Park Jin Hee, Jeong Eutteum, Lin Jingjing, Ko Ryeojin, Kim Ji Hee, Yi Sol, Choi Youngjin, Kang In-Cheol, Lee Daekee, Lee Soo Young
Department of Life Science, Ewha Womans University, Seoul, 03760, Korea.
The Research Center for Cellular Homeostasis, Ewha Womans University, Seoul, 03760, Korea.
Exp Mol Med. 2019 Jul 29;51(7):1-9. doi: 10.1038/s12276-019-0285-4.
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.
活化C激酶1（RACK1）的支架蛋白受体介导破骨细胞前体中核因子κB配体（RANKL）依赖性的p38丝裂原活化蛋白激酶（MAPK）激活；然而，RACK1在成熟破骨细胞中的作用尚不清楚。我们研究的目的是确定RACK1与c-Src之间的相互作用，这对破骨细胞功能至关重要。一种RACK1突变蛋白（酪氨酸228和246残基突变为苯丙氨酸；RACK1 Y228F/Y246F）不与c-Src相互作用。该突变体保留了分化为破骨细胞的能力；然而，RANKL介导的细胞骨架完整性、骨吸收活性和c-Src的磷酸化显著降低。重要的是，c-Src的Src同源2（SH2）结构域内的赖氨酸152（K152）参与RACK1结合。c-Src K152R突变体（赖氨酸152突变为精氨酸）损害破骨细胞对骨的吸收。这些发现不仅阐明了RACK1-c-Src轴作为破骨细胞功能关键调节因子的作用，也将有助于开发新的抗吸收疗法来预防与骨质流失相关的疾病。
