Xu Duorong, Wang Shunqing, Liu Wei, Liu Jianzhong, Feng Xu
Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
J Biol Chem. 2006 Feb 24;281(8):4678-90. doi: 10.1074/jbc.M510383200. Epub 2005 Dec 22.
Receptor activator of NF-kappaB (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.
核因子κB受体激活剂（RANK）配体（RANKL）及其受体RANK通过激活多种信号通路在破骨细胞生成和破骨细胞功能中发挥重要作用。然而，多项证据表明，RANK还传递一条对破骨细胞生成至关重要的未知信号通路。为了鉴定这条新的信号通路，我们对RANK胞质结构域进行了详细的结构/功能研究。一系列使用大量缺失/点突变体的研究阐明了一个对破骨细胞生成至关重要的特定4氨基酸基序（535IVVY538）。这个新基序在使巨噬细胞定向分化为破骨细胞谱系中起关键作用，但与破骨细胞功能或存活无关。此外，该基序不激活已知的RANK信号通路，表明它启动了一条新的信号通路。新基序的鉴定不仅为破骨细胞生成过程中的RANK信号传导提供了关键见解，更重要的是，RANK基序及其下游信号通路可能代表包括绝经后骨质疏松症在内的各种骨疾病的特定治疗靶点。
