Intrinsic Pathway for Apoptosis (Homo sapiens)

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58, 61, 757132, 8354, 55, 6517, 723025, 28, 41, 76, 782721, 51, 707, 29, 4910, 6035568230684, 10, 5113, 14, 20, 7623, 29, 32, 426446320, 24, 25, 63, 802918, 2231, 46, 738019, 20, 25, 47, 63...53309, 1624354329, 40, 48, 742, 7429, 40, 742656426, 34, 68, 80795913, 14, 20, 761, 50, 52, 776, 17, 7226397125, 28, 41, 76, 782012, 33, 37, 38, 628215, 57, 66513, 7, 29, 452430271969cytosolmitochondrial outer membranenucleoplasmmitochondrial inner membraneBAX SEPT4 ATPCYCS CASP8(217-374) CASP9(1-416) ATPGZMBCASP9(331-416) tBID:BCL-2E2F1 APAF1:ATP:CYCSheptamer:p-T125-CASP9CYCS PIP3 activates AKTsignalingNMT 1PMAIP1 Gene YWHAZ BAX BCL2L1 XIAP E2F1:TFDP1,TFDP2p-S15,S20-TP53Tetramerp14ARF:C1QBPAPAF1:ATP:CYCSYWHAZ p-S99-BAD TFDP1 BID(1-195)p-T308,S473-AKT1 CASP7(207-303) SFN CYCSCASP7(24-198) Dynein (DLC1) onmicrotubulesUACA APAF1 p-S15,S20-TP53Tetramer:PMAIP1Genep-BCL2L11 APAF1:CYCS:CASP9:XIAP:DIABLOAPAF1:CYCS:ATP:CASP9(1-416)dimerCASP9(331-416) XIAP CYCS ATPp-T309,S474-AKT2 p-BMF CASP3(176-277) (p-S15,S20-TP53,TP63,TP73):(PPP1R13B,TP53BP2)SFN p14ARF:C1QBPYWHAH p-T305,S472-AKT3 DYNLL2 APIPp14ARFCASP3(1-277) dimerCASP9:CARDp14ARF DIABLO CASP7(2-303) dimerSEPT4 dimer:XIAPBAK1 activated CYCS BAD CASP9(?-315) APAF1:ADPp-T125-CASP9(1-416) XIAP:apoptosomeBBC3BCL2 gene, BCL2L1geneTFDP1 PPP3R1 APAF1 ATPAPAF1 CASP3(1-277) BAX p-T,Y MAPK dimersMYS-BID(62-195) YWHAQ PPP1R13B XIAP DYNLL2 microtubules CYCS DYNLL1 UACA:apoptosomeCYCSSEPT4p-BCL2L11 BMF sequestered todynein (DLC2)APAF1:CYCS:ATP:APIPADP BAD(p-S15,S20-TP53,TP63,TP73):(PPP1R13B,TP53BP2):BBC3 GeneBAXBAK1 activatedATP APAF1 CASP8(385-479) APAF1 H2OMYS-BID(62-195) Bcl-2/Bcl-X(L)BID(62-195)BBC3 geneTP63 active caspase-8TP53BP2 CASP3(29-175) DIABLO:XIAP:Caspase-7p14ARF BCL2L11 YWHAE BAD XIAP 14-3-3 dimerBCL2 p-S99-BADPiBCL2 ATP MYS-BID(62-195) BBC3 gene XIAP p-S15,S20-TP53 XIAP:Caspase-3APIP XIAPp-Y705-STAT3 CASP7(24-198) PMAIP1 MYS-BID(62-195) UACAYWHAB CASP9(1-416) TP53BP2 APAF1 CASP9(331-416) BCL2CASP9(331-416) TP63 CASP9(?-315) CASP9(1-416) Calcineurin BcomplexDynein (DLC2) onmicrotubulesADPPMAIP1CYCS p-T202,Y204-MAPK3 p-BMF(1-89)BCL2L1 DIABLO CARD8BBC3 CASP9(?-315) E2F1:TFDP1:PMAIP1GeneCASP7(207-303) BCL2 YWHAQ MYS-BID(62-195)C1QBP APAF1:ATP:CYCSheptamer:CASP9YWHAE BAK1 activated BCL2L1 gene PPP3CC p-S15,S20-TP53 p-BCL2L11 C1QBP Caspase-7CASP7(2-303) PMAIP1 PPP1R13B p-T185,Y187-MAPK1 XIAP CASP7(24-198) CASP9(1-416) DIABLOCARD8 ApoptosomeCASP3(176-277) Bcl-XL interactingBH3-only proteinsBcl-XL:BH3-onlyprotein complexTFDP2 ApoptosomePMAIP1 DIABLO APAF1 CASP3(29-175) ADPDIABLO:XIAP:Caspase-3ADPAPAF1 DIABLO Bcl2:BH3-onlyprotein complexCYCS BAX activatedMYS-BID(62-195)PMAIP1AVENATP BAD:BCL-2APAF1:AVENBID(62-195) p-BCL2L11 BCL2 gene YWHAG DIABLOTFDP2 ATPSEPT4BADAPAF1 APAF1 microtubules BAD tBID bound toinactive BAKBBC3 CASP3(29-175) ADP E2F1 14-3-3proteins:p-S99-BADcomplexC1QBP ADPADPCaspase-3APAF1 CASP9(?-315) DIABLO dimer:XIAPSEPT4 dimerBAXAPAF1 XIAP microtubules BIM sequestered todynein (DLC1)TP73 CYCS p-Y705-STAT3 dimerBAD CASP9(?-315) BBC3 CYCS TFDP2 ADPPMAIP1 YWHAG p-BMFmicrotubules CASP7(207-303) PMAIP1 GeneBBC3 BCL2 p-S15,S20-TP53 ATP TP73 Bcl-2 interactingBH-3 only proteinsp-T,p-S-AKTPMAIP1 Gene MAPK8p-BMF BBC3 gene CASP9(1-416) tBID bound toinactive BAXADPp-BCL2L11CASP9(331-416) CYCS DIABLO AVEN p-S15,S20-TP53 E2F1:TFDP1:BBC3 GeneBAD BBC3DIABLO dimerBMF BCL2L1p-BCL2L11Activated BAXATPActivated BAX,BAKoligomersCASP9(1-416) CASP9(1-416)ATPSEPT4 Active oligomericBAKDYNLL1 XIAP:Caspase-7E2F1 ADPYWHAH C1QBP homotrimerYWHAB CASP3(176-277) BAK1TFDP1 XIAP BAK1 53308182816714, 2037, 62, 7030321037, 62, 7067678, 36678210, 11967679697010, 113225, 41


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: 75
Reactome Author 
Reactome Author: Matthews, Lisa

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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


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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)
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) Protein