A unique domain in RANK is required for Gab2 and PLCγ2 binding to establish osteoclastogenic signals
A unique domain in RANK is required for Gab2 and PLCγ2 binding to establish osteoclastogenic signals
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DOI：
10.1111/j.1365-2443.2009.01351.x
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发表时间：
2009-11
期刊：
影响因子：
2.1
通讯作者：
Yuu Taguchi;J. Gohda;T. Koga;H. Takayanagi;J. Inoue
中科院分区：
文献类型：
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作者：
Yuu Taguchi;J. Gohda;T. Koga;H. Takayanagi;J. Inoue
TRAF 6对破骨细胞生成以及RANK和CD 40介导的IKK和MAPK活化至关重要。RANK（而非CD 40）可促进破骨细胞生成，因为只有RANK通过PLCγ2诱导的Ca 2+振荡以及与含ITAM衔接子连接的免疫受体发出的共刺激信号诱导NFATc 1活化。这些先前的数据表明，RANK具有一个独特的结构域，在破骨细胞生成中与TRAF 6结合位点协同发挥作用。在这里，我们确定了这样一个结构域，RANK中的高度保守结构域（HCR），它在RANK和ITAM信号传导的早期阶段是必需的，但在其晚期信号传导中是必需的，包括NF-κB和PLCγ2的持续激活，导致NFATc 1激活。HCR募集衔接蛋白Gab 2，其在晚期进一步与PLCγ2结合。HCR介导的信号复合物的形成可以解释NF-κB和PLCγ2的持续激活。本研究将HCR确定为在RANK和ITAM信号之间的长期联系中起关键作用的独特结构域，为治疗策略提供了分子基础。
TRAF6 is essential for osteoclastogenesis and for both RANK‐ and CD40‐mediated activation of IKK and MAPKs. RANK, but not CD40, can promote osteoclastogenesis because only RANK induces NFATc1 activation through PLCγ2‐induced Ca2+ oscillations together with the co‐stimulatory signals emanating from immune receptors linked to ITAM‐containing adaptors. These previous data suggest that RANK harbors a unique domain that functions in concert with the TRAF6‐binding site in osteoclastogenesis. Here we identify such a domain, highly conserved domain in RANK (HCR), which is dispensable for the early phase of RANK and ITAM signaling but is essential for their late‐phase signaling, including sustained activation of NF‐κB and PLCγ2 leading to NFATc1 activation. HCR recruits an adaptor protein, Gab2, which further associates with PLCγ2 in the late phase. Formation of the HCR‐mediated signaling complex could account for the sustained activation of NF‐κB and PLCγ2. The present study identifies HCR as a unique domain that plays a critical role in the long‐term linkage between RANK and ITAM signals, providing a molecular basis for therapeutic strategies.