KEGG   PATHWAY: hhv04210
Entry
hhv04210                    Pathway                                
Name
Apoptosis - Hyaena hyaena (striped hyena)
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
hhv04210  Apoptosis
hhv04210

Other DBs
GO: 0006915
Organism
Hyaena hyaena (striped hyena) [GN:hhv]
Gene
120219677  [KO:K16060]
120219681  BIRC2; baculoviral IAP repeat-containing protein 2 [KO:K16060]
120219997  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
120220121  BCL2A1; bcl-2-related protein A1 [KO:K02162]
120220675  CASP8; caspase-8 [KO:K04398] [EC:3.4.22.61]
120220687  CASP10; caspase-10 isoform X1 [KO:K04400] [EC:3.4.22.63]
120220695  CFLAR; CASP8 and FADD-like apoptosis regulator isoform X1 [KO:K04724]
120220903  DFFB; DNA fragmentation factor subunit beta [KO:K02311] [EC:3.-.-.-]
120220979  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
120221151  TNFRSF1A; tumor necrosis factor receptor superfamily member 1A isoform X1 [KO:K03158]
120221184  [KO:K08738]
120221371  CTSO; cathepsin O isoform X1 [KO:K01374] [EC:3.4.22.42]
120221556  [KO:K08738]
120221655  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
120221913  TNF; tumor necrosis factor [KO:K03156]
120222015  [KO:K04426] [EC:2.7.11.25]
120222043  CTSB; cathepsin B isoform X1 [KO:K01363] [EC:3.4.22.1]
120222278  MAP3K14; mitogen-activated protein kinase kinase kinase 14 [KO:K04466] [EC:2.7.11.25]
120222817  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
120223012  [KO:K07374]
120223347  TRADD; tumor necrosis factor receptor type 1-associated DEATH domain protein isoform X1 [KO:K03171]
120223392  HRAS; GTPase HRas isoform X1 [KO:K02833]
120223402  PIDD1; p53-induced death domain-containing protein 1 isoform X1 [KO:K10130]
120223531  KRAS; GTPase KRas [KO:K07827]
120223778  FAS; tumor necrosis factor receptor superfamily member 6 [KO:K04390]
120224186  [KO:K01365] [EC:3.4.22.15]
120224188  [KO:K01365] [EC:3.4.22.15]
120224189  [KO:K01365] [EC:3.4.22.15]
120224190  [KO:K01365] [EC:3.4.22.15]
120224191  [KO:K01365] [EC:3.4.22.15]
120224193  [KO:K01365] [EC:3.4.22.15]
120224200  FASLG; tumor necrosis factor ligand superfamily member 6 [KO:K04389]
120224242  [KO:K08738]
120224892  NOL3; nucleolar protein 3 isoform X1 [KO:K28177]
120225026  APAF1; apoptotic protease-activating factor 1 isoform X1 [KO:K02084]
120225514  CTSD; cathepsin D [KO:K01379] [EC:3.4.23.5]
120225949  PARP2; poly [ADP-ribose] polymerase 2 [KO:K28005]
120226445  TRAF2; TNF receptor-associated factor 2 [KO:K03173] [EC:2.3.2.27]
120226506  [KO:K01365] [EC:3.4.22.15]
120226507  [KO:K01365] [EC:3.4.22.15]
120226622  IKBKG; NF-kappa-B essential modulator [KO:K07210]
120227184  [KO:K07374]
120227526  [KO:K07374]
120227529  [KO:K07374]
120228024  ACTB; actin, cytoplasmic 1 [KO:K05692]
120228299  BIRC5; baculoviral IAP repeat-containing protein 5 [KO:K08731]
120228303  ACTG1; actin, cytoplasmic 2 [KO:K05692]
120228924  [KO:K07374]
120229837  CASP9; caspase-9 isoform X1 [KO:K04399] [EC:3.4.22.62]
120229863  ATM; serine-protein kinase ATM isoform X1 [KO:K04728] [EC:2.7.11.1]
120230086  SPTAN1; spectrin alpha chain, non-erythrocytic 1 isoform X1 [KO:K06114]
120230105  ENDOG; endonuclease G, mitochondrial [KO:K01173]
120230330  [KO:K08738]
120230786  PMAIP1; phorbol-12-myristate-13-acetate-induced protein 1 [KO:K10131]
120231297  [KO:K08738]
120231327  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
120231386  TP53; cellular tumor antigen p53 isoform X1 [KO:K04451]
120231559  BCL2L11; bcl-2-like protein 11 isoform X1 [KO:K16341]
120231952  FOS; proto-oncogene c-Fos [KO:K04379]
120232476  PRF1; perforin-1 [KO:K07818]
120232638  GADD45A; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
120232774  [KO:K08738]
120232781  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
120233414  [KO:K19901]
120233425  TRAF1; TNF receptor-associated factor 1 isoform X1 [KO:K03172]
120233433  [KO:K08738]
120233608  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
120233646  DFFA; DNA fragmentation factor subunit alpha [KO:K02310]
120233869  FADD; FAS-associated death domain protein [KO:K02373]
120233928  [KO:K04722]
120233999  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
120234126  PARP1; poly [ADP-ribose] polymerase 1 [KO:K24070]
120234148  CAPN2; calpain-2 catalytic subunit [KO:K03853] [EC:3.4.22.53]
120234198  ERN1; serine/threonine-protein kinase/endoribonuclease IRE1 [KO:K08852] [EC:2.7.11.1 3.1.26.-]
120234588  TNFSF10; tumor necrosis factor ligand superfamily member 10 [KO:K04721]
120234734  LMNB1; lamin-B1 [KO:K07611]
120234857  CTSZ; cathepsin Z [KO:K08568] [EC:3.4.18.1]
120235229  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
120235277  AKT3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
120235365  CASP7; caspase-7 [KO:K04397] [EC:3.4.22.60]
120235381  BCL2L1; bcl-2-like protein 1 [KO:K04570]
120236153  CASP6; caspase-6 isoform X1 [KO:K04396] [EC:3.4.22.59]
120236173  [KO:K04725] [EC:2.3.2.27]
120236252  JUN; transcription factor AP-1 [KO:K04448]
120236951  [KO:K08738]
120237033  HTRA2; serine protease HTRA2, mitochondrial isoform X1 [KO:K08669] [EC:3.4.21.108]
120237135  ITPR1; inositol 1,4,5-trisphosphate receptor type 1 isoform X1 [KO:K04958]
120237180  TUBAL3; tubulin alpha chain-like 3 isoform X1 [KO:K07374]
120237420  EIF2S1; eukaryotic translation initiation factor 2 subunit 1 [KO:K03237]
120237482  ITPR2; inositol 1,4,5-trisphosphate receptor type 2 isoform X1 [KO:K04959]
120237885  [KO:K07374]
120237886  [KO:K07374]
120237943  GADD45G; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
120238181  ITPR3; inositol 1,4,5-trisphosphate receptor type 3 isoform X1 [KO:K04960]
120238210  DAXX; death domain-associated protein 6 isoform X1 [KO:K02308]
120238211  BAK1; bcl-2 homologous antagonist/killer isoform X1 [KO:K14021]
120238779  NGF; beta-nerve growth factor [KO:K02582]
120238803  [KO:K07374]
120238829  [KO:K07374]
120238830  MAPK1; mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]
120239002  CASP2; caspase-2 isoform X1 [KO:K02186] [EC:3.4.22.55]
120239233  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
120239371  [KO:K04426] [EC:2.7.11.25]
120239440  PARP3; protein mono-ADP-ribosyltransferase PARP3 isoform X1 [KO:K10798] [EC:2.4.2.-]
120240133  CAPN1; calpain-1 catalytic subunit [KO:K01367] [EC:3.4.22.52]
120240137  BAD; bcl2-associated agonist of cell death [KO:K02158]
120240185  RELA; transcription factor p65 [KO:K04735]
120240188  CTSW; cathepsin W [KO:K08569] [EC:3.4.22.-]
120240224  CTSF; cathepsin F isoform X1 [KO:K01373] [EC:3.4.22.41]
120240554  IL3RA; interleukin-3 receptor subunit alpha isoform X1 [KO:K04737]
120240822  CTSV; cathepsin L2 [KO:K01365] [EC:3.4.22.15]
120241180  CSF2RB; cytokine receptor common subunit beta [KO:K04738]
120241248  CTSS; cathepsin S [KO:K01368] [EC:3.4.22.27]
120241249  CTSK; cathepsin K [KO:K01371] [EC:3.4.22.38]
120241269  MCL1; induced myeloid leukemia cell differentiation protein Mcl-1 [KO:K02539]
120241444  RIPK1; receptor-interacting serine/threonine-protein kinase 1 [KO:K02861] [EC:2.7.11.1]
120241500  PDPK1; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
120241927  SEPTIN4; septin-4 isoform X1 [KO:K16943]
120242086  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
120242212  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
120242316  LMNB2; lamin-B2 isoform X1 [KO:K07611]
120242325  GADD45B; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
120243068  NRAS; GTPase NRas [KO:K07828]
120243217  CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha isoform X1 [KO:K04467] [EC:2.7.11.10]
120243716  BAX; apoptosis regulator BAX isoform X1 [KO:K02159]
120243772  TUBA8; tubulin alpha-8 chain [KO:K07374]
120243781  BID; BH3-interacting domain death agonist isoform X1 [KO:K04726]
120244177  PTPN13; tyrosine-protein phosphatase non-receptor type 13 isoform X1 [KO:K02374]
120244180  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
120244339  AIFM1; apoptosis-inducing factor 1, mitochondrial isoform X1 [KO:K04727] [EC:1.-.-.-]
120244480  BBC3; bcl-2-binding component 3 isoform X1 [KO:K10132]
120244665  NTRK1; high affinity nerve growth factor receptor [KO:K03176] [EC:2.7.10.1]
120244696  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
120244719  LMNA; lamin [KO:K12641]
120245032  BCL2; apoptosis regulator Bcl-2 [KO:K02161]
120245547  EIF2AK3; eukaryotic translation initiation factor 2-alpha kinase 3 [KO:K08860] [EC:2.7.11.1]
120245677  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
120245718  DIABLO; diablo homolog, mitochondrial isoform X1 [KO:K10522]
120246242  CTSC; dipeptidyl peptidase 1 isoform X1 [KO:K01275] [EC:3.4.14.1]
120246375  CASP3; caspase-3 isoform X1 [KO:K02187] [EC:3.4.22.56]
120246696  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
120246764  [KO:K04741] [EC:3.4.22.-]
120246996  [KO:K01353] [EC:3.4.21.79]
120246997  [KO:K01353] [EC:3.4.21.79]
120247050  [KO:K08738]
120247089  [KO:K02649]
120247509  HRK; activator of apoptosis harakiri [KO:K02512]
120247774  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
120248009  DDIT3; DNA damage-inducible transcript 3 protein [KO:K04452]
120248578  PARP4; protein mono-ADP-ribosyltransferase PARP4 [KO:K10798] [EC:2.4.2.-]
120248609  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
120249214  CTSH; pro-cathepsin H [KO:K01366] [EC:3.4.22.16]
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
Reference
PMID:36652128
  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
Apoptosis 28:313-325 (2023)
DOI:10.1007/s10495-022-01802-4
Related
pathway
hhv04010  MAPK signaling pathway
hhv04020  Calcium signaling pathway
hhv04064  NF-kappa B signaling pathway
hhv04115  p53 signaling pathway
hhv04141  Protein processing in endoplasmic reticulum
hhv04151  PI3K-Akt signaling pathway
hhv04650  Natural killer cell mediated cytotoxicity
hhv04668  TNF signaling pathway
KO pathway
ko04210   

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