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Gene Review

WNK4  -  WNK lysine deficient protein kinase 4

Homo sapiens

Synonyms: PHA2B, PRKWNK4, Protein kinase lysine-deficient 4, Protein kinase with no lysine 4, Serine/threonine-protein kinase WNK4
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Disease relevance of WNK4


High impact information on WNK4

  • A new mouse model provides compelling evidence that a kinase, WNK4, provides key signals for regulating blood pressure and potassium balance by controlling the structure and function of the distal convoluted tubule [6].
  • WNK1 is cytoplasmic, whereas WNK4 localizes to tight junctions [7].
  • We showed previously that WNK4 downregulates thiazide-sensitive NaCl cotransporter (NCC) activity, an effect suppressed by WNK1 [8].
  • Gain-of-function WNK1 mutations would be expected to inhibit WNK4 activity, thereby activating NCC, contributing to the PHAII phenotype [9].
  • In the kidney, WNK4 regulates the balance between NaCl reabsorption and K(+) secretion via variable inhibition of the thiazide-sensistive NaCl cotransporter and the K(+) channel ROMK [10].

Chemical compound and disease context of WNK4

  • These findings can explain the observed physiological abnormalities in patients with pseudohypoaldosteronism type II, and support a model in which WNK4 is a molecular switch that can alter the balance between chloride ion reabsorption and potassium ion secretion [11].
  • Kinases of the WNK family influence expression and function of the thiazide-sensitive Na+-Cl- cotransporter, and monogenic human hypertension has been linked to mutations in the gene coding for WNK4 [12].
  • WNK4, a protein serine/threonine kinase with gene mutations that cause familial hyperkalemic hypertension (FHH), including a subtype with hypercalciuria, is also localized in the distal tubule of the nephron [13].
  • This functional state for WNK4 would thus promote the desired physiologic response to hyperkalemia, and the fact that it is induced downstream of aldosterone signaling implicates WNK4 in the physiologic response to aldosterone with hyperkalemia [14].

Biological context of WNK4


Anatomical context of WNK4


Associations of WNK4 with chemical compounds

  • Recent physiological work has revealed that WNK4 alters the balance of NaCl reabsorption and K(+) secretion in the distal nephron by actions on both transcellular and paracellular ion-flux pathways [15].
  • In addition, WNK4 activity promotes paracellular chloride ion flux [11].
  • WNK1 and WNK4 are unusual serine/threonine kinases with atypical positioning of the catalytic active-site lysine (WNK: With-No-K[lysine]) [19].
  • Furthermore, a proton pump inhibitor, bafilomycin A1, partially reverses the inhibitory effect of WNK4 WT on NCC expression [20].
  • In this mini review, we discuss WNK1 and WNK4 gene products and their regulatory effects on sodium chloride and potassium handling in the aldosterone-sensitive distal nephron [21].

Enzymatic interactions of WNK4


Regulatory relationships of WNK4

  • Wild-type WNK4 inhibits NCCT-mediated Na-influx by reducing membrane expression of the cotransporter ((22)Na-influx reduced 50%, P < 1 x 10(-9), surface expression reduced 75%, P < 1 x 10(-14) in the presence of WNK4) [22].
  • WNK4 enhances TRPV5-mediated calcium transport: potential role in hypercalciuria of familial hyperkalemic hypertension caused by gene mutation of WNK4 [13].

Other interactions of WNK4

  • WNK4 mutations relieve the inhibition of NCCT, increase the inhibition of the renal outer medullary potassium ion channel, and further increase paracellular chloride ion flux [11].
  • The variants were: for EDNRA, a G-->A in the 5'-UTR and C-->T in exon 8; for WNK4, a tetranucleotide repeat in intron 10; and for FKBP1B, a T-->C in exon 4 [23].
  • In contrast, WNK4 showed no inhibition of pendrin, a related Cl(-)/base exchanger [10].
  • WNK1 affects surface expression of the ROMK potassium channel independent of WNK4 [24].
  • Disease-causing point mutations in WNK4 abrogate, but do not eliminate, the inhibitory effect on TRPV4 function [12].

Analytical, diagnostic and therapeutic context of WNK4

  • Here, we have studied NCC protein processing in mammalian cells in the presence or absence of WNK4 WT and its mutants, E562K and R1185C, by surface biotinylation, Western blot, co-immunoprecipitation (Co-IP) and immunostaining [20].
  • The reduction of NCC surface expression by WNK4 WT (62.9+/-3.3% of control group) is not altered by WT dynamin ((61.8+/-3.7% (P=NS)) or its mutant K44A ((65.4+/-14.1% (P=NS)) [20].


  1. 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]
  2. Protein kinase WNK3 increases cell survival in a caspase-3-dependent pathway. Veríssimo, F., Silva, E., Morris, J.D., Pepperkok, R., Jordan, P. Oncogene (2006) [Pubmed]
  3. Identification of 108 SNPs in TSC, WNK1, and WNK4 and their association with hypertension in a Japanese general population. Kokubo, Y., Kamide, K., Inamoto, N., Tanaka, C., Banno, M., Takiuchi, S., Kawano, Y., Tomoike, H., Miyata, T. J. Hum. Genet. (2004) [Pubmed]
  4. Hypercalciuria in familial hyperkalemia and hypertension accompanies hyperkalemia and precedes hypertension: description of a large family with the Q565E WNK4 mutation. Mayan, H., Munter, G., Shaharabany, M., Mouallem, M., Pauzner, R., Holtzman, E.J., Farfel, Z. J. Clin. Endocrinol. Metab. (2004) [Pubmed]
  5. Three novel missense mutations of WNK4, a kinase mutated in inherited hypertension, in Japanese hypertensives: implication of clinical phenotypes. Kamide, K., Takiuchi, S., Tanaka, C., Miwa, Y., Yoshii, M., Horio, T., Mannami, T., Kokubo, Y., Tomoike, H., Kawano, Y., Miyata, T. Am. J. Hypertens. (2004) [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. Mechanisms of WNK1 and WNK4 interaction in the regulation of thiazide-sensitive NaCl cotransport. Yang, C.L., Zhu, X., Wang, Z., Subramanya, A.R., Ellison, D.H. J. Clin. Invest. (2005) [Pubmed]
  9. WNK kinases regulate thiazide-sensitive Na-Cl cotransport. Yang, C.L., Angell, J., Mitchell, R., Ellison, D.H. J. Clin. Invest. (2003) [Pubmed]
  10. WNK4 regulates apical and basolateral Cl- flux in extrarenal epithelia. Kahle, K.T., Gimenez, I., Hassan, H., Wilson, F.H., Wong, R.D., Forbush, B., Aronson, P.S., Lifton, R.P. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  11. WNK kinases: molecular regulators of integrated epithelial ion transport. Kahle, K.T., Wilson, F.H., Lalioti, M., Toka, H., Qin, H., Lifton, R.P. Curr. Opin. Nephrol. Hypertens. (2004) [Pubmed]
  12. WNK kinases influence TRPV4 channel function and localization. Fu, Y., Subramanya, A., Rozansky, D., Cohen, D.M. Am. J. Physiol. Renal Physiol. (2006) [Pubmed]
  13. WNK4 enhances TRPV5-mediated calcium transport: potential role in hypercalciuria of familial hyperkalemic hypertension caused by gene mutation of WNK4. Jiang, Y., Ferguson, W.B., Peng, J.B. Am. J. Physiol. Renal Physiol. (2007) [Pubmed]
  14. An SGK1 site in WNK4 regulates Na+ channel and K+ channel activity and has implications for aldosterone signaling and K+ homeostasis. Ring, A.M., Leng, Q., Rinehart, J., Wilson, F.H., Kahle, K.T., Hebert, S.C., Lifton, R.P. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  15. 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]
  16. WNK kinases and the control of blood pressure. Cope, G., Golbang, A., O'Shaughnessy, K.M. Pharmacol. Ther. (2005) [Pubmed]
  17. Disease-causing mutant WNK4 increases paracellular chloride permeability and phosphorylates claudins. Yamauchi, K., Rai, T., Kobayashi, K., Sohara, E., Suzuki, T., Itoh, T., Suda, S., Hayama, A., Sasaki, S., Uchida, S. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  18. 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]
  19. Dietary electrolyte-driven responses in the renal WNK kinase pathway in vivo. O'Reilly, M., Marshall, E., Macgillivray, T., Mittal, M., Xue, W., Kenyon, C.J., Brown, R.W. J. Am. Soc. Nephrol. (2006) [Pubmed]
  20. WNK4 kinase regulates surface expression of the human sodium chloride cotransporter in mammalian cells. Cai, H., Cebotaru, V., Wang, Y.H., Zhang, X.M., Cebotaru, L., Guggino, S.E., Guggino, W.B. Kidney Int. (2006) [Pubmed]
  21. 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]
  22. Molecular pathogenesis of inherited hypertension with hyperkalemia: the Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4. Wilson, F.H., Kahle, K.T., Sabath, E., Lalioti, M.D., Rapson, A.K., Hoover, R.S., Hebert, S.C., Gamba, G., Lifton, R.P. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  23. Association of EDNRA, but not WNK4 or FKBP1B, polymorphisms with essential hypertension. Benjafield, A.V., Katyk, K., Morris, B.J. Clin. Genet. (2003) [Pubmed]
  24. 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]
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