TNF alpha Signaling Pathway (Bos taurus)

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Arachidonic acidROSCa2+Cytochrome CTNF alpha Signaling PathwayCYApoptosisCeramideNUPLA2CYNecrosisCytochrome CProcaspase 3/7HydroperoxidesROSNUTNFRSF1BMAP3K7IP1TANKPYGLTRAF2NOXO1TAB2BTRCDIABLOJUNSMPD2SELETNFRSF1BBIRC2TRAP1TXNOTUD7BPRKCZAKT1PPP2CAGRB2MAP3K3GLULPSMD2NFKBIEHRASDIABLOMAP4K2NFKBIBPLK1NFKB2BIRC2TAB3TRADDRIPK1MAP3K7MAP3K5CASP9MADDMAPK3TNFAPAF1SKP1TNFRSF1ACYBAMAP2K4IKBKGBADIL6TNFRSF1ATNFRSF1ATRAF1FADDRFFLIKBKBCCL2RELMAPK1TRADDKRASMAP3K14CSNK2A1HSP90AA1MAP3K8BAXMAP3K1FLIPFBXW11CREBBPSOS1BIRC3TNFRSF1BTRAF2TNFPro-CASP8MAPK9MAPK8TNFAIP3MAPK9KSR2BID2CASP3KSR1BIKBACUL1RAF1TNFTNFCDC37BIRC3TNFRIPK3MAP2K7BCL2L1RELMAP2K3RIPK1TNFTBK1PTPRCAPMAP2K6CASP8NSMAFNFKB2BCL2L1NOX1RAC1NFKB1RFKNFKB1MAPK8CHUKCASP7NRASRELPPUbPPPPCPUbPPPPPPPNUCYCYMTCYMTProteinReceptorProteinProteinmRNASmall 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 dissociation


Description

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. Please access this pathway at NetSlim database.

Comments

HomologyConvert 
This pathway was inferred from Homo sapiens pathway WP231(79942) with a 97.0% conversion rate.

Quality Tags

Ontology Terms

 

Bibliography

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History

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CompareRevisionActionTimeUserComment
89903view13:20, 6 October 2016EgonwModified description
80680view15:21, 30 June 2015Mkutmonhomology conversion
63380view23:07, 9 May 2013MaintBotUpdated to 2013 gpml schema
40552view19:31, 1 March 2011MaintBotRemoved redundant pathway information and comments
33791view00:12, 9 December 2009MaintBotAutomatic update of empty xrefs
32512view12:52, 17 August 2009MaintBotFixed text labels
32200view12:38, 15 August 2009MaintBotFixed text labels
31682view11:44, 14 August 2009MaintBotFixed group labels
31210view19:36, 13 August 2009MaintBotFixed text labels
30616view22:20, 29 July 2009MaintBotNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
AKT1ProteinENSBTAG00000017636 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:207
APAF1ProteinENSBTAG00000021661 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:317
BADProteinENSBTAG00000012511 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:572
BAXProteinENSBTAG00000013340 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:581
BCL2L1ProteinENSBTAG00000006526 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:598
BID2ProteinENSBTAG00000013988 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:637
BIKBAProteinENSBTAG00000016683 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4792
BIRC2RnaENSBTAG00000035735 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:329
BIRC3RnaENSBTAG00000024918 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:330
BTRCProteinENSBTAG00000007476 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8945
CASP3ProteinENSBTAG00000015874 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:836
CASP7ProteinENSBTAG00000006615 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:840
CASP8ProteinENSBTAG00000015718 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:841
CASP9ProteinENSBTAG00000002472 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:842
CCL2RnaENSBTAG00000037811 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6347
CDC37ProteinENSBTAG00000011699 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:11140
CHUKProteinENSBTAG00000007591 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1147
CREBBPProteinENSBTAG00000026403 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1387
CSNK2A1ProteinENSBTAG00000012341 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1457
CUL1ProteinENSBTAG00000008736 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8454
CYBAProteinENSBTAG00000003895 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1535
DIABLOProteinENSBTAG00000004199 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:56616
FADDProteinENSBTAG00000018274 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8772
FBXW11ProteinENSBTAG00000015376 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:23291
FLIPProteinENSBTAG00000010998 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8837
GLULProteinENSBTAG00000013631 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2752
GRB2ProteinENSBTAG00000004736 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2885
HRASGeneProductENSBTAG00000046644 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3265
HSP90AA1ProteinENSBTAG00000006270 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3320
IKBKBProteinENSBTAG00000007599 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3551
IKBKGProteinENSBTAG00000006268 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8517
IL6RnaENSBTAG00000014921 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3569
JUNProteinENSBTAG00000004037 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3725
KRASGeneProduct
KSR1ProteinENSBTAG00000006601 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8844
KSR2ProteinENSBTAG00000044119 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:283455
MADDProteinENSBTAG00000021700 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8567
MAP2K3ProteinENSBTAG00000010576 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5606
MAP2K4ProteinENSBTAG00000012103 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6416
MAP2K6ProteinENSBTAG00000001609 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5608
MAP2K7ProteinENSBTAG00000010639 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5609
MAP3K14Protein
MAP3K1ProteinENSBTAG00000013790 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4214
MAP3K3ProteinENSBTAG00000008151 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4215
MAP3K5ProteinENSBTAG00000009065 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4217
MAP3K7ProteinENSBTAG00000002625 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6885
MAP3K7IP1ProteinENSBTAG00000019828 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:10454
MAP3K8ProteinENSBTAG00000011600 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1326
MAP4K2ProteinENSBTAG00000001037 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5871
MAPK1ProteinENSBTAG00000010312 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5594
MAPK3ProteinENSBTAG00000016156 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5595
MAPK8ProteinENSBTAG00000007876 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5599
MAPK9ProteinENSBTAG00000004709 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5601
NFKB1ProteinENSBTAG00000020270 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4790
NFKB2ProteinENSBTAG00000006017 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4791
NFKBIBProteinENSBTAG00000001778 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4793
NFKBIEProteinENSBTAG00000013705 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4794
NOX1ProteinENSBTAG00000016761 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:27035
NOXO1ProteinENSBTAG00000020369 (Ensembl)
  • SH3 domain of NOXO1 interacts with TRADD in mouse embryonic fibroblasts and 293 cells.
  • HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:124056
NRASGeneProductENSBTAG00000046797 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4893
NSMAFProteinENSBTAG00000008958 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8439
OTUD7BProteinENSBTAG00000001586 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:56957
PLK1ProteinENSBTAG00000014453 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5347
PPP2CAProteinENSBTAG00000000469 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5515
PRKCZProteinENSBTAG00000014119 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5590
PSMD2ProteinENSBTAG00000005660 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5708
PTPRCAPProteinENSBTAG00000004782 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5790
PYGLProteinENSBTAG00000011494 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5836
Pro-CASP8Protein
RAC1ProteinENSBTAG00000009233 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5879
RAF1ProteinENSBTAG00000045748 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5894
RELProteinENSBTAG00000015386 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5966
RFFLProteinENSBTAG00000013645 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:117584
RFKProteinENSBTAG00000019345 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:55312
RIPK1ProteinENSBTAG00000006378 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8737
RIPK3ProteinENSBTAG00000018422 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:11035
SELERnaENSBTAG00000007307 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6401
SKP1ProteinENSBTAG00000025191 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6500
SMPD2ProteinENSBTAG00000008145 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6610
SOS1ProteinENSBTAG00000011643 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6654
TAB2ProteinENSBTAG00000013454 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:23118
TAB3ProteinENSBTAG00000048159 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:257397
TANKProteinENSBTAG00000006654 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:10010
TBK1ProteinENSBTAG00000017401 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:29110
TNFAIP3ProteinENSBTAG00000000436 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7128
TNFProteinENSBTAG00000025471 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7124
TNFRSF1AProteinENSBTAG00000004211 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7132
TNFRSF1BProteinENSBTAG00000024928 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7133
TRADDProteinENSBTAG00000012642 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8717
TRAF1ProteinENSBTAG00000003012 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7185
TRAF2ProteinENSBTAG00000010497 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7186
TRAP1ProteinENSBTAG00000020109 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:10131
TXNProteinENSBTAG00000002953 (Ensembl) HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7295

Annotated Interactions

No annotated interactions
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