| First Author | Izawa T | Year | 2012 |
| Journal | Mol Cell Biol | Volume | 32 |
| Issue | 14 | Pages | 2943-53 |
| PubMed ID | 22615494 | Mgi Jnum | J:186650 |
| Mgi Id | MGI:5432842 | Doi | 10.1128/MCB.00077-12 |
| Citation | Izawa T, et al. (2012) c-Src links a RANK/alphavbeta3 integrin complex to the osteoclast cytoskeleton. Mol Cell Biol 32(14):2943-53 |
| abstractText | 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 alphavbeta3-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, alphavbeta3 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 alphavbeta3 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/alphavbeta3 association. Thus, activated RANK prompts two distinct signaling pathways; one promotes osteoclast formation, and the other, in collaboration with c-Src-mediated linkage to alphavbeta3, organizes the cell's cytoskeleton. |
