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

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

Authors

  • Wong BR
  • Josien R
  • Lee SY
  • Vologodskaia M
  • Steinman RM
  • Choi Y

Journal

The Journal of biological chemistry

Publication Data

October 23, 1998

Associated Grants

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

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