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A unique domain in RANK is required for Gab2 and PLCγ2 binding to establish osteoclastogenic signals
Author(s) -
Taguchi Yuu,
Gohda Jin,
Koga Takako,
Takayanagi Hiroshi,
Inoue Junichiro
Publication year - 2009
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/j.1365-2443.2009.01351.x
Subject(s) - biology , rank (graph theory) , domain (mathematical analysis) , signal transduction , microbiology and biotechnology , mathematical analysis , mathematics , combinatorics
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 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‐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.