Cellular Signal Transduction

M.Prasad Naidu
MSc Medical Biochemistry,
Ph.D.Research Scholar

Monadresponds directly.
Multicellular organismssignal
through elaborate system of
intercellular or intracellular
communicationand consequently
regulate functions of organisms.



Signaling molecule
Receptor of target cell
Intracellular molecule
biological effect
Signal
transduction
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
Ca
2+
ions

DG, ceramide lipid derivatives
IP
3
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 Ca
2+
, DG, Cer, IP
3
,

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)
ligandreceptorion channel open or
close




1) 7-helices transmembrane
receptor



Cytosolic
side
Oligosaccharide
unit
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
Gprotein
Coupled Receptors (GPCR), that transduce
messages as diverse as light, smells, taste, and
hormones
An example is the beta-adrenergic receptor, that
mediates the effects of epinephrine on many
tissues:
G
s

s
ACcAMP
G
i

i
ACcAMP
G
q

q
PI-PLCIP
3
+DAG
G
o

o
ion channel
G
t

t
cGMP PDEcGMP
Rhodopsin

G
s
vs G
i
vs G
q


G
s
and G
i
coupled to adenylate cyclase [cAMP]
G
q
coupled to phospholipase C [Ca
2+
]
G
s
vs. G
i
Regulation of Adenylate Cyclase Activity
G
s
stimulates adenylate cyclase
G
i
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 G
s
, whereas

2
adrenergic receptors couple to G
i
Glucagon
-adrenaline
s
AC
ACTH
-adrenaline
angiotensin
acetylcholine(M
2
M
4
)
GF release inhibitory factor

i
AC
Inhibition of G
s
and G
i
by Bacterial Toxins
Cholera toxin effects on G
s
:
ADP ribosylation of an Arg residue
in the
s
subunit of G
s
inhibition of
associated GTPase activity
Pertussis toxin effects on G
i
:
ADP ribosylation of a Cys residue
in the
i
subunit of G
i
an inability
to inhibit adenylate cyclase activity.

Thus, both toxins cause increased
intracellular cAMP concentrations!
2000 by W. H. Freeman and Company. All rights reserved.

Tyrosine protein kinase Receptor
(catalytic receptor)
IGFR, EGFR

Non tyrosine protein kinase Receptor
Growth Hormone R, interferon R
Intracellular
insulin effects
Cytosol
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 D
3
, 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

Ca
2+
dependent PK pathway

Tyrosine protein Kinase pathway

NF-B pathway

H R
G protein
Phosphorylation of Es or functional proteins
Biological effects
PKA
cAMP AC



ATP
Mg
2+
PPi
cAMP
H
2
O
Mg
2+
5'-AMP
AC
PDE
AC Adenylate cyclase
PDE Phosphodiesterase
PDE
H
2
O
N
N
N
N
NH
2
O
H
OH OH
CH
2
H
H H
O P O
O
O
P O
O
O
P
O
O
O
ATP
AC
PPi
N
N
N
N
NH
2
O
H
OH O
CH
2
H
H H
O
P O
O
cAMP
N
N
N
N
NH
2
O
H
OH OH
CH
2
H
H H
O P O
O
O
5'-AMP
(3) PKA effect

Phosphorylate specifically
Ser/Thr residues in several
proteins
1Regulation of
metabolism
2Regulation 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
H
2
O
Pi
phosphorylase b
P
P
ATP
ADP
Pi
H
2
O
ATP ADP
glycogen
synthase
glycogen
synthase
P
H
2
O Pi
protein
phosphatase-1
(active) (inactive)
inhibitor-1
(active)
inhibitor-1
(inactive)
phosphorylase a
ATP
(1) Ca
2+
-DAG -dependent PKC pathway
H R
PIP
2
G protein PLC
IP
3
DG
ER
PKC
Ca
2+
Biological effects
Phosphorylation of Es or functional proteins
IP
3
+ Ropen of Ca
2

channel [Ca
2
] from ER
[Ca
2+
]
i
0.01-1 mol/L10
-7
mol/L


[Ca
2+
]
o
2.5mmol/L10
-3
mol/L


5000~10000

Ca
2
DG PKC
regulation of metabolism
PKC Ser/Thr-P of R, enzyme,
Protein of Mb.
Gene expression


H R G protein PLC
IP
3
Ca
2+
CaM
CaMK
Biological effects
Phosphorylation of Es or functional proteins
Ca
2
binding protein

4 Ca
2
+

CaM

Ca
2
-

CaM


CaM kinase

Ser/Thr - P

Ca
2
pump, AC GC
Es (glycogen synthase, phosphorylase
kinase)


Biological effects
Phosphorylation of Es or functional proteins
ANP
NO, CO
Soluble GC
PKG
cGMP
Receptor-
linked GC




(2) Function of PKG
Ser/Thr- P of protein and E
Mg
2+
PPi
H
2
O
Mg
2+
GTP
cGMP
5'-GMP
GC
PDE
GC: Guanylate cyclase
ANPatrial natriuretic peptides

GC NO

cGMP

PKG

Vascular dilatation
cis-acting element
nucleus
expression
cell memberane
phosphorylation of enzymes or proteins effects
CaM-PK
Ca
2+
-CaM Ca
2+
IP
3
DG
cAMP cGMP
PKA
PKG
PKC
ATP GTP PIP
2
(PC)
G AC
GC G PL
peptide hormones
neurotransmitters
AFP
neurotransmitters
hypothalamic pituitrin
P
trans-acting factor
TPK receptor is related to
proliferation, differentiation,
dissociation, carcinomatous
change.
TPK
receptor TPKMembrane.
non receptor TPKcytosol
GRB
2
, SOS, Ras, Raf
Small G protein: Ras
MAPK (mitogen-activated protein kinase)
MAPKMAPKKMAPKKK

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



TPK

EGF, PDGF
receptor TPK RasGTP
SOSP
GRB
2
P
RafP
MAPKKP
MAPKP
trans-acting factor
expression
nucleus
P

(2) JAKsSTAT pathway

JAKs(JANUS KINASES)

STAT: Signal transductors and
activator of transcription

- P P-
JAK
113
91
84
48
113
P
91 P
84
P
48
113
91
84
P
P
P
interferons & GH
inactive STAT
Plasma membrane
STAT complex
Nuclear membrane
gene
Interferons response element
transcription

Steroid H, VD
3
, 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, IP
3
, DG, Ca
2+
Proteins and peptides:
Hormones, cytokines
Amino acid derivatives:
Catecholamines
Fatty acid derivatives:
Prostaglandins
Steroid hormones,
Thyroxine, VD
3