Gene Symbol: Wnk4
Description: WNK lysine deficient protein kinase 4
Alias: Ac2-059, Prkwnk4, serine/threonine-protein kinase WNK4, WNK4 Ser/Thr kinase, protein kinase lysine-deficient 4, protein kinase with no lysine 4
Species: rat
Products:     Wnk4

Top Publications

  1. Yang C, Angell J, Mitchell R, Ellison D. WNK kinases regulate thiazide-sensitive Na-Cl cotransport. J Clin Invest. 2003;111:1039-45 pubmed
    ..Mutations in two members of the WNK kinase family, WNK1 and WNK4, cause the disease...
  2. Yang C, Liu X, Paliege A, Zhu X, Bachmann S, Dawson D, et al. WNK1 and WNK4 modulate CFTR activity. Biochem Biophys Res Commun. 2007;353:535-40 pubmed
    ..WNK kinases are widely expressed modulators of ion transport. WNK1 and WNK4, two WNK kinases that are mutated in familial hyperkalemic hypertension (FHHt), are co-expressed with CFTR in ..
  3. Vorontsova I, Lam L, Delpire E, Lim J, Donaldson P. Identification of the WNK-SPAK/OSR1 signaling pathway in rodent and human lenses. Invest Ophthalmol Vis Sci. 2014;56:310-21 pubmed publisher
    ..The increased susceptibility of SPAK lenses to opacification suggests that disruption of this signaling pathway may compromise the ability of the lens to control its volume, and its ability to maintain its transparency. ..
  4. Ponce Coria J, Markadieu N, Austin T, Flammang L, Rios K, Welling P, et al. 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. J Biol Chem. 2014;289:17680-8 pubmed publisher
    ..Serine threonine kinase WNK4 (With No K = lysine member 4) and members of the Ste20 kinase family, namely SPAK and OSR1 (Ste20-related proline/..
  5. Wakabayashi M, Mori T, Isobe K, Sohara E, Susa K, Araki Y, et al. Impaired KLHL3-mediated ubiquitination of WNK4 causes human hypertension. Cell Rep. 2013;3:858-68 pubmed publisher
    ..Here, we found that KLHL3 interacted with Cullin3 and WNK4, induced WNK4 ubiquitination, and reduced the WNK4 protein level...
  6. Wilson F, Disse Nicodeme S, Choate K, Ishikawa K, Nelson Williams C, Desitter I, et al. Human hypertension caused by mutations in WNK kinases. Science. 2001;293:1107-12 pubmed
    ..Disease-causing mutations in WNK1 are large intronic deletions that increase WNK1 expression. The mutations in WNK4 are missense, which cluster in a short, highly conserved segment of the encoded protein...
  7. Wilson F, Kahle K, Sabath E, Lalioti M, Rapson A, Hoover R, et al. Molecular pathogenesis of inherited hypertension with hyperkalemia: the Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4. Proc Natl Acad Sci U S A. 2003;100:680-4 pubmed
    Mutations in the serine-threonine kinases WNK1 and WNK4 [with no lysine (K) at a key catalytic residue] cause pseudohypoaldosteronism type II (PHAII), a Mendelian disease featuring hypertension, hyperkalemia, hyperchloremia, and metabolic ..
  8. Vitari A, Deak M, Morrice N, Alessi D. The WNK1 and WNK4 protein kinases that are mutated in Gordon's hypertension syndrome phosphorylate and activate SPAK and OSR1 protein kinases. Biochem J. 2005;391:17-24 pubmed
    Mutations in the human genes encoding WNK1 [with no K (lysine) protein kinase-1] and the related protein kinase WNK4 are the cause of Gordon's hypertension syndrome...
  9. Shibata S, Zhang J, Puthumana J, Stone K, Lifton R. Kelch-like 3 and Cullin 3 regulate electrolyte homeostasis via ubiquitination and degradation of WNK4. Proc Natl Acad Sci U S A. 2013;110:7838-43 pubmed publisher
    ..By MS and coimmunoprecipitation, we show that KLHL3 normally binds to WNK1 and WNK4, members of WNK (with no lysine) kinase family that have previously been found mutated in PHAII...

More Information


  1. Garzon Muvdi T, Pacheco Alvarez D, Gagnon K, Vazquez N, Ponce Coria J, Moreno E, et al. WNK4 kinase is a negative regulator of K+-Cl- cotransporters. Am J Physiol Renal Physiol. 2007;292:F1197-207 pubmed
    ..b>WNK4 inhibits the activity of NCC and NKCC1, while in the presence of the STE20-related proline-alanine-rich kinase SPAK ..
  2. Kahle K, Gimenez I, Hassan H, Wilson F, Wong R, Forbush B, et al. WNK4 regulates apical and basolateral Cl- flux in extrarenal epithelia. Proc Natl Acad Sci U S A. 2004;101:2064-9 pubmed
    Mutations in the serine-threonine kinase WNK4 [with no lysine (K) 4] cause pseudohypoaldosteronism type II, a Mendelian disease featuring hypertension with hyperkalemia...
  3. Park H, Kim J, Choi S, Lee Y, Zeng W, Kim K, et al. Serine-threonine kinase with-no-lysine 4 (WNK4) controls blood pressure via transient receptor potential canonical 3 (TRPC3) in the vasculature. Proc Natl Acad Sci U S A. 2011;108:10750-5 pubmed publisher
    Mutations in the serine-threonine kinase with-no-lysine 4 (WNK4) cause pseudohypoaldosteronism type 2 (PHAII), a Mendelian form of human hypertension...
  4. Tatum R, Zhang Y, Lu Q, Kim K, Jeansonne B, Chen Y. WNK4 phosphorylates ser(206) of claudin-7 and promotes paracellular Cl(-) permeability. FEBS Lett. 2007;581:3887-91 pubmed
    Mutations in WNK4 have been linked to hypertension in PHAII. Paracellular ion transport has been reported to be involved in this disease process; however, the specific molecular target has not been identified...
  5. Dorwart M, Shcheynikov N, Wang Y, Stippec S, Muallem S. SLC26A9 is a Cl(-) channel regulated by the WNK kinases. J Physiol. 2007;584:333-45 pubmed
    ..Co-expression of SLC26A9 with the WNK kinases WNK1, WNK3 or WNK4 inhibited SLC26A9 activity, and the inhibition was independent of WNK kinase activity...
  6. Mu S, Shimosawa T, Ogura S, Wang H, Uetake Y, Kawakami Mori F, et al. Epigenetic modulation of the renal ?-adrenergic-WNK4 pathway in salt-sensitive hypertension. Nat Med. 2011;17:573-80 pubmed publisher
    ..we found that ?(2)-adrenergic receptor (?(2)AR) stimulation led to decreased transcription of the gene encoding WNK4, a regulator of sodium reabsorption...
  7. Kahle K, Wilson F, Leng Q, Lalioti M, O Connell A, Dong K, et al. WNK4 regulates the balance between renal NaCl reabsorption and K+ secretion. Nat Genet. 2003;35:372-6 pubmed
    ..Positional cloning implicated the serine-threonine kinase WNK4 in this process; clustered mutations in PRKWNK4, encoding WNK4, cause hypertension and hyperkalemia (pseudohypoaldosteronism type II, PHAII) by altering renal ..
  8. Monti J, Zimdahl H, Schulz H, Plehm R, Ganten D, Hubner N. The role of Wnk4 in polygenic hypertension: a candidate gene analysis on rat chromosome 10. Hypertension. 2003;41:938-42 pubmed
    ..b>Wnk4, a gene previously identified to cause pseudohypoaldosteronism type II, a rare mendelian form of arterial ..
  9. Kamide K, Takiuchi S, Tanaka C, Miwa Y, Yoshii M, Horio T, et al. Three novel missense mutations of WNK4, a kinase mutated in inherited hypertension, in Japanese hypertensives: implication of clinical phenotypes. Am J Hypertens. 2004;17:446-9 pubmed
    Mutations in serine-threonine kinase WNK4 with no lysine (K) at a key catalytic residue cause familial hypertension known as pseudohypoaldosteronism type II (PHAII)...
  10. San Cristobal P, de los Heros P, Ponce Coria J, Moreno E, Gamba G. WNK kinases, renal ion transport and hypertension. Am J Nephrol. 2008;28:860-70 pubmed publisher
    ..The uncovered genes causing PHAII encode for serine/threonine kinases known as WNK1 and WNK4. Physiological and biochemical studies have revealed that WNK1 and WNK4 modulate the activity of several transport ..
  11. Ring A, Cheng S, Leng Q, Kahle K, Rinehart J, Lalioti M, et al. WNK4 regulates activity of the epithelial Na+ channel in vitro and in vivo. Proc Natl Acad Sci U S A. 2007;104:4020-4 pubmed
    ..Previous work has shown that mutations in WNK4 cause pseudohypoaldosteronism type II (PHAII), a disease featuring hypertension with hyperkalemia, due to altered ..
  12. Lee B, Min X, Heise C, Xu B, Chen S, Shu H, et al. WNK1 phosphorylates synaptotagmin 2 and modulates its membrane binding. Mol Cell. 2004;15:741-51 pubmed
    WNK (with no lysine [K]) protein kinases were named for their unique active site organization. Mutations in WNK1 and WNK4 cause a familial form of hypertension by undefined mechanisms...
  13. Yang D, Li Q, So I, Huang C, Ando H, Mizutani A, et al. IRBIT governs epithelial secretion in mice by antagonizing the WNK/SPAK kinase pathway. J Clin Invest. 2011;121:956-65 pubmed publisher
    ..They also have implications for WNK/SPAK kinase-regulated processes involved in systemic fluid homeostasis, hypertension, and cystic fibrosis. ..
  14. Subramanya A, Yang C, Zhu X, Ellison D. Dominant-negative regulation of WNK1 by its kidney-specific kinase-defective isoform. Am J Physiol Renal Physiol. 2006;290:F619-24 pubmed
    ..Through its catalytic activity, full-length kinase-sufficient WNK1 (L-WNK1) suppresses its paralog, WNK4, thereby upregulating thiazide-sensitive Na-Cl cotransporter (NCC) activity...