KEGG   PATHWAY: ko04210Help
Entry
ko04210                     Pathway                                

Name
Apoptosis
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
ko04210

All organismsOrtholog table
Module
M00685  
Apoptotic machinery [PATH:ko04210]
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
Other DBs
BSID: 
GO: 
Orthology
K04721  
tumor necrosis factor ligand superfamily member 10
K04722  
tumor necrosis factor receptor superfamily member 10
K04389  
tumor necrosis factor ligand superfamily member 6
K04390  
tumor necrosis factor receptor superfamily member 6
K02373  
FAS-associated death domain protein
K03156  
tumor necrosis factor superfamily, member 2
K03158  
tumor necrosis factor receptor superfamily member 1A
K03171  
tumor necrosis factor receptor type 1-associated DEATH domain protein
K04724  
CASP8 and FADD-like apoptosis regulator
K04398  
caspase 8 [EC:3.4.22.61]
K04400  
caspase 10 [EC:3.4.22.63]
K04396  
caspase 6 [EC:3.4.22.59]
K02187  
caspase 3 [EC:3.4.22.56]
K04397  
caspase 7 [EC:3.4.22.60]
K04726  
BH3 interacting domain death agonist
K02159  
apoptosis regulator BAX
K14021  
Bcl-2 homologous antagonist/killer
K10522  
diablo
K16943  
septin 4
K08669  
HtrA serine peptidase 2 [EC:3.4.21.108]
K08738  
cytochrome c
K02084  
apoptotic protease-activating factor
K04399  
caspase 9 [EC:3.4.22.62]
K07818  
perforin 1
K01353  
granzyme B [EC:3.4.21.79]
K07374  
tubulin alpha
K02539  
myeloid leukemia cell differntiation protein MCL-1
K05692  
actin beta/gamma 1
K06114  
spectrin alpha
K12641  
lamin A/C
K07611  
lamin B
K10798  
poly [ADP-ribose] polymerase [EC:2.4.2.30]
K02310  
DNA fragmentation factor, 45 kD, alpha subunit
K02311  
DNA fragmentation factor, 40 kD, beta subunit [EC:3.-.-.-]
K01173  
endonuclease G, mitochondrial
K04727  
programmed cell death 8 (apoptosis-inducing factor) [EC:1.-.-.-]
K08852  
serine/threonine-protein kinase/endoribonuclease IRE1 [EC:3.1.26.- 2.7.11.1]
K03173  
TNF receptor-associated factor 2 [EC:2.3.2.27]
K04958  
inositol 1,4,5-triphosphate receptor type 1
K04959  
inositol 1,4,5-triphosphate receptor type 2
K04960  
inositol 1,4,5-triphosphate receptor type 3
K01367  
calpain-1 [EC:3.4.22.52]
K03853  
calpain-2 [EC:3.4.22.53]
K04741  
caspase 12 [EC:3.4.22.-]
K08860  
eukaryotic translation initiation factor 2-alpha kinase 3 [EC:2.7.11.1]
K03237  
translation initiation factor 2 subunit 1
K04374  
cyclic AMP-dependent transcription factor ATF-4
K04452  
DNA damage-inducible transcript 3
K01363  
cathepsin B [EC:3.4.22.1]
K01275  
cathepsin C [EC:3.4.14.1]
K01379  
cathepsin D [EC:3.4.23.5]
K01373  
cathepsin F [EC:3.4.22.41]
K01366  
cathepsin H [EC:3.4.22.16]
K01371  
cathepsin K [EC:3.4.22.38]
K01365  
cathepsin L [EC:3.4.22.15]
K01374  
cathepsin O [EC:3.4.22.42]
K01368  
cathepsin S [EC:3.4.22.27]
K01375  
cathepsin V [EC:3.4.22.43]
K08569  
cathepsin W [EC:3.4.22.-]
K08568  
cathepsin X [EC:3.4.18.1]
K16060  
baculoviral IAP repeat-containing protein 2/3
K04725  
E3 ubiquitin-protein ligase XIAP [EC:2.3.2.27]
K08731  
baculoviral IAP repeat-containing protein 5
K16341  
Bcl-2-like protein 11
K04570  
Bcl-2-like 1 (apoptosis regulator Bcl-X)
K02161  
apoptosis regulator Bcl-2
K02308  
death-associated protein 6
K02861  
receptor-interacting serine/threonine-protein kinase 1 [EC:2.7.11.1]
K19901  
disabled homolog 2-interacting protein
K04426  
mitogen-activated protein kinase kinase kinase 5 [EC:2.7.11.25]
K04440  
c-Jun N-terminal kinase [EC:2.7.11.24]
K02158  
Bcl-2-antagonist of cell death
K04448  
transcription factor AP-1
K04379  
proto-oncogene protein c-fos
K04451  
tumor protein p53
K02512  
activator of apoptosis harakiri
K04466  
mitogen-activated protein kinase kinase kinase 14 [EC:2.7.11.25]
K04467  
inhibitor of nuclear factor kappa-B kinase subunit alpha [EC:2.7.11.10]
K07209  
inhibitor of nuclear factor kappa-B kinase subunit beta [EC:2.7.11.10]
K07210  
inhibitor of nuclear factor kappa-B kinase subunit gamma
K04734  
NF-kappa-B inhibitor alpha
K02580  
nuclear factor NF-kappa-B p105 subunit
K04735  
transcription factor p65
K02374  
tyrosine-protein phosphatase non-receptor type 13
K04402  
growth arrest and DNA-damage-inducible protein
K03172  
TNF receptor-associated factor 1
K02162  
hematopoietic Bcl-2-related protein A1
K04728  
ataxia telangiectasia mutated family protein [EC:2.7.11.1]
K10130  
leucine-rich repeats and death domain-containing protein
K13773  
p53-regulated apoptosis-inducing protein 1
K10132  
Bcl-2-binding component 3
K10131  
phorbol-12-myristate-13-acetate-induced protein 1
K02186  
caspase 2 [EC:3.4.22.55]
K02582  
nerve growth factor, beta
K03176  
neurotrophic tyrosine kinase receptor type 1 [EC:2.7.10.1]
K04736  
interleukin 3
K04737  
interleukin 3 receptor alpha
K04738  
cytokine receptor common subunit beta
K00922  
phosphatidylinositol-4,5-bisphosphate 3-kinase [EC:2.7.1.153]
K02649  
phosphoinositide-3-kinase, regulatory subunit
K06276  
3-phosphoinositide dependent protein kinase-1 [EC:2.7.11.1]
K04456  
RAC serine/threonine-protein kinase [EC:2.7.11.1]
K02833  
GTPase HRas
K07827  
GTPase KRas
K07828  
GTPase NRas
K04366  
RAF proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K04368  
mitogen-activated protein kinase kinase 1 [EC:2.7.12.2]
K04369  
mitogen-activated protein kinase kinase 2 [EC:2.7.12.2]
K04371  
mitogen-activated protein kinase 1/3 [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)

DBGET integrated database retrieval system