RANK-mediated amplification of TRAF6 signaling leads to NFATc1 induction during osteoclastogenesis
RANK-mediated amplification of TRAF6 signaling leads to NFATc1 induction during osteoclastogenesis
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DOI：
10.1038/sj.emboj.7600564
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发表时间：
2005-02-23
期刊：
影响因子：
11.4
通讯作者：
Inoue, J
中科院分区：
文献类型：
--
作者：
Gohda, J;Akiyama, T;Inoue, J
RANK和CD40通过TRAF6将NF-kappaB和MAPK激活到相似的水平。尽管过表达TRAF6会导致破骨细胞的形成，但RANK而不是CD40会促进破骨细胞的形成。为了了解RANK在破骨细胞发生中特异性活性的分子基础，我们建立了一个破骨细胞形成系统，该系统由抗人CD40抗体介导的h40/mRK嵌合受体的刺激驱动，该嵌合受体由人CD40的胞外区和小鼠RANK的跨膜区和胞内区组成。通过将突变引入三个TRAF6结合位点，我们发现具有单一TRAF6结合位点的h40/mRK有效地诱导了钙振荡和破骨细胞形成中的主开关NFATc1的表达，而携带单一TRAF6结合位点的CD40则不能。然而，CD40的表达大约是h40/mRK的100倍，导致破骨细胞的形成，这表明RANK-TRAF6信号在NFATc1激活和破骨细胞形成方面比CD40-TRAF6信号更有效。这些结果表明，RANK可能含有一个特定的结构域来放大TRAF6信号。
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 antihuman 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.