Entry Name TNF signaling pathway - Homo sapiens (human)
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 transductionBRITE hierarchy
Pathway map Ortholog table Network Element N00145 Extrinsic apoptotic pathway
N00151 TNF-NFKB signaling pathway
N00374 TNF-IRF1 signaling pathway
N00444 TNF-p38 signaling pathway
N00446 TNF-JNK signaling pathway
N01583 Regulation of extrinsic apoptotic pathway, XIAP
Drug D00754 Thalidomide (JAN/USP/INN)
D01583 Pirfenidone (JAN/USAN/INN)
D04687 Lenalidomide (JAN/USAN/INN)
D08976 Pomalidomide (JAN/USAN/INN)
D09813 Lenalidomide hydrate (JAN)
D11385 Inarigivir soproxil (USAN)
D12352 Eclitasertib (USAN/INN)
D12790 Adalimumab fosimdesonide (USAN/INN)
Other DBs Organism Homo sapiens (human) [GN:
hsa ]
Gene 7132 TNFRSF1A; TNF receptor superfamily member 1A [KO:K03158 ]
8717 TRADD; TNFRSF1A associated via death domain [KO:K03171 ]
7188 TRAF5; TNF receptor associated factor 5 [KO:K09849 ]
329 BIRC2; baculoviral IAP repeat containing 2 [KO:K16060 ]
330 BIRC3; baculoviral IAP repeat containing 3 [KO:K16060 ]
10454 TAB1; TGF-beta activated kinase 1 (MAP3K7) binding protein 1 [KO:K04403 ]
23118 TAB2; TGF-beta activated kinase 1 (MAP3K7) binding protein 2 [KO:K04404 ]
257397 TAB3; TGF-beta activated kinase 1 (MAP3K7) binding protein 3 [KO:K12793 ]
3725 JUN; Jun proto-oncogene, AP-1 transcription factor subunit [KO:K04448 ]
2353 FOS; Fos proto-oncogene, AP-1 transcription factor subunit [KO:K04379 ]
8837 CFLAR; CASP8 and FADD like apoptosis regulator [KO:K04724 ]
1051 CEBPB; CCAAT enhancer binding protein beta [KO:K10048 ]
8517 IKBKG; inhibitor of nuclear factor kappa B kinase regulatory subunit gamma [KO:K07210 ]
1147 CHUK; component of inhibitor of nuclear factor kappa B kinase complex [KO:K04467 ] [EC:2.7.11.10 ]
5970 RELA; RELA proto-oncogene, NF-kB subunit [KO:K04735 ]
4790 NFKB1; nuclear factor kappa B subunit 1 [KO:K02580 ]
1385 CREB1; cAMP responsive element binding protein 1 [KO:K05870 ]
10488 CREB3; cAMP responsive element binding protein 3 [KO:K09048 ]
90993 CREB3L1; cAMP responsive element binding protein 3 like 1 [KO:K09048 ]
64764 CREB3L2; cAMP responsive element binding protein 3 like 2 [KO:K09048 ]
84699 CREB3L3; cAMP responsive element binding protein 3 like 3 [KO:K09048 ]
148327 CREB3L4; cAMP responsive element binding protein 3 like 4 [KO:K09048 ]
1386 ATF2; activating transcription factor 2 [KO:K04450 ]
468 ATF4; activating transcription factor 4 [KO:K04374 ]
9586 CREB5; cAMP responsive element binding protein 5 [KO:K09047 ]
1388 ATF6B; activating transcription factor 6 beta [KO:K09049 ]
8772 FADD; Fas associated via death domain [KO:K02373 ]
192111 PGAM5; PGAM family member 5, mitochondrial serine/threonine protein phosphatase [KO:K15637 ] [EC:3.1.3.16 ]
6347 CCL2; C-C motif chemokine ligand 2 [KO:K14624 ]
6352 CCL5; C-C motif chemokine ligand 5 [KO:K12499 ]
6364 CCL20; C-C motif chemokine ligand 20 [KO:K14625 ]
2919 CXCL1; C-X-C motif chemokine ligand 1 [KO:K05505 ]
2920 CXCL2; C-X-C motif chemokine ligand 2 [KO:K05505 ]
2921 CXCL3; C-X-C motif chemokine ligand 3 [KO:K05505 ]
6374 CXCL5; C-X-C motif chemokine ligand 5 [KO:K05506 ]
6372 CXCL6; C-X-C motif chemokine ligand 6 [KO:K05506 ]
3627 CXCL10; C-X-C motif chemokine ligand 10 [KO:K12671 ]
6376 CX3CL1; C-X3-C motif chemokine ligand 1 [KO:K05508 ]
1435 CSF1; colony stimulating factor 1 [KO:K05453 ]
1437 CSF2; colony stimulating factor 2 [KO:K05427 ]
355 FAS; Fas cell surface death receptor [KO:K04390 ]
8809 IL18R1; interleukin 18 receptor 1 [KO:K05173 ]
182 JAG1; jagged canonical Notch ligand 1 [KO:K06052 ]
3976 LIF; LIF interleukin 6 family cytokine [KO:K05419 ]
602 BCL3; BCL3 transcription coactivator [KO:K09258 ]
9021 SOCS3; suppressor of cytokine signaling 3 [KO:K04696 ]
7185 TRAF1; TNF receptor associated factor 1 [KO:K03172 ]
3726 JUNB; JunB proto-oncogene, AP-1 transcription factor subunit [KO:K09028 ]
7424 VEGFC; vascular endothelial growth factor C [KO:K05449 ]
2277 VEGFD; vascular endothelial growth factor D [KO:K05449 ]
64127 NOD2; nucleotide binding oligomerization domain containing 2 [KO:K10165 ]
3383 ICAM1; intercellular adhesion molecule 1 [KO:K06490 ]
7412 VCAM1; vascular cell adhesion molecule 1 [KO:K06527 ]
7133 TNFRSF1B; TNF receptor superfamily member 1B [KO:K05141 ]
7187 TRAF3; TNF receptor associated factor 3 [KO:K03174 ]
5290 PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922 ] [EC:2.7.1.153 ]
5293 PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922 ] [EC:2.7.1.153 ]
5291 PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922 ] [EC:2.7.1.153 ]
5295 PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649 ]
5296 PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649 ]
8503 PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649 ]
3659 IRF1; interferon regulatory factor 1 [KO:K09444 ]
Reference Authors Chu WM
Title Tumor necrosis factor.
Journal Reference 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 Authors MacEwan DJ
Title TNF receptor subtype signalling: differences and cellular consequences.
Journal Reference Authors Newton K, Dixit VM
Title Signaling in innate immunity and inflammation.
Journal Reference Authors Pomerantz JL, Baltimore D
Title NF-kappaB activation by a signaling complex containing TRAF2, TANK and TBK1, a novel IKK-related kinase.
Journal Reference Authors Naude PJ, den Boer JA, Luiten PG, Eisel UL
Title Tumor necrosis factor receptor cross-talk.
Journal Reference Authors Faustman D, Davis M
Title TNF receptor 2 pathway: drug target for autoimmune diseases.
Journal Reference 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 Related KO pathway
