Intrinsic Pathway for Apoptosis (Homo sapiens)

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1, 16, 444, 13, 34, 39, 53...376, 574, 18, 34, 39, 5631184, 14, 46, 477, 11, 52271823, 25, 27403456, 57810, 19, 292039332712, 32, 46, 49, 5612, 32, 46, 49, 563632633338339, 154524, 28, 48, 54, 555450429, 21, 45, 512, 22, 30, 359, 21, 4537361334, 36, 40, 414, 14, 46, 47nucleoplasmmitochondrial outer membranecytosolmitochondrial inner membraneTFDP2 MYS-BID(62-195)E2F1 p-T308,S473-AKT1 tBID:BCL-2CASP3(1-277) PIP3 activates AKTsignalingCaspase-7CASP7(207-303) CASP9(1-416) ApoptosomeTP73 BID(62-195) PPP1R13B p-S99-BAD CASP3(29-175) YWHAH p-S15,S20-TP53TetramerCASP9(?-315) BAX BBC3 Bcl-2/Bcl-X(L)DIABLOYWHAB SMAC:XIAP:Caspase-9APAF1CASP3(29-175) BCL2L1 gene CASP3(176-277) DIABLO APAF1 BCL2L1 YWHAQ GZMBBBC3CYCSCASP9(?-315) 14-3-3proteins:p-S99-BADcomplexYWHAG ATPActivated BAXactive caspase-8SMAC:XIAPBCL2microtubules BCL2 gene, BCL2L1geneXIAP p-BMF CASP9(331-416) DYNLL1 BBC3TFDP1 YWHAZ PPP3CC Apaf-1:Cytochrome CBAD CASP8(217-374) ADPXIAP:Caspase-9SFN DYNLL1 ATPPMAIP1 p-S15,S20-TP53 PMAIP1 GeneYWHAE CASP8(385-479) CASP9(331-416) BAD TFDP2 TFDP1 Bcl-XL:BH3-onlyprotein complexPMAIP1p-BMF p-BCL2L11 DIABLO BCL2 Bcl-XL interactingBH3-only proteinsCASP7(207-303) BBC3 Genep-Y705-STAT3 p-S15,S20-TP53 BAX p-S15,S20-TP53 ATPBAD tBID bound toinactive BAXBBC3 BADBAK1 activatedtBID bound toinactive BAKCASP3(176-277) BAK1CASP7(2-303) dimerp-BCL2L11 p-BMFCASP7(2-303) (p-S15,S20-TP53,TP63,TP73):(PPP1R13B,TP53BP2)14-3-3 dimerBBC3 Gene ADPCASP9(331-416) YWHAE PMAIP1 Gene microtubules TP63 XIAP TP53BP2 CYCSCaspase-3CASP9(?-315) ATPE2F1 DIABLOCASP3(176-277) p-T305,S472-AKT3 MYS-BID(62-195) APAF1 PMAIP1 Gene E2F1 CASP7(24-198) PiSFN YWHAQ DYNLL2 BID(1-195)SMAC:XIAP:Caspase-7BADBMF TFDP2 CYCS p-BCL2L11 XIAP:Caspase-7BAX Dynein (DLC2) onmicrotubulesBAK1 activated BBC3 Gene ADPBBC3 Activated BAX,BAKoligomersADPDIABLO Dynein (DLC1) onmicrotubulesYWHAH BCL2L11 TP73 BAXCASP3(29-175) XIAP BMF sequestered todynein (DLC2)XIAP:Caspase-3p-T,p-S-AKTBAD PMAIP1 NMT 1MYS-BID(62-195) (p-S15,S20-TP53,TP63,TP73):(PPP1R13B,TP53BP2):BBC3 GeneBAK1 activated E2F1:TFDP1,TFDP2CASP9(?-315) BCL2L1 APAF1 BIM sequestered todynein (DLC1)p-BCL2L11 TP53BP2 Calcineurin BcomplexCASP7(207-303) CASP9(331-416) BCL2L1XIAP ATPATPCASP3(1-277) dimerPMAIP1YWHAG MAPK8microtubules PPP3R1 H2OBAD PPP1R13B BBC3 BCL2 PMAIP1 p-S15,S20-TP53 SMAC:XIAP:Caspase-3p-BCL2L11DIABLO Bcl-2 interactingBH-3 only proteinsp-T309,S474-AKT2 Active oligomericBAKBAXCYCS DYNLL2 CASP9(1-416)CASP7(24-198) E2F1:TFDP1:BBC3 GeneXIAP BCL2 gene ATP BID(62-195)BCL2 p-BMF(1-89)Cleaved Caspase-9microtubules PMAIP1 TFDP1 MYS-BID(62-195)p-S99-BADp-BCL2L11CytochromeC:Apaf-1:ATP:Procaspase-9E2F1:TFDP1:PMAIP1GeneTP63 BAX activatedADPYWHAB XIAP BCL2 ADPp-S15,S20-TP53Tetramer:PMAIP1GeneMYS-BID(62-195) XIAP Bcl2:BH3-onlyprotein complexYWHAZ BAK1 CYCS MYS-BID(62-195) CASP7(24-198) BAD:BCL-2p-Y705-STAT3 dimer38, 4317174, 141717823, 54, 5523, 54, 55331717812, 562333


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. View original pathway at:Reactome.</div>

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 109606
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: Matthews, Lisa

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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
(p-S15,S20-TP53,TP63,TP73):(PPP1R13B,TP53BP2):BBC3 GeneComplexR-HSA-4331345 (Reactome)
(p-S15,S20-TP53,TP63,TP73):(PPP1R13B,TP53BP2)ComplexR-HSA-6799788 (Reactome)
14-3-3

proteins:p-S99-BAD

complex		ComplexR-HSA-139904 (Reactome)
14-3-3 dimerComplexR-HSA-1445138 (Reactome)
ADPMetaboliteCHEBI:16761 (ChEBI)
APAF1 ProteinO14727 (Uniprot-TrEMBL)
APAF1ProteinO14727 (Uniprot-TrEMBL)
ATP MetaboliteCHEBI:15422 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Activated BAX,BAK oligomersComplexR-HSA-9029242 (Reactome)
Activated BAXComplexR-HSA-114269 (Reactome)
Active oligomeric BAKComplexR-HSA-114262 (Reactome)
Apaf-1:Cytochrome CComplexR-HSA-114253 (Reactome)
ApoptosomeComplexR-HSA-114258 (Reactome)
BAD ProteinQ92934 (Uniprot-TrEMBL)
BAD:BCL-2ComplexR-HSA-114268 (Reactome)
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 Gene ProteinENSG00000105327 (Ensembl)
BBC3 GeneGeneProductENSG00000105327 (Ensembl)
BBC3 ProteinQ9BXH1 (Uniprot-TrEMBL)
BBC3ProteinQ9BXH1 (Uniprot-TrEMBL)
BCL2 ProteinP10415 (Uniprot-TrEMBL)
BCL2 gene ProteinENSG00000171791 (Ensembl)
BCL2 gene, BCL2L1 geneComplexR-HSA-6790035 (Reactome)
BCL2L1 ProteinQ07817 (Uniprot-TrEMBL)
BCL2L1 gene ProteinENSG00000171552 (Ensembl)
BCL2L11 ProteinO43521 (Uniprot-TrEMBL)
BCL2L1ProteinQ07817 (Uniprot-TrEMBL)
BCL2ProteinP10415 (Uniprot-TrEMBL)
BID(1-195)ProteinP55957 (Uniprot-TrEMBL)
BID(62-195) ProteinP55957 (Uniprot-TrEMBL)
BID(62-195)ProteinP55957 (Uniprot-TrEMBL)
BIM sequestered to dynein (DLC1)ComplexR-HSA-140524 (Reactome)
BMF ProteinQ96LC9 (Uniprot-TrEMBL)
BMF sequestered to dynein (DLC2)ComplexR-HSA-140528 (Reactome)
Bcl-2 interacting BH-3 only proteinsComplexR-HSA-508157 (Reactome)
Bcl-2/Bcl-X(L)ComplexR-HSA-879209 (Reactome)
Bcl-XL interacting BH3-only proteinsComplexR-HSA-508161 (Reactome)
Bcl-XL:BH3-only protein complexComplexR-HSA-508159 (Reactome)
Bcl2:BH3-only protein complexComplexR-HSA-508158 (Reactome)
CASP3(1-277) ProteinP42574 (Uniprot-TrEMBL)
CASP3(1-277) dimerComplexR-HSA-6804299 (Reactome)
CASP3(176-277) ProteinP42574 (Uniprot-TrEMBL)
CASP3(29-175) ProteinP42574 (Uniprot-TrEMBL)
CASP7(2-303) ProteinP55210 (Uniprot-TrEMBL)
CASP7(2-303) dimerComplexR-HSA-6804324 (Reactome)
CASP7(207-303) ProteinP55210 (Uniprot-TrEMBL)
CASP7(24-198) ProteinP55210 (Uniprot-TrEMBL)
CASP8(217-374) ProteinQ14790 (Uniprot-TrEMBL)
CASP8(385-479) ProteinQ14790 (Uniprot-TrEMBL)
CASP9(1-416) ProteinP55211 (Uniprot-TrEMBL)
CASP9(1-416)ProteinP55211 (Uniprot-TrEMBL)
CASP9(331-416) ProteinP55211 (Uniprot-TrEMBL)
CASP9(?-315) ProteinP55211 (Uniprot-TrEMBL)
CYCS ProteinP99999 (Uniprot-TrEMBL)
CYCSProteinP99999 (Uniprot-TrEMBL)
Calcineurin B complexComplexR-HSA-140202 (Reactome)
Caspase-3ComplexR-HSA-350870 (Reactome)
Caspase-7ComplexR-HSA-141643 (Reactome) CASP7 heterotetramer consists of two anti-parallel arranged CASP7 heterodimers, each one formed by a 20 kDa (p20) and a 11 kDa (p11) subunit.
Cleaved Caspase-9ComplexR-HSA-141640 (Reactome)
Cytochrome C:Apaf-1:ATP:Procaspase-9ComplexR-HSA-114255 (Reactome)
DIABLO ProteinQ9NR28 (Uniprot-TrEMBL)
DIABLOProteinQ9NR28 (Uniprot-TrEMBL)
DYNLL1 ProteinP63167 (Uniprot-TrEMBL)
DYNLL2 ProteinQ96FJ2 (Uniprot-TrEMBL)
Dynein (DLC1) on microtubulesComplexR-HSA-140526 (Reactome)
Dynein (DLC2) on microtubulesComplexR-HSA-140530 (Reactome)
E2F1 ProteinQ01094 (Uniprot-TrEMBL)
E2F1:TFDP1,TFDP2ComplexR-HSA-68653 (Reactome)
E2F1:TFDP1:BBC3 GeneComplexR-HSA-4331325 (Reactome)
E2F1:TFDP1:PMAIP1 GeneComplexR-HSA-4331338 (Reactome)
GZMBProteinP10144 (Uniprot-TrEMBL)
H2OMetaboliteCHEBI:15377 (ChEBI)
MAPK8ProteinP45983 (Uniprot-TrEMBL)
MYS-BID(62-195) ProteinP55957 (Uniprot-TrEMBL)
MYS-BID(62-195)ProteinP55957 (Uniprot-TrEMBL)
NMT 1ProteinP30419 (Uniprot-TrEMBL)
PIP3 activates AKT signalingPathwayR-HSA-1257604 (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 Gene ProteinENSG00000141682 (Ensembl)
PMAIP1 GeneGeneProductENSG00000141682 (Ensembl)
PMAIP1 ProteinQ13794 (Uniprot-TrEMBL)
PMAIP1ProteinQ13794 (Uniprot-TrEMBL)
PPP1R13B ProteinQ96KQ4 (Uniprot-TrEMBL)
PPP3CC ProteinP48454 (Uniprot-TrEMBL)
PPP3R1 ProteinP63098 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:18367 (ChEBI)
SFN ProteinP31947 (Uniprot-TrEMBL)
SMAC:XIAP:Caspase-3ComplexR-HSA-114305 (Reactome)
SMAC:XIAP:Caspase-7ComplexR-HSA-114353 (Reactome)
SMAC:XIAP:Caspase-9ComplexR-HSA-114318 (Reactome)
SMAC:XIAPComplexR-HSA-114391 (Reactome)
TFDP1 ProteinQ14186 (Uniprot-TrEMBL)
TFDP2 ProteinQ14188 (Uniprot-TrEMBL)
TP53BP2 ProteinQ13625 (Uniprot-TrEMBL)
TP63 ProteinQ9H3D4 (Uniprot-TrEMBL)
TP73 ProteinO15350 (Uniprot-TrEMBL)
XIAP ProteinP98170 (Uniprot-TrEMBL)
XIAP:Caspase-3ComplexR-HSA-114304 (Reactome)
XIAP:Caspase-7ComplexR-HSA-114308 (Reactome)
XIAP:Caspase-9ComplexR-HSA-114317 (Reactome)
YWHAB ProteinP31946 (Uniprot-TrEMBL)
YWHAE ProteinP62258 (Uniprot-TrEMBL)
YWHAG ProteinP61981 (Uniprot-TrEMBL)
YWHAH ProteinQ04917 (Uniprot-TrEMBL)
YWHAQ ProteinP27348 (Uniprot-TrEMBL)
YWHAZ ProteinP63104 (Uniprot-TrEMBL)
active caspase-8ComplexR-HSA-2562550 (Reactome)
microtubules R-HSA-140523 (Reactome)
p-BCL2L11 ProteinO43521 (Uniprot-TrEMBL)
p-BCL2L11ProteinO43521 (Uniprot-TrEMBL)
p-BMF ProteinQ96LC9 (Uniprot-TrEMBL)
p-BMF(1-89)ProteinQ96LC9 (Uniprot-TrEMBL)
p-BMFProteinQ96LC9 (Uniprot-TrEMBL)
p-S15,S20-TP53

Tetramer:PMAIP1

Gene		ComplexR-HSA-4331332 (Reactome)
p-S15,S20-TP53 TetramerComplexR-HSA-3222171 (Reactome)
p-S15,S20-TP53 ProteinP04637 (Uniprot-TrEMBL)
p-S99-BAD ProteinQ92934 (Uniprot-TrEMBL)
p-S99-BADProteinQ92934 (Uniprot-TrEMBL)
p-T,p-S-AKTComplexR-HSA-202074 (Reactome)
p-T305,S472-AKT3 ProteinQ9Y243 (Uniprot-TrEMBL)
p-T308,S473-AKT1 ProteinP31749 (Uniprot-TrEMBL)
p-T309,S474-AKT2 ProteinP31751 (Uniprot-TrEMBL)
p-Y705-STAT3 ProteinP40763 (Uniprot-TrEMBL)
p-Y705-STAT3 dimerComplexR-HSA-1112525 (Reactome)
tBID bound to inactive BAKComplexR-HSA-168847 (Reactome)
tBID bound to inactive BAXComplexR-HSA-168850 (Reactome)
tBID:BCL-2ComplexR-HSA-114339 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
(p-S15,S20-TP53,TP63,TP73):(PPP1R13B,TP53BP2):BBC3 GeneArrowR-HSA-139913 (Reactome)
(p-S15,S20-TP53,TP63,TP73):(PPP1R13B,TP53BP2):BBC3 GeneArrowR-HSA-4331340 (Reactome)
(p-S15,S20-TP53,TP63,TP73):(PPP1R13B,TP53BP2)R-HSA-4331340 (Reactome)
14-3-3

proteins:p-S99-BAD

complex		ArrowR-HSA-139899 (Reactome)
14-3-3

proteins:p-S99-BAD

complex		R-HSA-139906 (Reactome)
14-3-3 dimerArrowR-HSA-139906 (Reactome)
14-3-3 dimerR-HSA-139899 (Reactome)
ADPArrowR-HSA-114252 (Reactome)
ADPArrowR-HSA-114259 (Reactome)
ADPArrowR-HSA-114261 (Reactome)
ADPArrowR-HSA-139908 (Reactome)
ADPArrowR-HSA-139918 (Reactome)
ADPArrowR-HSA-198347 (Reactome)
APAF1R-HSA-114254 (Reactome)
ATPR-HSA-114252 (Reactome)
ATPR-HSA-114256 (Reactome)
ATPR-HSA-114261 (Reactome)
ATPR-HSA-139908 (Reactome)
ATPR-HSA-139918 (Reactome)
ATPR-HSA-198347 (Reactome)
Activated BAX,BAK oligomersArrowR-HSA-114284 (Reactome)
Activated BAX,BAK oligomersArrowR-HSA-114307 (Reactome)
Activated BAXArrowR-HSA-114275 (Reactome)
Active oligomeric BAKArrowR-HSA-114263 (Reactome)
Apaf-1:Cytochrome CArrowR-HSA-114254 (Reactome)
Apaf-1:Cytochrome CR-HSA-114256 (Reactome)
ApoptosomeArrowR-HSA-114259 (Reactome)
Apoptosomemim-catalysisR-HSA-114252 (Reactome)
Apoptosomemim-catalysisR-HSA-114261 (Reactome)
BAD:BCL-2ArrowR-HSA-139897 (Reactome)
BADArrowR-HSA-139905 (Reactome)
BADArrowR-HSA-139906 (Reactome)
BADR-HSA-139897 (Reactome)
BADR-HSA-139905 (Reactome)
BADR-HSA-198347 (Reactome)
BAK1 activatedArrowR-HSA-139895 (Reactome)
BAK1 activatedR-HSA-114263 (Reactome)
BAK1R-HSA-168848 (Reactome)
BAX activatedArrowR-HSA-139917 (Reactome)
BAX activatedR-HSA-114264 (Reactome)
BAXArrowR-HSA-114264 (Reactome)
BAXR-HSA-114275 (Reactome)
BAXR-HSA-168849 (Reactome)
BBC3 GeneR-HSA-139913 (Reactome)
BBC3 GeneR-HSA-140221 (Reactome)
BBC3 GeneR-HSA-4331324 (Reactome)
BBC3 GeneR-HSA-4331340 (Reactome)
BBC3ArrowR-HSA-139913 (Reactome)
BBC3ArrowR-HSA-139914 (Reactome)
BBC3ArrowR-HSA-140221 (Reactome)
BBC3R-HSA-139914 (Reactome)
BCL2 gene, BCL2L1 geneR-HSA-6790025 (Reactome)
BCL2L1R-HSA-508162 (Reactome)
BCL2R-HSA-114352 (Reactome)
BCL2R-HSA-508163 (Reactome)
BID(1-195)R-HSA-139893 (Reactome)
BID(1-195)R-HSA-139898 (Reactome)
BID(62-195)ArrowR-HSA-139893 (Reactome)
BID(62-195)ArrowR-HSA-139898 (Reactome)
BID(62-195)ArrowR-HSA-139917 (Reactome)
BID(62-195)R-HSA-141367 (Reactome)
BID(62-195)R-HSA-168849 (Reactome)
BIM sequestered to dynein (DLC1)R-HSA-139918 (Reactome)
BMF sequestered to dynein (DLC2)R-HSA-139908 (Reactome)
Bcl-2 interacting BH-3 only proteinsR-HSA-508163 (Reactome)
Bcl-2/Bcl-X(L)ArrowR-HSA-6790025 (Reactome)
Bcl-XL interacting BH3-only proteinsR-HSA-508162 (Reactome)
Bcl-XL:BH3-only protein complexArrowR-HSA-508162 (Reactome)
Bcl2:BH3-only protein complexArrowR-HSA-508163 (Reactome)
CASP3(1-277) dimerR-HSA-114252 (Reactome)
CASP7(2-303) dimerR-HSA-114261 (Reactome)
CASP9(1-416)R-HSA-114256 (Reactome)
CYCSArrowR-HSA-114284 (Reactome)
CYCSR-HSA-114254 (Reactome)
CYCSR-HSA-114284 (Reactome)
Calcineurin B complexmim-catalysisR-HSA-139906 (Reactome)
Caspase-3ArrowR-HSA-114252 (Reactome)
Caspase-3ArrowR-HSA-114419 (Reactome)
Caspase-7ArrowR-HSA-114261 (Reactome)
Caspase-7ArrowR-HSA-114392 (Reactome)
Cleaved Caspase-9ArrowR-HSA-114440 (Reactome)
Cytochrome C:Apaf-1:ATP:Procaspase-9ArrowR-HSA-114256 (Reactome)
Cytochrome C:Apaf-1:ATP:Procaspase-9R-HSA-114259 (Reactome)
Cytochrome C:Apaf-1:ATP:Procaspase-9mim-catalysisR-HSA-114259 (Reactome)
DIABLOArrowR-HSA-114307 (Reactome)
DIABLOR-HSA-114306 (Reactome)
DIABLOR-HSA-114307 (Reactome)
DIABLOR-HSA-114354 (Reactome)
DIABLOR-HSA-114361 (Reactome)
Dynein (DLC1) on microtubulesArrowR-HSA-139918 (Reactome)
Dynein (DLC2) on microtubulesArrowR-HSA-139908 (Reactome)
E2F1:TFDP1,TFDP2R-HSA-4331324 (Reactome)
E2F1:TFDP1,TFDP2R-HSA-4331327 (Reactome)
E2F1:TFDP1:BBC3 GeneArrowR-HSA-140221 (Reactome)
E2F1:TFDP1:BBC3 GeneArrowR-HSA-4331324 (Reactome)
E2F1:TFDP1:PMAIP1 GeneArrowR-HSA-140217 (Reactome)
E2F1:TFDP1:PMAIP1 GeneArrowR-HSA-4331327 (Reactome)
GZMBmim-catalysisR-HSA-139893 (Reactome)
H2OR-HSA-139906 (Reactome)
MAPK8mim-catalysisR-HSA-139908 (Reactome)
MAPK8mim-catalysisR-HSA-139918 (Reactome)
MYS-BID(62-195)ArrowR-HSA-139895 (Reactome)
MYS-BID(62-195)ArrowR-HSA-139897 (Reactome)
MYS-BID(62-195)ArrowR-HSA-139920 (Reactome)
MYS-BID(62-195)ArrowR-HSA-141367 (Reactome)
MYS-BID(62-195)R-HSA-114352 (Reactome)
MYS-BID(62-195)R-HSA-139920 (Reactome)
MYS-BID(62-195)R-HSA-168848 (Reactome)
NMT 1mim-catalysisR-HSA-141367 (Reactome)
PMAIP1 GeneR-HSA-140214 (Reactome)
PMAIP1 GeneR-HSA-140217 (Reactome)
PMAIP1 GeneR-HSA-4331327 (Reactome)
PMAIP1 GeneR-HSA-4331331 (Reactome)
PMAIP1ArrowR-HSA-140214 (Reactome)
PMAIP1ArrowR-HSA-140216 (Reactome)
PMAIP1ArrowR-HSA-140217 (Reactome)
PMAIP1R-HSA-140216 (Reactome)
PiArrowR-HSA-139906 (Reactome)
R-HSA-114252 (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).
R-HSA-114254 (Reactome) Cytochrome c released to the cytosol from the mitochonridal intermembrane space binds APAF1 (Apaf-1) (Zou et al. 1997).
R-HSA-114256 (Reactome) Apaf-1 and Caspase-9 form a complex in the presence of dATP and cytochrome c (Li et al.,1997).
R-HSA-114259 (Reactome) Caspase-9 is activated in an ATP-dependent manner following association with Apaf-1 and cytochrome c (Li et al., 1997)
R-HSA-114261 (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).
R-HSA-114263 (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).
R-HSA-114264 (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).
R-HSA-114275 (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)
R-HSA-114284 (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).
R-HSA-114306 (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'.

R-HSA-114307 (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).
R-HSA-114352 (Reactome) BCL2 binds tBID and inhibits BID-induced cytochrome C release and apoptosis (Yi et al. 2003).
R-HSA-114354 (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'.

R-HSA-114361 (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'.

R-HSA-114392 (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).
R-HSA-114419 (Reactome) Binding of DIABLO (SMAC) to XIAP promotes the liberation of active caspase-3 from its complex with XIAP (Kashkar et al. 2003).
R-HSA-114440 (Reactome) Binding of DIABLO (SMAC) to XIAP promotes the release of caspase-9 from XIAP (Du et al. 2000).
R-HSA-139893 (Reactome) GZMB (granzyme B) cleaves BID to produce a p15 truncated form of BID (tBID) (Alimonti et al. 2001).
R-HSA-139895 (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).
R-HSA-139897 (Reactome) Short peptides representing BAD and BIX were found to bind BCL-2 displacing BID-like BH3 domains that initiate mitochondrial dysfunction.
R-HSA-139898 (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.
R-HSA-139899 (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).
R-HSA-139905 (Reactome) Dephosphorylated BAD translocates to the outer mitochondrial membrane (Wang et al. 1999).
R-HSA-139906 (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).
R-HSA-139908 (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).
R-HSA-139909 (Reactome) Once BMF dissociates from the cytoskeleton, it translocates to the outer mitochondrial membrane where it binds BCL2 (Puthalakath et al. 2001).
R-HSA-139913 (Reactome) TP53 (p53) stimulates the transcription of BBC3 (PUMA) (p53 upregulated modulator of apoptosis) (Nakano and Vousden 2001). The transcription of BBC3 is also stimulated by p53 family members TP63 (p63) and TP73 (p73) (Bergamaschi et al. 2004, Patel et al. 2008). ASPP proteins PPP1R13B (ASPP1) and TP53BP2 (ASPP2) form a complex with p53 family members and enhance transcriptional activation of BBC3 (Bergamaschi et al. 2004, Patel et al. 2008, Wilson et al. 2013).
R-HSA-139914 (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.
R-HSA-139917 (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.
R-HSA-139918 (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).
R-HSA-139919 (Reactome) Once BCL2L11 (BIM) dissociates from the cytoskeleton, it translocates to the outer mitochondrial membrane where it associates with BCL2 (Puthalakath et al. 1999).
R-HSA-139920 (Reactome) N-myristoylation targets tBID to the mitochondrial outer membrane (Zha et al. 2000).
R-HSA-140214 (Reactome) TP53 (p53) stimulates transcription of PMAIP1 (NOXA) (Oda et al. 2000, Li et al. 2004). The complex of TP53 with ASPP proteins PPP1R13B (ASPP1) or TP53BP2 (ASPP2) is likely involved in the transcriptional activation of PMAIP1 (Wang et al. 2012, Wilson et al. 2013).
R-HSA-140216 (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.
R-HSA-140217 (Reactome) E2F1 directly stimulates the transcription of PMAIP1 (NOXA) (Hershko and Ginsberg 2004).
R-HSA-140221 (Reactome) E2F1 directly stimulates the transcription of BBC3 (PUMA) (Hershko and Ginsberg 2004).
R-HSA-141367 (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.
R-HSA-168848 (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).
R-HSA-168849 (Reactome) tBID binds to inactive BAX in the cytosol (Eskes et al. 2000).
R-HSA-198347 (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).
R-HSA-4331324 (Reactome) E2F1, in complex with TFDP1 (DP-1), binds the promoter of BBC3 (PUMA) gene (Hershko and Ginsberg 2004).
R-HSA-4331327 (Reactome) E2F1, in complex with TFDP1 (DP-1), binds the promoter of PMAIP1 (NOXA) gene (Hershko and Ginsberg 2004).
R-HSA-4331331 (Reactome) TP53 (p53) binds the promoter of the PMAIP1 (NOXA) gene to induce PMAIP1 transcription (Oda et al. 2000, Li et al. 2004). TP53 likely associates with the PMAIP1 promoter as part of the complex with ASPP proteins PPP1R13B (ASPP1) or TP53BP2 (ASPP2) (Wang et al. 2012, Wilson et al. 2013).
R-HSA-4331340 (Reactome) TP53 (p53) binding sites are found in the promoter (Han et al. 2001) and intron 1 (Nakano and Vousden 2001) of the BBC3 (PUMA) gene, and are necessary for TP53-mediated induction of BBC3 transcription. TP53 family members TP63 (p63) and TP73 (p73) can also bind p53 response elements within the BBC3 gene locus (Bergamaschi et al. 2004, Patel et al. 2008). Formation of the complex between TP53 family members and ASPP proteins PPP1R13B (ASPP1) or TP53BP2 (ASPP2) enhances binding of the p53 family members to the BBC3 gene locus (Bergamaschi et al. 2004, Patel et al. 2008, Wilson et al. 2013).
R-HSA-508162 (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).
R-HSA-508163 (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.
R-HSA-6790025 (Reactome) Signal transducer and activator of transcription 3 (STAT3) is a key regulator of gene expression in response to signaling of many cytokines including interleukin-6 (IL6), Oncostatin M, and leukemia inhibitory factor. Using microarray techniques, hundreds of genes have been reported as potential STAT3 target genes (Dauer et al. 2005, Hsieh et al. 2005). Some of these genes have been proven to be direct STAT3 targets using genome-wide chromatin immunoprecipitation screening (Snyder et al. 2008, Carpenter & Lo 2014), including the mitochondrial outer membrane protein genes Apoptosis regulator BCL2 (Bhattacharya et al. 2005) and Bcl-2-like protein 1 (BCL2L1, Bcl-XL) (Catlett-Falcone et al. 1999).
SMAC:XIAP:Caspase-3ArrowR-HSA-114306 (Reactome)
SMAC:XIAP:Caspase-3R-HSA-114419 (Reactome)
SMAC:XIAP:Caspase-7ArrowR-HSA-114354 (Reactome)
SMAC:XIAP:Caspase-7R-HSA-114392 (Reactome)
SMAC:XIAP:Caspase-9ArrowR-HSA-114361 (Reactome)
SMAC:XIAP:Caspase-9R-HSA-114440 (Reactome)
SMAC:XIAPArrowR-HSA-114392 (Reactome)
SMAC:XIAPArrowR-HSA-114419 (Reactome)
SMAC:XIAPArrowR-HSA-114440 (Reactome)
XIAP:Caspase-3R-HSA-114306 (Reactome)
XIAP:Caspase-7R-HSA-114354 (Reactome)
XIAP:Caspase-9R-HSA-114361 (Reactome)
active caspase-8mim-catalysisR-HSA-139898 (Reactome)
p-BCL2L11ArrowR-HSA-139918 (Reactome)
p-BCL2L11ArrowR-HSA-139919 (Reactome)
p-BCL2L11R-HSA-139919 (Reactome)
p-BMF(1-89)ArrowR-HSA-139908 (Reactome)
p-BMF(1-89)R-HSA-139909 (Reactome)
p-BMFArrowR-HSA-139909 (Reactome)
p-S15,S20-TP53

Tetramer:PMAIP1

Gene		ArrowR-HSA-140214 (Reactome)
p-S15,S20-TP53

Tetramer:PMAIP1

Gene		ArrowR-HSA-4331331 (Reactome)
p-S15,S20-TP53 TetramerR-HSA-4331331 (Reactome)
p-S99-BADArrowR-HSA-198347 (Reactome)
p-S99-BADR-HSA-139899 (Reactome)
p-T,p-S-AKTmim-catalysisR-HSA-198347 (Reactome)
p-Y705-STAT3 dimerArrowR-HSA-6790025 (Reactome)
tBID bound to inactive BAKArrowR-HSA-168848 (Reactome)
tBID bound to inactive BAKR-HSA-139895 (Reactome)
tBID bound to inactive BAXArrowR-HSA-168849 (Reactome)
tBID bound to inactive BAXR-HSA-139917 (Reactome)
tBID:BCL-2ArrowR-HSA-114352 (Reactome)
tBID:BCL-2R-HSA-139897 (Reactome)

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