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EMBO J. 2005 Feb 23;24(4):790-9. Epub 2005 Jan 27.

RANK-mediated amplification of TRAF6 signaling leads to NFATc1 induction during osteoclastogenesis.

Author information

1
Division of Cellular and Molecular Biology, Department of Cancer Biology, The Institute of Medical Science, The University of Tokyo, Shirokane-dai, Minato-ku, Tokyo, Japan.

Abstract

RANK and CD40 activate NF-kappaB and MAPKs to similar levels via TRAF6. Even though overexpression of TRAF6 results in osteoclast formation, RANK but not CD40 promotes osteoclastogenesis. To understand the molecular basis for RANK-specific activity in osteoclastogenesis, we created an osteoclast formation system driven by anti-human CD40 antibody-mediated stimulation of a chimeric receptor, h40/mRK, which consists of the extracellular domain of human CD40 and the transmembrane and cytoplasmic domains of mouse RANK. By introducing mutations into three TRAF6-binding sites of RANK, we found that h40/mRK with a single TRAF6-binding site efficiently induced Ca2+ oscillation and expression of NFATc1, a master switch in osteoclastogenesis, whereas CD40 carrying a single TRAF6-binding site did not. However, expression of CD40 that was approximately 100 times greater than that of h40/mRK resulted in osteoclast formation, indicating that the RANK-TRAF6 signal is more potent than the CD40-TRAF6 signal in terms of NFATc1 activation and osteoclastogenesis. These results suggest that RANK may harbor a specific domain that amplifies TRAF6 signaling.

PMID:
15678102
PMCID:
PMC549623
DOI:
10.1038/sj.emboj.7600564
[Indexed for MEDLINE]
Free PMC Article

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