Apoptosis Signaling Pathway

Click on one of the buttons below to highlight the factors involved in either the extrinsic or intrinsic pathway of caspase activation.

Death Receptor Activation

Death Receptor Activation

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TNF-alpha
TNF-alpha
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TNF RI
TNF RI
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RIP1
RIP1
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TRADD
TRADD
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TRAF-2
TRAF-2
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TRADD
TRADD
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FADD
FADD
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Pro-Caspase-8
Pro-Caspase-10
Pro-Caspase-8
Pro-Caspase-10
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SODD
SODD
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Fas Ligand
Fas Ligand
Fas
Fas
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FADD
FADD
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Pro-Caspase-8
Pro-Caspase-10
Pro-Caspase-8
Pro-Caspase-10
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Daxx
Daxx
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FADD
FADD
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Pro-Caspase-8
Pro-Caspase-10
Pro-Caspase-8
Pro-Caspase-10
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Daxx
Daxx
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TRAIL
TRAIL
TRAIL R1
TRAIL R2
TRAIL R1
TRAIL R2
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FADD
FADD
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Pro-Caspase-8
Pro-Caspase-10
Pro-Caspase-8
Pro-Caspase-10
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FADD
FADD
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TWEAK
TWEAK
TWEAK R
TWEAK R
cIAP-1
cIAP-1
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TRAF-2
TRAF-2
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cIAP-1
cIAP-1
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TRAF-2
TRAF-2
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TL1A
TL1A
DR3
DR3
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TRADD
TRADD
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FADD
FADD
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Pro-Caspase-8
Pro-Caspase-10
Pro-Caspase-8
Pro-Caspase-10
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TRADD
TRADD
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TRAF-2
TRAF-2
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RIP1
RIP1
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Caspase-8
Caspase-10
Caspase-8
Caspase-10
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BID
BID
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tBID
tBID
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p53
p53
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p53
p53
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p53
p53
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Daxx
Daxx
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Axin
Axin
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HIPK2
HIPK2
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PIDD
PIDD
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CRADD/RAIDD
CRADD/RAIDD
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ARC
ARC
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Pro-Caspase-2
Pro-Caspase-2
PIDDosome
PIDDosome
Caspase-2
Caspase-2
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BID
BID
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tBID
tBID
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Cytochrome c
Cytochrome c
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Bad
Bad
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14-3-3
14-3-3
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Bad
Bad
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Bcl-2
Bcl-2
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Bax
Bax
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Bad
Bad
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Bax
Bax
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Bax
Bax
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tBID
tBID
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Bad
Bad
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14-3-3
14-3-3
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Bad
Bad
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BAK
BAK
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Bcl-xL
Bcl-xL
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Bcl-2
Bcl-2
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Bcl-xL
Bcl-xL
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Bad
Bad
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Bcl-xL
Bcl-xL
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Bax
Bax
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Bcl-xL
Bcl-xL
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tBID
tBID
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Bax
Bax
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tBID
tBID
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BAK
BAK
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Cytochrome c
Cytochrome c
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BAK
BAK
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Bad
Bad
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Bcl-2
Bcl-2
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BAK
BAK
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Bax
Bax
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tBID
tBID
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Cytochrome c
Cytochrome c
SMAC/Diablo
HTRA2/Omi
SMAC/Diablo
HTRA2/Omi
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Endo G
Endo G
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AIF
AIF
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IAPs
IAPs
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APAF-1
APAF-1
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Pro-Caspase-9
Pro-Caspase-9
Apoptosome
Apoptosome
HSPs
HSPs
Caspase-9
Caspase-9
IAPs
IAPs
Bad
Bad
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Bax
Bax
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BID
BID
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PUMA
PUMA
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PIDD
PIDD
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14-3-3
14-3-3
p21
p21
others
others
others
others
Pro-apoptotic:
Pro-apoptotic:
Anti-apoptotic:
Anti-apoptotic:

DNA Damage

DNA Damage

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DNA Fragmentation
DNA Fragmentation
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Pro-Caspase-3
Pro-Caspase-3
IAPs
IAPs
Caspase-3
Caspase-3
Pro-Caspase-7
Pro-Caspase-7
IAPs
IAPs
Caspase-7
Caspase-7
Pro-Caspase-6
Pro-Caspase-6
Caspase-6
Caspase-6
IAPs
IAPs

Cleavage of Target Molecules

Cleavage of Target Molecules

Overview of the Extrinsic and Intrinsic Pathways of Caspase Activation

Caspases are a family of aspartate-specific, cysteine proteases that serve as the primary mediators of apoptosis. All caspases are synthesized as inactive zymogens containing a variable length pro-domain, followed by a large (20 kDa) and a small subunit (10 kDa). Caspase activation occurs following receipt of an extrinsic or intrinsic death signal. The extrinsic pathway of caspase activation is initiated by ligand binding to cell surface death receptors, such as TNF RI, Fas/CD95, DR3, TRAIL R1/DR4, or TRAIL R2/DR5.Ligand binding to these receptors leads to receptor oligomerization and recruitment of FADD and/or TRADD, two death domain-containing adaptor proteins. FADD subsequently recruits Pro-Caspase-8 and Pro-Caspase-10 through its death effector domain. Clustering of pro-caspases in the cytosol near a death receptor leads to formation of the death-inducing signaling complex (DISC) and the subsequent cleavage of Pro-Caspase-8 and Pro-Caspase-10.

The intrinsic pathway of caspase activation is initiated by events such as DNA damage, growth factor withdrawal, or loss of contact with the extracellular matrix. These events ultimately lead to changes in the integrity of the mitochondrial membrane, which is regulated by Bcl-2 family proteins. The balance between pro- and anti-apoptotic Bcl-2 family members determines whether or not a cell will undergo apoptosis. In healthy cells, phosphorylated Bad is sequestered in the cytoplasm by the 14-3-3 protein, and Bcl-2 and Bcl-xL bind to the pro-apoptotic Bax and BAK proteins to inhibit apoptosis. When cytoplasmic levels of free Bad increase, Bcl-2 and Bcl-xL bind to Bad and release Bax and BAK. Bax and BAK, or processed forms of these proteins, can then insert into the mitochondrial membrane, compromising its integrity. Loss of mitochondrial integrity results in the release of pro-apoptotic proteins including Cytochrome c, Smac/Diablo, HTRA2/Omi, Apoptosis-Inducing Factor (AIF), and Endonuclease G. In the cytoplasm, Cytochrome c interacts with APAF-1, which recruits Pro-Caspase-9 to form the apoptosome. Within this complex, Caspase-9 is processed and activated. The intrinsic pathway of caspase activation can also lead to Caspase-2 activation. Following DNA damage, p53 induces the expression of PIDD (p53-induced protein with a death domain), which associates with the CRADD/RAIDD adaptor protein and Pro-Caspase-2 to form the PIDDosome. Formation of this complex leads to the cleavage and activation of Pro-Caspase-2. Once activated, the initiator caspases, Caspase-2, Caspase-8, Caspase-9, Caspase-10, cleave downstream effector caspases, Caspase-3, Caspase-6, Caspase-7, which then promote the ordered disassembly of the cell by targeting a number of critical cellular proteins, including structural proteins, DNA repair proteins, and proteins involved in signal transduction pathways.

To learn more, visit our Apoptosis Research Area.

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