ArticleProceedings of the National Academy of Sciences of the United States of America2017
Phosphorylation by PKC and PKA regulate the kinase activity and downstream signaling of WNK4.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed, 64 citations in OpenAlex.
- No lysine? No problem: the surprising roles of WNK kinases in physiology and disease.The Biochemical journal · 2026Review
- Exploring the Role of the SLC12A Cation-Coupled Chloride Cotransporters in the Cardiovascular System.Cells · 2026Review
- NRBP1 and TSC22D proteins affect distal convoluted tubule physiology through modulation of the WNK pathway.Science advances · 2025Article
- Article
- NRBP1 and TSC22D proteins impact distal convoluted tubule physiology through modulation of the WNK pathway.bioRxiv : the preprint server for biology · 2024Article
- Sodium Chloride Cotransporter in Hypertension.Biomedicines · 2024Review
- Inhibition of mTORC2 promotes natriuresis in Dahl salt-sensitive rats via the decrease of NCC and ENaC activity.American journal of physiology. Renal physiology · 2024Article
- Navigating the multifaceted intricacies of the NaPhysiological reviews · 2024Review
- KS-WNK1 is required for the renal response to extreme changes in potassium intake.American journal of physiology. Renal physiology · 2024Article
- Arginine vasopressin regulates the renal NaAmerican journal of physiology. Renal physiology · 2024Article
- Alpha 1-antitrypsin mitigates salt-sensitive hypertension in juvenile mice by reducing diacylglycerol concentrations and protein kinase C activity in kidney membranes.Frontiers in molecular biosciences · 2024Article
- Expression of the kidney anion exchanger 1 affects WNK4 and SPAK phosphorylation and results in claudin-4 phosphorylation.Heliyon · 2023Article
- Thirty years of the NaCl cotransporter: from cloning to physiology and structure.American journal of physiology. Renal physiology · 2023Review
- Mineralocorticoid Receptor Antagonists for Preventing Chronic Kidney Disease Progression: Current Evidence and Future Challenges.International journal of molecular sciences · 2023Review
- Aldosterone: Renal Action and Physiological Effects.Comprehensive Physiology · 2023Article
- 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
- Blood pressure effects of sodium transport along the distal nephron.Kidney international · 2022Review
- Multiple molecular mechanisms are involved in the activation of the kidney sodium-chloride cotransporter by hypokalemia.Kidney international · 2022Article
- The Post-Translational Modification Networking in WNK-Centric Hypertension Regulation and Electrolyte Homeostasis.Biomedicines · 2022Review
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
Abstract
With-no-lysine kinase 4 (WNK4) regulates electrolyte homeostasis and blood pressure. WNK4 phosphorylates the kinases SPAK (Ste20-related proline alanine-rich kinase) and OSR1 (oxidative stress responsive kinase), which then phosphorylate and activate the renal Na-Cl cotransporter (NCC). WNK4 levels are regulated by binding to Kelch-like 3, targeting WNK4 for ubiquitylation and degradation. Phosphorylation of Kelch-like 3 by PKC or PKA downstream of AngII or vasopressin signaling, respectively, abrogates binding. We tested whether these pathways also affect WNK4 phosphorylation and activity. By tandem mass spectrometry and use of phosphosite-specific antibodies, we identified five WNK4 sites (S47, S64, S1169, S1180, S1196) that are phosphorylated downstream of AngII signaling in cultured cells and in vitro by PKC and PKA. Phosphorylation at S64 and S1196 promoted phosphorylation of the WNK4 kinase T-loop at S332, which is required for kinase activation, and increased phosphorylation of SPAK. Volume depletion induced phosphorylation of these sites in vivo, predominantly in the distal convoluted tubule. Thus, AngII, in addition to increasing WNK4 levels, also modulates WNK4 kinase activity via phosphorylation of sites outside the kinase domain.
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