Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 32, Issue 14, Pages 2943-2953Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00077-12
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Funding
- Shriners Hospitals for Children [8590]
- National Institutes of Health [AR032788, AR046523, AR054618, AR057037, AR057235, AR047830]
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RANK ligand (RANKL), by mechanisms unknown, directly activates osteoclasts to resorb bone. Because c-Src is key to organizing the cell's cytoskeleton, we asked if the tyrosine kinase also mediates RANKL-stimulated osteoclast activity. RANKL induces c-Src to associate with RANK(369-373) in an alpha v beta 3-dependent manner. Furthermore, RANK(369-373) is the only one of six putative TRAF binding motifs sufficient to generate actin rings and activate the same cytoskeleton-organizing proteins as the integrin. While c-Src organizes the cell's cytoskeleton in response to the cytokine, it does not participate in RANKL-stimulated osteoclast formation. Attesting to their collaboration, alpha v beta 3 and activated RANK coprecipitate, but only in the presence of c-Src. c-Src binds activated RANK via its Src homology 2 (SH2) domain and alpha v beta 3 via its SH3 domain, suggesting the kinase links the two receptors. Supporting this hypothesis, deletion or inactivating point mutation of either the c-Src SH2 or SH3 domain obviates the RANK/alpha v beta 3 association. Thus, activated RANK prompts two distinct signaling pathways; one promotes osteoclast formation, and the other, in collaboration with c-Src-mediated linkage to alpha v beta 3, organizes the cell's cytoskeleton.
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