Search results for TRAF2

Showing 23 results out of 105

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Protein (4 results from a total of 13)

Identifier: R-HSA-66370
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: TRAF2: Q12933
Identifier: R-HSA-8862199
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: Q12933
Identifier: R-HSA-6782848
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: TRAF2: Q12933
Identifier: R-HSA-8862193
Species: Homo sapiens
Compartment: cytosol
Primary external reference: UniProt: Q12933

Interactor (2 results from a total of 2)

Identifier: Q12933-2
Species: Homo sapiens
Primary external reference: UniProt: Q12933-2
Identifier: Q92844-3
Species: Homo sapiens
Primary external reference: UniProt: Q92844-3

Reaction (4 results from a total of 46)

Identifier: R-HSA-5668414
Species: Homo sapiens
Compartment: plasma membrane, cytosol
Following recruitment to receptor, TRAF2 mediates K63-linked polyubiquitination of cIAP1 and cIAP2. In addition to being an adaptor that recruits cIAP1/2 and TRAF3 to the receptor TRAF2 is also an E3 that activates cIAP1/2, through their K63-linked ubiquitination. This K63-linked ubiquitination stimulates the K48-ubiquitin ligase function of cIAP1/2 and may impose a change in the substrate specificity of cIAP1/2. Thus, rather than ubiquitinating NIK, cIAP1/2 ubiquitinates TRAF3 leading to its degradation (Vallabhapurapu et al. 2008, Wallach & Kovalenko 2008).
Identifier: R-HSA-83656
Species: Homo sapiens
Compartment: plasma membrane, cytosol
Once the TNF-alpha:TNFR1:TRADD:RIPK1 complex has been formed there is concomitant recruitment of TRAF2, BIRC2/3 (cIAP1/2) and then of the TAB2:TAK1 and the IKK complex. TRAF2 and BIRC (cIAP1) were found to form a complex in solution (Zheng C et al. 2010), suggesting that TNFR1:TRADD:RIPK1 receptor complex recruits the TRAF2:BIRC complex as a whole. However, the expression levels of BIRCs are typically lower compared to TRAF2 suggesting that TNF-stimulated TNFR1 complex may also recruit TRAF2 alone. 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.
Identifier: R-HSA-5634221
Species: Homo sapiens
Compartment: cytosol, plasma membrane
TNF-induced NFkappaB activates a group of gene products including TNF receptor associated factor (TRAF) family members and inhibitor of apoptosis proteins (BIRC or cIAP1/2). TRAFs and cIAP1/2 proteins may function cooperatively at the earliest checkpoint to suppress TNF-alpha-induced apoptosis (Rothe M et al. 1994,1995; Wang CU et al. 1998).

The TRAFs (TRAF1 to TRAF6) are a group of structurally similar adaptor proteins, in most cases with E3 ligase activity, that are involved in downstream signaling of various cell surface receptors such as TNFR1, TNFR2, CD40, TLRs and TCR (Jang HD et al. 2001; Fotin-Mleczek M et al. 2004; Su X et al. 2006). The hallmark feature of all TRAFs is a C-terminal TRAF-domain of approximately 230 amino acids, which is responsible for homo- and heterooligomerization of TRAF molecules (Rothe M et al. 1994). The differences in amino acid sequences in TRAF-domains define the range of TRAF interaction partners. Another important structural element of TRAFs, with an exception of TRAF1, is the N-terminal RING finger domain that modulates induction of NFkappaB and MAPK activities. As TRAF1 has no RING finger domain, the effects of TRAF1 on NFkB activation are rather unclear. It is believed that TRAF1 regulates TNF receptor activity through its ability to interact with TRAF2 (Rothe M et al.1995; Zheng C et al. 2010; Fotin-Mleczek M et al. 2004). Structural and biochemical studies showed that TRAF1:TRAF2 heterotrimer (1:2) binds BIRC (cIAP2) more strongly than TRAF2 homotrimers, suggesting that TRAF1 may modulate the interaction between TRAF2 and BIRC (cIAP1/2) and thus suppress TNF-alpha induced apoptosis (Zheng C et al. 2010). Noteworthy, TRAF1:TRAF2 heterotrimers and TRAF2 homotrimers also differ in their capability with certain receptors but there seems to be no difference with respect to TNFR1 recruitment (Fotin-Mleczek M et al. 2004). On the contrary, TNF-induced caspase-mediated cleavage of TRAF1 generates a C-terminal fragment with NFkB-inhibitory, pro-apoptotic activity (Leo e et al. 2001; Jang HD et al. 2001; Henkler F et al. 2003). Thus, the current data suggest that depending on its cleavage status TRAF1 may exert either cytoprotective or cytotoxic effect in death domain-containing receptor signaling pathways.

The heteromeric complex TRAF1:TRAF2 has been also implicated in the cross-talk of TNFR1 and TNFR2 (Wicovsky A et al. 2009).

Identifier: R-HSA-8869456
Species: Homo sapiens
Compartment: cytosol
USP4 specifically interacts with tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) and TRAF6 but not TRAF3. It deubiquitinates both TRAF2 and TRAF6 in vivo and in vitro, negatively regulating TNFalpha and IL-1beta-induced NF-kappaB activation and cancer cell migration (Xiao et al. 2012). USP25, a negative regulator of the virus-triggered type I IFN signaling pathway, cleaves lysine 48- and lysine 63-linked polyubiquitin chains in vitro and in vivo from DDX58 (Retinoic acid-inducible gene I (RIG-I)), TRAF2, and TRAF6 to inhibit RIG-I-like receptor-mediated IFN signaling (Zhong et al. 2013).

Complex (4 results from a total of 33)

Identifier: R-HSA-140935
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-5668489
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-8862198
Species: Homo sapiens
Compartment: nucleoplasm
Identifier: R-HSA-140946
Species: Homo sapiens
Compartment: plasma membrane

Set (4 results from a total of 4)

Identifier: R-HSA-918188
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-5689607
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-6782832
Species: Homo sapiens
Compartment: cytosol
Identifier: R-HSA-6782771
Species: Homo sapiens
Compartment: cytosol

Pathway (4 results from a total of 6)

Identifier: R-HSA-5676594
Species: Homo sapiens
Compartment: plasma membrane, cytosol, extracellular region
Activation of NF-kB is fundamental to signal transduction by members of the TNFRSF. Expression of NF-kB target genes is essential for mounting innate immune responses to infectious microorganisms but is also important for the proper development and cellular compartmentalization of secondary lymphoid organs necessary to orchestrate an adaptive immune response.
NF-kB transcription factor family is activated by two distinct pathways: the canonical pathway involving NF-kB1 and the non-canonical pathway involving NF-kB2. Unlike NF-kB1 signalling, which can be activated by a wide variety of receptors, the NF-kB2 pathway is typically activated by a subset of receptor and ligand pairs belonging to the tumor necrosis factor receptor (TNF) super family (TNFRSF) members. These members include TNFR2 (Rauert et al. 2010), B cell activating factor of the TNF family receptor (BAFFR also known as TNFRSF13C) (Kayagaki et al. 2002, CD40 (also known as TNFRSF5) (Coope et al. 2002, lymphotoxin beta-receptor (LTBR also known as TNFRSF3) (Dejardin et al. 2002), receptor activator for nuclear factor kB (RANK also known as TNFRSF11A) (Novack et al. 2003), CD27 and Fibroblast growth factor-inducible immediate-early response protein 14 (FN14 also known as TNFRSF12A) etc. These receptors each mediate specific biological roles of the non-canonical NF-kB. These non-canonical NF-kB-stimulating receptors have one thing in common and is the presence of a TRAF-binding motif, which recruits different TNF receptor-associated factor (TRAF) members, particularly TRAF2 and TRAF3, to the receptor complex during ligand ligation (Grech et al. 2004, Bishop & Xie 2007). Receptor recruitment of these TRAF members leads to their degradation which is a critical step leading to the activation of NIK and induction of p100 processing (Sun 2011, 2012).
Identifier: R-HSA-5668541
Species: Homo sapiens
Compartment: plasma membrane, nucleoplasm
Tumor necrosis factor-alpha (TNFA) exerts a wide range of biological effects through TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). Under normal physiological conditions TNFR2 exhibits more restricted expression, being found on certain subpopulation of immune cells and few other cell types (Grell et al. 1995 ). TNFR1 mediated signalling pathways have been very well characterized but, TNFR2 has been much less well studied. TNFR1 upon activation by TNFA activates apoptosis through two pathways, involving the adaptor proteins TNFR1-associated death domain (TRADD) and fas-associated death domain (FADD). In contrast, TNFR2 signalling especially in highly activated T cells, induces cell survival pathways that can result in cell proliferation by activating transcription factor NF-kB (nuclear factor-kB) via the alternative non-canonical route. TNFR2 signalling seems to play an important role, in particular for the function of regulatory T cells. It offers protective roles in several disorders, including autoimmune diseases, heart diseases, demyelinating and neurodegenerative disorders and infectious diseases (Faustman & Davis 2010).
Activation of the non-canonical pathway by TNFR2 is mediated through a signalling complex that includes TNF receptor-associated factor (TRAF2 and TRAF3), cellular inhibitor of apoptosis (cIAP1 and cIAP2), and NF-kB-inducing kinase (NIK). In this complex TRAF3 functions as a bridging factor between the cIAP1/2:TRAF2 complex and NIK. In resting cells cIAP1/2 in the signalling complex mediates K48-linked polyubiquitination of NIK and subsequent proteasomal degradation making NIK levels invisible. Upon TNFR2 stimulation, TRAF2 is recruited to the intracellular TRAF binding motif and this also indirectly recruits TRAF1 and cIAP1/2, as well as TRAF3 and NIK which are already bound to TRAF2 in unstimulated cells. TRAF2 mediates K63-linked ubiquitination of cIAP1/2 and this in turn mediates cIAP dependent K48-linked ubiquitination of TRAF3 leading to the proteasome-dependent degradation of the latter. As TRAF3 is degraded, NIK can no longer interact with TRAF1/2:cIAP complex. As a result NIK concentration in the cytosol increases and NIK gets stabilised and activated. Activated NIK phosphorylates IKKalpha, which in turn phosphorylates p100 (NFkB2) subunit. Phosphorylated p100 is also ubiquitinated by the SCF-beta-TRCP ubiquitin ligase complex and is subsequently processed by the proteaseome to p52, which is a transcriptionally competent NF-kB subunit in conjunction with RelB (Petrus et al. 2011, Sun 2011, Vallabhapurapu & Karin 2009).
Identifier: R-HSA-193704
Species: Homo sapiens
Besides signalling through the tyrosine kinase receptors TRK A, B, and C, the mature neurotrophins NGF, BDNF, and NT3/4 signal through their common receptor p75NTR. NGF binding to p75NTR activates a number of downstream signalling events controlling survival, death, proliferation, and axonogenesis, according to the cellular context. p75NTR is devoid of enzymatic activity, and signals by recruiting other proteins to its own intracellular domain. p75 interacting proteins include NRIF, TRAF2, 4, and 6, NRAGE, necdin, SC1, NADE, RhoA, Rac, ARMS, RIP2, FAP and PLAIDD. Here we annotate only the proteins for which a clear involvement in p75NTR signalling was demonstrated.
A peculiarity of p75NTR is the ability to bind the pro-neurotrophins proNGF and proBDNF. Proneurotrophins do not associate with TRK receptors, whereas they efficiently signal cell death by apoptosis through p75NTR. The biological action of neurotrophins is thus regulated by proteolytic cleavage, with proforms preferentially activating p75NTR, mediating apoptosis, and mature forms activating TRK receptors, to promote survival. Moreover, the two receptors are utilised to differentially modulate neuronal plasticity. For instance, proBDNF-p75NTR signalling facilitates LTD, long term depression, in the hippocampus (Woo NH, et al, 2005), while BDNF-TRKB signalling promotes LTP (long term potentiation). Many biological observations indicate a functional interaction between p75NTR and TRKA signaling pathways.
Identifier: R-HSA-5357956
Species: Homo sapiens
Activation of tumor necrosis factor receptor 1 (TNFR1) can trigger multiple signal transduction pathways to induce inflammation, cell 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 the cellular context. TNF-alpha-induced signals lead to the activation of transcriptional factors such as nuclear factor-kappa B (NFkappaB) and activator protein-1 (AP1) (Ward C et al. 1999; Widera D et al. 2006; Tsou HK et al. 2012).

The binding of TNF-alpha to TNFR1 leads to recruitment of the adapter protein TNFR1-associated death domain (TRADD) and of receptor‑interacting protein 1 (RIPK1). TRADD subsequently recruits also TNF receptor-associated factor 2 (TRAF2). RIPK1 is promptly K63-polyubiquitinated which results in the recruitment of the TAB2:TAK1 complex and the IkB kinase (IKK) complex to TNFR1. The activated IKK complex mediates phosphorylation of the inhibitor of NFkappaB (IkB), which targets IkB for ubiquitination and subsequent degradation. Released NFkappaB induces the expression of a variety of genes including inflammation-related genes and anti-apoptotic genes encoding proteins such as inhibitor of apoptosis proteins cIAP1/2, Bcl-2, Bcl-xL or cellular FLICE-like inhibitory protein (FLIP) (Blonska M et al. 2005; Ea CK et al. 2006; Wu CJ et al. 2006; Chen C et al. 2000; Manna SK et al. 2000; Kreuz S et al. 2001; Micheau O et al. 2001). NFkB-mediated inhibition of cell death also involves attenuating TNF-induced activation of c-Jun activating kinase (JNK). Whereas transient activation of JNK upon TNF treatment is associated with cellular survival, prolonged JNK activation contributes to cell death. However, as caspases activate JNK quite efficiently, JNKs are also regularly stimulated in course of apoptosis without being essential for cell death (Wicovsky A et al. 2007). AP1-mediated gene induction results from activation of JNK via TRAF2 (not shown here) (Tsou HK et al. 2012). While pro-survival signaling is initiated and regulated via the activated TNFR1 receptor complex at the cell membrane, cell death signals are induced by internalization-associated fashion upon the release of RIPK1 from the membrane complex (Micheau O and Tschopp J 2003; Schneider-Brachert W et al. 2004; Tchikov V et al. 2011).

TNFR1-mediated transcriptional activity of NFkB is both antiapoptotic and highly proinflammatory and thus must be tightly regulated to prevent constitutive activation that leads to persistent inflammation and cancer (Ward C et al. 1999; Fujihara S et al. 2002; Pekalski J et al. 2013; Kankaanranta H et al. 2014; Shukla S and Gupta S 2004; Jackson-Bernitsas DG et al. 2007; Zhang JY et al. 2007). Multiple mechanisms normally ensure the proper control of NFkappaB activation including two negative feedback loops mediated by NFkappaB inducible inhibitors, IkB-alpha (NFKBIA) and ubiquitin-editing protein A20 (He KL & Ting AT 2002; Wertz IE et al. 2004; Vereecke L et al. 2009; Pekalski J et al. 2013).

Icon (1 results from a total of 1)

Species: Homo sapiens
Curator: Steve Jupe
Designer: Cristoffer Sevilla
TRAF2 icon
TNF receptor-associated factor 2
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