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
Cellular Processes; Cell growth and death
BRITE hierarchy
Pathway map
Apoptosis
hsa04210

All organismsOrtholog table
Module
Apoptotic machinery [PATH:hsa04210]
Disease
H00108  
Autoimmune lymphoproliferative syndromes (ALPS)
H00265  
Hereditary sensory and autonomic neuropathy (HSAN)
H00539  
PTEN hamartoma tumor syndrome (PHTS)
H00540  
Osteoporosis, lymphedema, anhydrotic ectodermal dysplasia with immunodeficiency (OLEDAID)
H00645  
Incontinentia pigmenti
H00721  
Pyogenic bacterial infections, recurrent, due to MYD88 deficiency
H00848  
Ataxia with ocular apraxia (AOA)
H00881  
Li-Fraumeni syndrome
H00882  
Cocoon syndrome
H00912  
Tumor necrosis factor receptor-associated periodic syndrome (TRAPS)
H01007  
Choroid plexus papilloma
H01102  
Pituitary adenomas
Drug
D00742  
Etanercept (USAN/INN)
D02597  
Adalimumab (USAN/INN)
D02598  
Infliximab (USAN/INN)
D02934  
Anakinra (USAN/INN)
D03441  
Certolizumab pegol (USAN/INN)
D03645  
Daniplestim (USAN/INN)
D04695  
Leridistim (USAN/INN)
D04858  
Mapatumumab (USAN/INN)
D05090  
Muplestim (USAN/INN)
D05146  
Nerelimomab (USAN/INN)
D05216  
Oblimersen sodium (USAN)
D06611  
Lexatumumab (USAN/INN)
D06635  
Rilonacept (USAN/INN)
D07436  
Afelimomab (INN)
D08290  
Oblimersen (INN)
D08954  
Obatoclax mesylate (USAN)
D09329  
Conatumumab (USAN/INN)
D09387  
Tanezumab (USAN/INN)
D09888  
Drozitumab (USAN/INN)
D09907  
Fulranumab (USAN/INN)
D10381  
Afuresertib (USAN)
D10382  
Afuresertib hydrochloride (USAN)
Other DBs
BSID: 
GO: 
Organism
Homo sapiens (human) [GN:hsa]
Gene
8743  
TNFSF10; tumor necrosis factor superfamily member 10 [KO:K04721]
8797  
TNFRSF10A; TNF receptor superfamily member 10a [KO:K04722]
8795  
TNFRSF10B; TNF receptor superfamily member 10b [KO:K04722]
8794  
TNFRSF10C; TNF receptor superfamily member 10c [KO:K04722]
8793  
TNFRSF10D; TNF receptor superfamily member 10d [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; 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]
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 kappa light polypeptide gene enhancer in B-cells, kinase beta [KO:K07209] [EC:2.7.11.10]
8517  
IKBKG; inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase 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]
5294  
PIK3CG; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma [KO:K00922] [EC:2.7.1.153]
5295  
PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
23533  
PIK3R5; phosphoinositide-3-kinase regulatory subunit 5 [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; neuroblastoma RAS viral oncogene homolog [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)
Reference
  Authors
Schleich K, Lavrik IN
  Title
Mathematical modeling of apoptosis.
  Journal
Cell Commun Signal 11:44 (2013)
Reference
  Authors
Lavrik I, Golks A, Krammer PH
  Title
Death receptor signaling.
  Journal
J Cell Sci 118:265-7 (2005)
Reference
  Authors
Jin Z, El-Deiry WS
  Title
Overview of cell death signaling pathways.
  Journal
Cancer Biol Ther 4:139-63 (2005)
Reference
  Authors
Benn SC, Woolf CJ
  Title
Adult neuron survival strategies--slamming on the brakes.
  Journal
Nat Rev Neurosci 5:686-700 (2004)
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)
Reference
  Authors
Clarke P, Tyler KL
  Title
Apoptosis in animal models of virus-induced disease.
  Journal
Nat Rev Microbiol 7:144-55 (2009)
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)
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)
Reference
  Authors
Philchenkov A
  Title
Caspases: potential targets for regulating cell death.
  Journal
J Cell Mol Med 8:432-44 (2004)
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)
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)
Reference
  Authors
Strasser A
  Title
The role of BH3-only proteins in the immune system.
  Journal
Nat Rev Immunol 5:189-200 (2005)
Reference
  Authors
Schonthal AH
  Title
Endoplasmic reticulum stress: its role in disease and novel prospects for therapy.
  Journal
Scientifica (Cairo) 2012:857516 (2012)
Reference
  Authors
Malhi H, Kaufman RJ
  Title
Endoplasmic reticulum stress in liver disease.
  Journal
J Hepatol 54:795-809 (2011)
Reference
  Authors
Malhotra JD, Kaufman RJ
  Title
The endoplasmic reticulum and the unfolded protein response.
  Journal
Semin Cell Dev Biol 18:716-31 (2007)
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)
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)
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)
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)
Reference
  Authors
Bouchier-Hayes L, Green DR
  Title
Caspase-2: the orphan caspase.
  Journal
Cell Death Differ 19:51-7 (2012)
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)
Reference
  Authors
Aggarwal BB
  Title
Signalling pathways of the TNF superfamily: a double-edged sword.
  Journal
Nat Rev Immunol 3:745-56 (2003)
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)
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)
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)
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)
Reference
  Authors
Logue SE, Martin SJ
  Title
Caspase activation cascades in apoptosis.
  Journal
Biochem Soc Trans 36:1-9 (2008)
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)
Reference
  Authors
Cullen SP, Brunet M, Martin SJ
  Title
Granzymes in cancer and immunity.
  Journal
Cell Death Differ 17:616-23 (2010)
KO pathway
 

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