RACK1 interaction with c-Src is essential for osteoclast function

The scaffolding protein receptor for activated C-kinase 1 (RACK1) mediates receptor activator of nuclear factor κΒ ligand (RANKL)-dependent activation of p38 MAPK in osteoclast precursors; however, the role of RACK1 in mature osteoclasts is unclear. The aim of our study was to identify the interaction between RACK1 and c-Src that is critical for osteoclast function. A RACK1 mutant protein (mutations of tyrosine 228 and 246 residues to phenylalanine; RACK1 Y228F/Y246F) did not interact with c-Src. The mutant retained its ability to differentiate into osteoclasts; however, the integrity of the RANKL-mediated cytoskeleton, bone resorption activity, and phosphorylation of c-Src was significantly decreased. Importantly, lysine 152 (K152) within the Src homology 2 (SH2) domain of c-Src is involved in RACK1 binding. The c-Src K152R mutant (mutation of lysine 152 into arginine) impaired the resorption of bone by osteoclasts. These findings not only clarify the role of the RACK1-c-Src axis as a key regulator of osteoclast function but will also help to develop new antiresorption therapies to prevent bone loss-related diseases. Bone disease: scaffolding protein essential for bone resorption The interaction between RACK1, a so-called scaffolding protein that can assemble components of a signaling pathway into complexes, and c-Src, an enzyme involved in the re-organization of the actin cytoskeleton, is crucial for bone resorption. Previous studies have implicated RACK1 in differentiation of osteoclasts, bone cells that resorb bone, but a study led by Soo Young Lee at Ewha Womans University, Seoul, South Korea, shows that it is also required for mature osteoclast function. Mutations in RACK1 or c-Src that prevented them from binding to each other impaired the bone resorption activity of osteoclasts seeded on bone slices. Osteoclasts bearing the mutated proteins were unable to form transient actin rings, cytoskeleton structures that are typically observed during bone resorption. These findings could lead to new targeted therapies against diseases characterized by bone loss such as osteoporosis.