Intrinsic Pathway for Apoptosis (Homo sapiens)

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2, 38, 411, 7, 24, 26, 35...22354, 1311432027, 3210, 31, 403, 12, 18, 24288525, 27, 3616, 17, 19, 2333292172915349, 152831, 7, 24, 35, 4325, 27, 36154, 1339142037431121433624Caspase-8 dimer cytosol14-3-3 gamma dimer mitochondrial inner membraneYWHAE dimer mitochondrial outer membraneDP-1E2F1 complex Activated BAX tBIDBCL-2 14-3-3zeta dimer Cleaved Caspase-9 BIM sequestered to dynein SMACXIAPCaspase-9 active caspase-7 BADBCL-2 SMACXIAPCaspase-7 SMACXIAPCaspase-3 Dynein 14-3-3 sigma dimer tBID bound to inactive BAX 14-3-3 eta dimer Cleaved Caspase-9 active caspase-7 active caspase-3 Active oligomeric BAK Dynein 14-3-3 dimer Bcl2BH3-only protein complex Apaf-1Cytochrome C active caspase-3 XIAPCaspase-9 Apaf-1Cytochrome C active caspase-3 SMACXIAP Apoptosome active caspase-7 XIAPCaspase-3 14-3-3zeta dimer 14-3-3 eta dimer Bcl-XL interacting BH3-only proteins YWHAB dimer 14-3-3 sigma dimer 14-3-3 gamma dimer tBID bound to inactive BAK Bcl-XLBH3-only protein complex Cleaved Caspase-9 Apaf-1Cytochrome C YWHAB dimer YWHAE dimer active caspase-8 Cytochrome CApaf-1ATPProcaspase-9 BMF sequestered to dynein Calcineurin B complex XIAPCaspase-9 XIAPCaspase-7 14-3-3 proteinsp-S99-BAD complex Cleaved Caspase-9 XIAPCaspase-3 14-3-3 dimer 14-3-3 theta dimer XIAPCaspase-7 14-3-3 theta dimer p-BCL2L11 DIABLO ATPYWHAZ APAF1PMAIP1ADPCYCSSMACXIAPADPYWHABCYCS XIAP Bcl-XLBH3-only protein complexBAK1 Activated BAXCytochrome CApaf-1ATPProcaspase-9Apaf-1Cytochrome CSFN BAXBCL2 ATPBADBCL-2CYCS CASP3CASP9BAXBAX YWHAQ YWHAGBIDADPCASP7CASP3p-S99-BAD CASP9tBID bound to inactive BAXActive AKTBADBAK1BMF sequestered to dynein ATPATP BIDXIAP SFN H2OCASP8NMT1CASP3DYNLL2 DIABLOPiXIAP BIDAPAF1 BAD tBIDBCL-2BBC3 CASP9 YWHAZ active caspase-7XIAPCaspase-7PPP3R1 PPP3CC DIABLOCASP3CASP9YWHAQ Active oligomeric BAKCleaved Caspase-9CASP3Dynein CASP9 BMF PIP3 activates AKT signalingCASP9CYCSDIABLO DIABLO DIABLO YWHAE YWHAH tBID bound to inactive BAKBBC3p-BCL2L11BIDYWHAH 14-3-3 dimerp-BMFBIDAPAF1 YWHAE CASP7ATPPMAIP1 Calcineurin B complexp-BMFBAX TFDP1active caspase-8Bcl2BH3-only protein complexBCL2L1DYNLL1 CASP3BAX activatedSMACXIAPCaspase-3DYNLL1 CASP8BBC3CASP7BCL2 MYS-BIDp-S99-BADE2F1 BCL2L11 MAPK8CASP7APAF1 YWHAGCASP9 p-BCL2L11SMACXIAPCaspase-9CASP7BCL2 BCL2BIM sequestered to dynein 14-3-3 proteinsp-S99-BAD complexBcl-2 interacting BH-3 only proteinsp-S15-TP53CASP9BCL2L1 XIAP XIAPCaspase-9Bcl-XL interacting BH3-only proteinsCYCS XIAP BIDDYNLL2 CASP9 PMAIP1CASP9DP-1E2F1 complexBIDCASP3XIAP active caspase-3SMACXIAPCaspase-7BAK1 activatedBADYWHABCASP7XIAP GZMBADPApoptosomeCASP7BAK1 activated BAD Dynein XIAPCaspase-36, 42303020203030303030


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Wikipathways-description 
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.

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Bibliography

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History

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CompareRevisionActionTimeUserComment
114961view16:48, 25 January 2021ReactomeTeamReactome version 75
113405view11:48, 2 November 2020ReactomeTeamReactome version 74
112608view15:58, 9 October 2020ReactomeTeamReactome version 73
101524view11:39, 1 November 2018ReactomeTeamreactome version 66
101060view21:21, 31 October 2018ReactomeTeamreactome version 65
100591view19:55, 31 October 2018ReactomeTeamreactome version 64
100140view16:40, 31 October 2018ReactomeTeamreactome version 63
99690view15:09, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99278view12:45, 31 October 2018ReactomeTeamreactome version 62
93878view13:42, 16 August 2017ReactomeTeamreactome version 61
93445view11:23, 9 August 2017ReactomeTeamreactome version 61
86537view09:20, 11 July 2016ReactomeTeamreactome version 56
83332view10:48, 18 November 2015ReactomeTeamVersion54
76964view08:24, 17 July 2014ReactomeTeamFixed remaining interactions
76669view12:03, 16 July 2014ReactomeTeamFixed remaining interactions
75997view10:05, 11 June 2014ReactomeTeamRe-fixing comment source
75700view11:04, 10 June 2014ReactomeTeamReactome 48 Update
75056view13:56, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74836view10:06, 30 April 2014ReactomeTeamReactome46
74700view08:46, 30 April 2014ReactomeTeamReactome46
44875view10:02, 6 October 2011MartijnVanIerselOntology Term : 'apoptotic cell death pathway' added !
42060view21:53, 4 March 2011MaintBotAutomatic update
39867view05:53, 21 January 2011MaintBotNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
14-3-3 dimerComplexREACT_147925 (Reactome)
14-3-3 proteins p-S99-BAD complexComplexREACT_5737 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
APAF1 ProteinO14727 (Uniprot-TrEMBL)
APAF1ProteinO14727 (Uniprot-TrEMBL)
ATP MetaboliteCHEBI:15422 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Activated BAXComplexREACT_2560 (Reactome)
Active AKTREACT_13319 (Reactome)
Active oligomeric BAKComplexREACT_4956 (Reactome)
Apaf-1 Cytochrome CComplexREACT_4880 (Reactome)
ApoptosomeComplexREACT_3569 (Reactome)
BAD BCL-2ComplexREACT_3232 (Reactome)
BAD ProteinQ92934 (Uniprot-TrEMBL)
BADProteinQ92934 (Uniprot-TrEMBL)
BAK1 ProteinQ16611 (Uniprot-TrEMBL)
BAK1 activated ProteinQ16611 (Uniprot-TrEMBL)
BAK1 activatedProteinQ16611 (Uniprot-TrEMBL)
BAK1ProteinQ16611 (Uniprot-TrEMBL)
BAX ProteinQ07812 (Uniprot-TrEMBL)
BAX activatedProteinQ07812 (Uniprot-TrEMBL)
BAXProteinQ07812 (Uniprot-TrEMBL)
BBC3 ProteinQ9BXH1 (Uniprot-TrEMBL)
BBC3ProteinQ9BXH1 (Uniprot-TrEMBL)
BCL2 ProteinP10415 (Uniprot-TrEMBL)
BCL2L1 ProteinQ07817 (Uniprot-TrEMBL)
BCL2L11 ProteinO43521 (Uniprot-TrEMBL)
BCL2L1ProteinQ07817 (Uniprot-TrEMBL)
BCL2ProteinP10415 (Uniprot-TrEMBL)
BIDProteinP55957 (Uniprot-TrEMBL)
BIM sequestered to dynein ComplexREACT_3567 (Reactome)
BMF ProteinQ96LC9 (Uniprot-TrEMBL)
BMF sequestered to dynein ComplexREACT_3065 (Reactome)
Bcl-2 interacting BH-3 only proteinsProteinREACT_21617 (Reactome)
Bcl-XL BH3-only protein complexComplexREACT_21559 (Reactome)
Bcl-XL interacting BH3-only proteinsProteinREACT_21650 (Reactome)
Bcl2 BH3-only protein complexComplexREACT_21874 (Reactome)
CASP3ProteinP42574 (Uniprot-TrEMBL)
CASP7ProteinP55210 (Uniprot-TrEMBL)
CASP8ProteinQ14790 (Uniprot-TrEMBL)
CASP9 ProteinP55211 (Uniprot-TrEMBL)
CASP9ProteinP55211 (Uniprot-TrEMBL)
CYCS ProteinP99999 (Uniprot-TrEMBL)
CYCSProteinP99999 (Uniprot-TrEMBL)
Calcineurin B complexComplexREACT_4613 (Reactome)
Cleaved Caspase-9ComplexREACT_5782 (Reactome)
Cytochrome C

Apaf-1 ATP

Procaspase-9		ComplexREACT_5647 (Reactome)
DIABLO ProteinQ9NR28 (Uniprot-TrEMBL)
DIABLOProteinQ9NR28 (Uniprot-TrEMBL)
DP-1 E2F1 complexComplexREACT_5400 (Reactome)
DYNLL1 ProteinP63167 (Uniprot-TrEMBL)
DYNLL2 ProteinQ96FJ2 (Uniprot-TrEMBL)
Dynein ComplexREACT_2522 (Reactome)
Dynein ComplexREACT_5554 (Reactome)
E2F1 ProteinQ01094 (Uniprot-TrEMBL)
GZMBProteinP10144 (Uniprot-TrEMBL)
H2OMetaboliteCHEBI:15377 (ChEBI)
MAPK8ProteinP45983 (Uniprot-TrEMBL)
MYS-BIDProteinP55957 (Uniprot-TrEMBL)
NMT1ProteinP30419 (Uniprot-TrEMBL)
PIP3 activates AKT signalingPathwayREACT_75829 (Reactome) 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 ProteinQ13794 (Uniprot-TrEMBL)
PMAIP1ProteinQ13794 (Uniprot-TrEMBL)
PPP3CC ProteinP48454 (Uniprot-TrEMBL)
PPP3R1 ProteinP63098 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:18367 (ChEBI)
SFN ProteinP31947 (Uniprot-TrEMBL)
SMAC

XIAP

Caspase-3		ComplexREACT_5281 (Reactome)
SMAC

XIAP

Caspase-7		ComplexREACT_3355 (Reactome)
SMAC

XIAP

Caspase-9		ComplexREACT_4472 (Reactome)
SMAC XIAPComplexREACT_5204 (Reactome)
TFDP1ProteinQ14186 (Uniprot-TrEMBL)
XIAP Caspase-3ComplexREACT_2704 (Reactome)
XIAP Caspase-7ComplexREACT_2853 (Reactome)
XIAP Caspase-9ComplexREACT_4334 (Reactome)
XIAP ProteinP98170 (Uniprot-TrEMBL)
YWHABProteinP31946 (Uniprot-TrEMBL)
YWHAE ProteinP62258 (Uniprot-TrEMBL)
YWHAGProteinP61981 (Uniprot-TrEMBL)
YWHAH ProteinQ04917 (Uniprot-TrEMBL)
YWHAQ ProteinP27348 (Uniprot-TrEMBL)
YWHAZ ProteinP63104 (Uniprot-TrEMBL)
active caspase-3ComplexREACT_2467 (Reactome)
active caspase-7ComplexREACT_3366 (Reactome)
active caspase-8ComplexREACT_151128 (Reactome)
p-BCL2L11 ProteinO43521 (Uniprot-TrEMBL)
p-BCL2L11ProteinO43521 (Uniprot-TrEMBL)
p-BMFProteinQ96LC9 (Uniprot-TrEMBL)
p-S15-TP53ProteinP04637 (Uniprot-TrEMBL)
p-S99-BAD ProteinQ92934 (Uniprot-TrEMBL)
p-S99-BADProteinQ92934 (Uniprot-TrEMBL)
tBID BCL-2ComplexREACT_5048 (Reactome)
tBID bound to inactive BAKComplexREACT_6608 (Reactome)
tBID bound to inactive BAXComplexREACT_6691 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
14-3-3 dimerArrowREACT_1663 (Reactome)
14-3-3 dimerREACT_1139 (Reactome)
14-3-3 proteins p-S99-BAD complexREACT_1663 (Reactome)
ADPArrowREACT_12565 (Reactome)
ADPArrowREACT_1460 (Reactome)
ADPArrowREACT_2116 (Reactome)
ADPArrowREACT_2165 (Reactome)
APAF1REACT_1640 (Reactome)
ATPREACT_12565 (Reactome)
ATPREACT_1460 (Reactome)
ATPREACT_2165 (Reactome)
ATPREACT_39 (Reactome)
Active AKTmim-catalysisREACT_12565 (Reactome)
Apaf-1 Cytochrome CREACT_39 (Reactome)
ApoptosomeArrowREACT_2116 (Reactome)
Apoptosomemim-catalysisREACT_1460 (Reactome)
Apoptosomemim-catalysisREACT_2165 (Reactome)
BAD BCL-2ArrowREACT_1062 (Reactome)
BADArrowREACT_1663 (Reactome)
BADREACT_1062 (Reactome)
BADREACT_12565 (Reactome)
BAK1 activatedArrowREACT_1424 (Reactome)
BAK1REACT_6153 (Reactome)
BAX activatedArrowREACT_1506 (Reactome)
BAXREACT_6160 (Reactome)
BCL2L1REACT_21278 (Reactome)
BCL2REACT_21389 (Reactome)
BCL2REACT_784 (Reactome)
BIDArrowREACT_1062 (Reactome)
BIDArrowREACT_1424 (Reactome)
BIDArrowREACT_1506 (Reactome)
BIDREACT_6153 (Reactome)
BIDREACT_6160 (Reactome)
BIDREACT_784 (Reactome)
Bcl-2 interacting BH-3 only proteinsREACT_21389 (Reactome)
Bcl-XL interacting BH3-only proteinsREACT_21278 (Reactome)
CASP3REACT_1460 (Reactome)
CASP7REACT_2165 (Reactome)
CASP9REACT_39 (Reactome)
CYCSREACT_1640 (Reactome)
Calcineurin B complexmim-catalysisREACT_1663 (Reactome)
Cleaved Caspase-9ArrowREACT_1035 (Reactome)
Cytochrome C

Apaf-1 ATP

Procaspase-9		mim-catalysisREACT_2116 (Reactome)
DIABLOREACT_1090 (Reactome)
DIABLOREACT_1312 (Reactome)
DIABLOREACT_2091 (Reactome)
DP-1 E2F1 complexArrowREACT_1872 (Reactome)
DP-1 E2F1 complexArrowREACT_284 (Reactome)
Dynein ArrowREACT_1888 (Reactome)
Dynein ArrowREACT_1981 (Reactome)
GZMBmim-catalysisREACT_1610 (Reactome)
H2OREACT_1663 (Reactome)
MAPK8mim-catalysisREACT_1888 (Reactome)
MAPK8mim-catalysisREACT_1981 (Reactome)
NMT1mim-catalysisREACT_1158 (Reactome)
PiArrowREACT_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 XIAPArrowREACT_1035 (Reactome)
SMAC XIAPArrowREACT_1300 (Reactome)
SMAC XIAPArrowREACT_2102 (Reactome)
XIAP Caspase-3REACT_1090 (Reactome)
XIAP Caspase-7REACT_2091 (Reactome)
XIAP Caspase-9REACT_1312 (Reactome)
active caspase-3ArrowREACT_1300 (Reactome)
active caspase-3ArrowREACT_1460 (Reactome)
active caspase-7ArrowREACT_2102 (Reactome)
active caspase-7ArrowREACT_2165 (Reactome)
active caspase-8mim-catalysisREACT_1320 (Reactome)
p-BCL2L11ArrowREACT_1888 (Reactome)
p-BMFArrowREACT_1981 (Reactome)
p-S15-TP53ArrowREACT_1555 (Reactome)
p-S15-TP53ArrowREACT_2201 (Reactome)
p-S99-BADArrowREACT_12565 (Reactome)
p-S99-BADREACT_1139 (Reactome)
tBID BCL-2REACT_1062 (Reactome)

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