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
100360940  Diablol1; diablo IAP-binding mitochondrial protein-like [KO:K10522]
100361457  Actg1l1; actin, gamma 1 propeptide-like [KO:K05692]
114214  Dffa; DNA fragmentation factor subunit alpha isoform 1 [KO:K02310]
116502  Bak1; bcl-2 homologous antagonist/killer [KO:K14021]
116554  Mapk8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
116590  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
116685  Lmnb1; lamin-B1 [KO:K07611]
117271  Hrk; activator of apoptosis harakiri [KO:K02512]
117279  Cflar; CASP8 and FADD-like apoptosis regulator isoform 1 [KO:K04724]
120098222  [KO:K05692]
120099910  [KO:K08738]
134484121  [KO:K00922] [EC:2.7.1.153]
140926  Daxx; death domain-associated protein 6 [KO:K02308]
156117  Casp12; caspase-12 [KO:K04741] [EC:3.4.22.-]
170851  Map2k1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
170911  Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
170929  Bcl2a1; bcl-2-related protein A1 [KO:K02162]
171081  Csf2rb; cytokine receptor common subunit beta precursor [KO:K04738]
171293  Ctsd; cathepsin D precursor [KO:K01379] [EC:3.4.23.5]
171528  Gzmb; granzyme B precursor [KO:K01353] [EC:3.4.21.79]
192126  Dab2ip; disabled homolog 2-interacting protein [KO:K19901]
24185  Akt1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
24224  Bcl2; apoptosis regulator Bcl-2 [KO:K02161]
24495  Il3; interleukin-3 precursor [KO:K04736]
24516  Jun; transcription factor Jun [KO:K04448]
24525  Kras; GTPase KRas [KO:K07827]
24605  Nras; GTPase NRas [KO:K07828]
246097  Fas; tumor necrosis factor receptor superfamily member 6 precursor [KO:K04390]
246144  Il3ra; interleukin-3 receptor subunit alpha precursor [KO:K04737]
246756  Tradd; tumor necrosis factor receptor type 1-associated DEATH domain protein [KO:K03171]
246775  Tnfsf10; tumor necrosis factor ligand superfamily member 10 [KO:K04721]
24703  Raf1; RAF proto-oncogene serine/threonine-protein kinase [KO:K04366] [EC:2.7.11.1]
24835  Tnf; tumor necrosis factor [KO:K03156]
24842  Tp53; cellular tumor antigen p53 [KO:K04451]
24887  Bax; apoptosis regulator BAX [KO:K02159]
24888  Bcl2l1; bcl-2-like protein 1 isoform 2 [KO:K04570]
25112  Gadd45a; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
25233  Akt2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
25262  Itpr1; inositol 1,4,5-trisphosphate receptor type 1 isoform 3 [KO:K04958]
25272  Mapk10; mitogen-activated protein kinase 10 isoform 2 [KO:K04440] [EC:2.7.11.24]
252929  Ctsz; cathepsin Z precursor [KO:K08568] [EC:3.4.18.1]
25309  Cycs; cytochrome c, somatic [KO:K08738]
25310  Cyct; cytochrome c, testis-specific [KO:K08738]
25385  Faslg; tumor necrosis factor ligand superfamily member 6 [KO:K04389]
25402  Casp3; caspase-3 [KO:K02187] [EC:3.4.22.56]
25423  Ctsc; dipeptidyl peptidase 1 precursor [KO:K01275] [EC:3.4.14.1]
25425  Ctsh; pro-cathepsin H precursor [KO:K01366] [EC:3.4.22.16]
25493  Nfkbia; NF-kappa-B inhibitor alpha [KO:K04734]
25513  Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
25591  Parp1; poly [ADP-ribose] polymerase 1 [KO:K24070]
25625  Tnfrsf1a; tumor necrosis factor receptor superfamily member 1A precursor [KO:K03158]
25679  Itpr3; inositol 1,4,5-trisphosphate receptor type 3 [KO:K04960]
25697  Ctsl; procathepsin L preproprotein [KO:K01365] [EC:3.4.22.15]
266610  Fadd; FAS-associated death domain protein [KO:K02373]
287606  Septin4; septin-4 isoform 1 [KO:K16943]
287876  Actg1; actin, cytoplasmic 2 [KO:K05692]
288753  Diablo; diablo IAP-binding mitochondrial protein [KO:K10522]
290019  Cycsl3; cytochrome c, somatic-like [KO:K08738]
290027  Parp2; poly [ADP-ribose] polymerase 2 [KO:K28005]
291005  Gadd45g; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
291287  Tubal3; tubulin alpha chain-like 3 [KO:K07374]
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]
29175  Ctsk; cathepsin K precursor [KO:K01371] [EC:3.4.22.38]
293621  Hras; GTPase HRas [KO:K02833]
293625  Pidd1; p53-induced death domain-containing protein 1 [KO:K10130]
293676  Ctsw; cathepsin W precursor [KO:K08569] [EC:3.4.22.-]
29414  Akt3; RAC-gamma serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
29467  Ddit3; DNA damage-inducible transcript 3 protein [KO:K04452]
29702  Eif2ak3; eukaryotic translation initiation factor 2-alpha kinase 3 precursor [KO:K08860] [EC:2.7.11.1]
297376  Htra2; serine protease HTRA2, mitochondrial [KO:K08669] [EC:3.4.21.108]
29741  Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
299625  Lmnb2; lamin-B2 [KO:K07611]
299626  Gadd45b; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
300218  Tuba1c; tubulin alpha-1C chain [KO:K07374]
300711  Atm; serine-protein kinase ATM [KO:K04728] [EC:2.7.11.1]
300985  Parp3; protein mono-ADP-ribosyltransferase PARP3 [KO:K10798] [EC:2.4.2.-]
306886  Ripk1; receptor-interacting serine/threonine-protein kinase 1 [KO:K02861] [EC:2.7.11.1]
309165  Rela; transcription factor p65 [KO:K04735]
309295  Ikbkg; NF-kappa-B essential modulator [KO:K07210]
309361  Chuk; inhibitor of nuclear factor kappa-B kinase subunit alpha [KO:K04467] [EC:2.7.11.10]
310738  Ngf; beta-nerve growth factor precursor [KO:K02582]
311786  Traf2; TNF receptor-associated factor 2 [KO:K03173] [EC:2.3.2.27]
314322  Fos; protein c-Fos [KO:K04379]
316531  Tuba4a; tubulin alpha-4A chain [KO:K07374]
317673  Bbc3; bcl-2-binding component 3 [KO:K10132]
360640  Map3k14; mitogen-activated protein kinase kinase kinase 14 [KO:K04466] [EC:2.7.11.25]
361046  Parp4; poly [ADP-ribose] polymerase 4 [KO:K10798] [EC:2.4.2.-]
361704  Ctsf; cathepsin F precursor [KO:K01373] [EC:3.4.22.41]
362100  Endog; endonuclease G, mitochondrial precursor [KO:K01173]
365057  Map3k5; mitogen-activated protein kinase kinase kinase 5 [KO:K04426] [EC:2.7.11.25]
366508  Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
367149  Bax-ps1; apoptosis regulator BAX-like [KO:K02159]
367858  Hrasl1; HRas proto-oncogene, GTPase like 1 [KO:K02833]
492821  Pmaip1; phorbol-12-myristate-13-acetate-induced protein 1 [KO:K10131]
498013  Ern1; serine/threonine-protein kinase/endoribonuclease IRE1 [KO:K08852] [EC:2.7.11.1 3.1.26.-]
498331  Ptpn13; tyrosine-protein phosphatase non-receptor type 13 [KO:K02374]
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]
50654  Ctss; cathepsin S preproprotein [KO:K01368] [EC:3.4.22.27]
50658  Mapk9; mitogen-activated protein kinase 9 isoform 2 [KO:K04440] [EC:2.7.11.24]
50669  Prf1; perforin-1 precursor [KO:K07818]
50689  Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
54318  Eif2s1; eukaryotic translation initiation factor 2 subunit 1 [KO:K03237]
58918  Casp9; caspase-9 [KO:K04399] [EC:3.4.22.62]
58960  Map2k2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
59109  Ntrk1; high affinity nerve growth factor receptor precursor [KO:K03176] [EC:2.7.10.1]
60371  Birc2; baculoviral IAP repeat-containing protein 2 [KO:K16060]
60374  Lmna; prelamin-A/C [KO:K12641]
60430  Mcl1; induced myeloid leukemia cell differentiation protein Mcl-1 homolog [KO:K02539]
60664  Pik3r3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
63879  Xiap; E3 ubiquitin-protein ligase XIAP [KO:K04725] [EC:2.3.2.27]
64026  Casp7; caspase-7 [KO:K04397] [EC:3.4.22.60]
64041  Birc5; baculoviral IAP repeat-containing protein 5 [KO:K08731]
64044  Casp8; caspase-8 [KO:K04398] [EC:3.4.22.61]
64158  Tuba1a; tubulin alpha-1A chain [KO:K07374]
64159  Sptan1; spectrin alpha chain, non-erythrocytic 1 [KO:K06114]
64314  Casp2; caspase-2 [KO:K02186] [EC:3.4.22.55]
64529  Ctsb; cathepsin B preproprotein [KO:K01363] [EC:3.4.22.1]
64547  Bcl2l11; bcl-2-like protein 11 [KO:K16341]
64625  Bid; BH3-interacting domain death agonist [KO:K04726]
64639  Bad; bcl2-associated agonist of cell death [KO:K02158]
679794  Cycsl1; cytochrome c, somatic-like [KO:K08738]
681314  [KO:K02159]
684529  Ctso; cathepsin O precursor [KO:K01374] [EC:3.4.22.42]
687813  Traf1; TNF receptor-associated factor 1 [KO:K03172]
690675  Cycsl2; cytochrome c, somatic-like [KO:K08738]
78963  Apaf1; apoptotic protease-activating factor 1 [KO:K02084]
78971  Birc3; baculoviral IAP repeat-containing protein 3 [KO:K16060]
79255  Atf4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
81678  Itpr2; inositol 1,4,5-trisphosphate receptor type 2 [KO:K04959]
81736  Nfkb1; nuclear factor NF-kappa-B p105 subunit isoform 2 [KO:K02580]
81745  Pdpk1; 3-phosphoinositide-dependent protein kinase 1 [KO:K06276] [EC:2.7.11.1]
81822  Actb; actin, cytoplasmic 1 [KO:K05692]
83533  Aifm1; apoptosis-inducing factor 1, mitochondrial precursor [KO:K04727] [EC:1.-.-.-]
83584  Casp6; caspase-6 [KO:K04396] [EC:3.4.22.59]
84351  Ikbkb; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
84359  Dffb; DNA fragmentation factor subunit beta [KO:K02311] [EC:3.-.-.-]
85243  Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
85383  Nol3; nucleolar protein 3 [KO:K28177]
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
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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