Intrinsic Pathway for Apoptosis (Homo sapiens)

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1, 16, 44334, 13, 34, 39, 53...3326503312, 32, 46, 49, 564010, 19, 29376, 5712, 32, 46, 49, 5689, 152727453934, 36, 40, 414, 14, 46, 4734374, 14, 46, 472, 22, 30, 353623, 25, 276, 5724, 28, 48, 54, 55837, 11, 5220559, 21, 4541833184, 18, 34, 39, 56139, 21, 45, 51364231nucleoplasmmitochondrial outer membranecytosolmitochondrial inner membraneADPMYS-BID(62-195) PMAIP1 TFDP2 BAK1 activatedAPAF1p-T305,S472-AKT3 Bcl-XL:BH3-onlyprotein complexAPAF1 Dynein (DLC2) onmicrotubulesCleaved Caspase-9microtubules YWHAB E2F1:TFDP1,TFDP2YWHAH CASP3(1-277) CASP7(207-303) PiBAXPIP3 activates AKTsignalingMYS-BID(62-195)YWHAG active caspase-8DYNLL2 BBC3 BCL2 gene E2F1 MYS-BID(62-195) SMAC:XIAP:Caspase-7CASP9(331-416) XIAP BCL2 SFN DIABLO p-S15,S20-TP53 BAX activatedCASP3(176-277) BAD:BCL-2PMAIP1SFN TP63 Bcl2:BH3-onlyprotein complexCASP9(?-315) BID(62-195)BAK1 activated BAXPPP3CC BBC3 p-S15,S20-TP53Tetramerp-Y705-STAT3 (p-S15,S20-TP53,TP63,TP73):(PPP1R13B,TP53BP2)p-S99-BADCASP9(?-315) CYCS DIABLOADPp-S15,S20-TP53 BAX tBID:BCL-2YWHAH TP63 CASP7(2-303) BIM sequestered todynein (DLC1)BAK1 activated XIAP ATPDIABLO p-BCL2L11 PMAIP1 PPP3R1 BBC3 Gene CASP9(331-416) ADPTFDP1 YWHAE SMAC:XIAP:Caspase-9CASP7(2-303) dimerBCL2 BBC3 TFDP1 YWHAG TFDP2 SMAC:XIAPCASP9(1-416) BID(1-195)BCL2L1 DIABLO BAD H2OPMAIP1 Gene BAK1 MYS-BID(62-195)p-S15,S20-TP53 ATPYWHAQ BCL2BAD BAK1Activated BAXmicrotubules p-BMF(1-89)p-BCL2L11p-T,p-S-AKTCYCSp-T308,S473-AKT1 XIAP ApoptosomeMYS-BID(62-195) CASP8(385-479) microtubules Dynein (DLC1) onmicrotubulesDYNLL1 CASP7(24-198) CASP3(29-175) TP53BP2 ADPXIAP XIAP:Caspase-3ADPE2F1 YWHAQ CASP7(24-198) BAD TP53BP2 DIABLO XIAP p-BCL2L11 p-BMF BBC3 p-BCL2L11 CASP7(207-303) TP73 p-S15,S20-TP53Tetramer:PMAIP1GeneTP73 Bcl-2 interactingBH-3 only proteinsp-T309,S474-AKT2 TFDP1 PPP1R13B CASP8(217-374) BAD p-S99-BAD ATPPPP1R13B Bcl-2/Bcl-X(L)CASP9(?-315) p-Y705-STAT3 dimerp-BMFCYCS YWHAZ ATP BCL2L1 YWHAB BCL2L1BID(62-195) XIAP:Caspase-9SMAC:XIAP:Caspase-3APAF1 BBC3CASP3(29-175) CASP9(1-416)BCL2 gene, BCL2L1geneATPBBC3 GeneBCL2 BCL2L1 gene BCL2L11 BMF (p-S15,S20-TP53,TP63,TP73):(PPP1R13B,TP53BP2):BBC3 Genep-S15,S20-TP53 Apaf-1:Cytochrome CTFDP2 PMAIP1 Gene CASP7(24-198) ADPBAD14-3-3proteins:p-S99-BADcomplexXIAP BBC3 Gene CASP3(176-277) PMAIP1 BAX GZMBATPp-BMF BAX CASP3(1-277) dimerCaspase-7Calcineurin BcomplexYWHAE E2F1:TFDP1:BBC3 GeneActive oligomericBAKBBC3MAPK8ATPPMAIP1BCL2 Caspase-3CYCS CASP3(176-277) CASP9(331-416) Bcl-XL interactingBH3-only proteinsXIAP BAD PMAIP1 YWHAZ DYNLL1 E2F1 XIAP:Caspase-7NMT 1APAF1 DIABLODYNLL2 CASP9(?-315) CYCSCASP3(29-175) tBID bound toinactive BAKp-BCL2L11 MYS-BID(62-195) CASP7(207-303) PMAIP1 GeneBMF sequestered todynein (DLC2)E2F1:TFDP1:PMAIP1Gene14-3-3 dimerCASP9(331-416) microtubules CytochromeC:Apaf-1:ATP:Procaspase-9Activated BAX,BAKoligomersBADp-BCL2L11tBID bound toinactive BAX23, 54, 5533174, 1423, 54, 551733823838, 431712, 56171717


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>


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

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  1. Wang X.; ''The expanding role of mitochondria in apoptosis.''; PubMed Europe PMC
  2. Subramanian RR, Masters SC, Zhang H, Fu H.; ''Functional conservation of 14-3-3 isoforms in inhibiting bad-induced apoptosis.''; PubMed Europe PMC
  3. Kashkar H, Haefs C, Shin H, Hamilton-Dutoit SJ, Salvesen GS, Kronke M, Jurgensmeier JM.; ''XIAP-mediated caspase inhibition in Hodgkin's lymphoma-derived B cells.''; PubMed Europe PMC
  4. Oda E, Ohki R, Murasawa H, Nemoto J, Shibue T, Yamashita T, Tokino T, Taniguchi T, Tanaka N.; ''Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis.''; PubMed Europe PMC
  5. Lei K, Davis RJ.; ''JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis.''; PubMed Europe PMC
  6. Arnoult D, Gaume B, Karbowski M, Sharpe JC, Cecconi F, Youle RJ.; ''Mitochondrial release of AIF and EndoG requires caspase activation downstream of Bax/Bak-mediated permeabilization.''; PubMed Europe PMC
  7. Carpenter RL, Lo HW.; ''STAT3 Target Genes Relevant to Human Cancers.''; PubMed Europe PMC
  8. Wei MC, Lindsten T, Mootha VK, Weiler S, Gross A, Ashiya M, Thompson CB, Korsmeyer SJ.; ''tBID, a membrane-targeted death ligand, oligomerizes BAK to release cytochrome c.''; PubMed Europe PMC
  9. Yang QH, Du C.; ''Smac/DIABLO selectively reduces the levels of c-IAP1 and c-IAP2 but not that of XIAP and livin in HeLa cells.''; PubMed Europe PMC
  10. Khor TO, Gul YA, Ithnin H, Seow HF.; ''Positive correlation between overexpression of phospho-BAD with phosphorylated Akt at serine 473 but not threonine 308 in colorectal carcinoma.''; PubMed Europe PMC
  11. Bhattacharya S, Ray RM, Johnson LR.; ''STAT3-mediated transcription of Bcl-2, Mcl-1 and c-IAP2 prevents apoptosis in polyamine-depleted cells.''; PubMed Europe PMC
  12. Han J, Flemington C, Houghton AB, Gu Z, Zambetti GP, Lutz RJ, Zhu L, Chittenden T.; ''Expression of bbc3, a pro-apoptotic BH3-only gene, is regulated by diverse cell death and survival signals.''; PubMed Europe PMC
  13. Puthalakath H, Villunger A, O'Reilly LA, Beaumont JG, Coultas L, Cheney RE, Huang DC, Strasser A.; ''Bmf: a proapoptotic BH3-only protein regulated by interaction with the myosin V actin motor complex, activated by anoikis.''; PubMed Europe PMC
  14. Li CQ, Robles AI, Hanigan CL, Hofseth LJ, Trudel LJ, Harris CC, Wogan GN.; ''Apoptotic signaling pathways induced by nitric oxide in human lymphoblastoid cells expressing wild-type or mutant p53.''; PubMed Europe PMC
  15. Vucic D, Stennicke HR, Pisabarro MT, Salvesen GS, Dixit VM.; ''ML-IAP, a novel inhibitor of apoptosis that is preferentially expressed in human melanomas.''; PubMed Europe PMC
  16. Salvesen GS, Duckett CS.; ''IAP proteins: blocking the road to death's door.''; PubMed Europe PMC
  17. Shi Y.; ''Mechanisms of caspase activation and inhibition during apoptosis.''; PubMed Europe PMC
  18. Wang HG, Pathan N, Ethell IM, Krajewski S, Yamaguchi Y, Shibasaki F, McKeon F, Bobo T, Franke TF, Reed JC.; ''Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD.''; PubMed Europe PMC
  19. Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME.; ''Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery.''; PubMed Europe PMC
  20. Ruffolo SC, Shore GC.; ''BCL-2 selectively interacts with the BID-induced open conformer of BAK, inhibiting BAK auto-oligomerization.''; PubMed Europe PMC
  21. Deveraux QL, Takahashi R, Salvesen GS, Reed JC.; ''X-linked IAP is a direct inhibitor of cell-death proteases.''; PubMed Europe PMC
  22. Chen XQ, Fung YW, Yu AC.; ''Association of 14-3-3gamma and phosphorylated bad attenuates injury in ischemic astrocytes.''; PubMed Europe PMC
  23. Thomsen ND, Koerber JT, Wells JA.; ''Structural snapshots reveal distinct mechanisms of procaspase-3 and -7 activation.''; PubMed Europe PMC
  24. Denault JB, Salvesen GS.; ''Human caspase-7 activity and regulation by its N-terminal peptide.''; PubMed Europe PMC
  25. Zou H, Li Y, Liu X, Wang X.; ''An APAF-1.cytochrome c multimeric complex is a functional apoptosome that activates procaspase-9.''; PubMed Europe PMC
  26. Du C, Fang M, Li Y, Li L, Wang X.; ''Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition.''; PubMed Europe PMC
  27. Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X.; ''Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade.''; PubMed Europe PMC
  28. Denault JB, Békés M, Scott FL, Sexton KM, Bogyo M, Salvesen GS.; ''Engineered hybrid dimers: tracking the activation pathway of caspase-7.''; PubMed Europe PMC
  29. del Peso L, González-García M, Page C, Herrera R, Nuñez G.; ''Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt.''; PubMed Europe PMC
  30. Datta SR, Katsov A, Hu L, Petros A, Fesik SW, Yaffe MB, Greenberg ME.; ''14-3-3 proteins and survival kinases cooperate to inactivate BAD by BH3 domain phosphorylation.''; PubMed Europe PMC
  31. Alimonti JB, Shi L, Baijal PK, Greenberg AH.; ''Granzyme B induces BID-mediated cytochrome c release and mitochondrial permeability transition.''; PubMed Europe PMC
  32. Bergamaschi D, Samuels Y, Jin B, Duraisingham S, Crook T, Lu X.; ''ASPP1 and ASPP2: common activators of p53 family members.''; PubMed Europe PMC
  33. Hershko T, Ginsberg D.; ''Up-regulation of Bcl-2 homology 3 (BH3)-only proteins by E2F1 mediates apoptosis.''; PubMed Europe PMC
  34. Yi X, Yin XM, Dong Z.; ''Inhibition of Bid-induced apoptosis by Bcl-2. tBid insertion, Bax translocation, and Bax/Bak oligomerization suppressed.''; PubMed Europe PMC
  35. 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
  36. Eskes R, Desagher S, Antonsson B, Martinou JC.; ''Bid induces the oligomerization and insertion of Bax into the outer mitochondrial membrane.''; PubMed Europe PMC
  37. Zha J, Weiler S, Oh KJ, Wei MC, Korsmeyer SJ.; ''Posttranslational N-myristoylation of BID as a molecular switch for targeting mitochondria and apoptosis.''; PubMed Europe PMC
  38. Watt W, Koeplinger KA, Mildner AM, Heinrikson RL, Tomasselli AG, Watenpaugh KD.; ''The atomic-resolution structure of human caspase-8, a key activator of apoptosis.''; PubMed Europe PMC
  39. Puthalakath H, Huang DC, O'Reilly LA, King SM, Strasser A.; ''The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex.''; PubMed Europe PMC
  40. Antonsson B, Montessuit S, Sanchez B, Martinou JC.; ''Bax is present as a high molecular weight oligomer/complex in the mitochondrial membrane of apoptotic cells.''; PubMed Europe PMC
  41. Bellosillo B, Villamor N, López-Guillermo A, Marcé S, Bosch F, Campo E, Montserrat E, Colomer D.; ''Spontaneous and drug-induced apoptosis is mediated by conformational changes of Bax and Bak in B-cell chronic lymphocytic leukemia.''; PubMed Europe PMC
  42. Fischer B, Coelho D, Dufour P, Bergerat JP, Denis JM, Gueulette J, Bischoff P.; ''Caspase 8-mediated cleavage of the pro-apoptotic BCL-2 family member BID in p53-dependent apoptosis.''; PubMed Europe PMC
  43. Blanchard H, Kodandapani L, Mittl PR, Marco SD, Krebs JF, Wu JC, Tomaselli KJ, Grütter MG.; ''The three-dimensional structure of caspase-8: an initiator enzyme in apoptosis.''; PubMed Europe PMC
  44. Saelens X, Festjens N, Vande Walle L, van Gurp M, van Loo G, Vandenabeele P.; ''Toxic proteins released from mitochondria in cell death.''; PubMed Europe PMC
  45. Huang Y, Park YC, Rich RL, Segal D, Myszka DG, Wu H.; ''Structural basis of caspase inhibition by XIAP: differential roles of the linker versus the BIR domain.''; PubMed Europe PMC
  46. Wilson AM, Morquette B, Abdouh M, Unsain N, Barker PA, Feinstein E, Bernier G, Di Polo A.; ''ASPP1/2 regulate p53-dependent death of retinal ganglion cells through PUMA and Fas/CD95 activation in vivo.''; PubMed Europe PMC
  47. Wang L, Xing H, Tian Z, Peng L, Li Y, Tang K, Rao Q, Wang M, Wang J.; ''iASPPsv antagonizes apoptosis induced by chemotherapeutic agents in MCF-7 cells and mouse thymocytes.''; PubMed Europe PMC
  48. Slee EA, Harte MT, Kluck RM, Wolf BB, Casiano CA, Newmeyer DD, Wang HG, Reed JC, Nicholson DW, Alnemri ES, Green DR, Martin SJ.; ''Ordering the cytochrome c-initiated caspase cascade: hierarchical activation of caspases-2, -3, -6, -7, -8, and -10 in a caspase-9-dependent manner.''; PubMed Europe PMC
  49. Patel S, George R, Autore F, Fraternali F, Ladbury JE, Nikolova PV.; ''Molecular interactions of ASPP1 and ASPP2 with the p53 protein family and the apoptotic promoters PUMA and Bax.''; PubMed Europe PMC
  50. Zou H, Henzel WJ, Liu X, Lutschg A, Wang X.; ''Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3.''; PubMed Europe PMC
  51. Abhari BA, Davoodi J.; ''A mechanistic insight into SMAC peptide interference with XIAP-Bir2 inhibition of executioner caspases.''; PubMed Europe PMC
  52. Catlett-Falcone R, Landowski TH, Oshiro MM, Turkson J, Levitzki A, Savino R, Ciliberto G, Moscinski L, Fernández-Luna JL, Nuñez G, Dalton WS, Jove R.; ''Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells.''; PubMed Europe PMC
  53. Yang E, Zha J, Jockel J, Boise LH, Thompson CB, Korsmeyer SJ.; ''Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death.''; PubMed Europe PMC
  54. Chai J, Wu Q, Shiozaki E, Srinivasula SM, Alnemri ES, Shi Y.; ''Crystal structure of a procaspase-7 zymogen: mechanisms of activation and substrate binding.''; PubMed Europe PMC
  55. Riedl SJ, Fuentes-Prior P, Renatus M, Kairies N, Krapp S, Huber R, Salvesen GS, Bode W.; ''Structural basis for the activation of human procaspase-7.''; PubMed Europe PMC
  56. Nakano K, Vousden KH.; ''PUMA, a novel proapoptotic gene, is induced by p53.''; PubMed Europe PMC
  57. Song Z, Yao X, Wu M.; ''Direct interaction between survivin and Smac/DIABLO is essential for the anti-apoptotic activity of survivin during taxol-induced apoptosis.''; PubMed Europe PMC


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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


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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)


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)


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

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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)


ArrowR-HSA-139899 (Reactome)


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)


ArrowR-HSA-140214 (Reactome)


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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