Affinage

WNK4

Serine/threonine-protein kinase WNK4 · UniProt Q96J92

Length
1243 aa
Mass
134.7 kDa
Annotated
2026-06-11
100 papers in source corpus 53 papers cited in narrative 53 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

WNK4 is a chloride-sensitive serine-threonine kinase that functions as a master regulatory switch in the distal nephron, balancing renal NaCl reabsorption against K+ secretion and thereby controlling blood pressure and electrolyte homeostasis (PMID:12515852, PMID:14608358, PMID:16964266). Its central effector arm is the WNK-SPAK/OSR1-NCC cascade: WNK4 binds and phosphorylates the T-loop residues of SPAK (Thr233) and OSR1 (Thr185) to activate them (PMID:16083423), and in vivo WNK4 is the dominant WNK kinase driving NCC phosphorylation and activation, since WNK4-/- mice lose nearly all phospho-NCC despite compensatory WNK1 upregulation (PMID:19633012, PMID:24655003). WNK4 activity is gated by intracellular chloride: under low [Cl-]i it autophosphorylates its T-loop (Ser335) and switches from an NCC inhibitor to an NCC activator, and a chloride-insensitive knockin mouse recapitulates pseudohypoaldosteronism type II (PHAII) and abolishes K+-dependent NCC regulation, establishing WNK4 as the physiological Cl- sensor that translates extracellular K+ into NCC activity (PMID:25542968, PMID:30765526, PMID:26422504). WNK4 abundance is set by CUL3-KLHL3-mediated ubiquitination and degradation; PHAII-causing mutations cluster in the acidic motif and impair KLHL3 binding, elevating WNK4 and constitutively activating the SPAK-NCC axis, with all PHAII phenotypes mediated through NCC and the SPAK/OSR1 cascade as shown by genetic epistasis (PMID:23576762, PMID:23387299, PMID:23453970, PMID:21486947, PMID:16964266). This degradation node is tuned by hormonal signaling — angiotensin II acts via PKC phosphorylation of KLHL3-Ser433 to stabilize WNK4, while aldosterone-induced SGK1 and Src-family kinases phosphorylate WNK4 directly to modulate its output toward NCC and ROMK (PMID:25313067, PMID:19690383, PMID:25805816, PMID:28096417). Beyond NCC, WNK4 acts as a broad transport coordinator, inhibiting ROMK via clathrin-dependent endocytosis (PMID:14608358), ENaC, KCCs, NKCC1, BK channels and SLC26A6, and phosphorylating tight-junction claudins to modulate paracellular Cl- permeability (PMID:15070779, PMID:14769928, PMID:15930150, PMID:17360470, PMID:17651736). Activating WNK4 mutations cause PHAII (familial hyperkalemic hypertension) (PMID:16964266, PMID:17488636).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2003 High

    Established WNK4 as a direct negative regulator of the thiazide-sensitive NCC and linked PHAII mutations to loss of this regulation, defining WNK4's core renal function.

    Evidence Xenopus oocyte heterologous expression with kinase-dead and PHAII mutants, surface biotinylation, and reciprocal Co-IP with NCC C-terminus

    PMID:12515852

    Open questions at the time
    • Did not resolve whether NCC inhibition is direct or via downstream kinases
    • Mechanism of PHAII gain-of-function not yet defined at the molecular level
  2. 2003 High

    Showed WNK4 simultaneously inhibits ROMK by a kinase-independent endocytic mechanism opposite in direction to its NCC effect, framing WNK4 as a molecular switch balancing Na+ reabsorption and K+ secretion.

    Evidence Xenopus oocyte electrophysiology with clathrin-dependent endocytosis assays and PHAII/kinase-dead mutants

    PMID:14608358

    Open questions at the time
    • Endocytic adaptor mediating ROMK internalization not identified
    • Physiological trigger that flips the switch in vivo not yet defined
  3. 2004 High

    Extended WNK4 substrate range to paracellular Cl- transport and extrarenal transporters, identifying claudins as phosphorylation substrates and NKCC1/SLC26A6 as targets.

    Evidence Inducible MDCK II epithelia with transepithelial permeability and in vitro claudin kinase assays; oocyte flux assays for NKCC1/SLC26A6

    PMID:14769928 PMID:15070779 PMID:15465913

    Open questions at the time
    • In vivo relevance of claudin phosphorylation to PHAII not established
    • Specific claudin phosphosites not yet mapped
  4. 2005 High

    Identified SPAK and OSR1 as direct downstream kinase substrates of WNK4, defining the WNK-SPAK/OSR1 module that transmits WNK4 activity to cation-chloride cotransporters.

    Evidence In vitro kinase assays with phosphopeptide mapping of SPAK Thr233/OSR1 Thr185, T-loop mutagenesis, yeast two-hybrid, and oocyte flux assays

    PMID:15841204 PMID:15930150 PMID:16083423

    Open questions at the time
    • How WNK1-WNK4 heterodimerization modulates the cascade quantitatively in vivo unclear
    • Whether SPAK/OSR1 mediate all WNK4 transport effects not yet tested genetically
  5. 2006 High

    Demonstrated in vivo that WNK4 controls blood pressure through DCT mass and NCC function, with NCC knockout fully reversing PHAII phenotypes, proving NCC is the principal mediator.

    Evidence Transgenic WNK4 mouse models with NCC-knockout epistasis and morphological/electrolyte phenotyping

    PMID:16964266

    Open questions at the time
    • Did not resolve whether transgenic effect reflects altered WNK4 abundance versus intrinsic activity
    • Contribution of ROMK/ENaC to phenotype not dissected
  6. 2006 High

    Defined the cellular route of WNK4-driven NCC downregulation, showing it reduces NCC surface expression via lysosomal rather than proteasomal or clathrin-dependent pathways.

    Evidence Surface biotinylation in Cos-7 cells with dominant-negative dynamin and bafilomycin A1 inhibition

    PMID:16688122

    Open questions at the time
    • Adaptor machinery routing NCC to lysosomes not yet identified
    • Whether wild-type-state lysosomal targeting differs mechanistically from PHAII-state not addressed
  7. 2007 High

    Broadened WNK4's regulatory targets to ENaC and connected WNK4 to aldosterone signaling via SGK1 phosphorylation, revealing a functional state opposite to PHAII.

    Evidence Oocyte co-expression with ENaC PY-motif mutants, in vivo colonic Na+ flux, and in vitro SGK1 phosphorylation with phosphomimetic mutagenesis

    PMID:17360470 PMID:17360471

    Open questions at the time
    • Number and identity of physiologically relevant SGK1 sites not fully resolved at this stage
    • Quantitative contribution of ENaC regulation to whole-animal phenotype unclear
  8. 2007 High

    Pinned PHAII pathogenesis in a knockin model to apical NCC and SPAK/OSR1 hyperphosphorylation, with ENaC activation a secondary compensatory event.

    Evidence Wnk4(D561A/+) knockin mice with immunohistochemistry, phospho-immunoblotting, patch clamp, and thiazide treatment

    PMID:17488636

    Open questions at the time
    • Did not explain how a remote PHAII mutation increases cascade activity at the molecular level
    • Claudin/paracellular contribution in vivo found minimal but not exhaustively excluded
  9. 2009 High

    Resolved the trafficking mechanism of WNK4-mediated NCC degradation as AP-3/sortilin-dependent diversion to lysosomes during forward trafficking rather than enhanced endocytosis.

    Evidence Forward-trafficking and surface-lifetime assays, endogenous AP-3 Co-IP, dominant-negative sortilin, and lysosomal protease inhibition

    PMID:19401467 PMID:19875813

    Open questions at the time
    • How WNK4 kinase activity directs NCC into AP-3/sortilin pathway not mechanistically resolved
    • Sortilin findings rest on a single lab without reconstitution
  10. 2009 High

    Reversed the early oocyte view by establishing WNK4 as a positive in vivo regulator of NCC and connecting WNK4 to angiotensin II signaling through SPAK.

    Evidence WNK4 knockout/hypomorphic mice with phospho-NCC/SPAK/OSR1 immunoblotting; oocyte and mpkDCT AngII/AT1R/SPAK dissection

    PMID:19240212 PMID:19633012 PMID:19690383

    Open questions at the time
    • Apparent inhibitor-versus-activator paradox not yet reconciled mechanistically
    • Direct sensor coupling AngII to WNK4 activity state not yet defined
  11. 2011 High

    Proved by triple-knockin genetics that PHAII phenotypes depend entirely on SPAK/OSR1 activation of NCC, and identified beta2AR-HDAC8-GR transcriptional control of WNK4 expression.

    Evidence Wnk4(D561A/+) crossed with Spak(T243A)/Osr1(T185A) knockin mice; HDAC8 activity assays, ChIP of GR at WNK4 promoter, and salt-sensitive rat models

    PMID:21486947 PMID:21499270

    Open questions at the time
    • Whether transcriptional and post-translational WNK4 control converge physiologically not integrated
    • Tissue specificity of beta2AR-HDAC8 axis beyond kidney not established
  12. 2011 Medium

    Documented WNK4 regulation of additional channels (BK, TRPC3, TRPV5) extending its role to K+ secretion, vascular tone, and Ca2+ handling.

    Evidence Patch clamp and surface-expression assays in HEK/intercalated cells, VSMC knockdown with vasoconstriction readouts, and oocyte TRPV5 endocytosis assays

    PMID:17018846 PMID:20061383 PMID:21613417 PMID:21670282 PMID:23673010 PMID:23885063

    Open questions at the time
    • These channel effects rely largely on single-lab oocyte/cell systems without in vivo confirmation
    • Mechanistic basis for kinase-dependent versus kinase-independent channel effects varies and is unresolved
  13. 2013 High

    Identified the CUL3-KLHL3 E3 ligase complex as the machinery that ubiquitinates and degrades WNK4, explaining how PHAII mutations in either WNK4 or KLHL3 elevate WNK4 abundance.

    Evidence Mass-spectrometry ubiquitination-site mapping, reconstituted in vitro ubiquitylation with recombinant CUL3-KLHL3, Co-IP, domain mapping, and in vivo kidney WNK4 levels

    PMID:23387299 PMID:23453970 PMID:23576762

    Open questions at the time
    • How specific acidic-motif mutations impair KLHL3 binding structurally not resolved here
    • Relative contribution of WNK4 abundance versus intrinsic activity to PHAII not fully partitioned
  14. 2014 High

    Established WNK4 as a chloride-sensing kinase whose low-Cl-induced T-loop autophosphorylation (Ser335) converts it to an NCC activator, and showed AngII tunes WNK4 stability via PKC phosphorylation of KLHL3-Ser433.

    Evidence Oocyte [Cl-]i measurement with chloride-pocket mutants (L322F) and autophosphorylation assays; in vitro PKC phosphorylation of KLHL3-S433 with in vivo AngII infusion

    PMID:25113964 PMID:25313067 PMID:25542968 PMID:26422504 PMID:29921588

    Open questions at the time
    • Structural basis of the WNK4 chloride-binding pocket not solved within the corpus
    • How PP1 dephosphorylation and WNK oligomerization integrate quantitatively with Cl- sensing unclear
  15. 2015 High

    Identified Src-family tyrosine phosphorylation and p62/SQSTM1-dependent selective autophagy as additional layers controlling WNK4 output toward ROMK and WNK4 turnover.

    Evidence Mass-spectrometry phosphosite mapping with Y1092/1094/1143 mutagenesis and oocyte ROMK assays; Co-IP and autophagy/proteasome inhibitor dissection of KLHL3-p62 complex

    PMID:25805816 PMID:26349538

    Open questions at the time
    • In vivo physiological trigger for Src-mediated WNK4 tyrosine phosphorylation not defined
    • Relative flux through autophagic versus proteasomal WNK4 degradation in kidney not quantified
  16. 2019 High

    Confirmed in vivo that WNK4 chloride sensing is the molecular basis of K+-dependent NCC regulation and described condensation of WNK4-SPAK/OSR1 into Kir4.1-dependent 'WNK bodies' during K+ deficiency.

    Evidence Cl--insensitive WNK4 knockin mice with dietary/acute K+ challenges; immunofluorescence of WNK bodies in WNK4-/- and DCT Kir4.1 conditional knockout mice; CaSR-WNK4 signaling assays

    PMID:29848507 PMID:30765526 PMID:31736353

    Open questions at the time
    • Functional role of WNK body condensation versus diffuse signaling not separated
    • Whether WNK bodies are required for, or merely accompany, NCC activation unresolved
  17. 2020 Medium

    Extended WNK4 regulation to NHA2-dependent stability control and dynamic K+-induced inactivation, and noted non-renal roles in adipogenesis and inflammation.

    Evidence NHA2-knockout mice with WNK4 ubiquitylation/KLHL3 phosphorylation assays; ex vivo/in vivo acute K+ dephosphorylation studies; WNK4-/- adipocyte and alveolar macrophage models

    PMID:28314693 PMID:29846116 PMID:31786261 PMID:32956652 PMID:33719576

    Open questions at the time
    • Extrarenal WNK4 functions rest on single-lab loss-of-function studies without mechanistic depth
    • How NHA2 mechanistically couples to KLHL3 phosphorylation unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple WNK4 inputs — chloride sensing, KLHL3-mediated degradation, hormonal phosphorylation, oligomerization, and WNK body condensation — are integrated quantitatively to set NCC activity under physiological conditions remains unresolved.
  • No integrated structural/biophysical model of WNK4 activation states
  • Relative weighting of transcriptional, degradative, and phosphorylation control in vivo not established
  • Mechanistic link between channel-level effects and whole-organism phenotypes for non-NCC targets incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016740 transferase activity 3 GO:0098772 molecular function regulator activity 3 GO:0140313 molecular sequestering activity 3
Localization
GO:0005886 plasma membrane 2 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-382551 Transport of small molecules 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-9609507 Protein localization 3
Partners
CAMCUL3KLHL3NCCOSR1SGK1SPAKWNK1
Complex memberships
WNK bodiesWNK kinase oligomer

Evidence

Reading pass · 53 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 Wild-type WNK4 inhibits NaCl cotransporter (NCC/NCCT)-mediated Na+ influx and reduces NCC membrane expression in Xenopus oocytes; this inhibition requires WNK4 kinase activity. PHAII-causing missense mutations in WNK4 (remote from kinase domain) abolish NCC inhibition. WNK4 and the C-terminus of NCC co-immunoprecipitate in HEK293T cells. Xenopus oocyte heterologous expression (22Na+ influx, surface biotinylation), kinase-dead mutagenesis, co-immunoprecipitation in HEK293T cells Proceedings of the National Academy of Sciences of the United States of America High 12515852
2003 WNK4 also inhibits the renal K+ channel ROMK via clathrin-dependent endocytosis, through a mechanism independent of WNK4 kinase activity and distinct from its inhibition of NCC. PHAII-causing WNK4 mutations increase ROMK inhibition while relieving NCC inhibition, establishing WNK4 as a molecular switch balancing NaCl reabsorption and K+ secretion. Xenopus oocyte expression, electrophysiology, clathrin-dependent endocytosis assays, mutagenesis Nature genetics High 14608358
2004 PHAII-causing mutant WNK4 (D564A) increases transepithelial paracellular Cl- permeability in MDCK II cells. Wild-type and mutant WNK4 bind and phosphorylate claudins 1–4 (major tight-junction proteins); mutant WNK4 causes greater claudin phosphorylation than wild-type. Stable MDCK II cell lines with inducible WNK4 expression, transepithelial permeability measurements, in vitro kinase assay (claudin phosphorylation), co-immunoprecipitation Proceedings of the National Academy of Sciences of the United States of America High 15070779
2004 Wild-type WNK4 increases paracellular chloride permeability in mammalian kidney epithelia (MDCK cells with inducible expression) through a kinase-dependent mechanism. PHAII-mutant WNK4 produces markedly larger effects; kinase-dead WNK4 has no effect. WNK4 did not alter flux of uncharged solutes or expression/localization of selected tight-junction proteins. Electrophysiology on mammalian kidney epithelia with inducible WNK4, kinase-dead and PHAII-mutant constructs, pharmacological and electrochemical characterization Proceedings of the National Academy of Sciences of the United States of America High 15465913
2004 WNK4 is expressed in extrarenal polarized epithelia (sweat ducts, colonic crypts, pancreatic ducts, bile ducts, epididymis, blood-brain barrier endothelium). In these tissues WNK4 potently inhibits NKCC1 (>95% inhibition of 86Rb influx) and the Cl-/base exchanger SLC26A6 (CFEX) (>80% inhibition of 14C-formate uptake), but not pendrin. Xenopus oocyte expression, 86Rb influx assay, 14C-formate uptake assay, WNK4 tissue localization Proceedings of the National Academy of Sciences of the United States of America High 14769928
2005 WNK1 and WNK4 both interact with and phosphorylate SPAK and OSR1 in vitro. WNK1/WNK4 phosphorylate the T-loop residues of SPAK (Thr233) and OSR1 (Thr185) and a C-terminal serine (Ser373/Ser325). Phosphorylation of Thr185 in OSR1 activates it; Thr185Ala prevents activation, and Thr185Glu (phosphomimetic) increases basal activity >20-fold. Catalytically inactive WNK1/WNK4 fail to activate SPAK/OSR1. Immunoprecipitation from rat testis, in vitro kinase assay, phosphopeptide mapping, site-directed mutagenesis of SPAK/OSR1 T-loop residues The Biochemical journal High 16083423
2005 WNK4 interacts with SPAK (via yeast two-hybrid and functional assays) and together activate NKCC1 and inhibit KCC2 in Xenopus oocytes. Catalytic activity of both WNK4 and SPAK is required. A SPAK-interaction-deficient WNK4 mutant (Phe997Ala) fails to activate NKCC1, establishing that WNK4 acts on NKCC1 indirectly through SPAK. Xenopus oocyte expression, yeast two-hybrid, kinase-dead mutagenesis, isotope flux assays American journal of physiology. Cell physiology High 15930150
2005 WNK1 kinase domain physically associates with WNK4 kinase domain (co-immunoprecipitation). WNK1 suppresses WNK4-mediated NCC inhibition via this interaction but requires intact WNK1 kinase activity. The WNK4 C-terminal 222 amino acids are sufficient to inhibit NCC but are not blocked by WNK1; WNK1 inhibition requires an intact WNK4 kinase domain. Xenopus oocyte expression, co-immunoprecipitation, domain deletion/mutagenesis, 22Na+ flux assays The Journal of clinical investigation High 15841204
2006 WNK4 wild-type significantly reduces NCC surface expression in Cos-7 mammalian cells; PHAII-mutant E562K does not. The effect is not due to clathrin-mediated endocytosis (dominant-negative dynamin K44A has no effect) but is reversed by the lysosomal inhibitor bafilomycin A1, indicating enhanced lysosomal degradation of NCC by WNK4. Surface biotinylation, co-immunoprecipitation, dominant-negative dynamin expression, pharmacological inhibitors (bafilomycin A1) in Cos-7 cells Kidney international High 16688122
2006 WNK4 controls blood pressure via regulation of mass and function of the distal convoluted tubule (DCT). TgWnk4(PHAII) mice show DCT hyperplasia, hypertension, hyperkalemia, and hypercalciuria; TgWnk4(WT) mice show opposite phenotypes. Genetic deficiency for NCC reverses all TgWnk4(PHAII) phenotypes, establishing that WNK4 PHAII effects are mediated through NCC. Transgenic mouse model (genomic WNK4 segments), NCC knockout epistasis, blood pressure/electrolyte measurements, kidney morphology Nature genetics High 16964266
2006 WNK4 enhances TRPV5-mediated Ca2+ uptake and increases TRPV5 surface expression in Xenopus oocytes; PHAII-causing WNK4 mutants retain ability to upregulate TRPV5. Xenopus oocyte expression, Ca2+ uptake assay, surface expression measurement American journal of physiology. Renal physiology Medium 17018846
2006 WNK4 is a negative regulator of K+-Cl- cotransporters KCC1, KCC3, and KCC4; this inhibition requires WNK4 catalytic activity (abolished by D318A mutation). PHAII-causing WNK4 missense mutations do not affect inhibition of KCC4. Xenopus oocyte expression, isotope flux assays, kinase-dead mutagenesis American journal of physiology. Renal physiology Medium 17182532
2007 WNK4 also inhibits ENaC (epithelial Na+ channel) activity via a kinase-independent mechanism requiring intact C-termini (PY motifs) in ENaC β- and γ-subunits. PHAII-causing WNK4 mutations eliminate ENaC inhibition. In vivo, PHAII-mutant WNK4 mice show markedly increased amiloride-sensitive Na+ flux in the colonic epithelium. Xenopus oocyte co-expression, C-terminal deletion/mutagenesis of ENaC subunits, amiloride-sensitive Na+ flux in transgenic mouse colonic epithelium Proceedings of the National Academy of Sciences of the United States of America High 17360470
2007 SGK1 phosphorylates WNK4 (aldosterone-dependent kinase), and a WNK4 phosphomimetic mutant at the SGK1 site (S1169D) relieves WNK4 inhibition of both ENaC and ROMK, promoting increased K+ secretion. This identifies a functional state of WNK4 that is the opposite of the PHAII state. Xenopus oocyte expression, in vitro phosphorylation by SGK1, phosphomimetic mutagenesis (S1169D) Proceedings of the National Academy of Sciences of the United States of America High 17360471
2007 In Wnk4(D561A/+) knockin mice (PHAII model), phosphorylated NCC is increased at the apical surface of distal convoluted tubule cells. OSR1 and SPAK phosphorylation are also increased. Apical ROMK localization and transepithelial Cl- permeability in cortical collecting ducts are unaffected. ENaC activation is a secondary compensatory effect (reversed by hydrochlorothiazide). PHAII pathogenesis is through OSR1/SPAK-NCC cascade activation. Knockin mouse model (D561A), immunohistochemistry, immunoblotting of phosphorylated NCC/OSR1/SPAK, patch clamp electrophysiology, hydrochlorothiazide treatment Cell metabolism High 17488636
2007 WNK4 phosphorylates claudin-7 at Ser206 in the COOH-terminus (identified as a WNK4 phosphorylation site by mutagenesis). WNK4 and claudin-7 co-immunoprecipitate in kidney epithelial cells and co-localize in renal tubules. The PHAII-causing mutant WNK4 enhances claudin-7 phosphorylation and paracellular Cl- permeability more than wild-type. Co-immunoprecipitation in kidney epithelial cells, in vitro kinase assay, site-directed mutagenesis (Ser206), paracellular permeability measurement FEBS letters Medium 17651736
2009 WNK4 diverts NCC to lysosomes for degradation via an AP-3-dependent mechanism, reducing forward trafficking from the trans-Golgi network to the plasma membrane rather than increasing endocytosis. WNK4 increases NCC association with AP-3 adaptor complexes and increases lysosomal NCC accumulation (reversed by lysosomal protease inhibitor leupeptin, not proteasome inhibition). Surface lifetime analysis, direct forward trafficking measurements (trans-Golgi to plasma membrane), co-immunoprecipitation with endogenous AP-3, subcellular localization with leupeptin/proteasome inhibitors, WNK4 knockdown The Journal of biological chemistry High 19401467
2009 Angiotensin II (AngII) increases NCC activity in Xenopus oocytes by abrogating WNK4 inhibition of NCC through a pathway requiring AngII receptor AT1R and WNK4. This effect is SPAK-dependent (dominant-negative SPAK or elimination of SPAK-binding motif in NCC prevents it). AngII does not alter WNK4 inhibition of ROMK. AngII increases phosphorylation of SPAK and NCC at activation sites in mpkDCT mammalian cells. Xenopus oocyte expression, dominant-negative SPAK, AT1R inhibitor losartan, immunoblotting of pSPAK and pNCC in mpkDCT cells Proceedings of the National Academy of Sciences of the United States of America High 19240212
2009 WNK4 knockout mice (WNK4-/-) exhibit reduced NCC expression and phosphorylation, low blood pressure and increased Na/K excretion on low-salt diet. Phosphorylation of OSR1/SPAK and NCC is significantly reduced, establishing wild-type WNK4 as a positive regulator of the WNK-OSR1/SPAK-NCC cascade in vivo. WNK4 hypomorphic/knockout mouse model, immunoblotting of pOSR1/pSPAK/pNCC, blood pressure and urinary electrolyte measurements Human molecular genetics High 19633012
2009 WNK4 enhances NCC degradation through a sortilin-mediated lysosomal pathway. Truncated sortilin (dominant-negative) prevents WNK4-induced NCC reduction. NCC co-immunoprecipitates with sortilin, and WNK4 increases co-localization of NCC with lysosomal marker cathepsin D. Co-transfection in Cos-7 cells, dominant-negative sortilin, co-immunoprecipitation, immunostaining with lysosomal marker Journal of the American Society of Nephrology : JASN Medium 19875813
2009 SGK1 binds and phosphorylates WNK4 in vitro and in a human kidney cell line at two serine residues including one in an established SGK1 consensus sequence. Phosphomimetic mutations (aspartate) at these SGK1 target serines attenuate WNK4 inhibition of NCC in Xenopus oocytes. This defines the aldosterone/SGK1 → WNK4 → NCC pathway. In vitro kinase assay (SGK1 phosphorylation of WNK4), co-immunoprecipitation, phosphomimetic mutagenesis, Xenopus oocyte functional assays The Journal of clinical investigation High 19690383
2010 WNK4 stimulates caveola-mediated endocytosis of TRPV5, decreasing its cell-surface abundance. A region outside the kinase domain of WNK4 mediates TRPV5 endocytosis stimulation. This sets a lower basal TRPV5 level that allows PKC stimulation to produce a larger relative increase in TRPV5 current. Xenopus oocyte expression, electrophysiology (TRPV5 current), deletion analysis of WNK4 domains, caveola-mediated endocytosis assays, PKC activator (OAG) experiments The Journal of biological chemistry Medium 20061383
2011 Phenotypes of PHAII in Wnk4(D561A/+) knockin mice depend entirely on the WNK-OSR1/SPAK-NCC cascade: crossing with Spak(T243A) and Osr1(T185A) knock-in mice that cannot be activated by WNK kinases almost completely abolishes NCC phosphorylation and corrects hypertension, hyperkalemia, and metabolic acidosis in triple knock-in mice. Genetic epistasis in mice (triple knock-in), immunoblotting of pNCC, blood pressure and electrolyte measurements Journal of cell science High 21486947
2011 β2-adrenergic receptor (β2AR) stimulation decreases WNK4 gene transcription via cAMP-dependent inhibition of HDAC8, increasing histone acetylation and glucocorticoid receptor binding to a negative glucocorticoid-responsive element in the WNK4 promoter, leading to NCC activation and salt-sensitive hypertension. In vitro β2AR stimulation, HDAC8 activity assay, chromatin immunoprecipitation (GR-promoter binding), rat models of salt-sensitive hypertension Nature medicine High 21499270
2011 WNK4 inhibits Maxi K (BK) channel activity in a kinase-dependent manner (kinase-dead D321A has no effect). WNK4 reduces total and cell-surface Maxi K expression through a lysosomal degradation pathway (reversed by bafilomycin A1 and leupeptin), not through clathrin-mediated endocytosis (dominant-negative dynamin K44A has no effect). Patch clamp electrophysiology in HEK αBK stable cells, surface biotinylation, pharmacological inhibitors, kinase-dead mutagenesis American journal of physiology. Renal physiology Medium 21613417
2011 WNK4 inhibits TRPC3-mediated Ca2+ influx in vascular smooth muscle cells (VSMCs), restricting vasoconstriction. WNK4 depletion increases TRPC3-mediated Ca2+ entry and vasoconstriction. PHAII-mutant (Q562E) and kinase-dead (D318A) WNK4 both fail to inhibit TRPC3, indicating kinase activity is required. WNK4 knockdown/knockout in VSMCs, Ca2+ influx measurements, vasoconstriction assays in small mesenteric arteries, kinase-dead and PHAII mutant expression Proceedings of the National Academy of Sciences of the United States of America Medium 21670282
2011 WNK4 inhibits ENaC activity in A6 distal nephron cells by reducing channel number at the apical membrane (not open probability) and by enhancing ENaC internalization independent of Nedd4-2-mediated ENaC ubiquitination. WNK4 also reduces the ENaC pool available for recycling. WNK4 associates with both wild-type and Liddle's mutant ENaC. Transepithelial current measurement and single-channel recording in A6 cells, Western blot of apical/total ENaC, internalization assays, Co-IP in HEK293 cells American journal of physiology. Renal physiology Medium 23594824
2012 AngII-mediated activation of NCC requires WNK4 in vivo: WNK4-/- mice cannot phosphorylate SPAK and NCC in response to low-salt diet or AngII infusion, placing WNK4 as an essential intermediary in the AngII→SPAK→NCC signaling pathway. WNK4 knockout mouse, AngII infusion and low-salt diet protocols, immunohistochemistry and immunoblotting of pSPAK and pNCC Proceedings of the National Academy of Sciences of the United States of America High 22550170
2013 KLHL3 (a BTB-Kelch adaptor) binds WNK4 and promotes its ubiquitination at ≥15 specific sites and subsequent degradation, thereby reducing WNK4 levels and ROMK surface reduction. PHAII-causing mutations in either KLHL3 or WNK4 impair this binding and ubiquitination. KLHL3 requires CUL3 (a RING E3 ligase scaffold) to form the functional complex. Mass spectrometry, co-immunoprecipitation (KLHL3-WNK4-CUL3), ubiquitination assay (polyubiquitination mapping of WNK4), in vivo WNK4 protein level measurement in mouse kidney Proceedings of the National Academy of Sciences of the United States of America High 23576762
2013 The CUL3-KLHL3 E3 ligase complex ubiquitylates WNK4 (and WNK1) in vitro. KLHL3 binds WNK1/WNK4 but not SPAK/OSR1 or NCC/NKCC1. 13 out of 15 dominant KLHL3 disease mutations inhibit WNK binding. The KLHL3 interaction site in WNK1 maps to residues 479–667; equivalent WNK4 residues harbor PHAII mutations (E562K, Q565E) that abolish KLHL3 interaction. Co-immunoprecipitation, in vitro ubiquitylation assay with recombinant CUL3-KLHL3, siRNA knockdown (CUL3 in HeLa cells), domain mapping The Biochemical journal High 23387299
2013 KLHL3 interacts with CUL3 and WNK4, induces WNK4 ubiquitination, and reduces WNK4 protein level. PHAII-causing mutations in KLHL3 or WNK4 reduce this interaction and ubiquitination, resulting in elevated WNK4 protein and increased SPAK/OSR1-NCC phosphorylation. Transgenic mice overexpressing WNK4 display PHAII phenotypes; WNK4 protein is increased in Wnk4(D561A/+) knockin mice. Co-immunoprecipitation (KLHL3-CUL3-WNK4), in vitro ubiquitination assay, transgenic mouse overexpression, Wnk4(D561A/+) knockin mouse immunoblot Cell reports High 23453970
2013 WNK4 inhibits BK channel (large-conductance Ca2+-activated K+ channel) activity. A region within WNK4 encompassing the autoinhibitory domain and a coiled-coil domain is required for BK inhibition. WNK4 increases ubiquitination and degradation of BK α-subunit, reducing plasma membrane expression. Electrophysiology in intercalated cell line and HEK293 cells, domain deletion of WNK4, ubiquitination assay, surface/whole-cell expression measurements American journal of physiology. Cell physiology Medium 23885063
2014 WNK4 effects on NCC are modulated by intracellular Cl- concentration ([Cl-]i). Under low [Cl-]i, WNK4 autophosphorylates at S335 (T-loop) and activates NCC. A chloride-binding pocket mutation (L322F) renders WNK4 constitutively autophosphorylated, converting it to a constitutive NCC activator. Eliminating kinase activity (D321A or D321K-K186D) or the autophosphorylation site (S335A) in WNK4-L322F abolishes NCC activation. Xenopus oocyte expression, measurement of [Cl-]i with Cl-sensitive fluorescent dye, WNK4 autophosphorylation assay, chloride-binding pocket mutagenesis, 22Na+ uptake Journal of the American Society of Nephrology : JASN High 25542968
2014 WNK4 is the major WNK kinase positively regulating NCC in the mouse kidney: WNK4-/- mice show near-complete loss of phosphorylated and total NCC despite compensatory upregulation of WNK1. Insulin- and low-potassium diet-induced NCC phosphorylation are both abolished in WNK4-/- mice. WNK4 knockout mouse, immunoblotting of pNCC/NCC, dietary and hormonal challenges (insulin, low-K diet) Bioscience reports High 24655003
2014 Angiotensin II signaling via protein kinase C (PKC) phosphorylates KLHL3 at serine 433 (a site frequently mutated in hypertension), preventing KLHL3 from binding and targeting WNK4 for degradation, thereby increasing WNK4 levels and NCC phosphorylation. AngII administration to mice induces renal KLHL3-S433 phosphorylation and increased WNK4 and NCC levels. In vitro PKC phosphorylation of KLHL3 at S433, co-immunoprecipitation, mouse AngII infusion with immunoblotting of pKLHL3-S433/WNK4/NCC, site-directed mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 25313067
2014 WNK4 C-terminal truncation variants found in kidney lack a protein phosphatase 1 (PP1)-binding site; deletion of this site increases WNK4 kinase activity toward SPAK. Co-transfection with PP1 dephosphorylates WNK4; a PP1-binding site mutant is resistant to PP1. Full-length WNK4 is cleaved by a Zn2+-dependent metalloprotease in kidney lysates. LC-MS/MS identification of short WNK4 variants, co-transfection with PP1, kinase activity assay, WNK4 dephosphorylation assay, kidney lysate protease assay The Journal of biological chemistry Medium 29921588
2014 WNK1 activates NCC via SPAK in a WNK4-independent manner. Conversely, WNK4 decreases WNK1- and WNK3-mediated NCC activation. WNK kinases form oligomers through their C-terminal coiled-coil domains, and this oligomerization is essential for their activity toward NCC. WNK1-FHHt/WNK4-/- double mutant mice, Xenopus oocyte expression, coiled-coil domain mutagenesis, co-immunoprecipitation Hypertension (Dallas, Tex. : 1979) High 25113964
2015 c-Src phosphorylates WNK4 at Tyr1092, Tyr1094, and Tyr1143 (identified by Western blot and mass spectrometry). Both c-Src and protein tyrosine phosphatase PTP-1D co-immunoprecipitate with WNK4. Tyr1092Phe mutation markedly reduces WNK4-mediated ROMK inhibition; double mutant Y1092/1094F completely abolishes it. c-Src also prevents SGK1-induced phosphorylation of WNK4 at Ser1196, restoring WNK4 inhibition of ROMK. Mass spectrometry identification of phosphorylation sites, co-immunoprecipitation of c-Src/PTP-1D with WNK4, mutagenesis (Y1092F, Y1143F, double mutant), oocyte electrophysiology for ROMK activity Proceedings of the National Academy of Sciences of the United States of America High 25805816
2016 Chloride inhibits WNK4 kinase activity at lower concentrations than WNK1 or WNK3, within the physiological range of distal cell chloride. Mutation of the WNK4 chloride-binding motif (equivalent to that identified in WNK1) converts WNK4 effects on SPAK from inhibitory to stimulatory in mammalian cells. This explains how extracellular K+ affects NCC via intracellular Cl- acting on WNK4. In vitro kinase assay (WNK4 vs WNK1 vs WNK3 Cl- inhibition), chloride-binding motif mutagenesis in mammalian cells, in vivo dietary K+ manipulation with NCC phosphorylation readout Kidney international High 26422504
2016 Osmotic stress induces phosphorylation of WNK4 at Ser575 via the p38MAPK-MAPK-activated protein kinase (MK) pathway. WNK4 interacts with ASK3 (a MAP3K), and ASK3 kinase activity is required for WNK4 Ser575 phosphorylation. Hypotonic low-chloride stimulation also increases WNK4-Ser575 phosphorylation via p38MAPK-MK. LC-MS/MS identification of Ser575 phosphorylation, co-immunoprecipitation of WNK4 with ASK3, kinase-dead ASK3 rescue, p38MAPK pathway inhibitors Scientific reports Medium 26732173
2017 PKC and PKA phosphorylate WNK4 at multiple sites (S47, S64, S1169, S1180, S1196) downstream of AngII signaling. Phosphorylation at S64 and S1196 promotes WNK4 T-loop phosphorylation at S332 (required for kinase activation) and increases SPAK phosphorylation. Volume depletion induces these phosphorylations in vivo predominantly in the distal convoluted tubule. Tandem mass spectrometry, phosphosite-specific antibodies, in vitro PKC/PKA kinase assays, in vivo volume depletion mouse model Proceedings of the National Academy of Sciences of the United States of America High 28096417
2017 WNK4 is expressed in adipose tissue and is induced early during adipocyte differentiation. WNK4 affects the DNA-binding ability of C/EBPβ and thereby regulates PPARγ expression. WNK4 siRNA-knockdown reduces PPARγ, C/EBPα expression and lipid accumulation. WNK4-/- mice show decreased PPARγ and C/EBPα in adipose tissue and partial resistance to high-fat diet-induced adiposity. WNK4 siRNA in 3T3-L1 and human mesenchymal stem cells, WNK4-/- mouse model, C/EBPβ DNA-binding assay, adipocyte differentiation assay EBioMedicine Medium 28314693
2018 Kidney-specific WNK1 isoform (KS-WNK1, which lacks the kinase domain) activates WNK4-T-loop phosphorylation at Ser335 and stimulates SPAK/NCC by physically interacting with WNK4 (co-immunoprecipitation) independent of changes in intracellular Cl-. Eliminating the WNK-WNK interaction domain in KS-WNK1 abolishes this activation. Xenopus oocyte expression, co-immunoprecipitation of KS-WNK1 and WNK4, WNK4-S335 phosphorylation assay, WNK interaction domain deletion, WNK inhibitor WNK463 American journal of physiology. Renal physiology Medium 29846116
2019 WNK4 is a physiological intracellular Cl- sensor: knockin mice carrying a Cl--insensitive WNK4 mutant fully recapitulate human PHAII. Dietary K+ restriction failed to increase NCC activity in knockin mice, and acute K+ administration failed to inactivate NCC in knockin mice (unlike wild-type). These results establish that Cl- regulation of WNK4 underlies the K+-mediated regulation of NCC. Cl--insensitive WNK4 knockin mouse model, NCC phosphorylation measurements under dietary K+ manipulation and acute K+ gavage Proceedings of the National Academy of Sciences of the United States of America High 30765526
2019 In K+ deficiency, WNK4 and SPAK/OSR1 concentrate in cytoplasmic spherical domains termed 'WNK bodies' in the DCT. Phosphorylated SPAK/OSR1 is present within WNK bodies. In WNK4-deficient mice, larger WNK bodies form containing unphosphorylated WNK1, SPAK, and OSR1, indicating WNK4 is the primary active kinase in WNK bodies. WNK body formation requires Kir4.1 K+ channel-mediated DCT K+ sensing. Mouse dietary K+ manipulation, immunofluorescence microscopy of WNK bodies, WNK4-/- mouse, DCT-specific Kir4.1 conditional knockout mouse American journal of physiology. Renal physiology Medium 31736353
2019 CaSR activation increases NCC activity via the WNK4-SPAK pathway: in Xenopus oocytes NCC stimulation by CaSR is WNK4-dependent; in HEK293 cells CaSR activation causes KLHL3 phosphorylation, increased WNK4 abundance and activity, and SPAK phosphorylation in a WNK4-dependent manner (blocked by WNK463). Acute CaSR agonist (R-568) in mice increases pNCC. Xenopus oocyte 22Na+ assay, HEK293 cell phosphorylation assays, WNK463 inhibitor, mouse in vivo CaSR activation Journal of the American Society of Nephrology : JASN Medium 29848507
2019 WNK4-SPAK signaling promotes NKCC1 phosphorylation and NFκB activation in alveolar macrophages stimulated with LPS. WNK4 or SPAK knockout suppresses NKCC1 phosphorylation, NFκB activation, and acute lung injury; WNK4 D561A knockin (PHAII mutation) enhances inflammatory responses. WNK4-/-, SPAK-/-, WNK4(D561A/+) mice, primary alveolar macrophage culture, LPS stimulation, intrapulmonary LPS delivery, NFκB activation assay, NKCC1 phosphorylation immunoblot Biochemical pharmacology Medium 31786261
2011 WNK4 inhibits BK (large-conductance Ca2+-activated K+) channels via activation of ERK and p38 MAPK (MAPK-dependent mechanism), partially through dynamin-dependent endocytosis. SGK1-mediated phosphorylation of WNK4 at S1169/S1196 abolishes WNK4's effects on BK channels and MAPK activation. The WNK4-ROMK inhibitory pathway, by contrast, is MAPK-independent. Perforated whole-cell patch clamp in HEK293T cells, MAPK inhibitors, dominant-negative dynamin (K44A), dynasore, SGK1 co-expression with phosphomimetic WNK4 mutants, native CCD electrophysiology Biochimica et biophysica acta Medium 23673010
2015 KLHL3-mediated WNK4 degradation is also mediated by p62/SQSTM1-dependent selective autophagy in addition to proteasomal degradation. KLHL3 forms a complex with p62 (co-immunoprecipitation via kelch repeat domain). Under proteasome inhibition, p62 overexpression decreases WNK4 levels and p62 knockdown increases them. WNK4 co-localizes with KLHL3, p62, and LC3 (autophagosome marker) in cytoplasmic puncta. Co-immunoprecipitation, p62 overexpression/knockdown, autophagy inhibitor (3-methyladenine), proteasome inhibitor (epoxomicin), immunofluorescence (LC3 co-localization) The Biochemical journal Medium 26349538
2012 The PHAII-causing WNK4 mutation R1185C is located in a calmodulin (CaM) binding site in the C-terminus and reduces WNK4 binding to Ca2+/CaM. The R1185C mutation disrupts SGK1 phosphorylation at S1190 (eliminates it) and alters phosphorylation at adjacent SGK1 sites S1201 and S1217. The R1185C mutant enhances positive WNK4 effects on NKCC2. Ca2+/CaM inhibits phosphorylation at S1201. CaM binding assay, in vitro SGK1 phosphorylation of WNK4, Xenopus oocyte NKCC2 functional assay, site-directed mutagenesis American journal of physiology. Renal physiology Medium 23054253
2014 Cab39 (calcium-binding protein 39) interacts with WNK4 and enables WNK4 to activate NKCC1 in a SPAK/OSR1-independent manner. WNK4 contains a PF2-like domain (resembling the SPAK/OSR1 CCT/PF2 domain) that directly interacts with the N-terminal domain of NKCC1, enabling WNK4 to anchor to and activate NKCC1 directly. Functional data and yeast two-hybrid confirm the WNK4-NKCC1 direct interaction via this domain. Yeast two-hybrid, modeling, Xenopus oocyte functional assays, domain deletion analysis, SPAK/OSR1-independent activation experiments The Journal of biological chemistry Medium 24811174
2020 NHA2 (sodium/proton exchanger) regulates WNK4 stability in the kidney: loss of NHA2 increases WNK4 ubiquitylation and proteasomal degradation via a KLHL3-dependent mechanism. NHA2 loss selectively attenuates KLHL3 phosphorylation, blunting PKA- and PKC-mediated decrease of WNK4 degradation. NHA2 knockout mouse, in vitro NHA2 knockdown, WNK4 ubiquitylation assay, KLHL3 phosphorylation assay, NHA2/NCC double knockout mice Kidney international Medium 32956652
2021 Rapid NCC dephosphorylation by high extracellular K+ requires inactivation of the WNK4-SPAK 'on switch': WNK4-SPAK signaling must be turned off for rapid NCC dephosphorylation by high K+ in vitro (HEK cells) and ex vivo (kidney slices). SPAK is rapidly dephosphorylated in DCT1 specifically upon acute K+ challenge in vivo. Extended WNK-SPAK activation attenuates sensitivity to subsequent rapid K+-induced dephosphorylation. HEK cell K+ challenge, ex vivo kidney slice acute K+ treatment, in vivo acute K+ loading with pSPAK/pNCC immunoblot, PP1/PP3 inhibitor studies American journal of physiology. Renal physiology Medium 33719576

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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
2003 Molecular pathogenesis of inherited hypertension with hyperkalemia: the Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4. Proceedings of the National Academy of Sciences of the United States of America 321 12515852
2003 WNK4 regulates the balance between renal NaCl reabsorption and K+ secretion. Nature genetics 301 14608358
2006 Wnk4 controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal convoluted tubule. Nature genetics 300 16964266
2007 Molecular pathogenesis of pseudohypoaldosteronism type II: generation and analysis of a Wnk4(D561A/+) knockin mouse model. Cell metabolism 266 17488636
2012 Activation of the renal Na+:Cl- cotransporter by angiotensin II is a WNK4-dependent process. Proceedings of the National Academy of Sciences of the United States of America 232 22550170
2005 Volume sensitivity of cation-Cl- cotransporters is modulated by the interaction of two kinases: Ste20-related proline-alanine-rich kinase and WNK4. American journal of physiology. Cell physiology 220 15930150
2016 Unique chloride-sensing properties of WNK4 permit the distal nephron to modulate potassium homeostasis. Kidney international 214 26422504
2004 Disease-causing mutant WNK4 increases paracellular chloride permeability and phosphorylates claudins. Proceedings of the National Academy of Sciences of the United States of America 213 15070779
2013 Kelch-like 3 and Cullin 3 regulate electrolyte homeostasis via ubiquitination and degradation of WNK4. Proceedings of the National Academy of Sciences of the United States of America 205 23576762
2009 Angiotensin II signaling increases activity of the renal Na-Cl cotransporter through a WNK4-SPAK-dependent pathway. Proceedings of the National Academy of Sciences of the United States of America 201 19240212
2011 Epigenetic modulation of the renal β-adrenergic-WNK4 pathway in salt-sensitive hypertension. Nature medicine 188 21499270
2013 Impaired KLHL3-mediated ubiquitination of WNK4 causes human hypertension. Cell reports 181 23453970
2013 The CUL3-KLHL3 E3 ligase complex mutated in Gordon's hypertension syndrome interacts with and ubiquitylates WNK isoforms: disease-causing mutations in KLHL3 and WNK4 disrupt interaction. The Biochemical journal 180 23387299
2005 Mechanisms of WNK1 and WNK4 interaction in the regulation of thiazide-sensitive NaCl cotransport. The Journal of clinical investigation 143 15841204
2004 Paracellular Cl- permeability is regulated by WNK4 kinase: insight into normal physiology and hypertension. Proceedings of the National Academy of Sciences of the United States of America 136 15465913
2014 The Effect of WNK4 on the Na+-Cl- Cotransporter Is Modulated by Intracellular Chloride. Journal of the American Society of Nephrology : JASN 134 25542968
2007 An SGK1 site in WNK4 regulates Na+ channel and K+ channel activity and has implications for aldosterone signaling and K+ homeostasis. Proceedings of the National Academy of Sciences of the United States of America 131 17360471
2004 WNK4 regulates apical and basolateral Cl- flux in extrarenal epithelia. Proceedings of the National Academy of Sciences of the United States of America 130 14769928
2009 Aldosterone mediates activation of the thiazide-sensitive Na-Cl cotransporter through an SGK1 and WNK4 signaling pathway. The Journal of clinical investigation 119 19690383
2006 WNK4 kinase regulates surface expression of the human sodium chloride cotransporter in mammalian cells. Kidney international 111 16688122
2007 WNK4 regulates activity of the epithelial Na+ channel in vitro and in vivo. Proceedings of the National Academy of Sciences of the United States of America 107 17360470
2014 WNK4 is the major WNK positively regulating NCC in the mouse kidney. Bioscience reports 101 24655003
2009 Targeted disruption of the Wnk4 gene decreases phosphorylation of Na-Cl cotransporter, increases Na excretion and lowers blood pressure. Human molecular genetics 93 19633012
2009 WNK4 diverts the thiazide-sensitive NaCl cotransporter to the lysosome and stimulates AP-3 interaction. The Journal of biological chemistry 89 19401467
2014 Angiotensin II signaling via protein kinase C phosphorylates Kelch-like 3, preventing WNK4 degradation. Proceedings of the National Academy of Sciences of the United States of America 85 25313067
2014 WNK-SPAK-NCC cascade revisited: WNK1 stimulates the activity of the Na-Cl cotransporter via SPAK, an effect antagonized by WNK4. Hypertension (Dallas, Tex. : 1979) 82 25113964
2019 WNK4 kinase is a physiological intracellular chloride sensor. Proceedings of the National Academy of Sciences of the United States of America 81 30765526
2012 Aldosterone does not require angiotensin II to activate NCC through a WNK4-SPAK-dependent pathway. Pflugers Archiv : European journal of physiology 76 22549242
2006 WNK4 enhances TRPV5-mediated calcium transport: potential role in hypercalciuria of familial hyperkalemic hypertension caused by gene mutation of WNK4. American journal of physiology. Renal physiology 74 17018846
2014 Impaired degradation of WNK1 and WNK4 kinases causes PHAII in mutant KLHL3 knock-in mice. Human molecular genetics 72 24821705
2004 Hypercalciuria in familial hyperkalemia and hypertension accompanies hyperkalemia and precedes hypertension: description of a large family with the Q565E WNK4 mutation. The Journal of clinical endocrinology and metabolism 72 15292344
2006 WNK1 affects surface expression of the ROMK potassium channel independent of WNK4. Journal of the American Society of Nephrology : JASN 71 16775035
2009 WNK4 enhances the degradation of NCC through a sortilin-mediated lysosomal pathway. Journal of the American Society of Nephrology : JASN 66 19875813
2006 WNK4 kinase is a negative regulator of K+-Cl- cotransporters. American journal of physiology. Renal physiology 66 17182532
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 A new kindred with pseudohypoaldosteronism type II and a novel mutation (564D>H) in the acidic motif of the WNK4 gene. Hypertension (Dallas, Tex. : 1979) 60 15998707
2013 Disease-causing mutations in KLHL3 impair its effect on WNK4 degradation. FEBS letters 58 23665031
2011 Phenotypes of pseudohypoaldosteronism type II caused by the WNK4 D561A missense mutation are dependent on the WNK-OSR1/SPAK kinase cascade. Journal of cell science 58 21486947
2019 WNK bodies cluster WNK4 and SPAK/OSR1 to promote NCC activation in hypokalemia. American journal of physiology. Renal physiology 54 31736353
2005 Regulation of diverse ion transport pathways by WNK4 kinase: a novel molecular switch. Trends in endocrinology and metabolism: TEM 54 15808806
2018 Kidney-specific WNK1 isoform (KS-WNK1) is a potent activator of WNK4 and NCC. American journal of physiology. Renal physiology 53 29846116
2017 Phosphorylation by PKC and PKA regulate the kinase activity and downstream signaling of WNK4. Proceedings of the National Academy of Sciences of the United States of America 53 28096417
2007 WNK4 phosphorylates ser(206) of claudin-7 and promotes paracellular Cl(-) permeability. FEBS letters 48 17651736
2006 WNK1 and WNK4 modulate CFTR activity. Biochemical and biophysical research communications 48 17194447
2011 Cyclosporine metabolic side effects: association with the WNK4 system. European journal of clinical investigation 47 21434893
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
2011 Immunolocalization of WNK4 in mouse kidney. Histochemistry and cell biology 43 21660484
2010 Angiotensin II diminishes the effect of SGK1 on the WNK4-mediated inhibition of ROMK1 channels. Kidney international 39 20927043
2018 The Calcium-Sensing Receptor Increases Activity of the Renal NCC through the WNK4-SPAK Pathway. Journal of the American Society of Nephrology : JASN 38 29848507
2011 Serine-threonine kinase with-no-lysine 4 (WNK4) controls blood pressure via transient receptor potential canonical 3 (TRPC3) in the vasculature. Proceedings of the National Academy of Sciences of the United States of America 38 21670282
2011 Antagonistic regulation of cystic fibrosis transmembrane conductance regulator cell surface expression by protein kinases WNK4 and spleen tyrosine kinase. Molecular and cellular biology 37 21807898
2013 WNK4 inhibition of ENaC is independent of Nedd4-2-mediated ENaC ubiquitination. American journal of physiology. Renal physiology 36 23594824
2014 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. The Journal of biological chemistry 35 24811174
2010 Mechanisms for hypercalciuria in pseudohypoaldosteronism type II-causing WNK4 knock-in mice. Endocrinology 35 20181799
2003 Association of EDNRA, but not WNK4 or FKBP1B, polymorphisms with essential hypertension. Clinical genetics 35 14616768
2013 Decrease of WNK4 ubiquitination by disease-causing mutations of KLHL3 through different molecular mechanisms. Biochemical and biophysical research communications 34 23962426
2008 WNK3 and WNK4 amino-terminal domain defines their effect on the renal Na+-Cl- cotransporter. American journal of physiology. Renal physiology 33 18701621
2013 Regulation of large-conductance Ca2+-activated K+ channels by WNK4 kinase. American journal of physiology. Cell physiology 32 23885063
2011 WNK4 kinase inhibits Maxi K channel activity by a kinase-dependent mechanism. American journal of physiology. Renal physiology 32 21613417
2009 Src family protein tyrosine kinase (PTK) modulates the effect of SGK1 and WNK4 on ROMK channels. Proceedings of the National Academy of Sciences of the United States of America 31 19706464
2011 Dietary salt modulates the sodium chloride cotransporter expression likely through an aldosterone-mediated WNK4-ERK1/2 signaling pathway. Pflugers Archiv : European journal of physiology 30 22200850
2010 WNK4 kinase stimulates caveola-mediated endocytosis of TRPV5 amplifying the dynamic range of regulation of the channel by protein kinase C. The Journal of biological chemistry 29 20061383
2004 Comparison of WNK4 and WNK1 kinase and inhibiting activities. Biochemical and biophysical research communications 29 15081430
2013 WNK4 inhibits Ca(2+)-activated big-conductance potassium channels (BK) via mitogen-activated protein kinase-dependent pathway. Biochimica et biophysica acta 26 23673010
2004 Three novel missense mutations of WNK4, a kinase mutated in inherited hypertension, in Japanese hypertensives: implication of clinical phenotypes. American journal of hypertension 26 15110905
2008 WNK4 regulates the secretory pathway via which TRPV5 is targeted to the plasma membrane. Biochemical and biophysical research communications 25 18703016
2003 Genetic variants of WNK4 in whites and African Americans with hypertension. Hypertension (Dallas, Tex. : 1979) 25 12719438
2018 Role of WNK4 and kidney-specific WNK1 in mediating the effect of high dietary K+ intake on ROMK channel in the distal convoluted tubule. American journal of physiology. Renal physiology 23 29667910
2017 WNK4 is indispensable for the pathogenesis of pseudohypoaldosteronism type II caused by mutant KLHL3. Biochemical and biophysical research communications 23 28743496
2005 Regulation of apical localization of the thiazide-sensitive NaCl cotransporter by WNK4 in polarized epithelial cells. Biochemical and biophysical research communications 23 15796898
2021 WNK4 kinase: from structure to physiology. American journal of physiology. Renal physiology 22 33491560
2020 WNK3 and WNK4 exhibit opposite sensitivity with respect to cell volume and intracellular chloride concentration. American journal of physiology. Cell physiology 22 32579473
2019 WNK4-SPAK modulates lipopolysaccharide-induced macrophage activation. Biochemical pharmacology 22 31786261
2012 Disease-causing R1185C mutation of WNK4 disrupts a regulatory mechanism involving calmodulin binding and SGK1 phosphorylation sites. American journal of physiology. Renal physiology 22 23054253
2021 Roles of WNK4 and SPAK in K+-mediated dephosphorylation of the NaCl cotransporter. American journal of physiology. Renal physiology 21 33719576
2009 Characterization of the kinase activity of a WNK4 protein complex. American journal of physiology. Renal physiology 20 19587141
2012 Disease-causing mutations in the acidic motif of WNK4 impair the sensitivity of WNK4 kinase to calcium ions. Biochemical and biophysical research communications 19 22342722
2016 Osmotic stress induces the phosphorylation of WNK4 Ser575 via the p38MAPK-MK pathway. Scientific reports 18 26732173
2015 Src-family protein tyrosine kinase phosphorylates WNK4 and modulates its inhibitory effect on KCNJ1 (ROMK). Proceedings of the National Academy of Sciences of the United States of America 18 25805816
2008 Distinct pathways for the involvement of WNK4 in the signaling of hypertonicity and EGF. The FEBS journal 18 18312414
2004 WNK4 intron 10 polymorphism is not associated with hypertension. Hypertension (Dallas, Tex. : 1979) 18 14967840
2018 C-terminally truncated, kidney-specific variants of the WNK4 kinase lack several sites that regulate its activity. The Journal of biological chemistry 17 29921588
2005 WNK4 regulates airway Na+ transport: study of familial hyperkalaemia and hypertension. European journal of clinical investigation 17 15948903
2023 Dysregulation of the WNK4-SPAK/OSR1 pathway has a minor effect on baseline NKCC2 phosphorylation. American journal of physiology. Renal physiology 16 37881876
2019 Activation of the Ca2+ sensing receptor and the PKC/WNK4 downstream signaling cascade induces incorporation of ZO-2 to tight junctions and its separation from 14-3-3. Molecular biology of the cell 16 31318316
2017 WNK4 is an Adipogenic Factor and Its Deletion Reduces Diet-Induced Obesity in Mice. EBioMedicine 16 28314693
2016 Phosphorylation of KLHL3 at serine 433 impairs its interaction with the acidic motif of WNK4: a molecular dynamics study. Protein science : a publication of the Protein Society 16 27727489
2013 SPAK deficiency corrects pseudohypoaldosteronism II caused by WNK4 mutation. PloS one 16 24039833
2007 WNK4-mediated regulation of renal ion transport proteins. American journal of physiology. Renal physiology 16 17634397
2003 The role of Wnk4 in polygenic hypertension: a candidate gene analysis on rat chromosome 10. Hypertension (Dallas, Tex. : 1979) 16 12642508
2019 Claudin-7 Modulates Cl- and Na+ Homeostasis and WNK4 Expression in Renal Collecting Duct Cells. International journal of molecular sciences 15 31382627
2008 A patient with pseudohypoaldosteronism type II caused by a novel mutation in WNK4 gene. Endocrine 14 19016006
2020 The sodium/proton exchanger NHA2 regulates blood pressure through a WNK4-NCC dependent pathway in the kidney. Kidney international 13 32956652
2008 The acidic motif of WNK4 is crucial for its interaction with the K channel ROMK. Biochemical and biophysical research communications 13 18755144
2019 Upregulation of the WNK4 Signaling Pathway Inhibits Epithelial Sodium Channels of Mouse Tracheal Epithelial Cells After Influenza A Infection. Frontiers in pharmacology 12 30723408
2017 Impaired degradation of medullary WNK4 in the kidneys of KLHL2 knockout mice. Biochemical and biophysical research communications 11 28414128
2015 Involvement of selective autophagy mediated by p62/SQSTM1 in KLHL3-dependent WNK4 degradation. The Biochemical journal 10 26349538
2010 A WNK4 gene variant relates to osteoporosis and not to hypertension in the Portuguese population. Molecular genetics and metabolism 10 21236712
2008 Association of Ala589Ser polymorphism of WNK4 gene with essential hypertension in a high-risk Chinese population. The journal of physiological sciences : JPS 10 19340547

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