TNF signaling (Homo sapiens)

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2831, 15368, 173, 4cytosolLigand-dependentcaspase activationTRADDZn2+ RIPK1 RIPK1(325-671) FADD CASP8(1-479) ADAM17TNF(77-233) TRAF2 TNFRSF1A(22-455) TNF(1-233) TRADD TNF-alphatrimer:TNF-R1trimerTNF-alpha:TNFR1FADD TNFRSF1A(22-455) TRAF2 TNF(77-233) TNF-alpha trimerTRADD TNFRSF1A:BAG4TRAF2:TRADD:RIPK1TRADD RIPK1TNF(1-233) TNF(77-233) RIPK1deubiquitinasesTNF-alpha trimerTNFRSF1A(22-455) TNF-alpha:TNFR1:TRADD:RIPK1:TRAF2TRADD:TRAF2:RIP1:FADDTRAF2 RIPK1 CASP8(1-479)BAG4TRAF2BAG4 ADAM17 TRAF2 TNFRSF1A(22-455) TRADD TNF(1-233) RIPK1 TRADD:TRAF2:RIP1:FADD:CASP8(1-479)FADDsolubleTNF-alpha:TNFR111511579, 10, 16, 18, 193, 411173, 4, 13, 1412


Description

The inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) is expressed in immune and nonimmune cell types including macrophages, T cells, mast cells, granulocytes, natural killer (NK) cells, fibroblasts, neurons, keratinocytes and smooth muscle cells as a response to tissue injury or upon immune responses to pathogenic stimuli (Köck A. et al. 1990; Dubravec DB et al. 1990; Walsh LJ et al. 1991; te Velde AA et al. 1990; Imaizumi T et al. 2000). TNF-alpha interacts with two receptors, namely TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). Activation of TNFR1 can trigger multiple signal transduction pathways inducing inflammation, proliferation, survival or cell death (Ward C et al. 1999; Micheau O and Tschopp J 2003; Widera D et al. 2006). Whether a TNF-alpha-stimulated cell will survive or die is dependent on autocrine/paracrine signals, and on the cellular context.

TNF binding to TNFR1 results initially in the formation of Complex I that consists of TNFR1, TRADD (TNFR1-associated death domain), TRAF2 (TNF receptor associated factor-2), RIPK1 (receptor interacting protein kinase 1), and BIRC1 and BIRC3 (cIAP1/2,cellular inhibitor of apoptosis) (Micheau O and Tschopp J 2003). This complex by default activates NFkappaB promoting cell survival (induction of anti-apoptotic proteins such as BIRC, cFLIP) and secretion of pro-inflammatory cytokines (TNF and IL-6). When the survival pathway is inhibited, TNF-induced signaling leads to the formation of Complex II that is made up of TRADD, FADD (Fas-associated death domain-containing protein, RIPK1,and procaspase-8 leading to the activation of caspase-8 and apoptotic cell death. When caspase activity is inhibited under certain pathophysiological conditions (e.g. caspase-8 inhibitory proteins such as CrmA and vICA after infection with cowpox virus or CMV) or by pharmacological agents, deubiquitinated RIPK1 is physically and functionally engaged by its homolog RIPK3 leading to formation of the necrosome, a necroptosis-inducing complex consisting of RIPK1 and RIPK3 (Tewari M & Dixit VM 1995; Fliss PM & Brune W 2012; Sawai H 2013; Moquin DM et al. 2013; Kalai M et al. 2002; Cho YS et al. 2009, He S et al. 2009, Zhang DW et al., 2009).TNF-alpha can also activate sphingomyelinase (SMASE, such as SMPD2,3) proteins to catalyze hydrolysis of sphingomyeline into ceramide (Adam D et al.1996; Adam-Klages S et al. 1998; Ségui B et al. 2001). Activation of neutral SMPD2,3 leads to an accumulation of ceramide at the cell surface and has proinflammatory effects. However, TNF can also activate the pro-apoptotic acidic SMASE via caspase-8 mediated activation of caspase-7 which in turn proteolytically cleaves and activates the 72kDa pro-A-SMase form (Edelmann B et al. 2011). Ceramide induces anti-proliferative and pro-apoptotic responses. Further, ceramide can be converted by ceramidase into sphingosine, which in turn is phosphorylated by sphingosine kinase into sphingosine-1-phosphate (S1P). S1P exerts the opposite biological effects to ceramide by activating cytoprotective signaling to promote cell growth counteracting the apoptotic stimuli (Cuvillier O et al. 1996). Thus, TNF-alpha-induced TNFR1 activation leads to divergent intracellular signaling networks with extensive cross-talk between the pro-apoptotic pathway, and the other NFkappaB, and JNK pathways providing highly specific cell responses initiated by various types of stimuli. Source:Reactome.</div>

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Bibliography

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History

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CompareRevisionActionTimeUserComment
114940view16:46, 25 January 2021ReactomeTeamReactome version 75
113385view11:45, 2 November 2020ReactomeTeamReactome version 74
112589view15:56, 9 October 2020ReactomeTeamReactome version 73
101505view11:37, 1 November 2018ReactomeTeamreactome version 66
101041view21:18, 31 October 2018ReactomeTeamreactome version 65
100572view19:51, 31 October 2018ReactomeTeamreactome version 64
100121view16:36, 31 October 2018ReactomeTeamreactome version 63
99671view15:07, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99267view12:45, 31 October 2018ReactomeTeamreactome version 62
93796view13:36, 16 August 2017ReactomeTeamreactome version 61
93333view11:20, 9 August 2017ReactomeTeamreactome version 61
88403view11:38, 5 August 2016FehrhartOntology Term : 'tumor necrosis factor mediated signaling pathway' added !
87132view18:49, 18 July 2016EgonwOntology Term : 'signaling pathway' added !
86420view09:17, 11 July 2016ReactomeTeamreactome version 56
83184view10:18, 18 November 2015ReactomeTeamVersion54
81554view13:05, 21 August 2015ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ADAM17 ProteinP78536 (Uniprot-TrEMBL)
ADAM17ComplexR-HSA-1251963 (Reactome)
BAG4 ProteinO95429 (Uniprot-TrEMBL)
BAG4ProteinO95429 (Uniprot-TrEMBL)
CASP8(1-479) ProteinQ14790 (Uniprot-TrEMBL)
CASP8(1-479)ProteinQ14790 (Uniprot-TrEMBL)
FADD ProteinQ13158 (Uniprot-TrEMBL)
FADDProteinQ13158 (Uniprot-TrEMBL)
Ligand-dependent caspase activationPathwayR-HSA-140534 (Reactome) Caspase-8 is synthesized as zymogen (procaspase-8) and is formed from procaspase-8 as a cleavage product. However, the cleavage itself appears not to be sufficient for the formation of an active caspase-8. Only the coordinated dimerization and cleavage of the zymogen produce efficient activation in vitro and apoptosis in cellular systems [Boatright KM and Salvesen GS 2003; Keller N et al 2010; Oberst A et al 2010].

The caspase-8 zymogens are present in the cells as inactive monomers, which are recruited to the death-inducing signaling complex (DISC) by homophilic interactions with the DED domain of FADD. The monomeric zymogens undergo dimerization and the subsequent conformational changes at the receptor complex, which results in the formation of catalytically active form of procaspase-8.[Boatright KM et al 2003; Donepudi M et al 2003; Keller N et al 2010; Oberst A et al 2010].

RIPK1 deubiquitinasesR-HSA-5357750 (Reactome)
RIPK1 ProteinQ13546 (Uniprot-TrEMBL)
RIPK1(325-671) ProteinQ13546 (Uniprot-TrEMBL)
RIPK1ProteinQ13546 (Uniprot-TrEMBL)
TNF(1-233) ProteinP01375 (Uniprot-TrEMBL)
TNF(77-233) ProteinP01375 (Uniprot-TrEMBL)
TNF-alpha

trimer:TNF-R1

trimer		R-HSA-3371401 (Reactome)
TNF-alpha trimerComplexR-HSA-3371351 (Reactome)
TNF-alpha trimerComplexR-HSA-3371370 (Reactome)
TNF-alpha:TNFR1:TRADD:RIPK1:TRAF2ComplexR-HSA-140946 (Reactome)
TNF-alpha:TNFR1ComplexR-HSA-74277 (Reactome)
TNFRSF1A(22-455) ProteinP19438 (Uniprot-TrEMBL)
TNFRSF1A:BAG4ComplexR-HSA-5634181 (Reactome)
TRADD ProteinQ15628 (Uniprot-TrEMBL)
TRADD:TRAF2:RIP1:FADD:CASP8(1-479)ComplexR-HSA-140976 (Reactome)
TRADD:TRAF2:RIP1:FADDComplexR-HSA-140977 (Reactome)
TRADDProteinQ15628 (Uniprot-TrEMBL)
TRAF2 ProteinQ12933 (Uniprot-TrEMBL)
TRAF2:TRADD:RIPK1ComplexR-HSA-140935 (Reactome)
TRAF2ProteinQ12933 (Uniprot-TrEMBL)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
soluble TNF-alpha:TNFR1ComplexR-HSA-3371397 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADAM17mim-catalysisR-HSA-3371385 (Reactome)
BAG4ArrowR-HSA-3371353 (Reactome)
BAG4ArrowR-HSA-83660 (Reactome)
CASP8(1-479)R-HSA-75240 (Reactome)
FADDR-HSA-140978 (Reactome)
R-HSA-140978 (Reactome) Once formed in context of the TNFR1 signaling complex the TRADD:TRAF2:RIPK1 complex may dissociate from the TNF:TNFR1 platform. With the recruitment of FADD and caspase-8 to the TRADD:TRAF2:RIPK1 complex the cell is pushed along the apoptotic pathway provided that the protective FLIP protein and TRAF2-associated BIRC (cIAPs) do not inhibit caspase-8 activation by RIPK1 and RIPK3-mediated activation of the necroptotic pathway.
R-HSA-3371353 (Reactome) The soluble form of TNF-alpha is cleaved from membrane-anchored TNF-alpha and retains the ability to bind to TNF receptor 1(TNFR1) and TNFR2.

BAG4, also known as silencer of death domain (SODD), belongs to the BAG family of anti-apoptotic proteins. Mammalian BAG4 was found to associate with TNFR1 preventing receptor signaling in the absence of ligand (Jiang Y et al. 1999; Miki K and Eddy EM 2002). Furthermore, crystallographic data and biochemical analysis showed that TNFR1 forms inactive homodimers or homotrimers in the absence of TNF by the N-terminal domain, the pre ligand assembly domain (PLAD) (Chan FK et al. 2000; Wang YL et al. 2011). Upon TNF-alpha binding BAG4 is quickly released from TNFR1 and three receptor molecules form a complex with the TNF trimer. The TNF-alpha homologue ligand, lymphotoxin-alpha (LTA, also known as TNF-beta), which as homotrimer only occurs as a soluble ligand, also interacts with TNFR1. LTA binds three receptor molecules and triggers the same effects as soluble TNF-alpha (Banner DW et al. 1993; Etemadi N et al. 2013).

The TNF-alpha:TNFR1 receptor complex then transmits the signal leading to cell death or survival. However, it remains unclear whether BAG4 binds to death domain of monomeric TNFR1 to prevent receptor oligomerization or recognizes receptor trimers to facilitate ATP-dependent TNFR1 trimer disassembly (Jiang Y et al. 1999; Miki K and Eddy EM 2002). Additionally, BAG4 is known to interact with HSP70, death receptor 3, and the anti-apoptotic protein Bcl-2 (Antoku et al. 2001; Brockmann et al. 2004; Jiang et al. 1999).

BAG4-overexpressing HeLa cells showed reduced cellular sensitivity to treatment with extracellular TNFalpha and CD95 ligand (Eichholtz-Wirth H et al. 2003). In addition, increased expression level of BAG4 in tumor cells leads to resistance of TNFalpha-induced cell death and is associated with pancreatic cancer, some types of melanoma, acute lymphoblastic leukemia etc.(Ozawa et al. 2000; Tao H et ql. 2007; Reuland SN et al. 2013). The physiological relevance of BAG4 for TNFR1 signaling, however, is difficult to judge because BAG4 knockout mice have no or only a mild effect on pro-inflammatory TNF signaling and give no evidence for an inhibitory role of BAG4 in TNFR1-induced cell death (Takada H et al. 2003; Endres R et al. 2003).

R-HSA-3371385 (Reactome) TNF-alpha is initially synthesized as a 26kDa transmembrane protein (membrane TNF-alpha), which is processed by proteolytic cleavage known as ectodomain shedding (Tang P et al. 1996). TNF-alpha-converting enzyme (TACE or ADAM17) mediates the cleavage of TNF-alpha generating the soluble 17kDa form (Robertshaw HJ & Brennan FM 2005). Inhibition of TACE activity resulted in an accumulation of unprocessed TNF-alpha on the cell surface of human monocytic cells (THP1) (Tabaka HN et al. 2012). Both membrane-bound and secreted forms of TNF-alpha are biologically active and may trigger different activities due to their differential capacities to stimulate TNFR1 and TNFR2. TNFR1 is efficiently activated by soluble and membrane TNF-alpha, TNFR2 signaling, however, is preferentially stimulated by membrane TNF-alpha while the soluble form has limited activity on this receptor despite efficient binding (Grell M et al. 1995; Grell M et al. 1998).
R-HSA-75240 (Reactome) Caspase-8-precursor (pro-caspase-8) binds TRAF2:TRADD:RIP1:FADD complex (Micheau and Tschopp, 2003).
R-HSA-83582 (Reactome) Once formed in context of the TNFR1 signaling complex the TRADD:TRAF2:RIPK1 complex may dissociate from the TNF:TNFR1 platform. With the recruitment of FADD and caspase-8 to the TRADD:TRAF2:RIPK1 complex the cell is pushed along the apoptotic pathway provided that the protective FLIP protein and TRAF2-associated BIRC (cIAPs) do not inhibit caspase-8 activation by RIPK1 and RIPK3-mediated activation of the necroptotic pathway.
R-HSA-83656 (Reactome) Once the TNF-alpha:TNFR1:TRADD:RIPK1 complex has been formed there is concomitant recruitment of TRAF2:cIAP1/2 complex and then of the TAB2:TAK1 and the IKK complex. RIPK1 and the TRAF2:cIAP1/2 can be released from TNFR1 receptor complex in a poorly understood process associated with internalization and after that there is the formation of a so called complex II containing the adapter protein FADD, caspase-8 and RIPK1. Complex II has the potential to activate caspase-8 (Micheau O & Tschopp J 2003). The steps leading to the JUN, NF kappaB or apoptotic pathways are rife with opportunities for modulation.
R-HSA-83660 (Reactome) BAG4, also known as silencer of death domain (SODD), belongs to the BAG family of anti-apoptotic proteins. Mammalian BAG4 was found to associate with TNFR1 preventing receptor signaling in the absence of ligand (Jiang Y et al. 1999; Miki K and Eddy EM 2002). Furthermore, crystallographic data and biochemical analysis showed that TNFR1 forms inactive homodimers or homotrimers in the absence of TNF by the N-terminal domain, the pre ligand assembly domain (PLAD) (Chan FK et al. 2000; Wang YL et al. 2011). Upon TNF-alpha binding BAG4 is quickly released from TNFR1 and three receptor molecules form a complex with the TNF trimer.

The TNF-alpha:TNFR1 receptor complex then transmits the signal leading to cell death or survival. However, it remains unclear whether BAG4 binds to death domain of monomeric TNFR1 to prevent receptor oligomerization or recognizes receptor trimers to facilitate ATP-dependent TNFR1 trimer disassembly (Jiang Y et al. 1999; Miki K and Eddy EM 2002). Additionally, BAG4 is known to interact with HSP70, death receptor 3, and the anti-apoptotic protein Bcl-2 (Antoku et al. 2001; Brockmann et al. 2004; Jiang et al. 1999).

BAG4-overexpressing HeLa cells showed reduced cellular sensitivity to treatment with extracellular TNFalpha and CD95 ligand (Eichholtz-Wirth H et al. 2003). In addition, increased expression level of BAG4 in tumor cells leads to resistance of TNFalpha-induced cell death and is associated with pancreatic cancer, some types of melanoma, acute lymphoblastic leukemia etc.(Ozawa et al. 2000; Tao H et ql. 2007; Reuland SN et al. 2013). The physiological relevance of BAG4 for TNFR1 signaling, however, is difficult to judge because BAG4 knockout mice have no or only a mild effect on pro-inflammatory TNF signaling and give no evidence for an inhibitory role of BAG4 in TNFR1-induced cell death (Takada H et al. 2003; Endres R et al. 2003).

RIPK1 deubiquitinasesArrowR-HSA-140978 (Reactome)
RIPK1R-HSA-83656 (Reactome)
TNF-alpha

trimer:TNF-R1

trimer		ArrowR-HSA-83582 (Reactome)
TNF-alpha

trimer:TNF-R1

trimer		R-HSA-83656 (Reactome)
TNF-alpha trimerArrowR-HSA-3371385 (Reactome)
TNF-alpha trimerR-HSA-3371353 (Reactome)
TNF-alpha trimerR-HSA-3371385 (Reactome)
TNF-alpha trimerR-HSA-83660 (Reactome)
TNF-alpha:TNFR1:TRADD:RIPK1:TRAF2ArrowR-HSA-83656 (Reactome)
TNF-alpha:TNFR1:TRADD:RIPK1:TRAF2R-HSA-83582 (Reactome)
TNF-alpha:TNFR1ArrowR-HSA-83660 (Reactome)
TNFRSF1A:BAG4R-HSA-3371353 (Reactome)
TNFRSF1A:BAG4R-HSA-83660 (Reactome)
TRADD:TRAF2:RIP1:FADD:CASP8(1-479)ArrowR-HSA-75240 (Reactome)
TRADD:TRAF2:RIP1:FADDArrowR-HSA-140978 (Reactome)
TRADD:TRAF2:RIP1:FADDR-HSA-75240 (Reactome)
TRADDR-HSA-83656 (Reactome)
TRAF2:TRADD:RIPK1ArrowR-HSA-83582 (Reactome)
TRAF2:TRADD:RIPK1R-HSA-140978 (Reactome)
TRAF2R-HSA-83656 (Reactome)
soluble TNF-alpha:TNFR1ArrowR-HSA-3371353 (Reactome)

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