Intrinsic Pathway for Apoptosis (Homo sapiens)

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15, 25, 562, 11, 20, 786456338, 47, 654834, 546818, 7512, 24, 46, 64, 68804153, 57, 77422, 4, 32, 344670169634716, 515038, 6582, 18, 5844482, 11, 7131, 33, 55558068796, 51, 5543, 81412, 10, 18, 587, 13, 37, 73, 74635022762222, 46, 67, 6924836312, 17, 21, 23, 623927, 61, 8228, 35, 52, 599, 36, 6012, 17, 21, 23, 62223, 29, 30, 6423, 29, 30, 6414, 45493, 8, 12, 24, 46...mitochondrial inner membranemitochondrial outer membranecytosolnucleoplasmp-BMF BIM sequestered todynein (DLC1)CASP8(385-479) BAD CASP9(?-315) p-Y705-STAT3 dimerDynein (DLC1) onmicrotubulesBADAPAF1:CYCS:CASP9:XIAP:DIABLOBAD E2F1:TFDP1:PMAIP1GeneAPAF1 DYNLL2 PPP1R13B DIABLOp-S15,S20-TP53 CASP7(24-198) APIP ApoptosomeCASP9(331-416) PPP1R13B CYCSAPAF1:ATP:CYCSheptamer:CASP9p-T305,S472-AKT3 BCL2ATPUACA:apoptosomep-T308,S473-AKT1 ATP XIAP:Caspase-3TP63 CASP9:CARDPMAIP1 APAF1 microtubules PIP3 activates AKTsignalingp14ARF:C1QBPCYCSPMAIP1 PiTP53BP2 p-T125-CASP9(1-416) BMF sequestered todynein (DLC2)MYS-BID(62-195)CASP7(2-303) microtubules DIABLO p-S99-BADXIAP p-T,Y MAPK dimersCASP9(?-315) DIABLO:XIAP:Caspase-3MAPK8p-BCL2L11CASP9(1-416) AVENH2OBAX activatedBAK1 activatedCaspase-3E2F1 PMAIP1 GeneMYS-BID(62-195) PMAIP1 XIAP C1QBP microtubules p-S15,S20-TP53 CASP3(1-277) p-BCL2L11 CYCS CASP9(1-416) CYCS BBC3 geneCASP9(331-416) APAF1 Activated BAXAPAF1 XIAPBAD MYS-BID(62-195) APAF1 ATP p-BMF CASP7(24-198) YWHAE APAF1 DYNLL2 ADP BCL2 DIABLO Dynein (DLC2) onmicrotubulesMYS-BID(62-195)CYCS SFN TFDP2 TFDP2 Active oligomericBAKE2F1:TFDP1,TFDP2p-S15,S20-TP53 BAX tBID bound toinactive BAXATP CASP9(331-416) BAK1 activated APIPSEPT4 dimerp-BCL2L11 YWHAB Bcl-XL:BH3-onlyprotein complexBAX CARD8p-BCL2L11CASP9(1-416) APAF1 ADPYWHAZ p-T185,Y187-MAPK1 ATP DIABLO DIABLO dimer:XIAPCASP7(24-198) BMF ATPBID(62-195) TFDP2 TP73 SFN YWHAG ATPBcl-2/Bcl-X(L)XIAP AVEN ADP p14ARFBAK1XIAP p-S15,S20-TP53Tetramerp14ARF ADPTP53BP2 XIAP Bcl-2 interactingBH-3 only proteins14-3-3proteins:p-S99-BADcomplexCASP8(217-374) p-S15,S20-TP53 p-BMF(1-89)YWHAH YWHAB APAF1 YWHAG BBC3CARD8 ATPAPAF1 ATPXIAP APAF1:AVENMYS-BID(62-195) CYCS APAF1:ATP:CYCSheptamer:p-T125-CASP9Bcl2:BH3-onlyprotein complexAPAF1:ATP:CYCSCASP9(1-416) CYCS BCL2 gene, BCL2L1geneE2F1 APAF1 CASP9(1-416) APAF1 DIABLO BBC3 gene p-S99-BAD BBC3 gene CASP3(176-277) C1QBP homotrimerSEPT4 dimer:XIAPNMT 1BBC3 active caspase-8YWHAE MYS-BID(62-195) BAD C1QBP DIABLOCASP7(207-303) CASP3(29-175) CASP9(?-315) PMAIP1 Gene XIAP CASP3(176-277) APAF1 14-3-3 dimerBBC3 PPP3CC ADPCASP7(207-303) BAK1 TP63 PMAIP1BID(62-195)tBID:BCL-2p-Y705-STAT3 BID(1-195)PMAIP1 TP73 CYCS p-BCL2L11 C1QBP CYCS DYNLL1 YWHAZ CASP7(207-303) CASP3(176-277) UACA CYCS CASP3(29-175) GZMBUACADIABLO:XIAP:Caspase-7APAF1:CYCS:ATP:APIPE2F1 ADPTFDP1 BCL2L1tBID bound toinactive BAKBcl-XL interactingBH3-only proteinsPPP3R1 DYNLL1 CASP3(29-175) ADPCASP3(1-277) dimerp-BCL2L11 SEPT4 BBC3 microtubules p-T202,Y204-MAPK3 CASP9(1-416) CASP9(331-416) (p-S15,S20-TP53,TP63,TP73):(PPP1R13B,TP53BP2)E2F1:TFDP1:BBC3 GeneBAXATP(p-S15,S20-TP53,TP63,TP73):(PPP1R13B,TP53BP2):BBC3 GeneCYCS BCL2L1 TFDP1 APAF1:ADPBCL2 p-S15,S20-TP53Tetramer:PMAIP1GeneADPBAD:BCL-2DIABLO SEPT4YWHAH APAF1:CYCS:ATP:CASP9(1-416)dimerBAK1 activated p14ARF:C1QBPBBC3 CASP9(?-315) p-BMFCASP9(?-315) BAX PMAIP1 Gene BCL2 ADPCaspase-7p-T,p-S-AKTXIAP:Caspase-7p-T309,S474-AKT2 CASP9(331-416) BBC3BCL2L1 gene SEPT4 BCL2 gene CASP7(2-303) dimerApoptosomep14ARF PMAIP1XIAP:apoptosomeBAD YWHAQ TFDP1 BCL2L11 XIAP DIABLO dimerBADBCL2L1 Activated BAX,BAKoligomersCASP9(1-416)CYCS ATPADPYWHAQ SEPT4BCL2 Calcineurin BcomplexBAX51, 667251, 662657272637, 33, 735063512672763319, 407250723430, 6445453412, 217, 33, 73


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: 73
Reactome Author 
Reactome Author: Matthews, Lisa

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Bibliography

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  1. Chen XQ, Fung YW, Yu AC.; ''Association of 14-3-3gamma and phosphorylated bad attenuates injury in ischemic astrocytes.''; PubMed Europe PMC Scholia
  2. 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 Scholia
  3. Paulsen M, Ussat S, Jakob M, Scherer G, Lepenies I, Schütze S, Kabelitz D, Adam-Klages S.; ''Interaction with XIAP prevents full caspase-3/-7 activation in proliferating human T lymphocytes.''; PubMed Europe PMC Scholia
  4. Hu Q, Wu D, Chen W, Yan Z, Yan C, He T, Liang Q, Shi Y.; ''Molecular determinants of caspase-9 activation by the Apaf-1 apoptosome.''; PubMed Europe PMC Scholia
  5. Shiozaki EN, Chai J, Rigotti DJ, Riedl SJ, Li P, Srinivasula SM, Alnemri ES, Fairman R, Shi Y.; ''Mechanism of XIAP-mediated inhibition of caspase-9.''; PubMed Europe PMC Scholia
  6. 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 Scholia
  7. Scott FL, Denault JB, Riedl SJ, Shin H, Renatus M, Salvesen GS.; ''XIAP inhibits caspase-3 and -7 using two binding sites: evolutionarily conserved mechanism of IAPs.''; PubMed Europe PMC Scholia
  8. 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 Scholia
  9. Reingewertz TH, Shalev DE, Sukenik S, Blatt O, Rotem-Bamberger S, Lebendiker M, Larisch S, Friedler A.; ''Mechanism of the interaction between the intrinsically disordered C-terminus of the pro-apoptotic ARTS protein and the Bir3 domain of XIAP.''; PubMed Europe PMC Scholia
  10. Cheng TC, Hong C, Akey IV, Yuan S, Akey CW.; ''A near atomic structure of the active human apoptosome.''; PubMed Europe PMC Scholia
  11. Yuan S, Yu X, Topf M, Ludtke SJ, Wang X, Akey CW.; ''Structure of an apoptosome-procaspase-9 CARD complex.''; PubMed Europe PMC Scholia
  12. 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 Scholia
  13. 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 Scholia
  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 Scholia
  15. 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 Scholia
  16. Bornstein B, Gottfried Y, Edison N, Shekhtman A, Lev T, Glaser F, Larisch S.; ''ARTS binds to a distinct domain in XIAP-BIR3 and promotes apoptosis by a mechanism that is different from other IAP-antagonists.''; PubMed Europe PMC Scholia
  17. 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 Scholia
  18. Gottfried Y, Rotem A, Lotan R, Steller H, Larisch S.; ''The mitochondrial ARTS protein promotes apoptosis through targeting XIAP.''; PubMed Europe PMC Scholia
  19. 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 Scholia
  20. 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 Scholia
  21. 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 Scholia
  22. Larisch S, Yi Y, Lotan R, Kerner H, Eimerl S, Tony Parks W, Gottfried Y, Birkey Reffey S, de Caestecker MP, Danielpour D, Book-Melamed N, Timberg R, Duckett CS, Lechleider RJ, Steller H, Orly J, Kim SJ, Roberts AB.; ''A novel mitochondrial septin-like protein, ARTS, mediates apoptosis dependent on its P-loop motif.''; PubMed Europe PMC Scholia
  23. Srinivasula SM, Hegde R, Saleh A, Datta P, Shiozaki E, Chai J, Lee RA, Robbins PD, Fernandes-Alnemri T, Shi Y, Alnemri ES.; ''A conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO regulates caspase activity and apoptosis.''; PubMed Europe PMC Scholia
  24. 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 Scholia
  25. Nakano K, Vousden KH.; ''PUMA, a novel proapoptotic gene, is induced by p53.''; PubMed Europe PMC Scholia
  26. Eskes R, Desagher S, Antonsson B, Martinou JC.; ''Bid induces the oligomerization and insertion of Bax into the outer mitochondrial membrane.''; PubMed Europe PMC Scholia
  27. Lei K, Davis RJ.; ''JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis.''; PubMed Europe PMC Scholia
  28. 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 Scholia
  29. 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 Scholia
  30. Hershko T, Ginsberg D.; ''Up-regulation of Bcl-2 homology 3 (BH3)-only proteins by E2F1 mediates apoptosis.''; PubMed Europe PMC Scholia
  31. Yuan S, Topf M, Reubold TF, Eschenburg S, Akey CW.; ''Changes in Apaf-1 conformation that drive apoptosome assembly.''; PubMed Europe PMC Scholia
  32. Chai J, Du C, Wu JW, Kyin S, Wang X, Shi Y.; ''Structural and biochemical basis of apoptotic activation by Smac/DIABLO.''; PubMed Europe PMC Scholia
  33. Denault JB, Salvesen GS.; ''Human caspase-7 activity and regulation by its N-terminal peptide.''; PubMed Europe PMC Scholia
  34. 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 Scholia
  35. Itahana K, Zhang Y.; ''Mitochondrial p32 is a critical mediator of ARF-induced apoptosis.''; PubMed Europe PMC Scholia
  36. 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 Scholia
  37. 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 Scholia
  38. 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 Scholia
  39. Chau BN, Cheng EH, Kerr DA, Hardwick JM.; ''Aven, a novel inhibitor of caspase activation, binds Bcl-xL and Apaf-1.''; PubMed Europe PMC Scholia
  40. Deveraux QL, Takahashi R, Salvesen GS, Reed JC.; ''X-linked IAP is a direct inhibitor of cell-death proteases.''; PubMed Europe PMC Scholia
  41. 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 Scholia
  42. Wu G, Chai J, Suber TL, Wu JW, Du C, Wang X, Shi Y.; ''Structural basis of IAP recognition by Smac/DIABLO.''; PubMed Europe PMC Scholia
  43. Ruffolo SC, Shore GC.; ''BCL-2 selectively interacts with the BID-induced open conformer of BAK, inhibiting BAK auto-oligomerization.''; PubMed Europe PMC Scholia
  44. 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 Scholia
  45. Chai J, Shiozaki E, Srinivasula SM, Wu Q, Datta P, Alnemri ES, Shi Y.; ''Structural basis of caspase-7 inhibition by XIAP.''; PubMed Europe PMC Scholia
  46. 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 Scholia
  47. 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 Scholia
  48. Abhari BA, Davoodi J.; ''A mechanistic insight into SMAC peptide interference with XIAP-Bir2 inhibition of executioner caspases.''; PubMed Europe PMC Scholia
  49. Bratton SB, Walker G, Srinivasula SM, Sun XM, Butterworth M, Alnemri ES, Cohen GM.; ''Recruitment, activation and retention of caspases-9 and -3 by Apaf-1 apoptosome and associated XIAP complexes.''; PubMed Europe PMC Scholia
  50. Subramanian RR, Masters SC, Zhang H, Fu H.; ''Functional conservation of 14-3-3 isoforms in inhibiting bad-induced apoptosis.''; PubMed Europe PMC Scholia
  51. 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 Scholia
  52. Won J, Kim DY, La M, Kim D, Meadows GG, Joe CO.; ''Cleavage of 14-3-3 protein by caspase-3 facilitates bad interaction with Bcl-x(L) during apoptosis.''; PubMed Europe PMC Scholia
  53. Pathan N, Marusawa H, Krajewska M, Matsuzawa S, Kim H, Okada K, Torii S, Kitada S, Krajewski S, Welsh K, Pio F, Godzik A, Reed JC.; ''TUCAN, an antiapoptotic caspase-associated recruitment domain family protein overexpressed in cancer.''; PubMed Europe PMC Scholia
  54. 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 Scholia
  55. 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 Scholia
  56. Martin MC, Allan LA, Mancini EJ, Clarke PR.; ''The docking interaction of caspase-9 with ERK2 provides a mechanism for the selective inhibitory phosphorylation of caspase-9 at threonine 125.''; PubMed Europe PMC Scholia
  57. 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 Scholia
  58. Salvesen GS, Duckett CS.; ''IAP proteins: blocking the road to death's door.''; PubMed Europe PMC Scholia
  59. Alimonti JB, Shi L, Baijal PK, Greenberg AH.; ''Granzyme B induces BID-mediated cytochrome c release and mitochondrial permeability transition.''; PubMed Europe PMC Scholia
  60. Renatus M, Stennicke HR, Scott FL, Liddington RC, Salvesen GS.; ''Dimer formation drives the activation of the cell death protease caspase 9.''; PubMed Europe PMC Scholia
  61. 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 Scholia
  62. 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 Scholia
  63. 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 Scholia
  64. 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 Scholia
  65. 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 Scholia
  66. Carpenter RL, Lo HW.; ''STAT3 Target Genes Relevant to Human Cancers.''; PubMed Europe PMC Scholia
  67. Shi Y.; ''Mechanisms of caspase activation and inhibition during apoptosis.''; PubMed Europe PMC Scholia
  68. 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 Scholia
  69. Kang W, Hong SH, Lee HM, Kim NY, Lim YC, Le le TM, Lim B, Kim HC, Kim TY, Ashida H, Yokota A, Hah SS, Chun KH, Jung YK, Yang JK.; ''Structural and biochemical basis for the inhibition of cell death by APIP, a methionine salvage enzyme.''; PubMed Europe PMC Scholia
  70. Thomsen ND, Koerber JT, Wells JA.; ''Structural snapshots reveal distinct mechanisms of procaspase-3 and -7 activation.''; PubMed Europe PMC Scholia
  71. 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 Scholia
  72. 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 Scholia
  73. Shakeri R, Kheirollahi A, Davoodi J.; ''Apaf-1: Regulation and function in cell death.''; PubMed Europe PMC Scholia
  74. 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 Scholia
  75. Wang X.; ''The expanding role of mitochondria in apoptosis.''; PubMed Europe PMC Scholia
  76. 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 Scholia
  77. 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 Scholia
  78. Bergamaschi D, Samuels Y, Jin B, Duraisingham S, Crook T, Lu X.; ''ASPP1 and ASPP2: common activators of p53 family members.''; PubMed Europe PMC Scholia
  79. Sakai T, Liu L, Teng X, Mukai-Sakai R, Shimada H, Kaji R, Mitani T, Matsumoto M, Toida K, Ishimura K, Shishido Y, Mak TW, Fukui K.; ''Nucling recruits Apaf-1/pro-caspase-9 complex for the induction of stress-induced apoptosis.''; PubMed Europe PMC Scholia
  80. 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 Scholia
  81. Kim HE, Du F, Fang M, Wang X.; ''Formation of apoptosome is initiated by cytochrome c-induced dATP hydrolysis and subsequent nucleotide exchange on Apaf-1.''; PubMed Europe PMC Scholia
  82. 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 Scholia
  83. Gao Z, Tian Y, Wang J, Yin Q, Wu H, Li YM, Jiang X.; ''A dimeric Smac/diablo peptide directly relieves caspase-3 inhibition by XIAP. Dynamic and cooperative regulation of XIAP by Smac/Diablo.''; PubMed Europe PMC Scholia

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)
ADP MetaboliteCHEBI:456216 (ChEBI)
ADPMetaboliteCHEBI:456216 (ChEBI)
APAF1 ProteinO14727 (Uniprot-TrEMBL)
APAF1:ADPComplexR-HSA-9627055 (Reactome)
APAF1:ATP:CYCS heptamer:CASP9ComplexR-HSA-6804619 (Reactome)
APAF1:ATP:CYCS heptamer:p-T125-CASP9ComplexR-HSA-9628212 (Reactome)
APAF1:ATP:CYCSComplexR-HSA-6804555 (Reactome)
APAF1:AVENComplexR-HSA-6805523 (Reactome)
APAF1:CYCS:ATP:APIPComplexR-HSA-6804605 (Reactome)
APAF1:CYCS:ATP:CASP9(1-416)dimerComplexR-HSA-6804630 (Reactome)
APAF1:CYCS:CASP9:XIAP:DIABLOComplexR-HSA-114318 (Reactome)
APIP ProteinQ96GX9 (Uniprot-TrEMBL)
APIPProteinQ96GX9 (Uniprot-TrEMBL)
ATP MetaboliteCHEBI:30616 (ChEBI)
ATPMetaboliteCHEBI:30616 (ChEBI)
AVEN ProteinQ9NQS1 (Uniprot-TrEMBL)
AVENProteinQ9NQS1 (Uniprot-TrEMBL)
Activated BAX,BAK oligomersComplexR-HSA-9029242 (Reactome)
Activated BAXComplexR-HSA-114269 (Reactome)
Active oligomeric BAKComplexR-HSA-114262 (Reactome)
ApoptosomeComplexR-HSA-114258 (Reactome)
ApoptosomeComplexR-HSA-6804662 (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 ProteinQ9BXH1 (Uniprot-TrEMBL)
BBC3 gene ProteinENSG00000105327 (Ensembl)
BBC3 geneGeneProductENSG00000105327 (Ensembl)
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)
C1QBP ProteinQ07021 (Uniprot-TrEMBL)
C1QBP homotrimerComplexR-HSA-9645765 (Reactome)
CARD8 ProteinQ9Y2G2 (Uniprot-TrEMBL)
CARD8ProteinQ9Y2G2 (Uniprot-TrEMBL)
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)
CASP9:CARDComplexR-HSA-6805422 (Reactome)
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.
DIABLO ProteinQ9NR28 (Uniprot-TrEMBL)
DIABLO dimer:XIAPComplexR-HSA-9627391 (Reactome)
DIABLO dimerComplexR-HSA-9627054 (Reactome)
DIABLO:XIAP:Caspase-3ComplexR-HSA-114305 (Reactome)
DIABLO:XIAP:Caspase-7ComplexR-HSA-114353 (Reactome)
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)
SEPT4 ProteinO43236-6 (Uniprot-TrEMBL)
SEPT4 dimer:XIAPComplexR-HSA-9627441 (Reactome)
SEPT4 dimerComplexR-HSA-9627347 (Reactome)
SEPT4ProteinO43236-6 (Uniprot-TrEMBL)
SFN ProteinP31947 (Uniprot-TrEMBL)
TFDP1 ProteinQ14186 (Uniprot-TrEMBL)
TFDP2 ProteinQ14188 (Uniprot-TrEMBL)
TP53BP2 ProteinQ13625 (Uniprot-TrEMBL)
TP63 ProteinQ9H3D4 (Uniprot-TrEMBL)
TP73 ProteinO15350 (Uniprot-TrEMBL)
UACA ProteinQ9BZF9 (Uniprot-TrEMBL)
UACA:apoptosomeComplexR-HSA-6804657 (Reactome)
UACAProteinQ9BZF9 (Uniprot-TrEMBL)
XIAP ProteinP98170 (Uniprot-TrEMBL)
XIAP:Caspase-3ComplexR-HSA-114304 (Reactome)
XIAP:Caspase-7ComplexR-HSA-114308 (Reactome)
XIAP:apoptosomeComplexR-HSA-9627066 (Reactome)
XIAPProteinP98170 (Uniprot-TrEMBL)
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,Y MAPK dimersComplexR-HSA-1268261 (Reactome)
p-T,p-S-AKTComplexR-HSA-202074 (Reactome)
p-T125-CASP9(1-416) ProteinP55211 (Uniprot-TrEMBL)
p-T185,Y187-MAPK1 ProteinP28482 (Uniprot-TrEMBL)
p-T202,Y204-MAPK3 ProteinP27361 (Uniprot-TrEMBL)
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)
p14ARF ProteinQ8N726 (Uniprot-TrEMBL)
p14ARF:C1QBPComplexR-HSA-9645693 (Reactome)
p14ARF:C1QBPComplexR-HSA-9645711 (Reactome)
p14ARFProteinQ8N726 (Uniprot-TrEMBL)
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-114254 (Reactome)
ADPArrowR-HSA-114259 (Reactome)
ADPArrowR-HSA-114261 (Reactome)
ADPArrowR-HSA-139908 (Reactome)
ADPArrowR-HSA-139918 (Reactome)
ADPArrowR-HSA-198347 (Reactome)
ADPArrowR-HSA-9627089 (Reactome)
APAF1:ADPR-HSA-114254 (Reactome)
APAF1:ADPR-HSA-6805507 (Reactome)
APAF1:ATP:CYCS heptamer:CASP9ArrowR-HSA-114256 (Reactome)
APAF1:ATP:CYCS heptamer:CASP9R-HSA-6804596 (Reactome)
APAF1:ATP:CYCS heptamer:CASP9R-HSA-9627056 (Reactome)
APAF1:ATP:CYCS heptamer:CASP9R-HSA-9627089 (Reactome)
APAF1:ATP:CYCS heptamer:p-T125-CASP9ArrowR-HSA-9627089 (Reactome)
APAF1:ATP:CYCSArrowR-HSA-114254 (Reactome)
APAF1:ATP:CYCSR-HSA-114256 (Reactome)
APAF1:AVENArrowR-HSA-6805507 (Reactome)
APAF1:CYCS:ATP:APIPArrowR-HSA-6804596 (Reactome)
APAF1:CYCS:ATP:CASP9(1-416)dimerArrowR-HSA-9627056 (Reactome)
APAF1:CYCS:ATP:CASP9(1-416)dimerR-HSA-114259 (Reactome)
APAF1:CYCS:ATP:CASP9(1-416)dimermim-catalysisR-HSA-114259 (Reactome)
APAF1:CYCS:CASP9:XIAP:DIABLOArrowR-HSA-114361 (Reactome)
APAF1:CYCS:CASP9:XIAP:DIABLOR-HSA-114440 (Reactome)
APIPR-HSA-6804596 (Reactome)
APIPTBarR-HSA-114256 (Reactome)
ATPR-HSA-114252 (Reactome)
ATPR-HSA-114254 (Reactome)
ATPR-HSA-114261 (Reactome)
ATPR-HSA-139908 (Reactome)
ATPR-HSA-139918 (Reactome)
ATPR-HSA-198347 (Reactome)
ATPR-HSA-9627089 (Reactome)
AVENR-HSA-6805507 (Reactome)
AVENTBarR-HSA-114256 (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)
ApoptosomeArrowR-HSA-114259 (Reactome)
ApoptosomeArrowR-HSA-114440 (Reactome)
ApoptosomeR-HSA-6804652 (Reactome)
ApoptosomeR-HSA-9627078 (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)
C1QBP homotrimerR-HSA-9645694 (Reactome)
CARD8R-HSA-6805426 (Reactome)
CARD8TBarR-HSA-114256 (Reactome)
CASP3(1-277) dimerR-HSA-114252 (Reactome)
CASP7(2-303) dimerR-HSA-114261 (Reactome)
CASP9(1-416)R-HSA-114256 (Reactome)
CASP9(1-416)R-HSA-6805426 (Reactome)
CASP9:CARDArrowR-HSA-6805426 (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-3R-HSA-9627104 (Reactome)
Caspase-7ArrowR-HSA-114261 (Reactome)
Caspase-7ArrowR-HSA-114392 (Reactome)
Caspase-7R-HSA-9627107 (Reactome)
DIABLO dimer:XIAPArrowR-HSA-114392 (Reactome)
DIABLO dimer:XIAPArrowR-HSA-114419 (Reactome)
DIABLO dimer:XIAPArrowR-HSA-114440 (Reactome)
DIABLO dimer:XIAPArrowR-HSA-9627350 (Reactome)
DIABLO dimerArrowR-HSA-9627106 (Reactome)
DIABLO dimerR-HSA-114306 (Reactome)
DIABLO dimerR-HSA-114354 (Reactome)
DIABLO dimerR-HSA-114361 (Reactome)
DIABLO dimerR-HSA-9627350 (Reactome)
DIABLO dimerTBarR-HSA-9627078 (Reactome)
DIABLO dimerTBarR-HSA-9627107 (Reactome)
DIABLO:XIAP:Caspase-3ArrowR-HSA-114306 (Reactome)
DIABLO:XIAP:Caspase-3R-HSA-114419 (Reactome)
DIABLO:XIAP:Caspase-3TBarR-HSA-9627104 (Reactome)
DIABLO:XIAP:Caspase-7ArrowR-HSA-114354 (Reactome)
DIABLO:XIAP:Caspase-7R-HSA-114392 (Reactome)
DIABLOArrowR-HSA-114307 (Reactome)
DIABLOR-HSA-114307 (Reactome)
DIABLOR-HSA-9627106 (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) The apoptotic protease‑activating factor 1 (APAF1) is a cytosolic multidomain adapter protein containing an N‑terminal caspase recruitment domain (CARD), followed by a central nucleotide‑binding & oligomerization domain (NOD, also known as NB‑ARC) and a C‑terminal regulatory region with WD40 repeats which form the 7- and 8-bladed β-propellers (Inohara N and Nunez G 2003; Danot O et al. 2009; Yuan S et al. 2011). Under steady‑state, non‑apoptotic conditions, APAF1 exists as an ADP‑bound, autoinhibited monomer (Riedl SJ et al. 2005; Reubold TF et al. 2009). During apoptosis, cytochrome c (CYCS) is released from the mitochondrial intermembrane space to the cytosol where it binds APAF1 between the two WD40 repeat domains in the C‑terminal regulatory region (Zou et al. 1997; Liu X et al. 1996; Shalaeva DN et al. 2015; Zhou M et al. 2015). CYCS binding causes an upward rotation of the β-propeller region which is accompanied by conformational changes in APAF1 and the replacement of ADP by dATP or ATP triggering APAF1 oligomerization into a heptameric, wheel‑shaped signaling platform (Acehan D et al. 2002; Yu X et al. 2005, Kim HE et al. 2005; Yuan S et al. 2010, 2013; Li P et al. 1997; Jiang X & Wang X 2000; Zhou M et al. 2015). Moreover, the N-terminal CARD in the inactive APAF1 monomer is not shielded from other proteins by β–propellers. Hence, the APAF1 CARD may be free to interact with a procaspase-9 CARD either before or during apoptosome assembly (Yuan S et al. 2013). Physiological concentrations of calcium ion negatively affect the assembly of apoptosome and activation of CASP9 by inhibiting nucleotide exchange in the monomeric, autoinhibited APAF1 (Bao Q et al. 2007).
R-HSA-114256 (Reactome) The protease caspase‑9 (CASP9) is normally present as an inactive monomeric propeptide (procaspase‑9 or zymogen). Upon apoptosis procaspase‑9 (CASP9(1‑416) is recruited to APAF1:cytochrome C (CYCS):ATP complex to form the caspase‑activating apoptosome (Hu Q et al. 2014; Cheng TC et al. 2016). The cryo-EM structures have established that the nucleotide-binding oligomerization domain (NOD) of APAF1 mediates the heptameric oligomerization of APAF1, while its tryptophan-aspartic acid (WD40) domain interacts with CYCS (Yuan S & Akey CW 2013). The caspase recruitment domain (CARD) of APAF1 recruits the N‑terminal CARD of CASP9(1‑416) through homotypic CARD:CARD interactions (Li P et al. 1997; Qin H et al. 1999; Yuan S et al. 2010; Yuan S & Akey CW 2013). These homotypic interaction motifs are thought to interact with each other through three types of interfaces, type I, II, and III, which cooperate to generate homo- and hetero-oligomers from relatively small assemblies to open-ended filaments (Ferrao R & Wu H 2012). Structural and mutagenesis studies showed that all type I, II, and III interfaces are involved in the caspase-9 activation by APAF1-mediated helical oligomerization of CARDs (Hu Q et al. 2014; Cheng TC et al. 2016; Su TW et al. 2017; Li Y et al. 2017). Cryo-EM structure of the holo-apoptosome revealed an oligomeric CARD disk above the heptameric apoptosome ring with estimated molecular ratios between 2-5 zymogens per 7 APAF1 molecules (Hu Q et al. 2014; Cheng TC et al. 2016). The structural and biochemical studies showed that APAF1-CARD and CASP9-CARD initially formed a 1:1 complex in solution, which at higher concentrations is further oligomerized into a 3:3 complex. The 3:3 complex was reported as a core arrangement of the 4:3 or 4:4 APAF1-CARD:CASP9-CARD complex in the helical assembly of the CARD disk (Cheng TC et al. 2016; Su TW et al. 2017; Li Y et al. 2017; Dorstyn L et al. 2018). Thus, APAF1:CASP9 (1-416) heterodimers may be recruted to the assembling apoptosome as part of its activation.

The Reactome event describes the apoptosome assembly with the stoichiometry of 4 procaspase-9 zymogens per 7 APAF1 molecules. The formation of 1:1 and other combinations of APAF1:CASP9(1-416) complexes is not shown.

R-HSA-114259 (Reactome) Procaspase‑9 is processed in an ATP‑dependent manner following association with APAF1 and cytochrome c (CYCS) within the apoptosome complex (Li P et al. 1997). However, caspase‑9 (CASP9) has an unusually active zymogen that does not require proteolytic processing (Stennicke HR et al. 1999). Though dispensable for catalytic activity, CASP9 processing was suggested to serve as a "molecular timer" that can limit the proteolytic activity of this complex through displacement of bound caspase‑9 molecules (Malladi S et al. 2009). In addition, this cleavage exposes a neo‑epitope comprising the NH2‑terminal four amino acids (ATPF) of the small p12 subunit of CASP9 that has been shown to be both necessary and sufficient for binding to the baculovirus IAP repeat 3 (BIR3) domain of XIAP, leading to inhibition of CASP9 activity (Srinivasula SM et al. 2001; Shiozaki EN et al. 2003).
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) Binding of a dimeric SMAC (DIABLO) N‑terminal peptide with the BIR2 domain of XIAP effectively antagonizes inhibition of caspase‑3 by XIAP (Wu G et al. 2000; Chai J et al. 2000). SMAC (DIABLO) interacts with the BIR3 and then BIR2 domains of XIAP sequentially, and such dynamic interaction cooperatively neutralizes inhibition of caspase‑3 by the linker region of XIAP (Gao Z et al. 2007).
R-HSA-114307 (Reactome) Permeabilization of the outer mitochondrial membrane by pro-apoptotic BCL2 family members BAK and BAX allows release of direct IAP-binding protein with low pI (DIABLO, also known as SMAC) from the mitochondrial intermembrane space into the cytosol (Du C et al, 2000; Arnoult D et al. 2003). When released from mitochondria, DIABLO acts as a natural antagonist of inhibitor of apoptosis proteins (IAPs). DIABLO antagonistic activity is based on its N-terminal tetrapeptide (AVPI) that binds baculoviral IAP repeat (BIR) domains of IAPs, releasing their inhibitory effects on both initiator and effector caspases, thus promoting cell death (Du C et al. 2000; Gao Z et al. 2007). Binding of DIABLO (SMAC) to survivin leads to the inhibition of apoptosis (Song Z 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) The linker region preceding BIR2 of XIAP is responsible for the inhibition of caspase‑3 and ‑7, which is further stabilized by interaction with the BIR2 domain itself (Scott et al. 2005). Binding of a dimeric SMAC (DIABLO) N‑terminal peptide with the BIR2 domain of XIAP effectively antagonized inhibition of caspase‑7 by XIAP (Wu G et al. 2000; Chai J et al. 2000).
R-HSA-114361 (Reactome) X linked inhibitor of apoptosis protein (XIAP) associates with the active caspase 9 (CASP9) within the APAF1 apoptosome complex. XIAP consists of three baculoviral IAP repeat (BIR) domains and a COOH terminal RING domain (Duckett CS et al. 1996). The BIR3 region of XIAP binds to the amino terminus of the linker peptide on the small subunit of CASP9, which becomes exposed after proteolytic processing of procaspase 9 at Asp315 (Srinivasula SM et al. 2001). SMAC (DIABLO) competes with CASP9 for binding to BIR3 domain of XIAP promoting the release of XIAP from the CASP9:apoptosome complex (Du et al. 2000; Liu Z et al. 2000; Srinivasula SM et al. 2001).
R-HSA-114392 (Reactome) The linker region preceding BIR2 of XIAP is responsible for the inhibition of caspase-3 and -7, which is further stabilized by interaction with the BIR2 domain itself (Scott et al. 2005). Binding of a dimeric SMAC (DIABLO) N-terminal peptide with the BIR2 domain of XIAP effectively antagonized inhibition of caspase-7 by XIAP (Wu G et al. 2000; Chai J et al. 2000). 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) The linker region preceding BIR2 of XIAP is responsible for the inhibition of caspase-3 and -7, which is further stabilized by interaction with the BIR2 domain itself (Scott et al. 2005). Binding of DIABLO (SMAC) to BIR2 domain of XIAP can destabillize the XIAP:CASP3 interaction promoting the liberation of active caspase-3 from its complex with XIAP (Kashkar et al. 2003). Furthermore, SMAC (DIABLO) interacted with the BIR3 and then BIR2 domains of XIAP sequentially, and such dynamic interaction cooperatively neutralized inhibition of caspase-3 by the linker region of XIAP (Gao Z et al. 2007).
R-HSA-114440 (Reactome) X linked inhibitor of apoptosis protein (XIAP) associates with the active caspase 9 (CASP9) within APAF1 apoptosome complex. Binding of DIABLO (SMAC) to XIAP promotes the release of caspase-9 from XIAP (Du et al. 2000). XIAP consists of three baculoviral IAP repeat (BIR) domains and a COOH terminal RING domain (Duckett CS et al. 1996). The BIR3 region binds to the amino terminus of the linker peptide on the small subunit of CASP9, which becomes exposed after proteolytic processing of procaspase 9 at Asp315 (Srinivasula SM et al. 2001). SMAC (DIABLO) competes with CASP9 for binding to BIR3 domain of XIAP promoting the release of XIAP from the CASP9:apoptosome complex (Du et al. 2000; Srinivasula SM et al. 2001).
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).
R-HSA-6804596 (Reactome) The APAF1 interacting protein (APIP) is an endogenous regulators of the apoptosome apparatus. APIP is thought to bind to the CARD domain of APAF1 preventing procaspase-9 recruitment to the apoptosome (Cho DH et al., 2004; Cao G et al., 2004; Kang W et al. 2014). Moreover, during hypoxic conditions, APIP may also induce sustained activation of AKT and ERK1/2 kinases, which directly phosphorylate procaspase-9 to inhibit its activation in the apoptosome (Cho DH et al., 2007).
R-HSA-6804652 (Reactome) Uveal autoantigen with coiled coil domains and ankyrin repeats (UACA) is a regulatory molecule for stress-induced apoptosis. The human UACA event is inferred from the manually curated orthological Uaca event in mice.

Mouse Uaca (or nucling) is thought to interact with the Apaf1/pro-caspase-9 complex, thereby acting as a stabilizer for the apoptosome (Sakai T et al. 2004). Uaca was shown to induce apoptosis in mammalian cells (Sakai T et al. 2004). Cells prepared from Uaca-knockout mice were resistant to proapoptotic stress induced by UV irradiation, LPS ot TNFalpha (Sakai T et al. 2004; Kim SM et al. 2013). Moreover, Uaca-deficiency in mice was linked to the development of hepatic inflammation and hepatocellular carcinoma (HCC) (Sakai T et al. 2010). The findings in mouse disease model are in line with the data showing a significantly lower expression of UACA mRNAs and protein levels in human non-small cell lung carcinoma (NSCLC) cell lines and NSCLC tumours suggesting that the loss of UACA might contribute to tumor progression due to a reduction in the UACA-assisted
cell death (Moravcikova E et al. 2012).

The mechanism of the UACA proapoptotic activity remains unclear. Mouse Uaca, showing both cytoplasmic and perinuclear/nuclear localization, was suggested to translocate Apaf1-apoptosome to the nucleus after proapoptotic stress (Sakai T et al. 2004). Uaca also reduced expression of the NFkappaB-targeted genes by preventing the nuclear translocation of NFkappaB (Liu L et al. 2004).

R-HSA-6805426 (Reactome) Caspase activating and recruitment domain 8 protein (CARD8, also known as TUCAN, CARDINAL) has been implicated as a regulator of several pro-inflammatory and apoptotic signaling pathways. The C-terminal CARD domain of CARD8 (TUCAN) binds procaspase-9 (CASP9(1-416)) and interferes with binding of APAF1 to procaspase-9 thus suppressing caspase activation induced by the APAF1:cytochrome c (CYCS) axis (Pathan N et al. 2001). The structural studies of CARD8 suggest that in addition to intermolecular CARD-CARD interactions, CARD domain may intramolecularly associate with the N-terminal function to find domain (FIIND) to regulate apoptotic and inflammatory signaling pathways (Jin T et al. 2013).

Several binding partners of CARD8 have been reported. CARD8 can interact physically via CARD domain with caspase-1 and negatively regulates caspase-1-dependent IL-1beta generation in the THP-1 monocytic cell line (Razmara M et al. 2002). The FIIND domain of CARD8 may inhibit NFkappaB activation, possibly through interaction with IKKgamma (Bouchier-Hayes L et al. 2001). FIIND may also bind the nucleotide-binding domain (NBD) domain of NOD2 and NLRP3 to regulate the immune response to bacterial infections (Kampen O et al. 2010).

High levels of CARD8 expression have been observed in several tumor cell lines and malignant specimens from human patients underlying its importance in regulating inflammatory and apoptotic pathways (Bouchier-Hayes L et al. 2001; Pathan N et al. 2001; Razmara M et al. 2002; Zhang H & Fu W 2002; Yamamoto M et al. 2005).

R-HSA-6805507 (Reactome) The binding of AVEN to apoptotic protease activating factor 1 (APAF1) is thought to interfere with the ability of APAF1 to self-associate during apoptosome assembly (Chau BN et al. 2000). The anti-apoptotic function of AVEN may require the proteolytic removal of the inhibitory N-terminus of AVEN (Melzer IM et al. 2012).
R-HSA-6805811 (Reactome) Septin 4 gene (SEPT4) encodes several protein isoforms including SEPT4_i2 (also known as apoptosis-related protein in the TGF-beta signaling pathway (ARTS)) (Larisch S et al. 2000).

ARTS (SEPT4_i2) is a mitochondrial pro-apoptotic tumor suppressor protein (Larisch S et al. 2000; Elhasid et al. 2004; Gottfried Y et al. 2004; Lotan R et al. 2005). Following induction of apoptosis, ARTS rapidly translocates to the cytosol where it binds and inhibits X-linked inhibitor of apoptosis protein (XIAP). ARTS is thought to induce apoptosis by promoting the proteasome-mediated degradation of XIAP and blocking its ability to inhibit caspases (Gottfried Y et al. 2004; Bornstein B et al. 2011; Garrison JB et al. 2011; Reingewertz TH et al. 2011). The release of ARTS from mitochondria and its accumulation in the cytosol appears to be a caspase-independent event (Gottfried Y et al. 2004). The protein level of ARTS is tightly regulated through ubiquitin mediated degradation (Lotan R et al. 2005). The translocation of ARTS (SEPT4) from mitochondria precedes the release of both cytochrome c (CYCS) and SMAC (DIABLO) and leads to degradation of XIAP before the release of SMAC (Edison N et al. 2012).

R-HSA-9627056 (Reactome) CASP9 is normally present as an inactive monomeric propeptide (procaspase‑9 or zymogen). Upon apoptosis, the N‑terminal caspase recruitment domain (CARD) of procaspase‑9 binds to the exposed CARD of the apoptotic protease‑activating factor‑1 (APAF1) through homotypic interactions (Qin H et al. 1999). Procaspase-9 has been estimated to bind to the apoptosome with ratios between 2–5 zymogens per 7 APAF:cytochrome c (CYCS) molecules (Cheng TC et al. 2016). The function of the apoptosome is to promote homodimerization of CASP9 (Jiang X and Wang X 2000; Srinivasula SM et al. 2001; Shiozaki EN et al. 2002). While activation of CASP9 involves dimerization, proteolytic cleavage of CASP9 may not be required. The unprocessed CASP9 exhibited high catalytic activity (Renatus et al. 2001; Acehan D et al. 2002). Furthermore, unlike other initiator caspases, including caspases‑2, ‑8 and ‑10, the prodomain of CASP9 is not removed during apoptosis; in fact, CASP9 (in both its procaspase‑9 and processed forms) must remain bound to the apoptosome to retain substantial catalytic activity (Bratton et al. 2001; Rodriguez and Lazebnik 1999). Once activated in the apoptosome, CASP9 dimer cleaves and activates procaspase‑3 and ‑7.
R-HSA-9627078 (Reactome) X‑linked inhibitor‑of‑apoptosis protein (XIAP) associates with the cleaved form of CASP9. It does not influence pro‑caspase‑9 auto‑processing but inhibits the activity of processed caspase‑9 and then the activation of effector caspases within the apoptosome complex (Srinivasula SM et al. 2001; Bratton SB et al. 2001). BIR3 domain of XIAP binds IAP binding motif (IBM) at the amino terminus on the small subunit of CASP9, which becomes exposed after proteolytic processing of procaspase‑9 at Asp315 (Srinivasula SM et al. 2001). Furthermore, the C‑terminal extremity of BIR3 binds the dimer interface of CASP9, interfering with CASP9 dimerization and hiding the catalytic residue (Srinivasula SM et al. 2001, Shiozaki EN et al. 2003).
R-HSA-9627089 (Reactome) Phosphorylation of caspase 9 (CASP9) may contribute to the suppression of apoptosis. A major inhibitory phosphorylation site in CASP9 is Thr125, which forms part of a Thr‑Pro motif (Allan LA & Clarke PR 2007; Martin MC et al. 2008). This motif is targeted by multiple proline‑directed kinases such as ERK1/2 in response to extracellular growth/survival signals or CDK1‑cyclin B1 during mitosis (Allan LA et al. 2003; Allan LA & Clarke PR 2007; Martin MC et al. 2008). Thr125 is also phosphorylated by DYRK1A, which regulates apoptosis during development (Seifert A et al. 2008).
R-HSA-9627104 (Reactome) X‑linked inhibitor of apoptosis protein (XIAP) suppresses cell death by inhibiting the catalytic activity of caspases (Deveraux QL et al. 1997; Paulsen M et al. 2008). XIAP consists of three bacculoviral inhibitory repeat (BIR) domains and a C‑terminal ring finger. Biochemical and structural analyses revealed that the linker connecting BIR1 to BIR2 inhibits executioner caspase‑3 and ‑7 by positioning itself at the active site (Sun C et al. 1999; Riedl SJ et al. 2001; Huang Y et al. 2001; Chai J et al. 2001). Formation of a complex between caspase‑3 or caspase‑7 and the XIAP BIR2‑linker region appears to be driven by interactions between XIAP's Leu141 and Val146 and a hydrophobic site present on both caspases. This hydrophobic site is not found in caspase‑8 or caspase‑9, perhaps explaining the binding specificity of XIAP (Riedl SJ et al. 2001). BIR2 domain of XIAP may also contribute to inhibition of executioner caspases by interacting with additional sites on the enzymes (Scott FL et al. 2005; Abhari BA & Davoodi J 2008).
R-HSA-9627106 (Reactome) The crystal structure of SMAC(DIABLO) at 2.2A resolution revealed that it homodimerized through an extensive hydrophobic interface and formed an elongated arch shaped quaternary structure (Chai J et al. 2000). Missense mutations that disrupt SMAC (DIABLO) dimeric interface, abrogated the XIAP‑neutralizing function of SMAC (DIABLO), suggesting that SMAC dimerization is essential for its pro‑apoptotic activity (Chai et al. 2000). SMAC (DIABLO) was also found to adopt a tetrameric assembly in solution (Mastrangelo E et al. 2015).

R-HSA-9627107 (Reactome) The inhibitor‑of‑apoptosis (IAP) family of proteins such as X‑linked IAP (XIAP) suppress cell death by inhibiting the catalytic activity of caspases (Deveraux QL et al. 1997; Paulsen M et al. 2008). XIAP consists of three bacculoviral inhibitory repeat (BIR) domains and a C‑terminal ring finger. Biochemical and structural analyses revealed that the linker connecting BIR1 to BIR2 inhibits executioner caspase‑3 and ‑7 by positioning itself at the active site (Sun C et al. 1999; Riedl SJ et al. 2001; Huang Y et al. 2001; Chai J et al. 2001). Formation of a complex between caspase‑3 or caspase‑7 and the XIAP BIR2‑linker region appears to be driven by interactions between XIAP's Leu141 and Val146 and a hydrophobic site present on both caspases. This hydrophobic site is not found in caspase‑8 or caspase‑9, perhaps explaining the binding specificity of XIAP (Riedl SJ et al. 2001). BIR2 domain of XIAP may also contribute to inhibition of executioner caspases by interacting with additional sites on the enzymes (Scott FL et al. 2005; Abhari BA & Davoodi J 2008).
R-HSA-9627350 (Reactome) Second mitochondria derived activator of caspase/direct inhibitor of apoptosis binding protein with low pI (SMAC, also known as DIABLO) is normally a mitochondrial protein but is released into the cytosol when cells undergo apoptosis (Du C et al. 2000). Mitochondrial import and cleavage of its signal peptide are required for SMAC to gain its apoptotic activity (Du C et al. 2000). In vitro studies revealed that dimerization was required for its function, while monomerization of cytosolic mature SMAC attenuated interaction with XIAP (Chai J et al. 2000; Burke SP & Smith JB 2010). Moreover, SMAC dimer showed high stability in vitro as measured by high hydrostatic pressure, low and high temperatures, and chemical denaturation (Goncalves RB et al. 2008). Binding of SMAC (DIABLO) to the BIR3 region of X linked inhibitor of apoptosis protein (XIAP) competitively inhibits binding of XIAP to caspase 9, while binding to the BIR2 region sterically hinders the interaction of XIAP with CASP3 and CASP7 (Srinivasula SM et al. 2001; Abhari BA & Davoodi J 2008).
R-HSA-9627369 (Reactome) SEPT4 (known also as ARTS, an apoptosis-related protein in the TGF-beta signaling pathway) is a pro-apoptotic mitochondrial protein (Gottfried Y et al. 2004). SEPT4 is an unique member of the septin family which functions as a tumor suppressor. SEPT4 promotes apoptosis through binding and antagonizing inhibitor of apoptosis (IAP) proteins and specifically X linked IAP (XIAP) (Gottfried Y et al. 2004). NMR and fluorescence spectroscopy showed that the C-terminal domain (CTD) of SEPT4 directly binds BIR3 domain of XIAP. The BIR3 interacting region in SEPT4 CTD was mapped to SEPT4 residues 266 - 274, which are the nine C-terminal residues in the protein (Bornstein B et al. 2011; Reingewertz TH et al. 2011).
R-HSA-9645692 (Reactome) The complex of p14ARF and C1QBP (p32) changes the mitochondrial membrane potential and facilitates p53-mediated apoptosis (Itahana and Zhang 2008), but the mechanism has not been elucidated.
It has been reported that p14ARF can localize to the mitochondrion independently of C1QBP and trigger p53-independent apoptosis (Irvine et al. 2010).
A short isoform of p14ARF, smARF, which lacks 47 N-terminal amino acids, has been reported to localize exclusively to mitochondria where it binds to C1QBP and promotes autophagy (Reef et al. 2007). However, exclusive mitochondrial localization of smARF was not reproduced by other studies (Itahana, Clegg et al. 2008, Irvine et al. 2010). Several mutations in exon 2 of the CDKN2A gene that affect p14ARF, but not p16INK4A, have been reported to impair p14ARF-mediated autophagy through an unknown mechanism (Budina-Kolomets et al. 2013).
R-HSA-9645694 (Reactome) p14ARF (CDKN2A-4) forms a complex with a mitochondrial matrix protein C1QBP (p32). The complex formation involves the arginine-rich C-terminal region of p14ARF (Itahana and Zhang 2008).
SEPT4 dimer:XIAPArrowR-HSA-9627369 (Reactome)
SEPT4 dimerR-HSA-9627369 (Reactome)
SEPT4ArrowR-HSA-6805811 (Reactome)
SEPT4R-HSA-6805811 (Reactome)
UACA:apoptosomeArrowR-HSA-6804652 (Reactome)
UACAR-HSA-6804652 (Reactome)
XIAP:Caspase-3ArrowR-HSA-9627104 (Reactome)
XIAP:Caspase-3R-HSA-114306 (Reactome)
XIAP:Caspase-7ArrowR-HSA-9627107 (Reactome)
XIAP:Caspase-7R-HSA-114354 (Reactome)
XIAP:apoptosomeArrowR-HSA-9627078 (Reactome)
XIAP:apoptosomeR-HSA-114361 (Reactome)
XIAPR-HSA-9627078 (Reactome)
XIAPR-HSA-9627104 (Reactome)
XIAPR-HSA-9627107 (Reactome)
XIAPR-HSA-9627350 (Reactome)
XIAPR-HSA-9627369 (Reactome)
XIAPTBarR-HSA-114252 (Reactome)
XIAPTBarR-HSA-114261 (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,Y MAPK dimersmim-catalysisR-HSA-9627089 (Reactome)
p-T,p-S-AKTmim-catalysisR-HSA-198347 (Reactome)
p-Y705-STAT3 dimerArrowR-HSA-6790025 (Reactome)
p14ARF:C1QBPArrowR-HSA-9645692 (Reactome)
p14ARF:C1QBPArrowR-HSA-9645694 (Reactome)
p14ARF:C1QBPR-HSA-9645692 (Reactome)
p14ARFR-HSA-9645694 (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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