PS?

Engulfng
phagocyte
Apoptotic
cell
Phagocytosis
ATP
Phosphatidyl serine (PS)
normally on the inner leafet
of the plasma membrane
fips to the outer leafet
TSP, macrophage
secreted
glycoprotein
which provides a
bridge between
the macrophage
and an apoptotic cell
Exposure of sugar
residues on cell-surface
carbohydrates
Lectins
recognize and interact
with sugars
CDI4
Plasma membrane-bound
glycoprotein which binds
lipid molecules
Ion fux
*vB3
*CD36
Croquemort
(drosophila)
DOCK I80
(CED5 homolog)
PS receptor
(CDI4?)
Contains SH3 domain
which allows
interaction with
signaling pathways -
regulation of
cytoskeleton and
cell motility?
ABC Transporter
(CED7 homolog)
role in phagocytosis
unclear
*Adhesion molecules
which bind TSP
and signal via
tyrosine kinases
Thrombospondin
(TSP) moiety
Mitochondria
Pro-apoptotic Bcl-2 family members promote,
and anti-apoptotic Bcl-2 family members block
mitochondrial cytochrome c release
Bax
Cytochrome c
Apaf-I
Apoptosome
Caspase-9
tetramer
Procaspase-9
Bcl-xL blocks?
Caspases-
3,6,7
BH2 BHI BH3 BH4 TM
BH2 BHI BH3 BH4 TM
BH2 BHI BH3 BH4 TM
BH3 BH4 TM
BH3 TM
N
C
Bax, Bak,
Mtd/Bok
Bcl-xS
Bik, Hrk,
Bim, Blk
Bad,Bid
Pro-apoptotic
Bcl-2, Bcl-xL,
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, contact
residues in red)
Active
caspase-8
tetramer
Apoptosis
TNF-family death receptors
TNF FasL TRAIL TRAIL
TNFR TRAIL-R2
FADD FADD
c-IAP
TRAF- I
TRAF-2
?
TRAIL-RI
TRADD
Recruits and permits
caspase-8 transactivation
Recruits and permits
caspase-8 transactivation
Unknown adaptor
recruits and permits
caspase-8 transactivation
Inhibits TNF-
induced apoptosis
p53
Nuclear
signal
IKKI/IKK2
Calcineurin
JNK/SAPK
EGR-3 AP-I
IKKI/IKK2
Phosphorylation
and dissociation
Active
Inactive
complex
Transcriptional
regulation
e.g.Bax
Death
NF-AT
NF-AT
Stress signals
T- cell receptor activation
DNA damage
Fos/Jun
heterodimers
NF-B
NF-B NF-B
NF-B
IB
IB
FasL transcription
EGR-3
IL-3
IL-3R
IGF-I
IGF-IR
PI 3-kinase
AKT (PKB)
SCF
Ceramide wortmannin
Bad
Akt
P
Bcl-2
Bax
Bcl-xL
Bcl-xL
Bad
P
Survival
signals
Kit
(SCF-R )
Phosphorylation and
inactivation
of Bad
*SerI36
P
Bad
*SerI36
SerII2
*SerI36
SerII2
Sequestration
of Bad
14-3-3
Bad
*Required for
survival-promoting activity
Dissociation
of Bad/Bcl-2 and
Bad/Bcl-xL
heterodimers
Neutralization of
pro-apoptotic efects
of Bax
Perforin Granzyme 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 perforin
entry unknown
Executioner
caspase
Activated
caspase tetramer
Cytosolic
granzymeB
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 Infammatorycaspases
Executioner caspase Initiator
caspase
Adaptors
Caspases
Transactivation Active caspase
tetramer (2 heterodimers)
Active
caspase-3
DNA fragmentation
I80 bp oligo-
nucleosomal
fragments
Internucleosomal
DNA cleavage
CAD/
DFF40/
CPAN
Active
nuclease
iCAD/
DFF45
PARP
Other target substrates:
pro-IL-I (caspase-I)
lamins A/C (caspase-6)
fodrin, Mdm2, UI -70 kDa, actin (caspase-3)
FAK Focal adhesion kinase
ICAD-L Inhibitor of caspase-activated DNAse
PAK-2 p2I-associated kinase
PARP Poly-ADP-ribose polymerase
PKC Protein kinaseC
IGF-IR Insulin-like growth
factor I receptor
IL-3R Interleukin-3receptor
SCF-R Stem cell factor
receptor
PA-DEVD
213
G-RP
DNA-PK
DNA-DEVD
2712
N-PK
Retinoblastoma
Retino-DEAD
886
G-blastoma
PKC-
PKC- DMQD
330
N-
PAK-2
PA-EVD
212
G-K-2
Gelsolin
Gel-DQTD
352
G-solin
MEKK- I
ME-DTVD
874
G-KK- I
Substrate
cleavage
Mediate membrane and
morphological changes
ICAD-L (-S)
IC-DEPD
117
-AD-L
IC-DAVD
224
-AD-S
DNA fragmentation
Disruption of cell-cycle
control
FAK
F-VSWD
704
S-AK
F-DQTD
772
S-AK
Loss of cellular adhesion
Disable DNA repair
mechanisms
Death efector domain
Caspase recruitment domain
Prodomain
Protease subunits
TNF
TRAIL
TRADD
FADD
TRAF
IAP
Death efector domain
Death domain
Tumor necrosis factor
TNF-related apoptosis-inducing ligand
TNF-receptor-associated death domain
Fas-associated death domain
TNFR-associated factor
Inhibitor of apoptosis protein
Death
domain
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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