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Module 4 Class 1 Online

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16 views

Module 4 Class 1 Online

Uploaded by

shalinim8387
Copyright
© © All Rights Reserved
Available Formats
Download as PPTX, PDF, TXT or read online on Scribd
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Mechanisms of Cell

Communication
Suman Bhattacharjee
Types of response : Fast and Slow

cAMP mediated
PKA signaling

Glycogen Somatostatin release


metabolism
Four forms of intercellular signaling

Extracellular signal molecules can act over either short or long distances
Extracellular signal molecules bind to specific receptors
Receptor Types

Regardless of the nature of the signal, the target cell responds by means of a receptor
protein, which specifically binds the signal molecule and initiates a response
The three largest classes of cell-surface receptor proteins are ion-channel-linked,
G-protein-linked, and enzyme-linked receptors

Nicotinic receptor

Receptor Types
Beta adrenergic
receptor

Tyrosine kinase receptor


Signaling through G-protein-coupled cell-surface receptors (GPCRs)
and small intracellular mediators

GPCR
cAMP response element binding (CREB) protein

Cyclic AMP induced responses could be rapid or slow. In


skeletal muscle cells, PKA
induces a rapid response by phosphorylating enzymes
involved in glycogen metabolism.
In an example of a slow response, cAMP activates
transcription of a gene for a hormone,
such as somatostatin

G protein signaling
Overview
Some G proteins activate the inositol phospholipid signaling pathway by
activating phospholipase C-b

IP3 Pathway
The effects of IP3 can be mimicked by a Ca2+ ionophore (A23187 or ionomycin
and the effects of diacylglycerol can be mimicked by phorbol esters
GPCR desensitization depends on receptor phosphorylation

Pathway termination
Enzyme-coupled cell-surface receptors

1. Receptor tyrosine kinases


2. Tyrosine-kinase-associated receptors
3. Receptor serine/threonine kinases
4. Histidine-kinase-associated receptors
5. Receptor guanylyl cyclases
Activation and inactivation of RTKs by dimerization

RTK
Docking of intracellular signaling
proteins on phosphotyrosines on an
activated RTK
G protein receptor :
Varieties
Secondary
messengers
Secondary messengers are one of the
initiating components of intracellular
signal transduction cascades. Examples
of second messenger molecules
include

cyclic AMP
cyclic GMP
inositol trisphosphate
diacylglycerol
calcium
Jak-stat pathway
Overview
Jak-stat pathway : Inhibition and
cross talk

Protein tyrosine
phosphatase
Molecular and Cellular
Aspects of
Biosignaling
Signaling, Cell Cycle, and
Cancer
The Cell Cycle

M-phase: mitosis and


cytokinesis

Interphase

G1 (Gap1)

S: DNA replication

G2

G0: quiescent or
senescent
The cell cycle controlled by inhibition

for DNA integrity

Cyclin-dependent kinase
(CDK): key molecule

cyclin: activator

Kinase
Phosphatase

Ubiquitin-dependent
proteolysis
Cell cycle regulators destructed by ubiquitin-proteasome
system

M-phase
M-cyclin
APC E3 system

G1/S-phase
G1/S-cyclins
SCF E3 system
Life cycle of CDK/ Cyclin

Cyclin-dependent kinase (CDK):


key molecule
Cyclin: activator

Wee1: inhibitory kinase


CAK: CDK-activating kinase
Mitosis (M-phase) controlled
CDC25: phosphatase
by CDK and cyclin
APC-dependent ubiquitylation of cyclin
Regulation of Cell cycle
checkpoint events
How does extracellular signals induce cell growth?
Growth factor and G1/S

Entry into S phase

Growth factor:
autocrine or paracrine

PDGF
RTK
Ras
MAPK module
Jun/Fos: transcription factors
G1/S cyclins

Receptor tyrosine kinase


for growth factor PDGF
Receptor tyrosine kinase

Growth factors: EGF, PDGF etc


Example – MAP kinase
RTK signaling and Ras GTPase
MAPK cascade
in RTS-Ras signaling

RTK: kinase receptor


Ras: GTPase

MAPKKK: kinase
MAPKK: kinase
MAPK: kinase

Transcription factors
(e.g., c-Fos)

Why multi-step in
signaling?
Signal amplified in number
and duration
Signal fine regulated
Signal cross talks
Rb in G1/S progression

Rb
Retinoblastoma sensitivity protein

CDK substrate

E2F transcription factor

Rb-E2F: inactive

Rb-P + E2F

G1/S protein expression


Cell cycle checkpoint
(1. G1/S Checkpoint)
Cell cycle arrest when
DNA damage found

p53: transcription factor G1/S checkpoint by p53


Cell cycle check point protein

p53 phosphorylation
p21: CDK inhibitor

DNA repair
Apoptosis
Function of Checkpoints
2. Spindle assembly checkpoint
Role of APC
How is p53 activity induced by DNA damage?
DNA damage and cell cycle arrest

p53: transcription factor

p53 transcribes p21.


Cell cycle check point

p53 induces E3 MDM2


transcription.

MDM2 ubiquitylates p53.


About p53
p53
Stops Cell division Begin apoptosis

Initiate DNA repair


p53: cell cycle arrest and apoptosis

The transcription factor p53

The ubiquitin ligase MDM2


p53 degradation

DNA damage
ATM, ATR kinases

p53 phosphorylation and stabilization


Cell cycle arrest (p21) and apoptosis
How is p53 activity induced by DNA damage?
DNA damage and cell cycle arrest

DNA damage
DNA kinase

p53 phosphorylation
p21: CDK inhibitor

DNA repair
Apoptosis

p53 mutation in >50%


of cancers
DNA damage response pathways

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