A unique domain in RANK is required for Gab2 and PLCgamma2 binding to establish osteoclastogenic signals.
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.
Division of Cellular and Molecular Biology, Department of Cancer Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Yuu
Y
Taguchi
Jin
J
Gohda
Takako
T
Koga
Hiroshi
H
Takayanagi
Jun-ichiro
J
Inoue
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D019013:CD40 Antigens / Q000378:metabolism; D002454:Cell Differentiation; D017124:Conserved Sequence; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D008969:Molecular Sequence Data; D050778:NFATC Transcription Factors / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology*; D051966:Phospholipase C gamma / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics* / Q000378:metabolism*; D016415:Sequence Alignment; D015398:Signal Transduction; D015533:Transcriptional Activation
D048868:Adaptor Proteins, Signal Transducing; D019013:CD40 Antigens; C490895:GAB2 protein, human; D050778:NFATC Transcription Factors; D053246:Receptor Activator of Nuclear Factor-kappa B; D051966:Phospholipase C gamma