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Genes Cells. 2009 Nov;14(11):1331-45. doi: 10.1111/j.1365-2443.2009.01351.x. Epub 2009 Oct 20.

A unique domain in RANK is required for Gab2 and PLCgamma2 binding to establish osteoclastogenic signals.

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Division of Cellular and Molecular Biology, Department of Cancer Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.


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 PLCgamma2-induced Ca(2+) 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-kappaB and PLCgamma2 leading to NFATc1 activation. HCR recruits an adaptor protein, Gab2, which further associates with PLCgamma2 in the late phase. Formation of the HCR-mediated signaling complex could account for the sustained activation of NF-kappaB and PLCgamma2. 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.

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