{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T01:51:14Z","timestamp":1785376274125,"version":"3.55.0"},"reference-count":26,"publisher":"Portland Press Ltd.","issue":"03","license":[{"start":{"date-parts":[[2025,1,10]],"date-time":"2025-01-10T00:00:00Z","timestamp":1736467200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"HHS | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R01-GM140632-A1"],"award-info":[{"award-number":["R01-GM140632-A1"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,2,5]]},"abstract":"<jats:p>The sodium phosphate cotransporter-2A (NPT2A) mediates basal and parathyroid hormone (PTH)- and fibroblast growth factor-23 (FGF23)-regulated phosphate transport in proximal tubule cells of the kidney. Both basal and hormone-sensitive transport require sodium hydrogen exchanger regulatory factor-1 (NHERF1), a scaffold protein with tandem PDZ domains, PDZ1 and PDZ2. NPT2A binds to PDZ1. RGS14 persistently represses hormone action by binding to PDZ2. The RGS14 canonical RGS domain, Ras\/Rap-binding domains, and G protein regulatory motif cannot explain its regulatory effects on hormone-sensitive phosphate transport because these actions are mediated not only by the PTH receptor, a G protein-coupled receptor (GPCR), but also by the fibroblast growth factor receptor-1, a receptor tyrosine kinase that is not governed by G protein activity. Here, we identify the structural elements of RGS14 that mutually control the action of PTH and FGF23. RGS14 truncation constructs lacking upstream sequence and the RGS domain were fully functional. Removing the linker sequence between the RGS and RBD1 domains abolished RGS14 action. Examination of the \u03b1-helical linker region suggested candidate serine residues that might facilitate regulatory activities. RGS14 Ser266 and Ser269 are phosphorylated in response to PTH and FGF23, and replacement of these residues by Ala eliminated the actions of RGS14 on hormone-sensitive phosphate transport. PTH and FGF23 stimulated the phosphorylation of a peptide construct harboring the sites of purported phosphorylation and full-length RGS14. Mutating Ser266Ala and Ser269Ala abolished phosphorylation. The results establish that RGS14 regulation of phosphate transport requires targeted phosphorylation within the linker and an intact PDZ ligand.<\/jats:p>","DOI":"10.1042\/bcj20240122","type":"journal-article","created":{"date-parts":[[2025,1,10]],"date-time":"2025-01-10T14:57:26Z","timestamp":1736521046000},"page":"135-146","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Noncanonical RGS14 structural determinants control hormone-sensitive NPT2A-mediated phosphate transport"],"prefix":"10.1042","volume":"482","author":[{"given":"W. Bruce","family":"Sneddon","sequence":"first","affiliation":[{"name":"1Laboratory for GPCR Biology, Departments of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suneela","family":"Ramineni","sequence":"additional","affiliation":[{"name":"2Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. Emme","family":"Van Doorn","sequence":"additional","affiliation":[{"name":"2Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John R.","family":"Hepler","sequence":"additional","affiliation":[{"name":"2Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1905-1468","authenticated-orcid":false,"given":"Peter A.","family":"Friedman","sequence":"additional","affiliation":[{"name":"1Laboratory for GPCR Biology, Departments of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, U.S.A"},{"name":"3Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2025,1,30]]},"reference":[{"key":"2025020517014974100_BCJ-2024-0122C1","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1038\/nature00816","article-title":"Na+\/H+ exchanger regulatory factor 2 directs parathyroid hormone 1 receptor signalling","volume":"417","author":"Mahon","year":"2002","journal-title":"Nature New Biol."},{"key":"2025020517014974100_BCJ-2024-0122C2","doi-asserted-by":"crossref","first-page":"43787","DOI":"10.1074\/jbc.M306019200","article-title":"Activation-independent parathyroid hormone receptor internalization is regulated by NHERF1 (EBP50)","volume":"278","author":"Sneddon","year":"2003","journal-title":"J. Biol. Chem."},{"key":"2025020517014974100_BCJ-2024-0122C3","doi-asserted-by":"crossref","first-page":"37216","DOI":"10.1074\/jbc.M111.288357","article-title":"Fibroblast growth factor-23-mediated inhibition of renal phosphate transport in mice requires sodium-hydrogen exchanger regulatory factor-1 (NHERF-1) and synergizes with parathyroid hormone","volume":"286","author":"Weinman","year":"2011","journal-title":"J. Biol. Chem."},{"key":"2025020517014974100_BCJ-2024-0122C4","doi-asserted-by":"crossref","first-page":"18632","DOI":"10.1074\/jbc.M116.744052","article-title":"Convergent signaling pathways regulate parathyroid hormone and fibroblast growth factor-23 action on NPT2A-mediated phosphate transport","volume":"291","author":"Sneddon","year":"2016","journal-title":"J. Biol. 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