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Chapter 15
Cellular Signal Transduction
The biochemistry and molecular biology department of CMU
2. Intracellular receptor (transcription regulated recepto
r) Intracellular R is trans-acting
elememt cis-acting element gene expression
Localized in the cytosol and/or in the nucleus.
ligand: Steroid H, VD3, Thyroxine
3. Properties of binding of H and R
• highly specificity
• highly affinity
• saturation
• reversible binding
• special function model
4. Control of receptor activity
• Phosphorylation or dephosphorylation of R
• Phospholipid of membrane
• Enzyme catalyzed hydrolysis
• G protein regulation
(1) Recognize the special ligand
(2) Binding to special ligand
(3) Signal transduction biological effect
5. Function of receptor
§3 Pathway of Signal
Transduction
Signal transduction mediated by membrane receptor
• cAMP dependent-protein kinase A pathway
• cGMP dependent PKG pathway • Ca2+ dependent PK pathway • Tyrosine protein Kinase pathway
• NF-κB pathway • TGF- βpathway
1. cAMP dependent-protein kinase A pathway
H R
G protein
Phosphorylation of Es or functional proteins
Biological effects
PKA
cAMPAC
(1) cAMP metabolism
ATPMg2+
PPi
cAMP
H2OMg2+ 5'-AMP
AC PDE
AC : Adenylate cyclase
PDE : Phosphodiesterase
PDE
H2O
N
N N
N
NH2
O
H
OHOH
CH2
H
H H
OPO
O
O
PO
O
O
P
O
O
O ATP
ACPPi
N
N N
N
NH2
O
H
OHO
CH2
H
H H
O
PO
O
cAMP
N
N N
N
NH2
O
H
OHOH
CH2
H
H H
OPO
O
O
5'-AMP
(2) Mechanism of cAMP effect
Activate cAMP-dependent protein kinase (PKA).
(3) PKA effect
Phosphorylate specifically Ser/
Thr residues in several proteins
( 1 ) Regulation of metabolism
( 2 ) Regulation of gene e
xpression
hormons: glucagon, epinephrine
inactive AC active AC
ATP cAMP
inactive PKA active PKA
phosphorylase b kinase
phosphorylase b kinase
P
ATP
ADP
H2O
Pi
phosphorylase b
P
P
ATP ADP
Pi
H2OATP ADP
glycogen synthase
glycogen synthase
P
H2OPi protein phosphatase-1
(active) (inactive)
inhibitor-1 (active)
inhibitor-1 (inactive)
phosphorylase a
ATP
CRE : cAMP response element (T
GACGTCA)
CREB: CRE binding protein
DNACRE
CREB
PKA
P
Transcription
mRNA
CREB
PKA
P
CREBP
CR
EBP
CR
EB
P
CREBP
CR
EB
P
CR
EB
P
2. Ca2+ dependent PK pathway
(1) Ca2+ -DAG -dependent PKC pathway
H R
PIP2
G protein PLC
IP3 DG
ERPKC
Ca2+ PS
Biological effects
Phosphorylation of Es or functional proteins
[Ca 2+]i 0.01-1 mol/L ( 10-7 mol/L )
[Ca 2+]o 2.5mmol/L ( 10-3 mol/L )
5000~10000×
1 ) Function of DG and IP3
IP3 + R→open of Ca2 + channel →[Ca2 + ]↑
PS, Ca2 +DG PKC ↑
2 ) Function of PKC
• regulation of metabolism
PKC →Ser/Thr-P of R, enzyme,
Protein of Mb.
• Gene expression
Late response:
Trans-acting factor-P
Third messengerImmediate early genes
Third messenger-P
Activate genes
Cell proliferation
PKC
PKC
Early response:
(2) Ca2 + -CaM dependent protein kinase pathway
H R G protein PLC
IP3
Ca2+ CaM
CaMK
Biological effects
Phosphorylation of Es or functional proteins
Calmodulin (CaM ): Ca2 + binding protein
4 Ca2 + + CaM → Ca2 + - CaM
↓ CaM kinase↑
↓ Ser/Thr - P ↓
Ca2 + pump, AC ↑ GC ↑
Es (glycogen synthase, phosphorylase kinase)
3. cGMP-dependent PKG pathway
Biological effects
Phosphorylation of Es or functional proteins
ANPNO, CO
Soluble GC
PKG
cGMPReceptor-linked GC
(1) cGMP
(2) Function of PKG
Ser/Thr- P of protein and E
Mg2+
PPi H2O
Mg2+GTP cGMP 5'-GMP
GC PDE
GC: Guanylate cyclase
ANP ( atrial natriuretic peptides ) ↓
GC NO
↓
cGMP
↓
PKG
↓
Vascular dilatation
cis-acting elementnucleus
expression
cell memberane
phosphorylation of enzymes or proteins effects
CaM-PK
Ca2+-CaMCa2+
IP3DGcAMP cGMP
PKA PKG PKC
ATP GTP PIP2(PC)
G AC GC G PL
peptide hormonesneurotransmitters AFP
neurotransmittershypothalamic pituitrin
Ptrans-acting factor
4. Tyrosine-protein kinase pathway (TPK)
• TPK receptor is related to proliferation, differentiation, dissociation, carcinomatous change.
• TPK:receptor TPK : Mb.
non receptor TPK : cytosol
(1) Receptor TPK - Ras - MAPK pathway
• GRB2, SOS, Ras, Raf
• Small G protein: Ras
• MAPK (mitogen-activated protein kinase):
MAPK、MAPKK、MAPKKK
ÊÜÌå ÐÍTPKϸ°ûĤ
EGF, PDGF
receptor TPK Ras - GTPSOS - PGRB2 - P
Raf - P
MAPKK - P
MAPK - Ptrans-acting factor
expression
nucleus
- P
(2) JAKs - STAT pathway
ligand
non TPK receptor
JAKs STAT
gene expression
• JAKs
• STAT: Signal transductors and activa
tor of transcription
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»ùÒò
£ PP£
JAK
11391
84
48
113
P
91P 84 P
48
113
91 84P P
P
interferons
inactive STAT
Plasma membrane
STAT complex
Nuclear membrane
geneInterferons response element
transcription
Dimerization of Receptor
Interferon
Autophosphorylation of JAK
Phosphorylation of STAT
Nuclear translocation of STAT
Interferon response element
Expression of gene
5. Nuclear factor-κB pathway
6. TGF-βpathway
Intracellular receptor (DNA transcription regulated
receptor)
• Steroid H, VD3, Thyroxine
• Cytosolic R: glycocorticosteroid H
• Nuclear R: thyroxine, estrogen, androgen, progesterone
Serum binding proteinWith bound bormone