ArticleAmerican journal of physiology. Renal physiology2013
Disease-causing R1185C mutation of WNK4 disrupts a regulatory mechanism involving calmodulin binding and SGK1 phosphorylation sites.
Article in American journal of physiology. Renal physiology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 26 citations in OpenAlex.
- Navigating the multifaceted intricacies of the NaPhysiological reviews · 2024Review
- The Post-Translational Modification Networking in WNK-Centric Hypertension Regulation and Electrolyte Homeostasis.Biomedicines · 2022Review
- Aldosterone-Regulated Sodium Transport and Blood Pressure.Frontiers in physiology · 2022Review
- WNK4 kinase: from structure to physiology.American journal of physiology. Renal physiology · 2021Review
- Review
- The Enigmatic Role of Serum & Glucocorticoid Inducible Kinase 1 in the Endometrium.Frontiers in cell and developmental biology · 2020Review
- Review
- With no lysine kinase 4 modulates sodium potassium 2 chloride cotransporter activity in vivo.American journal of physiology. Renal physiology · 2018Article
- WNK signalling pathways in blood pressure regulation.Cellular and molecular life sciences : CMLS · 2017Review
- Phosphorylation of KLHL3 at serine 433 impairs its interaction with the acidic motif of WNK4: a molecular dynamics study.Protein science : a publication of the Protein Society · 2017Article
- Phosphorylation by PKC and PKA regulate the kinase activity and downstream signaling of WNK4.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Regulation of the epithelial Na+ channel by the mTORC2/SGK1 pathway.Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association · 2016Review
- Disease-causing mutations in KLHL3 impair its effect on WNK4 degradation.FEBS letters · 2013Article
- WNK4 is an essential effector of anterior formation in FGF signaling.Genes to cells : devoted to molecular & cellular mechanisms · 2013Article
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
The R1185C mutation in WNK4 is associated with pseudohypoaldosteronism type II (PHAII). Unlike other PHAII-causing mutations in the acidic motif, the R1185C mutation is located in the COOH-terminal region of WNK4. The goal of the study is to determine what properties of WNK4 are disrupted by the R1185C mutation. We found that the R1185C mutation is situated in the middle of a calmodulin (CaM) binding site and the mutation reduces the binding of WNK4 to Ca(2+)/CaM. The R1185C mutation is also close to serum- and glucocorticoid-induced protein kinase (SGK1) phosphorylation sites S1190 and S1217. In addition, we identified a novel SGK1 phosphorylation site (S1201) in WNK4, and phosphorylation at this site is reduced by Ca(2+)/CaM. In the wild-type WNK4, the level of phosphorylation at S1190 is the lowest and that at S1217 is the highest. In the R1185C mutant, phosphorylation at S1190 is eliminated and that at S1201 becomes the strongest. The R1185C mutation enhances the positive effect of WNK4 on the Na(+)-K(+)-2Cl(-) cotransporter 2 (NKCC2) as tested in Xenopus laevis oocytes. Deletion of the CaM binding site or phospho-mimicking at two or three of the SGK1 sites enhances the WNK4 effects on NKCC2. These results indicate that the R1185C mutation disrupts an inhibitory domain as part of the suppression mechanism of WNK4, leading to an elevated WNK4 activity at baseline. The presence of CaM binding and SGK1 phosphorylation sites in or close to the inhibitory domain suggests that WNK4 activity is subject to the regulation by intracellular Ca(2+) and phosphorylation.
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