Search results for TRAF2

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Protein (4 results from a total of 13)

Identifier: R-HSA-9641123
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: PARK7: Q99497
Identifier: R-HSA-9641122
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: PCNT: O95613
Identifier: R-HSA-9641110
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: CETN1: Q12798
Identifier: R-HSA-9641114
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: IFT88: Q13099

Reaction (4 results from a total of 62)

Identifier: R-HSA-5668417
Species: Homo sapiens
Compartment: plasma membrane, cytosol
Tumor necrosis factor receptor 2 (TNFR2) signalling starts with recruitment of the adaptor protein TNF receptor-associated factor 2 (TRAF2) to the intracellular TRAF-binding motif and consequently to indirect recruitment of the TRAF2 associated proteins cellular inhibitors of apoptosis 1 and 2 (cIAP1 and cIAP2), along with a complex of TRAF3 and NF-kB-inducing kinase (NIK) which already interact with TRAF2 in unstimulated cells (Song & Donner. 1994, Rothe et al. 1995, Rothe et al. 1994). In resting cells usually NIK is targeted for ubiquitination and proteasomal degradation however in stimulated cells NIK escapes the ubiquitination by the cIAP1,2:TRAF2::TRAF3 complex due to rapid degradation of TRAF3.
Identifier: R-HSA-9796342
Species: Homo sapiens
Compartment: cytosol
Ligation of TNF-α to TNF receptor 1 (TNFR1) results in the sequential formation of several signaling complexes (Walczak H 2011). The rapidly forming complex-I (TNFR1 signaling complex) is assembled at the receptor’s cytoplasmic tail and consists of TNFR1, TRADD (TNFR1-associated death domain), TRAF2 (TNF receptor associated factor-2), RIPK1 (receptor-interacting serine/threonine protein kinase 1), and E3 ubiquitin (Ub) ligases BIRC2, BIRC3 (cIAP1/2, cellular inhibitor of apoptosis) and LUBAC (linear ubiquitin chain assembly complex) (Micheau O and Tschopp J 2003; Yuan J et al. 2019). Within this complex, RIPK1 and other proteins are rapidly conjugated with Ub chains by various E3 ligases. The ubiquitination status of RIPK1 determines cell fate downstream of the TNFR1 signaling complex. The conjugation of K63-linked Ub chains by BIRC2/3 or Met1-linked Ub chains by LUBAC, have been shown to promote RIPK1-dependent pro-survival NF-kappa-B signaling while inhibiting RIPK1-mediated apoptosis and necroptosis (Micheau O and Tschopp J 2003; Yuan J et al. 2019). Deubiquitinating enzymes, such as Ub carboxyl-terminal hydrolase CYLD, remove Ub chains from RIPK1 leading to the formation of the cytosolic complex IIa, TRADD:TRAF2:RIPK1:FADD:caspase-8 (CASP8), which activates apoptosis. In addition, RIPK1 also interacts with RIPK3 and MLKL to form the cytosolic complex IIb, which activates necroptosis (Micheau O and Tschopp J 2003; Yuan J et al. 2019). In these cell death-inducing complexes, RIPK1 activity is also regulated by ubiquitination (Amin P et al. 2018; de Almagro M et al. 2015). Besides, a RING-type E3 Ub ligase mind bomb-2 (MIB2) is also recruited to the TNFR1 signaling complex-I, where it conjugates inhibitory Ub chains to RIPK1 (Feltham R et al. 2018; Nakabayashi O et al. 2021). Studies in TNF-α-stimulated epithelial cells including human breast carcinoma MDA-MB-231, fibrosarcoma HT1080, and renal adenocarcinoma 786-0 cell lines showed that endogenous MIB2 is recruited to the TNFR1 complex in a time-dependent manner, peaking at 15 min (Feltham R et al 2018). Similar results were obtained in HeLa cells (Nakabayashi O et al. 2021). Endogenous MIB2 co-immunoprecipitated with ubiquitylated RIPK1 and other components of complex-I such as TRADD, TNFR1, and SHARPIN in TNF-treated MDA-MB-231 and 786-0 cells (Feltham R et al. 2018). RIPK1 is thought to mediate the recruitment of MIB2 to the TNFR1 complex (Feltham R et al. 2018). Co-immunoprecipitation analysis showed interaction between MIB2 and RIPK1 upon co-expression of tagged proteins in human embryonic kidney 293T (HEK293T) cells (Feltham R et al. 2018). In vitro-synthesized MIB2 co-purified RIPK1 from cellular extract of MDA-MB-231 cells upon TNF/Smac mimetic-164/zVAD-fm-induced cell death. Mutagenesis studies using overexpressed proteins revealed that the N-terminal MZM region of MIB2, which contains two Mib-HERC2 domains and a ZZ-type zinc finger motif (ZZ domain), interacted with the linker region of RIPK1 in HEK293T cells (Feltham R et al. 2018). Further, mutant MIB2 carrying mutation of the coordinating Cys residue of the ZZ domain within the MZM region did not interact with RIPK1 (Feltham R et al. 2018). When compared to wild-type (wt) MIB2, mutant MIB2 lacking the functional ZZ domain required for RIPK1 binding, failed to suppress TNF-induced CASP8 activation and cell death in MIB2-deficient MDA-MB-231 cells reconstituted with either wt MIB2 or mutant MIB2 (Feltham R et al. 2018). Structural and biochemical studies of MIB1, a paralogue of MIB2, further support the essential role of the MZM region in a substrate recognition (McMillan BJ et al. 2015; Guo B et al. 2016). MIB1 also interacted with RIPK1 in overexpression experiments using HEK293T cells (not shown here). However, RIPK1 was less efficiently ubiquitinated by MIB1 than by MIB2 (Feltham R et al. 2018). Upon TNF stimulation, recruited MIB2 conjugates different types of polyUb chains to RIPK1 targeting multiple lysine (K) residues (Feltham R et al. 2018). MIB2-mediated ubiquitination of K377 is thought to suppress auto-phosphorylation of RIPK1 at S166. Auto-phosphorylated RIPK1 provides a platform to form downstream death-inducing signalling complexes-IIa and IIb, causing apoptosis or necroptosis respectively (Laurien L et al. 2020; Chen X et al. 2022). MIB2-mediated ubiquitination of K604 and K634 within the death-domain (DD) of RIPK1 is predicted to affect both DD-mediated homotypic as well as heterotypic interactions of RIPK1 (Feltham R et al. 2018). MIB2 deficiency enhanced TNF-induced phosphorylation of RIPK1 at S166 in HeLa cells (Nakabayashi O et al. 2021). Depletion of MIB2 sensitized 786-0 cells to TNF-Induced and RIPK1-dependent cell death (Feltham R et al. 2018). Further, MIB2 deficiency had no effect on TNF-α-induced NF-kappa-B signaling pathway in human colorectal carcinoma HCT116 cells, HeLa cells (Nakabayashi O et al. 2021), MDA-MB-231, 786-0 and HEK293T cells (Feltham R et al. 2018) suggesting that the E3 Ub ligase activity of MIB2 protects cells from TNF-induced cell death without affecting the NF-kappa-B-mediated signaling.

Besides RIPK1, MIB2 was found to interact with other components downstream of the TNFR1 signaling complex. MIB2-mediated K48-linked ubiquitination of CYLD targets CYLD for proteasomal degradation thus preventing CYLD-mediated deubiquitination of RIPK1 and RIPK1-dependent cell death (Uematsu A et al. 2019). In addition, MIB2 binds cellular FLICE-like inhibitory protein long (FLIP(L) encoded by the CFLAR gene) in a RIPK1-independent manner (Nakabayashi O et al. 2021). As a homolog of caspase-8 (CASP8), CFLAR controls the pro-apoptotic function of CASP8 within the complex-IIa, TRADD:FADD:TRAF2:RIPK1:CASP8. The MIB2:CFLAR interaction increased stability of CFLAR (FLIP(L)) thereby attenuating TNF-α–induced apoptosis (Nakabayashi O et al. 2021). Thus, MIB2 is thought to suppress both RIPK1 kinase activity-dependent and -independent cell death, through ubiquitination of RIPK1 and cFLIPL, respectively (Nakabayashi O et al. 2021). Together, these data suggest that the E3 ligase activity of MIB2 suppresses the TNF-induced cell death by attaching polyUb chains to RIPK1, CFLAR and CYLD (Feltham R et al. 2018; Uematsu A et al. 2019; Nakabayashi O et al. 2021).

This Reactome event describes MIB2 binding to RIPK1 within the TNF-α:TNFR1:TRADD:RIPK1:TRAF2 complex.

Identifier: R-HSA-5676593
Species: Homo sapiens
Compartment: plasma membrane, cytosol
After clustering or dimerisation lymphotoxin-beta receptor (LTBR) initiates signal transduction by recruiting different TNF receptor-associated factor (TRAF) adaptors to the cytoplasmic domain. LTBR directly binds to several TRAFs, including TRAF2 and TRAF3 through its TRAF-interacting peptide motif (VanArsdale et al. 1997, Nakano et al. 1996, Sanjo et al. 2010).
Mitogen-activated protein kinase kinase kinase 14 (MAP3K14 also named as NIK) is a central signalling component of the non-canonical pathway and a tight control of NIK activation by TRAFs is essential to achieve controlled activation of the noncanonical NF-kB signalling. In unstimulated cells ubiquitin:NIK E3 ligase complex catalyses K48-linked ubiquitination of NIK, leading to constitutive NIK degradation. The ubiquitin:NIK E3 ligase is a multisubunit complex comprised of TRAF3 and TRAF2 in association with cellular inhibitors of apoptosis (cIAP1,2). In the activated state the TRAF2:cIAP1,2:TRAF3:NIK complex is recruited to the receptor upon ligand binding whereupon TRAF2-mediated, K63-linked ubiquitination of cIAP1,2 switches its K48 ubiquitin ligase activity from NIK to TRAF3. The resultant TRAF3 degradation destabilizes the TRAF-cIAP complex, so allowing the accumulation of newly synthesised NIK (Razani et al. 2011, Sun 2011).
Identifier: R-HSA-5676597
Species: Homo sapiens
Compartment: plasma membrane, cytosol
After its ligation with CD40 ligand (CD40L), CD40 is activated and triggers direct recruitment of multiple TRAF proteins and initiate non-canonical NF-kB pathway. TRAF1, TRAF2, TRAF3, and TRAF6, but not TRAF4 or TRAF5, shown to bind directly to the CD40 cytoplasmic domain (Pullen et al. 1998). TRAF2 is part of the regulatory complex which includes cellular inhibitor of apoptosis (cIAP) 1 and 2 and which in turn interacts with TRAF3 and NFkB-inducing kinase (NIK). In unstimulated cells this regulatory complex acts as a negative regulator of non-canonical NFkB pathway by constantly degrading NIK, whereas up on recruitment to CD40 this complex leads to accumulation of NIK (Elgueta et al. 2009, Schonbeck & Libby 2001).

Complex (4 results from a total of 38)

Identifier: R-HSA-5668475
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-5668435
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-5357866
Species: Homo sapiens
Compartment: plasma membrane
Identifier: R-HSA-8869451
Species: Homo sapiens
Compartment: cytosol
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