KEGG   PATHWAY: mlx04210
Entry
mlx04210                    Pathway                                
Name
Apoptosis - Mirounga leonina (Southern elephant seal)
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
mlx04210  Apoptosis
mlx04210

Other DBs
GO: 0006915
Organism
Mirounga leonina (Southern elephant seal) [GN:mlx]
Gene
118006404  TNFSF10; tumor necrosis factor ligand superfamily member 10 [KO:K04721]
118014469  FASLG; LOW QUALITY PROTEIN: tumor necrosis factor ligand superfamily member 6 [KO:K04389]
118012958  FAS; tumor necrosis factor receptor superfamily member 6 [KO:K04390]
118016168  FADD; FAS-associated death domain protein [KO:K02373]
118027255  TNF; tumor necrosis factor [KO:K03156]
118025746  TNFRSF1A; tumor necrosis factor receptor superfamily member 1A isoform X1 [KO:K03158]
118023691  TRADD; tumor necrosis factor receptor type 1-associated DEATH domain protein isoform X1 [KO:K03171]
118012153  CFLAR; CASP8 and FADD-like apoptosis regulator isoform X1 [KO:K04724]
118012152  CASP8; caspase-8 isoform X1 [KO:K04398] [EC:3.4.22.61]
118012154  CASP10; caspase-10 [KO:K04400] [EC:3.4.22.63]
118027087  CASP6; caspase-6 isoform X1 [KO:K04396] [EC:3.4.22.59]
118010074  CASP3; caspase-3 isoform X1 [KO:K02187] [EC:3.4.22.56]
118026509  CASP7; caspase-7 isoform X1 [KO:K04397] [EC:3.4.22.60]
118025823  BID; BH3-interacting domain death agonist isoform X1 [KO:K04726]
117998245  BAX; apoptosis regulator BAX isoform X1 [KO:K02159]
118000738  BAK1; bcl-2 homologous antagonist/killer isoform X1 [KO:K14021]
118018428  DIABLO; diablo homolog, mitochondrial isoform X1 [KO:K10522]
118024702  SEPTIN4; septin-4 isoform X1 [KO:K16943]
118007942  HTRA2; LOW QUALITY PROTEIN: serine protease HTRA2, mitochondrial [KO:K08669] [EC:3.4.21.108]
118012283  cytochrome c, testis-specific [KO:K08738]
118019630  cytochrome c-like [KO:K08738]
118020883  cytochrome c [KO:K08738]
117998841  APAF1; apoptotic protease-activating factor 1 isoform X1 [KO:K02084]
118019979  CASP9; caspase-9 isoform X1 [KO:K04399] [EC:3.4.22.62]
118018380  perforin-1-like isoform X1 [KO:K07818]
118019135  perforin-1-like isoform X1 [KO:K07818]
118003297  granzyme B-like [KO:K01353] [EC:3.4.21.79]
118003491  LOW QUALITY PROTEIN: mast cell protease 1A-like [KO:K01353] [EC:3.4.21.79]
118008882  tubulin alpha-1B chain [KO:K07374]
118008883  tubulin alpha-1A chain [KO:K07374]
118008885  TUBA1C; tubulin alpha-1C chain [KO:K07374]
118025829  TUBA8; tubulin alpha-8 chain isoform X1 [KO:K07374]
118012024  tubulin alpha-4A chain [KO:K07374]
118014190  tubulin alpha-8 chain-like [KO:K07374]
117999803  tubulin alpha-3 chain-like [KO:K07374]
117999807  tubulin alpha-3 chain [KO:K07374]
118021622  TUBAL3; tubulin alpha chain-like 3 [KO:K07374]
118000307  MCL1; induced myeloid leukemia cell differentiation protein Mcl-1 [KO:K02539]
118024176  ACTG1; actin, cytoplasmic 2 [KO:K05692]
117999316  ACTB; actin, cytoplasmic 1 [KO:K05692]
118017624  spectrin alpha chain, non-erythrocytic 1 isoform X1 [KO:K06114]
118013902  LMNA; lamin [KO:K12641]
118016588  LMNB1; lamin-B1 [KO:K07611]
118004910  LMNB2; lamin-B2 isoform X1 [KO:K07611]
118013019  PARP1; poly [ADP-ribose] polymerase 1 [KO:K24070] [EC:2.4.2.30]
118009612  PARP4; protein mono-ADP-ribosyltransferase PARP4 [KO:K10798] [EC:2.4.2.30]
118003160  PARP2; poly [ADP-ribose] polymerase 2 [KO:K10798] [EC:2.4.2.30]
118005145  PARP3; LOW QUALITY PROTEIN: protein mono-ADP-ribosyltransferase PARP3 [KO:K10798] [EC:2.4.2.30]
118020017  DFFA; DNA fragmentation factor subunit alpha [KO:K02310]
118020076  DFFB; DNA fragmentation factor subunit beta isoform X1 [KO:K02311] [EC:3.-.-.-]
118017617  ENDOG; endonuclease G, mitochondrial [KO:K01173]
118012968  AIFM1; apoptosis-inducing factor 1, mitochondrial [KO:K04727] [EC:1.-.-.-]
118024372  ERN1; serine/threonine-protein kinase/endoribonuclease IRE1 isoform X1 [KO:K08852] [EC:2.7.11.1 3.1.26.-]
118017503  TRAF2; TNF receptor-associated factor 2 [KO:K03173] [EC:2.3.2.27]
118005236  ITPR1; inositol 1,4,5-trisphosphate receptor type 1 isoform X1 [KO:K04958]
118025560  ITPR2; inositol 1,4,5-trisphosphate receptor type 2 isoform X1 [KO:K04959]
118001326  ITPR3; inositol 1,4,5-trisphosphate receptor type 3 isoform X1 [KO:K04960]
118016038  CAPN1; calpain-1 catalytic subunit [KO:K01367] [EC:3.4.22.52]
118012992  CAPN2; calpain-2 catalytic subunit [KO:K03853] [EC:3.4.22.53]
118013166  caspase-12-like [KO:K04741] [EC:3.4.22.-]
118007879  EIF2AK3; eukaryotic translation initiation factor 2-alpha kinase 3 isoform X1 [KO:K08860] [EC:2.7.11.1]
118002128  EIF2S1; eukaryotic translation initiation factor 2 subunit 1 [KO:K03237]
117998657  ATF4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
118008672  DDIT3; DNA damage-inducible transcript 3 protein [KO:K04452]
118022144  CTSB; cathepsin B [KO:K01363] [EC:3.4.22.1]
118013461  CTSC; dipeptidyl peptidase 1 isoform X1 [KO:K01275] [EC:3.4.14.1]
118016198  CTSD; cathepsin D [KO:K01379] [EC:3.4.23.5]
118016101  CTSF; LOW QUALITY PROTEIN: cathepsin F [KO:K01373] [EC:3.4.22.41]
118023131  CTSH; pro-cathepsin H [KO:K01366] [EC:3.4.22.16]
118000314  CTSK; cathepsin K [KO:K01371] [EC:3.4.22.38]
118023332  LOW QUALITY PROTEIN: cathepsin L1-like [KO:K01365] [EC:3.4.22.15]
118023333  cathepsin L1-like [KO:K01365] [EC:3.4.22.15]
118023348  cathepsin L1 [KO:K01365] [EC:3.4.22.15]
118022211  CTSO; cathepsin O isoform X1 [KO:K01374] [EC:3.4.22.42]
118000310  CTSS; cathepsin S isoform X1 [KO:K01368] [EC:3.4.22.27]
118016071  CTSW; cathepsin W [KO:K08569] [EC:3.4.22.-]
118024013  CTSZ; cathepsin Z [KO:K08568] [EC:3.4.18.1]
118013143  BIRC3; baculoviral IAP repeat-containing protein 3 isoform X1 [KO:K16060]
118013146  BIRC2; baculoviral IAP repeat-containing protein 2 isoform X1 [KO:K16060]
118012582  XIAP; E3 ubiquitin-protein ligase XIAP isoform X1 [KO:K04725] [EC:2.3.2.27]
118024214  BIRC5; baculoviral IAP repeat-containing protein 5 [KO:K08731]
118007843  BCL2L11; bcl-2-like protein 11 isoform X1 [KO:K16341]
118011353  BCL2L1; bcl-2-like protein 1 [KO:K04570]
118004389  BCL2; apoptosis regulator Bcl-2 isoform X1 [KO:K02161]
118000578  DAXX; death domain-associated protein 6 isoform X1 [KO:K02308]
118027395  RIPK1; receptor-interacting serine/threonine-protein kinase 1 isoform X1 [KO:K02861] [EC:2.7.11.1]
118017736  DAB2IP; disabled homolog 2-interacting protein isoform X1 [KO:K19901]
118000829  MAP3K5; mitogen-activated protein kinase kinase kinase 5 [KO:K04426] [EC:2.7.11.25]
118022776  MAPK8; mitogen-activated protein kinase 8 isoform X1 [KO:K04440] [EC:2.7.11.24]
118010368  mitogen-activated protein kinase 10 isoform X1 [KO:K04440] [EC:2.7.11.24]
118026506  MAPK9; mitogen-activated protein kinase 9 isoform X1 [KO:K04440] [EC:2.7.11.24]
118016000  BAD; bcl2-associated agonist of cell death [KO:K02158]
118019356  JUN; transcription factor AP-1 [KO:K04448]
118002212  FOS; proto-oncogene c-Fos [KO:K04379]
118000034  TP53; cellular tumor antigen p53 [KO:K04451]
118018514  HRK; activator of apoptosis harakiri [KO:K02512]
118024997  MAP3K14; mitogen-activated protein kinase kinase kinase 14 isoform X1 [KO:K04466] [EC:2.7.11.25]
118024839  CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha isoform X1 [KO:K04467] [EC:2.7.11.10]
118009921  IKBKB; inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1 [KO:K07209] [EC:2.7.11.10]
118014480  IKBKG; NF-kappa-B essential modulator isoform X1 [KO:K07210]
118002835  NF-kappa-B inhibitor alpha [KO:K04734]
118002880  NF-kappa-B inhibitor alpha [KO:K04734]
118027047  NFKB1; nuclear factor NF-kappa-B p105 subunit isoform X1 [KO:K02580]
118016059  RELA; transcription factor p65 [KO:K04735]
118010366  PTPN13; tyrosine-protein phosphatase non-receptor type 13 isoform X1 [KO:K02374]
118026375  GADD45G; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
118019290  GADD45A; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
118006001  GADD45B; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
118017749  TRAF1; TNF receptor-associated factor 1 [KO:K03172]
118023129  BCL2A1; bcl-2-related protein A1 [KO:K02162]
118013186  ATM; serine-protein kinase ATM isoform X1 [KO:K04728] [EC:2.7.11.1]
118016213  PIDD1; LOW QUALITY PROTEIN: p53-induced death domain-containing protein 1 [KO:K10130]
117998194  BBC3; bcl-2-binding component 3 [KO:K10132]
118004507  PMAIP1; phorbol-12-myristate-13-acetate-induced protein 1 [KO:K10131]
118021190  CASP2; caspase-2 isoform X1 [KO:K02186] [EC:3.4.22.55]
118000488  NGF; beta-nerve growth factor [KO:K02582]
118013921  NTRK1; high affinity nerve growth factor receptor [KO:K03176] [EC:2.7.10.1]
118017097  interleukin-3-like [KO:K04736]
118026667  IL3RA; interleukin-3 receptor subunit alpha isoform X1 [KO:K04737]
117998726  CSF2RB; cytokine receptor common subunit beta isoform X1 [KO:K04738]
118004424  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
118020028  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
118006556  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
118016863  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
118019468  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
118006042  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
118021736  PDPK1; 3-phosphoinositide-dependent protein kinase 1 isoform X1 [KO:K06276] [EC:2.7.11.1]
118022658  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
118002024  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
118014553  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
118016228  HRAS; GTPase HRas isoform X1 [KO:K02833]
118025572  KRAS; GTPase KRas isoform X1 [KO:K07827]
118000495  NRAS; GTPase NRas [KO:K07828]
118005431  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
118003336  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
118004882  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
117999637  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
117999826  MAPK1; mitogen-activated protein kinase 1 isoform X1 [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
mlx04010  MAPK signaling pathway
mlx04020  Calcium signaling pathway
mlx04064  NF-kappa B signaling pathway
mlx04115  p53 signaling pathway
mlx04141  Protein processing in endoplasmic reticulum
mlx04151  PI3K-Akt signaling pathway
mlx04650  Natural killer cell mediated cytotoxicity
mlx04668  TNF signaling pathway
KO pathway
ko04210   
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