apoptosis - microsoft · apoptosis tnf-family death receptors tnf fasl trail trail tnfr trail-r2...
TRANSCRIPT
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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