ArticleThe Journal of clinical investigation2015
Alternatively spliced proline-rich cassettes link WNK1 to aldosterone action.
Article in The Journal of clinical investigation, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 67 citations in OpenAlex.
- No lysine? No problem: the surprising roles of WNK kinases in physiology and disease.The Biochemical journal · 2026Review
- The Story of Aldosterone Escape.Journal of the American Society of Nephrology : JASN · 2026Review
- SMURF1/2 Are Novel Regulators of WNK1 Stability.Kinases and phosphatases · 2024Article
- Navigating the multifaceted intricacies of the NaPhysiological reviews · 2024Review
- Dietary sodium alters aldosterone's effect on renal sodium transporter expression and distal convoluted tubule remodelling.The Journal of physiology · 2024Article
- Article
- UBR5 is a novel regulator of WNK1 stability.American journal of physiology. Cell physiology · 2022Article
- Nedd4-2 binding to 14-3-3 modulates the accessibility of its catalytic site and WW domains.Biophysical journal · 2022Article
- Review
- Does the early aldosterone-induced SGK1 play a role in early Kaliuresis?Physiological reports · 2022Article
- ROMK channels are inhibited in the aldosterone-sensitive distal nephron of renal tubule Nedd4-2-deficient mice.American journal of physiology. Renal physiology · 2022Article
- WNK1 in Malignant Behaviors: A Potential Target for Cancer?Frontiers in cell and developmental biology · 2022Review
- The E3 ubiquitin-protein ligase Nedd4-2 regulates the sodium chloride cotransporter NCC but is not required for a potassium-induced reduction of NCC expression.Frontiers in physiology · 2022Article
- L-WNK1 is required for BK channel activation in intercalated cells.American journal of physiology. Renal physiology · 2021Article
- Deletion of renal Nedd4-2 abolishes the effect of high KAmerican journal of physiology. Renal physiology · 2021Article
- With-No-Lysine Kinase 1 (WNK1) Augments TRPV4 Function in the Aldosterone-Sensitive Distal Nephron.Cells · 2021Article
- Sexual Dimorphism of Corticosteroid Signaling during Kidney Development.International journal of molecular sciences · 2021Review
- Deletion of renal Nedd4-2 abolishes the effect of high sodium intake (HS) on Kir4.1, ENaC, and NCC and causes hypokalemia during high HS.American journal of physiology. Renal physiology · 2021Article
- The WNK signaling pathway and salt-sensitive hypertension.Hypertension research : official journal of the Japanese Society of Hypertension · 2020Review
- Role of the Ubiquitin Proteasome System in the Regulation of Blood Pressure: A Review.International journal of molecular sciences · 2020Review
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12 authors at 2 institutions in 2 countries.
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Abstract
The thiazide-sensitive NaCl cotransporter (NCC) is important for renal salt handling and blood-pressure homeostasis. The canonical NCC-activating pathway consists of With-No-Lysine (WNK) kinases and their downstream effector kinases SPAK and OSR1, which phosphorylate NCC directly. The upstream mechanisms that connect physiological stimuli to this system remain obscure. Here, we have shown that aldosterone activates SPAK/OSR1 via WNK1. We identified 2 alternatively spliced exons embedded within a proline-rich region of WNK1 that contain PY motifs, which bind the E3 ubiquitin ligase NEDD4-2. PY motif-containing WNK1 isoforms were expressed in human kidney, and these isoforms were efficiently degraded by the ubiquitin proteasome system, an effect reversed by the aldosterone-induced kinase SGK1. In gene-edited cells, WNK1 deficiency negated regulatory effects of NEDD4-2 and SGK1 on NCC, suggesting that WNK1 mediates aldosterone-dependent activity of the WNK/SPAK/OSR1 pathway. Aldosterone infusion increased proline-rich WNK1 isoform abundance in WT mice but did not alter WNK1 abundance in hypertensive Nedd4-2 KO mice, which exhibit high baseline WNK1 and SPAK/OSR1 activity toward NCC. Conversely, hypotensive Sgk1 KO mice exhibited low WNK1 expression and activity. Together, our findings indicate that the proline-rich exons are modular cassettes that convert WNK1 into a NEDD4-2 substrate, thereby linking aldosterone and other NEDD4-2-suppressing antinatriuretic hormones to NCC phosphorylation status.
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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.