{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T22:00:46Z","timestamp":1778277646708,"version":"3.51.4"},"reference-count":35,"publisher":"American Physiological Society","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Renal Physiology"],"published-print":{"date-parts":[[2012,7,1]]},"abstract":"<jats:p> With-no-Lysine kinase 4 (WNK4) inhibited ROMK (Kir1.1) channels and the inhibitory effect of WNK4 was abolished by serum-glucocorticoid-induced kinase 1 (SGK1) but restored by c-Src. The aim of the present study is to explore the mechanism by which Src-family tyrosine kinase (SFK) modulates the effect of SGK1 on WNK4 and to test the role of SFK-WNK4-SGK1 interaction in regulating ROMK channels in the kidney. Immunoprecipitation demonstrated that protein phosphatase 1 (PP1) binds to WNK4 at amino acid (aa) residues 695\u2013699 (PP1<jats:sup>#1<\/jats:sup>) and at aa 1211\u20131215 (PP1<jats:sup>#2<\/jats:sup>). WNK4<jats:sup>\u2212PP1#1<\/jats:sup> and WNK4<jats:sup>\u2212PP1#2<\/jats:sup>, in which the PP1<jats:sup>#1<\/jats:sup> or PP1<jats:sup>#2<\/jats:sup> binding site was deleted or mutated, inhibited ROMK channels as potently as WNK4. However, c-Src restored the inhibitory effect of WNK4 but not WNK4<jats:sup>\u2212PP1#1<\/jats:sup> on ROMK channels in the presence of SGK1. Moreover, expression of c-Src inhibited SGK1-induced phosphorylation of WNK4 but not WNK4<jats:sup>\u2212PP1#1<\/jats:sup> at serine residue 1196 (Ser<jats:sup>1196<\/jats:sup>). In contrast, coexpression of c-Src restored the inhibitory effect of WNK4<jats:sup>\u2212PP1#2<\/jats:sup> on ROMK in the presence of SGK1 and diminished SGK1-induced WNK4 phosphorylation at Ser<jats:sup>1196<\/jats:sup> in cells transfected with WNK4<jats:sup>\u2212PP1#2<\/jats:sup>. This suggests the possibility that c-Src regulates the interaction between WNK4 and SGK1 through activating PP1 binding to aa 695\u20139 thereby decreasing WNK4 phosphorylation and restoring the inhibitory effect of WNK4. This mechanism plays a role in suppressing ROMK channel activity during the volume depletion because inhibition of SFK or serine\/threonine phosphatases increases ROMK channel activity in the cortical collecting duct of rats on a low-Na diet. We conclude that regulation of phosphatase activity by SFK plays a role in determining the effect of aldosterone on ROMK channels and on renal K secretion. <\/jats:p>","DOI":"10.1152\/ajprenal.00676.2011","type":"journal-article","created":{"date-parts":[[2012,4,19]],"date-time":"2012-04-19T04:28:58Z","timestamp":1334809738000},"page":"F110-F119","source":"Crossref","is-referenced-by-count":38,"title":["Protein phosphatase 1 modulates the inhibitory effect of With-no-Lysine kinase 4 on ROMK channels"],"prefix":"10.1152","volume":"303","author":[{"given":"Dao-Hong","family":"Lin","sequence":"first","affiliation":[{"name":"Department of Pharmacology, New York Medical College, Valhalla, New York;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peng","family":"Yue","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, New York Medical College, Valhalla, New York;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jesse","family":"Rinehart","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut;"},{"name":"Systems Biology Institute, Yale University, West Haven, Connecticut; 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