Signaling pathways

Apoptosis 1. Introduction 2. Extrinsic pathway 3. Intrinsic pathway

Apoptosis

apoptosis autofphagy necrosis

1.

T cell

Viral infection

Death receptors

Cell stress (growth factor depletion, cytoplasmic stress, free radicals), serum starvation

Ionizing radiation

Death receptors

Extrinsic pathway:

- Ligands: cytokines, TNF, Fas ligand - Receptors: cytokine receptors, TNF receptor, Fas receptor

Intrinsic pathway: 1. Withdrawal of survival factors 2. Direct mitochondrial 2. ER stress 3. p53-mediated 4. Viruses

Apoptotic pathways

Survival factor receptors

p53

ER

2.

caspase 3 pro-caspase 3

Cyt c

Apoptotosome

Apaf-1

CAD

I-CAD

CAD

CAD

Intrinsic pathway of apoptosis

Bax & Bak

Radiation: UV, ionizing radiation

Cellular stress: hypoxia

I-CAD

APOPTOSIS

APOPTOSIS

Apaf-1 procaspase 9

Cyt c

3.

BAX: BCL2-associated X protein BAK: BCL2 antagonist/killer CAD: caspase-activated Dnase Cyt c: cytochrome C Apaf-1: apoptotic protease activating factor-1

caspase 9

3b.

Knockout mice

4.

Caspase cascade

The three classes of Bcl-2 proteins

PROTECTORS

KILLERS

REGULATORS

5.

Regulation of apoptosis by Bcl-2 proteins 6.

IAP (inhibitor of apoptosis protein): apoptózis inhibítor

Smac (second mitochondrial activator of apoptosis): az apoptózis második mitokondriális aktivátora

IAP és Smac/DABLO

SMAC/DIABLO

IAP Kaszpáz 3

Cyt C

Kaszpáz 9

APOPTÓZIS

DNS fragmentáció

7.

Roles of IAPs and anti-IAPs in apoptosis 8.

caspase 3 pro-caspase 3

Cyt c

Apoptotosome

Apaf-1 procaspase 9

caspase 9

CAD

I-CAD

CAD

I-CAD

CAD

Intrinsic pathway of apoptosis – the ER stress

Ca++ Ca++

Ca++

Ca++

Ca++ Ca++

Ca++

Ca++

ER stress: misfolded proteins

pro-caspase 12

caspase 12

IP3R Bax & Bak

Ca++

Ca++

Ca++ Ca++

Ca++ Ca++

Ca++

Radiation: UV, ionizing

Cellular stress: hypoxia

DNA damage

APOPTOSIS

APOPTOSIS

Cyt c

9.

ER stress-induced apoptosis 9b.

caspase 8

caspase 3 pro-caspase 3

FASL

FAS

FADD

pro-caspase 8

APOPTOSIS

cytokine

Cytokine receptor

TRADD

FADD

pro-caspase 8

TNF-

TNFR1 receptor

TRADD

FADD

pro-caspase 8

The extrinsic pathway of apoptosis

death domain

INITIATOR CASPASE

EFFECTOR CASPASE

CAD: caspase-activated Dnase I-CAD: inhibitor of CAD

CAD

I-CAD CAD

I-CAD

CAD

Death receptors

APOPTOSIS

10.

DISC

TRADD

FADD

caspase 8

pro-caspase 8

caspase 3 pro-caspase 3

Bid

t-Bid

Cyt c

Apoptotosome

Apaf-1 procaspase 9

caspase 9 caspase 6+7

CAD

I-CAD CAD

I-CAD

CAD

Membrane –bound FASL

FAS

death domain

Death receptor

Bax & Bak

The extrinsic pathway - enhancement

Secreted FASL

APOPTOSIS

APOPTOSIS

11.

Signaling through PI 3-kinase promotes cell survival

Activated PI 3-kinase

PIP2 PIP3

PDK1

PH Domains

Activated receptor Tyrosine kinase

PKB

Active PKB

Dissociation

Activation of PKB by PDK1

Phosphorylation of BAD BAD

Inactive death-inhibitory protein Active death-inhibitory protein

Inactive BAD

14-3-3 protein

Inhibition of apoptosis

mTOR

RTK

12.

Withdraval of survival factor apoptosis

3 ways that survival factors can inhibit apoptosis 13.

M

G1

G2

S

Cell cycle

UUU

E2F

pRB

E2F

pRB

Cyclin E

CDK2

p14

p53 p53

p21

Degradation Apoptosis

Cell cycle arrest

proteasome

Radiation

A key role for p53

MDM2

Cyclin D1

CDK4

P p21

p53

p16

14.

p53

APOPTOSIS

Caspase activation

nucleus

Cytosolic apoptotic pathway

Mitochondrial apoptotic pathway

15.