TNF-alpha signaling pathway (WP1047)

Bos taurus

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 [http://www.netpath.org/netslim/tnf_alpha_pathway.html NetSlim] database.

Authors

Martina Summer-Kutmon , Egon Willighagen , and Eric Weitz

Activity

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Organisms

Bos taurus

Communities

Annotations

Pathway Ontology

tumor necrosis factor mediated signaling pathway

Participants

Label Type Compact URI Comment
NRAS GeneProduct ensembl:ENSBTAG00000046797 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4893
HRAS GeneProduct ensembl:ENSBTAG00000046644 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3265
TNF Protein ensembl:ENSBTAG00000025471 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7124
TNFRSF1A Protein ensembl:ENSBTAG00000004211 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7132
TNFRSF1B Protein ensembl:ENSBTAG00000024928 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7133
TRADD Protein ensembl:ENSBTAG00000012642 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8717
TRAF2 Protein ensembl:ENSBTAG00000010497 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7186
MAP4K2 Protein ensembl:ENSBTAG00000001037 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5871
MAP2K4 Protein ensembl:ENSBTAG00000012103 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6416
MAP2K7 Protein ensembl:ENSBTAG00000010639 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5609
MAPK8 Protein ensembl:ENSBTAG00000007876 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5599
MAPK9 Protein ensembl:ENSBTAG00000004709 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5601
JUN Protein ensembl:ENSBTAG00000004037 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3725
MAP3K5 Protein ensembl:ENSBTAG00000009065 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4217
TXN Protein ensembl:ENSBTAG00000002953 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7295
MAP2K3 Protein ensembl:ENSBTAG00000010576 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5606
MAP2K6 Protein ensembl:ENSBTAG00000001609 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5608
MAPK3 Protein ensembl:ENSBTAG00000016156 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5595
MAPK1 Protein ensembl:ENSBTAG00000010312 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5594
GRB2 Protein ensembl:ENSBTAG00000004736 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2885
SOS1 Protein ensembl:ENSBTAG00000011643 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6654
RAF1 Protein ensembl:ENSBTAG00000045748 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5894
NSMAF Protein ensembl:ENSBTAG00000008958 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8439
SMPD2 Protein ensembl:ENSBTAG00000008145 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6610
PSMD2 Protein ensembl:ENSBTAG00000005660 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5708
TRAP1 Protein ensembl:ENSBTAG00000020109 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:10131
MADD Protein ensembl:ENSBTAG00000021700 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8567
KSR1 Protein ensembl:ENSBTAG00000006601 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8844
KSR2 Protein ensembl:ENSBTAG00000044119 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:283455
FADD Protein ensembl:ENSBTAG00000018274 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8772
CASP8 Protein ensembl:ENSBTAG00000015718 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:841
FLIP Protein ensembl:ENSBTAG00000010998 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8837
RIPK1 Protein ensembl:ENSBTAG00000006378 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8737
MAP3K7 Protein ensembl:ENSBTAG00000002625 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6885
MAP3K7IP1 Protein ensembl:ENSBTAG00000019828 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:10454
TAB2 Protein ensembl:ENSBTAG00000013454 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:23118
TAB3 Protein ensembl:ENSBTAG00000048159 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:257397
CHUK Protein ensembl:ENSBTAG00000007591 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1147
IKBKB Protein ensembl:ENSBTAG00000007599 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3551
IKBKG Protein ensembl:ENSBTAG00000006268 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8517
AKT1 Protein ensembl:ENSBTAG00000017636 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:207
NFKBIB Protein ensembl:ENSBTAG00000001778 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4793
PTPRCAP Protein ensembl:ENSBTAG00000004782 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5790
BIKBA Protein ensembl:ENSBTAG00000016683 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4792
SKP1 Protein ensembl:ENSBTAG00000025191 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:6500
CUL1 Protein ensembl:ENSBTAG00000008736 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8454
FBXW11 Protein ensembl:ENSBTAG00000015376 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:23291
NFKBIE Protein ensembl:ENSBTAG00000013705 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4794
REL Protein ensembl:ENSBTAG00000015386 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5966
NFKB1 Protein ensembl:ENSBTAG00000020270 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4790
NFKB2 Protein ensembl:ENSBTAG00000006017 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4791
MAP3K3 Protein ensembl:ENSBTAG00000008151 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4215
BTRC Protein ensembl:ENSBTAG00000007476 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:8945
PPP2CA Protein ensembl:ENSBTAG00000000469 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5515
PRKCZ Protein ensembl:ENSBTAG00000014119 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5590
CREBBP Protein ensembl:ENSBTAG00000026403 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1387
MAP3K1 Protein ensembl:ENSBTAG00000013790 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:4214
CSNK2A1 Protein ensembl:ENSBTAG00000012341 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1457
TBK1 Protein ensembl:ENSBTAG00000017401 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:29110
TANK Protein ensembl:ENSBTAG00000006654 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:10010
PLK1 Protein ensembl:ENSBTAG00000014453 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5347
TRAF1 Protein ensembl:ENSBTAG00000003012 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7185
TNFAIP3 Protein ensembl:ENSBTAG00000000436 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:7128
BIRC2 Protein ensembl:ENSBTAG00000035735 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:329
BIRC3 Protein ensembl:ENSBTAG00000024918 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:330
CASP3 Protein ensembl:ENSBTAG00000015874 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:836
DIABLO Protein ensembl:ENSBTAG00000004199 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:56616
OTUD7B Protein ensembl:ENSBTAG00000001586 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:56957
RFFL Protein ensembl:ENSBTAG00000013645 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:117584
RIPK3 Protein ensembl:ENSBTAG00000018422 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:11035
RFK Protein ensembl:ENSBTAG00000019345 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:55312
CYBA Protein ensembl:ENSBTAG00000003895 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1535
NOX1 Protein ensembl:ENSBTAG00000016761 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:27035
NOXO1 Protein ensembl:ENSBTAG00000020369 SH3 domain of NOXO1 interacts with TRADD in mouse embryonic fibroblasts and 293 cells.
HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:124056
RAC1 Protein ensembl:ENSBTAG00000009233 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5879
HSP90AA1 Protein ensembl:ENSBTAG00000006270 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:3320
CDC37 Protein ensembl:ENSBTAG00000011699 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:11140
MAP3K8 Protein ensembl:ENSBTAG00000011600 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:1326
BID2 Protein ensembl:ENSBTAG00000013988 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:637
BAX Protein ensembl:ENSBTAG00000013340 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:581
BCL2L1 Protein ensembl:ENSBTAG00000006526 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:598
BAD Protein ensembl:ENSBTAG00000012511 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:572
APAF1 Protein ensembl:ENSBTAG00000021661 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:317
CASP9 Protein ensembl:ENSBTAG00000002472 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:842
CASP7 Protein ensembl:ENSBTAG00000006615 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:840
GLUL Protein ensembl:ENSBTAG00000013631 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:2752
PYGL Protein ensembl:ENSBTAG00000011494 HomologyConvert: Homo sapiens to Bos taurus: Original ID = L:5836

References