KEGG   PATHWAY: mmu04668
mmu04668                    Pathway                                
TNF signaling pathway - Mus musculus (house mouse)
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.
Environmental Information Processing; Signal transduction
Pathway map
mmu04668  TNF signaling pathway

Other DBs
GO: 0033209
Mus musculus (house mouse) [GN:mmu]
21926  Tnf; tumor necrosis factor [KO:K03156]
21937  Tnfrsf1a; tumor necrosis factor receptor superfamily, member 1a [KO:K03158]
67384  Bag4; BCL2-associated athanogene 4 [KO:K09558]
71609  Tradd; TNFRSF1A-associated via death domain [KO:K03171]
22030  Traf2; TNF receptor-associated factor 2 [KO:K03173] [EC:]
22033  Traf5; TNF receptor-associated factor 5 [KO:K09849]
19766  Ripk1; receptor (TNFRSF)-interacting serine-threonine kinase 1 [KO:K02861] [EC:]
11797  Birc2; baculoviral IAP repeat-containing 2 [KO:K16060]
11796  Birc3; baculoviral IAP repeat-containing 3 [KO:K16060]
26409  Map3k7; mitogen-activated protein kinase kinase kinase 7 [KO:K04427] [EC:]
66513  Tab1; TGF-beta activated kinase 1/MAP3K7 binding protein 1 [KO:K04403]
68652  Tab2; TGF-beta activated kinase 1/MAP3K7 binding protein 2 [KO:K04404]
66724  Tab3; TGF-beta activated kinase 1/MAP3K7 binding protein 3 [KO:K12793]
26398  Map2k4; mitogen-activated protein kinase kinase 4 [KO:K04430] [EC:]
26400  Map2k7; mitogen-activated protein kinase kinase 7 [KO:K04431] [EC:]
26419  Mapk8; mitogen-activated protein kinase 8 [KO:K04440] [EC:]
26420  Mapk9; mitogen-activated protein kinase 9 [KO:K04440] [EC:]
26414  Mapk10; mitogen-activated protein kinase 10 [KO:K04440] [EC:]
16476  Jun; jun proto-oncogene [KO:K04448]
14281  Fos; FBJ osteosarcoma oncogene [KO:K04379]
16396  Itch; itchy, E3 ubiquitin protein ligase [KO:K05632] [EC:]
12633  Cflar; CASP8 and FADD-like apoptosis regulator [KO:K04724]
26397  Map2k3; mitogen-activated protein kinase kinase 3 [KO:K04432] [EC:]
26399  Map2k6; mitogen-activated protein kinase kinase 6 [KO:K04433] [EC:]
26416  Mapk14; mitogen-activated protein kinase 14 [KO:K04441] [EC:]
19094  Mapk11; mitogen-activated protein kinase 11 [KO:K04441] [EC:]
29857  Mapk12; mitogen-activated protein kinase 12 [KO:K04441] [EC:]
26415  Mapk13; mitogen-activated protein kinase 13 [KO:K04441] [EC:]
12608  Cebpb; CCAAT/enhancer binding protein (C/EBP), beta [KO:K10048]
26408  Map3k5; mitogen-activated protein kinase kinase kinase 5 [KO:K04426] [EC:]
53859  Map3k14; mitogen-activated protein kinase kinase kinase 14 [KO:K04466] [EC:]
16151  Ikbkg; inhibitor of kappaB kinase gamma [KO:K07210]
16150  Ikbkb; inhibitor of kappaB kinase beta [KO:K07209] [EC:]
12675  Chuk; conserved helix-loop-helix ubiquitous kinase [KO:K04467] [EC:]
18035  Nfkbia; nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor, alpha [KO:K04734]
19697  Rela; v-rel reticuloendotheliosis viral oncogene homolog A (avian) [KO:K04735]
18033  Nfkb1; nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105 [KO:K02580]
26410  Map3k8; mitogen-activated protein kinase kinase kinase 8 [KO:K04415] [EC:]
26395  Map2k1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:]
26413  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:]
26417  Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:]
73086  Rps6ka5; ribosomal protein S6 kinase, polypeptide 5 [KO:K04445] [EC:]
56613  Rps6ka4; ribosomal protein S6 kinase, polypeptide 4 [KO:K16510] [EC:]
12912  Creb1; cAMP responsive element binding protein 1 [KO:K05870]
12913  Creb3; cAMP responsive element binding protein 3 [KO:K09048]
26427  Creb3l1; cAMP responsive element binding protein 3-like 1 [KO:K09048]
208647  Creb3l2; cAMP responsive element binding protein 3-like 2 [KO:K09048]
208677  Creb3l3; cAMP responsive element binding protein 3-like 3 [KO:K09048]
78284  Creb3l4; cAMP responsive element binding protein 3-like 4 [KO:K09048]
11909  Atf2; activating transcription factor 2 [KO:K04450]
11911  Atf4; activating transcription factor 4 [KO:K04374]
231991  Creb5; cAMP responsive element binding protein 5 [KO:K09047]
12915  Atf6b; activating transcription factor 6 beta [KO:K09049]
56532  Ripk3; receptor-interacting serine-threonine kinase 3 [KO:K08847] [EC:]
74568  Mlkl; mixed lineage kinase domain-like [KO:K08849] [EC:]
72542  Pgam5; phosphoglycerate mutase family member 5 [KO:K15637] [EC:]
74006  Dnm1l; dynamin 1-like [KO:K17065] [EC:]
14082  Fadd; Fas (TNFRSF6)-associated via death domain [KO:K02373]
12370  Casp8; caspase 8 [KO:K04398] [EC:]
12369  Casp7; caspase 7 [KO:K04397] [EC:]
12367  Casp3; caspase 3 [KO:K02187] [EC:]
20296  Ccl2; chemokine (C-C motif) ligand 2 [KO:K14624]
20293  Ccl12; chemokine (C-C motif) ligand 12 [KO:K14624]
20304  Ccl5; chemokine (C-C motif) ligand 5 [KO:K12499]
20297  Ccl20; chemokine (C-C motif) ligand 20 [KO:K14625]
14825  Cxcl1; chemokine (C-X-C motif) ligand 1 [KO:K05505]
20310  Cxcl2; chemokine (C-X-C motif) ligand 2 [KO:K05505]
330122  Cxcl3; chemokine (C-X-C motif) ligand 3 [KO:K05505]
20311  Cxcl5; chemokine (C-X-C motif) ligand 5 [KO:K05506]
15945  Cxcl10; chemokine (C-X-C motif) ligand 10 [KO:K12671]
20312  Cx3cl1; chemokine (C-X3-C motif) ligand 1 [KO:K05508]
12977  Csf1; colony stimulating factor 1 (macrophage) [KO:K05453]
12981  Csf2; colony stimulating factor 2 (granulocyte-macrophage) [KO:K05427]
14102  Fas; Fas (TNF receptor superfamily member 6) [KO:K04390]
16182  Il18r1; interleukin 18 receptor 1 [KO:K05173]
16449  Jag1; jagged 1 [KO:K06052]
16176  Il1b; interleukin 1 beta [KO:K04519]
16193  Il6; interleukin 6 [KO:K05405]
16168  Il15; interleukin 15 [KO:K05433]
16878  Lif; leukemia inhibitory factor [KO:K05419]
16992  Lta; lymphotoxin A [KO:K05468]
12051  Bcl3; B cell leukemia/lymphoma 3 [KO:K09258]
12702  Socs3; suppressor of cytokine signaling 3 [KO:K04696]
21929  Tnfaip3; tumor necrosis factor, alpha-induced protein 3 [KO:K11859] [EC:]
22029  Traf1; TNF receptor-associated factor 1 [KO:K03172]
15953  Ifi47; interferon gamma inducible protein 47 [KO:K17072]
432555  Gm5431; predicted gene 5431 [KO:K17072]
16477  Junb; jun B proto-oncogene [KO:K09028]
17392  Mmp3; matrix metallopeptidase 3 [KO:K01394] [EC:]
17395  Mmp9; matrix metallopeptidase 9 [KO:K01403] [EC:]
17387  Mmp14; matrix metallopeptidase 14 (membrane-inserted) [KO:K07763] [EC:]
13614  Edn1; endothelin 1 [KO:K16366]
22341  Vegfc; vascular endothelial growth factor C [KO:K05449]
14205  Vegfd; vascular endothelial growth factor D [KO:K05449]
257632  Nod2; nucleotide-binding oligomerization domain containing 2 [KO:K10165]
15894  Icam1; intercellular adhesion molecule 1 [KO:K06490]
20339  Sele; selectin, endothelial cell [KO:K06494]
22329  Vcam1; vascular cell adhesion molecule 1 [KO:K06527]
19225  Ptgs2; prostaglandin-endoperoxide synthase 2 [KO:K11987] [EC:]
21938  Tnfrsf1b; tumor necrosis factor receptor superfamily, member 1b [KO:K05141]
22031  Traf3; TNF receptor-associated factor 3 [KO:K03174]
18706  Pik3ca; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:]
18707  Pik3cd; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:]
74769  Pik3cb; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:]
18709  Pik3r2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
18708  Pik3r1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
18710  Pik3r3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
11651  Akt1; thymoma viral proto-oncogene 1 [KO:K04456] [EC:]
11652  Akt2; thymoma viral proto-oncogene 2 [KO:K04456] [EC:]
23797  Akt3; thymoma viral proto-oncogene 3 [KO:K04456] [EC:]
69601  Dab2ip; disabled 2 interacting protein [KO:K19901]
16362  Irf1; interferon regulatory factor 1 [KO:K09444]
15977  Ifnb1; interferon beta 1, fibroblast [KO:K05415]
Chu WM
Tumor necrosis factor.
Cancer Lett 328:222-5 (2013)
Shuh M, Bohorquez H, Loss GE Jr, Cohen AJ
Tumor Necrosis Factor-alpha: Life and Death of Hepatocytes During Liver Ischemia/Reperfusion Injury.
Ochsner J 13:119-30 (2013)
MacEwan DJ
TNF receptor subtype signalling: differences and cellular consequences.
Cell Signal 14:477-92 (2002)
Newton K, Dixit VM
Signaling in innate immunity and inflammation.
Cold Spring Harb Perspect Biol 4:a006049 (2012)
Pomerantz JL, Baltimore D
NF-kappaB activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKK-related kinase.
EMBO J 18:6694-704 (1999)
Naude PJ, den Boer JA, Luiten PG, Eisel UL
Tumor necrosis factor receptor cross-talk.
FEBS J 278:888-98 (2011)
Faustman D, Davis M
TNF receptor 2 pathway: drug target for autoimmune diseases.
Nat Rev Drug Discov 9:482-93 (2010)
Chan FK, Shisler J, Bixby JG, Felices M, Zheng L, Appel M, Orenstein J, Moss B, Lenardo MJ
A role for tumor necrosis factor receptor-2 and receptor-interacting protein in programmed necrosis and antiviral responses.
J Biol Chem 278:51613-21 (2003)
mmu04010  MAPK signaling pathway
mmu04064  NF-kappa B signaling pathway
mmu04120  Ubiquitin mediated proteolysis
mmu04151  PI3K-Akt signaling pathway
mmu04210  Apoptosis
KO pathway

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