ArticleProceedings of the National Academy of Sciences of the United States of America2015
Src-family protein tyrosine kinase phosphorylates WNK4 and modulates its inhibitory effect on KCNJ1 (ROMK).
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 21 citations in OpenAlex.
- Mechanistic target of rapamycin complex-1 plays a role in inhibiting kidney KAmerican journal of physiology. Renal physiology · 2026Article
- The endocytic adaptor ARH facilitates potassium conservation by regulating ROMK and BK.American journal of physiology. Renal physiology · 2025Article
- Role of calcineurin in regulating renal potassium (KActa physiologica (Oxford, England) · 2024Review
- Control of sodium and potassium homeostasis by renal distal convoluted tubules.Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologica · 2023Article
- The serine-threonine protein phosphatases that regulate the thiazide-sensitive NaCl cotransporter.Frontiers in physiology · 2023Review
- Analysis of multiple gene co-expression networks to discover interactions favoring CFTR biogenesis and ΔF508-CFTR rescue.BMC medical genomics · 2021Article
- WNK4 kinase: from structure to physiology.American journal of physiology. Renal physiology · 2021Review
- Role of WNK4 and kidney-specific WNK1 in mediating the effect of high dietary KAmerican journal of physiology. Renal physiology · 2018Article
- ENaC and ROMK activity are inhibited in the DCT2/CNT of TgWnk4American journal of physiology. Renal physiology · 2017Article
- Potassium Homeostasis: The Knowns, the Unknowns, and the Health Benefits.Physiology (Bethesda, Md.) · 2017Review
- Role and mechanisms of regulation of the basolateral KActa physiologica (Oxford, England) · 2017Review
- ROMK expression remains unaltered in a mouse model of familial hyperkalemic hypertension caused by the CUL3Δ403-459 mutation.Physiological reports · 2016Article
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
With-no-lysine kinase 4 (WNK4) inhibits the activity of the potassium channel KCNJ1 (ROMK) in the distal nephron, thereby contributing to the maintenance of potassium homeostasis. This effect is inhibited via phosphorylation at Ser1196 by serum/glucocorticoid-induced kinase 1 (SGK1), and this inhibition is attenuated by the Src-family protein tyrosine kinase (SFK). Using Western blot and mass spectrometry, we now identify three sites in WNK4 that are phosphorylated by c-Src: Tyr(1092), Tyr(1094), and Tyr(1143), and show that both c-Src and protein tyrosine phosphatase type 1D (PTP-1D) coimmunoprecipitate with WNK4. Mutation of Tyr(1092) or Tyr(1143) to phenylalanine decreased the association of c-Src or PTP-1D with WNK4, respectively. Moreover, the Tyr1092Phe mutation markedly reduced ROMK inhibition by WNK4; this inhibition was completely absent in the double mutant WNK4(Y1092/1094F). Similarly, c-Src prevented SGK1-induced phosphorylation of WNK4 at Ser(1196), an effect that was abrogated in the double mutant. WNK4(Y1143F) inhibited ROMK activity as potently as wild-type (WT) WNK4, but unlike WT, the inhibitory effect of WNK4(Y1143F) could not be reversed by SGK1. The failure to reverse WNK4(Y1143F)-induced inhibition of ROMK by SGK1 was possibly due to enhancing endogenous SFK effect on WNK4 by decreasing the WNK4-PTP-1D association because inhibition of SFK enabled SGK1 to reverse WNK4(Y1143F)-induced inhibition of ROMK. We conclude that WNK4 is a substrate of SFKs and that the association of c-Src and PTP-1D with WNK4 at Tyr(1092) and Tyr(1143) plays an important role in modulating the inhibitory effect of WNK4 on ROMK.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.