Intrinsic Pathway for Apoptosis (Homo sapiens)

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The intrinsic (Bcl-2 inhibitable or mitochondrial) pathway of apoptosis functions in response to various types of intracellular stress including growth factor withdrawal, DNA damage, unfolding stresses in the endoplasmic reticulum and death receptor stimulation. Following the reception of stress signals, proapoptotic BCL-2 family proteins are activated and subsequently interact with and inactivate antiapoptotic BCL-2 proteins. This interaction leads to the destabilization of the mitochondrial membrane and release of apoptotic factors. These factors induce the caspase proteolytic cascade, chromatin condensation, and DNA fragmentation, ultimately leading to cell death. The key players in the Intrinsic pathway are the Bcl-2 family of proteins that are critical death regulators residing immediately upstream of mitochondria. The Bcl-2 family consists of both anti- and proapoptotic members that possess conserved alpha-helices with sequence conservation clustered in BCL-2 Homology (BH) domains. Proapoptotic members are organized as follows:

1. "Multidomain" BAX family proteins such as BAX, BAK etc. that display sequence conservation in their BH1-3 regions. These proteins act downstream in mitochondrial disruption. <p> 2. "BH3-only" proteins such as BID,BAD, NOXA, PUMA,BIM, and BMF have only the short BH3 motif. These act upstream in the pathway, detecting developmental death cues or intracellular damage. Anti-apoptotic members like Bcl-2, Bcl-XL and their relatives exhibit homology in all segments BH1-4. One of the critical functions of BCL-2/BCL-XL proteins is to maintain the integrity of the mitochondrial outer membrane.Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=109606</div>

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52. Won J, Kim DY, La M, Kim D, Meadows GG, Joe CO.; ''Cleavage of 14-3-3 protein by caspase-3 facilitates bad interaction with Bcl-x(L) during apoptosis.''; PubMed Europe PMC Scholia
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History

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Compare	Revision	Action	Time	User	Comment
	114961	view	16:48, 25 January 2021	ReactomeTeam	Reactome version 75
	113405	view	11:48, 2 November 2020	ReactomeTeam	Reactome version 74
	112608	view	15:58, 9 October 2020	ReactomeTeam	Reactome version 73
	101524	view	11:39, 1 November 2018	ReactomeTeam	reactome version 66
	101060	view	21:21, 31 October 2018	ReactomeTeam	reactome version 65
	100591	view	19:55, 31 October 2018	ReactomeTeam	reactome version 64
	100140	view	16:40, 31 October 2018	ReactomeTeam	reactome version 63
	99690	view	15:09, 31 October 2018	ReactomeTeam	reactome version 62 (2nd attempt)
	99278	view	12:45, 31 October 2018	ReactomeTeam	reactome version 62
	93878	view	13:42, 16 August 2017	ReactomeTeam	reactome version 61
	93445	view	11:23, 9 August 2017	ReactomeTeam	reactome version 61
	86537	view	09:20, 11 July 2016	ReactomeTeam	reactome version 56
	83332	view	10:48, 18 November 2015	ReactomeTeam	Version54
	76964	view	08:24, 17 July 2014	ReactomeTeam	Fixed remaining interactions
	76669	view	12:03, 16 July 2014	ReactomeTeam	Fixed remaining interactions
	75997	view	10:05, 11 June 2014	ReactomeTeam	Re-fixing comment source
	75700	view	11:04, 10 June 2014	ReactomeTeam	Reactome 48 Update
	75056	view	13:56, 8 May 2014	Anwesha	Fixing comment source for displaying WikiPathways description
	74836	view	10:06, 30 April 2014	ReactomeTeam	Reactome46
	74700	view	08:46, 30 April 2014	ReactomeTeam	Reactome46
	44875	view	10:02, 6 October 2011	MartijnVanIersel	Ontology Term : 'apoptotic cell death pathway' added !
	42060	view	21:53, 4 March 2011	MaintBot	Automatic update
	39867	view	05:53, 21 January 2011	MaintBot	New pathway

External references

DataNodes

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Name	Type	Database reference	Comment
14-3-3 proteins:p-S99-BAD complex	Complex	REACT_5737 (Reactome)
14-3-3 dimer	Complex	REACT_147925 (Reactome)
ADP	Metabolite	CHEBI:16761 (ChEBI)
APAF1 [cytosol]	Protein	O14727 (Uniprot-TrEMBL)
APAF1	Protein	O14727 (Uniprot-TrEMBL)
ATP [cytosol]	Metabolite	CHEBI:15422 (ChEBI)
ATP	Metabolite	CHEBI:15422 (ChEBI)
Activated BAX	Complex	REACT_2560 (Reactome)
Active AKT		REACT_13319 (Reactome)
Active oligomeric BAK	Complex	REACT_4956 (Reactome)
Apaf-1:Cytochrome C	Complex	REACT_4880 (Reactome)
Apoptosome	Complex	REACT_3569 (Reactome)
BAD [mitochondrial outer membrane]	Protein	Q92934 (Uniprot-TrEMBL)
BAD:BCL-2	Complex	REACT_3232 (Reactome)
BAD	Protein	Q92934 (Uniprot-TrEMBL)
BAK1 [mitochondrial outer membrane]	Protein	Q16611 (Uniprot-TrEMBL)
BAK1 activated [mitochondrial outer membrane]	Protein	Q16611 (Uniprot-TrEMBL)
BAK1 activated	Protein	Q16611 (Uniprot-TrEMBL)
BAK1	Protein	Q16611 (Uniprot-TrEMBL)
BAX [cytosol]	Protein	Q07812 (Uniprot-TrEMBL)
BAX [mitochondrial outer membrane]	Protein	Q07812 (Uniprot-TrEMBL)
BAX activated	Protein	Q07812 (Uniprot-TrEMBL)
BAX	Protein	Q07812 (Uniprot-TrEMBL)
BBC3 [mitochondrial outer membrane]	Protein	Q9BXH1 (Uniprot-TrEMBL)
BBC3	Protein	Q9BXH1 (Uniprot-TrEMBL)
BCL2 [mitochondrial outer membrane]	Protein	P10415 (Uniprot-TrEMBL)
BCL2L1 [mitochondrial outer membrane]	Protein	Q07817 (Uniprot-TrEMBL)
BCL2L11 [cytosol]	Protein	O43521 (Uniprot-TrEMBL)
BCL2L1	Protein	Q07817 (Uniprot-TrEMBL)
BCL2	Protein	P10415 (Uniprot-TrEMBL)
BID(1-195) [mitochondrial outer membrane]	Protein	P55957 (Uniprot-TrEMBL)
BID(1-195) [cytosol]	Protein	P55957 (Uniprot-TrEMBL)
BID(1-195)	Protein	P55957 (Uniprot-TrEMBL)
BIM sequestered to dynein (DLC1)	Complex	REACT_3567 (Reactome)
BMF [plasma membrane]	Protein	Q96LC9 (Uniprot-TrEMBL)
BMF sequestered to dynein (DLC2)	Complex	REACT_3065 (Reactome)
Bcl-2 interacting BH-3 only proteins	Protein	REACT_21617 (Reactome)
Bcl-XL interacting BH3-only proteins	Protein	REACT_21650 (Reactome)
Bcl-XL:BH3-only protein complex	Complex	REACT_21559 (Reactome)
Bcl2:BH3-only protein complex	Complex	REACT_21874 (Reactome)
CASP3(1-277)	Protein	P42574 (Uniprot-TrEMBL)
CASP3(176-277) [cytosol]	Protein	P42574 (Uniprot-TrEMBL)
CASP3(29-175) [cytosol]	Protein	P42574 (Uniprot-TrEMBL)
CASP7(1-303)	Protein	P55210 (Uniprot-TrEMBL)
CASP7(199-303) [cytosol]	Protein	P55210 (Uniprot-TrEMBL)
CASP7(23-198) [cytosol]	Protein	P55210 (Uniprot-TrEMBL)
CASP8(217-374) [cytosol]	Protein	Q14790 (Uniprot-TrEMBL)
CASP8(385-479) [cytosol]	Protein	Q14790 (Uniprot-TrEMBL)
CASP9 [cytosol]	Protein	P55211 (Uniprot-TrEMBL)
CASP9(1-416) [cytosol]	Protein	P55211 (Uniprot-TrEMBL)
CASP9(1-416)	Protein	P55211 (Uniprot-TrEMBL)
CASP9(?-315) [cytosol]	Protein	P55211 (Uniprot-TrEMBL)
CYCS [cytosol]	Protein	P99999 (Uniprot-TrEMBL)
CYCS	Protein	P99999 (Uniprot-TrEMBL)
Calcineurin B complex	Complex	REACT_4613 (Reactome)
Cleaved Caspase-9	Complex	REACT_5782 (Reactome)
Cytochrome C:Apaf-1:ATP:Procaspase-9	Complex	REACT_5647 (Reactome)
DIABLO [cytosol]	Protein	Q9NR28 (Uniprot-TrEMBL)
DIABLO	Protein	Q9NR28 (Uniprot-TrEMBL)
DP-1:E2F1 complex	Complex	REACT_5400 (Reactome)
DYNLL1 [plasma membrane]	Protein	P63167 (Uniprot-TrEMBL)
DYNLL2 [plasma membrane]	Protein	Q96FJ2 (Uniprot-TrEMBL)
Dynein (DLC1) on microtubules	Complex	REACT_2522 (Reactome)
Dynein (DLC2) on microtubules	Complex	REACT_5554 (Reactome)
E2F1 [nucleoplasm]	Protein	Q01094 (Uniprot-TrEMBL)
GZMB	Protein	P10144 (Uniprot-TrEMBL)
H2O	Metabolite	CHEBI:15377 (ChEBI)
MAPK8	Protein	P45983 (Uniprot-TrEMBL)
MYS-BID(1-195)	Protein	P55957 (Uniprot-TrEMBL)
NMT1(1-?)	Protein	P30419 (Uniprot-TrEMBL)
PIP3 activates AKT signaling	Pathway	WP2653 (WikiPathways)	Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007.
PMAIP1 [mitochondrial outer membrane]	Protein	Q13794 (Uniprot-TrEMBL)
PMAIP1	Protein	Q13794 (Uniprot-TrEMBL)
PPP3CC [cytosol]	Protein	P48454 (Uniprot-TrEMBL)
PPP3R1 [cytosol]	Protein	P63098 (Uniprot-TrEMBL)
Pi	Metabolite	CHEBI:18367 (ChEBI)
SFN [cytosol]	Protein	P31947 (Uniprot-TrEMBL)
SMAC:XIAP:Caspase-3	Complex	REACT_5281 (Reactome)
SMAC:XIAP:Caspase-7	Complex	REACT_3355 (Reactome)
SMAC:XIAP:Caspase-9	Complex	REACT_4472 (Reactome)
SMAC:XIAP	Complex	REACT_5204 (Reactome)
TFDP1(1-410) [nucleoplasm]	Protein	Q14186 (Uniprot-TrEMBL)
XIAP [cytosol]	Protein	P98170 (Uniprot-TrEMBL)
XIAP:Caspase-3	Complex	REACT_2704 (Reactome)
XIAP:Caspase-7	Complex	REACT_2853 (Reactome)
XIAP:Caspase-9	Complex	REACT_4334 (Reactome)
YWHAB(1-246) [cytosol]	Protein	P31946 (Uniprot-TrEMBL)
YWHAE [cytosol]	Protein	P62258 (Uniprot-TrEMBL)
YWHAG(1-247) [cytosol]	Protein	P61981 (Uniprot-TrEMBL)
YWHAH [cytosol]	Protein	Q04917 (Uniprot-TrEMBL)
YWHAQ [cytosol]	Protein	P27348 (Uniprot-TrEMBL)
YWHAZ [cytosol]	Protein	P63104 (Uniprot-TrEMBL)
active caspase-3	Complex	REACT_2467 (Reactome)
active caspase-7	Complex	REACT_3366 (Reactome)
active caspase-8	Complex	REACT_151128 (Reactome)
p-BCL2L11 [mitochondrial outer membrane]	Protein	O43521 (Uniprot-TrEMBL)
p-BCL2L11	Protein	O43521 (Uniprot-TrEMBL)
p-BMF(1-89)	Protein	Q96LC9 (Uniprot-TrEMBL)
p-BMF	Protein	Q96LC9 (Uniprot-TrEMBL)
p-S15-TP53	Protein	P04637 (Uniprot-TrEMBL)
p-S99-BAD [cytosol]	Protein	Q92934 (Uniprot-TrEMBL)
p-S99-BAD	Protein	Q92934 (Uniprot-TrEMBL)
tBID bound to inactive BAK	Complex	REACT_6608 (Reactome)
tBID bound to inactive BAX	Complex	REACT_6691 (Reactome)
tBID:BCL-2	Complex	REACT_5048 (Reactome)

Annotated Interactions

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Source	Target	Type	Database reference	Comment
	14-3-3 proteins:p-S99-BAD complex	Arrow	REACT_1139 (Reactome)
14-3-3 proteins:p-S99-BAD complex			REACT_1663 (Reactome)
	14-3-3 dimer	Arrow	REACT_1663 (Reactome)
14-3-3 dimer			REACT_1139 (Reactome)
	ADP	Arrow	REACT_12565 (Reactome)
	ADP	Arrow	REACT_1460 (Reactome)
	ADP	Arrow	REACT_2116 (Reactome)
	ADP	Arrow	REACT_2165 (Reactome)
APAF1			REACT_1640 (Reactome)
ATP			REACT_12565 (Reactome)
ATP			REACT_1460 (Reactome)
ATP			REACT_2165 (Reactome)
ATP			REACT_39 (Reactome)
	Activated BAX	Arrow	REACT_341 (Reactome)
Active AKT		mim-catalysis	REACT_12565 (Reactome)
	Active oligomeric BAK	Arrow	REACT_507 (Reactome)
	Apaf-1:Cytochrome C	Arrow	REACT_1640 (Reactome)
Apaf-1:Cytochrome C			REACT_39 (Reactome)
	Apoptosome	Arrow	REACT_2116 (Reactome)
Apoptosome		mim-catalysis	REACT_1460 (Reactome)
Apoptosome		mim-catalysis	REACT_2165 (Reactome)
	BAD:BCL-2	Arrow	REACT_1062 (Reactome)
	BAD	Arrow	REACT_1663 (Reactome)
	BAD	Arrow	REACT_2046 (Reactome)
BAD			REACT_1062 (Reactome)
BAD			REACT_12565 (Reactome)
BAD			REACT_2046 (Reactome)
	BAK1 activated	Arrow	REACT_1424 (Reactome)
BAK1 activated			REACT_507 (Reactome)
BAK1			REACT_6153 (Reactome)
	BAX activated	Arrow	REACT_1506 (Reactome)
BAX activated			REACT_1286 (Reactome)
	BAX	Arrow	REACT_1286 (Reactome)
BAX			REACT_341 (Reactome)
BAX			REACT_6160 (Reactome)
	BBC3	Arrow	REACT_104 (Reactome)
	BBC3	Arrow	REACT_1555 (Reactome)
	BBC3	Arrow	REACT_284 (Reactome)
BBC3			REACT_104 (Reactome)
BCL2L1			REACT_21278 (Reactome)
BCL2			REACT_21389 (Reactome)
BCL2			REACT_784 (Reactome)
	BID(1-195)	Arrow	REACT_1062 (Reactome)
	BID(1-195)	Arrow	REACT_1320 (Reactome)
	BID(1-195)	Arrow	REACT_1370 (Reactome)
	BID(1-195)	Arrow	REACT_1424 (Reactome)
	BID(1-195)	Arrow	REACT_1506 (Reactome)
	BID(1-195)	Arrow	REACT_1610 (Reactome)
BID(1-195)			REACT_1158 (Reactome)
BID(1-195)			REACT_1320 (Reactome)
BID(1-195)			REACT_1610 (Reactome)
BID(1-195)			REACT_6153 (Reactome)
BID(1-195)			REACT_6160 (Reactome)
BID(1-195)			REACT_784 (Reactome)
BIM sequestered to dynein (DLC1)			REACT_1888 (Reactome)
BMF sequestered to dynein (DLC2)			REACT_1981 (Reactome)
Bcl-2 interacting BH-3 only proteins			REACT_21389 (Reactome)
Bcl-XL interacting BH3-only proteins			REACT_21278 (Reactome)
	Bcl-XL:BH3-only protein complex	Arrow	REACT_21278 (Reactome)
	Bcl2:BH3-only protein complex	Arrow	REACT_21389 (Reactome)
CASP3(1-277)			REACT_1460 (Reactome)
CASP7(1-303)			REACT_2165 (Reactome)
CASP9(1-416)			REACT_39 (Reactome)
	CYCS	Arrow	REACT_535 (Reactome)
CYCS			REACT_1640 (Reactome)
CYCS			REACT_535 (Reactome)
Calcineurin B complex		mim-catalysis	REACT_1663 (Reactome)
	Cleaved Caspase-9	Arrow	REACT_1035 (Reactome)
	Cytochrome C:Apaf-1:ATP:Procaspase-9	Arrow	REACT_39 (Reactome)
Cytochrome C:Apaf-1:ATP:Procaspase-9			REACT_2116 (Reactome)
Cytochrome C:Apaf-1:ATP:Procaspase-9		mim-catalysis	REACT_2116 (Reactome)
	DIABLO	Arrow	REACT_1101 (Reactome)
DIABLO			REACT_1090 (Reactome)
DIABLO			REACT_1101 (Reactome)
DIABLO			REACT_1312 (Reactome)
DIABLO			REACT_2091 (Reactome)
DP-1:E2F1 complex		Arrow	REACT_1872 (Reactome)
DP-1:E2F1 complex		Arrow	REACT_284 (Reactome)
	Dynein (DLC1) on microtubules	Arrow	REACT_1888 (Reactome)
	Dynein (DLC2) on microtubules	Arrow	REACT_1981 (Reactome)
GZMB		mim-catalysis	REACT_1610 (Reactome)
H2O			REACT_1663 (Reactome)
MAPK8		mim-catalysis	REACT_1888 (Reactome)
MAPK8		mim-catalysis	REACT_1981 (Reactome)
	MYS-BID(1-195)	Arrow	REACT_1158 (Reactome)
MYS-BID(1-195)			REACT_1370 (Reactome)
NMT1(1-?)		mim-catalysis	REACT_1158 (Reactome)
	PMAIP1	Arrow	REACT_1585 (Reactome)
	PMAIP1	Arrow	REACT_1872 (Reactome)
	PMAIP1	Arrow	REACT_2201 (Reactome)
PMAIP1			REACT_1585 (Reactome)
	Pi	Arrow	REACT_1663 (Reactome)
			REACT_1035 (Reactome)	Binding of DIABLO (SMAC) to XIAP promotes the release of caspase-9 from XIAP (Du et al. 2000).
			REACT_104 (Reactome)	It is thought that due to its p53 dependence for expression, PUMA could function as a mediator of p53-induced apoptosis. Newly synthesized PUMA protein translocates to mitochondria and binds to BCL-2 and Bcl-X(L) through a BH3 domain.
			REACT_1062 (Reactome)	Short peptides representing BAD and BIX were found to bind BCL-2 displacing BID-like BH3 domains that initiate mitochondrial dysfunction.
			REACT_1090 (Reactome)	At the beginning of this reaction, 1 molecule of 'SMAC', and 1 molecule of 'XIAP:Caspase-3' are present. At the end of this reaction, 1 molecule of 'SMAC:XIAP:Caspase-3' is present. This reaction takes place in the 'cytosol'.
			REACT_1101 (Reactome)	Permeabilization of the outer mitochondrial membrane by pro-apoptotic BCL2 family members BAK and BAX allows release of DIABLO (SMAC) from the mitochondrial intermembrane space into the cytosol (Arnoult et al. 2003). Binding of DIABLO (SMAC) to survivin leads to the inhibition of apoptosis (Song et al. 2003).
			REACT_1139 (Reactome)	14-3-3 proteins bind BAD phosphorylated by activated AKT on serine residue S99 (corresponds to mouse Bad serine residue S136). Binding of 14-3-3 proteins to p-S99-BAD facilitates subsequent phosphorylation of BAD on serine residue S118 (corresponds to mouse serine S155), which disrupts binding of BAD to BCL2 proteins and promotes cell survival (Datta et al. 2000). Caspase-3 mediated cleavage of 14-3-3 proteins releases BAD and promotes apoptosis (Won et al. 2003). All known 14-3-3 protein isoforms (beta/alpha i.e. YWHAB, gamma i.e. YWHAG, zeta/delta i.e. YWHAZ, epsilon i.e. YWHAE, eta i.e. YWHAH, sigma i.e. SFN and theta i.e. YWHAQ) can interact with BAD and inhibit it (Subramanian et al. 2001, Chen et al. 2005).
			REACT_1158 (Reactome)	After proteolytic activation, tBID is myristoylated by NMT-1 at an exposed glycine. N-myristoylation may enable the activated tBID to associate with the lipid components of the mitochondrial membrane.
			REACT_12565 (Reactome)	Activated AKT phosphorylates the BCL-2 family member BAD at serine 99 (corresponds to serine residue S136 of mouse Bad), blocking the BAD-induced cell death (Datta et al. 1997, del Peso et al. 1997, Khor et al. 2004).
			REACT_1286 (Reactome)	Activated BAX integrates in the outer mitochondrial membrane (Eskes et al. 2000, Antonsson et al. 2001, Bellosillo et al. 2002, Yi et al. 2003).
			REACT_1300 (Reactome)	Binding of DIABLO (SMAC) to XIAP promotes the liberation of active caspase-3 from its complex with XIAP (Kashkar et al. 2003).
			REACT_1312 (Reactome)	At the beginning of this reaction, 1 molecule of 'SMAC', and 1 molecule of 'XIAP:Caspase-9' are present. At the end of this reaction, 1 molecule of 'SMAC:XIAP:Caspase-9' is present. This reaction takes place in the 'cytosol'.
			REACT_1320 (Reactome)	The caspase 8 -mediated cleavage of cytosolic, inactive p22 BID at internal Asp sites yields a major p15 and minor p13 and p11 fragments. After myristoylation, tBID translocates to mitochondria as an integral membrane protein.
			REACT_1370 (Reactome)	N-myristoylation targets tBID to the mitochondrial outer membrane (Zha et al. 2000).
			REACT_1424 (Reactome)	tBID binds to its mitochondrial partner BAK to release cytochrome c. It has been observed in mouse systems that the activated tBID results in an allosteric activation of BAK. Activated BAK induces intramembranous oligomerization leading to a pore for cytochrome c efflux (Wei et al. 2000).
			REACT_1460 (Reactome)	Caspases-3 and -7 are directly cleaved downstream of caspase-9 in the cytochrome c/Apaf-1-inducible caspase cascade (Slee et al., 1999).
			REACT_1506 (Reactome)	During certain types of apoptosis, activated tBID (p15) induces a change in conformation of Bax which leads to the unmasking of its NH2-terminal domain. This change in confirmation usually results in the release of cytochrome c from mitochondria.
			REACT_1555 (Reactome)	TP53 (p53) stimulates the transcription of PUMA (p53 upregulated modulator of apoptosis) (Nakano and Vousden 2001).
			REACT_1585 (Reactome)	It was observed that cytosolic Noxa underwent BH3 motif-dependent localization to mitochondria and interacted with anti-apoptotic Bcl-2 family members, resulting in the activation of caspase-9.
			REACT_1610 (Reactome)	GZMB (granzyme B) cleaves BID to produce a p15 truncated form of BID (tBID) (Alimonti et al. 2001).
			REACT_1640 (Reactome)	Cytochrome c released to the cytosol from the mitochonridal intermembrane space binds APAF1 (Apaf-1) (Zou et al. 1997).
			REACT_1663 (Reactome)	Calcineurin, the Ca2+ activated protein phosphatase, dephosphorylates BAD, promoting dissociation of BAD from 14-3-3 proteins and the translocation of BAD to the outer mitochondrial membrane (Wang et al. 1999).
			REACT_1872 (Reactome)	E2F1 directly stimulates the transcription of PMAIP1 (NOXA) (Hershko and Ginsberg 2004).
			REACT_1888 (Reactome)	MAPK8 (JNK) phosphorylates BCL2L11 (BIM) on a DLC-binding motif (DKSTQTP), involved in dynein (DYNLL2 i.e. DLC1) binding and sequestration of BCL2L11 (BIM) to the cytoskeleton. Phosphorylated BCL2L11 dissociates from dynein. Three sites in BCL2L11 match the JNK consensus: S44, T56 and S58 in BCL2L11 isoform BimL (these residues correspond to S104, T116 and S118 in BCL2L11 isoform BimEL), and all sites appear to be phosphorylated by MAPK8 (JNK) both in vitro and in vivo (Lei and Davis 2003).
			REACT_1981 (Reactome)	MAPK8 (JNK) phosphorylates BMF on a DLC binding motif DKATQTLSP involved in interaction with dynein DYNLL2 (DLC2), which sequesters BMF to the cytoskeleton. Phosphorylated BMF dissociates from dynein. Two JNK consensus sites exist in BMF: S74 and S77 (Lei and Davis 2003).
			REACT_2046 (Reactome)	Dephosphorylated BAD translocates to the outer mitochondrial membrane (Wang et al. 1999).
			REACT_2091 (Reactome)	At the beginning of this reaction, 1 molecule of 'XIAP:Caspase-7', and 1 molecule of 'SMAC' are present. At the end of this reaction, 1 molecule of 'SMAC:XIAP:Caspase-7' is present. This reaction takes place in the 'cytosol'.
			REACT_2102 (Reactome)	Binding of DIABLO (SMAC) to the BIR2 domain of XIAP competes with binding of caspase-7 to the same domain of BIR2. As DIABLO has a higher affinity for the BIR2 domain than caspase-7, DIABLO (SMAC) binding to XIAP results in the liberation of caspase-7 (Huang et al. 2001).
			REACT_2116 (Reactome)	Caspase-9 is activated in an ATP-dependent manner following association with Apaf-1 and cytochrome c (Li et al., 1997)
			REACT_21278 (Reactome)	BH3-only proteins (tBid, BIM, PUMA, BAD, NOXA) associate with and inactivate anti-apoptotic protein Bcl-XL( Yi et al., 2003; Puthalakath et al., 1999; Nakano and Vousden, 2001; Wang et al., 1999; Oda et al., 2000). The interactions of NOXA with Bcl-XL are inferred from experiments performed in mice (Oda et al., 2000).
			REACT_21389 (Reactome)	Bcl-2 interacts with tBid (Yi et al. 2003), BIM (Puthalakath et al. 1999), PUMA (Nakano and Vousden 2001), NOXA (Oda et al. 2000), BAD (Yang et al. 2005), BMF (Puthalakath et al. 2001), resulting in inactivation of BCL2.
			REACT_2165 (Reactome)	Caspases-3 and -7 are directly cleaved downstream of caspase-9 in the cytochrome c/Apaf-1-inducible caspase cascade (Slee et al., 1999).
			REACT_2201 (Reactome)	TP53 (p53) stimulates transcription of PMAIP1 (NOXA) in response to nitric oxide (Li et al. 2004).
			REACT_284 (Reactome)	E2F1 directly stimulates the transcription of PUMA (Hershko and Ginsberg 2004).
			REACT_341 (Reactome)	Once integrated in the outer mitochondrial membrane, BAX forms oligomeric complexes which play an important role in cytochrome C release (Antonsson et al. 2001)
			REACT_39 (Reactome)	Apaf-1 and Caspase-9 form a complex in the presence of dATP and cytochrome c (Li et al.,1997).
			REACT_507 (Reactome)	Once activated BAK insterts in the outer mitochondrial membrane, it oligomerizes and these oligomeric BAK complexes are important for the cytochrome C efflux (Ruffolo and Shore 2003).
			REACT_535 (Reactome)	Permeabilization of the outer mitochondrial membrane by pro-apoptotic BCL2 family proteins, such as BAK and BAX, allows cytochrome c eflux from the mitochondrial intermembrane space into the cytosol (Arnoult et al. 2003).
			REACT_600 (Reactome)	Once BMF dissociates from the cytoskeleton, it translocates to the outer mitochondrial membrane where it binds BCL2 (Puthalakath et al. 2001).
			REACT_6153 (Reactome)	tBID binds to its mitochondrial partner BAK to release cytochrome c. It has been observed in mouse systems that the activated tBID results in an allosteric activation of BAK. Activated BAK induces intramembranous oligomerization leading to a pore for cytochrome c efflux (Wei et al. 2000).
			REACT_6160 (Reactome)	tBID binds to inactive BAX in the cytosol (Eskes et al. 2000).
			REACT_750 (Reactome)	Once BCL2L11 (BIM) dissociates from the cytoskeleton, it translocates to the outer mitochondrial membrane where it associates with BCL2 (Puthalakath et al. 1999).
			REACT_784 (Reactome)	BCL2 binds tBID and inhibits BID-induced cytochrome C release and apoptosis (Yi et al. 2003).
	SMAC:XIAP:Caspase-3	Arrow	REACT_1090 (Reactome)
SMAC:XIAP:Caspase-3			REACT_1300 (Reactome)
	SMAC:XIAP:Caspase-7	Arrow	REACT_2091 (Reactome)
SMAC:XIAP:Caspase-7			REACT_2102 (Reactome)
	SMAC:XIAP:Caspase-9	Arrow	REACT_1312 (Reactome)
SMAC:XIAP:Caspase-9			REACT_1035 (Reactome)
	SMAC:XIAP	Arrow	REACT_1035 (Reactome)
	SMAC:XIAP	Arrow	REACT_1300 (Reactome)
	SMAC:XIAP	Arrow	REACT_2102 (Reactome)
XIAP:Caspase-3			REACT_1090 (Reactome)
XIAP:Caspase-7			REACT_2091 (Reactome)
XIAP:Caspase-9			REACT_1312 (Reactome)
	active caspase-3	Arrow	REACT_1300 (Reactome)
	active caspase-3	Arrow	REACT_1460 (Reactome)
	active caspase-7	Arrow	REACT_2102 (Reactome)
	active caspase-7	Arrow	REACT_2165 (Reactome)
active caspase-8		mim-catalysis	REACT_1320 (Reactome)
	p-BCL2L11	Arrow	REACT_1888 (Reactome)
	p-BCL2L11	Arrow	REACT_750 (Reactome)
p-BCL2L11			REACT_750 (Reactome)
	p-BMF(1-89)	Arrow	REACT_1981 (Reactome)
p-BMF(1-89)			REACT_600 (Reactome)
	p-BMF	Arrow	REACT_600 (Reactome)
p-S15-TP53		Arrow	REACT_1555 (Reactome)
p-S15-TP53		Arrow	REACT_2201 (Reactome)
	p-S99-BAD	Arrow	REACT_12565 (Reactome)
p-S99-BAD			REACT_1139 (Reactome)
	tBID bound to inactive BAK	Arrow	REACT_6153 (Reactome)
tBID bound to inactive BAK			REACT_1424 (Reactome)
	tBID bound to inactive BAX	Arrow	REACT_6160 (Reactome)
tBID bound to inactive BAX			REACT_1506 (Reactome)
	tBID:BCL-2	Arrow	REACT_784 (Reactome)
tBID:BCL-2			REACT_1062 (Reactome)