Disease relevance of TRAF2

• CD30 induction of human immunodeficiency virus gene transcription is mediated by TRAF2 [1].
• The KSHV oncoprotein vFLIP contains a TRAF-interacting motif and requires TRAF2 and TRAF3 for signalling [2].
• In a selective portion of cases, examination of HRS cells for Epstein-Barr virus (EBV)-encoded RNA was performed by in situ hybridization, and the results were compared with the magnitude of TRAF1 and TRAF2 staining [3].
• We investigated the constitutive expression of TRAF1 and TRAF2 in Hodgkin and Reed-Sternberg (HRS) cells from archived paraffin-embedded tissues obtained from 21 patients diagnosed with classical Hodgkin's disease (HD) [3].
• Hepatitis C virus core protein potentiates TNF-alpha-induced NF-kappaB activation through TRAF2-IKKbeta-dependent pathway [4].

Psychiatry related information on TRAF2

• The point of bifurcation of this pathway and the decision-making molecules FADD, TRAF2 and RIP are discussed [5].

High impact information on TRAF2

• The stronger affinity and unique specificity of the TRADD-TRAF2 interaction are crucial for the suppression of apoptosis and provide a mechanistic basis for the perturbation of TRAF recruitment in sensitizing cell death induction [6].
• TRAF1 interacts with TNF-R2 indirectly through heterodimer formation with TRAF2 [7].
• The nature of the interaction indicates that an SXXE motif may be a TRAF2-binding consensus sequence [8].
• Dominant-negative TRAF2 inhibited activation of JNK by IRE1 [9].
• The cytoplasmic part of IRE1 bound TRAF2, an adaptor protein that couples plasma membrane receptors to JNK activation [9].

Chemical compound and disease context of TRAF2

• Our finding identifies p38, TNFalpha and NF-kappaB among key players that efficiently sensitizes melanoma cells to UV-, ribotoxic (anisomycin) and radiomimetic chemicals-induced programmed cell death in response to aberrant TRAF2 signaling [10].

Biological context of TRAF2

• Here we show that TRAF1 and TRAF2 interact with A20, a zinc finger protein, whose expression is induced by agents that activate NF-kappaB [11].
• This treatment leads to the rapid downregulation of FLIP but not to that of TRAF2 [12].
• Our findings provide evidence that a MC159/TRAF2/TRAF3 complex regulates a new aspect of Fas signaling, and identify MC159 FLIP as a molecule that targets multiple features of Fas-induced cell death [13].
• These observations suggest that TRAF2 may reside in the nucleus and directly regulate transcription, independent of its role in cytoplasmic signal transduction [14].
• In contrast, TRAF2 appears to play a positive role in B cell differentiation, and this activity is apparent even when its binding site on CD40 is disrupted [15].

Anatomical context of TRAF2

• Transient overexpression of TRAF2, but not TRAF1, induced NF-kappaB activation and HIV-1-long terminal repeat-driven transcription in the T cell line, KT3 [1].
• TRAF2 and TANK individually formed weak interactions with germinal center kinase (GCK)-related kinase (GCKR) [16].
• Previously, we found that a dominant-negative TRAF2 molecule inhibits CD40-mediated Ab secretion by the mouse B cell line CH12.LX [17].
• Rabbit antisera reactive with either amino- or carboxyl-terminal TRAF2 peptides frequently but not uniformly stain nuclei of cultured HUVEC or the established human endothelial cell line, ECV304 [14].
• In cultured human umbilical vein endothelial cells, endogenous TRAF2 colocalizes with the membrane-organizing protein caveolin-1 at regions of enrichment subjacent to the plasma membrane as detected by confocal fluorescence microscopy [18].

Associations of TRAF2 with chemical compounds

• A20 zinc finger protein inhibits TNF-induced apoptosis and stress response early in the signaling cascades and independently of binding to TRAF2 or 14-3-3 proteins [19].
• Substitution of alanine for threonine at 463 abolished the interaction with TRAF2 [20].
• Anatomy of TRAF2. Distinct domains for nuclear factor-kappaB activation and association with tumor necrosis factor signaling proteins [21].
• TNF-induced activation of stress activated protein kinases (SAPKs, Jun NH2-terminal kinases) requires TNF receptor associated factor 2 (TRAF2) [22].
• We now report a novel mechanism of TRAF2-mediated signal transduction revealed by an association of TRAF2 with sphingosine kinase (SphK), a lipid kinase that is responsible for the production of sphingosine 1-phosphate [23].

Physical interactions of TRAF2

• A20 has been shown to bind to TNF-receptor-associated factor 2 (TRAF2) and 14-3-3 chaperone proteins [19].
• By immunoprecipitation, overexpression of epitope-tagged IFNAR1 constructs, and glutathione S-transferase pulldown experiments, we demonstrate that TRAF2 rapidly binds to the IFNAR1 subunit of the IFN receptor upon IFN binding [24].

Regulatory relationships of TRAF2

• Human glutathione S-transferase P1-1 interacts with TRAF2 and regulates TRAF2-ASK1 signals [25].
• Under normal conditions, CYLD dominantly suppresses the ubiquitination of TRAF2 [26].
• Overexpression of the icp75TNFR cDNA results in TNF-induced activation of NFkappaB in a TNF receptor-associated factor 2 (TRAF2)-dependent manner [27].
• Thus, TRAF2 overexpression does not only block apoptosis induction by CD95 but also converts this death receptor into a mediator of invasiveness [28].

Other interactions of TRAF2

• The tumor necrosis factor receptor 2 signal transducers TRAF2 and c-IAP1 are components of the tumor necrosis factor receptor 1 signaling complex [29].
• Here we show that the TNF-R2 signal transducers TRAF2 and c-IAP1 are a part of the TNF-R1 signaling complex [29].
• Activation of stress-activated protein kinase/c-Jun N-terminal kinase, but not NF-kappaB, by the tumor necrosis factor (TNF) receptor 1 through a TNF receptor-associated factor 2- and germinal center kinase related-dependent pathway [30].
• The intracellular domains of human and mouse ATAR share only 25% identity, yet both interact with TRAF5 and TRAF2 [31].
• TNF-mediated activation of the stress-activated protein kinase pathway: TNF receptor-associated factor 2 recruits and activates germinal center kinase related [22].

Analytical, diagnostic and therapeutic context of TRAF2

• A novel heterotypic association between TRAF2 and -3 was detected and confirmed by immunoprecipitation in Ramos B cells that constitutively express both TRAF2 and -3 [32].
• Yeast two-hybrid assays and studies in HEK293 cells and primary lymphocytes indicated interactions between TRAF2 and GITR mediated by acidic residues in the cytoplasmic domain of the receptor [33].
• The NF-kappaB activation was analyzed using the electrophoresis mobility shift assay; TRAF1, TRAF2, TANK/I-TRAF, and caspase 3 expression were studied using Western blot analysis [34].
• The complete murine TRAF2 gene was obtained using a lambda phage and PCR cloning strategy [35].
• These results suggest that CD30 ligation may enhance the expression of HIV via TRAF-2-mediated activation of NF-kappaB [1].

References