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Cited by 27Ion Transport and Channel RegulationPI3K/AKT/mTOR signaling in cancerIon channel regulation and function

WNK1 is a chloride-stimulated scaffold that regulates mTORC2 activity and ion transport

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Saha, Bidisha, Leite-Dellova, Deise C. A., Demko, John, Sørensen, Mads Vaarby, Takagi, Enzo, Gleason, Catherine E., Shabbir, Waheed, Pearce, David·2022·Journal of Cell Science
DOI 10.1242/jcs.260313PMC PMC9789407
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Abstract

Mammalian (or mechanistic) target of rapamycin complex 2 (mTORC2) is a kinase complex that targets predominantly Akt family proteins, SGK1 and protein kinase C (PKC), and has well-characterized roles in mediating hormone and growth factor effects on a wide array of cellular processes. Recent evidence suggests that mTORC2 is also directly stimulated in renal tubule cells by increased extracellular K+ concentration, leading to activation of the Na+ channel, ENaC, and increasing the electrical driving force for K+ secretion. We identify here a signaling mechanism for this local effect of K+. We show that an increase in extracellular [K+] leads to a rise in intracellular chloride (Cl−), which stimulates a previously unknown scaffolding activity of the protein ‘with no lysine-1’ (WNK1) kinase. WNK1 interacts selectively with SGK1 and recruits it to mTORC2, resulting in enhanced SGK1 phosphorylation and SGK1-dependent activation of ENaC. This scaffolding effect of WNK1 is independent of its own kinase activity and does not cause a generalized stimulation of mTORC2 kinase activity. These findings establish a novel WNK1-dependent regulatory mechanism that harnesses mTORC2 kinase activity selectively toward SGK1 to control epithelial ion transport and electrolyte homeostasis.

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Cited by

Sorted by citations

Authors
Saha, B., Leite-Dellova, D. C. A., Demko, J., Sørensen, M. V., Takagi, E., Gleason, C. E., Shabbir, W., & Pearce, D.
Affiliations
  • University of California, San Francisco (US)
  • Faculty of Animal Science and Food Engineering, University of São Paulo 2 Department of Veterinary Medicine , , Pirassununga, Sao Paulo 13635-900 , Brazil
  • Aarhus University (DK)
Corresponding author
Saha, Bidisha
ORCID
Venue
Journal of Cell Science
Publisher
The Company of Biologists
Published
2022-12-01
Volume
135
Issue
23
ISSN
  • 0021-9533 (ISSN-L)
  • 1477-9137
DOI
10.1242/jcs.260313
PMC
PMC9789407
OpenAlex
W4308957437
Cited by
27
References
1
Citations by year
2026: 5 · 2025: 3 · 2024: 12 · 2023: 7
FWCI
1.80
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Cell Science (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (R01-DK56695)
  • James Hilton Manning and Emma Austin Manning Foundation
  • University of California, San Francisco
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
Keywords
WNK1, mTORC2, SGK1, extracellular potassium, epithelial sodium channel, sodium channels, ion transport, renal tubular epithelial cells, protein scaffolding, kinase-independent signaling, electrolyte balance, potassium secretion
MeSH terms
Mechanistic Target of Rapamycin Complex 2, Animals, Chlorides, Mammals, Minor Histocompatibility Antigens, Ion Transport, Protein Serine-Threonine Kinases, Immediate-Early Proteins, Epithelial Sodium Channels, TOR Serine-Threonine Kinases

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