KEGG   PATHWAY: ngi04210
Entry
ngi04210                    Pathway                                
Name
Apoptosis - Nannospalax galili (Upper Galilee mountains blind mole rat)
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
ngi04210  Apoptosis
ngi04210

Other DBs
GO: 0006915
Organism
Nannospalax galili (Upper Galilee mountains blind mole rat) [GN:ngi]
Gene
103739879  Tnfsf10; tumor necrosis factor superfamily member 10 [KO:K04721]
108491686  tumor necrosis factor receptor superfamily member 10B-like [KO:K04722]
103740694  Faslg; Fas ligand [KO:K04389]
103738053  Fas; Fas cell surface death receptor [KO:K04390]
103751502  Fadd; Fas associated via death domain [KO:K02373]
103724452  Tnf; tumor necrosis factor [KO:K03156]
103727530  Tnfrsf1a; TNF receptor superfamily member 1A [KO:K03158]
103738912  Tradd; TNFRSF1A associated via death domain [KO:K03171]
103738673  Cflar; CASP8 and FADD like apoptosis regulator [KO:K04724]
103738672  Casp8; caspase 8 [KO:K04398] [EC:3.4.22.61]
103742454  Casp6; caspase 6 [KO:K04396] [EC:3.4.22.59]
103744668  caspase-3-like [KO:K02187] [EC:3.4.22.56]
103750475  Casp3; caspase 3 [KO:K02187] [EC:3.4.22.56]
103731752  Casp7; caspase 7 [KO:K04397] [EC:3.4.22.60]
103745898  Bid; BH3 interacting domain death agonist [KO:K04726]
103743639  Bax; BCL2 associated X, apoptosis regulator [KO:K02159]
103739733  Bak1; BCL2 antagonist/killer 1 [KO:K14021]
103739058  Diablo; diablo IAP-binding mitochondrial protein [KO:K10522]
103741778  Sept4; septin 4 [KO:K16943]
103726986  Htra2; HtrA serine peptidase 2 [KO:K08669] [EC:3.4.21.108]
103740800  cytochrome c, somatic [KO:K08738]
103751785  cytochrome c, testis-specific [KO:K08738]
103733246  Apaf1; apoptotic peptidase activating factor 1 [KO:K02084]
103725336  Casp9; caspase 9 [KO:K04399] [EC:3.4.22.62]
103736978  Prf1; perforin 1 [KO:K07818]
103739490  granzyme B-like [KO:K01353] [EC:3.4.21.79]
103744106  granzyme B-like [KO:K01353] [EC:3.4.21.79]
103751171  granzyme B-like [KO:K01353] [EC:3.4.21.79]
103732523  granzyme B-like [KO:K01353] [EC:3.4.21.79]
103733937  tubulin alpha-1B chain [KO:K07374]
108489984  tubulin alpha-1B chain-like [KO:K07374]
103745382  tubulin alpha-3 chain-like [KO:K07374]
108491798  tubulin alpha-3 chain [KO:K07374]
103745161  Tuba8; tubulin alpha 8 [KO:K07374]
103725897  Tubal3; tubulin alpha like 3 [KO:K07374]
103727749  Tuba4a; tubulin alpha 4a [KO:K07374]
103729108  Mcl1; BCL2 family apoptosis regulator [KO:K02539]
103730387  Actg1; actin gamma 1 [KO:K05692]
103748659  Actb; actin beta [KO:K05692]
103742859  Sptan1; spectrin alpha, non-erythrocytic 1 [KO:K06114]
103750617  Lmna; lamin A/C [KO:K12641]
103737287  Lmnb2; lamin B2 [KO:K07611]
103740405  Lmnb1; lamin B1 [KO:K07611]
103725101  Parp1; poly(ADP-ribose) polymerase 1 [KO:K24070] [EC:2.4.2.30]
103733671  Parp2; poly(ADP-ribose) polymerase 2 [KO:K10798] [EC:2.4.2.30]
103747361  Parp3; poly(ADP-ribose) polymerase family member 3 [KO:K10798] [EC:2.4.2.30]
103726735  Parp4; poly(ADP-ribose) polymerase family member 4 [KO:K10798] [EC:2.4.2.30]
103732987  Dffa; DNA fragmentation factor subunit alpha [KO:K02310]
103749808  Dffb; DNA fragmentation factor subunit beta [KO:K02311] [EC:3.-.-.-]
103742866  Endog; endonuclease G [KO:K01173]
103728755  Aifm1; apoptosis inducing factor mitochondria associated 1 [KO:K04727] [EC:1.-.-.-]
103744745  Ern1; endoplasmic reticulum to nucleus signaling 1 [KO:K08852] [EC:2.7.11.1 3.1.26.-]
103741188  Traf2; TNF receptor associated factor 2 [KO:K03173] [EC:2.3.2.27]
103751203  Itpr1; inositol 1,4,5-trisphosphate receptor type 1 [KO:K04958]
103739696  Itpr3; inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960]
103724977  Capn1; calpain 1 [KO:K01367] [EC:3.4.22.52]
103726266  Capn2; calpain 2 [KO:K03853] [EC:3.4.22.53]
103740131  Eif2ak3; eukaryotic translation initiation factor 2 alpha kinase 3 [KO:K08860] [EC:2.7.11.1]
103749287  Eif2s1; eukaryotic translation initiation factor 2 subunit alpha [KO:K03237]
103748563  Atf4; activating transcription factor 4 [KO:K04374]
103742913  Ddit3; DNA damage inducible transcript 3 [KO:K04452]
103729973  Ctsb; cathepsin B [KO:K01363] [EC:3.4.22.1]
103742959  Ctsc; cathepsin C [KO:K01275] [EC:3.4.14.1]
103738995  Ctsd; cathepsin D [KO:K01379] [EC:3.4.23.5]
103725560  Ctsf; cathepsin F [KO:K01373] [EC:3.4.22.41]
103726016  Ctsh; cathepsin H [KO:K01366] [EC:3.4.22.16]
103729102  Ctsk; cathepsin K [KO:K01371] [EC:3.4.22.38]
103751610  Ctsv; cathepsin V [KO:K01365] [EC:3.4.22.15]
103734205  cathepsin M-like [KO:K01365] [EC:3.4.22.15]
103744689  cathepsin M-like [KO:K01365] [EC:3.4.22.15]
103751035  Ctso; cathepsin O [KO:K01374] [EC:3.4.22.42]
103729103  Ctss; cathepsin S [KO:K01368] [EC:3.4.22.27]
103725005  Ctsw; cathepsin W [KO:K08569] [EC:3.4.22.-]
103741460  Ctsz; cathepsin Z [KO:K08568] [EC:3.4.18.1]
103731538  Birc2; baculoviral IAP repeat-containing protein 2 [KO:K16060]
103746493  Birc3; baculoviral IAP repeat containing 3 [KO:K16060]
103734850  Xiap; X-linked inhibitor of apoptosis [KO:K04725] [EC:2.3.2.27]
103747285  Birc5; baculoviral IAP repeat containing 5 [KO:K08731]
103750963  Bcl2l11; BCL2 like 11 [KO:K16341]
103731080  Bcl2l1; BCL2 like 1 [KO:K04570]
103740099  Bcl2; BCL2, apoptosis regulator [KO:K02161]
103739701  Daxx; death domain associated protein [KO:K02308]
103732937  Ripk1; receptor interacting serine/threonine kinase 1 [KO:K02861] [EC:2.7.11.1]
103734486  Dab2ip; DAB2 interacting protein [KO:K19901]
103724902  Map3k5; mitogen-activated protein kinase kinase kinase 5 [KO:K04426] [EC:2.7.11.25]
103735023  Mapk8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
103748972  Mapk10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
103749366  Mapk9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
103738795  Bad; BCL2 associated agonist of cell death [KO:K02158]
103737138  Jun; Jun proto-oncogene, AP-1 transcription factor subunit [KO:K04448]
103747342  Fos; Fos proto-oncogene, AP-1 transcription factor subunit [KO:K04379]
103752115  Tp53; tumor protein p53 [KO:K04451]
103738320  Map3k14; mitogen-activated protein kinase kinase kinase 14 [KO:K04466] [EC:2.7.11.25]
103743976  Chuk; conserved helix-loop-helix ubiquitous kinase [KO:K04467] [EC:2.7.11.10]
103726621  Ikbkb; inhibitor of nuclear factor kappa B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
103731232  Ikbkg; inhibitor of nuclear factor kappa B kinase subunit gamma [KO:K07210]
103734016  Nfkbia; NFKB inhibitor alpha [KO:K04734]
103728077  Nfkb1; nuclear factor kappa B subunit 1 [KO:K02580]
103724994  Rela; RELA proto-oncogene, NF-kB subunit [KO:K04735]
103748971  Ptpn13; protein tyrosine phosphatase, non-receptor type 13 [KO:K02374]
103737285  Gadd45b; growth arrest and DNA damage inducible beta [KO:K04402]
103743354  Gadd45a; growth arrest and DNA damage inducible alpha [KO:K04402]
103751225  Gadd45g; growth arrest and DNA damage inducible gamma [KO:K04402]
103734496  Traf1; TNF receptor associated factor 1 [KO:K03172]
103726049  Bcl2a1; bcl-2-related protein A1 [KO:K02162]
103729441  bcl-2-related protein A1-like [KO:K02162]
103731335  Atm; ATM serine/threonine kinase [KO:K04728] [EC:2.7.11.1]
103751091  Pidd1; p53-induced death domain protein 1 [KO:K10130]
103724866  Bbc3; BCL2 binding component 3 [KO:K10132]
103739615  Pmaip1; phorbol-12-myristate-13-acetate-induced protein 1 [KO:K10131]
103730398  Casp2; caspase 2 [KO:K02186] [EC:3.4.22.55]
103734944  Ngf; nerve growth factor [KO:K02582]
103750263  Ntrk1; neurotrophic receptor tyrosine kinase 1 [KO:K03176] [EC:2.7.10.1]
103750125  Il3ra; interleukin 3 receptor subunit alpha [KO:K04737]
103748646  cytokine receptor common subunit beta-like [KO:K04738]
103748645  interleukin-3 receptor class 2 subunit beta-like [KO:K04738]
103738596  Pik3ca; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
103733121  Pik3cd; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
103742946  Pik3cb; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
103738715  Pik3r1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
103726879  Pik3r2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
103730305  Pik3r3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
103743959  Pdpk1; 3-phosphoinositide dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
103746884  Akt3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1]
103750757  Akt2; AKT serine/threonine kinase 2 [KO:K04456] [EC:2.7.11.1]
103752536  Akt1; AKT serine/threonine kinase 1 [KO:K04456] [EC:2.7.11.1]
103751075  Hras; HRas proto-oncogene, GTPase [KO:K02833]
103736717  Kras; KRAS proto-oncogene, GTPase [KO:K07827]
103734938  Nras; neuroblastoma RAS viral oncogene homolog [KO:K07828]
103751450  Raf1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1]
103736801  Map2k1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
103737276  Map2k2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
103741442  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
103726390  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
ngi04010  MAPK signaling pathway
ngi04020  Calcium signaling pathway
ngi04064  NF-kappa B signaling pathway
ngi04115  p53 signaling pathway
ngi04141  Protein processing in endoplasmic reticulum
ngi04151  PI3K-Akt signaling pathway
ngi04650  Natural killer cell mediated cytotoxicity
ngi04668  TNF signaling pathway
KO pathway
ko04210   
LinkDB

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