KEGG   PATHWAY: bta04210
bta04210                    Pathway                                
Apoptosis - Bos taurus (cow)
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.
Cellular Processes; Cell growth and death
Pathway map
bta04210  Apoptosis

Other DBs
GO: 0006915
Bos taurus (cow) [GN:bta]
507215  TNFSF10; tumor necrosis factor ligand superfamily member 10 [KO:K04721]
784541  tumor necrosis factor receptor superfamily member 10A isoform X1 [KO:K04722]
104968444  tumor necrosis factor receptor superfamily member 10C [KO:K04722]
407111  FASLG; tumor necrosis factor ligand superfamily member 6 [KO:K04389]
282488  FAS; tumor necrosis factor receptor superfamily member 6 precursor [KO:K04390]
493720  FADD; FAS-associated death domain protein [KO:K02373]
280943  TNF; tumor necrosis factor [KO:K03156]
282527  TNFRSF1A; tumor necrosis factor receptor superfamily member 1A precursor [KO:K03158]
504707  TRADD; tumor necrosis factor receptor type 1-associated DEATH domain protein [KO:K03171]
497199  CFLAR; CASP8 and FADD-like apoptosis regulator [KO:K04724]
507481  CASP8; caspase-8 [KO:K04398] [EC:]
100848685  caspase-10 [KO:K04400] [EC:]
538409  CASP6; caspase-6 [KO:K04396] [EC:]
408016  CASP3; caspase-3 [KO:K02187] [EC:]
526279  CASP7; caspase-7 [KO:K04397] [EC:]
510373  BID; BH3-interacting domain death agonist [KO:K04726]
280730  BAX; apoptosis regulator BAX [KO:K02159]
514090  BAK1; bcl-2 homologous antagonist/killer [KO:K14021]
493999  DIABLO; diablo IAP-binding mitochondrial protein [KO:K10522]
538801  SEPTIN4; septin-4 [KO:K16943]
523039  HTRA2; serine protease HTRA2, mitochondrial precursor [KO:K08669] [EC:]
510767  CYCS; cytochrome c [KO:K08738]
781996  CYCT; cytochrome c 2 [KO:K08738]
100847700  cytochrome c [KO:K08738]
100847304  cytochrome c-like [KO:K08738]
112447733  cytochrome c-like [KO:K08738]
537782  APAF1; apoptotic protease-activating factor 1 [KO:K02084]
100140945  CASP9; caspase-9 [KO:K04399] [EC:]
369025  PRF1; perforin-1 precursor [KO:K07818]
508646  granzyme B [KO:K01353] [EC:]
281731  GZMB; duodenase-1 precursor [KO:K01353] [EC:]
505326  mast cell protease 1A [KO:K01353] [EC:]
508858  duodenase-1 [KO:K01353] [EC:]
786126  duodenase-1 [KO:K01353] [EC:]
404053  TUBA1A; tubulin alpha-1B chain [KO:K07374]
504244  TUBA1C; tubulin alpha-1C chain [KO:K07374]
534900  TUBA3E; tubulin alpha-3 chain [KO:K07374]
535605  TUBA1D; tubulin alpha-1D chain [KO:K07374]
768036  TUBA8; tubulin alpha-8 chain [KO:K07374]
777775  TUBA4A; tubulin alpha-4A chain [KO:K07374]
782966  tubulin alpha-1 chain [KO:K07374]
100141266  tubulin alpha-1C chain [KO:K07374]
539882  TUBA1B; tubulin alpha-1B chain [KO:K07374]
100295712  tubulin alpha-3 chain isoform X1 [KO:K07374]
112443216  tubulin alpha-1C chain [KO:K07374]
788087  MCL1; induced myeloid leukemia cell differentiation protein Mcl-1 [KO:K02539]
404122  ACTG1; actin, cytoplasmic 2 [KO:K05692]
280979  ACTB; actin, cytoplasmic 1 [KO:K05692]
540108  SPTAN1; spectrin alpha chain, non-erythrocytic 1 [KO:K06114]
404144  LMNA; lamin [KO:K12641]
516326  LMNB2; lamin-B2 [KO:K07611]
540643  LMNB1; lamin-B1 [KO:K07611]
286764  PARP1; poly [ADP-ribose] polymerase 1 [KO:K24070] [EC:]
615359  PARP4; protein mono-ADP-ribosyltransferase PARP4 [KO:K10798] [EC:]
505828  PARP2; poly [ADP-ribose] polymerase 2 [KO:K10798] [EC:]
507426  PARP3; LOW QUALITY PROTEIN: protein mono-ADP-ribosyltransferase PARP3 [KO:K10798] [EC:]
507981  DFFA; DNA fragmentation factor subunit alpha [KO:K02310]
512730  DFFB; DNA fragmentation factor subunit beta [KO:K02311] [EC:3.-.-.-]
327707  ENDOG; endonuclease G, mitochondrial precursor [KO:K01173]
535714  AIFM1; apoptosis-inducing factor 1, mitochondrial [KO:K04727] [EC:1.-.-.-]
112442685  ERN1; serine/threonine-protein kinase/endoribonuclease IRE1 isoform X2 [KO:K08852] [EC: 3.1.26.-]
512355  TRAF2; TNF receptor-associated factor 2 [KO:K03173] [EC:]
317697  ITPR1; inositol 1,4,5-trisphosphate receptor type 1 [KO:K04958]
281878  ITPR2; inositol 1,4,5-trisphosphate receptor type 2 [KO:K04959]
281879  ITPR3; inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960]
281661  CAPN1; calpain-1 catalytic subunit [KO:K01367] [EC:]
281662  CAPN2; calpain-2 catalytic subunit [KO:K03853] [EC:]
535820  EIF2AK3; eukaryotic translation initiation factor 2-alpha kinase 3 precursor [KO:K08860] [EC:]
327694  EIF2S1; eukaryotic translation initiation factor 2 subunit 1 [KO:K03237]
509107  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
777788  DDIT3; DNA damage-inducible transcript 3 protein [KO:K04452]
281105  CTSB; cathepsin B precursor [KO:K01363] [EC:]
352958  CTSC; dipeptidyl peptidase 1 precursor [KO:K01275] [EC:]
282883  CTSD; cathepsin D precursor [KO:K01379] [EC:]
509715  CTSF; cathepsin F precursor [KO:K01373] [EC:]
510524  CTSH; pro-cathepsin H precursor [KO:K01366] [EC:]
513038  CTSK; cathepsin K precursor [KO:K01371] [EC:]
281108  CTSV; cathepsin L2 precursor [KO:K01365] [EC:]
515200  CTSL; procathepsin L precursor [KO:K01365] [EC:]
616804  CTSO; cathepsin O [KO:K01374] [EC:]
327711  CTSS; cathepsin S precursor [KO:K01368] [EC:]
510967  CTSW; cathepsin W precursor [KO:K08569] [EC:3.4.22.-]
404187  CTSZ; cathepsin Z precursor [KO:K08568] [EC:]
539314  BIRC2; baculoviral IAP repeat-containing protein 2 isoform X2 [KO:K16060]
514386  BIRC3; baculoviral IAP repeat-containing protein 3 [KO:K16060]
101905053  LOW QUALITY PROTEIN: baculoviral IAP repeat-containing protein 2-like [KO:K16060]
281647  XIAP; E3 ubiquitin-protein ligase XIAP [KO:K04725] [EC:]
414925  BIRC5; baculoviral IAP repeat-containing protein 5 [KO:K08731]
507390  BCL2L11; bcl-2-like protein 11 [KO:K16341]
282152  BCL2L1; bcl-2-like protein 1 [KO:K04570]
281020  BCL2; apoptosis regulator Bcl-2 [KO:K02161]
504336  DAXX; death domain-associated protein 6 [KO:K02308]
504727  RIPK1; receptor-interacting serine/threonine-protein kinase 1 [KO:K02861] [EC:]
541268  DAB2IP; disabled homolog 2-interacting protein [KO:K19901]
537380  MAP3K5; mitogen-activated protein kinase kinase kinase 5 [KO:K04426] [EC:]
539941  MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:]
534125  MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:]
537631  MAPK10; mitogen-activated protein kinase 10 isoform 2 [KO:K04440] [EC:]
615013  BAD; bcl2-associated agonist of cell death [KO:K02158]
280831  JUN; transcription factor Jun [KO:K04448]
280795  FOS; protein c-Fos [KO:K04379]
281542  TP53; cellular tumor antigen p53 [KO:K04451]
787139  HRK; activator of apoptosis harakiri [KO:K02512]
508367  MAP3K14; mitogen-activated protein kinase kinase kinase 14 [KO:K04466] [EC:]
281073  CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha [KO:K04467] [EC:]
281854  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:]
281855  IKBKG; NF-kappa-B essential modulator [KO:K07210]
282291  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
616115  NFKB1; nuclear factor NF-kappa-B p105 subunit [KO:K02580]
508233  RELA; transcription factor p65 [KO:K04735]
282333  PTPN13; tyrosine-protein phosphatase non-receptor type 13 [KO:K02374]
504939  GADD45G; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
618405  GADD45B; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
505463  GADD45A; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
540944  TRAF1; TNF receptor-associated factor 1 [KO:K03172]
282151  BCL2A1; bcl-2-related protein A1 [KO:K02162]
526824  ATM; serine-protein kinase ATM [KO:K04728] [EC:]
100137737  PIDD1; p53-induced death domain-containing protein 1 [KO:K10130]
782359  BBC3; bcl-2-binding component 3 isoform X3 [KO:K10132]
100296226  PMAIP1; phorbol-12-myristate-13-acetate-induced protein 1 [KO:K10131]
531419  CASP2; caspase-2 [KO:K02186] [EC:]
281350  NGF; beta-nerve growth factor precursor [KO:K02582]
353111  NTRK1; high affinity nerve growth factor receptor isoform X1 [KO:K03176] [EC:]
280823  IL3; interleukin-3 precursor [KO:K04736]
100299249  IL3RA; interleukin-3 receptor subunit alpha isoform X3 [KO:K04737]
132342083  interleukin-3 receptor subunit alpha-like isoform X1 [KO:K04737]
528530  CSF2RB; cytokine receptor common subunit beta precursor [KO:K04738]
282306  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:]
517948  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:]
504531  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:]
282308  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
286865  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
282307  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
100138102  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:]
534923  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:]
280991  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:]
100137872  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:]
100298939  HRAS; GTPase HRas isoform 1 [KO:K02833]
100847184  GTPase HRas-like [KO:K02833]
541140  KRAS; GTPase KRas [KO:K07827]
506322  NRAS; GTPase NRas [KO:K07828]
521196  RAF1; RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:]
533199  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:]
101905399  LOW QUALITY PROTEIN: dual specificity mitogen-activated protein kinase kinase 1-like [KO:K04368] [EC:]
510434  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:]
327672  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:]
531391  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:]
C00027  Hydrogen peroxide
C00076  Calcium cation
C00319  Sphingosine
C05981  Phosphatidylinositol-3,4,5-trisphosphate
Savitskaya MA, Onishchenko GE
Mechanisms of Apoptosis.
Biochemistry (Mosc) 80:1393-417 (2015)
Schleich K, Lavrik IN
Mathematical modeling of apoptosis.
Cell Commun Signal 11:44 (2013)
Lavrik I, Golks A, Krammer PH
Death receptor signaling.
J Cell Sci 118:265-7 (2005)
Jin Z, El-Deiry WS
Overview of cell death signaling pathways.
Cancer Biol Ther 4:139-63 (2005)
Benn SC, Woolf CJ
Adult neuron survival strategies--slamming on the brakes.
Nat Rev Neurosci 5:686-700 (2004)
Orrenius S, Zhivotovsky B, Nicotera P
Regulation of cell death: the calcium-apoptosis link.
Nat Rev Mol Cell Biol 4:552-65 (2003)
Clarke P, Tyler KL
Apoptosis in animal models of virus-induced disease.
Nat Rev Microbiol 7:144-55 (2009)
Wen X, Lin ZQ, Liu B, Wei YQ
Caspase-mediated programmed cell death pathways as potential therapeutic targets in cancer.
Cell Prolif 45:217-24 (2012)
Shalini S, Dorstyn L, Dawar S, Kumar S
Old, new and emerging functions of caspases.
Cell Death Differ 22:526-39 (2015)
Philchenkov A
Caspases: potential targets for regulating cell death.
J Cell Mol Med 8:432-44 (2004)
Stroh C, Schulze-Osthoff K
Death by a thousand cuts: an ever increasing list of caspase substrates.
Cell Death Differ 5:997-1000 (1998)
Safa AR
c-FLIP, a master anti-apoptotic regulator.
Exp Oncol 34:176-84 (2012)
Jeong SY, Seol DW
The role of mitochondria in apoptosis.
BMB Rep 41:11-22 (2008)
Parsons MJ, Green DR
Mitochondria in cell death.
Essays Biochem 47:99-114 (2010)
Strasser A
The role of BH3-only proteins in the immune system.
Nat Rev Immunol 5:189-200 (2005)
Schonthal AH
Endoplasmic reticulum stress: its role in disease and novel prospects for therapy.
Scientifica (Cairo) 2012:857516 (2012)
Malhi H, Kaufman RJ
Endoplasmic reticulum stress in liver disease.
J Hepatol 54:795-809 (2011)
Malhotra JD, Kaufman RJ
The endoplasmic reticulum and the unfolded protein response.
Semin Cell Dev Biol 18:716-31 (2007)
Wu J, Kaufman RJ
From acute ER stress to physiological roles of the Unfolded Protein Response.
Cell Death Differ 13:374-84 (2006)
Repnik U, Stoka V, Turk V, Turk B
Lysosomes and lysosomal cathepsins in cell death.
Biochim Biophys Acta 1824:22-33 (2012)
Cesen MH, Pegan K, Spes A, Turk B
Lysosomal pathways to cell death and their therapeutic applications.
Exp Cell Res 318:1245-51 (2012)
Dashzeveg N, Yoshida K
Cell death decision by p53 via control of the mitochondrial membrane.
Cancer Lett 367:108-12 (2015)
Bouchier-Hayes L, Green DR
Caspase-2: the orphan caspase.
Cell Death Differ 19:51-7 (2012)
Baptiste-Okoh N, Barsotti AM, Prives C
A role for caspase 2 and PIDD in the process of p53-mediated apoptosis.
Proc Natl Acad Sci U S A 105:1937-42 (2008)
Aggarwal BB
Signalling pathways of the TNF superfamily: a double-edged sword.
Nat Rev Immunol 3:745-56 (2003)
Steelman LS, Pohnert SC, Shelton JG, Franklin RA, Bertrand FE, McCubrey JA.
JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis.
Leukemia 18:189-218 (2004)
Dragovich T, Rudin CM, Thompson CB
Signal transduction pathways that regulate cell survival and cell death.
Oncogene 17:3207-13 (1998)
Sofroniew MV, Howe CL, Mobley WC
Nerve growth factor signaling, neuroprotection, and neural repair.
Annu Rev Neurosci 24:1217-81 (2001)
Kristiansen M, Ham J
Programmed cell death during neuronal development: the sympathetic neuron model.
Cell Death Differ 21:1025-35 (2014)
Logue SE, Martin SJ
Caspase activation cascades in apoptosis.
Biochem Soc Trans 36:1-9 (2008)
Boivin WA, Cooper DM, Hiebert PR, Granville DJ
Intracellular versus extracellular granzyme B in immunity and disease: challenging the dogma.
Lab Invest 89:1195-220 (2009)
Cullen SP, Brunet M, Martin SJ
Granzymes in cancer and immunity.
Cell Death Differ 17:616-23 (2010)
bta04010  MAPK signaling pathway
bta04020  Calcium signaling pathway
bta04064  NF-kappa B signaling pathway
bta04115  p53 signaling pathway
bta04141  Protein processing in endoplasmic reticulum
bta04151  PI3K-Akt signaling pathway
bta04650  Natural killer cell mediated cytotoxicity
bta04668  TNF signaling pathway
KO pathway

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