ArticleCell2022
WNK kinases sense molecular crowding and rescue cell volume via phase separation.
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Article in Cell, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 127 papers, 1 of them a synthesis that pooled it.
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127citing papers in PubMed, 1 pooled it
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127 citing papers in PubMed, 1 synthesis or guideline pooled it, 187 citations in OpenAlex.
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- Bilirubin as a Modulator of WNK1 Protein Signaling: Implications for Neuroinflammatory Diseases.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
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- Stress Granule Sequestration of CCR4-NOT Promotes Poly(A) Lengthening of Stress-Survival Transcripts.bioRxiv : the preprint server for biology · 2026Article
- The WNK-OXSR1 osmosensing pathway mediates intestinal regeneration via Hippo-YAP signaling.The EMBO journal · 2026Article
- PHGDH phosphorylation mediated by WNK1 serves as a dual marker of metabolic vulnerability and responsiveness to oxaliplatin treatment.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
67 more citing papers are in PubMed but not listed here.
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Authors and funding
23 authors at 3 institutions in 1 country.
Cary R Boyd-ShiwarskiDepartment of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; Pittsburgh Center for Kidney Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Daniel J ShiwarskiDepartment of Biomedical Engineering, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
Shawn E GriffithsDepartment of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Rebecca T BeachamDepartment of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Logan NorrellMolecular Medicine Program, University of Utah, Salt Lake City, UT 84132, USA.
Daryl E MorrisonMolecular Medicine Program, University of Utah, Salt Lake City, UT 84132, USA.
Jun WangDepartment of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Jacob MannDepartment of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
William TennantDepartment of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Eric N AndersonDepartment of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Jonathan FranksCenter for Biological Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Michael CalderonCenter for Biological Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Kelly A ConnollyDepartment of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Muhammad Umar CheemaDepartment of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Claire J WeaverDepartment of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Lubika J NkashamaDepartment of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Claire C WeckerlyDepartment of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Katherine E QuerryDepartment of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Udai Bhan PandeyDepartment of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; Center for Protein Conformational Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Christopher J DonnellyDepartment of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; Center for Protein Conformational Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Dandan SunDepartment of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; VA Pittsburgh Healthcare System, Pittsburgh, PA 15240, USA.
Aylin R RodanDepartment of Human Genetics, University of Utah, Salt Lake City, UT 84132, USA; Molecular Medicine Program, University of Utah, Salt Lake City, UT 84132, USA; Department of Internal Medicine, Division of Nephrology and Hypertension, University of Utah, Salt Lake City, UT 84132, USA; Medical Service, VA Salt Lake City Health Care System, Salt Lake City, UT 84148, USA.
Arohan R SubramanyaDepartment of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; Center for Protein Conformational Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; Pittsburgh Center for Kidney Research, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; VA Pittsburgh Healthcare System, Pittsburgh, PA 15240, USA. Electronic address: ars129@pitt.edu.
University of Pittsburgh · USUniversity of Utah · USCarnegie Mellon University · US
Funding
Single Nephron and MetabolomicsP30DK079307 · NIDDK · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI KLEYMAN, THOMAS R · 2008 to 2022
$13.4MTraining in the Neurobiology of Neurological DiseaseT32NS086749 · NINDS · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI Omar El Gharbawie, REBECCA P SEAL · 2014 to 2026
$4.8MControl of the Renal WNK Signaling Pathway by Phase TransitionsR01DK098145 · NIDDK · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI AYLIN RACHEL RODAN, AROHAN R SUBRAMANYA · 2014 to 2026
$4.2MRegulation of WNK signaling by potassium and Mo25: structure, function and physiologyR01DK110358 · NIDDK · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · PI RODAN, AYLIN RACHEL · 2016 to 2025
$4.1MRegulation of Renal WNK Signaling in Intercalated CellsR01DK119252 · NIDDK · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI SUBRAMANYA, AROHAN R · 2019 to 2023
$2.0MAn optogenetic approach to establish the interplay between stress granules and TDP-43 proteinopathy in ALS/FTDR01NS105756 · NINDS · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI DONNELLY, CHRISTOPHER JAMES · 2018 to 2022
$1.8MThe function of kidney specific (KS)-WNK1 condensates during potassium stressK08DK118211 · NIDDK · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI BOYD-SHIWARSKI, CARY RAGAN · 2018 to 2022
$923kThe University of Pittsburgh Summer Research Internship Program kidney workshop (SRIP-Kid)R25DK119180 · NIDDK · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI JACQUELINE HO, Sunder Sims-Lucas · 2021 to 2026
$648kLeica Stellaris Confocal for Kidney Imaging CoreS10OD028596 · OD · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI APODACA, GERARD L · 2021 to 2021
$596kIntegrated perfusion and confocal imaging systemS10OD021627 · OD · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI WEISZ, ORA A · 2016 to 2016
$479kNuclear export inhibition as a novel therapeutic target for C9ORF72 ALS/FTDR21NS098379 · NINDS · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI DONNELLY, CHRISTOPHER JAMES, PANDEY, UDAI B · 2017 to 2018
$429kDevelopment of a Collagen-based 3D Bioprinted Microfluidic Platform for Vascular Tissue Engineering and Disease ModelingK99HL155777 · NHLBI · CARNEGIE-MELLON UNIVERSITY · PI SHIWARSKI, DANIEL J · 2021 to 2022
$222kBLRD VA I01 BX002891BLRD VA IK6 BX005647NHLBI NIH HHS K99 HL155777NIDDK NIH HHS K08 DK118211NIDDK NIH HHS P30 DK079307NIDDK NIH HHS R01 DK098145NIDDK NIH HHS R01 DK110358NIDDK NIH HHS R01 DK119252NIDDK NIH HHS R25 DK119180NIH HHS S10 OD021627NIH HHS S10 OD028596NINDS NIH HHS R01 NS105756NINDS NIH HHS R21 NS098379NINDS NIH HHS T32 NS086749
Abstract
When challenged by hypertonicity, dehydrated cells must recover their volume to survive. This process requires the phosphorylation-dependent regulation of SLC12 cation chloride transporters by WNK kinases, but how these kinases are activated by cell shrinkage remains unknown. Within seconds of cell exposure to hypertonicity, WNK1 concentrates into membraneless condensates, initiating a phosphorylation-dependent signal that drives net ion influx via the SLC12 cotransporters to restore cell volume. WNK1 condensate formation is driven by its intrinsically disordered C terminus, whose evolutionarily conserved signatures are necessary for efficient phase separation and volume recovery. This disorder-encoded phase behavior occurs within physiological constraints and is activated in vivo by molecular crowding rather than changes in cell size. This allows kinase activity despite an inhibitory ionic milieu and permits cell volume recovery through condensate-mediated signal amplification. Thus, WNK kinases are physiological crowding sensors that phase separate to coordinate a cell volume rescue response.
Indexed as
Protein Serine-Threonine KinasesCell SizePhosphorylationProtein Serine-Threonine Kinasesbiomolecular condensatescell volume regulationhyperosmotic stressK-Cl cotransportmacromolecular crowdingNa-K-2Cl cotransportphase separationSLC12 cotransporterWNK kinase
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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 Socratic graph.