A unique domain in RANK is required for Gab2 and PLCγ2 binding to establish osteoclastogenic signals

Abstract

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-γB 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-γB 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. © 2009 The Authors. Journal compilation © 2009 by the Molecular Biology Society of Japan/Blackwell Publishing Ltd.