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 Other DBs Orthology K00922 PIK3CA_B_D; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153 ]
K01173 ENDOG; endonuclease G, mitochondrial
K02084 APAF1; apoptotic protease-activating factor
K02158 BAD; Bcl-2-antagonist of cell death
K02159 BAX; apoptosis regulator BAX
K02161 BCL2; apoptosis regulator Bcl-2
K02162 BCL2A1; hematopoietic Bcl-2-related protein A1
K02308 DAXX; death-associated protein 6
K02310 DFFA, DFF45; DNA fragmentation factor, 45 kD, alpha subunit
K02311 DFFB, DFF40; DNA fragmentation factor, 40 kD, beta subunit [EC:3.-.-.-]
K02373 FADD; FAS-associated death domain protein
K02374 PTPN13, FAP-1; tyrosine-protein phosphatase non-receptor type 13
K02512 HRK; activator of apoptosis harakiri
K02539 MCL1; myeloid leukemia cell differntiation protein MCL-1
K02580 NFKB1; nuclear factor NF-kappa-B p105 subunit
K02582 NGFB; nerve growth factor, beta
K02649 PIK3R1_2_3; phosphoinositide-3-kinase regulatory subunit alpha/beta/delta
K02861 RIPK1, RIP1; receptor-interacting serine/threonine-protein kinase 1 [EC:2.7.11.1 ]
K03156 TNF, TNFA; tumor necrosis factor superfamily, member 2
K03158 TNFRSF1A, TNFR1, CD120a; tumor necrosis factor receptor superfamily member 1A
K03171 TRADD; tumor necrosis factor receptor type 1-associated DEATH domain protein
K03172 TRAF1; TNF receptor-associated factor 1
K03176 NTRK1, TRKA; neurotrophic tyrosine kinase receptor type 1 [EC:2.7.10.1 ]
K03237 EIF2S1; translation initiation factor 2 subunit 1
K04366 RAF1; RAF proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1 ]
K04368 MAP2K1, MEK1; mitogen-activated protein kinase kinase 1 [EC:2.7.12.2 ]
K04369 MAP2K2, MEK2; mitogen-activated protein kinase kinase 2 [EC:2.7.12.2 ]
K04374 ATF4, CREB2; cyclic AMP-dependent transcription factor ATF-4
K04379 FOS; proto-oncogene protein c-fos
K04389 TNFSF6, FASL, CD178; tumor necrosis factor ligand superfamily member 6
K04390 TNFRSF6, FAS, CD95; tumor necrosis factor receptor superfamily member 6
K04402 GADD45; growth arrest and DNA-damage-inducible protein
K04426 MAP3K5, ASK1; mitogen-activated protein kinase kinase kinase 5 [EC:2.7.11.25 ]
K04440 JNK; mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:2.7.11.24 ]
K04448 JUN; transcription factor AP-1
K04451 TP53, P53; tumor protein p53
K04452 DDIT3, GADD153; DNA damage-inducible transcript 3
K04466 MAP3K14, NIK; mitogen-activated protein kinase kinase kinase 14 [EC:2.7.11.25 ]
K04467 IKBKA, IKKA, CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha [EC:2.7.11.10 ]
K04570 BCL2L1, bcl-xL; Bcl-2-like 1 (apoptosis regulator Bcl-X)
K04721 TNFSF10, TRAIL, CD253; tumor necrosis factor ligand superfamily member 10
K04722 TNFRSF10A_B, TRAILR1_2, DR4_5, CD261_2; tumor necrosis factor receptor superfamily member 10A/B
K04724 CFLAR, FLIP; CASP8 and FADD-like apoptosis regulator
K04726 BID; BH3 interacting domain death agonist
K04727 AIFM1, PDCD8; apoptosis-inducing factor 1 [EC:1.-.-.-]
K04734 NFKBIA; NF-kappa-B inhibitor alpha
K04735 RELA; transcription factor p65
K04737 IL3RA, CD123; interleukin 3 receptor alpha
K04738 CSF2RB, IL3RB, CD131; cytokine receptor common subunit beta
K04741 CASP12; caspase 12 [EC:3.4.22.-]
K04958 ITPR1; inositol 1,4,5-triphosphate receptor type 1
K04959 ITPR2; inositol 1,4,5-triphosphate receptor type 2
K04960 ITPR3; inositol 1,4,5-triphosphate receptor type 3
K05692 ACTB_G1; actin beta/gamma 1
K06114 SPTAN; spectrin alpha, non-erythrocytic (fodrin)
K06276 PDPK1; 3-phosphoinositide dependent protein kinase-1 [EC:2.7.11.1 ]
K07209 IKBKB, IKKB; inhibitor of nuclear factor kappa-B kinase subunit beta [EC:2.7.11.10 ]
K07210 IKBKG, IKKG, NEMO; inhibitor of nuclear factor kappa-B kinase subunit gamma
K07827 KRAS, KRAS2; GTPase KRas
K08569 CTSW; cathepsin W [EC:3.4.22.-]
K08731 BIRC5; baculoviral IAP repeat-containing protein 5
K08852 ERN1; serine/threonine-protein kinase/endoribonuclease IRE1 [EC:2.7.11.1 3.1.26.-]
K08860 EIF2AK3, PERK; eukaryotic translation initiation factor 2-alpha kinase 3 [EC:2.7.11.1 ]
K10130 LRDD, PIDD; leucine-rich repeats and death domain-containing protein
K10131 PMAIP1, NOXA; phorbol-12-myristate-13-acetate-induced protein 1
K10132 BBC3, PUMA; Bcl-2-binding component 3
K10798 PARP3_4; protein mono-ADP-ribosyltransferase 3/4 [EC:2.4.2.-]
K13773 TP53AIP1; p53-regulated apoptosis-inducing protein 1
K14021 BAK, BAK1; Bcl-2 homologous antagonist/killer
K16060 BIRC2_3; baculoviral IAP repeat-containing protein 2/3
K16341 BCL2L11, BIM; Bcl-2-like protein 11
K19901 DAB2IP, AIP1; disabled homolog 2-interacting protein
K24070 PARP1; poly [ADP-ribose] polymerase 1
K28005 PARP2; poly [ADP-ribose] polymerase 2
K28177 NOL3, ARC; nucleolar protein 3
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 Reference Authors Liu K, Lan D, Li C, Liu S, Dai X, Song T, Wang X, Kong Q, He Z, Tan J, Zhang J
Title A double-edged sword: role of apoptosis repressor with caspase recruitment domain (ARC) in tumorigenesis and ischaemia/reperfusion (I/R) injury.
Journal Related ko04064 NF-kappa B signaling pathway
ko04141 Protein processing in endoplasmic reticulum
ko04650 Natural killer cell mediated cytotoxicity
