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7/28/2019 Signal Transduction and Regulation Lecture 1 Pw Point 2003
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SIGNAL TRANSDUCTION
AND
REGULATIONSigit Purwantomo
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Subject of this weeks lecture
The importance of signal transduction
Malfunction on signaling pathways
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Weekly objective
Cell signaling and signal transduction
Regulation of the cell cycle
Malfunction of signaling pathways
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Lecture 1
Cell signaling & signal transduction
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Cell signaling
Signal transduction
Cell communication
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Why we need communication?
Pay attention for the next slide!
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? =+/
Theres something wrong with
your phoneI cant hear you
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The important of communication
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Signal
Signal perception
Signal transduction
Response
Cell
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General feature of
cell signaling &
signal transduction
Blue : terminator signal
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Modes of Cell-Cell Signaling
Cell signaling can take place
either through direct cell-cell
contacts or through the action
of secreted signaling molecules.
In endocrine signaling,
hormones are carried
through the circulatorysystem to act on distant
target cells.
In paracrine signaling, a
molecule released from one
cell acts locally to affectnearby target cells.
In autocrine signaling, a
cell produces a signaling
molecule to which it alsoresponds.
1
2
Endocrine
http://localhost/var/www/apps/conversion/tmp/My%20Documents/endocrine.mp4http://localhost/var/www/apps/conversion/tmp/My%20Documents/endocrine.mp47/28/2019 Signal Transduction and Regulation Lecture 1 Pw Point 2003
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Type of signal transducers
1
2
3
4
5
6
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Gated ion-channel (1)
http://localhost/var/www/apps/conversion/tmp/My%20Documents/neorotrasmitte%20action.swfhttp://localhost/var/www/apps/conversion/tmp/My%20Documents/neorotrasmitte%20action.swf7/28/2019 Signal Transduction and Regulation Lecture 1 Pw Point 2003
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Na/K ATPase
Membrane potential
3 Na = 2 K
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Na K ATPase
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Gated Na channel: structure
Consist of 4 domainsThere are 6 helices in each domain
Helix no. 4 function = voltage sensorHelix no. 6 function = activating gate
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Activation gate
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5 subunit
L H
Acetylcholine will bind to alpha
Nicotinic acetylcholine receptor: structure
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Nicotinic acetylcholine receptor: mechanism
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4 helices in each subunit
Subunit folds into
4 transmembranes helices
l h l
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Nicotinic acetylcholine receptor: in action
hydrophobicpolar
Keyword : twisting
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Gate closed
(resting)
Gate open
(exited)
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Gated K channel: structure
4 subunit
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Cl h l
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Cl channel
Cl h l
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Cl channel
H d th hl id h l k?
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How does the chloride channel work?
The chloride channel is made from a protein
called CF transmembrane regulator (CFTR)
protein.
Its normal function is to
control the flow of chloride
ions from the cell.
H d th hl id h l k?
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The channel is
closed
Phosphate groups (P) add to
the R-domain.
Cyclic AMP (cAMP)
stimulates the enzyme,protein kinase (PKA), to add
the phosphate groups.
ATP is bound . . .
. . . and hydrolysed to
ADP+Pi
The shape of CFTR
changes, opening the Cl-
channel
How does the chloride channel work?
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Cl channel & cystic fibrosis (CF)
The basics
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The basic defect in CF arises particularly in the
epithelial cells lining the airways of the lunghttp://resources.schoolscience.co.uk/MRC/3/page3.html
There are channels in these lining cellsthrough which ions can pass.
Normally, the movements of ions
brings water to the surface of theairway and keeps the mucus moist.
The basics
How do the channels keep the mucus moist?
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The lining cells have channelson their outside surface (on the
side of the airway).
One of the channels allows sodiumions to flow into the cell and the
other controls the passage of
chloride ions out ofthe cell into the
mucus on the airway surface.
How do the channels keep the mucus moist?
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Wh t h i CF?
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In the lining cell of a personwith CF, the vital chloride
channel is blocked.
This means that there is nomovement of chloride ions into the
mucus.
With no ionic gradient, there is no
need for water to move towards the
surface and the mucus dries out.
What happens in CF?
T f i l t d
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Type of signal transducers
1
2
3
4
5
6
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Receptor enzyme (2)
Receptor Protein Tyrosine Kinases
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Receptor Protein-Tyrosine Kinases
Dimerization and autophosphorylation
of receptor protein-tyrosine kinases
Growth factor binding induces receptor dimerization, which
results in receptor autophosphorylation as the two
polypeptide chains phosphorylate one another.
Directly linked to intracellular enzyme
Some examples
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EGF : epidermal growth factorPDGF : platelet derived growth factor (blood vessel formation, angiogenesis)
Some examples
D t i li l l
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Downstream signaling molecules
with receptor protein-tyrosine kinases
SH2 domains bind to specific phosphotyrosine-
containing peptides of the activated receptors.
SH2 : Src homology 2
Src (pronounced sarcas it is short for sarcoma) SH2 : Src homology 2
Insulin receptor
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Extracellular
Insulin receptor
Insulin structure
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Insulin structure
Insulin biosynthesis
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Insulin biosynthesis
Release of insulin by the b cells
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Glucose enters the cell
Release of insulin by the b-cells
[ATP]/[ADP] ratio increases,ATP-dependent K channel (K
ATP) is closed
The closing of this channelleads to a membrane
depolarization
Ca2 enter the cell such that
intracellular Ca2 levelsincrease
The increase in intracellular
Ca2 stimulates insulin
secretion
Type of signal transducers
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Type of signal transducers
1
2
3
4
5
6
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Protein receptor (3)
G protein coupled-receptor
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Characterized by seventransmembranea helices.
Structure of a G protein-
coupled receptor
G protein coupled-receptor
Regulation of G proteins
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Regulation of G proteins
1
23
4
Hormonal activation of adenylyl cyclase
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A guanine nucleotide-binding protein
(called a G protein) is an intermediaryin adenylyl cyclase activation
Hormonal activation of adenylyl cyclase
cAMP synthesis and degradation
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cAMP is synthesized from
ATP by adenylyl cyclase
cAMP synthesis and degradation
Cyclic AMP is degraded to AMP
by cAMP phosphodiesterase.
Cyclic AMP-inducible gene expression
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CRE : cAMP response element
Cyclic AMP inducible gene expressionThe free catalytic subunit of protein kinase A
translocates to the nucleus and phosphorylates the
transcription factor CREB (CRE-binding protein),
leading to the recruitment of coactivators andexpression of cAMP-inducible genes.
Activation protein kinase A
1
2 Phosphorilation CREB
3 Expression cAMP-inducible genes
Regulation of protein kinase A
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Binding of cAMP to the regulatorysubunits induces dissociation of the
catalytic subunits, which are then
enzymatically active.
Regulation of protein kinase A
The inactive form of protein kinase
A consists of two regulatory (R) and
two catalytic (C) subunits.
1
2
Type of signal transducers
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Type of signal transducers
1
2
3
4
5
6
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Steroid receptor (4)
Principles of hormone action
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Principles of hormone action
Mechanism of action
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The receptor
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The receptor
Type of signal transducers
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Type of signal transducers
1
2
3
4
5
6
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Receptor with no enzyme activity (5)
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The JAK/STAT pathway
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STAT : signal transducer and activator transcription
The phosphorylated STAT proteins
dimerize and translocate to the nucleus
/ p y
In unstimulated cells, STAT proteins are
inactive in the cytosol.
STAT proteins are phosphorylated by the
receptor-associated JAK protein-tyrosine
kinases.
Activation of transcription of target genes.
Type of signal transducers
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Type of signal transducers
1
2
3
4
5
6
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Adhesion receptor (6)
Signal Transduction and the Cytoskeleton
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g y
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