Protein phosphatase 1 modulates the inhibitory effect of With-no-Lysine kinase 4 on ROMK channels

Dao Hong Lin, Peng Yue, Jesse Rinehart, Peng Sun, Zhijian Wang, Richard Lifton, Wen Hui Wang

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32 Scopus citations


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 695-699 (PP1#1) and at aa 1211-1215 (PP1#2). WNK4-PP1#1 and WNK4-PP1#2, in which the PP1#1 or PP1#2 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-PP1#1 on ROMK channels in the presence of SGK1. Moreover, expression of c-Src inhibited SGK1-induced phosphorylation of WNK4 but not WNK4-PP1#1 at serine residue 1196 (Ser1196). In contrast, coexpression of c-Src restored the inhibitory effect of WNK4-PP1#2 on ROMK in the presence of SGK1 and diminished SGK1-induced WNK4 phosphorylation at Ser1196 in cells transfected with WNK4-PP1#2. This suggests the possibility that c-Src regulates the interaction between WNK4 and SGK1 through activating PP1 binding to aa 695-9 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.

Original languageEnglish
Pages (from-to)F110-F119
JournalAmerican Journal of Physiology - Renal Physiology
Issue number1
StatePublished - 2012
Externally publishedYes


  • C-Src
  • Collecting duct
  • Renal K secretion
  • SGK1


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