KEGG   PATHWAY: hsa04210Help
Entry
hsa04210                    Pathway                                

Name
Apoptosis - Homo sapiens (human)
Description
Apoptosis is a genetically programmed process for the elimination of damaged or redundant cells by activation of caspases (aspartate-specific cysteine proteases). The onset of apoptosis is controlled by numerous interrelating processes. The 'extrinsic' pathway involves stimulation of members of the tumor necrosis factor (TNF) receptor subfamily, such as TNFRI, CD95/Fas or TRAILR (death receptors), located at the cell surface, by their specific ligands, such as TNF-alpha, FasL or TRAIL, respectively. The 'intrinsic' pathway is activated mainly by non-receptor stimuli, such as DNA damage, ER stress, metabolic stress, UV radiation or growth-factor deprivation. The central event in the 'intrinsic' pathway is the mitochondrial outer membrane permeabilization (MOMP), which leads to the release of cytochrome c. These two pathways converge at the level of effector caspases, such as caspase-3 and caspase-7. The third major pathway is initiated by the constituents of cytotoxic granules (e.g. Perforin and Granzyme B) that are released by CTLs (cytotoxic T-cells) and NK (natural killer) cells. Granzyme B, similarly to the caspases, cleaves its substrates after aspartic acid residues, suggesting that this protease has the ability to activate members of the caspase family directly. It is the balance between the pro-apoptotic and anti-apoptotic signals that eventually determines whether cells will undergo apoptosis, survive or proliferate. TNF family of ligands activates anti-apoptotic or cell-survival signals as well as apoptotic signals. NGF and Interleukin-3 promotes the survival, proliferation and differentiation of neurons or hematopoietic cells, respectively. Withdrawal of these growth factors leads to cell death, as described above.
Class
09140 Cellular Processes; 09143 Cell growth and death
BRITE hierarchy
Pathway map
hsa04210  Apoptosis
hsa04210

Ortholog table
Module
hsa_M00685  Apoptotic machinery [PATH:hsa04210]
Network
N00098  Intrinsic apoptotic pathway
N00145  Extrinsic apoptotic pathway
N00146  Crosstalk between extrinsic and intrinsic apoptotic pathways
Disease
H00108  Autoimmune lymphoproliferative syndromes (ALPS)
H00265  Hereditary sensory and autonomic neuropathy (HSAN)
H00540  Osteoporosis, lymphedema, anhydrotic ectodermal dysplasia with immunodeficiency (OLEDAID)
H00645  Incontinentia pigmenti
H00721  Pyogenic bacterial infections, recurrent, due to MYD88 deficiency
H00881  Li-Fraumeni syndrome
H00882  Cocoon syndrome
H00912  Tumor necrosis factor receptor-associated periodic syndrome (TRAPS)
H01007  Choroid plexus papilloma
H01102  Pituitary adenomas
H01969  X-linked lymphoproliferative syndrome
Drug
D00742  Etanercept (USAN/INN)
D02597  Adalimumab (USAN/INN)
D02598  Infliximab (USAN/INN)
D03441  Certolizumab pegol (USAN/INN)
D03645  Daniplestim (USAN/INN)
D04358  Golimumab (USAN/INN)
D04687  Lenalidomide (USAN/INN)
D04695  Leridistim (USAN/INN)
D04858  Mapatumumab (USAN/INN)
D05090  Muplestim (USAN/INN)
D05146  Nerelimomab (USAN/INN)
D05216  Oblimersen sodium (USAN)
D07436  Afelimomab (INN)
D08290  Oblimersen (INN)
D08954  Obatoclax mesylate (USAN)
D08976  Pomalidomide (JAN/USAN/INN)
D09692  Veliparib (JAN/USAN/INN)
D09730  Olaparib (JAN/USAN/INN)
D09813  Lenalidomide hydrate (JAN)
D09888  Drozitumab (USAN/INN)
D09907  Fulranumab (USAN/INN)
D09913  Iniparib (USAN/INN)
D10079  Rucaparib (USAN/INN)
D10140  Niraparib (USAN)
D10157  Rucaparib phosphate (USAN)
D10381  Afuresertib (USAN)
D10382  Afuresertib hydrochloride (USAN)
D10560  Idelalisib (JAN/USAN/INN)
D10679  Venetoclax (JAN/USAN/INN)
D10732  Talazoparib (USAN/INN)
D10733  Talazoparib tosylate (USAN)
D10982  Rucaparib camsylate (USAN)
D10988  Selonsertib (USAN/INN)
Other DBs
BSID: 83060
GO: 0006915
Organism
Homo sapiens (human) [GN:hsa]
Gene
8743  TNFSF10; TNF superfamily member 10 [KO:K04721]
8797  TNFRSF10A; TNF receptor superfamily member 10a [KO:K04722]
8795  TNFRSF10B; TNF receptor superfamily member 10b [KO:K04722]
356  FASLG; Fas ligand [KO:K04389]
355  FAS; Fas cell surface death receptor [KO:K04390]
8772  FADD; Fas associated via death domain [KO:K02373]
7124  TNF; tumor necrosis factor [KO:K03156]
7132  TNFRSF1A; TNF receptor superfamily member 1A [KO:K03158]
8717  TRADD; TNFRSF1A associated via death domain [KO:K03171]
8837  CFLAR; CASP8 and FADD like apoptosis regulator [KO:K04724]
841  CASP8; caspase 8 [KO:K04398] [EC:3.4.22.61]
843  CASP10; caspase 10 [KO:K04400] [EC:3.4.22.63]
839  CASP6; caspase 6 [KO:K04396] [EC:3.4.22.59]
836  CASP3; caspase 3 [KO:K02187] [EC:3.4.22.56]
840  CASP7; caspase 7 [KO:K04397] [EC:3.4.22.60]
637  BID; BH3 interacting domain death agonist [KO:K04726]
581  BAX; BCL2 associated X, apoptosis regulator [KO:K02159]
578  BAK1; BCL2 antagonist/killer 1 [KO:K14021]
56616  DIABLO; diablo IAP-binding mitochondrial protein [KO:K10522]
5414  SEPT4; septin 4 [KO:K16943]
27429  HTRA2; HtrA serine peptidase 2 [KO:K08669] [EC:3.4.21.108]
54205  CYCS; cytochrome c, somatic [KO:K08738]
317  APAF1; apoptotic peptidase activating factor 1 [KO:K02084]
842  CASP9; caspase 9 [KO:K04399] [EC:3.4.22.62]
5551  PRF1; perforin 1 [KO:K07818]
3002  GZMB; granzyme B [KO:K01353] [EC:3.4.21.79]
10376  TUBA1B; tubulin alpha 1b [KO:K07374]
7277  TUBA4A; tubulin alpha 4a [KO:K07374]
7278  TUBA3C; tubulin alpha 3c [KO:K07374]
7846  TUBA1A; tubulin alpha 1a [KO:K07374]
84790  TUBA1C; tubulin alpha 1c [KO:K07374]
51807  TUBA8; tubulin alpha 8 [KO:K07374]
112714  TUBA3E; tubulin alpha 3e [KO:K07374]
113457  TUBA3D; tubulin alpha 3d [KO:K07374]
79861  TUBAL3; tubulin alpha like 3 [KO:K07374]
4170  MCL1; MCL1, BCL2 family apoptosis regulator [KO:K02539]
60  ACTB; actin beta [KO:K05692]
71  ACTG1; actin gamma 1 [KO:K05692]
6708  SPTA1; spectrin alpha, erythrocytic 1 [KO:K06114]
6709  SPTAN1; spectrin alpha, non-erythrocytic 1 [KO:K06114]
4000  LMNA; lamin A/C [KO:K12641]
4001  LMNB1; lamin B1 [KO:K07611]
84823  LMNB2; lamin B2 [KO:K07611]
10038  PARP2; poly(ADP-ribose) polymerase 2 [KO:K10798] [EC:2.4.2.30]
142  PARP1; poly(ADP-ribose) polymerase 1 [KO:K10798] [EC:2.4.2.30]
10039  PARP3; poly(ADP-ribose) polymerase family member 3 [KO:K10798] [EC:2.4.2.30]
143  PARP4; poly(ADP-ribose) polymerase family member 4 [KO:K10798] [EC:2.4.2.30]
1676  DFFA; DNA fragmentation factor subunit alpha [KO:K02310]
1677  DFFB; DNA fragmentation factor subunit beta [KO:K02311] [EC:3.-.-.-]
2021  ENDOG; endonuclease G [KO:K01173]
9131  AIFM1; apoptosis inducing factor mitochondria associated 1 [KO:K04727] [EC:1.-.-.-]
2081  ERN1; endoplasmic reticulum to nucleus signaling 1 [KO:K08852] [EC:3.1.26.- 2.7.11.1]
7186  TRAF2; TNF receptor associated factor 2 [KO:K03173] [EC:2.3.2.27]
3708  ITPR1; inositol 1,4,5-trisphosphate receptor type 1 [KO:K04958]
3709  ITPR2; inositol 1,4,5-trisphosphate receptor type 2 [KO:K04959]
3710  ITPR3; inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960]
823  CAPN1; calpain 1 [KO:K01367] [EC:3.4.22.52]
824  CAPN2; calpain 2 [KO:K03853] [EC:3.4.22.53]
100506742  CASP12; caspase 12 (gene/pseudogene) [KO:K04741] [EC:3.4.22.-]
9451  EIF2AK3; eukaryotic translation initiation factor 2 alpha kinase 3 [KO:K08860] [EC:2.7.11.1]
1965  EIF2S1; eukaryotic translation initiation factor 2 subunit alpha [KO:K03237]
468  ATF4; activating transcription factor 4 [KO:K04374]
1649  DDIT3; DNA damage inducible transcript 3 [KO:K04452]
1508  CTSB; cathepsin B [KO:K01363] [EC:3.4.22.1]
1075  CTSC; cathepsin C [KO:K01275] [EC:3.4.14.1]
1509  CTSD; cathepsin D [KO:K01379] [EC:3.4.23.5]
8722  CTSF; cathepsin F [KO:K01373] [EC:3.4.22.41]
1512  CTSH; cathepsin H [KO:K01366] [EC:3.4.22.16]
1513  CTSK; cathepsin K [KO:K01371] [EC:3.4.22.38]
1514  CTSL; cathepsin L [KO:K01365] [EC:3.4.22.15]
1519  CTSO; cathepsin O [KO:K01374] [EC:3.4.22.42]
1520  CTSS; cathepsin S [KO:K01368] [EC:3.4.22.27]
1515  CTSV; cathepsin V [KO:K01375] [EC:3.4.22.43]
1521  CTSW; cathepsin W [KO:K08569] [EC:3.4.22.-]
1522  CTSZ; cathepsin Z [KO:K08568] [EC:3.4.18.1]
329  BIRC2; baculoviral IAP repeat containing 2 [KO:K16060]
330  BIRC3; baculoviral IAP repeat containing 3 [KO:K16060]
331  XIAP; X-linked inhibitor of apoptosis [KO:K04725] [EC:2.3.2.27]
332  BIRC5; baculoviral IAP repeat containing 5 [KO:K08731]
10018  BCL2L11; BCL2 like 11 [KO:K16341]
598  BCL2L1; BCL2 like 1 [KO:K04570]
596  BCL2; BCL2, apoptosis regulator [KO:K02161]
1616  DAXX; death domain associated protein [KO:K02308]
8737  RIPK1; receptor interacting serine/threonine kinase 1 [KO:K02861] [EC:2.7.11.1]
153090  DAB2IP; DAB2 interacting protein [KO:K19901]
4217  MAP3K5; mitogen-activated protein kinase kinase kinase 5 [KO:K04426] [EC:2.7.11.25]
5599  MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
5602  MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
5601  MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
572  BAD; BCL2 associated agonist of cell death [KO:K02158]
3725  JUN; Jun proto-oncogene, AP-1 transcription factor subunit [KO:K04448]
2353  FOS; Fos proto-oncogene, AP-1 transcription factor subunit [KO:K04379]
7157  TP53; tumor protein p53 [KO:K04451]
8739  HRK; harakiri, BCL2 interacting protein [KO:K02512]
9020  MAP3K14; mitogen-activated protein kinase kinase kinase 14 [KO:K04466] [EC:2.7.11.25]
1147  CHUK; conserved helix-loop-helix ubiquitous kinase [KO:K04467] [EC:2.7.11.10]
3551  IKBKB; inhibitor of nuclear factor kappa B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
8517  IKBKG; inhibitor of nuclear factor kappa B kinase subunit gamma [KO:K07210]
4792  NFKBIA; NFKB inhibitor alpha [KO:K04734]
4790  NFKB1; nuclear factor kappa B subunit 1 [KO:K02580]
5970  RELA; RELA proto-oncogene, NF-kB subunit [KO:K04735]
5783  PTPN13; protein tyrosine phosphatase, non-receptor type 13 [KO:K02374]
1647  GADD45A; growth arrest and DNA damage inducible alpha [KO:K04402]
4616  GADD45B; growth arrest and DNA damage inducible beta [KO:K04402]
10912  GADD45G; growth arrest and DNA damage inducible gamma [KO:K04402]
7185  TRAF1; TNF receptor associated factor 1 [KO:K03172]
597  BCL2A1; BCL2 related protein A1 [KO:K02162]
472  ATM; ATM serine/threonine kinase [KO:K04728] [EC:2.7.11.1]
55367  PIDD1; p53-induced death domain protein 1 [KO:K10130]
63970  TP53AIP1; tumor protein p53 regulated apoptosis inducing protein 1 [KO:K13773]
27113  BBC3; BCL2 binding component 3 [KO:K10132]
5366  PMAIP1; phorbol-12-myristate-13-acetate-induced protein 1 [KO:K10131]
835  CASP2; caspase 2 [KO:K02186] [EC:3.4.22.55]
4803  NGF; nerve growth factor [KO:K02582]
4914  NTRK1; neurotrophic receptor tyrosine kinase 1 [KO:K03176] [EC:2.7.10.1]
3562  IL3; interleukin 3 [KO:K04736]
3563  IL3RA; interleukin 3 receptor subunit alpha [KO:K04737]
1439  CSF2RB; colony stimulating factor 2 receptor beta common subunit [KO:K04738]
5290  PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
5293  PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
5291  PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
5295  PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
5296  PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
8503  PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
5170  PDPK1; 3-phosphoinositide dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
207  AKT1; AKT serine/threonine kinase 1 [KO:K04456] [EC:2.7.11.1]
208  AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:2.7.11.1]
10000  AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1]
3265  HRAS; HRas proto-oncogene, GTPase [KO:K02833]
3845  KRAS; KRAS proto-oncogene, GTPase [KO:K07827]
4893  NRAS; NRAS proto-oncogene, GTPase [KO:K07828]
5894  RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1]
5604  MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
5605  MAP2K2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
5594  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
5595  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
Compound
C00027  Hydrogen peroxide
C00076  Calcium cation
C00319  Sphingosine
C05981  Phosphatidylinositol-3,4,5-trisphosphate
Reference
  Authors
Savitskaya MA, Onishchenko GE
  Title
Mechanisms of Apoptosis.
  Journal
Biochemistry (Mosc) 80:1393-417 (2015)
DOI:10.1134/S0006297915110012
Reference
  Authors
Schleich K, Lavrik IN
  Title
Mathematical modeling of apoptosis.
  Journal
Cell Commun Signal 11:44 (2013)
DOI:10.1186/1478-811X-11-44
Reference
  Authors
Lavrik I, Golks A, Krammer PH
  Title
Death receptor signaling.
  Journal
J Cell Sci 118:265-7 (2005)
DOI:10.1242/jcs.01610
Reference
  Authors
Jin Z, El-Deiry WS
  Title
Overview of cell death signaling pathways.
  Journal
Cancer Biol Ther 4:139-63 (2005)
DOI:10.4161/cbt.4.2.1508
Reference
  Authors
Benn SC, Woolf CJ
  Title
Adult neuron survival strategies--slamming on the brakes.
  Journal
Nat Rev Neurosci 5:686-700 (2004)
DOI:10.1038/nrn1477
Reference
  Authors
Orrenius S, Zhivotovsky B, Nicotera P
  Title
Regulation of cell death: the calcium-apoptosis link.
  Journal
Nat Rev Mol Cell Biol 4:552-65 (2003)
DOI:10.1038/nrm1150
Reference
  Authors
Clarke P, Tyler KL
  Title
Apoptosis in animal models of virus-induced disease.
  Journal
Nat Rev Microbiol 7:144-55 (2009)
DOI:10.1038/nrmicro2071
Reference
  Authors
Wen X, Lin ZQ, Liu B, Wei YQ
  Title
Caspase-mediated programmed cell death pathways as potential therapeutic targets in cancer.
  Journal
Cell Prolif 45:217-24 (2012)
DOI:10.1111/j.1365-2184.2012.00814.x
Reference
  Authors
Shalini S, Dorstyn L, Dawar S, Kumar S
  Title
Old, new and emerging functions of caspases.
  Journal
Cell Death Differ 22:526-39 (2015)
DOI:10.1038/cdd.2014.216
Reference
  Authors
Philchenkov A
  Title
Caspases: potential targets for regulating cell death.
  Journal
J Cell Mol Med 8:432-44 (2004)
DOI:10.1111/j.1582-4934.2004.tb00468.x
Reference
PMID:9894605
  Authors
Stroh C, Schulze-Osthoff K
  Title
Death by a thousand cuts: an ever increasing list of caspase substrates.
  Journal
Cell Death Differ 5:997-1000 (1998)
DOI:10.1038/sj.cdd.4400451
Reference
  Authors
Safa AR
  Title
c-FLIP, a master anti-apoptotic regulator.
  Journal
Exp Oncol 34:176-84 (2012)
Reference
  Authors
Jeong SY, Seol DW
  Title
The role of mitochondria in apoptosis.
  Journal
BMB Rep 41:11-22 (2008)
Reference
  Authors
Parsons MJ, Green DR
  Title
Mitochondria in cell death.
  Journal
Essays Biochem 47:99-114 (2010)
DOI:10.1042/bse0470099
Reference
  Authors
Strasser A
  Title
The role of BH3-only proteins in the immune system.
  Journal
Nat Rev Immunol 5:189-200 (2005)
DOI:10.1038/nri1568
Reference
  Authors
Schonthal AH
  Title
Endoplasmic reticulum stress: its role in disease and novel prospects for therapy.
  Journal
Scientifica (Cairo) 2012:857516 (2012)
DOI:10.6064/2012/857516
Reference
  Authors
Malhi H, Kaufman RJ
  Title
Endoplasmic reticulum stress in liver disease.
  Journal
J Hepatol 54:795-809 (2011)
DOI:10.1016/j.jhep.2010.11.005
Reference
  Authors
Malhotra JD, Kaufman RJ
  Title
The endoplasmic reticulum and the unfolded protein response.
  Journal
Semin Cell Dev Biol 18:716-31 (2007)
DOI:10.1016/j.semcdb.2007.09.003
Reference
  Authors
Wu J, Kaufman RJ
  Title
From acute ER stress to physiological roles of the Unfolded Protein Response.
  Journal
Cell Death Differ 13:374-84 (2006)
DOI:10.1038/sj.cdd.4401840
Reference
  Authors
Repnik U, Stoka V, Turk V, Turk B
  Title
Lysosomes and lysosomal cathepsins in cell death.
  Journal
Biochim Biophys Acta 1824:22-33 (2012)
DOI:10.1016/j.bbapap.2011.08.016
Reference
  Authors
Cesen MH, Pegan K, Spes A, Turk B
  Title
Lysosomal pathways to cell death and their therapeutic applications.
  Journal
Exp Cell Res 318:1245-51 (2012)
DOI:10.1016/j.yexcr.2012.03.005
Reference
  Authors
Dashzeveg N, Yoshida K
  Title
Cell death decision by p53 via control of the mitochondrial membrane.
  Journal
Cancer Lett 367:108-12 (2015)
DOI:10.1016/j.canlet.2015.07.019
Reference
  Authors
Bouchier-Hayes L, Green DR
  Title
Caspase-2: the orphan caspase.
  Journal
Cell Death Differ 19:51-7 (2012)
DOI:10.1038/cdd.2011.157
Reference
  Authors
Baptiste-Okoh N, Barsotti AM, Prives C
  Title
A role for caspase 2 and PIDD in the process of p53-mediated apoptosis.
  Journal
Proc Natl Acad Sci U S A 105:1937-42 (2008)
DOI:10.1073/pnas.0711800105
Reference
  Authors
Aggarwal BB
  Title
Signalling pathways of the TNF superfamily: a double-edged sword.
  Journal
Nat Rev Immunol 3:745-56 (2003)
DOI:10.1038/nri1184
Reference
  Authors
Steelman LS, Pohnert SC, Shelton JG, Franklin RA, Bertrand FE, McCubrey JA.
  Title
JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis.
  Journal
Leukemia 18:189-218 (2004)
DOI:10.1038/sj.leu.2403241
Reference
PMID:9916983
  Authors
Dragovich T, Rudin CM, Thompson CB
  Title
Signal transduction pathways that regulate cell survival and cell death.
  Journal
Oncogene 17:3207-13 (1998)
DOI:10.1038/sj.onc.1202587
Reference
  Authors
Sofroniew MV, Howe CL, Mobley WC
  Title
Nerve growth factor signaling, neuroprotection, and neural repair.
  Journal
Annu Rev Neurosci 24:1217-81 (2001)
DOI:10.1146/annurev.neuro.24.1.1217
Reference
  Authors
Kristiansen M, Ham J
  Title
Programmed cell death during neuronal development: the sympathetic neuron model.
  Journal
Cell Death Differ 21:1025-35 (2014)
DOI:10.1038/cdd.2014.47
Reference
  Authors
Logue SE, Martin SJ
  Title
Caspase activation cascades in apoptosis.
  Journal
Biochem Soc Trans 36:1-9 (2008)
DOI:10.1042/BST0360001
Reference
  Authors
Boivin WA, Cooper DM, Hiebert PR, Granville DJ
  Title
Intracellular versus extracellular granzyme B in immunity and disease: challenging the dogma.
  Journal
Lab Invest 89:1195-220 (2009)
DOI:10.1038/labinvest.2009.91
Reference
  Authors
Cullen SP, Brunet M, Martin SJ
  Title
Granzymes in cancer and immunity.
  Journal
Cell Death Differ 17:616-23 (2010)
DOI:10.1038/cdd.2009.206
KO pathway
ko04210   
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