KEGG   PATHWAY: uah04210
Entry
uah04210                    Pathway                                
Name
Apoptosis - Ursus arctos (brown bear)
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
uah04210  Apoptosis
uah04210

Other DBs
GO: 0006915
Organism
Ursus arctos (brown bear) [GN:uah]
Gene
113240790  [KO:K04737]
113240885  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
113241127  TUBAL3; tubulin alpha chain-like 3 [KO:K07374]
113241758  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
113242278  BCL2L11; bcl-2-like protein 11 isoform X3 [KO:K16341]
113242534  [KO:K07374]
113242766  LMNB2; lamin-B2 [KO:K07611]
113242768  GADD45B; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
113242804  EIF2AK3; eukaryotic translation initiation factor 2-alpha kinase 3 [KO:K08860] [EC:2.7.11.1]
113242822  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
113243106  MAPK8; mitogen-activated protein kinase 8 isoform X2 [KO:K04440] [EC:2.7.11.24]
113243380  BBC3; bcl-2-binding component 3 [KO:K10132]
113243572  AKT2; RAC-beta serine/threonine-protein kinase isoform X2 [KO:K04456] [EC:2.7.11.1]
113243611  HTRA2; serine protease HTRA2, mitochondrial isoform X1 [KO:K08669] [EC:3.4.21.108]
113243711  TNF; tumor necrosis factor [KO:K03156]
113243804  DAXX; death domain-associated protein 6 isoform X1 [KO:K02308]
113243812  BAK1; bcl-2 homologous antagonist/killer [KO:K14021]
113243814  ITPR3; inositol 1,4,5-trisphosphate receptor type 3 isoform X1 [KO:K04960]
113243953  CTSD; cathepsin D [KO:K01379] [EC:3.4.23.5]
113243978  FADD; FAS-associated death domain protein [KO:K02373]
113244059  CTSF; cathepsin F isoform X2 [KO:K01373] [EC:3.4.22.41]
113244090  CTSW; cathepsin W [KO:K08569] [EC:3.4.22.-]
113244102  RELA; LOW QUALITY PROTEIN: transcription factor p65 [KO:K04735]
113244126  CAPN1; calpain-1 catalytic subunit [KO:K01367] [EC:3.4.22.52]
113244178  BAD; bcl2-associated agonist of cell death [KO:K02158]
113244387  NGF; beta-nerve growth factor [KO:K02582]
113244394  NRAS; GTPase NRas isoform X2 [KO:K07828]
113244519  ACTG1; actin, cytoplasmic 2 isoform X2 [KO:K05692]
113244569  BIRC5; baculoviral IAP repeat-containing protein 5 isoform X2 [KO:K08731]
113245211  NTRK1; high affinity nerve growth factor receptor isoform X2 [KO:K03176] [EC:2.7.10.1]
113245246  LMNA; lamin [KO:K12641]
113245405  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X2 [KO:K06276] [EC:2.7.11.1]
113245546  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X2 [KO:K07209] [EC:2.7.11.10]
113245958  [KO:K07374]
113245994  [KO:K01353] [EC:3.4.21.79]
113246198  MCL1; induced myeloid leukemia cell differentiation protein Mcl-1 [KO:K02539]
113246210  CTSS; cathepsin S isoform X2 [KO:K01368] [EC:3.4.22.27]
113246211  CTSK; cathepsin K [KO:K01371] [EC:3.4.22.38]
113247020  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
113247033  [KO:K07374]
113248303  EIF2S1; eukaryotic translation initiation factor 2 subunit 1 [KO:K03237]
113248645  TRAF2; TNF receptor-associated factor 2 isoform X3 [KO:K03173] [EC:2.3.2.27]
113248814  PIDD1; p53-induced death domain-containing protein 1 [KO:K10130]
113248950  PARP2; poly [ADP-ribose] polymerase 2 [KO:K28005]
113250431  [KO:K07374]
113250592  CASP8; caspase-8 [KO:K04398] [EC:3.4.22.61]
113250594  CASP10; caspase-10 isoform X1 [KO:K04400] [EC:3.4.22.63]
113250596  CFLAR; CASP8 and FADD-like apoptosis regulator isoform X1 [KO:K04724]
113251159  PARP4; protein mono-ADP-ribosyltransferase PARP4 [KO:K10798] [EC:2.4.2.-]
113251823  CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha isoform X1 [KO:K04467] [EC:2.7.11.10]
113251949  CASP7; caspase-7 [KO:K04397] [EC:3.4.22.60]
113252355  TRADD; tumor necrosis factor receptor type 1-associated DEATH domain protein isoform X1 [KO:K03171]
113252357  NOL3; nucleolar protein 3 [KO:K28177]
113253468  PMAIP1; phorbol-12-myristate-13-acetate-induced protein 1 [KO:K10131]
113253490  BCL2; apoptosis regulator Bcl-2 isoform X3 [KO:K02161]
113253989  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
113254548  GADD45A; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
113254611  JUN; transcription factor Jun [KO:K04448]
113254730  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X2 [KO:K02649]
113254799  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
113255024  TNFSF10; tumor necrosis factor ligand superfamily member 10 [KO:K04721]
113255266  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
113255556  CASP6; caspase-6 isoform X1 [KO:K04396] [EC:3.4.22.59]
113255784  CTSO; cathepsin O [KO:K01374] [EC:3.4.22.42]
113255980  CSF2RB; cytokine receptor common subunit beta [KO:K04738]
113256111  APAF1; apoptotic protease-activating factor 1 isoform X1 [KO:K02084]
113256705  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
113256932  PARP3; protein mono-ADP-ribosyltransferase PARP3 isoform X1 [KO:K10798] [EC:2.4.2.-]
113257114  ITPR1; inositol 1,4,5-trisphosphate receptor type 1 [KO:K04958]
113257190  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X2 [KO:K04366] [EC:2.7.11.1]
113257653  [KO:K07374]
113257654  [KO:K07374]
113257657  [KO:K07374]
113257782  ITPR2; inositol 1,4,5-trisphosphate receptor type 2 isoform X1 [KO:K04959]
113257792  KRAS; GTPase KRas isoform X1 [KO:K07827]
113257988  TNFRSF1A; tumor necrosis factor receptor superfamily member 1A isoform X1 [KO:K03158]
113258065  BID; BH3-interacting domain death agonist [KO:K04726]
113258067  TUBA8; tubulin alpha-8 chain isoform X1 [KO:K07374]
113258461  BCL2L1; bcl-2-like protein 1 [KO:K04570]
113258770  CTSZ; cathepsin Z [KO:K08568] [EC:3.4.18.1]
113258968  FAS; tumor necrosis factor receptor superfamily member 6 isoform X1 [KO:K04390]
113259145  PRF1; perforin-1 [KO:K07818]
113259481  MAP3K5; mitogen-activated protein kinase kinase kinase 5 [KO:K04426] [EC:2.7.11.25]
113259719  [KO:K04741] [EC:3.4.22.-]
113260096  ATM; serine-protein kinase ATM isoform X1 [KO:K04728] [EC:2.7.11.1]
113260143  BIRC2; baculoviral IAP repeat-containing protein 2 [KO:K16060]
113260144  [KO:K16060]
113261548  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
113261670  LMNB1; lamin-B1 [KO:K07611]
113261698  [KO:K08738]
113261704  [KO:K04736]
113262259  CASP3; caspase-3 isoform X3 [KO:K02187] [EC:3.4.22.56]
113262825  FASLG; tumor necrosis factor ligand superfamily member 6 [KO:K04389]
113262899  CAPN2; calpain-2 catalytic subunit isoform X2 [KO:K03853] [EC:3.4.22.53]
113262926  PARP1; poly [ADP-ribose] polymerase 1 [KO:K24070]
113262966  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
113263101  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X3 [KO:K02580]
113263179  PTPN13; tyrosine-protein phosphatase non-receptor type 13 isoform X1 [KO:K02374]
113263180  MAPK10; mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
113263367  [KO:K08738]
113263784  BCL2A1; bcl-2-related protein A1 [KO:K02162]
113263792  CTSH; pro-cathepsin H [KO:K01366] [EC:3.4.22.16]
113264397  RIPK1; receptor-interacting serine/threonine-protein kinase 1 isoform X1 [KO:K02861] [EC:2.7.11.1]
113265323  MAP3K14; mitogen-activated protein kinase kinase kinase 14 isoform X2 [KO:K04466] [EC:2.7.11.25]
113265500  CASP2; caspase-2 isoform X1 [KO:K02186] [EC:3.4.22.55]
113265667  ERN1; serine/threonine-protein kinase/endoribonuclease IRE1 isoform X1 [KO:K08852] [EC:2.7.11.1 3.1.26.-]
113266131  NFKBIA; NF-kappa-B inhibitor alpha [KO:K04734]
113266352  TRAF1; TNF receptor-associated factor 1 [KO:K03172]
113266367  DAB2IP; disabled homolog 2-interacting protein isoform X9 [KO:K19901]
113266474  SPTAN1; spectrin alpha chain, non-erythrocytic 1 isoform X5 [KO:K06114]
113266486  ENDOG; endonuclease G, mitochondrial [KO:K01173]
113266927  DIABLO; diablo IAP-binding mitochondrial protein isoform X1 [KO:K10522]
113267009  HRK; activator of apoptosis harakiri [KO:K02512]
113267192  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
113267646  MAPK3; LOW QUALITY PROTEIN: mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
113267965  ACTB; LOW QUALITY PROTEIN: actin, cytoplasmic 1 [KO:K05692]
113268878  SEPTIN4; septin-4 isoform X2 [KO:K16943]
113269415  CTSC; dipeptidyl peptidase 1 isoform X1 [KO:K01275] [EC:3.4.14.1]
113269768  [KO:K01365] [EC:3.4.22.15]
113269787  [KO:K01365] [EC:3.4.22.15]
113269880  [KO:K01365] [EC:3.4.22.15]
113269920  CTSB; cathepsin B isoform X1 [KO:K01363] [EC:3.4.22.1]
113270128  GADD45G; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
113270317  FOS; protein c-Fos [KO:K04379]
113270476  CASP9; caspase-9 [KO:K04399] [EC:3.4.22.62]
113270520  DFFA; DNA fragmentation factor subunit alpha [KO:K02310]
113270537  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
113270585  DFFB; DNA fragmentation factor subunit beta isoform X1 [KO:K02311] [EC:3.-.-.-]
113270927  XIAP; E3 ubiquitin-protein ligase XIAP isoform X2 [KO:K04725] [EC:2.3.2.27]
113270952  AIFM1; apoptosis-inducing factor 1, mitochondrial isoform X1 [KO:K04727] [EC:1.-.-.-]
113271152  TP53; cellular tumor antigen p53 isoform X1 [KO:K04451]
125282300  HRAS; GTPase HRas isoform X1 [KO:K02833]
130541828  DDIT3; DNA damage-inducible transcript 3 protein [KO:K04452]
130544379  [KO:K04737]
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
uah04010  MAPK signaling pathway
uah04020  Calcium signaling pathway
uah04064  NF-kappa B signaling pathway
uah04115  p53 signaling pathway
uah04141  Protein processing in endoplasmic reticulum
uah04151  PI3K-Akt signaling pathway
uah04650  Natural killer cell mediated cytotoxicity
uah04668  TNF signaling pathway
KO pathway
ko04210   

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