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J. Biol. Chem., Vol. 281, Issue 8, 4678-4690, February 24, 2006

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A Novel Receptor Activator of NF-B (RANK) Cytoplasmic Motif Plays an Essential Role in Osteoclastogenesis by Committing Macrophages to the Osteoclast Lineage^*

From the Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294

Receptor activator of NF-B (RANK) ligand (RANKL) and its receptor RANK play an essential role in osteoclastogenesis and osteoclast function by activating several signaling pathways. However, several lines of evidence suggest that RANK also transmits an unidentified signaling pathway(s) essential for osteoclastogenesis. To identify the novel pathway(s), we carried out a detailed structure/function study of the RANK cytoplasmic domain. A series of studies using numerous deletion/point mutants elucidated a specific 4-amino acid motif (⁵³⁵IVVY⁵³⁸) essential for osteoclastogenesis. This novel motif plays a crucial role in committing macrophages to the osteoclast lineage but is not implicated in osteoclast function or survival. Moreover, this motif does not activate the known RANK signaling pathways, indicating that it initiates a novel pathway(s). The identification of the novel motif not only provides critical insight into RANK signaling in osteoclastogenesis, but more importantly, the RANK motif and its downstream signaling pathways may represent specific therapeutic targets for various bone diseases, including postmenopausal osteoporosis.

Received for publication, September 21, 2005 , and in revised form, December 12, 2005.

^* This work is supported by National Institutes of Health Grant AR 47830 (to X. F.), National Institutes of Health Research Core Center Grant P30AR46031 (to the University of Alabama at Birmingham Core Center for Musculoskeletal Disorders), and by a National Osteoporosis Foundation grant (to X. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Pathology, University of Alabama at Birmingham, 1670 University Blvd., VH G046B, Birmingham, AL 35294. Tel.: 205-975-0990; Fax: 205-934-1775; E-mail: xfeng{at}path.uab.edu.

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