TNF-alpha signaling pathway (Homo sapiens)

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Ca2+ROSCytochrome CNecrosisCytochrome CTNF-alpha signaling pathwayROSApoptosisCYNUCYProcaspase 3/7HydroperoxidesCeramidePLA2NUKSR2TRAF2RIPK1BIRC2MAPK9BCL2L1TNFRELBAXDIABLOBADAKT1NFKB2MAP3K14TAB3RIPK1KRASPLK1TAB1GLULPro-CASP8BIRC2NRASTXNTNFRSF1BCASP9NFKBIBMAPK1MAPK8TRAP1TRAF2NFKB2TNFRSF1APRKCZMAP2K6KSR1IKBKGBIRC3MAP2K3PPP2CATBK1MAP2K4JUNOTUD7BCSNK2A1NFKBIABIDFADDMAP2K7TNFNFKB1CREBBPCDC37RAC1CASP3CHUKRFKCUL1RIPK3TRAF1TNFRSF1BMAP3K1RELCCL2SMPD2RELABTRCPYGLPSMD2MAPK8TANKBIRC3TNFNOXO1FBXW11NOX1MAPK9BCL2L1TNFRAF1TAB2NFKB1TRADDGRB2CASP8TNFSOS1MAP3K7RELACFLARDIABLOMAP3K5MADD IL6TNFRSF1BNFKBIETRADDMAPK3CYBAHSP90AA1APAF1HRASTNFRSF1AMAP3K3CASP7NSMAFMAP4K2RFFLSKP1TNFAIP3TNFTNFRSF1AMAP3K8SELEIKBKBPCPPPPPPPPUbPPPPPUbNUCYCYMTCYMTProteinReceptorProteinProteinmRNASmall moleculeLigandInduced activationEnzyme complexInhibitionAuto catalysisTransportPositive regulation of gene expressionLeads to through unknown mechanismNegative regulation of gene expressionTranslocation UbiquitinationDeubiquitinationSumoylationInduced catalysisProtein-protein interactionAcetylationDephosphorylationLEGENDPhosphorylationDeacetylationGolgi apparatusEndosomeNucleusMitochondrionDesumoylationMethylationDemethylationPalmitoylationCytoplasmECPlasma membraneMTEndoplasmic reticulumCYPMGONUExtracellularERENProteolytic cleavageMoleculeProtein-protein dissociationArachidonic acid


Tumor necrosis factor alpha (TNFα) is a proinflammatory cytokine involved in various biological processes including regulation of cell proliferation, differentiation, apoptosis and immune response. TNFα is mainly produced by macrophages, also by other tissues including lymphoid cells, mast cells, endothelial cells, fibroblasts and neuronal tissues. TNF was identified as a soluble cytokine produced upon the activation by the immune system and able to exert cytotoxicity on tumor cell lines and cause tumor necrosis in animal models. TNF is primarily produced as a type II transmembrane protein arranged as stable homotrimers. The members of TNFα family exert their cellular effect through two distinct surface receptors of the TNF receptor family, TNFRSF1A (TNF-R1) and TNFRSF1B (TNF-R2). TNF-R1 is ubiquitously expressed, whereas TNF-R2 is found typically on cells of the immune system and is highly regulated. TNF-R1 and TNF-R2 binds membrane-integrated TNF (memTNF) as well as soluble TNF (sTNF) TNF-R1 contains a protein-protein interaction domain, called death domain (DD). This domain interacts with other DD-containing proteins and couples the death receptors to caspase activation and apoptosis. TNF-R2 induces gene expression by a TRAF-2 dependent signaling mechanism and also crosstalk's with TNF-R1. The pleiotropic biological effects of TNF can be attributed to its ability to simultaneously activate multiple signaling pathways in cells. Binding of TNFα to TNF-R1 on the cell surface triggers trimerization of the receptor and exposes intracellular domain of TNF-R1 following the release of an inhibitory protein. This intracellular domain recruits a death-domain containing adaptor protein, TRADD by homophilic interactions. TRADD, which acts as a scaffold protein, recruits TRAF2 and RIPK1 to form a complex , referred to as complex 1. Complex 1 is believed to be important in NF-κB activation and JNK activation. Complex 1 eventually dissociates from the receptor and integrates FADD and procaspase8 to form a complex referred to as the complex 2. In some cases, FADD/CASP8 association depends on high molecular weight complexes containing unubiquitinated RIPK1 as scaffold. Activated CASP8 induces CASP3 activity and execution of apoptosis. CASP8 activates apoptotic signal through another mechanism involving BID cleavage to truncated BID (tBID). tBID translocates to the mitochondria, increasing its outer membrane permeability. This results in cytochrome C release and activation of other caspases ultimately leading to apoptosis. Reactive oxygen species (ROS) have been found to increase during or after complex 1 and 2 formation to mediate or potentiate apoptosis upon TNF stimulation. TRAF-2 in complex 1 also activates the MAP kinase cascade, that leads to the activation of JNK, which on prolonged activation is believed to mediate both apoptosis and necrotic cell death. On complex 1 formation, NF-κB regulated anti-apoptotic gene products efficiently block initiation of apoptosis by complex 2. There is evidence of an early attempt to signal for apoptosis, which precedes the activation of NF-κB. The intracellular part of TNF-R1 binds to NSMAF which in turn mediates SMPD2-dependant ceramide production from cell membrane. Ceramide induces membrane permeabilization and apoptosis. This is observed before TNF-R1 internalization and NF-κB activation. This process is repressed on TNF-R1 internalization. This signal however is enough to initiate apoptosis in some cells. Another form of cell death, necrosis, is also mediated through TNF stimulation. On TNF stimulation, deubiquitinated RIPK1 dissociates from complex 1 and recruits RIPK3, FADD and CASP8. RIPK3 is autophosphorylated and phosphorylates RIPK1. Taken together, it has been speculated that RIP1 and RIP3 increase carbohydrate and glutamine metabolism of the cell, leading to increased ROS production and eventual necrosis. Recruitment of CASP8, activation of FADD/RIP1 and apoptosis induction, is blunted when RIPK1 becomes ubiquitinated. IKBKG binds to ubiquitinated RIPK1 to induce the activation of NF-κB, which exerts antiapoptotic effects. Cellular inhibitor of apoptosis, BIRC2 and BIRC3 has E3-ubiquitin ligase activity and functionally interact with TRAF2 and RIPK1 to induce polyubiquitination of RIPK1 upon TNF stimulation. Loss of these inhibitors attenuates TNF-induced NF-κB activation. The adaptor proteins TAB2 and TAB3 bind preferentially to Lys-63 polyubiquitinated RIPK1. This facilitates dimerization of MAP3K7, promoting its phosphorylation and activation. The IKK complex, consisting of CHUK, IKBKB and IKBKG, is recruited to RIP1 through binding of IKBKG to the ubiquitin chain of RIP1. Activated TAK1 directly phosphorylates IKBKB within the activation loop, leading to activation of the IKK complex and NF-κB. Certain regulatory proteins have been known to intercept NF-κB activation at the level of ubiquitinated RIP1. TNFAIP3, an NF-κB inhibitory protein, removes Lys-63 polyubiquitin chain and promotes Lys-48 linked ubiquitination of RIPK1 leading to its degradation and NF-κB signal termination. IKBKG stabilizes the bound polyubiquitinated RIPK1 by inhibiting its degradation, most probably by impairing its interaction with TNFAIP3. OTUD7B is recruited to the activated TNF-R1 and promotes RIP1 deubiquitination, thereby attenuating NF-κB activation. At internalized TNF-receptosomes, RIPK1 is ubiquitinated by endocytic vesicle associated RFFL, inducing RIPK1 degradation, which terminates NF-κB activation. When successful, TNF-induced NF-κB activation induces transcription and expression of genes encoding proinflammatory IL-6, anti-apoptotic factors BIRC2, BIRC3 and BCL-2 homologue BCL2L1. This causes the cell to remain inert to apoptotic stimuli.

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Proteins on this pathway have targeted assays available via the CPTAC Assay Portal.

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124583view05:13, 13 November 2022EgonwRemoved outdated license info: all CCZero now
124582view05:11, 13 November 2022EgonwConverted a label ("ROS") to a metabolite node with identifier
120699view13:12, 23 December 2021EweitzStandardize font, weight, case
116472view10:16, 7 May 2021EweitzModified title
111053view14:57, 3 July 2020L DupuisConverted interactions to graphical lines in legend
105836view23:09, 15 August 2019KhanspersModified description
89895view13:10, 6 October 2016EgonwModified description
81070view19:14, 19 July 2015EgonwAdded three missing ChEBI metabolite IDs.
79942view08:40, 28 April 2015Zariadded annotation for RAS
79280view22:53, 19 March 2015ZariAdded Identifier for SELE,CCL2 and NOXO1
78500view10:28, 7 January 2015MaintBotadded missing graphIds
72093view21:34, 24 October 2013Mkutmonadded datasource to "TNF"
71708view20:00, 17 October 2013MaintBotremoved data source from nodes without identifier
70103view18:53, 12 July 2013MaintBotupdated to 2013 schema
67700view11:51, 26 June 2013DdiglesOntology Term : 'tumor necrosis factor mediated signaling pathway' added !
47978view14:38, 23 April 2012NetPathModified description
44640view18:30, 22 September 2011Khanspersadded description
44639view18:29, 22 September 2011KhanspersModified categories
44638view18:29, 22 September 2011KhanspersUpdating content to NetSlim
41210view23:44, 1 March 2011MaintBotRemoved redundant pathway information and comments
36762view19:39, 29 April 2010Khansperstest
35303view23:33, 11 February 2010NsalomonisModified description
32365view13:44, 15 August 2009MaintBotFixed text labels
32004view13:18, 14 August 2009MaintBotFixed group labels
28972view11:00, 19 March 2009EveloSpecify description
28971view10:54, 19 March 2009EveloJus alignments
28970view10:42, 19 March 2009Evelocleaned up a bit
28911view08:09, 12 March 2009AlexanderPicoconnecting edges
28908view07:04, 12 March 2009AlexanderPicoconnecting edges
28907view06:23, 12 March 2009AlexanderPicoconnecting edges
28906view05:04, 12 March 2009Burakconnected the edges
28905view04:54, 12 March 2009BurakPeriodical save, work in progress
21163view11:30, 14 November 2008MaintBot[[Pathway:Homo sapiens:TNF-alpha-NF-kB NetPath 9]] moved to [[Pathway:WP231]]: Moved to stable identifier
8446view13:46, 7 January 2008MaintBot[[Pathway:Human:TNF-alpha-NF-kB NetPath 9]] moved to [[Pathway:Homo sapiens:TNF-alpha-NF-kB NetPath 9]]: Renaming species
7839view16:21, 18 December 2007MaintBotfixed category names
7307view12:42, 4 November 2007MaintBotAdded categories to GPML
6399view22:18, 22 May 2007A.Pandeygpml file for [[Human:TNF-alpha-NF-kB_NetPath_9]]

External references


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NameTypeDatabase referenceComment
IL6Rna3569 (Entrez Gene)
AKT1Protein207 (Entrez Gene)
APAF1Protein317 (Entrez Gene)
Arachidonic acidMetaboliteCHEBI:15843 (ChEBI)
BADProtein572 (Entrez Gene)
BAXProtein581 (Entrez Gene)
BCL2L1Protein598 (Entrez Gene)
BIDProtein637 (Entrez Gene)
BIRC2Protein329 (Entrez Gene)
BIRC3Protein330 (Entrez Gene)
BTRCProtein8945 (Entrez Gene)
CASP3Protein836 (Entrez Gene)
CASP7Protein840 (Entrez Gene)
CASP8Protein841 (Entrez Gene)
CASP9Protein842 (Entrez Gene)
CCL2Rna6347 (Entrez Gene)
CDC37Protein11140 (Entrez Gene)
CFLARProtein8837 (Entrez Gene)
CHUKProtein1147 (Entrez Gene)
CREBBPProtein1387 (Entrez Gene)
CSNK2A1Protein1457 (Entrez Gene)
CUL1Protein8454 (Entrez Gene)
CYBAProtein1535 (Entrez Gene)
CeramideMetaboliteCHEBI:17761 (ChEBI)
DIABLOProtein56616 (Entrez Gene)
FADDProtein8772 (Entrez Gene)
FBXW11Protein23291 (Entrez Gene)
GLULProtein2752 (Entrez Gene)
GRB2Protein2885 (Entrez Gene)
HRASGeneProduct3265 (Entrez Gene)
HSP90AA1Protein3320 (Entrez Gene)
HydroperoxidesMetaboliteCHEBI:35923 (ChEBI)
IKBKBProtein3551 (Entrez Gene)
IKBKGProtein8517 (Entrez Gene)
JUNProtein3725 (Entrez Gene)
KRASGeneProduct3845 (Entrez Gene)
KSR1Protein8844 (Entrez Gene)
KSR2Protein283455 (Entrez Gene)
MADDProtein8567 (Entrez Gene)
MAP2K3Protein5606 (Entrez Gene)
MAP2K4Protein6416 (Entrez Gene)
MAP2K6Protein5608 (Entrez Gene)
MAP2K7Protein5609 (Entrez Gene)
MAP3K1Protein4214 (Entrez Gene)
MAP3K14Protein9020 (Entrez Gene)
MAP3K3Protein4215 (Entrez Gene)
MAP3K5Protein4217 (Entrez Gene)
MAP3K7Protein6885 (Entrez Gene)
MAP3K8Protein1326 (Entrez Gene)
MAP4K2Protein5871 (Entrez Gene)
MAPK1Protein5594 (Entrez Gene)
MAPK3Protein5595 (Entrez Gene)
MAPK8Protein5599 (Entrez Gene)
MAPK9Protein5601 (Entrez Gene)
NFKB1Protein4790 (Entrez Gene)
NFKB2Protein4791 (Entrez Gene)
NFKBIAProtein4792 (Entrez Gene)
NFKBIBProtein4793 (Entrez Gene)
NFKBIEProtein4794 (Entrez Gene)
NOX1Protein27035 (Entrez Gene)
NOXO1Protein124056 (Entrez Gene) SH3 domain of NOXO1 interacts with TRADD in mouse embryonic fibroblasts and 293 cells.
NRASGeneProduct4893 (Entrez Gene)
NSMAFProtein8439 (Entrez Gene)
OTUD7BProtein56957 (Entrez Gene)
PLK1Protein5347 (Entrez Gene)
PPP2CAProtein5515 (Entrez Gene)
PRKCZProtein5590 (Entrez Gene)
PSMD2Protein5708 (Entrez Gene)
PYGLProtein5836 (Entrez Gene)
Pro-CASP8Protein541 (Entrez Gene)
RAC1Protein5879 (Entrez Gene)
RAF1Protein5894 (Entrez Gene)
RELProtein5966 (Entrez Gene)
RELAProtein5790 (Entrez Gene)
RELAProtein5966 (Entrez Gene)
RFFLProtein117584 (Entrez Gene)
RFKProtein55312 (Entrez Gene)
RIPK1Protein8737 (Entrez Gene)
RIPK3Protein11035 (Entrez Gene)
ROSMetaboliteCHEBI:26523 (ChEBI)
SELERna6401 (Entrez Gene)
SKP1Protein6500 (Entrez Gene)
SMPD2Protein6610 (Entrez Gene)
SOS1Protein6654 (Entrez Gene)
TAB1Protein10454 (Entrez Gene)
TAB2Protein23118 (Entrez Gene)
TAB3Protein257397 (Entrez Gene)
TANKProtein10010 (Entrez Gene)
TBK1Protein29110 (Entrez Gene)
TNFProtein7124 (Entrez Gene)
TNFAIP3Protein7128 (Entrez Gene)
TNFRSF1AProtein7132 (Entrez Gene)
TNFRSF1BProtein7133 (Entrez Gene)
TRADDProtein8717 (Entrez Gene)
TRAF1Protein7185 (Entrez Gene)
TRAF2Protein7186 (Entrez Gene)
TRAP1Protein10131 (Entrez Gene)
TXNProtein7295 (Entrez Gene)

Annotated Interactions

No annotated interactions

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