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Cell Signlaing 1

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52 views73 pages

Cell Signlaing 1

Uploaded by

Sayan Konar
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
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Download as PDF, TXT or read online on Scribd
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Cell Signaling

Section 1 Overview of cell signaling


1. Signal transduction
Cell Signaling

Some of the basic


characteristics of
cell signaling:

Cell must respond


appropriately to
external stimuli to
survive;
Cells respond to
stimuli via cell
signaling.
Forms of intercellular signaling
2. Signal Molecules and Receptors

2.1 Signal molecules:

◆ Lipid-soluble hormones;

◆ Water-soluble hormones;
◆ Nitric oxide (NO) and carbon monoxide(CO)

as cellular messengers.
2.2 Types of receptors
Cell surface receptors include three classes: glycoproteins
Extracellular signals can act slowly or rapidly to change
the behavior of a target cell
2.3 Second messengers and molecular switch

Second messengers:
The first second messenger molecular——cAMP.
The Nobel Prize in Physiology or Medicine 1971.

cAMP, cGMP, Ca2+, DAG, IP3


Two types of intracellular signaling proteins that
act as Molecular Switches
The regulation of a monomeric GTPase

GAP (GTPase-
activating proteins)
GEFs (Guanine
nucleotide-exchange
factors)
3. Cell signaling systems
Three types of intracellular signaling
complexes (1)
Three types of intracellular signaling
complexes (2)
Three types of intracellular signaling
complexes (3)
A specific signaling complex formed using
modular interaction domains
Signaling integration
Section 2. Cell signaling
mediated by intracellular receptor
1. Some small hydrophobic hormones (steroid
hormones) whose receprors are intracellular
gene regulatory proteins.
2. Nitric oxide couples G protein-linked receptor
stimulation in endothelial cells to relaxation of
smooth muscle cells in blood vessels

It has been known for many years that acetylcholine


dilate blood vessels by causing their smooth muscles
to relax. In 1980, Furchgott concluded that blood
vessels are dilated because the endothelial cells
produce a signal molecule that makes smooth muscle
cells relax. In 1986 work by Furchgott and parallel
work by Louis Ignarro identified NO as the signal that
cause relaxation of the vascular smooth muscle.

The Nobel Prize in Physiology or Medicine 1998.


Nitric Oxide and Carbon Monoxide
◼ The nitric oxide (NO) is a major paracrine
signaling molecule in the nervous, immune, and
circulatory systems. NO is able to diffuse directly
across the plasma membrane of its target cells. The
molecular basis of NO action, however, is distinct
from that of steroid action; rather than binding to
a receptor that regulates transcription, NO alters
the activity of intracellular target enzymes.
◼ The carbon monoxide (CO) acts as a cellular
messenger to stimulate the production of cGMP by
stimulating G-cyclase.
The production of NO
The signaling of NO
The signaling of NO
Section 3. Signal transduction mediated
by the receptors on the cell surface
1. Mediated by the Ion-Linked Receptors which
convert chemical signals into electrical ones
2. Signal transduction mediated by G protein-
linked receptors
Two major pathways by which G-protein-linked cell-surface receptors
generate small intracellular mediators. In both cases the binding of an
extracellular ligand alters the conformation of the cytoplasmic domain of the receptor,
causing it to bind to a G protein that activates (or inactivates) a plasma membrane
enzyme. In the cyclic AMP (cAMP) pathway the enzyme directly produces cyclic AMP. In
the Ca2+ pathway the enzyme produces a soluble mediator (inositol trisphosphate) that
releases Ca2+ from the endoplasmic reticulum.
2.1 Cyclic AMP signaling pathway

➢ Second messengers (cAMP).


➢ An effector(AC), amplify the response to a single
extracellular ligand by cAMP to trigger a reaction
cascade.
➢ The cascade starts with the binding of cAMP to cAMP-
dependent protein kinase A.
➢ PKA inhibits glycogen synthase and activates
phosphorylase kinase.
The activation of protein kinase A by cyclic AMPs
A current model of how Gs
couples receptor activation to
adenylyl cyclase activation. As
long as the extracellular signaling ligand
remains bound, the receptor protein can
continue to activate molecules of Gs
protein, thereby amplifying the response.
More important, an alphas can remain
active and continue to stimulate a
cyclase molecule for many seconds after
the signaling ligand dissociates from the
receptor, providing even greater
amplification.
2.2 Double Messenger system
The pathway through phospholipase C results
in a rise in intracellular Ca2+

Cytolasmic
calcium levels
are determined
by events within
a membrane.
Two intracellular pathways by which activated C-kinase can activate the
transcription of specific genes. In one (red arrows) C-kinase activates a
phosphorylation cascade that leads to the phosphorylation of a pivotal protein kinase
called MAP-kinase, which in turn phosphorylates and activates the gene regulatory
protein Elk-1. Elk-1 is bound to a short DNA sequence in association with another DNA-
binding protein. In the other pathway (green arrows) C-kinase activation leads to the
phosphorylation of Ik-B, which releases the gene regulatory protein NF-kB so that it can
migrate into the nucleus and activate the transcription of specific genes.
Ca2+ release induced by IP3
◆ IP3 molecules formed at the membrane diffuse into
the cytosol and bind to a specific IP3 receptor
located at the surface of the smooth endoplasmic
reticulum.
◆ The IP3 receptor does more than bind a ligand; it is
also a tetrameric Ca2+ channel. Binding of IP3 opens
the channel, allowing Ca2+ ions to diffuse into the
cytoplasm.
◆Calcium ions can also be considered as
intracellular messengers because they bind to
various target molecules, triggering specific
responses.
The structure of Ca2+/calmodulin based
on X-ray diffraction and NMR studies
The stepwise activation of CAM-kinase Ⅱ
G-protein-linked receptor desensitization depends
on receptor phosphorylation by PKA, PKC, CaMK or
G-protein-linked receptor kinases (GRKs)
Section 4. Enzyme-linked receptors
and signaling pathway

Five classes of enzyme-linked receptors


have thus far been identified:
➢ Receptor tyrosine kinase (RTK);
➢ Receptor serine/threonine kinase;
➢ Receptor tyrosine phosphatases;
➢ Receptor guanylyl cyclases;
➢ Tyrosine-kinase-associated receptor;
Seven subfamilies of receptor tyrosine kinases

Only one or two members of each subfamily are indicated. Note that the
tyrosine kinase domain is interrupted by a "kinase insert region" in some
of the subfamilies. The functional significance of the cysteine-rich and
immunoglobulin like domains is unknown.
4.1 Receptor tyrosine kinase (RTK)

Activation of RTK by dimerization


Inactivation of RTK by dimerization
The docking of intracellular signaling proteins on
phosphotyrosines on an activated RTK
➢Phsphorylated Tyrosine Serve as docking sites for
protein with SH2 domains (Src homology region).
➢Other protein modules such as SH3 binds to proline-
rich motifs in intracellular proteins.
Activation of Ras by RTK
Steps in activation of Ras by RTKs

➢Phosphotyrosines of RTK act as binding sites for a specific SH2


protein called GRB2 (Growth factor receptor binding protein in
mammalian).
➢GRB2 is not a protein with catalytic activity, but one that functions
solely as an adapter molecule that links other proteins into a complex.
➢Sos (son of sevenless) is a guanine nucleotide exchange factor for
Ras (Ras-GEF)
➢When a ligand binds to the RTK and recruits the Grb2-Sos to the
inner surface of the membrane, the Sos protein binds to Ras causing
GDP/GTP exchange, thus activating Ras.
The switch mechanism of Ras

Ras activity is regulated by GAPs( GTPase-Activating


proteins) 100 000-fold
MAP-kinase serine/threonine phosphorylation
Pathway activated by Ras

Ras-activated
phosphorylation
cascade

MAP kinase=mitogen-activated protein kinase; MAP-KKK=Raf (Ser/Thr-PK)


The organization of two MAP-kinase modules
by scaffold proteins in budding yeast
PI3K-PKB(Akt) signaling pathway
TGF-β-Smad signaling pathway
The Smad-dependent signaling pathway
activated by TGF-β
Jak-STAT signaling pathway

Janus kinases (Jaks) and STATs :


➢Jaks: A class of cytoplasmic tyrosine kinases,
including Jak1, Jak2, Jak3, and Tyk2, and each is
associated with particular cytokine receptors;
➢STATs: Jaks then phosphorylate and activate a set of
latent gene regulatory proteins called STATs(signal
transducers and activators of transcription, which have
an SH2 domain),which move into the nucleus and
stimulate the transcription of specific genes.
MBC 885: 15-63

The Jak-STAT signaling pathway avtivated by -


interferon. Providing a fast track to the nucleus.
Wnt-β-catenin signaling pathway
Hedgehog signaling pathway
NF-kB signaling pathway
TNF-

TRADD
g
RIP
P b 
26S P IKK
Protosome P
I-kB
p50
cytoplasm
p65

Nuclear Expression

kB site gene
Notch-Delta signaling pathway

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