KEGG   PATHWAY: rno04668
Entry
rno04668                    Pathway                                
Name
TNF signaling pathway - Rattus norvegicus (rat)
Description
Tumor necrosis factor (TNF), as a critical cytokine, can induce a wide range of intracellular signal pathways including apoptosis and cell survival as well as inflammation and immunity. Activated TNF is assembled to a homotrimer and binds to its receptors (TNFR1, TNFR2) resulting in the trimerization of TNFR1 or TNFR2. TNFR1 is expressed by nearly all cells and is the major receptor for TNF (also called TNF-alpha). In contrast, TNFR2 is expressed in limited cells such as CD4 and CD8 T lymphocytes, endothelial cells, microglia, oligodendrocytes, neuron subtypes, cardiac myocytes, thymocytes and human mesenchymal stem cells. It is the receptor for both TNF and LTA (also called TNF-beta). Upon binding of the ligand, TNFR mediates the association of some adaptor proteins such as TRADD or TRAF2, which in turn initiate recruitment of signal transducers. TNFR1 signaling induces activation of many genes, primarily controlled by two distinct pathways, NF-kappa B pathway and the MAPK cascade, or apoptosis and necroptosis. TNFR2 signaling activates NF-kappa B pathway including PI3K-dependent NF-kappa B pathway and JNK pathway leading to survival.
Class
Environmental Information Processing; Signal transduction
Pathway map
rno04668  TNF signaling pathway
rno04668

Other DBs
GO: 0033209
Organism
Rattus norvegicus (rat) [GN:rno]
Gene
24835  Tnf; tumor necrosis factor [KO:K03156]
25625  Tnfrsf1a; tumor necrosis factor receptor superfamily member 1A precursor [KO:K03158]
361167  Bag4; BAG family molecular chaperone regulator 4 [KO:K09558]
57027  Adam17; disintegrin and metalloproteinase domain-containing protein 17 precursor [KO:K06059] [EC:3.4.24.86]
303008  Rhbdf1; inactive rhomboid protein 1 [KO:K27588]
303690  Rhbdf2; inactive rhomboid protein 2 [KO:K27588]
309172  Frmd8; FERM domain-containing protein 8 [KO:K23972]
246756  Tradd; tumor necrosis factor receptor type 1-associated DEATH domain protein [KO:K03171]
311786  Traf2; TNF receptor-associated factor 2 [KO:K03173] [EC:2.3.2.27]
684173  Traf5; TNF receptor-associated factor 5 [KO:K09849]
306886  Ripk1; receptor-interacting serine/threonine-protein kinase 1 [KO:K02861] [EC:2.7.11.1]
60371  Birc2; baculoviral IAP repeat-containing protein 2 [KO:K16060]
78971  Birc3; baculoviral IAP repeat-containing protein 3 [KO:K16060]
313121  Map3k7; mitogen-activated protein kinase kinase kinase 7 [KO:K04427] [EC:2.7.11.25]
315139  Tab1; TGF-beta-activated kinase 1 and MAP3K7-binding protein 1 [KO:K04403]
308267  Tab2; TGF-beta-activated kinase 1 and MAP3K7-binding protein 2 [KO:K04404]
317546  Tab3; TGF-beta-activated kinase 1 and MAP3K7-binding protein 3 isoform X1 [KO:K12793]
287398  Map2k4; dual specificity mitogen-activated protein kinase kinase 4 [KO:K04430] [EC:2.7.12.2]
363855  Map2k7; dual specificity mitogen-activated protein kinase kinase 7 isoform 1 [KO:K04431] [EC:2.7.12.2]
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]
24516  Jun; transcription factor Jun [KO:K04448]
314322  Fos; protein c-Fos [KO:K04379]
311567  Itch; E3 ubiquitin-protein ligase Itchy homolog [KO:K05632] [EC:2.3.2.26]
117279  Cflar; CASP8 and FADD-like apoptosis regulator isoform 1 [KO:K04724]
303200  Map2k3; dual specificity mitogen-activated protein kinase kinase 3 [KO:K04432] [EC:2.7.12.2]
114495  Map2k6; dual specificity mitogen-activated protein kinase kinase 6 [KO:K04433] [EC:2.7.12.2]
81649  Mapk14; mitogen-activated protein kinase 14 [KO:K04441] [EC:2.7.11.24]
60352  Mapk12; mitogen-activated protein kinase 12 [KO:K04441] [EC:2.7.11.24]
29513  Mapk13; mitogen-activated protein kinase 13 [KO:K04441] [EC:2.7.11.24]
689314  Mapk11; mitogen-activated protein kinase 11 [KO:K04441] [EC:2.7.11.24]
24253  Cebpb; CCAAT/enhancer-binding protein beta isoform LAP1 [KO:K10048]
365057  Map3k5; mitogen-activated protein kinase kinase kinase 5 [KO:K04426] [EC:2.7.11.25]
360640  Map3k14; mitogen-activated protein kinase kinase kinase 14 [KO:K04466] [EC:2.7.11.25]
309295  Ikbkg; NF-kappa-B essential modulator [KO:K07210]
84351  Ikbkb; inhibitor of nuclear factor kappa-B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
309361  Chuk; inhibitor of nuclear factor kappa-B kinase subunit alpha [KO:K04467] [EC:2.7.11.10]
25493  Nfkbia; NF-kappa-B inhibitor alpha [KO:K04734]
309165  Rela; transcription factor p65 [KO:K04735]
81736  Nfkb1; nuclear factor NF-kappa-B p105 subunit isoform 2 [KO:K02580]
116596  Map3k8; mitogen-activated protein kinase kinase kinase 8 [KO:K04415] [EC:2.7.11.25]
170851  Map2k1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [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]
314384  Rps6ka5; ribosomal protein S6 kinase alpha-5 [KO:K04445] [EC:2.7.11.1]
361715  Rps6ka4; ribosomal protein S6 kinase alpha-4 [KO:K16510] [EC:2.7.11.1]
81646  Creb1; cyclic AMP-responsive element-binding protein 1 isoform A [KO:K05870]
310616  Creb3l4; cyclic AMP-responsive element-binding protein 3-like protein 4 isoform 1 [KO:K09048]
362165  Creb3l1; cyclic AMP-responsive element-binding protein 3-like protein 1 [KO:K09048]
362339  Creb3l2; cyclic AMP-responsive element-binding protein 3-like protein 2 [KO:K09048]
314638  Creb3l3; cyclic AMP-responsive element-binding protein 3-like protein 3 [KO:K09048]
81647  Atf2; cyclic AMP-dependent transcription factor ATF-2 [KO:K04450]
79255  Atf4; cyclic AMP-dependent transcription factor ATF-4 [KO:K04374]
500131  Creb5; cyclic AMP-responsive element-binding protein 5 [KO:K09047]
406169  Atf6b; cyclic AMP-dependent transcription factor ATF-6 beta [KO:K09049]
246240  Ripk3; receptor-interacting serine/threonine-protein kinase 3 [KO:K08847] [EC:2.7.11.1]
266610  Fadd; FAS-associated death domain protein [KO:K02373]
64044  Casp8; caspase-8 [KO:K04398] [EC:3.4.22.61]
64026  Casp7; caspase-7 [KO:K04397] [EC:3.4.22.60]
25402  Casp3; caspase-3 [KO:K02187] [EC:3.4.22.56]
690743  Mlkl; mixed lineage kinase domain-like protein [KO:K08849] [EC:2.7.11.1]
288731  Pgam5; serine/threonine-protein phosphatase PGAM5, mitochondrial [KO:K15637] [EC:3.1.3.16]
114114  Dnm1l; dynamin-1-like protein [KO:K17065] [EC:3.6.5.5]
312937  Cyld; ubiquitin carboxyl-terminal hydrolase CYLD [KO:K08601] [EC:3.4.19.12]
63879  Xiap; E3 ubiquitin-protein ligase XIAP [KO:K04725] [EC:2.3.2.27]
287562  Ccl12; C-C motif chemokine ligand 12 precursor [KO:K14624]
24770  Ccl2; C-C motif chemokine 2 precursor [KO:K14624]
81780  Ccl5; C-C motif chemokine 5 precursor [KO:K12499]
29538  Ccl20; C-C motif chemokine 20 precursor [KO:K14625]
81503  Cxcl1; growth-regulated alpha protein precursor [KO:K05505]
114105  Cxcl2; C-X-C motif chemokine 2 precursor [KO:K05505]
171551  Cxcl3; C-X-C motif chemokine 3 precursor [KO:K05505]
60665  Cxcl6; C-X-C motif chemokine 5 precursor [KO:K05506]
245920  Cxcl10; C-X-C motif chemokine 10 precursor [KO:K12671]
89808  Cx3cl1; fractalkine precursor [KO:K05508]
78965  Csf1; macrophage colony-stimulating factor 1 precursor [KO:K05453]
116630  Csf2; granulocyte-macrophage colony-stimulating factor precursor [KO:K05427]
246097  Fas; tumor necrosis factor receptor superfamily member 6 precursor [KO:K04390]
301365  Il18r1; interleukin-18 receptor 1 precursor [KO:K05173]
29146  Jag1; protein jagged-1 precursor [KO:K06052]
24494  Il1b; interleukin-1 beta [KO:K04519]
24498  Il6; interleukin-6 precursor [KO:K05405]
25670  Il15; interleukin-15 preproprotein [KO:K05433]
60584  Lif; leukemia inhibitory factor precursor [KO:K05419]
25008  Lta; lymphotoxin-alpha precursor [KO:K05468]
680611  Bcl3; B-cell lymphoma 3 protein [KO:K09258]
89829  Socs3; suppressor of cytokine signaling 3 [KO:K04696]
683206  Tnfaip3; TNF alpha induced protein 3 [KO:K11859] [EC:3.4.19.12]
687813  Traf1; TNF receptor-associated factor 1 [KO:K03172]
246208  Ifi47; interferon gamma inducible protein 47 [KO:K17072]
24517  Junb; transcription factor JunB [KO:K09028]
171045  Mmp3; stromelysin-1 preproprotein [KO:K01394] [EC:3.4.24.17]
81687  Mmp9; matrix metalloproteinase-9 precursor [KO:K01403] [EC:3.4.24.35]
81707  Mmp14; matrix metalloproteinase-14 precursor [KO:K07763] [EC:3.4.24.80]
24323  Edn1; endothelin-1 preproprotein [KO:K16366]
114111  Vegfc; vascular endothelial growth factor C precursor [KO:K05449]
360457  Vegfd; vascular endothelial growth factor D precursor [KO:K05449]
291912  Nod2; nucleotide-binding oligomerization domain-containing protein 2 [KO:K10165]
25464  Icam1; intercellular adhesion molecule 1 precursor [KO:K06490]
25544  Sele; E-selectin precursor [KO:K06494]
25361  Vcam1; vascular cell adhesion protein 1 precursor [KO:K06527]
29527  Ptgs2; prostaglandin G/H synthase 2 precursor [KO:K11987] [EC:1.14.99.1]
156767  Tnfrsf1b; tumor necrosis factor receptor superfamily member 1B precursor [KO:K05141]
362788  Traf3; TNF receptor-associated factor 3 [KO:K03174]
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]
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]
192126  Dab2ip; disabled homolog 2-interacting protein [KO:K19901]
24508  Irf1; interferon regulatory factor 1 [KO:K09444]
24481  Ifnb1; interferon beta precursor [KO:K05415]
Reference
PMID:23085193
  Authors
Chu WM
  Title
Tumor necrosis factor.
  Journal
Cancer Lett 328:222-5 (2013)
DOI:10.1016/j.canlet.2012.10.014
Reference
PMID:23531747
  Authors
Shuh M, Bohorquez H, Loss GE Jr, Cohen AJ
  Title
Tumor Necrosis Factor-alpha: Life and Death of Hepatocytes During Liver Ischemia/Reperfusion Injury.
  Journal
Ochsner J 13:119-30 (2013)
Reference
PMID:11897488
  Authors
MacEwan DJ
  Title
TNF receptor subtype signalling: differences and cellular consequences.
  Journal
Cell Signal 14:477-92 (2002)
DOI:10.1016/S0898-6568(01)00262-5
Reference
PMID:22296764
  Authors
Newton K, Dixit VM
  Title
Signaling in innate immunity and inflammation.
  Journal
Cold Spring Harb Perspect Biol 4:a006049 (2012)
DOI:10.1101/cshperspect.a006049
Reference
PMID:10581243
  Authors
Pomerantz JL, Baltimore D
  Title
NF-kappaB activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKK-related kinase.
  Journal
EMBO J 18:6694-704 (1999)
DOI:10.1093/emboj/18.23.6694
Reference
PMID:21232019
  Authors
Naude PJ, den Boer JA, Luiten PG, Eisel UL
  Title
Tumor necrosis factor receptor cross-talk.
  Journal
FEBS J 278:888-98 (2011)
DOI:10.1111/j.1742-4658.2011.08017.x
Reference
PMID:20489699
  Authors
Faustman D, Davis M
  Title
TNF receptor 2 pathway: drug target for autoimmune diseases.
  Journal
Nat Rev Drug Discov 9:482-93 (2010)
DOI:10.1038/nrd3030
Reference
PMID:14532286
  Authors
Chan FK, Shisler J, Bixby JG, Felices M, Zheng L, Appel M, Orenstein J, Moss B, Lenardo MJ
  Title
A role for tumor necrosis factor receptor-2 and receptor-interacting protein in programmed necrosis and antiviral responses.
  Journal
J Biol Chem 278:51613-21 (2003)
DOI:10.1074/jbc.M305633200
Reference
PMID:26869525
  Authors
Lee MY, Nam KH, Choi KC
  Title
iRhoms; Its Functions and Essential Roles.
  Journal
Biomol Ther (Seoul) 24:109-14 (2016)
DOI:10.4062/biomolther.2015.149
Related
pathway
rno04010  MAPK signaling pathway
rno04064  NF-kappa B signaling pathway
rno04120  Ubiquitin mediated proteolysis
rno04151  PI3K-Akt signaling pathway
rno04210  Apoptosis
KO pathway
ko04668   
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