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G-protein-coupled receptors (GPCRs) are the targets for \u223c35% 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. We show that Kp-10 binding to Gpr54 leads to the up-regulation of Dusp18.\n                    <jats:italic>Kiss1<\/jats:italic>\n                    ,\n                    <jats:italic>Gpr54<\/jats:italic>\n                    and\n                    <jats:italic>Dusp18<\/jats:italic>\n                    knockout mice all exhibit osteoclast hyperactivation and bone loss, and Kp-10 abrogated bone loss by suppressing osteoclast activity in vivo. Therefore, Kp-10\/Gpr54 is a promising therapeutic target to abrogate bone resorption by Dusp18-mediated Src dephosphorylation.\n                  <\/jats:p>","DOI":"10.1038\/s41467-024-44852-9","type":"journal-article","created":{"date-parts":[[2024,2,12]],"date-time":"2024-02-12T12:02:35Z","timestamp":1707739355000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Kisspeptin-10 binding to Gpr54 in osteoclasts prevents bone loss by activating Dusp18-mediated dephosphorylation of 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