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Gene Review

WNK1  -  WNK lysine deficient protein kinase 1

Homo sapiens

Synonyms: Erythrocyte 65 kDa protein, HSAN2, HSN2, KDP, KIAA0344, ...
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Disease relevance of WNK1


High impact information on WNK1


Chemical compound and disease context of WNK1


Biological context of WNK1


Anatomical context of WNK1

  • Depletion of WNK1 from HeLa cells by using small interfering RNA reduces OSR1 kinase activity [14].
  • The results of co-expressing WNK1 with ROMK in Xenopus oocytes are reported for the first time [15].
  • The goal of this study was to determine the effect of aldosterone, the main hormonal regulator of Na(+) homeostasis, on the transcription of WNK1 isoforms in renal target cells, by using an unique mouse cortical collecting duct cell line that stably expresses functional mineralocorticoid receptors [16].
  • Similarly, coexpression of KS-WNK1 and the epithelial Na(+) channel in Fischer rat thyroid epithelial cells also stimulates Na(+) current, suggesting that KS-WNK1 affects the subcellular location or activity but not the expression of epithelial Na(+) channel [16].
  • Whereas small interfering RNA-induced loss of WNK1 protein did not significantly affect insulin-stimulated glucose transport in 3T3-L1 adipocytes, it significantly enhanced insulin-stimulated thymidine incorporation by about 2-fold [17].

Associations of WNK1 with chemical compounds

  • Phosphorylation by WNK1 increases the amount of Ca2+ required for Syt2 binding to phospholipid vesicles; mutation of threonine 202, a WNK1 phosphorylation site, partially prevents this change [1].
  • The same amino acid alteration was recently described for rat WNK1 (with no K=lysine) in which another nearby lysine residue was shown to confer kinase activity to the protein [11].
  • Mutation of Ser325 in OSR1 to alanine or glutamic acid did not affect the basal activity of OSR1 or its ability to be activated by WNK1 [8].
  • WNK kinases are a recently discovered class of serine-threonine kinases that are distinctive because of the substitution of cysteine for lysine in subdomain II of the catalytic domain [18].
  • The kidney-specific WNK1 isoform is induced by aldosterone and stimulates epithelial sodium channel-mediated Na+ transport [16].

Physical interactions of WNK1

  • Moreover, both MEKK2 and MEKK3 coimmunoprecipitated with endogenous WNK1 from cell lysates [19].

Enzymatic interactions of WNK1

  • However, WNK1 phosphorylated both WNK4 and WNK2 [4].
  • We establish that an intact CCT domain is required for WNK1 to efficiently phosphorylate and activate OSR1 [20].

Co-localisations of WNK1


Regulatory relationships of WNK1


Other interactions of WNK1

  • The predicted WNK3 protein has a similar structural organization to the other human WNK kinases [25].
  • Together, these findings emphasize that the molecular mechanisms that underpin WNK1 regulation of ROMK expression are distinct from those that affect NCCT expression [15].
  • The effect of the related kinase WNK1 on TRPV4 function and surface expression was similar to that of WNK4 [10].
  • Overexpression of human WNK1 increases paracellular chloride permeability and phosphorylation of claudin-4 in MDCKII cells [5].
  • Increased channel activity induced by WNK1 depends on SGK1 and the E3 ubiquitin ligase Nedd4-2 [24].

Analytical, diagnostic and therapeutic context of WNK1

  • Gel filtration suggested that WNK1 exists as a tetramer, and yeast two-hybrid data showed that the N terminus of WNK1 (residues 1-222) interacts with residues 481-660, which includes the WNK1 autoinhibitory domain and a C-terminal coiled-coil domain [4].
  • Through the analysis of enzyme fragments and sequence alignments, we have identified an autoinhibitory domain of WNK1 [26].
  • In immunoprecipitation experiments, we were unable to detect direct interaction between TRPV4 and either WNK kinase [10].
  • Here we report the effects of dissolved metal complexes of Fe(III), Al(III), and Cr(III) on the step velocities of the [100] face of KH2PO4 (KDP) as observed with atomic force microscopy [27].


  1. WNK1 phosphorylates synaptotagmin 2 and modulates its membrane binding. Lee, B.H., Min, X., Heise, C.J., Xu, B.E., Chen, S., Shu, H., Luby-Phelps, K., Goldsmith, E.J., Cobb, M.H. Mol. Cell (2004) [Pubmed]
  2. Antagonistic regulation of ROMK by long and kidney-specific WNK1 isoforms. Lazrak, A., Liu, Z., Huang, C.L. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  3. WNK1 regulates phosphorylation of cation-chloride-coupled cotransporters via the STE20-related kinases, SPAK and OSR1. Moriguchi, T., Urushiyama, S., Hisamoto, N., Iemura, S., Uchida, S., Natsume, T., Matsumoto, K., Shibuya, H. J. Biol. Chem. (2005) [Pubmed]
  4. Properties of WNK1 and implications for other family members. Lenertz, L.Y., Lee, B.H., Min, X., Xu, B.E., Wedin, K., Earnest, S., Goldsmith, E.J., Cobb, M.H. J. Biol. Chem. (2005) [Pubmed]
  5. Overexpression of human WNK1 increases paracellular chloride permeability and phosphorylation of claudin-4 in MDCKII cells. Ohta, A., Yang, S.S., Rai, T., Chiga, M., Sasaki, S., Uchida, S. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  6. A WNK in the kidney controls blood pressure. Coffman, T.M. Nat. Genet. (2006) [Pubmed]
  7. Human hypertension caused by mutations in WNK kinases. Wilson, F.H., Disse-Nicodème, S., Choate, K.A., Ishikawa, K., Nelson-Williams, C., Desitter, I., Gunel, M., Milford, D.V., Lipkin, G.W., Achard, J.M., Feely, M.P., Dussol, B., Berland, Y., Unwin, R.J., Mayan, H., Simon, D.B., Farfel, Z., Jeunemaitre, X., Lifton, R.P. Science (2001) [Pubmed]
  8. The WNK1 and WNK4 protein kinases that are mutated in Gordon's hypertension syndrome phosphorylate and activate SPAK and OSR1 protein kinases. Vitari, A.C., Deak, M., Morrice, N.A., Alessi, D.R. Biochem. J. (2005) [Pubmed]
  9. WNK kinases regulate sodium chloride and potassium transport by the aldosterone-sensitive distal nephron. Subramanya, A.R., Yang, C.L., McCormick, J.A., Ellison, D.H. Kidney Int. (2006) [Pubmed]
  10. WNK kinases influence TRPV4 channel function and localization. Fu, Y., Subramanya, A., Rozansky, D., Cohen, D.M. Am. J. Physiol. Renal Physiol. (2006) [Pubmed]
  11. WNK kinases, a novel protein kinase subfamily in multi-cellular organisms. Veríssimo, F., Jordan, P. Oncogene (2001) [Pubmed]
  12. Role of WNK kinases in regulating tubular salt and potassium transport and in the development of hypertension. Gamba, G. Am. J. Physiol. Renal Physiol. (2005) [Pubmed]
  13. Association of WNK1 gene polymorphisms and haplotypes with ambulatory blood pressure in the general population. Tobin, M.D., Raleigh, S.M., Newhouse, S., Braund, P., Bodycote, C., Ogleby, J., Cross, D., Gracey, J., Hayes, S., Smith, T., Ridge, C., Caulfield, M., Sheehan, N.A., Munroe, P.B., Burton, P.R., Samani, N.J. Circulation (2005) [Pubmed]
  14. WNK1 and OSR1 regulate the Na+, K+, 2Cl- cotransporter in HeLa cells. Anselmo, A.N., Earnest, S., Chen, W., Juang, Y.C., Kim, S.C., Zhao, Y., Cobb, M.H. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  15. WNK1 affects surface expression of the ROMK potassium channel independent of WNK4. Cope, G., Murthy, M., Golbang, A.P., Hamad, A., Liu, C.H., Cuthbert, A.W., O'Shaughnessy, K.M. J. Am. Soc. Nephrol. (2006) [Pubmed]
  16. The kidney-specific WNK1 isoform is induced by aldosterone and stimulates epithelial sodium channel-mediated Na+ transport. Náray-Fejes-Tóth, A., Snyder, P.M., Fejes-Tóth, G. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  17. Identification of WNK1 as a substrate of Akt/protein kinase B and a negative regulator of insulin-stimulated mitogenesis in 3T3-L1 cells. Jiang, Z.Y., Zhou, Q.L., Holik, J., Patel, S., Leszyk, J., Coleman, K., Chouinard, M., Czech, M.P. J. Biol. Chem. (2005) [Pubmed]
  18. Regulation of diverse ion transport pathways by WNK4 kinase: a novel molecular switch. Kahle, K.T., Wilson, F.H., Lifton, R.P. Trends Endocrinol. Metab. (2005) [Pubmed]
  19. WNK1 activates ERK5 by an MEKK2/3-dependent mechanism. Xu, B.E., Stippec, S., Lenertz, L., Lee, B.H., Zhang, W., Lee, Y.K., Cobb, M.H. J. Biol. Chem. (2004) [Pubmed]
  20. Functional interactions of the SPAK/OSR1 kinases with their upstream activator WNK1 and downstream substrate NKCC1. Vitari, A.C., Thastrup, J., Rafiqi, F.H., Deak, M., Morrice, N.A., Karlsson, H.K., Alessi, D.R. Biochem. J. (2006) [Pubmed]
  21. WNK1 and WNK4 modulate CFTR activity. Yang, C.L., Liu, X., Paliege, A., Zhu, X., Bachmann, S., Dawson, D.C., Ellison, D.H. Biochem. Biophys. Res. Commun. (2007) [Pubmed]
  22. WNK1, the kinase mutated in an inherited high-blood-pressure syndrome, is a novel PKB (protein kinase B)/Akt substrate. Vitari, A.C., Deak, M., Collins, B.J., Morrice, N., Prescott, A.R., Phelan, A., Humphreys, S., Alessi, D.R. Biochem. J. (2004) [Pubmed]
  23. WNK kinases regulate thiazide-sensitive Na-Cl cotransport. Yang, C.L., Angell, J., Mitchell, R., Ellison, D.H. J. Clin. Invest. (2003) [Pubmed]
  24. WNK1 activates SGK1 to regulate the epithelial sodium channel. Xu, B.E., Stippec, S., Chu, P.Y., Lazrak, A., Li, X.J., Lee, B.H., English, J.M., Ortega, B., Huang, C.L., Cobb, M.H. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  25. Cloning, genomic organization, alternative splicing and expression analysis of the human gene WNK3 (PRKWNK3). Holden, S., Cox, J., Raymond, F.L. Gene (2004) [Pubmed]
  26. Regulation of WNK1 by an autoinhibitory domain and autophosphorylation. Xu, B.E., Min, X., Stippec, S., Lee, B.H., Goldsmith, E.J., Cobb, M.H. J. Biol. Chem. (2002) [Pubmed]
  27. In situ atomic force microscopy investigation of the [100] face of KH2PO4 in the presence of Fe(III), Al(III), and Cr(III). Thomas, T.N., Land, T.A., DeYoreo, J.J., Casey, W.H. Langmuir : the ACS journal of surfaces and colloids. (2004) [Pubmed]
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