Affinage

WNK1

Serine/threonine-protein kinase WNK1 · UniProt Q9H4A3

Length
2382 aa
Mass
250.8 kDa
Annotated
2026-06-11
100 papers in source corpus 46 papers cited in narrative 45 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

WNK1 is a structurally atypical serine/threonine kinase that functions as a master regulator of intracellular ion homeostasis and a chloride sensor coupling chloride concentration to cell-signaling output (PMID:10828064, PMID:24803536). It is catalytically unique: the active-site lysine (Lys-233) emanates from strand β2 rather than β3, and a high-resolution crystal structure places WNK1 in a novel kinase subfamily with an autoinhibited activation loop (PMID:10828064, PMID:15242606). Activity is gated by autophosphorylation of activation-loop Ser-382, which is relieved from an intramolecular autoinhibitory domain; intracellular chloride binds directly within the active-site cavity to stabilize the inactive state and suppress autophosphorylation, making WNK1 sensitive to changes in Cl- (PMID:12374799, PMID:24803536). The central effector axis is the phosphorylation and activation of the STE20-family kinases SPAK and OSR1, which WNK1 engages through an RFXV motif that docks the SPAK/OSR1 CCT domain and which it activates by T-loop phosphorylation; activated OSR1/SPAK in turn phosphorylate the cation-chloride cotransporter NKCC1 and the K-Cl cotransporter KCC2 to set epithelial and neuronal ion balance (PMID:16083423, PMID:16669787, PMID:16832045, PMID:29176664). Through this cascade WNK1 governs cell-volume regulation, NCC/ROMK activity in the distal nephron, T-cell adhesion and migration, and macrophage NLRP3 inflammasome activation via Cl-/K- balancing (PMID:16428287, PMID:24555568, PMID:27400149, PMID:34315884). Beyond catalysis, WNK1 acts as a non-catalytic scaffold: it recruits SGK1 to mTORC2 in a chloride-stimulated, kinase-independent manner to activate ENaC, and serves as an assembly factor for the ER membrane protein complex through a conserved amphipathic helix that stabilizes EMC2 (PMID:33964204, PMID:36373794). WNK1 abundance is controlled by ubiquitin-mediated proteasomal degradation through the KLHL3-Cullin3 E3 ligase and through NEDD4-2 acting on PY-motif-bearing isoforms, with both pathways feeding into the WNK→SPAK/OSR1→NCC cascade (PMID:24821705, PMID:26241057, PMID:32790646). WNK1 is required in vivo for endothelial angiogenesis and cardiac development via an OSR1-dependent axis, and tissue-specific isoforms diversify its function: the kinase-domain-lacking KS-WNK1 antagonizes L-WNK1 and nucleates membraneless WNK signaling bodies in distal tubule cells, while a nervous-system-specific WNK1/HSN2 isoform is expressed in peripheral sensory neurons (PMID:19644017, PMID:23386621, PMID:29237822, PMID:18521183). Loss-of-function mutations in the WNK1/HSN2 exon cause hereditary sensory and autonomic neuropathy type II, and impaired KLHL3/KS-WNK1 degradation underlies pseudohypoaldosteronism type II (PMID:18521183, PMID:32790646).

Mechanistic history

Synthesis pass · year-by-year structured walk · 36 steps
  1. 2000 High

    Established that WNK1 is an active serine/threonine kinase with an unprecedented catalytic architecture, answering whether and how a kinase lacking the canonical subdomain-II lysine could function.

    Evidence In vitro kinase assay on MBP plus K233M mutagenesis and structural modeling

    PMID:10828064

    Open questions at the time
    • Physiological substrates not yet identified
    • Regulation of activity in cells unknown
  2. 2002 High

    Defined how WNK1 activity is controlled, showing an autoinhibitory domain suppresses the kinase and that activation-loop Ser-382 autophosphorylation is required for activity.

    Evidence In vitro kinase assays with autoinhibitory-domain fragments and Ser-382 mutagenesis

    PMID:12374799

    Open questions at the time
    • Upstream signal triggering activation not defined
    • Whether autophosphorylation is cis or trans unresolved
  3. 2004 High

    Provided atomic-resolution confirmation of the unique active-site geometry (Lys-233 from β2) and an inactive activation-loop conformation, placing WNK1 in a distinct structural subfamily.

    Evidence X-ray crystallography of the WNK1 kinase domain at 1.8 Å

    PMID:15242606

    Open questions at the time
    • Structure of active/phosphorylated state not captured
    • No substrate-bound complex
  4. 2003 High

    Connected WNK1 to MAPK signaling by showing it acts upstream of MEKK2/3 to activate the ERK5 cascade, broadening its role beyond ion transport.

    Evidence Reciprocal Co-IP, in vitro phosphorylation of MEKK2/3, dominant-negative and siRNA in HEK293

    PMID:14681216

    Open questions at the time
    • Physiological context of ERK5 activation by WNK1 unclear
    • In vivo relevance not tested
  5. 2004 High

    Placed WNK1 downstream of insulin/IGF-1 signaling by identifying PKB/Akt phosphorylation at Thr-60, while showing this does not directly alter kinase activity.

    Evidence Phosphospecific antibody, PI3K inhibitors, PDK1-null cells, peptide mapping

    PMID:14611643

    Open questions at the time
    • Functional consequence of Thr-60 phosphorylation initially unclear
    • Downstream effectors of this input not defined here
  6. 2004 High

    Identified a neuronal/secretory substrate, synaptotagmin 2, demonstrating WNK1 can tune Ca2+-sensing of vesicle fusion machinery.

    Evidence Co-IP, colocalization on granules, in vitro phosphorylation at Thr-202, phospholipid-binding assay

    PMID:15350218

    Open questions at the time
    • In vivo relevance to secretion not established
    • Cell-type specificity of this function unknown
  7. 2005 High

    Defined the core effector axis: WNK1 phosphorylates and activates SPAK and OSR1 via their T-loops, establishing the kinase cascade that controls ion cotransporters.

    Evidence In vitro kinase assay, phosphopeptide mapping, T-loop/C-terminal mutagenesis, testis IP

    PMID:16083423

    Open questions at the time
    • Substrate selection mechanism not fully defined
    • In vivo cotransporter consequences shown later
  8. 2005 High

    Revealed a non-catalytic scaffolding function in which WNK1's N-terminus activates SGK1 (PI3K-dependent) to stimulate ENaC via Nedd4-2, distinguishing kinase-independent from kinase-dependent WNK1 roles.

    Evidence Domain deletions, kinase-dead mutants, siRNA, Xenopus oocyte ENaC currents

    PMID:16006511 PMID:16081417

    Open questions at the time
    • Molecular details of SGK1 recruitment defined later
    • Chloride dependence not yet appreciated
  9. 2005 High

    Showed WNK kinases interact and cross-regulate, with catalytically active WNK1 suppressing WNK4-mediated NCC inhibition, linking WNK1 to renal sodium handling.

    Evidence Co-IP, kinase-dead controls, in vitro phosphorylation of WNK paralogs, oocyte Na+ flux

    PMID:15841204 PMID:15883153

    Open questions at the time
    • In vivo NCC regulation by WNK1 not directly tested here
    • Stoichiometry of WNK1-WNK4 complex unclear
  10. 2005 Medium

    Identified WNK1 as an Akt substrate in adipocytes and a negative regulator of mitogenesis, linking insulin signaling to proliferation control.

    Evidence Anti-pAkt-substrate IP/MS, siRNA, thymidine incorporation and proliferation assays in 3T3-L1

    PMID:15799971

    Open questions at the time
    • Mechanism by which WNK1 restrains proliferation unknown
    • Single cell-line context
  11. 2006 High

    Defined the docking logic of the WNK→SPAK/OSR1→NKCC1 cascade, showing the SPAK/OSR1 CCT domain binds the WNK1 RFXV motif and is required for efficient substrate phosphorylation.

    Evidence In vitro kinase assays, peptide-binding, CCT/RFXV mutagenesis, NKCC1 phosphosite mapping

    PMID:16669787

    Open questions at the time
    • How osmotic stress triggers WNK1 not yet at chloride-level detail
    • Other RFXV-bearing partners not enumerated
  12. 2006 High

    Placed WNK1 functionally upstream of OSR1 and NKCC in cell-volume regulation and showed osmotic-stress-induced WNK1 activation and vesicular relocalization.

    Evidence Co-IP, siRNA of WNK1/OSR1, in vitro OSR1 activation, Rb+ uptake, live imaging and fractionation

    PMID:16832045 PMID:17190791

    Open questions at the time
    • Direct osmosensing mechanism not yet defined
    • Functional role of vesicular relocalization unclear
  13. 2006 High

    Established L-WNK1 versus KS-WNK1 isoform antagonism in the kidney, showing L-WNK1 inhibits ROMK endocytically (partly kinase-independent) while KS-WNK1 reverses this, defining isoform-based regulation of renal K+ handling.

    Evidence Oocyte ROMK electrophysiology, truncations, kinase-dead (D368A), dynamin DN, Co-IP, dietary K+ in rats

    PMID:16204408 PMID:16428287 PMID:16775035 PMID:18550644

    Open questions at the time
    • Structural basis of intramolecular domain regulation incomplete
    • In vivo ROMK regulation tied to physiology shown later
  14. 2006 Medium

    Extended WNK1's channel-regulatory reach to CFTR and paracellular permeability, indicating broad control of epithelial chloride flux.

    Evidence Oocyte CFTR currents with kinase-dead WNK1; MDCKII Cl- flux and phospho-claudin-4

    PMID:16949040 PMID:17194447

    Open questions at the time
    • Single-lab overexpression systems
    • Direct substrate of claudin-4 phosphorylation not shown to be WNK1
  15. 2007 Medium

    Identified WNK1 as a dual modulator of TGF-β–Smad2 signaling, binding and phosphorylating Smad2 and controlling its levels and nuclear activity.

    Evidence siRNA, Western blot, nuclear pSmad2 immunofluorescence, in vitro kinase, reporter assay in HeLa

    PMID:17392271

    Open questions at the time
    • Phosphosite on Smad2 not mapped
    • Transcriptional versus post-translational contributions intertwined
  16. 2008 Medium

    Characterized the nervous-system-specific WNK1/HSN2 isoform and linked its loss-of-function to hereditary sensory and autonomic neuropathy type II, tying WNK1 to peripheral sensory neuron biology.

    Evidence Immunodetection in mouse nervous tissue, human isoform expression and mutation spectrum analysis

    PMID:18521183

    Open questions at the time
    • Molecular function of HSN2 isoform not defined
    • Mechanism linking mutations to neuropathy unclear
  17. 2009 Medium

    Revealed an OSR1-independent role of WNK1 in mitosis, with localization to spindles and knockdown causing spindle and abscission defects.

    Evidence Immunofluorescence/live imaging, siRNA of WNK1 and OSR1, mitotic phenotype analysis

    PMID:21220314

    Open questions at the time
    • Mitotic substrates of WNK1 not identified
    • Mechanism of spindle association unknown
  18. 2009 Medium

    Connected WNK1 to neuronal Nogo/RhoA inhibitory signaling through interaction with LINGO-1 and Rho-GDI1, implicating it in neurite outgrowth control.

    Evidence Y2H, FRET, Co-IP, siRNA, RhoA pull-down, neurite extension in cortical neurons

    PMID:19363035

    Open questions at the time
    • Whether kinase activity is required not resolved
    • Single-lab interaction data
  19. 2009 Medium

    Defined the enzymatic mechanism of WNK1 toward OSR1 as random sequential and characterized ATP-competitive inhibition, enabling biochemical inhibitor work.

    Evidence Microfluidic capillary-electrophoresis kinase assay, Lineweaver-Burk kinetics, PP1/PP2 competition

    PMID:19739668

    Open questions at the time
    • Inhibitors are non-selective tool compounds
    • Single in vitro study
  20. 2013 High

    Established the WNK1→OSR1 axis as essential for embryonic angiogenesis and cardiac development in vivo via genetic epistasis and endothelial rescue.

    Evidence Global and endothelial Wnk1/Osr1 knockouts, constitutively active OSR1 knock-in rescue, embryo phenotyping

    PMID:19644017 PMID:23386621

    Open questions at the time
    • Downstream effectors of OSR1 in endothelium not fully defined here
    • Cotransporter contribution to vascular phenotype unclear
  21. 2014 High

    Identified chloride as a direct allosteric ligand binding the WNK1 active site to inhibit autophosphorylation, establishing WNK1 as a bona fide chloride sensor.

    Evidence X-ray crystallography with Cl-, autophosphorylation assays across Cl- concentrations, Cl--site mutagenesis

    PMID:24803536

    Open questions at the time
    • How physiological Cl- transients are integrated in cells not fully resolved
    • Other ion sensitivities not excluded
  22. 2014 Medium

    Connected the WNK1-OSR1-NKCC1 axis to disease-relevant cell behavior, showing it drives glioma volume regulation and migration.

    Evidence siRNA of WNK1/OSR1, intracellular K+/Cl- indicators, NKCC1 phospho Western, migration assays

    PMID:24555568

    Open questions at the time
    • In vivo tumor relevance not tested
    • Single cell-context
  23. 2014 High

    Defined ubiquitin-mediated control of WNK1 abundance by the KLHL3-Cullin3 ligase, and showed disease mutations stabilizing WNK1 hyperactivate the NCC cascade in PHAII.

    Evidence KLHL3 R528H knock-in mouse, peptide-binding (FCS), WNK1/WNK4 Western, NCC phosphorylation

    PMID:24821705

    Open questions at the time
    • Degron determinants on WNK1 not fully mapped here
    • Isoform selectivity of degradation addressed later
  24. 2014 Medium

    Dissected divergent roles of WNK1 effectors in endothelial cells, with OSR1 driving chemotaxis/invasion and SPAK driving proliferation, plus regulation of Slug.

    Evidence siRNA of WNK1/OSR1/SPAK in HUVECs, cord-formation, chemotaxis/invasion, proliferation, gene expression

    PMID:25362046

    Open questions at the time
    • Mechanism of Slug regulation unknown
    • Single-lab cell-based data
  25. 2015 High

    Linked aldosterone signaling to WNK1 stability, showing SGK1-phosphorylated NEDD4-2 spares PY-motif WNK1 isoforms from degradation to activate the NCC pathway.

    Evidence PY-motif exon analysis, Co-IP with NEDD4-2, proteasome inhibition, gene-edited cells, aldosterone infusion in mice

    PMID:26241057

    Open questions at the time
    • Quantitative contribution relative to KLHL3 pathway unclear
    • Isoform-specific effects not fully resolved
  26. 2016 High

    Established a physiological immune role, with WNK1 (via OXSR1/STK39 and SLC12A2) negatively regulating T-cell adhesion while promoting migration and lymphoid homing.

    Evidence RNAi screen, T-cell conditional knockout, adhesion/migration assays, in vivo homing

    PMID:27400149

    Open questions at the time
    • How TCR/chemokine signals activate WNK1 in T cells not fully defined
    • Chloride-sensing contribution in T cells unaddressed
  27. 2016 Medium

    Identified WNK1 as a negative regulator of autophagy, acting partly through binding the PI3KC3 component UVRAG and through SPAK.

    Evidence siRNA, autophagosome/flux assays, ULK1/AMPK Western, in vitro WNK1 N-terminus–UVRAG binding, colocalization

    PMID:27911840

    Open questions at the time
    • Whether kinase activity is required not fully resolved
    • Direct versus indirect effects on PI3KC3 unclear
  28. 2017 Medium

    Demonstrated a nuclear, transcription-associated function: WNK1 phosphorylates the termination factor PCF11 to weaken its Pol II CTD interaction and promote transcript release and mRNA export.

    Evidence In vitro kinase on PCF11 CID, phosphorylation-dependent CTD binding, nuclear localization, mRNA export assay

    PMID:29196535

    Open questions at the time
    • In vivo significance for gene expression not established
    • Single-lab study
  29. 2017 High

    Showed WNK1 couples GABA_A inhibitory activity to KCC2 surface stability via phosphorylation at Thr-906/1007, integrating chloride sensing with neuronal inhibition.

    Evidence Single-particle tracking of KCC2, GABA_A pharmacology, phospho-specific antibodies, WNK1 inhibition

    PMID:29176664

    Open questions at the time
    • Direct versus SPAK/OSR1-mediated KCC2 phosphorylation not fully separated
    • In vivo neuronal consequences not tested here
  30. 2017 Medium

    Established that the KS-WNK1 isoform nucleates membraneless WNK signaling bodies in distal tubule cells, providing a spatial organizing principle for the pathway under K+ challenge.

    Evidence KS-WNK1 knockout mouse, live imaging, colocalization, cell reconstitution, cysteine-rich motif mutagenesis

    PMID:29237822

    Open questions at the time
    • Biophysical basis of body formation incompletely defined
    • Functional output of WNK bodies on signaling not fully quantified
  31. 2019 Medium

    Showed WNK1 drives TRPC6-mediated Ca2+ influx via PI4KIIIα/PLC-β/NFATc1, promoting renal carcinoma proliferation and migration, extending the non-catalytic PLC pathway to cancer.

    Evidence Patch-clamp, Ca2+ imaging, PI4KIIIα activity, NFATc1 reporter, siRNA/inhibitor, migration assays

    PMID:22119528 PMID:31022353

    Open questions at the time
    • In vivo tumor relevance not established
    • Kinase-independence of the full pathway not exhaustively tested
  32. 2020 High

    Refined disease genetics by showing acidic-motif mutations selectively impair KS-WNK1 (not L-WNK1) degradation by KLHL3-CUL3, causing a hyperkalemic hyperchloremic acidosis via NCC and ROMK dysregulation.

    Evidence Exome sequencing, oocyte/HEK293T ubiquitination and NCC assays, CRISPR mouse, renal phospho-NCC/ROMK analysis

    PMID:32790646

    Open questions at the time
    • Mechanism of isoform-selective degron recognition not fully resolved
    • Quantitative contribution of ROMK versus NCC to phenotype unclear
  33. 2021 High

    Uncovered a kinase-independent moonlighting role as an EMC assembly factor, with a WNK1 amphipathic helix stabilizing EMC2 against degradation to permit ER membrane protein complex assembly.

    Evidence Reconstitution, Co-IP with EMC2/EMC subunits, interface structural analysis, E3-ligase competition, depletion of EMC clients

    PMID:33964204

    Open questions at the time
    • How this function is partitioned from ion-signaling roles unknown
    • In vivo importance not assessed
  34. 2021 High

    Established WNK1 as a brake on innate immune activation, negatively regulating NLRP3 inflammasome and pyroptosis by balancing intracellular Cl-/K+.

    Evidence Kinase-inactive and protein-knockout macrophages, IL-1β/pyroptosis assays, macrophage-specific conditional KO mouse, ion measurement

    PMID:34315884

    Open questions at the time
    • Relative roles of kinase versus scaffold functions partially defined
    • Direct effector linking WNK1 to NLRP3 not pinpointed
  35. 2022 Medium

    Defined the molecular basis of WNK1-mediated SGK1 activation as chloride-stimulated scaffolding that recruits SGK1 to mTORC2 selectively, integrating extracellular K+/intracellular Cl- with ENaC control.

    Evidence Co-IP of WNK1-SGK1-mTORC2 ternary complex, kinase-dead mutant, Cl- manipulation, ENaC activity, SGK1 phospho Western

    PMID:36373794

    Open questions at the time
    • Structural basis of the scaffolding interaction unknown
    • Single-lab study
  36. 2022 Medium

    Connected WNK1 to angiogenic tight-junction and receptor remodeling, showing WNK1 inhibition blocks TGF-β-driven AXL degradation and that OSR1 binds occludin during junction turnover.

    Evidence WNK1 inhibitor in HUVECs and aortic sprouting, OSR1-occludin Co-IP, AXL degradation assay, embryo vessel extension

    PMID:35867836

    Open questions at the time
    • Direct substrates in junction remodeling not mapped
    • Mechanism of AXL stabilization unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How WNK1 dynamically integrates its chloride-sensing kinase activity with its multiple kinase-independent scaffolding functions (SGK1/mTORC2, EMC assembly, PLC-β/PI4KIIIα) across distinct subcellular compartments remains unresolved.
  • No unified structural model spanning kinase and scaffold states
  • Compartment-specific isoform contributions not integrated
  • Substrate repertoire in nucleus and during mitosis incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0016740 transferase activity 4 GO:0098772 molecular function regulator activity 3 GO:0140299 molecular sensor activity 3 GO:0060090 molecular adaptor activity 2 GO:0140657 ATP-dependent activity 2
Localization
GO:0005829 cytosol 2 GO:0005634 nucleus 1 GO:0005783 endoplasmic reticulum 1 GO:0005856 cytoskeleton 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-382551 Transport of small molecules 5 R-HSA-162582 Signal Transduction 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-1266738 Developmental Biology 3 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 2 R-HSA-74160 Gene expression (Transcription) 1 R-HSA-9612973 Autophagy 1
Partners
EMC2KLHL3NEDD4-2OXSR1SGK1STK39UVRAGWNK4
Complex memberships
ER membrane protein complex (EMC)KLHL3-Cullin3 E3 ligase complex (substrate)WNK signaling bodies

Evidence

Reading pass · 45 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 WNK1 is a serine/threonine protein kinase that phosphorylates myelin basic protein and itself, but uniquely lacks the invariant catalytic lysine in subdomain II; instead, Lys-233 in subdomain I performs the catalytic function, as mutation of Lys-233 to Met eliminates kinase activity. In vitro kinase assay with MBP substrate, site-directed mutagenesis (K233M), sequence analysis and structural modeling based on cAMP-dependent protein kinase structure The Journal of biological chemistry High 10828064
2002 WNK1 contains an autoinhibitory domain (conserved in all four WNKs) that suppresses kinase-domain activity; mutation of two key residues in this domain attenuates inhibition and increases kinase activity. Autophosphorylation on Ser-382 in the activation loop is required for WNK1 activity. Enzyme fragment analysis, sequence alignment, in vitro kinase assays with autoinhibitory domain constructs, site-directed mutagenesis of activation-loop Ser-382 The Journal of biological chemistry High 12374799
2003 WNK1 activates the ERK5 MAP kinase pathway upstream of MEKK2 and MEKK3: WNK1 overexpression increases ERK5 activity in a MEK5-dependent manner; dominant-negative MEKK2/MEKK3 block this effect; both MEKK2 and MEKK3 co-immunoprecipitate with endogenous WNK1; WNK1 phosphorylates MEKK2 and MEKK3 in vitro and activates MEKK3 in cells; WNK1 siRNA knockdown attenuates EGF-stimulated ERK5 activation. Co-immunoprecipitation, in vitro kinase assay, dominant-negative mutant expression, siRNA knockdown, cotransfection in HEK293 cells The Journal of biological chemistry High 14681216
2004 Crystal structure of the WNK1 kinase domain at 1.8 Å resolution reveals that the catalytic Lys-233 emanates from strand β2 (not β3 as in all other kinases), the activation loop adopts a unique well-folded inactive conformation, and the overall architecture places WNK1 in a novel structural subfamily of serine/threonine kinases. X-ray crystallography (1.8 Å resolution), homology modeling for substrate-specificity groove identification Structure High 15242606
2004 WNK1 is phosphorylated at Thr-60 by PKB/Akt in response to IGF-1 stimulation; this phosphorylation is PI3K-dependent, occurs on endogenous WNK1, and is abolished in PDK1-null cells where PKB is inactive. Phosphorylation of Thr-60 by PKB does not directly regulate WNK1 kinase activity or localization. Phosphospecific antibody to pThr-60, PI3K inhibitor treatment (wortmannin, LY294002), PDK1-null and PDK1-knock-in ES cell experiments, peptide mapping and mutagenesis The Biochemical journal High 14611643
2004 WNK1 selectively binds to and phosphorylates synaptotagmin 2 (Syt2) within its C2 calcium-binding domains. Endogenous WNK1 and Syt2 coimmunoprecipitate and colocalize on secretory granules in INS-1 cells. WNK1-mediated phosphorylation at Thr-202 of Syt2 increases the Ca2+ concentration required for Syt2 binding to phospholipid vesicles. Co-immunoprecipitation, colocalization by fluorescence microscopy, in vitro phosphorylation assay, phospholipid-vesicle binding assay, site-directed mutagenesis (T202 mutant) Molecular cell High 15350218
2005 WNK1 and WNK4 phosphorylate and activate the STE20-family kinases SPAK and OSR1 by phosphorylating the T-loop (Thr-233 in SPAK; Thr-185 in OSR1) and a C-terminal serine (Ser-373 in SPAK; Ser-325 in OSR1). T-loop phosphorylation is required for activation; catalytically inactive WNK1 fails to activate SPAK/OSR1. WNK1 was found associated with SPAK in rat testis immunoprecipitates. Immunoprecipitation from rat testis, in vitro kinase assay, phosphopeptide mapping, site-directed mutagenesis (T185A, T185E, S325A/E in OSR1) The Biochemical journal High 16083423
2005 WNK1 activates SGK1 by a PI3K-dependent but non-catalytic mechanism: the N-terminal 220 residues of WNK1 are necessary and sufficient to activate SGK1, and activated SGK1 in turn stimulates the epithelial sodium channel (ENaC) via Nedd4-2 in a WNK1-dependent manner. Phosphorylation of WNK1 Thr-58 contributes to SGK1 activation. WNK1 is also required for IGF-1-induced SGK1 activation. Cotransfection in HEK293/oocytes, deletion mutants of WNK1, PI3K inhibitor (wortmannin), siRNA depletion, Xenopus oocyte ENaC current measurements Proceedings of the National Academy of Sciences of the United States of America / The Journal of biological chemistry High 16006511 16081417
2005 WNK1 and WNK4 interact via their kinase domains (shown by co-immunoprecipitation). WNK1 suppresses WNK4-mediated inhibition of the NCC cotransporter; this requires WNK1 catalytic activity and an intact WNK1 protein. A kinase-dead WNK1 associates with WNK4 but fails to suppress WNK4-mediated NCC inhibition. WNK1 also phosphorylates WNK4 and WNK2 in vitro. Co-immunoprecipitation, Xenopus oocyte Na+ flux assay for NCC activity, kinase-dead mutants, deletion constructs, in vitro kinase assay The Journal of clinical investigation / The Journal of biological chemistry High 15841204 15883153
2005 WNK1 is identified as a substrate of Akt/PKB in adipocytes; insulin stimulates WNK1 phosphorylation via PI3K/Akt1/Akt2. WNK1 knockdown (siRNA) in 3T3-L1 cells significantly enhances insulin-stimulated thymidine incorporation (~2-fold) and serum-stimulated cell proliferation, identifying WNK1 as a negative regulator of mitogenesis. Immunoprecipitation with anti-pAkt-substrate antibody + mass spectrometry, siRNA depletion of Akt1/Akt2, PI3K inhibitors, thymidine incorporation assay, cell-count proliferation assay The Journal of biological chemistry Medium 15799971
2006 WNK1 phosphorylates SPAK and OSR1; the CCT (conserved C-terminal) domain of SPAK/OSR1 binds an RFXV motif present in WNK1 (and WNK4), and an intact CCT domain is required for WNK1 to efficiently phosphorylate and activate OSR1. SPAK/OSR1 then phosphorylate NKCC1 at Thr-203/207/212 (human). Mutation of the RFXV-binding residues within the CCT domain inhibits NKCC1 phosphorylation. In vitro kinase assay, peptide binding/affinity purification, site-directed mutagenesis of CCT domain and RFXV motif, phosphopeptide mapping, osmotic-stress stimulation of HEK-293 cells The Biochemical journal High 16669787
2006 WNK1 is rapidly activated and phosphorylated at multiple sites including the T-loop Ser-382 upon hyperosmotic stress, possibly by transautophosphorylation. Activation coincides with SPAK/OSR1 phosphorylation/activation, and siRNA depletion of WNK1 impairs SPAK/OSR1 activity and phosphorylation under hyperosmotic conditions. Under hyperosmotic stress, WNK1 redistributes from the cytosol to vesicular structures (TGN/recycling endosomes) marked by clathrin, AP-1, and TGN46; the C-terminal non-catalytic domain mediates vesicle localization. siRNA knockdown, phospho-specific antibodies, immunofluorescence colocalization, live-cell imaging, mutational analysis of C-terminal domain, fractionation The Journal of cell biology High 17190791
2006 OSR1 exists in a complex with WNK1 in cells and is phosphorylated in a WNK1-dependent manner; depletion of WNK1 by siRNA reduces OSR1 kinase activity; depletion of either WNK1 or OSR1 reduces NKCC activity in HeLa cells, placing WNK1 upstream of OSR1 upstream of NKCC1 in a pathway for volume regulation. Co-immunoprecipitation, siRNA depletion of WNK1 and OSR1, in vitro OSR1 activation assay, Rb+ uptake assay for NKCC activity Proceedings of the National Academy of Sciences of the United States of America High 16832045
2006 Long WNK1 (L-WNK1) inhibits the ROMK1 potassium channel by stimulating its endocytosis; the N-terminal amino acids 1–491 are sufficient for ROMK inhibition; this inhibition is synergistic with WNK4 but independent of it. The kidney-specific KS-WNK1 isoform lacks inhibitory activity but reverses L-WNK1-mediated ROMK inhibition. Dietary K+ restriction in rats increases L-WNK1 while decreasing KS-WNK1 expression. Xenopus oocyte electrophysiology (ROMK current), truncation constructs of WNK1, dietary K+ manipulation in rats with qRT-PCR/Western blot Proceedings of the National Academy of Sciences of the United States of America High 16428287
2006 KS-WNK1 functions as a dominant-negative regulator of L-WNK1: it forms a protein complex with L-WNK1 in oocytes (co-IP) and attenuates L-WNK1 kinase activity in vitro, leading to downregulation of NCC activity in Xenopus oocytes. Co-immunoprecipitation in Xenopus oocytes, in vitro kinase assay, Xenopus oocyte Na+ flux assay (22Na+ uptake) American journal of physiology. Renal physiology High 16204408
2006 WNK1 suppresses ROMK surface expression independently of WNK4 in Xenopus oocytes; this effect requires the region encompassing amino acids 502–1100 (containing the acidic motif) and is dynamin-dependent. Surprisingly, a kinase-dead WNK1 (D368A) mimics the effect, indicating ROMK inhibition does not require catalytic activity. Xenopus oocyte ROMK current measurement, kinase-dead mutant (D368A), truncation constructs, dominant-negative dynamin coexpression Journal of the American Society of Nephrology Medium 16775035
2006 WNK1 and WNK4 suppress CFTR chloride channel activity when coexpressed in Xenopus oocytes. WNK4 reduces CFTR surface expression in a kinase-independent manner. WNK1 suppression of CFTR requires intact WNK1 kinase activity. WNK1 colocalizes with CFTR in pulmonary epithelial cells. Xenopus oocyte electrophysiology (CFTR Cl- current), kinase-dead WNK1, CFTR surface expression assay, immunofluorescence colocalization Biochemical and biophysical research communications Medium 17194447
2006 WNK1 overexpression in MDCKII cells increases paracellular chloride permeability 2–3-fold and induces phosphorylation of claudin-4, phenocopying effects of disease-causing WNK4 mutants. Stable WNK1-overexpressing MDCKII cell lines, Cl- flux assay, Western blot for phospho-claudin-4 Biochemical and biophysical research communications Medium 16949040
2006 WNK1 kinase domain (but not isolated autoinhibitory domain) phosphorylates WNK4 and WNK2 in vitro. WNK1 exists as a tetramer in solution (gel filtration). The WNK1 N-terminus (residues 1–222) interacts with residues 481–660 (autoinhibitory domain + coiled-coil domain) by yeast two-hybrid assay. In vitro kinase assay, gel filtration chromatography, yeast two-hybrid The Journal of biological chemistry Medium 15883153
2007 WNK1 directly binds to and phosphorylates Smad2. WNK1 siRNA knockdown in HeLa cells reduces Smad2 protein expression (at least partly by reducing Smad2 transcription), but also causes nuclear accumulation of phosphorylated Smad2 and increased TGF-β-mediated transcriptional responses, identifying WNK1 as a dual modulator of TGF-β–Smad2 signaling. siRNA knockdown of WNK1 in HeLa cells, Western blot for Smad2, immunofluorescence for nuclear pSmad2, in vitro kinase assay, reporter gene assay for TGF-β target genes The Journal of biological chemistry Medium 17392271
2008 The HSN2 exon of WNK1 encodes a nervous system-specific exon; the WNK1/HSN2 isoform is expressed in satellite cells, Schwann cells, and sensory neurons of the peripheral nervous system and is more abundant in sensory neurons than motor neurons. Loss-of-function mutations in this exon cause HSAN type II. Immunodetection (immunofluorescence, IHC) in mouse nervous system tissues, analysis of human WNK1/HSN2 isoform expression, characterization of mutation spectrum The Journal of clinical investigation Medium 18521183
2008 Multiple WNK1 domains interact intramolecularly to regulate ROMK1 inhibition: the N-terminal proline-rich domain (aa 1–119) is necessary and sufficient for ROMK1 inhibition; the N-linker (aa 120–220) antagonizes inhibition; the kinase domain reverses this antagonism via conserved residues Lys-233 and Asp-368 (not kinase activity per se); the autoinhibitory domain (aa 491–555) modulates the kinase domain via two critical Phe residues; and the first coiled-coil (aa 555–640) alleviates the AID effect. Xenopus oocyte ROMK current measurements with WNK1 truncation and point mutants (K233M, D368A, Phe mutations in AID) American journal of physiology. Renal physiology Medium 18550644
2009 WNK1 localizes to cytoplasmic puncta in resting cells and to mitotic spindles during cell division. WNK1 knockdown causes defects in mitotic spindles, abscission failures, and reduced cell survival. These cell-division defects are independent of the WNK1 effector kinase OSR1 (OSR1 knockdown does not cause spindle defects). Immunofluorescence localization (live imaging and fixed cells), siRNA knockdown of WNK1 and OSR1, analysis of mitotic phenotypes (spindle morphology, abscission, survival) Proceedings of the National Academy of Sciences of the United States of America Medium 21220314
2009 WNK1 interacts with LINGO-1 (identified by yeast two-hybrid, validated by FRET and co-IP) in cortical neurons. This interaction is intensified by Nogo66 treatment. WNK1 suppression or overexpression of a dominant-negative WNK1 fragment attenuates Nogo66-induced inhibition of neurite extension and reduces RhoA activation. WNK1 also interacts with Rho-GDI1, an interaction weakened by Nogo66. Yeast two-hybrid screen, FRET, co-immunoprecipitation, siRNA knockdown, RhoA pull-down activity assay, neurite extension assay in cortical neurons The Journal of biological chemistry Medium 19363035
2009 WNK1 kinase uses a random sequential mechanism to phosphorylate its substrate OSR1 (OXSR1), as shown by double-reciprocal kinetic analysis. ATP-competitive inhibitors PP1 and PP2 inhibit WNK1 with Ki ~12.7 μM (PP1), acting as pure ATP competitors. Microfluidic capillary-electrophoresis kinase assay, double-reciprocal (Lineweaver-Burk) kinetic analysis, inhibitor competition assays Biochemistry Medium 19739668
2009 Endothelial-specific deletion of Wnk1 in mice phenocopies global Wnk1 knockout (cardiovascular developmental defects: small heart chambers, reduced trabeculation, defective angiogenesis starting at E10.5); endothelial-specific transgenic rescue of WNK1 corrects these defects, establishing that WNK1 function in endothelial cells is required for angiogenesis and heart development. Conditional endothelial-specific Cre-mediated Wnk1 knockout, transgenic rescue with endothelial WNK1 expression, embryo phenotype analysis The American journal of pathology High 19644017
2010 WNK1 promotes cell-surface expression of GLUT1 by phosphorylating TBC1D4 (AS160) in vitro, which increases TBC1D4 binding to 14-3-3 proteins and reduces its interaction with the exocytic GTPase Rab8A. This effect requires WNK1 catalytic activity (kinase-dead WNK1 has no effect). Co-immunoprecipitation (WNK1-TBC1D4 complex), in vitro kinase assay, 14-3-3 and Rab8A binding assays, surface GLUT1 expression measurement, kinase-dead WNK1 mutant The Journal of biological chemistry Medium 20937822
2011 WNK1 stimulates PLC-β signaling by promoting synthesis of the PIP2 substrate via activation of phosphatidylinositol 4-kinase IIIα (PI4KIIIα). This effect does not require WNK1 kinase activity and is synergistic with Gαq. WNK1 activity is essential for Gq-coupled receptor regulation of PLC-β. Akt-mediated phosphorylation of WNK1 further amplifies PLC-β signaling via this mechanism. DAG biosensor (TRPC6) and IP3-Ca2+ reporter assays in cells, WNK1 kinase-dead mutant, PI4KIIIα manipulation, Gq inhibitors Current biology Medium 22119528
2013 WNK1 activates OSR1 downstream to regulate embryonic angiogenesis and cardiac development: global Osr1 deletion phenocopies Wnk1 knockout (identical yolk-sac and embryo angiogenesis defects from E11); endothelial-specific active-OSR1 transgene rescues cardiovascular defects in global Wnk1-null embryos, establishing a WNK1→OSR1 epistatic axis in embryonic cardiovascular development. Genetic epistasis: global Osr1 knockout, endothelial-specific Osr1 knockout (Tie2-Cre), constitutively active OSR1 knock-in at ROSA26, embryo phenotype analysis The Journal of biological chemistry High 23386621
2014 Chloride directly binds to the catalytic site of WNK1, stabilizing its inactive conformation and inhibiting autophosphorylation. Crystallographic studies of inactive WNK1 in the presence of chloride reveal the Cl- binding site in the active site cavity. Mutagenesis of the chloride-binding site renders WNK1 less sensitive to chloride-mediated inhibition of autophosphorylation, validating WNK1 as a chloride sensor. X-ray crystallography of WNK1 kinase domain with chloride, autophosphorylation assays under varying Cl- concentrations, site-directed mutagenesis of Cl-binding site residues Science signaling High 24803536
2014 WNK1 and its substrate kinase OSR1 have distinct roles in endothelial cells: OSR1 is required for HUVEC chemotaxis and invasion, while SPAK is required for endothelial cell proliferation. WNK1 loss of function impairs cord formation. WNK1 also regulates expression of the transcription factor Slug in endothelial cells. siRNA knockdown of WNK1, OSR1, and SPAK in HUVECs, Matrigel cord-formation assay, chemotaxis/invasion assay, proliferation assay, gene expression analysis for Slug Proceedings of the National Academy of Sciences of the United States of America Medium 25362046
2014 KLHL3 mediates ubiquitination and degradation of WNK1 (and WNK4) as part of the KLHL3-Cullin3 E3 ligase complex; KLHL3 R528H mutation impairs binding to WNK1 and WNK4 peptides, leading to increased WNK1 and WNK4 protein levels and hyperactivation of the WNK→OSR1/SPAK→NCC phosphorylation cascade, causing PHAII. KLHL3 R528H knock-in mouse model, Western blot for WNK1/WNK4 protein levels, fluorescence correlation spectroscopy peptide-binding assay, NCC phosphorylation analysis Human molecular genetics High 24821705
2014 WNK1-OSR1-mediated phosphorylation of NKCC1 is required for regulatory volume increase and promotes glioma cell migration. siRNA-mediated knockdown of WNK1 or OSR1 reduces intracellular K+ and Cl- content, abolishes NKCC1 phospho-activation, and significantly decreases glioma cell migration following temozolomide treatment. siRNA knockdown of WNK1 and OSR1, fluorescent ion indicators for intracellular K+/Cl-, microchemotaxis migration assay, NKCC1 phosphorylation Western blot Molecular cancer Medium 24555568
2015 WNK1 isoforms containing PY-motif-bearing alternatively spliced exons within a proline-rich region are substrates of the E3 ligase NEDD4-2 and are degraded by the ubiquitin-proteasome system. SGK1 (aldosterone-induced kinase) phosphorylates NEDD4-2 and prevents WNK1 degradation, thereby linking aldosterone to activation of the WNK/SPAK/OSR1/NCC pathway. WNK1 deficiency negates regulatory effects of NEDD4-2 and SGK1 on NCC. Identification of PY-motif exons by cDNA analysis, co-IP of WNK1 with NEDD4-2, proteasome inhibitor experiments, SGK1 activity assays, gene-edited WNK1-deficient cells, aldosterone infusion in WT and Nedd4-2 KO mice The Journal of clinical investigation High 26241057
2016 WNK1 negatively regulates integrin-mediated T cell adhesion while positively regulating T cell migration via OXSR1/STK39 (OSR1/SPAK) and SLC12A2 (NKCC1). WNK1-deficient T cells (identified by RNAi screen) home less efficiently to lymphoid organs and migrate more slowly through them. RNAi screen, conditional T cell-specific knockout, cell migration and adhesion assays in vitro, in vivo homing assay to lymphoid organs Nature immunology High 27400149
2016 WNK1 inhibits autophagy by multiple mechanisms: WNK1 depletion increases autophagosome formation and autophagic flux, stimulates PI3KC3 complex activity, increases ULK1 expression and AMPK-mediated phosphorylation. The N-terminal region of WNK1 binds UVRAG (a PI3KC3 component) in vitro and WNK1 partially colocalizes with UVRAG; colocalization decreases upon starvation. Depletion of SPAK (but not OSR1) also induces autophagy. siRNA knockdown of WNK1, autophagosome/flux assays, ULK1 expression and phosphorylation Western blot, AMPK activation assay, in vitro binding of WNK1 N-terminus to UVRAG, colocalization by fluorescence microscopy Proceedings of the National Academy of Sciences of the United States of America Medium 27911840
2017 The KS-WNK1 isoform is critical for WNK body formation in distal tubule cells. WNK bodies are dynamic, membraneless foci distinct from conventional organelles that colocalize with ribosomal protein L22 and cluster WNK signaling components. KS-WNK1 knockout mice fail to form WNK bodies under dietary K+ challenge. A cysteine-rich hydrophobic motif in KS-WNK1's unique N-terminal exon is required for WNK body formation. KS-WNK1 knockout mouse model, live-cell imaging of WNK bodies, colocalization with organelle markers, reconstitution in cell culture, mutagenesis of the cysteine-rich motif Molecular biology of the cell Medium 29237822
2017 GABA_A receptor-mediated synaptic inhibition regulates KCC2 surface expression via the Cl--sensing kinase WNK1: enhanced GABA_A inhibition confines KCC2 to the plasma membrane, while blocking inhibition increases KCC2 lateral diffusion and endocytosis. This mechanism is dependent on WNK1-mediated phosphorylation of KCC2 at Thr-906 and Thr-1007. Single-particle tracking of KCC2 in hippocampal neurons, pharmacological manipulation of GABA_A activity, phospho-specific antibodies for KCC2 Thr-906/1007, WNK1 inhibitor experiments Nature communications High 29176664
2017 WNK1 phosphorylates the transcription termination factor PCF11 on its CID (CTD-interacting domain), and this phosphorylation weakens the CID's interaction with RNA polymerase II CTD, thereby promoting transcript release from chromatin-associated Pol II and facilitating mRNA export. In vitro kinase assay (WNK1 phosphorylation of PCF11 CID), phosphorylation-dependent Pol II CTD binding assay, nuclear WNK1 localization, mRNA export assay Genes & development Medium 29196535
2019 WNK1 activates TRPC6-mediated Ca2+ influx by stimulating PI4KIIIα, activating Gαq-coupled/PLC-β signaling and downstream NFATc1, promoting proliferation and migration of clear-cell renal carcinoma cells. Inhibition of WNK1 attenuates TRPC6-mediated Ca2+ influx and NFATc1-dependent gene expression. Patch-clamp electrophysiology for TRPC6 current, Ca2+ imaging, PI4KIIIα activity assay, NFATc1 reporter assay, WNK1 siRNA knockdown and pharmacological inhibition, cell migration/proliferation assays FASEB journal Medium 31022353
2020 Mutations in the conserved acidic motif of WNK1 preferentially impair ubiquitination and degradation of the KS-WNK1 isoform (not L-WNK1) by the KLHL3-CUL3 E3 ligase complex, leading to increased SPAK-NCC phosphorylation cascade activity and impaired ROMK apical expression in the distal nephron, causing a normotenive hyperkalemic hyperchloremic acidosis. Exome sequencing, Xenopus oocyte and HEK293T functional assays for ubiquitination and NCC activity, CRISPR/Cas9 engineered mouse model, renal phospho-NCC and ROMK expression analysis The Journal of clinical investigation High 32790646
2021 WNK1 functions as an assembly factor for the human ER membrane protein complex (EMC): WNK1 uses a conserved amphipathic helix to stabilize the soluble EMC subunit EMC2 by binding at the EMC2-8 interface, shielding a hydrophobic surface from promiscuous interactions and competing with E3 ubiquitin ligases to permit proper EMC assembly. WNK1 depletion destabilizes both EMC and its membrane-protein clients. Biochemical reconstitution, co-immunoprecipitation of WNK1 with EMC2/EMC subunits, structural analysis of amphipathic helix interaction, E3 ligase competition binding assay, WNK1 depletion with analysis of EMC client stability Molecular cell High 33964204
2021 WNK1 negatively regulates NLRP3 inflammasome activation and pyroptosis by balancing intracellular Cl- and K+ concentrations. WNK1-deficient macrophages (kinase knockout or protein knockout) show increased NLRP3 activation and pyroptosis. Macrophage-specific WNK1 conditional knockout mice produce more IL-1β in response to NLRP3 stimulation. WNK1 kinase-inactive and protein-knockout macrophages, NLRP3 activation assays (IL-1β secretion, pyroptosis), macrophage-specific conditional knockout mouse model, intracellular Cl-/K+ measurement Nature communications High 34315884
2022 WNK1 acts as a chloride-stimulated scaffold (kinase-activity independent) that recruits SGK1 to mTORC2, resulting in enhanced SGK1 phosphorylation and SGK1-dependent ENaC activation. An increase in extracellular K+ raises intracellular Cl-, which triggers this WNK1 scaffolding activity. This effect is selective for SGK1 and does not cause generalized mTORC2 activation. Co-immunoprecipitation of WNK1-SGK1-mTORC2, kinase-dead WNK1 mutant experiments, intracellular Cl- manipulation, ENaC activity assay, SGK1 phosphorylation Western blot Journal of cell science Medium 36373794
2022 WNK1 inhibition prevents TGF-β-dependent degradation of the tyrosine kinase receptor AXL in endothelial cells, and OSR1 (WNK1 substrate) physically interacts with occludin (a tight junction protein), a step required for tight junction turnover during angiogenesis. Both phenomena are WNK1-dependent and TGF-β-sensitive. WNK1 inhibitor treatment of HUVECs and aortic ex vivo sprouting assay, co-immunoprecipitation of OSR1-occludin, AXL expression/degradation assay in presence/absence of WNK1 inhibitor, embryo vessel extension assay Proceedings of the National Academy of Sciences of the United States of America Medium 35867836

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 WNK1, a novel mammalian serine/threonine protein kinase lacking the catalytic lysine in subdomain II. The Journal of biological chemistry 440 10828064
2005 The WNK1 and WNK4 protein kinases that are mutated in Gordon's hypertension syndrome phosphorylate and activate SPAK and OSR1 protein kinases. The Biochemical journal 435 16083423
2014 Chloride sensing by WNK1 involves inhibition of autophosphorylation. Science signaling 329 24803536
2003 Wnk1 kinase deficiency lowers blood pressure in mice: a gene-trap screen to identify potential targets for therapeutic intervention. Proceedings of the National Academy of Sciences of the United States of America 295 14610273
2006 Functional interactions of the SPAK/OSR1 kinases with their upstream activator WNK1 and downstream substrate NKCC1. The Biochemical journal 262 16669787
2006 Regulation of activity and localization of the WNK1 protein kinase by hyperosmotic stress. The Journal of cell biology 176 17190791
2005 WNK1 activates SGK1 to regulate the epithelial sodium channel. Proceedings of the National Academy of Sciences of the United States of America 170 16006511
2004 Crystal structure of the kinase domain of WNK1, a kinase that causes a hereditary form of hypertension. Structure (London, England : 1993) 165 15242606
2006 WNK1 and OSR1 regulate the Na+, K+, 2Cl- cotransporter in HeLa cells. Proceedings of the National Academy of Sciences of the United States of America 158 16832045
2006 Antagonistic regulation of ROMK by long and kidney-specific WNK1 isoforms. Proceedings of the National Academy of Sciences of the United States of America 149 16428287
2003 Multiple promoters in the WNK1 gene: one controls expression of a kidney-specific kinase-defective isoform. Molecular and cellular biology 144 14645531
2005 Mechanisms of WNK1 and WNK4 interaction in the regulation of thiazide-sensitive NaCl cotransport. The Journal of clinical investigation 143 15841204
2002 Regulation of WNK1 by an autoinhibitory domain and autophosphorylation. The Journal of biological chemistry 131 12374799
2003 WNK1 activates ERK5 by an MEKK2/3-dependent mechanism. The Journal of biological chemistry 123 14681216
2013 WNK1-related Familial Hyperkalemic Hypertension results from an increased expression of L-WNK1 specifically in the distal nephron. Proceedings of the National Academy of Sciences of the United States of America 113 23940364
2006 WNK1 kinase isoform switch regulates renal potassium excretion. Proceedings of the National Academy of Sciences of the United States of America 113 16709664
2004 Identification of a novel gene (HSN2) causing hereditary sensory and autonomic neuropathy type II through the Study of Canadian Genetic Isolates. American journal of human genetics 112 15060842
2005 Properties of WNK1 and implications for other family members. The Journal of biological chemistry 110 15883153
2005 Association of WNK1 gene polymorphisms and haplotypes with ambulatory blood pressure in the general population. Circulation 101 16301342
2010 Decreased ENaC expression compensates the increased NCC activity following inactivation of the kidney-specific isoform of WNK1 and prevents hypertension. Proceedings of the National Academy of Sciences of the United States of America 97 20921400
2003 WNK1, a kinase mutated in inherited hypertension with hyperkalemia, localizes to diverse Cl- -transporting epithelia. Proceedings of the National Academy of Sciences of the United States of America 96 12522152
2005 Dominant-negative regulation of WNK1 by its kidney-specific kinase-defective isoform. American journal of physiology. Renal physiology 95 16204408
2009 Endothelial-specific expression of WNK1 kinase is essential for angiogenesis and heart development in mice. The American journal of pathology 93 19644017
2008 Mutations in the nervous system--specific HSN2 exon of WNK1 cause hereditary sensory neuropathy type II. The Journal of clinical investigation 93 18521183
2010 Downregulation of NCC and NKCC2 cotransporters by kidney-specific WNK1 revealed by gene disruption and transgenic mouse models. Human molecular genetics 85 21131289
2021 Chloride sensing by WNK1 regulates NLRP3 inflammasome activation and pyroptosis. Nature communications 84 34315884
2005 WNK1 activates SGK1 by a phosphatidylinositol 3-kinase-dependent and non-catalytic mechanism. The Journal of biological chemistry 83 16081417
2004 WNK1, the kinase mutated in an inherited high-blood-pressure syndrome, is a novel PKB (protein kinase B)/Akt substrate. The Biochemical journal 83 14611643
2017 GABAA receptor dependent synaptic inhibition rapidly tunes KCC2 activity via the Cl--sensitive WNK1 kinase. Nature communications 82 29176664
2014 WNK1-OSR1 kinase-mediated phospho-activation of Na+-K+-2Cl- cotransporter facilitates glioma migration. Molecular cancer 80 24555568
2005 Identification of WNK1 as a substrate of Akt/protein kinase B and a negative regulator of insulin-stimulated mitogenesis in 3T3-L1 cells. The Journal of biological chemistry 78 15799971
2017 Potassium-regulated distal tubule WNK bodies are kidney-specific WNK1 dependent. Molecular biology of the cell 73 29237822
2014 Impaired degradation of WNK1 and WNK4 kinases causes PHAII in mutant KLHL3 knock-in mice. Human molecular genetics 72 24821705
2006 WNK1 affects surface expression of the ROMK potassium channel independent of WNK4. Journal of the American Society of Nephrology : JASN 71 16775035
2012 A new methodology for quantification of alternatively spliced exons reveals a highly tissue-specific expression pattern of WNK1 isoforms. PloS one 68 22701532
2006 Regulation of the expression of the Na/Cl cotransporter by WNK4 and WNK1: evidence that accelerated dynamin-dependent endocytosis is not involved. American journal of physiology. Renal physiology 65 16788137
2005 WNK1 kinase polymorphism and blood pressure response to a thiazide diuretic. Hypertension (Dallas, Tex. : 1979) 65 16172412
2004 WNK1 phosphorylates synaptotagmin 2 and modulates its membrane binding. Molecular cell 65 15350218
2011 WNK1 regulates vasoconstriction and blood pressure response to α 1-adrenergic stimulation in mice. Hypertension (Dallas, Tex. : 1979) 64 21768522
2016 WNK1 kinase balances T cell adhesion versus migration in vivo. Nature immunology 62 27400149
2014 Actions of the protein kinase WNK1 on endothelial cells are differentially mediated by its substrate kinases OSR1 and SPAK. Proceedings of the National Academy of Sciences of the United States of America 61 25362046
2015 New somatic mutations and WNK1-B4GALNT3 gene fusion in papillary thyroid carcinoma. Oncotarget 57 25803323
2015 Alternatively spliced proline-rich cassettes link WNK1 to aldosterone action. The Journal of clinical investigation 57 26241057
2016 miR-93 inhibits the invasive potential of triple-negative breast cancer cells in vitro via protein kinase WNK1. International journal of oncology 56 27840899
2018 Kidney-specific WNK1 isoform (KS-WNK1) is a potent activator of WNK4 and NCC. American journal of physiology. Renal physiology 53 29846116
2011 WNK1 is required for mitosis and abscission. Proceedings of the National Academy of Sciences of the United States of America 53 21220314
2007 Biological cross-talk between WNK1 and the transforming growth factor beta-Smad signaling pathway. The Journal of biological chemistry 52 17392271
2006 Down-regulation of WNK1 protein kinase in neural progenitor cells suppresses cell proliferation and migration. Journal of neurochemistry 52 17018027
2005 WNK1: analysis of protein kinase structure, downstream targets, and potential roles in hypertension. Cell research 50 15686619
2009 LINGO-1 interacts with WNK1 to regulate nogo-induced inhibition of neurite extension. The Journal of biological chemistry 49 19363035
2013 WNK1 protein kinase regulates embryonic cardiovascular development through the OSR1 signaling cascade. The Journal of biological chemistry 48 23386621
2010 Regulation of WNK1 expression by miR-192 and aldosterone. Journal of the American Society of Nephrology : JASN 48 20813867
2006 WNK1 and WNK4 modulate CFTR activity. Biochemical and biophysical research communications 48 17194447
2004 Identification of 108 SNPs in TSC, WNK1, and WNK4 and their association with hypertension in a Japanese general population. Journal of human genetics 46 15309683
2016 Multistep regulation of autophagy by WNK1. Proceedings of the National Academy of Sciences of the United States of America 45 27911840
2009 Regulation of ROMK channel and K+ homeostasis by kidney-specific WNK1 kinase. The Journal of biological chemistry 44 19244242
2011 Rice WNK1 is regulated by abiotic stress and involved in internal circadian rhythm. Plant signaling & behavior 43 21178395
2020 WNK1 Kinase Stimulates Angiogenesis to Promote Tumor Growth and Metastasis. Cancers 41 32131390
2020 Mutation affecting the conserved acidic WNK1 motif causes inherited hyperkalemic hyperchloremic acidosis. The Journal of clinical investigation 41 32790646
2016 Renal tubular SGK1 deficiency causes impaired K+ excretion via loss of regulation of NEDD4-2/WNK1 and ENaC. American journal of physiology. Renal physiology 41 27009335
2006 Overexpression of human WNK1 increases paracellular chloride permeability and phosphorylation of claudin-4 in MDCKII cells. Biochemical and biophysical research communications 41 16949040
2019 WNK1 promotes renal tumor progression by activating TRPC6-NFAT pathway. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 39 31022353
2017 WNK1 is an unexpected autophagy inhibitor. Autophagy 39 28282258
2016 Inhibition of the kinase WNK1/HSN2 ameliorates neuropathic pain by restoring GABA inhibition. Science signaling 39 27025876
2009 Polymorphisms in the WNK1 gene are associated with blood pressure variation and urinary potassium excretion. PloS one 39 19347040
2014 Zebrafish WNK lysine deficient protein kinase 1 (wnk1) affects angiogenesis associated with VEGF signaling. PloS one 37 25171174
2005 Two mutations in the HSN2 gene explain the high prevalence of HSAN2 in French Canadians. Neurology 37 15911806
2021 WNK1 Enhances Migration and Invasion in Breast Cancer Models. Molecular cancer therapeutics 36 34253593
2017 Akt3 inhibits adipogenesis and protects from diet-induced obesity via WNK1/SGK1 signaling. JCI insight 36 29202451
2014 WNK1 activates large-conductance Ca2+-activated K+ channels through modulation of ERK1/2 signaling. Journal of the American Society of Nephrology : JASN 36 25145935
2012 Kidney-specific WNK1 inhibits sodium reabsorption in the cortical thick ascending limb. American journal of physiology. Renal physiology 36 22791335
2004 A mutation in the HSN2 gene causes sensory neuropathy type II in a Lebanese family. Annals of neurology 36 15455397
2008 Deletion of WNK1 first intron results in misregulation of both isoforms in renal and extrarenal tissues. Hypertension (Dallas, Tex. : 1979) 35 18955660
2014 Generation of WNK1 knockout cell lines by CRISPR/Cas-mediated genome editing. American journal of physiology. Renal physiology 34 25477473
2021 WNK1 is an assembly factor for the human ER membrane protein complex. Molecular cell 33 33964204
2011 WNK1 promotes PIP₂ synthesis to coordinate growth factor and GPCR-Gq signaling. Current biology : CB 32 22119528
2006 Cardiovascular expression of the mouse WNK1 gene during development and adulthood revealed by a BAC reporter assay. The American journal of pathology 32 16816365
2022 WNK1 collaborates with TGF-β in endothelial cell junction turnover and angiogenesis. Proceedings of the National Academy of Sciences of the United States of America 31 35867836
2010 Protein kinase WNK1 promotes cell surface expression of glucose transporter GLUT1 by regulating a Tre-2/USP6-BUB2-Cdc16 domain family member 4 (TBC1D4)-Rab8A complex. The Journal of biological chemistry 29 20937822
2004 Comparison of WNK4 and WNK1 kinase and inhibiting activities. Biochemical and biophysical research communications 29 15081430
2019 Regulation of CFTR Bicarbonate Channel Activity by WNK1: Implications for Pancreatitis and CFTR-Related Disorders. Cellular and molecular gastroenterology and hepatology 28 31561038
2006 Novel mutations in the HSN2 gene causing hereditary sensory and autonomic neuropathy type II. Neurology 28 16534117
2022 WNK1 is a chloride-stimulated scaffold that regulates mTORC2 activity and ion transport. Journal of cell science 25 36373794
2020 miR-524-5p inhibits angiogenesis through targeting WNK1 in colon cancer cells. American journal of physiology. Gastrointestinal and liver physiology 25 32174132
2010 Regulation of WNK1 kinase by extracellular potassium. Clinical and experimental nephrology 25 21107632
2021 Role of KLHL3 and dietary K+ in regulating KS-WNK1 expression. American journal of physiology. Renal physiology 24 33682442
2019 Suppression of WNK1-SPAK/OSR1 Attenuates Bone Cancer Pain by Regulating NKCC1 and KCC2. The journal of pain 24 31085334
2017 WNK1 is required for proliferation induced by hypotonic challenge in rat vascular smooth muscle cells. Acta pharmacologica Sinica 24 28770829
2012 Kidney-specific WNK1 regulates sodium reabsorption and potassium secretion in mouse cortical collecting duct. American journal of physiology. Renal physiology 22 23195681
2013 WNK1/HSN2 mutation in human peripheral neuropathy deregulates KCC2 expression and posterior lateral line development in zebrafish (Danio rerio). PLoS genetics 21 23300475
2008 Domains of WNK1 kinase in the regulation of ROMK1. American journal of physiology. Renal physiology 21 18550644
2022 WNK1 kinase signaling in metastasis and angiogenesis. Cellular signalling 19 35649473
2020 WNK1 regulates uterine homeostasis and its ability to support pregnancy. JCI insight 19 33048843
2014 Pathogenesis of spinal cord injury induced edema and neuropathic pain: expression of multiple isoforms of wnk1. Annals of neurosciences 19 25206073
2012 Pathogenesis of pseudohypoaldosteronism type 2 by WNK1 mutations. Current opinion in nephrology and hypertension 19 22080857
2006 Novel mutation in the HSN2 gene in a Korean patient with hereditary sensory and autonomic neuropathy type 2. Journal of human genetics 19 16946995
2017 WNK1 kinase and the termination factor PCF11 connect nuclear mRNA export with transcription. Genes & development 18 29196535
2015 Cell-specific regulation of L-WNK1 by dietary K. American journal of physiology. Renal physiology 18 26662201
2009 Kinetic mechanism and inhibitor characterization of WNK1 kinase. Biochemistry 18 19739668
2006 New HSN2 mutation in Japanese patient with hereditary sensory and autonomic neuropathy type 2. Neurology 18 16636245

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