Entry 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 deathBRITE hierarchy
Pathway map Ortholog table Other DBs Orthology K04721 tumor necrosis factor ligand superfamily member 10
K04722 tumor necrosis factor receptor superfamily member 10A/B
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
K04726 BH3 interacting domain death agonist
K02159 apoptosis regulator BAX
K14021 Bcl-2 homologous antagonist/killer
K02084 apoptotic protease-activating factor
K02539 myeloid leukemia cell differntiation protein MCL-1
K06114 spectrin alpha, non-erythrocytic (fodrin)
K02310 DNA fragmentation factor, 45 kD, alpha subunit
K02311 DNA fragmentation factor, 40 kD, beta subunit [EC:3.-.-.-]
K01173 endonuclease G, mitochondrial
K04727 apoptosis-inducing factor 1 [EC:1.-.-.-]
K08852 serine/threonine-protein kinase/endoribonuclease IRE1 [EC:2.7.11.1 3.1.26.-]
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
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
K08569 cathepsin W [EC:3.4.22.-]
K16060 baculoviral IAP repeat-containing protein 2/3
K08731 baculoviral IAP repeat-containing protein 5
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
K04440 mitogen-activated protein kinase 8/9/10 (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
K02512 activator of apoptosis harakiri
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
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
K02582 nerve growth factor, beta
K04737 interleukin 3 receptor alpha
K04738 cytokine receptor common subunit beta
K00922 phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153 ]
K02649 phosphoinositide-3-kinase regulatory subunit alpha/beta/delta
K04366 RAF proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1 ]
Compound C05981 Phosphatidylinositol-3,4,5-trisphosphate
Reference Authors Savitskaya MA, Onishchenko GE
Title Mechanisms of Apoptosis.
Journal Reference Authors Schleich K, Lavrik IN
Title Mathematical modeling of apoptosis.
Journal Reference Authors Lavrik I, Golks A, Krammer PH
Title Death receptor signaling.
Journal Reference Authors Jin Z, El-Deiry WS
Title Overview of cell death signaling pathways.
Journal Reference Authors Benn SC, Woolf CJ
Title Adult neuron survival strategies--slamming on the brakes.
Journal Reference Authors Orrenius S, Zhivotovsky B, Nicotera P
Title Regulation of cell death: the calcium-apoptosis link.
Journal Reference Authors Clarke P, Tyler KL
Title Apoptosis in animal models of virus-induced disease.
Journal Reference Authors Wen X, Lin ZQ, Liu B, Wei YQ
Title Caspase-mediated programmed cell death pathways as potential therapeutic targets in cancer.
Journal Reference Authors Shalini S, Dorstyn L, Dawar S, Kumar S
Title Old, new and emerging functions of caspases.
Journal Reference Authors Philchenkov A
Title Caspases: potential targets for regulating cell death.
Journal Reference Authors Stroh C, Schulze-Osthoff K
Title Death by a thousand cuts: an ever increasing list of caspase substrates.
Journal 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 Reference Authors Parsons MJ, Green DR
Title Mitochondria in cell death.
Journal Reference Authors Strasser A
Title The role of BH3-only proteins in the immune system.
Journal Reference Authors Schonthal AH
Title Endoplasmic reticulum stress: its role in disease and novel prospects for therapy.
Journal Reference Authors Malhi H, Kaufman RJ
Title Endoplasmic reticulum stress in liver disease.
Journal Reference Authors Malhotra JD, Kaufman RJ
Title The endoplasmic reticulum and the unfolded protein response.
Journal Reference Authors Wu J, Kaufman RJ
Title From acute ER stress to physiological roles of the Unfolded Protein Response.
Journal Reference Authors Repnik U, Stoka V, Turk V, Turk B
Title Lysosomes and lysosomal cathepsins in cell death.
Journal Reference Authors Cesen MH, Pegan K, Spes A, Turk B
Title Lysosomal pathways to cell death and their therapeutic applications.
Journal Reference Authors Dashzeveg N, Yoshida K
Title Cell death decision by p53 via control of the mitochondrial membrane.
Journal Reference Authors Bouchier-Hayes L, Green DR
Title Caspase-2: the orphan caspase.
Journal 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 Reference Authors Aggarwal BB
Title Signalling pathways of the TNF superfamily: a double-edged sword.
Journal 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 Reference Authors Dragovich T, Rudin CM, Thompson CB
Title Signal transduction pathways that regulate cell survival and cell death.
Journal Reference Authors Sofroniew MV, Howe CL, Mobley WC
Title Nerve growth factor signaling, neuroprotection, and neural repair.
Journal Reference Authors Kristiansen M, Ham J
Title Programmed cell death during neuronal development: the sympathetic neuron model.
Journal Reference Authors Logue SE, Martin SJ
Title Caspase activation cascades in apoptosis.
Journal Reference Authors Boivin WA, Cooper DM, Hiebert PR, Granville DJ
Title Intracellular versus extracellular granzyme B in immunity and disease: challenging the dogma.
Journal Reference Authors Cullen SP, Brunet M, Martin SJ
Title Granzymes in cancer and immunity.
Journal Related ko04064 NF-kappa B signaling pathway
ko04141 Protein processing in endoplasmic reticulum
ko04650 Natural killer cell mediated cytotoxicity
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