanism of VSMC or myocardial Hypertrophy
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BODYBUILDING
Mechanic pressure stimulation
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5. Principles for Treatment

• ?To regulate ligands
• ?To regulate receptors
• ?To regulate intracellular messenger and
  transducers
• ?To regulate nuclear transcription factors

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Thanks
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