KEGG   PATHWAY: dle04210
Entry
dle04210                    Pathway                                
Name
Apoptosis - Delphinapterus leucas (beluga whale)
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
Pathway map
dle04210  Apoptosis
dle04210

Other DBs
GO: 0006915
Organism
Delphinapterus leucas (beluga whale) [GN:dle]
Gene
111173963  TNFSF10; tumor necrosis factor ligand superfamily member 10 isoform X1 [KO:K04721]
111185435  TNFRSF10A; tumor necrosis factor receptor superfamily member 10A isoform X1 [KO:K04722]
111185436  tumor necrosis factor receptor superfamily member 10B-like isoform X1 [KO:K04722]
111170265  FASLG; tumor necrosis factor ligand superfamily member 6 [KO:K04389]
111172519  FAS; tumor necrosis factor receptor superfamily member 6 isoform X1 [KO:K04390]
111183629  FADD; FAS-associated death domain protein [KO:K02373]
111170657  TNF; tumor necrosis factor [KO:K03156]
111176656  TNFRSF1A; tumor necrosis factor receptor superfamily member 1A [KO:K03158]
111179654  TRADD; tumor necrosis factor receptor type 1-associated DEATH domain protein [KO:K03171]
111171724  CFLAR; CASP8 and FADD-like apoptosis regulator isoform X1 [KO:K04724]
111171726  CASP8; caspase-8 [KO:K04398] [EC:3.4.22.61]
111171725  CASP10; caspase-10 [KO:K04400] [EC:3.4.22.63]
111171500  CASP6; caspase-6 isoform X1 [KO:K04396] [EC:3.4.22.59]
111173401  CASP3; caspase-3 isoform X1 [KO:K02187] [EC:3.4.22.56]
111172296  CASP7; caspase-7 [KO:K04397] [EC:3.4.22.60]
111176587  BID; BH3-interacting domain death agonist isoform X1 [KO:K04726]
111180640  BAX; apoptosis regulator BAX isoform X1 [KO:K02159]
111178690  BAK1; bcl-2 homologous antagonist/killer isoform X1 [KO:K14021]
111186886  DIABLO; diablo homolog, mitochondrial isoform X1 [KO:K10522]
111163631  SEPTIN4; septin-4 isoform X2 [KO:K16943]
111169079  HTRA2; serine protease HTRA2, mitochondrial [KO:K08669] [EC:3.4.21.108]
111180543  cytochrome c [KO:K08738]
111174575  cytochrome c-like [KO:K08738]
111174031  cytochrome c-like [KO:K08738]
111172911  cytochrome c 2 [KO:K08738]
111174197  cytochrome c-like [KO:K08738]
111175930  cytochrome c-like [KO:K08738]
111187821  APAF1; apoptotic protease-activating factor 1 [KO:K02084]
111187099  CASP9; caspase-9 [KO:K04399] [EC:3.4.22.62]
111183477  PRF1; perforin-1 [KO:K07818]
111164234  granzyme B-like isoform X1 [KO:K01353] [EC:3.4.21.79]
111164169  LOW QUALITY PROTEIN: mast cell protease 3-like [KO:K01353] [EC:3.4.21.79]
111163074  tubulin alpha-3 chain-like [KO:K07374]
111162959  tubulin alpha-3 chain [KO:K07374]
111171848  tubulin alpha-4A chain [KO:K07374]
111171851  tubulin alpha-1 chain-like [KO:K07374]
111170121  tubulin alpha chain-like 3 [KO:K07374]
111176582  TUBA8; tubulin alpha-8 chain isoform X2 [KO:K07374]
111174050  tubulin alpha-1A chain [KO:K07374]
111174051  tubulin alpha-1B chain [KO:K07374]
111174052  tubulin alpha-1C chain-like [KO:K07374]
111176583  tubulin alpha-8 chain [KO:K07374]
111169732  MCL1; induced myeloid leukemia cell differentiation protein Mcl-1 isoform X1 [KO:K02539]
111182710  ACTG1; actin, cytoplasmic 2 [KO:K05692]
111170344  ACTB; actin, cytoplasmic 1 [KO:K05692]
111177157  SPTAN1; spectrin alpha chain, non-erythrocytic 1 isoform X1 [KO:K06114]
111167038  LMNA; lamin isoform X1 [KO:K12641]
111170921  LMNB2; lamin-B2 isoform X1 [KO:K07611]
111182378  LMNB1; lamin-B1 [KO:K07611]
111177530  PARP1; poly [ADP-ribose] polymerase 1 isoform X2 [KO:K24070] [EC:2.4.2.30]
111174336  PARP3; LOW QUALITY PROTEIN: protein mono-ADP-ribosyltransferase PARP3 [KO:K10798] [EC:2.4.2.30]
111181802  PARP2; poly [ADP-ribose] polymerase 2 isoform X1 [KO:K10798] [EC:2.4.2.30]
111187197  DFFA; DNA fragmentation factor subunit alpha isoform X1 [KO:K02310]
111187285  DFFB; DNA fragmentation factor subunit beta [KO:K02311] [EC:3.-.-.-]
111177150  ENDOG; endonuclease G, mitochondrial [KO:K01173]
111168016  AIFM1; apoptosis-inducing factor 1, mitochondrial isoform X1 [KO:K04727] [EC:1.-.-.-]
111182623  ERN1; serine/threonine-protein kinase/endoribonuclease IRE1 [KO:K08852] [EC:2.7.11.1 3.1.26.-]
111177009  TRAF2; TNF receptor-associated factor 2 [KO:K03173] [EC:2.3.2.27]
111174169  ITPR1; inositol 1,4,5-trisphosphate receptor type 1 isoform X1 [KO:K04958]
111176861  ITPR2; inositol 1,4,5-trisphosphate receptor type 2 isoform X1 [KO:K04959]
111178692  ITPR3; inositol 1,4,5-trisphosphate receptor type 3 isoform X1 [KO:K04960]
111183768  CAPN1; calpain-1 catalytic subunit [KO:K01367] [EC:3.4.22.52]
111177507  CAPN2; calpain-2 catalytic subunit isoform X1 [KO:K03853] [EC:3.4.22.53]
111187362  EIF2AK3; eukaryotic translation initiation factor 2-alpha kinase 3 isoform X1 [KO:K08860] [EC:2.7.11.1]
111173047  EIF2S1; eukaryotic translation initiation factor 2 subunit 1 [KO:K03237]
111186212  ATF4; cyclic AMP-dependent transcription factor ATF-4 isoform X1 [KO:K04374]
111173840  DDIT3; DNA damage-inducible transcript 3 protein [KO:K04452]
111185365  CTSB; cathepsin B isoform X1 [KO:K01363] [EC:3.4.22.1]
111184954  CTSC; dipeptidyl peptidase 1 isoform X1 [KO:K01275] [EC:3.4.14.1]
111170294  CTSD; cathepsin D [KO:K01379] [EC:3.4.23.5]
111183702  CTSF; LOW QUALITY PROTEIN: cathepsin F [KO:K01373] [EC:3.4.22.41]
111164745  CTSH; pro-cathepsin H [KO:K01366] [EC:3.4.22.16]
111169765  CTSK; cathepsin K isoform X1 [KO:K01371] [EC:3.4.22.38]
111166812  cathepsin L1 isoform X1 [KO:K01365] [EC:3.4.22.15]
111166814  CTSL; cathepsin L1 [KO:K01365] [EC:3.4.22.15]
111179011  CTSO; cathepsin O isoform X2 [KO:K01374] [EC:3.4.22.42]
111169766  CTSS; cathepsin S [KO:K01368] [EC:3.4.22.27]
111183735  CTSW; cathepsin W isoform X1 [KO:K08569] [EC:3.4.22.-]
111186744  CTSZ; cathepsin Z [KO:K08568] [EC:3.4.18.1]
111168369  BIRC2; baculoviral IAP repeat-containing protein 2 [KO:K16060]
111168370  BIRC3; baculoviral IAP repeat-containing protein 3 isoform X1 [KO:K16060]
111168228  XIAP; E3 ubiquitin-protein ligase XIAP [KO:K04725] [EC:2.3.2.27]
111182765  BIRC5; baculoviral IAP repeat-containing protein 5 [KO:K08731]
111187462  BCL2L11; bcl-2-like protein 11 isoform X1 [KO:K16341]
111184326  BCL2L1; bcl-2-like protein 1 isoform X1 [KO:K04570]
111180199  BCL2; apoptosis regulator Bcl-2 [KO:K02161]
111178680  DAXX; death domain-associated protein 6 isoform X1 [KO:K02308]
111181305  RIPK1; receptor-interacting serine/threonine-protein kinase 1 isoform X1 [KO:K02861] [EC:2.7.11.1]
111177256  DAB2IP; disabled homolog 2-interacting protein isoform X1 [KO:K19901]
111166150  MAP3K5; mitogen-activated protein kinase kinase kinase 5 isoform X1 [KO:K04426] [EC:2.7.11.25]
111168108  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
111169265  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
111169895  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
111183810  BAD; bcl2-associated agonist of cell death [KO:K02158]
111175871  JUN; transcription factor AP-1 [KO:K04448]
111176238  FOS; proto-oncogene c-Fos [KO:K04379]
111185755  TP53; cellular tumor antigen p53 [KO:K04451]
111186988  HRK; activator of apoptosis harakiri [KO:K02512]
111170190  MAP3K14; mitogen-activated protein kinase kinase kinase 14 isoform X1 [KO:K04466] [EC:2.7.11.25]
111172396  CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha isoform X1 [KO:K04467] [EC:2.7.11.10]
111173552  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
111170969  IKBKG; NF-kappa-B essential modulator isoform X1 [KO:K07210]
111173225  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
111179110  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
111183745  RELA; transcription factor p65 isoform X1 [KO:K04735]
111168083  PTPN13; tyrosine-protein phosphatase non-receptor type 13 isoform X1 [KO:K02374]
111170922  GADD45B; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
111178438  GADD45A; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
111167640  GADD45G; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
111177267  TRAF1; TNF receptor-associated factor 1 [KO:K03172]
111164703  BCL2A1; bcl-2-related protein A1 [KO:K02162]
111168050  ATM; serine-protein kinase ATM isoform X1 [KO:K04728] [EC:2.7.11.1]
111170295  PIDD1; p53-induced death domain-containing protein 1 isoform X1 [KO:K10130]
111180693  BBC3; bcl-2-binding component 3 [KO:K10132]
111180211  PMAIP1; phorbol-12-myristate-13-acetate-induced protein 1 [KO:K10131]
111177325  CASP2; caspase-2 isoform X1 [KO:K02186] [EC:3.4.22.55]
111179989  NGF; beta-nerve growth factor isoform X2 [KO:K02582]
111167102  NTRK1; high affinity nerve growth factor receptor [KO:K03176] [EC:2.7.10.1]
111182348  interleukin-3-like [KO:K04736]
111168262  IL3RA; interleukin-3 receptor subunit alpha isoform X1 [KO:K04737]
111186251  CSF2RB; cytokine receptor common subunit beta [KO:K04738]
111173839  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
111179235  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
111187262  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
111166652  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
111185984  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
111175760  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
111185202  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
111177559  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
111176008  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
111180855  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
111170340  HRAS; GTPase HRas isoform X1 [KO:K02833]
111176851  KRAS; GTPase KRas [KO:K07827]
111179996  NRAS; GTPase NRas [KO:K07828]
111168973  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
111177745  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
111165994  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:2.7.12.2]
111163022  MAPK1; mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]
111182181  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
PMID:26615431
  Authors
Savitskaya MA, Onishchenko GE
  Title
Mechanisms of Apoptosis.
  Journal
Biochemistry (Mosc) 80:1393-417 (2015)
DOI:10.1134/S0006297915110012
Reference
PMID:23803157
  Authors
Schleich K, Lavrik IN
  Title
Mathematical modeling of apoptosis.
  Journal
Cell Commun Signal 11:44 (2013)
DOI:10.1186/1478-811X-11-44
Reference
PMID:15654015
  Authors
Lavrik I, Golks A, Krammer PH
  Title
Death receptor signaling.
  Journal
J Cell Sci 118:265-7 (2005)
DOI:10.1242/jcs.01610
Reference
PMID:15725726
  Authors
Jin Z, El-Deiry WS
  Title
Overview of cell death signaling pathways.
  Journal
Cancer Biol Ther 4:139-63 (2005)
DOI:10.4161/cbt.4.2.1508
Reference
PMID:15322527
  Authors
Benn SC, Woolf CJ
  Title
Adult neuron survival strategies--slamming on the brakes.
  Journal
Nat Rev Neurosci 5:686-700 (2004)
DOI:10.1038/nrn1477
Reference
PMID:12838338
  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)
DOI:10.1038/nrm1150
Reference
PMID:19148180
  Authors
Clarke P, Tyler KL
  Title
Apoptosis in animal models of virus-induced disease.
  Journal
Nat Rev Microbiol 7:144-55 (2009)
DOI:10.1038/nrmicro2071
Reference
PMID:22429822
  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)
DOI:10.1111/j.1365-2184.2012.00814.x
Reference
PMID:25526085
  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)
DOI:10.1038/cdd.2014.216
Reference
PMID:15601572
  Authors
Philchenkov A
  Title
Caspases: potential targets for regulating cell death.
  Journal
J Cell Mol Med 8:432-44 (2004)
DOI:10.1111/j.1582-4934.2004.tb00468.x
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)
DOI:10.1038/sj.cdd.4400451
Reference
PMID:23070002
  Authors
Safa AR
  Title
c-FLIP, a master anti-apoptotic regulator.
  Journal
Exp Oncol 34:176-84 (2012)
Reference
PMID:18304445
  Authors
Jeong SY, Seol DW
  Title
The role of mitochondria in apoptosis.
  Journal
BMB Rep 41:11-22 (2008)
DOI:10.5483/bmbrep.2008.41.1.011
Reference
PMID:20533903
  Authors
Parsons MJ, Green DR
  Title
Mitochondria in cell death.
  Journal
Essays Biochem 47:99-114 (2010)
DOI:10.1042/bse0470099
Reference
PMID:15719025
  Authors
Strasser A
  Title
The role of BH3-only proteins in the immune system.
  Journal
Nat Rev Immunol 5:189-200 (2005)
DOI:10.1038/nri1568
Reference
PMID:24278747
  Authors
Schonthal AH
  Title
Endoplasmic reticulum stress: its role in disease and novel prospects for therapy.
  Journal
Scientifica (Cairo) 2012:857516 (2012)
DOI:10.6064/2012/857516
Reference
PMID:21145844
  Authors
Malhi H, Kaufman RJ
  Title
Endoplasmic reticulum stress in liver disease.
  Journal
J Hepatol 54:795-809 (2011)
DOI:10.1016/j.jhep.2010.11.005
Reference
PMID:18023214
  Authors
Malhotra JD, Kaufman RJ
  Title
The endoplasmic reticulum and the unfolded protein response.
  Journal
Semin Cell Dev Biol 18:716-31 (2007)
DOI:10.1016/j.semcdb.2007.09.003
Reference
PMID:16397578
  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)
DOI:10.1038/sj.cdd.4401840
Reference
PMID:21914490
  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)
DOI:10.1016/j.bbapap.2011.08.016
Reference
PMID:22465226
  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)
DOI:10.1016/j.yexcr.2012.03.005
Reference
PMID:26231733
  Authors
Dashzeveg N, Yoshida K
  Title
Cell death decision by p53 via control of the mitochondrial membrane.
  Journal
Cancer Lett 367:108-12 (2015)
DOI:10.1016/j.canlet.2015.07.019
Reference
PMID:22075987
  Authors
Bouchier-Hayes L, Green DR
  Title
Caspase-2: the orphan caspase.
  Journal
Cell Death Differ 19:51-7 (2012)
DOI:10.1038/cdd.2011.157
Reference
PMID:18238895
  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)
DOI:10.1073/pnas.0711800105
Reference
PMID:12949498
  Authors
Aggarwal BB
  Title
Signalling pathways of the TNF superfamily: a double-edged sword.
  Journal
Nat Rev Immunol 3:745-56 (2003)
DOI:10.1038/nri1184
Reference
PMID:14737178
  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)
DOI:10.1038/sj.leu.2403241
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)
DOI:10.1038/sj.onc.1202587
Reference
PMID:11520933
  Authors
Sofroniew MV, Howe CL, Mobley WC
  Title
Nerve growth factor signaling, neuroprotection, and neural repair.
  Journal
Annu Rev Neurosci 24:1217-81 (2001)
DOI:10.1146/annurev.neuro.24.1.1217
Reference
PMID:24769728
  Authors
Kristiansen M, Ham J
  Title
Programmed cell death during neuronal development: the sympathetic neuron model.
  Journal
Cell Death Differ 21:1025-35 (2014)
DOI:10.1038/cdd.2014.47
Reference
PMID:18208375
  Authors
Logue SE, Martin SJ
  Title
Caspase activation cascades in apoptosis.
  Journal
Biochem Soc Trans 36:1-9 (2008)
DOI:10.1042/BST0360001
Reference
PMID:19770840
  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)
DOI:10.1038/labinvest.2009.91
Reference
PMID:20075940
  Authors
Cullen SP, Brunet M, Martin SJ
  Title
Granzymes in cancer and immunity.
  Journal
Cell Death Differ 17:616-23 (2010)
DOI:10.1038/cdd.2009.206
Related
pathway
dle04010  MAPK signaling pathway
dle04020  Calcium signaling pathway
dle04064  NF-kappa B signaling pathway
dle04115  p53 signaling pathway
dle04141  Protein processing in endoplasmic reticulum
dle04151  PI3K-Akt signaling pathway
dle04650  Natural killer cell mediated cytotoxicity
dle04668  TNF signaling pathway
KO pathway
ko04210   
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