Zhenxi Li, Xinghai Yang, Ruifeng Fu, Zhipeng Wu, Shengzhao Xu, Jian Jiao, Ming Qian, Long Zhang, Chunbiao Wu, Tianying Xie, Jiqiang Yao, Zhixiang Wu, Wenjun Li, Guoli Ma, Yu You, Yihua Chen, Han-Kun Zhang, Yiyun Cheng, Xiaolong Tang, Pengfei Wu, Gewei Lian, Haifeng Wei, Jian Zhao, Jianrong Xu, Lianzhong Ai, Stefan Siwko, Yue Wang, Jin Ding, Gaojie Song, Jian Luo, Mingyao Liu, Jianru Xiao
Osteoclasts are over-activated as we age, which results in bone loss. Src deficiency in mice leads to severe osteopetrosis due to a functional defect in osteoclasts, indicating that Src function is essential in osteoclasts. G-protein-coupled receptors (GPCRs) are the targets for ∼35% of approved drugs but it is still unclear how GPCRs regulate Src kinase activity. Here, we reveal that GPR54 activation by its natural ligand Kisspeptin-10 (Kp-10) causes Dusp18 to dephosphorylate Src at Tyr 416. Mechanistically, Gpr54 recruits both active Src and the Dusp18 phosphatase at its proline/arginine-rich motif in its C terminus...
February 12, 2024: Nature Communications