A novel receptor activator of NF-kappaB (RANK) cytoplasmic motif plays an essential role in osteoclastogenesis by committing macrophages to the osteoclast lineage.
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.
Xu
Duorong
D
Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Wang
Shunqing
S
Liu
Wei
W
Liu
Jianzhong
J
Feng
Xu
X
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D001862:Bone Resorption; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D019070:Cell Lineage; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D005434:Flow Cytometry; D017353:Gene Deletion; D007249:Inflammation; D008264:Macrophages / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009154:Mutation; D010010:Osteoclasts / Q000378:metabolism*; D010024:Osteoporosis / Q000473:pathology; D017354:Point Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics; D012190:Retroviridae / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D013329:Structure-Activity Relationship
D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse