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Activation of NF-kappaB by RANK requires tumor necrosis factor receptor-associated factor (TRAF) 6 and NF-kappaB-inducing kinase. Identification of a novel TRAF6 interaction motif.

Various members of the tumor necrosis factor (TNF) receptor superfamily activate nuclear factor kappaB (NF-kappaB) and the c-Jun N-terminal kinase (JNK) pathways through their interaction with TNF receptor-associated factors (TRAFs) and NF-kappaB-inducing kinase (NIK). We have previously shown that the cytoplasmic domain of receptor activator of NF-kappaB (RANK) interacts with TRAF2, TRAF5, and TRAF6 and that its overexpression activates NF-kappaB and JNK pathways. Through a detailed mutational analysis of the cytoplasmic domain of RANK, we demonstrate that TRAF2 and TRAF5 bind to consensus TRAF binding motifs located in the C terminus at positions 565-568 and 606-611, respectively. In contrast, TRAF6 interacts with a novel motif located between residues 340 and 358 of RANK. Furthermore, transfection experiments with RANK and its deletion mutants in human embryonic 293 cells revealed that the TRAF6-binding region (340-358), but not the TRAF2 or TRAF5-binding region, is necessary and sufficient for RANK-induced NF-kappaB activation. Moreover, a kinase mutant of NIK (NIK-KM) inhibited RANK-induced NF-kappaB activation. However, RANK-mediated JNK activation required a distal portion (427-603) of RANK containing the TRAF2-binding domain. Thus, our results indicate that RANK interacts with various TRAFs through distinct motifs and activates NF-kappaB via a novel TRAF6 interaction motif, which then activates NIK, thus leading to NF-kappaB activation, whereas RANK most likely activates JNK through a TRAF2-interacting region in RANK.

Pubmed ID: 10075662


  • Darnay BG
  • Ni J
  • Moore PA
  • Aggarwal BB


The Journal of biological chemistry

Publication Data

March 19, 1999

Associated Grants


Mesh Terms

  • Amino Acid Sequence
  • Binding Sites
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Carrier Proteins
  • Humans
  • JNK Mitogen-Activated Protein Kinases
  • Membrane Glycoproteins
  • Mitogen-Activated Protein Kinases
  • Molecular Sequence Data
  • NF-kappa B
  • Protein-Serine-Threonine Kinases
  • Proteins
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Receptors, Tumor Necrosis Factor
  • TNF Receptor-Associated Factor 2
  • TNF Receptor-Associated Factor 5
  • TNF Receptor-Associated Factor 6