KEGG   PATHWAY: rno04210
Entry
rno04210                    Pathway                                
Name
Apoptosis - Rattus norvegicus (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
rno04210  Apoptosis
rno04210

Other DBs
GO: 0006915
Organism
Rattus norvegicus (rat) [GN:rno]
Gene
246775  Tnfsf10; tumor necrosis factor ligand superfamily member 10 [KO:K04721]
25385  Faslg; tumor necrosis factor ligand superfamily member 6 [KO:K04389]
246097  Fas; tumor necrosis factor receptor superfamily member 6 precursor [KO:K04390]
266610  Fadd; FAS-associated death domain protein [KO:K02373]
24835  Tnf; tumor necrosis factor [KO:K03156]
25625  Tnfrsf1a; tumor necrosis factor receptor superfamily member 1A precursor [KO:K03158]
246756  Tradd; tumor necrosis factor receptor type 1-associated DEATH domain protein [KO:K03171]
117279  Cflar; CASP8 and FADD-like apoptosis regulator isoform 1 [KO:K04724]
64044  Casp8; caspase-8 [KO:K04398] [EC:3.4.22.61]
83584  Casp6; caspase-6 [KO:K04396] [EC:3.4.22.59]
25402  Casp3; caspase-3 [KO:K02187] [EC:3.4.22.56]
64026  Casp7; caspase-7 [KO:K04397] [EC:3.4.22.60]
64625  Bid; BH3-interacting domain death agonist [KO:K04726]
24887  Bax; apoptosis regulator BAX [KO:K02159]
367149  Bax-ps1; apoptosis regulator BAX-like [KO:K02159]
681314  apoptosis regulator BAX-like [KO:K02159]
116502  Bak1; bcl-2 homologous antagonist/killer [KO:K14021]
288753  Diablo; diablo IAP-binding mitochondrial protein [KO:K10522]
100360940  Diablol1; diablo IAP-binding mitochondrial protein-like [KO:K10522]
287606  Septin4; septin-4 isoform 1 [KO:K16943]
297376  Htra2; serine protease HTRA2, mitochondrial [KO:K08669] [EC:3.4.21.108]
25309  Cycs; cytochrome c, somatic [KO:K08738]
25310  Cyct; cytochrome c, testis-specific [KO:K08738]
120099910  cytochrome c, somatic-like [KO:K08738]
690675  Cycsl2; cytochrome c, somatic-like [KO:K08738]
679794  Cycsl1; cytochrome c, somatic-like [KO:K08738]
290019  Cycsl3; cytochrome c, somatic-like [KO:K08738]
78963  Apaf1; apoptotic protease-activating factor 1 [KO:K02084]
58918  Casp9; caspase-9 [KO:K04399] [EC:3.4.22.62]
50669  Prf1; perforin-1 precursor [KO:K07818]
171528  Gzmb; granzyme B precursor [KO:K01353] [EC:3.4.21.79]
64158  Tuba1a; tubulin alpha-1A chain [KO:K07374]
291287  Tubal3; tubulin alpha chain-like 3 [KO:K07374]
300218  Tuba1c; tubulin alpha-1C chain [KO:K07374]
316531  Tuba4a; tubulin alpha-4A chain [KO:K07374]
500319  Tuba3a; tubulin alpha-3 chain [KO:K07374]
500363  Tuba3b; tubulin alpha-3 chain [KO:K07374]
500377  Tuba8; tubulin alpha-8 chain [KO:K07374]
500929  Tuba1b; tubulin alpha-1B chain [KO:K07374]
60430  Mcl1; induced myeloid leukemia cell differentiation protein Mcl-1 homolog [KO:K02539]
100361457  Actg1l1; actin, gamma 1 propeptide-like [KO:K05692]
81822  Actb; actin, cytoplasmic 1 [KO:K05692]
287876  Actg1; actin, cytoplasmic 2 [KO:K05692]
120098222  POTE ankyrin domain family member F [KO:K05692]
64159  Sptan1; spectrin alpha chain, non-erythrocytic 1 [KO:K06114]
60374  Lmna; prelamin-A/C [KO:K12641]
116685  Lmnb1; lamin-B1 [KO:K07611]
299625  Lmnb2; lamin-B2 [KO:K07611]
25591  Parp1; poly [ADP-ribose] polymerase 1 [KO:K24070] [EC:2.4.2.30]
290027  Parp2; poly [ADP-ribose] polymerase 2 [KO:K10798] [EC:2.4.2.30]
300985  Parp3; protein mono-ADP-ribosyltransferase PARP3 [KO:K10798] [EC:2.4.2.30]
361046  Parp4; poly [ADP-ribose] polymerase 4 [KO:K10798] [EC:2.4.2.30]
84359  Dffb; DNA fragmentation factor subunit beta [KO:K02311] [EC:3.-.-.-]
362100  Endog; endonuclease G, mitochondrial precursor [KO:K01173]
83533  Aifm1; apoptosis-inducing factor 1, mitochondrial precursor [KO:K04727] [EC:1.-.-.-]
498013  Ern1; serine/threonine-protein kinase/endoribonuclease IRE1 [KO:K08852] [EC:2.7.11.1 3.1.26.-]
311786  Traf2; TNF receptor-associated factor 2 [KO:K03173] [EC:2.3.2.27]
25262  Itpr1; inositol 1,4,5-trisphosphate receptor type 1 isoform 3 [KO:K04958]
81678  Itpr2; inositol 1,4,5-trisphosphate receptor type 2 [KO:K04959]
25679  Itpr3; inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960]
29153  Capn1; calpain-1 catalytic subunit [KO:K01367] [EC:3.4.22.52]
29154  Capn2; calpain-2 catalytic subunit [KO:K03853] [EC:3.4.22.53]
156117  Casp12; caspase-12 [KO:K04741] [EC:3.4.22.-]
29702  Eif2ak3; eukaryotic translation initiation factor 2-alpha kinase 3 precursor [KO:K08860] [EC:2.7.11.1]
54318  Eif2s1; eukaryotic translation initiation factor 2 subunit 1 [KO:K03237]
79255  Atf4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
29467  Ddit3; DNA damage-inducible transcript 3 protein [KO:K04452]
64529  Ctsb; cathepsin B preproprotein [KO:K01363] [EC:3.4.22.1]
25423  Ctsc; dipeptidyl peptidase 1 precursor [KO:K01275] [EC:3.4.14.1]
171293  Ctsd; cathepsin D precursor [KO:K01379] [EC:3.4.23.5]
361704  Ctsf; cathepsin F precursor [KO:K01373] [EC:3.4.22.41]
25425  Ctsh; pro-cathepsin H precursor [KO:K01366] [EC:3.4.22.16]
29175  Ctsk; cathepsin K precursor [KO:K01371] [EC:3.4.22.38]
25697  Ctsl; procathepsin L preproprotein [KO:K01365] [EC:3.4.22.15]
684529  Ctso; cathepsin O precursor [KO:K01374] [EC:3.4.22.42]
50654  Ctss; cathepsin S preproprotein [KO:K01368] [EC:3.4.22.27]
293676  Ctsw; cathepsin W precursor [KO:K08569] [EC:3.4.22.-]
252929  Ctsz; cathepsin Z precursor [KO:K08568] [EC:3.4.18.1]
60371  Birc2; baculoviral IAP repeat-containing protein 2 [KO:K16060]
78971  Birc3; baculoviral IAP repeat-containing protein 3 [KO:K16060]
63879  Xiap; E3 ubiquitin-protein ligase XIAP [KO:K04725] [EC:2.3.2.27]
64041  Birc5; baculoviral IAP repeat-containing protein 5 [KO:K08731]
64547  Bcl2l11; bcl-2-like protein 11 [KO:K16341]
24888  Bcl2l1; bcl-2-like protein 1 isoform 2 [KO:K04570]
24224  Bcl2; apoptosis regulator Bcl-2 [KO:K02161]
140926  Daxx; death domain-associated protein 6 [KO:K02308]
306886  Ripk1; receptor-interacting serine/threonine-protein kinase 1 [KO:K02861] [EC:2.7.11.1]
192126  Dab2ip; disabled homolog 2-interacting protein [KO:K19901]
365057  Map3k5; mitogen-activated protein kinase kinase kinase 5 [KO:K04426] [EC:2.7.11.25]
25272  Mapk10; mitogen-activated protein kinase 10 isoform 2 [KO:K04440] [EC:2.7.11.24]
50658  Mapk9; mitogen-activated protein kinase 9 isoform 2 [KO:K04440] [EC:2.7.11.24]
116554  Mapk8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
64639  Bad; bcl2-associated agonist of cell death [KO:K02158]
24516  Jun; transcription factor Jun [KO:K04448]
314322  Fos; protein c-Fos [KO:K04379]
24842  Tp53; cellular tumor antigen p53 [KO:K04451]
117271  Hrk; activator of apoptosis harakiri [KO:K02512]
360640  Map3k14; mitogen-activated protein kinase kinase kinase 14 [KO:K04466] [EC:2.7.11.25]
309361  Chuk; inhibitor of nuclear factor kappa-B kinase subunit alpha [KO:K04467] [EC:2.7.11.10]
84351  Ikbkb; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
309295  Ikbkg; NF-kappa-B essential modulator [KO:K07210]
25493  Nfkbia; NF-kappa-B inhibitor alpha [KO:K04734]
81736  Nfkb1; nuclear factor NF-kappa-B p105 subunit isoform 2 [KO:K02580]
309165  Rela; transcription factor p65 [KO:K04735]
498331  Ptpn13; tyrosine-protein phosphatase non-receptor type 13 [KO:K02374]
25112  Gadd45a; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
291005  Gadd45g; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
299626  Gadd45b; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
687813  Traf1; TNF receptor-associated factor 1 [KO:K03172]
170929  Bcl2a1; bcl-2-related protein A1 [KO:K02162]
300711  Atm; serine-protein kinase ATM [KO:K04728] [EC:2.7.11.1]
293625  Pidd1; p53-induced death domain-containing protein 1 [KO:K10130]
317673  Bbc3; bcl-2-binding component 3 [KO:K10132]
492821  Pmaip1; phorbol-12-myristate-13-acetate-induced protein 1 [KO:K10131]
64314  Casp2; caspase-2 [KO:K02186] [EC:3.4.22.55]
310738  Ngf; beta-nerve growth factor precursor [KO:K02582]
59109  Ntrk1; high affinity nerve growth factor receptor precursor [KO:K03176] [EC:2.7.10.1]
24495  Il3; interleukin-3 precursor [KO:K04736]
246144  Il3ra; interleukin-3 receptor subunit alpha precursor [KO:K04737]
171081  Csf2rb; cytokine receptor common subunit beta precursor [KO:K04738]
85243  Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
170911  Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
366508  Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
134484121  LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform-like [KO:K00922] [EC:2.7.1.153]
25513  Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
60664  Pik3r3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
29741  Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
81745  Pdpk1; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
24185  Akt1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
25233  Akt2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
29414  Akt3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
293621  Hras; GTPase HRas [KO:K02833]
367858  Hrasl1; HRas proto-oncogene, GTPase like 1 [KO:K02833]
24525  Kras; GTPase KRas [KO:K07827]
24605  Nras; GTPase NRas [KO:K07828]
24703  Raf1; RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:2.7.11.1]
170851  Map2k1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
58960  Map2k2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
116590  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
50689  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
rno04010  MAPK signaling pathway
rno04020  Calcium signaling pathway
rno04064  NF-kappa B signaling pathway
rno04115  p53 signaling pathway
rno04141  Protein processing in endoplasmic reticulum
rno04151  PI3K-Akt signaling pathway
rno04650  Natural killer cell mediated cytotoxicity
rno04668  TNF signaling pathway
KO pathway
ko04210   
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