Signal Transduction and Regulation Lecture 1 Pw Point 2003

7/28/2019 Signal Transduction and Regulation Lecture 1 Pw Point 2003

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SIGNAL TRANSDUCTION

AND

REGULATIONSigit Purwantomo

[email protected]


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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.mp4


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Type of signal transducers

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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.swf


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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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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



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1

2

3

4

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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



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1

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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



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1

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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.



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1

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Adhesion receptor (6)

Signal Transduction and the Cytoskeleton


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g y


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Signal Transduction and Regulation Lecture 1 Pw Point 2003

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