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KEGG   PATHWAY: hsa04668
hsa04668                    Pathway                                
TNF signaling pathway - Homo sapiens (human)
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
hsa04668  TNF signaling pathway

nt06131  Apoptosis (viruses and bacteria)
nt06160  Human T-cell leukemia virus 1 (HTLV-1)
nt06161  Human immunodeficiency virus type 1 (HIV-1)
nt06163  Hepatitis C virus (HCV)
nt06164  Kaposi sarcoma-associated herpesvirus (KSHV)
nt06165  Epstein-Barr virus (EBV)
nt06166  Human papillomavirus (HPV)
nt06167  Human cytomegalovirus (HCMV)
nt06168  Herpes simplex virus 1 (HSV-1)
nt06223  TNF signaling
nt06231  Apoptosis
nt06263  Hepatocellular carcinoma
nt06414  Apoptosis
nt06416  TNF signaling
nt06461  Huntington disease
nt06516  TNF signaling
nt06524  Apoptosis
nt06527  Necroptosis
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
D00754  Thalidomide (JAN/USP/INN)
D01583  Pirfenidone (JAN/USAN/INN)
D03793  Ilomastat (USAN/INN)
D03795  Marimastat (USAN/INN)
D03797  Prinomastat (USAN/INN)
D03800  Rebimastat (USAN/INN)
D04687  Lenalidomide (JAN/USAN/INN)
D04690  Lenercept (USAN/INN)
D06017  Tebufelone (USAN/INN)
D06570  Camobucol (USAN/INN)
D06582  Elsibucol (USAN/INN)
D06619  Mifamurtide (USAN)
D06648  Succinobucol (USAN)
D08562  Tasonermin (INN)
D08976  Pomalidomide (JAN/USAN/INN)
D09813  Lenalidomide hydrate (JAN)
D11121  Gimsilumab (USAN/INN)
D11385  Inarigivir soproxil (USAN)
D11498  Quetmolimab (USAN)
D11703  Opinercept (INN)
D12306  Ordesekimab (USAN)
D12352  Eclitasertib (USAN/INN)
D12464  Dazukibart (USAN)
Other DBs
GO: 0033209
Homo sapiens (human) [GN:hsa]
7124  TNF; tumor necrosis factor [KO:K03156]
7132  TNFRSF1A; TNF receptor superfamily member 1A [KO:K03158]
9530  BAG4; BAG cochaperone 4 [KO:K09558]
8717  TRADD; TNFRSF1A associated via death domain [KO:K03171]
7186  TRAF2; TNF receptor associated factor 2 [KO:K03173] [EC:]
7188  TRAF5; TNF receptor associated factor 5 [KO:K09849]
8737  RIPK1; receptor interacting serine/threonine kinase 1 [KO:K02861] [EC:]
329  BIRC2; baculoviral IAP repeat containing 2 [KO:K16060]
330  BIRC3; baculoviral IAP repeat containing 3 [KO:K16060]
6885  MAP3K7; mitogen-activated protein kinase kinase kinase 7 [KO:K04427] [EC:]
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]
6416  MAP2K4; mitogen-activated protein kinase kinase 4 [KO:K04430] [EC:]
5609  MAP2K7; mitogen-activated protein kinase kinase 7 [KO:K04431] [EC:]
5599  MAPK8; mitogen-activated protein kinase 8 [KO:K04440] [EC:]
5602  MAPK10; mitogen-activated protein kinase 10 [KO:K04440] [EC:]
5601  MAPK9; mitogen-activated protein kinase 9 [KO:K04440] [EC:]
3725  JUN; Jun proto-oncogene, AP-1 transcription factor subunit [KO:K04448]
2353  FOS; Fos proto-oncogene, AP-1 transcription factor subunit [KO:K04379]
83737  ITCH; itchy E3 ubiquitin protein ligase [KO:K05632] [EC:]
8837  CFLAR; CASP8 and FADD like apoptosis regulator [KO:K04724]
5606  MAP2K3; mitogen-activated protein kinase kinase 3 [KO:K04432] [EC:]
5608  MAP2K6; mitogen-activated protein kinase kinase 6 [KO:K04433] [EC:]
5600  MAPK11; mitogen-activated protein kinase 11 [KO:K04441] [EC:]
6300  MAPK12; mitogen-activated protein kinase 12 [KO:K04441] [EC:]
5603  MAPK13; mitogen-activated protein kinase 13 [KO:K04441] [EC:]
1432  MAPK14; mitogen-activated protein kinase 14 [KO:K04441] [EC:]
1051  CEBPB; CCAAT enhancer binding protein beta [KO:K10048]
4217  MAP3K5; mitogen-activated protein kinase kinase kinase 5 [KO:K04426] [EC:]
9020  MAP3K14; mitogen-activated protein kinase kinase kinase 14 [KO:K04466] [EC:]
8517  IKBKG; inhibitor of nuclear factor kappa B kinase regulatory subunit gamma [KO:K07210]
3551  IKBKB; inhibitor of nuclear factor kappa B kinase subunit beta [KO:K07209] [EC:]
1147  CHUK; component of inhibitor of nuclear factor kappa B kinase complex [KO:K04467] [EC:]
4792  NFKBIA; NFKB inhibitor alpha [KO:K04734]
5970  RELA; RELA proto-oncogene, NF-kB subunit [KO:K04735]
4790  NFKB1; nuclear factor kappa B subunit 1 [KO:K02580]
1326  MAP3K8; mitogen-activated protein kinase kinase kinase 8 [KO:K04415] [EC:]
5604  MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:]
5594  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:]
5595  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:]
9252  RPS6KA5; ribosomal protein S6 kinase A5 [KO:K04445] [EC:]
8986  RPS6KA4; ribosomal protein S6 kinase A4 [KO:K16510] [EC:]
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]
11035  RIPK3; receptor interacting serine/threonine kinase 3 [KO:K08847] [EC:]
8772  FADD; Fas associated via death domain [KO:K02373]
841  CASP8; caspase 8 [KO:K04398] [EC:]
843  CASP10; caspase 10 [KO:K04400] [EC:]
840  CASP7; caspase 7 [KO:K04397] [EC:]
836  CASP3; caspase 3 [KO:K02187] [EC:]
197259  MLKL; mixed lineage kinase domain like pseudokinase [KO:K08849] [EC:]
192111  PGAM5; PGAM family member 5, mitochondrial serine/threonine protein phosphatase [KO:K15637] [EC:]
10059  DNM1L; dynamin 1 like [KO:K17065] [EC:]
1540  CYLD; CYLD lysine 63 deubiquitinase [KO:K08601] [EC:]
331  XIAP; X-linked inhibitor of apoptosis [KO:K04725] [EC:]
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]
3553  IL1B; interleukin 1 beta [KO:K04519]
3569  IL6; interleukin 6 [KO:K05405]
3600  IL15; interleukin 15 [KO:K05433]
3976  LIF; LIF interleukin 6 family cytokine [KO:K05419]
4049  LTA; lymphotoxin alpha [KO:K05468]
602  BCL3; BCL3 transcription coactivator [KO:K09258]
9021  SOCS3; suppressor of cytokine signaling 3 [KO:K04696]
7128  TNFAIP3; TNF alpha induced protein 3 [KO:K11859] [EC:]
7185  TRAF1; TNF receptor associated factor 1 [KO:K03172]
3726  JUNB; JunB proto-oncogene, AP-1 transcription factor subunit [KO:K09028]
4314  MMP3; matrix metallopeptidase 3 [KO:K01394] [EC:]
4318  MMP9; matrix metallopeptidase 9 [KO:K01403] [EC:]
4323  MMP14; matrix metallopeptidase 14 [KO:K07763] [EC:]
1906  EDN1; endothelin 1 [KO:K16366]
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]
6401  SELE; selectin E [KO:K06494]
7412  VCAM1; vascular cell adhesion molecule 1 [KO:K06527]
5743  PTGS2; prostaglandin-endoperoxide synthase 2 [KO:K11987] [EC:]
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:]
5293  PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:]
5291  PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:]
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]
207  AKT1; AKT serine/threonine kinase 1 [KO:K04456] [EC:]
208  AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:]
10000  AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:]
153090  DAB2IP; DAB2 interacting protein [KO:K19901]
3659  IRF1; interferon regulatory factor 1 [KO:K09444]
3456  IFNB1; interferon beta 1 [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)
hsa04010  MAPK signaling pathway
hsa04064  NF-kappa B signaling pathway
hsa04120  Ubiquitin mediated proteolysis
hsa04151  PI3K-Akt signaling pathway
hsa04210  Apoptosis
KO pathway

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