PATHWAY: ko04668 Help
Entry Name TNF signaling pathway
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 Other DBs Orthology K00922 PIK3CA_B_D; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153 ]
K01394 MMP3; matrix metalloproteinase-3 (stromelysin 1, progelatinase) [EC:3.4.24.17 ]
K02373 FADD; FAS-associated death domain protein
K02580 NFKB1; nuclear factor NF-kappa-B p105 subunit
K02649 PIK3R1_2_3; phosphoinositide-3-kinase regulatory subunit alpha/beta/delta
K02861 RIPK1, RIP1; receptor-interacting serine/threonine-protein kinase 1 [EC:2.7.11.1 ]
K03156 TNF, TNFA; tumor necrosis factor superfamily, member 2
K03158 TNFRSF1A, TNFR1, CD120a; tumor necrosis factor receptor superfamily member 1A
K03171 TRADD; tumor necrosis factor receptor type 1-associated DEATH domain protein
K03172 TRAF1; TNF receptor-associated factor 1
K03174 TRAF3; TNF receptor-associated factor 3
K04368 MAP2K1, MEK1; mitogen-activated protein kinase kinase 1 [EC:2.7.12.2 ]
K04374 ATF4, CREB2; cyclic AMP-dependent transcription factor ATF-4
K04379 FOS; proto-oncogene protein c-fos
K04390 TNFRSF6, FAS, CD95; tumor necrosis factor receptor superfamily member 6
K04403 MAP3K7IP1, TAB1; TAK1-binding protein 1
K04404 MAP3K7IP2, TAB2; TAK1-binding protein 2
K04415 MAP3K8, COT; mitogen-activated protein kinase kinase kinase 8 [EC:2.7.11.25 ]
K04426 MAP3K5, ASK1; mitogen-activated protein kinase kinase kinase 5 [EC:2.7.11.25 ]
K04427 MAP3K7, TAK1; mitogen-activated protein kinase kinase kinase 7 [EC:2.7.11.25 ]
K04430 MAP2K4, MKK4; mitogen-activated protein kinase kinase 4 [EC:2.7.12.2 ]
K04431 MAP2K7, MKK7; mitogen-activated protein kinase kinase 7 [EC:2.7.12.2 ]
K04432 MAP2K3, MKK3; mitogen-activated protein kinase kinase 3 [EC:2.7.12.2 ]
K04433 MAP2K6, MKK6; mitogen-activated protein kinase kinase 6 [EC:2.7.12.2 ]
K04440 JNK; mitogen-activated protein kinase 8/9/10 (c-Jun N-terminal kinase) [EC:2.7.11.24 ]
K04445 RPS6KA5, MSK1; ribosomal protein S6 kinase alpha-5 [EC:2.7.11.1 ]
K04448 JUN; transcription factor AP-1
K04450 ATF2, CREBP1; cyclic AMP-dependent transcription factor ATF-2
K04466 MAP3K14, NIK; mitogen-activated protein kinase kinase kinase 14 [EC:2.7.11.25 ]
K04467 IKBKA, IKKA, CHUK; inhibitor of nuclear factor kappa-B kinase subunit alpha [EC:2.7.11.10 ]
K04519 IL1B; interleukin 1 beta
K04696 SOCS3, CIS3; suppressor of cytokine signaling 3
K04724 CFLAR, FLIP; CASP8 and FADD-like apoptosis regulator
K04734 NFKBIA; NF-kappa-B inhibitor alpha
K04735 RELA; transcription factor p65
K05141 TNFRSF1B, TNFR2, CD120b; tumor necrosis factor receptor superfamily member 1B
K05173 IL18R1, IL1RRP, CD218a; interleukin 18 receptor 1
K05419 LIF; leukemia inhibitory factor
K05427 CSF2, GMCSF; granulocyte-macrophage colony-stimulating factor
K05449 VEGFC_D; vascular endothelial growth factor C/D
K05453 CSF1, MCSF; macrophage colony-stimulating factor 1
K05468 LTA, TNFB; lymphotoxin alpha (TNF superfamily, member 1)
K05505 CXCL1_2_3, GRO; C-X-C motif chemokine 1/2/3
K05506 CXCL5_6, SCYB5_6; C-X-C motif chemokine 5/6
K05508 CX3CL1, NTT; C-X3-C motif chemokine 1
K05870 CREB1; cyclic AMP-responsive element-binding protein 1
K06059 ADAM17, TACE, CD156b; disintegrin and metalloproteinase domain-containing protein 17 [EC:3.4.24.86 ]
K06490 ICAM1, CD54; intercellular adhesion molecule 1
K06494 SELE, CD62E; selectin, endothelial cell
K06527 VCAM1, CD106; vascular cell adhesion molecule 1
K07209 IKBKB, IKKB; inhibitor of nuclear factor kappa-B kinase subunit beta [EC:2.7.11.10 ]
K07210 IKBKG, IKKG, NEMO; inhibitor of nuclear factor kappa-B kinase subunit gamma
K07763 MMP14; matrix metalloproteinase-14 (membrane-inserted) [EC:3.4.24.80 ]
K08601 CYLD, USLP2; ubiquitin carboxyl-terminal hydrolase CYLD [EC:3.4.19.12 ]
K08847 RIPK3; receptor-interacting serine/threonine-protein kinase 3 [EC:2.7.11.1 ]
K09028 JUNB; transcription factor jun-B
K09047 CREB5, CREBPA; cyclic AMP-responsive element-binding protein 5
K09048 CREB3; cyclic AMP-responsive element-binding protein 3
K09049 ATF6B, CREBL1; cyclic AMP-dependent transcription factor ATF-6 beta
K09258 BCL3; B-cell CLL/lymphoma 3 protein
K09444 IRF1; interferon regulatory factor 1
K09558 BAG4; BCL2-associated athanogene 4
K09849 TRAF5; TNF receptor-associated factor 5
K10048 CEBPB; CCAAT/enhancer binding protein (C/EBP), beta
K10165 NOD2, CARD15; nucleotide-binding oligomerization domain-containing protein 2
K11859 TNFAIP3, A20, OTUD7C; tumor necrosis factor, alpha-induced protein 3 [EC:3.4.19.12 ]
K12499 CCL5; C-C motif chemokine 5
K12671 CXCL10, IP10; C-X-C motif chemokine 10
K12793 MAP3K7IP3, TAB3; TAK1-binding protein 3
K14624 CCL2, MCP1; C-C motif chemokine 2
K14625 CCL20; C-C motif chemokine 20
K15637 PGAM5; serine/threonine-protein phosphatase PGAM5 [EC:3.1.3.16 ]
K16060 BIRC2_3; baculoviral IAP repeat-containing protein 2/3
K16510 RPS6KA4, MSK2; ribosomal protein S6 kinase alpha-4 [EC:2.7.11.1 ]
K17072 IFI47; interferon gamma inducible protein 47
K19901 DAB2IP, AIP1; disabled homolog 2-interacting protein
K23972 FRMD8; FERM domain-containing protein 8
K27588 RHBDF; inactive rhomboid protein
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 Reference Authors Lee MY, Nam KH, Choi KC
Title iRhoms; Its Functions and Essential Roles.
Journal Related ko04064 NF-kappa B signaling pathway
ko04120 Ubiquitin mediated proteolysis
