Signal transduction
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Transcript of Signal transduction
Cellular Signal Transduction
M.Prasad NaiduMSc Medical Biochemistry,Ph.D.Research Scholar
Monad——responds directly.
Multicellular organisms——signal through elaborate system of intercellular or intracellular communication , and consequently regulate functions of organisms.
Signaling molecule
Receptor of target cell
Intracellular molecule
biological effect
Signaltransduction
• Signaling molecules, which are released by signal-producing cells, reach and transfer biological signals to their target cells to initiate specific cellular responses.
protein & peptides: Hormone, cytokine
AA & its derivatives: Gly, Glu, adrenaline, thyroxine
Steroid: Sex Hormone, glucocorticosteroid
Fatty acid derivatives: prostaglandin
• Secreted by common cells.• Reach neighboring target cells by
passive diffusion.• Time of action is short.• Such as GF, PG
• Secreted by endocrine cells.• Reach target cells by blood
circulation.• Time of action is long.• Such as insulin, thyroxine, adrenalin
• Secreted by neuronal cells.• Reach another neuron by synaptic
gap.• Time of action is short.• Such as Acetylcholine (Ach),
noradrenaline
• Simple structure, half life is short and active in chemistry .
• Such as NO, CO.
• Act back to their own cells.• Such as GF, cytokine, interferon,
interleukin.
GAS MOLECULE
• Ca2+ ions
• DG, ceramide lipid derivatives• IP3 carbohydrate
derivatives
• cAMP cGMP nucleotides
• Ras, JAK, Raf proteins
Small molecules synthesized in cells in response to an external signal are the second messengers, which are responsible for intracellular signal transduction.
Such as Ca2+, DG, Cer, IP3, cAMP, cGMP
Third messengers are the molecules which transmit message from outside to inside of nucleous or from inside to outside of nucleous, also called DNA binding protein.
Receptors are specific membrane proteins, which are able to recognize and bind to corresponding ligand molecules, become activated, and transduce signal to next signaling molecules.
Glycoprotein or Lipoprotein
ligand A small molecule that binds
specifically to a larger one; for example, a hormone is the ligand for
its specific protein receptor.
(1) Ligand-gate ion channels type
(cyclic receptor)
ligand→receptor→ion channel open or close
1) 7-helices transmembrane receptor
Cytosolicside
Oligosaccharideunit
• G protein refers to any protein which binds to GDP or GTP and act as signal transduction.
• G proteins consist of three different subunits (, , -subunit).
• -subunit carries GTPase activity, binding and hydrolysis of GTP.
G protein Coupled Receptors• The human genome encodes more than 1000 GproteinCoupled Receptors (GPCR), that transducemessages as diverse as light, smells, taste, andhormones• An example is the beta-adrenergic receptor, thatmediates the effects of epinephrine on manytissues:…
Gs→ s→AC→cAMP↑
Gi→ i→AC→cAMP↓
Gq→ q →PI-PLC→IP3+DAG
Go→ o→ion channel
Gt→ t →cGMP PDE→cGMP→
Rhodopsin
Gs vs Gi vs Gq
Gs and Gi coupled to adenylate cyclase [cAMP] G q coupled to phospholipase C [Ca2+]
Gs vs. Gi
Regulation of Adenylate Cyclase Activity
Gs stimulates adenylate cyclase
Gi inhibits adenylate cyclase
e.g. epinephrine can increase or decrease intracellular cAMP concentrations,depending upon the receptor to which it binds
adrenergic receptors couple to Gs, whereas
2 adrenergic receptors couple to Gi
Glucagon
-adrenaline →s →AC↑
ACTH
-adrenaline
angiotensin Ⅱ
acetylcholine(M2 M4)
GF release inhibitory factor
→i→AC↓
Inhibition of Gs and Gi by Bacterial Toxins
Cholera toxin effects on Gs:ADP ribosylation of an Arg residuein the s subunit of Gs inhibition ofassociated GTPase activity
Pertussis toxin effects on Gi:ADP ribosylation of a Cys residuein the i subunit of Gi an inabilityto inhibit adenylate cyclase activity.
Thus, both toxins cause increasedintracellular cAMP concentrations!
© 2000 by W. H. Freeman and Company. All rights reserved.
• Tyrosine protein kinase Receptor (catalytic receptor)
IGF - R, EGF - R
• Non tyrosine protein kinase Receptor
Growth Hormone R, interferon R
Intracellularinsulin effectsCytosol
Insulin
Membrane receptor –ANP
Soluble receptor – NO, CO
(4) Guanylate cyclase (GC) receptor
Intracellular R is trans-acting element cis-acting element gene expression
Localized in the cytosol and/or in the nucleus.
ligand: Steroid H, Vit D3, Thyroxine
• 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
• cAMP dependent-protein kinase A pathway
• cGMP dependent PKG pathway
• Ca2+ dependent PK pathway • • Tyrosine protein Kinase pathway
• NF-κB pathway
H R
G protein
Phosphorylation of Es or functional proteins
Biological effects
PKA
cAMPAC
ATP
Mg2+
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
(3) PKA effect
Phosphorylate specifically Ser/Thr residues in several proteins
( 1 ) Regulation of metabolism
( 2 ) Regulation of gene
expression
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
(1) Ca2+ -DAG -dependent PKC pathway
H R
PIP2
G protein PLC
IP3 DG
ERPKC
Ca2+
Biological effects
Phosphorylation of Es or functional proteins
IP3 + R→open of Ca2 + channel →[Ca2 + ]↑ from ER
[Ca 2+]i 0.01-1 mol/L ( 10-7 mol/L )
[Ca 2+]o 2.5mmol/L ( 10-3 mol/L )
5000~10000×
Ca2 +DG PKC ↑
• regulation of metabolism
PKC →Ser/Thr-P of R, enzyme,
Protein of Mb.
• Gene expression
H R G protein PLC
IP3
Ca2+ CaM
CaMK
Biological effects
Phosphorylation of Es or functional proteins
Ca2 + binding protein 4 Ca2 + + CaM → Ca2 + - CaM
↓ CaM kinase↑
↓ Ser/Thr - P ↓
Ca2 + pump, AC ↑ GC ↑ Es (glycogen synthase, phosphorylase
kinase)
Biological effects
Phosphorylation of Es or functional proteins
ANPNO, CO
Soluble GC
PKG
cGMPReceptor-linked GC
(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
• TPK receptor is related to proliferation, differentiation, dissociation, carcinomatous change.
• TPK:receptor TPK : Membrane.
non receptor TPK : cytosol
• GRB2, SOS, Ras, Raf• Small G protein: Ras• MAPK (mitogen-activated protein kinase):
MAPK 、 MAPKK 、 MAPKKK
• MAPKs belong to a family of serine/threonine kinases (kinases add
phosphate groups to/phosphorylate other proteins)
• They participate in cell growth, differentiation, transformation,
apoptosis (controlled cell death) and others
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
• JAKs(JANUS KINASES)
• STAT: Signal transductors and
activator of transcription
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¸ÉÈÅËØÓ¦´ð Ôª¼þ
ºËĤ
»ùÒò
£ PP£
JAK
11391
84
48
113
P
91P 84 P
48
113
91 84P P
P
interferons & GH
inactive STAT
Plasma membrane
STAT complex
Nuclear membrane
geneInterferons response element
transcription
• Steroid H, VD3, Thyroxine
• Cytosolic R: glycocorticosteroid H
• Nuclear R: thyroxine, estrogen, androgen, progesterone
Effect by membrane receptors
Effect by intracellular receptors
Intracellular molecules
Extracellular molecules
Signal molecules
cAMP, cGMP, IP3, DG, Ca2+
Proteins and peptides:
Hormones, cytokines
Amino acid derivatives:
Catecholamines
Fatty acid derivatives:
Prostaglandins
Steroid hormones, Thyroxine, VD3