PS?

Engul�ngphagocyte

Apoptoticcell

Phagocytosis

ATP

Phosphatidyl serine (PS)normally on the inner lea�et

of the plasma membrane‘�ips’ to the outer lea�et

TSP, macrophagesecreted

glycopr oteinwhich provides a‘bridge’ betw eenthe macrophage

and an apoptotic cell

Exposure of sugarresidues on cell-surface

carbohydratesLectins

recognize and interactwith sugars

CDI4Plasma membrane-boundglycoprotein which binds

lipid molecules

Ion �ux

*αvB3

*CD36Croquemort(drosophila)

DOCK I80(CED5 homolog)

PS receptor(CDI4?)

Contains SH3 domainwhich allows

interaction withsignaling pathways -

regulation ofcytoskeleton and

cell motility ?

ABC Transporter(CED7 homolog)

role in phagocytosisunclear

*Adhesion moleculeswhich bind TSP

and signal viatyrosine kinasesThrombospondin

(TSP) moiety

Mitochondria

Pro-apoptotic Bcl-2 family members promote,and anti-apoptotic Bcl-2 family members block

mitochondrial cytochrome c releaseBax

Cytochrome c

Apaf-I

Apoptosome

Caspase-9tetramer

Procaspase-9Bcl-xL blocks?

Caspases-3,6,7

BH2BHIBH3BH4 TM

BH2BHIBH3BH4 TM

BH2BHIBH3BH4 TM

BH3BH4 TM

BH3 TM

NC

Bax, Bak,Mtd/Bok

Bcl-xS

Bik, Hrk,Bim, Blk

Bad, Bid

Pro-apoptotic

Bcl-2, Bcl-x L,Mcl-I

Bcl-w, A-I

Anti-apoptotic

BH3

The Bcl-2 Family

TNF receptor (TNFR)(monomer, cysteines in yellow,

contact residues in red)

Ligand (TNF)(trimer, contactresidues in red)

Activecaspase-8tetramer

Apoptosis

TNF-family death receptorsTNF FasL TRAILTRAIL

TNFR TRAIL-R2

FADDFADD

c-IAP

TRAF- ITRAF-2

?

TRAIL-RI

TRADD

Recruits and permitscaspase-8 transactivation

Recruits and permitscaspase-8 transactivation

Unknown adaptorrecruits and permits

caspase-8 transactivationInhibits TNF-

induced apoptosis

p53

Nuclearsignal

IKKI/IKK2

Calcineurin JNK/SAPK

EGR-3 AP-I

IKKI/IKK2

Phosphorylationand dissociation

Active

Inactivecomplex

Transcriptionalregulation

e.g. Bax

Death

NF-AT

NF-AT

Stress signals

T- cell receptor activation

DNA damage

Fos/Junheterodimers

NF-κB

NF-κB NF-κB

NF-κBIκB

IκB

FasL transcriptionEGR-3

IL-3

IL-3R

IGF-I

IGF-IR

PI 3-kinase

AKT (PKB)

SCF

Ceramide wortmannin

BadAkt

P

Bcl-2

BaxBcl-xL

Bcl-xLBad

P

Survivalsignals

Kit(SCF-R )

Phosphorylation andinactivation

of Bad

*SerI36

PBad

*SerI36

SerII2

*SerI36

SerII2

Sequestrationof Bad

14-3-3Bad

*Required forsurvival-promoting activity

Dissociationof Bad/Bcl-2 and

Bad/Bcl-xLheterodimers

Neutralization ofpro-apoptotic e�ects

of Bax

PerforinGranzyme B(GrB )

?

Perforin

Death

Granzyme B

Cytotoxic T cell

Gr B+

rab5+

Gr B+

rab4+

Gr B+

Gr B+

Non-classical receptor-mediated entry

Mechanism of perforinentry unknown

Executionercaspase

Activatedcaspase tetramer

Cytosolicgranzyme B

rab5 –

rab4 –

lgpI20 –

Cathepsin D –

Cytochrome c –

M-6-P-R –

Target cell

3 6 7 8 10 9 I 4 5 2

Executioner caspases Initiator caspases In�ammatory caspases

Executioner caspase Initiatorcaspase

Adaptors

Caspases

Transactivation Active caspasetetramer (2 heterodimers)

Activecaspase-3

DNA fragmentationI80 bp oligo-nucleosomalfragments

InternucleosomalDNA cleavage

CAD/DFF40/CPAN

Activenuclease iC AD/

DFF45

PARP

Other target substrates:pro-IL-I β (caspase-I)lamins A/C (caspase-6)fodrin, Mdm2, UI -70 kDa, actin (caspase-3)

FAK Focal adhesion kinaseIC AD-L Inhibitor of caspase-activated DNAsePAK-2 p2I-associated kinasePARP Poly-ADP-ribose polymerasePKC Protein kinase C

IGF-IR Insulin-like growth factor I receptorIL-3R Interleukin-3 receptorSCF-R Stem cell factor receptor

PA-DEVD 213 G-RP

DNA-PK

DNA-DEVD 2712N-PK

Retinoblastoma

Retino-DEAD 886 G-blastoma

PKC-δ

PKC- DMQD330 N -δ

PAK-2

PA-EVD212G-K-2

Gelsolin

Gel-DQTD352 G-solin

MEKK- I

ME-DTVD874 G-KK- I

Substratecleavage

Mediate membrane andmorphological changes

IC AD-L (-S)

IC -DEPD117 -AD-LIC -DAVD224-AD-S

DNA fragmentation

Disruption of cell-cyclecontrol

FAK

F-VSWD704 S-AKF-DQTD 772 S-AK

Loss of cellular adhesion

Disable DNA repairmechanisms

Death e�ector domain

Caspase recruitment domain

Prodomain

Protease subunits

TNFTRAILTRADDFADDTRAFIAP

Death e�ector domainDeath domainTumor necrosis factorTNF-related apoptosis-inducing ligandTNF-receptor-associated death domainFas-associated death domainTNFR-associated factorInhibitor of apoptosis protein

Deathdomain

Fas

SerII2

P

Apoptosis

Burial

Execution

Initiation

LIT.APOP.2010.1

Copyright © 1998 Elsevier Science Ltd. All rights reserved. Based on an original design by Sheila Betts.

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