Intrinsic Pathway for Apoptosis (Homo sapiens)

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1-3127271661016, 21, 2224, 251315430-3227, 2814, 16-1911, 14, 16-18824, 254261127149291332, 332330-3220152130mitochondrial outer membranecytosolmitochondrial inner membraneNOXA proteinCytochrome cADPNOXA proteinApoptosis regulator Bcl-XBcl-2 proteinSMAC:XIAP:Caspase-7Cytochrome cAKT1Bcl-XL interacting BH3-only proteinsactive caspase-7Cytochrome C:Apaf-1:ATP:Procaspase-9SMACBcl-2 interacting BH-3 only proteinsActivated BAK proteinNMT 1tBIDBcl2:BH3-only protein complexADPApoptosomeActivated BAX inserted into mitochondrial membrane143B:phospo-BAD complexCaspase-3 precursorCaspase-9 precursorSmac protein, mitochondrial precursorPUMA proteinSMAC:XIAP:Caspase-3PUMA protein14-3-3 protein beta/alphaBMFBIDSMAC:XIAP:Caspase-9BMF sequestered to dynein (DLC2)Phospho-BADBMFActive oligomeric BAKMitogen-activated protein kinase 8BAD:BCL-2tBID bound to inactive BAXCaspase-7 precursorBAD proteinBIM sequestered to dynein (DLC1)active caspase-3Granzyme BCaspase-8 dimerATPATPActivated BAXXIAP:Caspase-9XIAP:Caspase-7Inactive BAK proteinSMAC:XIAPtBID bound to inactive BAKtBID-p15tBID:BCL-2Apaf-1Apaf-1:Cytochrome CBIMCleaved Caspase-9XIAP:Caspase-3ATPCalcineurin B complextBIDBcl-XL:BH3-only protein complexActivated BAXphospho-dynein(DLC1) on microtubulesBIMDP-1:E2F1 complexInactive Bax alpha proteinBAD proteinADPphospho-dynein(DLC2) on microtubules544


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.</div>

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Bibliography

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History

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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
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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

View all...
NameTypeDatabase referenceComment
14-3-3 protein

beta/alpha

ProteinP31946 (UniProt)
143B:phospo-BAD

complex

ComplexREACT_5737 (Reactome)
ADP Metabolite16761 (ChEBI)
AKT1 ProteinP31749 (UniProt)
ATP Metabolite15422 (ChEBI)
Activated BAK

protein

ProteinQ16611 (UniProt)
Activated BAX ProteinQ07812 (UniProt)
Activated BAX ComplexREACT_2560 (Reactome)
Activated BAX

inserted into mitochondrial membrane

ProteinQ07812 (UniProt)
Active oligomeric

BAK

ComplexREACT_4956 (Reactome)
Apaf-1 ProteinO14727 (UniProt)
Apaf-1:Cytochrome

C

ComplexREACT_4880 (Reactome)
Apoptosis regulator

Bcl-X

ProteinQ07817 (UniProt)
Apoptosome ComplexREACT_3569 (Reactome)
BAD

protein

ProteinQ92934 (UniProt)
BAD:BCL-2 ComplexREACT_3232 (Reactome)
BID ProteinP55957 (UniProt)
BIM ProteinO43521-1 (UniProt)
BIM sequestered

to dynein (DLC1)

ComplexREACT_3567 (Reactome)
BMF ProteinQ96LC9 (UniProt)
BMF sequestered

to dynein (DLC2)

ComplexREACT_3065 (Reactome)
Bcl-2 interacting BH-

3 only proteins

ProteinREACT_21617 (Reactome)
Bcl-2 protein ProteinP10415 (UniProt)
Bcl-XL interacting

BH3-only proteins

ProteinREACT_21650 (Reactome)
Bcl-XL:BH3-only

protein complex

ComplexREACT_21559 (Reactome)
Bcl2:BH3-only

protein complex

ComplexREACT_21874 (Reactome)
Calcineurin B

complex

ComplexREACT_4613 (Reactome)
Caspase-3

precursor

ProteinP42574 (UniProt)
Caspase-7

precursor

ProteinP55210 (UniProt)
Caspase-8 dimer ComplexREACT_4185 (Reactome)
Caspase-9

precursor

ProteinP55211 (UniProt)
Cleaved

Caspase-9

ComplexREACT_5782 (Reactome)
Cytochrome C:Apaf-

1:ATP:Procaspase-9

ComplexREACT_5647 (Reactome)
Cytochrome c ProteinP99999 (UniProt)
DP-1:E2F1

complex

ComplexREACT_5400 (Reactome)
Granzyme B ProteinP10144 (UniProt)
Inactive BAK

protein

ProteinQ16611 (UniProt)
Inactive Bax alpha

protein

ProteinQ07812 (UniProt)
Mitogen-activated

protein kinase 8

ProteinP45983 (UniProt)
NMT 1 ProteinP30419 (UniProt)
NOXA

protein

ProteinQ13794 (UniProt)
PUMA

protein

ProteinQ9BXH1 (UniProt)
Phospho-BAD ProteinQ92934 (UniProt)
SMAC ProteinQ9NR28 (UniProt)
SMAC:XIAP ComplexREACT_5204 (Reactome)
SMAC:XIAP:

Caspase-3

ComplexREACT_5281 (Reactome)
SMAC:XIAP:

Caspase-7

ComplexREACT_3355 (Reactome)
SMAC:XIAP:

Caspase-9

ComplexREACT_4472 (Reactome)
Smac protein,

mitochondrial precursor

ProteinQ9NR28 (UniProt)
XIAP:Caspase-3 ComplexREACT_2704 (Reactome)
XIAP:Caspase-7 ComplexREACT_2853 (Reactome)
XIAP:Caspase-9 ComplexREACT_4334 (Reactome)
active caspase-3 ComplexREACT_2467 (Reactome)
active caspase-7 ComplexREACT_3366 (Reactome)
phospho-dynein

(DLC1) on microtubules

ComplexREACT_2522 (Reactome)
phospho-dynein

(DLC2) on microtubules

ComplexREACT_5554 (Reactome)
tBID ProteinP55957 (UniProt)
tBID bound to inactive

BAK

ComplexREACT_6608 (Reactome)
tBID bound to inactive

BAX

ComplexREACT_6691 (Reactome)
tBID-p15 ProteinP55957 (UniProt)
tBID:BCL-

2

ComplexREACT_5048 (Reactome)

Annotated Interactions

No annotated interactions

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