ArticleThe Journal of biological chemistry2014
A novel Ste20-related proline/alanine-rich kinase (SPAK)-independent pathway involving calcium-binding protein 39 (Cab39) and serine threonine kinase with no lysine member 4 (WNK4) in the activation of Na-K-Cl cotransporters.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 40 citations in OpenAlex.
- Calcium-binding protein 39 in with-no-lysine kinase signaling and the modulation of renal tubular transport.Current opinion in nephrology and hypertension · 2025Review
- Kinase Scaffold Cab39 Is Necessary for Phospho-Activation of the Thiazide-Sensitive NCC.Hypertension (Dallas, Tex. : 1979) · 2024Article
- The Post-Translational Modification Networking in WNK-Centric Hypertension Regulation and Electrolyte Homeostasis.Biomedicines · 2022Review
- Deletion of Kir5.1 abolishes the effect of high NaAmerican journal of physiology. Renal physiology · 2021Article
- WNK4 kinase: from structure to physiology.American journal of physiology. Renal physiology · 2021Review
- Molecular characteristics and physiological roles of NaJournal of cellular physiology · 2021Review
- Deletion of Kir5.1 Impairs Renal Ability to Excrete Potassium during Increased Dietary Potassium Intake.Journal of the American Society of Nephrology : JASN · 2019Article
- Kir4.1/Kir5.1 Activity Is Essential for Dietary Sodium Intake-Induced Modulation of Na-Cl Cotransporter.Journal of the American Society of Nephrology : JASN · 2019Article
- Norepinephrine-Induced Stimulation of Kir4.1/Kir5.1 Is Required for the Activation of NaCl Transporter in Distal Convoluted Tubule.Hypertension (Dallas, Tex. : 1979) · 2019Article
- With no lysine kinase 4 modulates sodium potassium 2 chloride cotransporter activity in vivo.American journal of physiology. Renal physiology · 2018Article
- WNK-SPAK/OSR1 signaling: lessons learned from an insect renal epithelium.American journal of physiology. Renal physiology · 2018Review
- C-terminally truncated, kidney-specific variants of the WNK4 kinase lack several sites that regulate its activity.The Journal of biological chemistry · 2018Article
- Mistargeting of a truncated Na-K-2Cl cotransporter in epithelial cells.American journal of physiology. Cell physiology · 2018Article
- Intracellular Chloride and Scaffold Protein Mo25 Cooperatively Regulate Transepithelial Ion Transport through WNK Signaling in the Malpighian Tubule.Journal of the American Society of Nephrology : JASN · 2018Article
- Potassium intake modulates the thiazide-sensitive sodium-chloride cotransporter (NCC) activity via the Kir4.1 potassium channel.Kidney international · 2018Article
- Consequences of SPAK inactivation on Hyperkalemic Hypertension caused by WNK1 mutations: evidence for differential roles of WNK1 and WNK4.Scientific reports · 2018Article
- Article
- Emerging Targets of Diuretic Therapy.Clinical pharmacology and therapeutics · 2017Review
- The Mechanistic Links between Insulin and Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) ClInternational journal of molecular sciences · 2017Review
- WNK-Cab39-NKCC1 signaling increases the susceptibility to ischemic brain damage in hypertensive rats.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2017Article
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Na(+)-dependent chloride cotransporters (NKCC1, NKCC2, and NCC) are activated by phosphorylation to play critical roles in diverse physiological responses, including renal salt balance, hearing, epithelial fluid secretion, and volume regulation. Serine threonine kinase WNK4 (With No K = lysine member 4) and members of the Ste20 kinase family, namely SPAK and OSR1 (Ste20-related proline/alanine-rich kinase, Oxidative stress-responsive kinase) govern phosphorylation. According to present understanding, WNK4 phosphorylates key residues within SPAK/OSR1 leading to kinase activation, allowing SPAK/OSR1 to bind to and phosphorylate NKCC1, NKCC2, and NCC. Recently, the calcium-binding protein 39 (Cab39) has emerged as a binding partner and enhancer of SPAK/OSR1 activity, facilitating kinase autoactivation and promoting phosphorylation of the cotransporters. In the present study, we provide evidence showing that Cab39 differentially interacts with WNK4 and SPAK/OSR1 to switch the classic two kinase cascade into a signal kinase transduction mechanism. We found that WNK4 in association with Cab39 activates NKCC1 in a SPAK/OSR1-independent manner. We discovered that WNK4 possesses a domain that bears close resemblance to the SPAK/OSR1 C-terminal CCT/PF2 domain, which is required for physical interaction between the Ste20 kinases and the Na(+)-driven chloride cotransporters. Modeling, yeast two-hybrid, and functional data reveal that this PF2-like domain located downstream of the catalytic domain in WNK4 promotes the direct interaction between the kinase and NKCC1. We conclude that in addition to SPAK and OSR1, WNK4 is able to anchor itself to the N-terminal domain of NKCC1 and to promote cotransporter activation.
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