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The TRAF family of signal transducers mediates NF-kappaB activation by the TRANCE receptor.

http://www.ncbi.nlm.nih.gov/pubmed/9774460

Tumor necrosis factor (TNF)-related activation-induced cytokine (TRANCE), a member of the TNF family expressed on activated T-cells, bone marrow stromal cells, and osteoblasts, regulates the function of dendritic cells (DC) and osteoclasts. The TRANCE receptor (TRANCE-R), recently identified as receptor activator of NF-kappabeta (RANK), activates NF-kappaB, a transcription factor critical in the differentiation and activation of those cells. In this report we identify the TNF receptor-associated factor (TRAF) family of signal transducers as important components of TRANCE-R-mediated NF-kappaB activation. Coimmunoprecipitation experiments suggested potential interactions between the cytoplasmic tail of TRANCE-R with TRAF1, TRAF2, TRAF3, TRAF5, and TRAF6. Dominant negative forms of TRAF2, TRAF5, and TRAF6 and an endogenous inhibitor of TRAF2, TRAF-interacting protein (TRIP), substantially inhibited TRANCE-R-mediated NF-kappaB activation, suggesting a role of TRAFs in regulating DC and osteoclast function. Overexpression of combinations of TRAF dominant negative proteins revealed competition between TRAF proteins for the TRANCE-R and the possibility of a TRAF-independent NF-kappaB pathway. Analysis of TRANCE-R deletion mutants suggested that the TRAF2 and TRAF5 interaction sites were restricted to the C-terminal 93 amino acids (C-region). TRAF6 also complexed to the C-region in addition to several regions N-terminal to the TRAF2 and TRAF5 association sites. Furthermore, transfection experiments with TRANCE-R deletion mutants revealed that multiple regions of the TRANCE-R can mediate NF-kappaB activation.

Pubmed ID: 9774460 RIS Download

Mesh terms: Binding Sites | Binding, Competitive | Carrier Proteins | Cell Differentiation | DNA-Binding Proteins | Dendritic Cells | Membrane Glycoproteins | NF-kappa B | Osteoclasts | Peptide Fragments | Protein Binding | Proteins | Proto-Oncogene Proteins | Proto-Oncogene Proteins c-jun | RANK Ligand | Receptors, Tumor Necrosis Factor | Signal Transduction | Suppression, Genetic | TNF Receptor-Associated Factor 2 | TNF Receptor-Associated Factor 5 | TNF Receptor-Associated Factor 6 | Transcription Factors | Tumor Necrosis Factor-alpha | ets-Domain Protein Elk-1

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Associated grants

  • Agency: NIAID NIH HHS, Id: AI13013
  • Agency: NIAID NIH HHS, Id: AI41082
  • Agency: NIGMS NIH HHS, Id: GM07739

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