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RANK‐mediated amplification of TRAF6 signaling leads to NFATc1 induction during osteoclastogenesis
Author(s) -
Gohda Jin,
Akiyama Toru,
Koga Takako,
Takayanagi Hiroshi,
Tanaka Sakae,
Inoue Junichiro
Publication year - 2005
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600564
Subject(s) - biology , osteoclast , cd40 , microbiology and biotechnology , rank (graph theory) , signal transduction , extracellular , luciferase , cytoplasm , nf κb , receptor , transfection , cell culture , biochemistry , genetics , in vitro , mathematics , combinatorics , cytotoxic t cell
RANK and CD40 activate NF‐κB 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 Ca 2+ 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.