WNK4

Summary

Gene Symbol: WNK4
Description: WNK lysine deficient protein kinase 4
Alias: PHA2B, PRKWNK4, serine/threonine-protein kinase WNK4, protein kinase lysine-deficient 4, protein kinase with no lysine 4
Species: human
Products:     WNK4

Top Publications

  1. Cao F, Zhang H, Wang F, Chen X, Wang X, Lin R, et al. [Association of the C1155547T polymorphism in WNK4 gene with essential hypertension in Xinjiang Kazakhs]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2010;27:546-9 pubmed publisher
    To investigate whether the WNK lysine deficient protein kinase 4 (WNK4) gene C1155547T polymorphism is associated with essential hypertension (EH) in Xinjiang Kazakhs and to assess the effect of the interaction between this polymorphism ..
  2. Han Y, Fan X, Sun K, Wang X, Wang Y, Chen J, et al. Hypertension associated polymorphisms in WNK1/WNK4 are not associated with hydrochlorothiazide response. Clin Biochem. 2011;44:1045-1049 pubmed publisher
    Our purpose was to investigate whether with-no-K[Lys] kinase (WNK) 1 and WNK4 genetic polymorphisms are associated with both hypertension and diuretics response...
  3. Speirs H, Morris B. WNK4 intron 10 polymorphism is not associated with hypertension. Hypertension. 2004;43:766-8 pubmed
    A polymorphism in intron 10 of the serine-threonine kinase with no lysine (K) 4 gene WNK4 (G-->A, base 1156666 on chromosome 17) has recently been associated with essential hypertension in a white American population...
  4. Sun Z, Li Y, Lu J, Ding Q, Liang Y, Shi J, et al. Association of Ala589Ser polymorphism of WNK4 gene with essential hypertension in a high-risk Chinese population. J Physiol Sci. 2009;59:81-6 pubmed publisher
    ..between particular single nucleotide polymorphisms of serine-threonine kinase with no lysine (K) 4 gene (WNK4) and essential hypertension have yielded controversial results...
  5. Wu G, Peng J. Disease-causing mutations in KLHL3 impair its effect on WNK4 degradation. FEBS Lett. 2013;587:1717-22 pubmed publisher
    Mutations in with-no-lysine (K) kinase 4 (WNK4) and a ubiquitin E3 ligase complex component kelch-like 3 (KLHL3) both cause pseudohypoaldosteronism II (PHAII), a hereditary form of hypertension...
  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. Verissimo F, Jordan P. WNK kinases, a novel protein kinase subfamily in multi-cellular organisms. Oncogene. 2001;20:5562-9 pubmed
    ..Three additional, partial human protein kinase sequences, WNK2, WNK3 and WNK4, are also reported here with catalytic domains that are 95% homologous to WNK1...
  8. 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)...
  9. Mendes A, Mascarenhas M, Matos S, Sousa I, Ferreira J, Barbosa A, et al. A WNK4 gene variant relates to osteoporosis and not to hypertension in the Portuguese population. Mol Genet Metab. 2011;102:465-9 pubmed publisher
    Germline mutations in the WNK4 gene originate Gordon syndrome or pseudohypoaldosteronism type II, a familial form of hypertension with hyperkalemia and hypercalciuria...

More Information

Publications123 found, 100 shown here

  1. Erlich P, Cui J, Chazaro I, Farrer L, Baldwin C, Gavras H, et al. Genetic variants of WNK4 in whites and African Americans with hypertension. Hypertension. 2003;41:1191-5 pubmed
    ..This region contains the WNK4 gene that causes the mendelian disorder pseudohypoaldosteronism type II, characterized by high potassium levels and ..
  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. Lu M, Wang X, Wang F, Wang S, Lin R, Wang S, et al. WNK4 polymorphisms and essential hypertension in the Uyghur population. Clin Exp Hypertens. 2009;31:179-85 pubmed publisher
    ..polymorphisms (T1155547C at exon7, G1155942T at exon8, G1156666A at intron10, and C1163527T at intron14) of WNK4 (with-no-kinase) gene on the prevalence of essential hypertension in a Chinese minority ethnic group-the Uyghur ..
  4. 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...
  5. Mori Y, Wakabayashi M, Mori T, Araki Y, Sohara E, Rai T, et al. Decrease of WNK4 ubiquitination by disease-causing mutations of KLHL3 through different molecular mechanisms. Biochem Biophys Res Commun. 2013;439:30-4 pubmed publisher
    Recently, we demonstrated that WNK4 is a substrate for KLHL3-Cullin3 (CUL3) E3 ubiquitin ligase complexes and that impaired WNK4 ubiquitination is a common mechanism for pseudohypoaldosteronism type II (PHAII) caused by WNK4, KLHL3, and ..
  6. Mayan H, Munter G, Shaharabany M, Mouallem M, Pauzner R, Holtzman E, et al. Hypercalciuria in familial hyperkalemia and hypertension accompanies hyperkalemia and precedes hypertension: description of a large family with the Q565E WNK4 mutation. J Clin Endocrinol Metab. 2004;89:4025-30 pubmed
    ..WNK1 kinase overexpression and WNK4 kinase inactivating missense mutations cause FHH...
  7. Cao F, Han H, Wang F, Chen X, Lu M, Wang X, et al. [Study on the association between genetic polymorphism on WNK4 genes and essential hypertension among Kazakhs ethnic population, in Xinjiang]. Zhonghua Liu Xing Bing Xue Za Zhi. 2010;31:375-8 pubmed
    To investigate whether G1155942T polymorphism in WNK4 gene is associated with essential hypertension in a population with Kazakhs ethnicity, in Xinjiang. This study covered 563 hypertension patients and 346 normotensive controls...
  8. Ohta A, Schumacher F, Mehellou Y, Johnson C, Knebel A, MacArtney T, et al. 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. Biochem J. 2013;451:111-22 pubmed publisher
    ..Interestingly, the equivalent region in WNK4 encompasses residues that are mutated in Gordon's syndrome patients...
  9. 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...
  10. Takahashi D, Mori T, Wakabayashi M, Mori Y, Susa K, Zeniya M, et al. KLHL2 interacts with and ubiquitinates WNK kinases. Biochem Biophys Res Commun. 2013;437:457-62 pubmed publisher
    Mutations in the WNK1 and WNK4 genes result in an inherited hypertensive disease, pseudohypoaldosteronism type II (PHAII). Recently, the KLHL3 and Cullin3 genes were also identified as responsible genes for PHAII...
  11. Wu A, Wolley M, Stowasser M. The interplay of renal potassium and sodium handling in blood pressure regulation: critical role of the WNK-SPAK-NCC pathway. J Hum Hypertens. 2019;: pubmed publisher
    ..Mutations in genes encoding WNK1 and WNK4 or components of an ubiquitin ligase complex, cullin3, and kelch-like family member 3 (KLHL3), cause FHHt by ..
  12. Liu Y, Song X, Shi Y, Shi Z, Niu W, Feng X, et al. WNK1 activates large-conductance Ca2+-activated K+ channels through modulation of ERK1/2 signaling. J Am Soc Nephrol. 2015;26:844-54 pubmed publisher
    With no lysine (WNK) kinases are members of the serine/threonine kinase family. We previously showed that WNK4 inhibits renal large-conductance Ca(2+)-activated K(+) (BK) channel activity by enhancing its degradation through a lysosomal ..
  13. Bazúa Valenti S, Gamba G. Revisiting the NaCl cotransporter regulation by with-no-lysine kinases. Am J Physiol Cell Physiol. 2015;308:C779-91 pubmed publisher
    ..Two genes encode for with-no-lysine (K) kinases WNK1 and WNK4, while two encode for kelch-like 3 (KLHL3) and cullin 3 (CUL3) proteins that form a RING type E3 ubiquitin ligase ..
  14. Mishra S, Ingole S, Jain R. Salt sensitivity and its implication in clinical practice. Indian Heart J. 2018;70:556-564 pubmed publisher
    ..activity of the renin-angiotensin-aldosterone system (RAAS), adrenal Rac1-MR-Sgk1-NCC/ENaC pathway, renal SNS-GR-WNK4-NCC pathway, defect of membrane ion transportation, inflammation and abnormalities of Na+/Ca2+..
  15. Mayan H, Carmon V, Oleinikov K, London S, Halevy R, Holtzman E, et al. Hypercalciuria in familial hyperkalemia and hypertension with KLHL3 mutations. Nephron. 2015;130:59-65 pubmed publisher
    ..Hypercalciuria is another accompanying feature. Mutations in WNK4 and WNK1 were found initially, and recently additional mutations were found in two genes, KLHL3 and CUL3, which are ..
  16. Nishimoto M, Fujita T. Renal mechanisms of salt-sensitive hypertension: contribution of two steroid receptor-associated pathways. Am J Physiol Renal Physiol. 2015;308:F377-87 pubmed publisher
    ..8 activity via cAMP/PKA signaling, increasing the accessibility of GRs to the negative GR response element in the WNK4 promoter...
  17. Rodan A, Jenny A. WNK Kinases in Development and Disease. Curr Top Dev Biol. 2017;123:1-47 pubmed publisher
    ..Mutations in human WNK1 or WNK4 cause an autosomal dominant syndrome of hypertension and hyperkalemia, reflecting the fact that WNK kinases are ..
  18. Hadchouel J, Ellison D, Gamba G. Regulation of Renal Electrolyte Transport by WNK and SPAK-OSR1 Kinases. Annu Rev Physiol. 2016;78:367-89 pubmed publisher
    ..Two of these genes encode the serine-threonine kinases WNK1 and WNK4. The other two genes [kelch-like 3 (KLHL3) and cullin 3 (CUL3)] form a RING-type E3-ubiquitin ligase complex that ..
  19. Nomura N, Shoda W, Wang Y, Mandai S, Furusho T, Takahashi D, et al. Role of ClC-K and barttin in low potassium-induced sodium chloride cotransporter activation and hypertension in mouse kidney. Biosci Rep. 2018;38: pubmed publisher
    ..Thus, our study provides in vivo evidence that, in response to a low-potassium diet, ClC-K and barttin play important roles in the activation of the WNK4-SPAK-NCC cascade and blood pressure regulation.
  20. Bazúa Valenti S, Chávez Canales M, Rojas Vega L, González Rodríguez X, Vázquez N, Rodríguez Gama A, et al. The Effect of WNK4 on the Na+-Cl- Cotransporter Is Modulated by Intracellular Chloride. J Am Soc Nephrol. 2015;26:1781-6 pubmed publisher
    ..of the renal Na(+)-Cl(-) cotransporter (NCC) because of altered regulation by with no-lysine-kinase 1 (WNK1) or WNK4. The effect of WNK4 on NCC, however, has been controversial because both inhibition and activation have been ..
  21. West C, McDonough A, Masilamani S, Verlander J, Baylis C. Renal NCC is unchanged in the midpregnant rat and decreased in the late pregnant rat despite avid renal Na+ retention. Am J Physiol Renal Physiol. 2015;309:F63-70 pubmed publisher
    ..kinase network, serum and glucocorticoid-regulated kinase (SGK)1, total with no lysine kinase (WNK)1, WNK3, and WNK4. Additionally, we performed immunohistochemistry for NCC kidneys from virgin and pregnant rats...
  22. Sasaki E, Susa K, Mori T, Isobe K, Araki Y, Inoue Y, et al. KLHL3 Knockout Mice Reveal the Physiological Role of KLHL3 and the Pathophysiology of Pseudohypoaldosteronism Type II Caused by Mutant KLHL3. Mol Cell Biol. 2017;37: pubmed publisher
    Mutations in the with-no-lysine kinase 1 (WNK1), WNK4, kelch-like 3 (KLHL3), and cullin3 (CUL3) genes are known to cause the hereditary disease pseudohypoaldosteronism type II (PHAII)...
  23. Tang B. (WNK)ing at death: With-no-lysine (Wnk) kinases in neuropathies and neuronal survival. Brain Res Bull. 2016;125:92-8 pubmed publisher
    ..Mutations in WNK1 and WNK4 are linked to a hereditary form of hypertension, and WNKs have been extensively investigated pertaining to their ..
  24. Takahashi D, Mori T, Sohara E, Tanaka M, Chiga M, Inoue Y, et al. WNK4 is an Adipogenic Factor and Its Deletion Reduces Diet-Induced Obesity in Mice. EBioMedicine. 2017;18:118-127 pubmed publisher
    ..In this study, we found that WNK4 was expressed in mouse adipose tissue and 3T3-L1 adipocytes...
  25. Yang T, Zhao K, Shu H, Chen X, Cheng J, Li S, et al. The Nogo receptor inhibits proliferation, migration and axonal extension by transcriptionally regulating WNK1 in PC12 cells. Neuroreport. 2017;28:533-539 pubmed publisher
    ..of NgR, and the regulation is specific to WNK1, which is not the same for its family members, WNK2, WNK3 and WNK4. Furthermore, NgR inhibition by NEP fails to affect WNK1, which indicates that WNK1 functions outside of the Nogo-A/..
  26. Zeniya M, Morimoto N, Takahashi D, Mori Y, Mori T, Ando F, et al. Kelch-Like Protein 2 Mediates Angiotensin II-With No Lysine 3 Signaling in the Regulation of Vascular Tonus. J Am Soc Nephrol. 2015;26:2129-38 pubmed publisher
    ..was identified as an E3 ubiquitin ligase for with no lysine (WNK) kinases, and the impaired ubiquitination of WNK4 causes pseudohypoaldosteronism type II (PHAII), a hereditary hypertensive disease...
  27. Terker A, Zhang C, Erspamer K, Gamba G, Yang C, Ellison D. Unique chloride-sensing properties of WNK4 permit the distal nephron to modulate potassium homeostasis. Kidney Int. 2016;89:127-34 pubmed publisher
    ..Kinase assay studies showed that chloride inhibits WNK4 kinase activity at lower concentrations than it inhibits activity of WNK1 or WNK3...
  28. Maruyama J, Kobayashi Y, Umeda T, Vandewalle A, Takeda K, Ichijo H, et al. Osmotic stress induces the phosphorylation of WNK4 Ser575 via the p38MAPK-MK pathway. Sci Rep. 2016;6:18710 pubmed publisher
    ..In this report, we identified WNK4 as an interacting partner of a recently identified MAP3K, apoptosis signal-regulating kinase 3 (ASK3)...
  29. Al Qusairi L, Basquin D, Roy A, Rajaram R, Maillard M, Subramanya A, et al. Renal Tubular Ubiquitin-Protein Ligase NEDD4-2 Is Required for Renal Adaptation during Long-Term Potassium Depletion. J Am Soc Nephrol. 2017;28:2431-2442 pubmed publisher
    ..Moreover, K+ restriction increased WNK1 and WNK4 expression and enhanced SPAK-mediated NCC phosphorylation in Nedd4LPax8/LC1 mice, with no change ..
  30. Matayoshi T, Kamide K, Takiuchi S, Yoshii M, Miwa Y, Takami Y, et al. The thiazide-sensitive Na(+)-Cl(-) cotransporter gene, C1784T, and adrenergic receptor-beta3 gene, T727C, may be gene polymorphisms susceptible to the antihypertensive effect of thiazide diuretics. Hypertens Res. 2004;27:821-33 pubmed
    ..Forty-eight SNPs in 17 genes (ADD1, GNB3, TSC [SLC12A3], MLR [NR3C2], NCX1 [SLC8A1], WNK1, WNK4, AGT, ACE, AT1 [AGTR1], CYP11B2, ADRB1, ADRB2, ADRB3, ADRA1A, ADRA1B, ADRA2A) were genotyped in the 76 patients...
  31. Huang C, Cheng C. A unifying mechanism for WNK kinase regulation of sodium-chloride cotransporter. Pflugers Arch. 2015;467:2235-41 pubmed publisher
    ..Mutations of WNK1 and WNK4 in humans cause pseudohypoaldosteronism type II (PHA2), an autosomal-dominant disease characterized by hypertension ..
  32. Araki Y, Rai T, Sohara E, Mori T, Inoue Y, Isobe K, et al. Generation and analysis of knock-in mice carrying pseudohypoaldosteronism type II-causing mutations in the cullin 3 gene. Biol Open. 2015;4:1509-17 pubmed publisher
    ..Cul3 and KLHL3 form an E3 ligase complex that ubiquitinates and reduces the expression level of WNK4. PHAII-causing mutations in WNK4 and KLHL3 impair WNK4 ubiquitination...
  33. Yoshida S, Araki Y, Mori T, Sasaki E, Kasagi Y, Isobe K, et al. Decreased KLHL3 expression is involved in the pathogenesis of pseudohypoaldosteronism type II caused by cullin 3 mutation in vivo. Clin Exp Nephrol. 2018;22:1251-1257 pubmed publisher
    ..Pseudohypoaldosteronism type II (PHAII) is a hereditary hypertensive disease caused by mutations in four genes: WNK1, WNK4, Kelch-like3 (KLHL3), and cullin3 (CUL3)...
  34. Cornelius R, Si J, Cuevas C, Nelson J, Gratreak B, Pardi R, et al. Renal COP9 Signalosome Deficiency Alters CUL3-KLHL3-WNK Signaling Pathway. J Am Soc Nephrol. 2018;29:2627-2640 pubmed publisher
    ..Conversely, the protein abundances of WNK1, WNK4, and SPAK kinases were substantially higher...
  35. Gong H, Tang Z, Yang Y, Sun L, Zhang W, Wang W, et al. A patient with pseudohypoaldosteronism type II caused by a novel mutation in WNK4 gene. Endocrine. 2008;33:230-4 pubmed publisher
    ..However, these features were absent in his parents. Sequencing analysis found the patient with a WNK4 gene mutation, 1682 C > T in Exon 7, which resulted a missense mutation at codon 561 (P561L)...
  36. Ghodsian N, Ismail P, Ahmadloo S, Heidari F, Haghvirdizadeh P, Ataollahi Eshkoor S, et al. Novel Association of WNK4 Gene, Ala589Ser Polymorphism in Essential Hypertension, and Type 2 Diabetes Mellitus in Malaysia. J Diabetes Res. 2016;2016:8219543 pubmed publisher
    With-no-lysine (K) Kinase-4 (WNK4) consisted of unique serine and threonine protein kinases, genetically associated with an autosomal dominant form of hypertension...
  37. Gong Y, Wang J, Yang J, Gonzales E, Perez R, Hou J. KLHL3 regulates paracellular chloride transport in the kidney by ubiquitination of claudin-8. Proc Natl Acad Sci U S A. 2015;112:4340-5 pubmed publisher
    ..Genetic linkage studies and exome sequencing have identified four genes--with no lysine kinase 1 (wnk1), wnk4, Kelch-like 3 (KLHL3), and Cullin 3 (Cul3)--mutations of which all caused PHA-II phenotypes...
  38. Malik R, Musca F, Gunew M, Menrath V, Simpson C, Culvenor J, et al. Periodic hypokalaemic polymyopathy in Burmese and closely related cats: a review including the latest genetic data. J Feline Med Surg. 2015;17:417-26 pubmed publisher
    ..Recent molecular genetics research has identified a single nonsense mutation in the gene (WNK4) coding for lysine-deficient 4 protein kinase, an enzyme present primarily in the distal nephron...
  39. Park S, Ku S, Ji H, Choi J, Shin D. Ca(2+) is a Regulator of the WNK/OSR1/NKCC Pathway in a Human Salivary Gland Cell Line. Korean J Physiol Pharmacol. 2015;19:249-55 pubmed publisher
    ..we found that the HSG cell line expressed molecules participating in the WNK-OSR1-NKCC pathway, such as Wnk1, Wnk4, OSR1, SPAK, and NKCC1...
  40. Murthy M, Kurz T, O Shaughnessy K. ROMK expression remains unaltered in a mouse model of familial hyperkalemic hypertension caused by the CUL3?403-459 mutation. Physiol Rep. 2016;4: pubmed publisher
    ..expressing wild-type but not the CUL3(?403-459) mutant form of CUL3 prevented the suppression of ROMK currents by WNK4 expressed in Xenopus oocytes...
  41. Shoda W, Nomura N, Ando F, Mori Y, Mori T, Sohara E, et al. Calcineurin inhibitors block sodium-chloride cotransporter dephosphorylation in response to high potassium intake. Kidney Int. 2017;91:402-411 pubmed publisher
    ..Previously, it was shown that NCC is activated by the WNK4-SPAK cascade and dephosphorylated by protein phosphatase...
  42. Murillo de Ozores A, Rodríguez Gama A, Bazúa Valenti S, Leyva Ríos K, Vazquez N, Pacheco Alvarez D, et al. C-terminally truncated, kidney-specific variants of the WNK4 kinase lack several sites that regulate its activity. J Biol Chem. 2018;293:12209-12221 pubmed publisher
    WNK lysine-deficient protein kinase 4 (WNK4) is an important regulator of renal salt handling...
  43. Murthy M, Cope G, O Shaughnessy K. The acidic motif of WNK4 is crucial for its interaction with the K channel ROMK. Biochem Biophys Res Commun. 2008;375:651-4 pubmed publisher
    ..all WNKs contain a unique run of predominantly negatively charged amino acids dubbed the acidic motif, where the WNK4 disease mutations causing Gordon's syndrome also cluster...
  44. Feng X, Zhang Y, Shao N, Wang Y, Zhuang Z, Wu P, et al. Aldosterone modulates thiazide-sensitive sodium chloride cotransporter abundance via DUSP6-mediated ERK1/2 signaling pathway. Am J Physiol Renal Physiol. 2015;308:F1119-27 pubmed publisher
    ..Previous studies reported that dietary salts modulated NCC abundance through either WNK4 [with no lysine (k) kinase 4]-SPAK (Ste20-related proline alanine-rich kinase) or WNK4-extracellular signal-..
  45. O Shaughnessy K. Gordon Syndrome: a continuing story. Pediatr Nephrol. 2015;30:1903-8 pubmed publisher
    ..In 2001, mutations in genes encoding two serine/threonine kinases, WNK1 and WNK4, were identified as causing GS...
  46. Gong Y, Hou J. Claudins in barrier and transport function-the kidney. Pflugers Arch. 2017;469:105-113 pubmed publisher
    ..Aldosterone, WNK4, Cap1, and KLHL3 are powerful regulators of claudin and the paracellular chloride permeability...
  47. Putku M, Kepp K, Org E, Sõber S, Comas D, Viigimaa M, et al. Novel polymorphic AluYb8 insertion in the WNK1 gene is associated with blood pressure variation in Europeans. Hum Mutat. 2011;32:806-14 pubmed publisher
    Mutations in WNK1 and WNK4 cause familial hypertension, the Gordon syndrome. WNK1 and WNK4 conserved noncoding regions were targeted to polymorphism screening using DHPLC and DGGE...
  48. 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/..
  49. Roy A, Goodman J, Begum G, Donnelly B, Pittman G, Weinman E, et al. Generation of WNK1 knockout cell lines by CRISPR/Cas-mediated genome editing. Am J Physiol Renal Physiol. 2015;308:F366-76 pubmed publisher
    ..Both cell lines exhibited reduced endogenous WNK4 protein abundance, indicating that WNK1 is required for WNK4 stability...
  50. Bazúa Valenti S, Rojas Vega L, Castañeda Bueno M, Barrera Chimal J, Bautista R, Cervantes Pérez L, et al. The Calcium-Sensing Receptor Increases Activity of the Renal NCC through the WNK4-SPAK Pathway. J Am Soc Nephrol. 2018;29:1838-1848 pubmed publisher
    ..Because the KLHL3-WNK4-SPAK pathway is involved in regulating NaCl reabsorption in the DCT, we assessed the involvement of this pathway as ..
  51. Webb T, Carrisoza Gaytán R, Montalbetti N, Rued A, Roy A, Socovich A, et al. Cell-specific regulation of L-WNK1 by dietary K. Am J Physiol Renal Physiol. 2016;310:F15-26 pubmed publisher
    ..This disorder is linked to mutations in genes encoding with-no-lysine kinase 1 (WNK1), WNK4, and Kelch-like 3/Cullin 3, two components of an E3 ubiquitin ligase complex that degrades WNKs...
  52. Jing H, Na T, Zhang W, Wu G, Liu C, Peng J. Concerted actions of NHERF2 and WNK4 in regulating TRPV5. Biochem Biophys Res Commun. 2011;404:979-84 pubmed publisher
    With-no-lysine (K) kinase 4 (WNK4) is a protein serine/threonine kinase associated with a Mendelian form of hypertension. WNK4 is an integrative regulator of renal transport of Na(+), K(+), and Cl(-) as shown in Xenopus oocyte system...
  53. Frenette Cotton R, Marcoux A, Garneau A, Noël M, Isenring P. Phosphoregulation of K+ -Cl- cotransporters during cell swelling: Novel insights. J Cell Physiol. 2018;233:396-408 pubmed publisher
    ..We have found that WNK4 and PP1 regulate KCC4 activity as part of a common signaling module, but that they do not exert their effects ..
  54. Chung W, Han J, Heo W, Lee M, Kim J. Overexpression of WNK1 in POMC-expressing neurons reduces weigh gain via WNK4-mediated degradation of Kir6.2. Mol Cell Biochem. 2018;447:165-174 pubmed publisher
    ..In this study, we discovered that WNK1 and WNK4 in POMC-expressing neuronal cells in WNK1 overexpressed transgenic mice (WNK1 TG) decrease appetite via degradation ..
  55. Rozansky D, Cornwall T, Subramanya A, Rogers S, Yang Y, David L, et al. Aldosterone mediates activation of the thiazide-sensitive Na-Cl cotransporter through an SGK1 and WNK4 signaling pathway. J Clin Invest. 2009;119:2601-12 pubmed publisher
    ..The serine/threonine kinase with-no-lysine 4 (WNK4) has previously been shown to reduce cell surface expression of NCC...
  56. Lan C, Peng C, Tang S, Lin H, Yang S, Wu C, et al. Inhibition of Na-K-Cl cotransporter isoform 1 reduces lung injury induced by ischemia-reperfusion. J Thorac Cardiovasc Surg. 2017;153:206-215 pubmed publisher
    ..Wild-type, SPAK knockout (SPAK-/-), and WNK4 knockin (WNK4D561A/+) mice were divided into control, ischemia-reperfusion, and ischemia-reperfusion + ..
  57. Zhang C, Wang L, Su X, Zhang J, Lin D, Wang W. ENaC and ROMK activity are inhibited in the DCT2/CNT of TgWnk4PHAII mice. Am J Physiol Renal Physiol. 2017;312:F682-F688 pubmed publisher
    Mice transgenic for genomic segments harboring PHAII (pseudohypoaldosteronism type II) mutant Wnk4 (with-No-Lysine kinase 4) (TgWnk4PHAII) have hyperkalemia which is currently believed to be the result of high activity of Na-Cl ..
  58. Molina Jijón E, Rodríguez Muñoz R, González Ramírez R, Namorado Tónix C, Pedraza Chaverri J, Reyes J. Aldosterone signaling regulates the over-expression of claudin-4 and -8 at the distal nephron from type 1 diabetic rats. PLoS ONE. 2017;12:e0177362 pubmed publisher
    ..of claudin-4 and -8, through a serum and glucocorticoid-induced kinase 1 (SGK1), and with-no-lysine kinase 4 (WNK4) signaling pathway...
  59. Zhang C, Meermeier N, Terker A, Blankenstein K, Singer J, Hadchouel J, et al. Degradation by Cullin 3 and effect on WNK kinases suggest a role of KLHL2 in the pathogenesis of Familial Hyperkalemic Hypertension. Biochem Biophys Res Commun. 2016;469:44-48 pubmed publisher
    Mutations in WNK1 and WNK4, and in components of the Cullin-Ring Ligase system, kelch-like 3 (KLHL3) and Cullin 3 (CUL3), can cause the rare hereditary disease, Familial Hyperkalemic Hypertension (FHHt)...
  60. Ishizawa K, Xu N, Loffing J, Lifton R, Fujita T, Uchida S, et al. Potassium depletion stimulates Na-Cl cotransporter via phosphorylation and inactivation of the ubiquitin ligase Kelch-like 3. Biochem Biophys Res Commun. 2016;480:745-751 pubmed publisher
    ..These changes are accompanied by the accumulation of the target substrate WNK4, and activation of the downstream kinases SPAK (STE20/SPS1-related proline-alanine-rich protein kinase) and OSR1 (..
  61. Castañeda Bueno M, Arroyo J, Zhang J, Puthumana J, Yarborough O, Shibata S, et al. Phosphorylation by PKC and PKA regulate the kinase activity and downstream signaling of WNK4. Proc Natl Acad Sci U S A. 2017;114:E879-E886 pubmed publisher
    With-no-lysine kinase 4 (WNK4) regulates electrolyte homeostasis and blood pressure...
  62. Kasagi Y, Takahashi D, Aida T, Nishida H, Nomura N, Zeniya M, et al. Impaired degradation of medullary WNK4 in the kidneys of KLHL2 knockout mice. Biochem Biophys Res Commun. 2017;487:368-374 pubmed publisher
    Mutations in the with-no-lysine kinase 1 (WNK1), WNK4, Kelch-like 3 (KLHL3), and Cullin3 (CUL3) genes were identified as being responsible for hereditary hypertensive disease pseudohypoaldosteronism type II (PHAII)...
  63. Gagnon K, England R, Delpire E. Volume sensitivity of cation-Cl- cotransporters is modulated by the interaction of two kinases: Ste20-related proline-alanine-rich kinase and WNK4. Am J Physiol Cell Physiol. 2006;290:C134-42 pubmed
    ..study, we have demonstrated functional interaction between Ste20-related proline-alanine-rich kinase (SPAK), WNK4 [with no lysine (K)], and the widely expressed Na+-K+-2Cl- cotransporter type 1 (NKCC1)...
  64. Fu Y, Subramanya A, Rozansky D, Cohen D. WNK kinases influence TRPV4 channel function and localization. Am J Physiol Renal Physiol. 2006;290:F1305-14 pubmed
    ..Na+-Cl- cotransporter, and monogenic human hypertension has been linked to mutations in the gene coding for WNK4. Along with TRPV4, WNK isoforms are highly expressed in the distal nephron...
  65. Zhou B, Zhuang J, Gu D, Wang H, Cebotaru L, Guggino W, et al. WNK4 enhances the degradation of NCC through a sortilin-mediated lysosomal pathway. J Am Soc Nephrol. 2010;21:82-92 pubmed publisher
    WNK kinase is a serine/threonine kinase that plays an important role in electrolyte homeostasis. WNK4 significantly inhibits the surface expression of the sodium chloride co-transporter (NCC) by enhancing the degradation of NCC through a ..
  66. Chávez Canales M, Zhang C, Soukaseum C, Moreno E, Pacheco Alvarez D, Vidal Petiot E, et al. WNK-SPAK-NCC cascade revisited: WNK1 stimulates the activity of the Na-Cl cotransporter via SPAK, an effect antagonized by WNK4. Hypertension. 2014;64:1047-53 pubmed publisher
    The with-no-lysine (K) kinases, WNK1 and WNK4, are key regulators of blood pressure. Their mutations lead to familial hyperkalemic hypertension (FHHt), associated with an activation of the Na-Cl cotransporter (NCC)...
  67. Wolley M, Wu A, Xu S, Gordon R, Fenton R, Stowasser M. In Primary Aldosteronism, Mineralocorticoids Influence Exosomal Sodium-Chloride Cotransporter Abundance. J Am Soc Nephrol. 2017;28:56-63 pubmed publisher
    ..on the abundance of NCC and its phosphorylated form (pNCC) as well as WNK lysine deficient protein kinase 4 (WNK4) and STE20/SPS1-related, proline alanine-rich kinase (SPAK) in human urinary exosomes...
  68. Cuevas C, Su X, Wang M, Terker A, Lin D, McCormick J, et al. Potassium Sensing by Renal Distal Tubules Requires Kir4.1. J Am Soc Nephrol. 2017;28:1814-1825 pubmed publisher
    ..Although renal WNK4 abundance increased after Kir4...
  69. Chung W, Park H, Han J, Lee M, Kim J. WNK4 inhibits plasma membrane targeting of NCC through regulation of syntaxin13 SNARE formation. Cell Signal. 2013;25:2469-77 pubmed publisher
    b>WNK4, a serine/threonine kinase, plays a critical role in the expression of membrane proteins in the cell surface; however, the underlying mechanism of WNK4 is not clear...
  70. Park J, Park E, Hyun H, Ahn Y, Kang H, Ha I, et al. Three cases of Gordon syndrome with dominant KLHL3 mutations. J Pediatr Endocrinol Metab. 2017;30:361-364 pubmed publisher
    ..To date, four genes causing GS have been identified as: WNK1, WNK4, CUL3, and KLHL3. We report three cases of GS in two families...
  71. Rafael C, Soukaseum C, Baudrie V, Frère P, Hadchouel J. Consequences of SPAK inactivation on Hyperkalemic Hypertension caused by WNK1 mutations: evidence for differential roles of WNK1 and WNK4. Sci Rep. 2018;8:3249 pubmed publisher
    Mutations of the gene encoding WNK1 [With No lysine (K) kinase 1] or WNK4 cause Familial Hyperkalemic Hypertension (FHHt)...
  72. Guo X, Ding J, Xu H, Xuan T, Jin W, Yin X, et al. Comprehensive assessment of the association of WNK4 polymorphisms with hypertension: evidence from a meta-analysis. Sci Rep. 2014;4:6507 pubmed publisher
    The relationship between with-no-lysine [K] kinase 4 (WNK4) gene polymorphisms and hypertension has been widely investigated, However, the studies yielded contradictory results...
  73. Subramanya A, Yang C, McCormick J, Ellison D. WNK kinases regulate sodium chloride and potassium transport by the aldosterone-sensitive distal nephron. Kidney Int. 2006;70:630-4 pubmed
    ..Mutations in the genes encoding two family members, WNK1 and WNK4, cause a chloride-dependent, thiazide-sensitive inherited syndrome of hypertension and hyperkalemia...
  74. Peng J, Warnock D. WNK4-mediated regulation of renal ion transport proteins. Am J Physiol Renal Physiol. 2007;293:F961-73 pubmed
    Point mutations in WNK4 [for With No K (lysine)], a serine-threonine kinase that is expressed in the distal nephron of the kidney, are linked to familial hyperkalemic hypertension (FHH)...
  75. Mao J, Li C, Zhang Y, Li Y, Zhao Y. Human with-no-lysine kinase-4 3'-UTR acting as the enhancer and being targeted by miR-296. Int J Biochem Cell Biol. 2010;42:1536-43 pubmed publisher
    ..The coordinated modulation of miR-296 and cofactors on the 3'-UTR may be attributed to hWNK4 physiopathological function. ..
  76. Yoshizaki Y, Mori Y, Tsuzaki Y, Mori T, Nomura N, Wakabayashi M, et al. Impaired degradation of WNK by Akt and PKA phosphorylation of KLHL3. Biochem Biophys Res Commun. 2015;467:229-34 pubmed publisher
    Mutations in with-no-lysine kinase (WNK) 1, WNK4, Kelch-like 3 (KLHL3), and Cullin3 result in an inherited hypertensive disease, pseudohypoaldosteronism type II...
  77. Wang L, Peng J. Phosphorylation of KLHL3 at serine 433 impairs its interaction with the acidic motif of WNK4: a molecular dynamics study. Protein Sci. 2017;26:163-173 pubmed publisher
    Interaction between the acidic motif (AM) of protein kinase WNK4 and the Kelch domain of KLHL3 are involved in the pathogenesis of pseudohypoaldosteronism type II, a hereditary form of hypertension...
  78. Sun Z, Wang X, Lu J, Ding Q, Dong L, Zhao Y. [Correlation analysis between WNK4 gene and essential hypertension]. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2003;25:145-8 pubmed
    To investigate association of mutation in WNK4 gene with essential hypertension and to analyze the expression of WNK4 gene...
  79. Ring A, Leng Q, Rinehart J, Wilson F, Kahle K, Hebert S, et al. An SGK1 site in WNK4 regulates Na+ channel and K+ channel activity and has implications for aldosterone signaling and K+ homeostasis. Proc Natl Acad Sci U S A. 2007;104:4025-9 pubmed
    ..Mutations in WNK4 cause pseudohypoaldosteronism type II (PHAII), a disease featuring increased renal NaCl reabsorption and impaired K(..
  80. Zhang Y, Li C, Li W, Zhao Y. Estrogen regulation of human with-no-lysine (K) kinase-4 gene expression involves AP-1 transcription factor. Mol Cell Endocrinol. 2011;332:140-8 pubmed publisher
    With-no-lysine (K) kinase-4 (WNK4) is a serine/threonine protein kinase and plays a crucial role in the regulation of blood pressure and electrolyte homeostasis...
  81. Lin D, Yue P, Yarborough O, Scholl U, Giebisch G, Lifton R, et al. Src-family protein tyrosine kinase phosphorylates WNK4 and modulates its inhibitory effect on KCNJ1 (ROMK). Proc Natl Acad Sci U S A. 2015;112:4495-500 pubmed publisher
    With-no-lysine kinase 4 (WNK4) inhibits the activity of the potassium channel KCNJ1 (ROMK) in the distal nephron, thereby contributing to the maintenance of potassium homeostasis...
  82. Mendes A, Matos P, Moniz S, Luz S, Amaral M, Farinha C, et al. Antagonistic regulation of cystic fibrosis transmembrane conductance regulator cell surface expression by protein kinases WNK4 and spleen tyrosine kinase. Mol Cell Biol. 2011;31:4076-86 pubmed publisher
    ..the cell surface expression of the cystic fibrosis transmembrane conductance regulator (CFTR) is also regulated by WNK4 in mammalian cells...
  83. Yu L, Cai H, Yue Q, Alli A, Wang D, Al Khalili O, et al. WNK4 inhibition of ENaC is independent of Nedd4-2-mediated ENaC ubiquitination. Am J Physiol Renal Physiol. 2013;305:F31-41 pubmed publisher
    A serine-threonine protein kinase, WNK4, reduces Na⁺ reabsorption and K⁺ secretion in the distal convoluted tubule by reducing trafficking of the thiazide-sensitive Na-Cl cotransporter to and enhancing renal outer medullary potassium ..
  84. 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 ..
  85. Zhang C, Wang Z, Xie J, Yan F, Wang W, Feng X, et al. Identification of a novel WNK4 mutation in Chinese patients with pseudohypoaldosteronism type II. Nephron Physiol. 2011;118:p53-61 pubmed publisher
    It has been reported that mutations in WNK1 and WNK4 cause pseudohypoaldosteronism type II (PHA2), an autosomal dominant renal disease...
  86. Andérica Romero A, Escobar L, Padilla Flores T, Pedraza Chaverri J. Insights in cullin 3/WNK4 and its relationship to blood pressure regulation and electrolyte homeostasis. Cell Signal. 2014;26:1166-72 pubmed publisher
    ..In this work we focused on highlighting how Cul3 system is involved in the regulation of electrolyte homeostasis and blood pressure. ..
  87. Shibata S, Arroyo J, Castañeda Bueno M, Puthumana J, Zhang J, Uchida S, et al. Angiotensin II signaling via protein kinase C phosphorylates Kelch-like 3, preventing WNK4 degradation. Proc Natl Acad Sci U S A. 2014;111:15556-61 pubmed publisher
    ..Mutations in the kinases with-no-lysine 4 (WNK4) or WNK1, or in either Cullin 3 (CUL3) or Kelch-like 3 (KLHL3)--components of an E3 ubiquitin ligase complex that ..
  88. Villa F, Goebel J, Rafiqi F, Deak M, Thastrup J, Alessi D, et al. Structural insights into the recognition of substrates and activators by the OSR1 kinase. EMBO Rep. 2007;8:839-45 pubmed
    ..peptide (Arg-Phe-Xaa-Val) motif present in OSR1- and SPAK-activating kinases (with-no-lysine kinase 1 (WNK1) and WNK4) as well as its substrates (NKCC1 and NKCC2)...
  89. Li M, Zhao Y, Li Y, Li C, Chen F, Mao J, et al. Upregulation of human with-no-lysine kinase-4 gene expression by GATA-1 acetylation. Int J Biochem Cell Biol. 2009;41:872-8 pubmed publisher
    With-no-lysine kinase-4 (WNK4), a member of the serine-threonine protein kinase family, acts as a multifunctional regulator of diverse ion transporters...
  90. Subramanya A, Liu J, Ellison D, Wade J, Welling P. WNK4 diverts the thiazide-sensitive NaCl cotransporter to the lysosome and stimulates AP-3 interaction. J Biol Chem. 2009;284:18471-80 pubmed publisher
    With-no-lysine kinase 4 (WNK4) inhibits electroneutral sodium chloride reabsorption by attenuating the cell surface expression of the thiazide-sensitive NaCl cotransporter (NCC)...
  91. Zhuang J, Zhang X, Wang D, Li J, Zhou B, Shi Z, et al. WNK4 kinase inhibits Maxi K channel activity by a kinase-dependent mechanism. Am J Physiol Renal Physiol. 2011;301:F410-9 pubmed publisher
    ..Recent studies showed that both WNK1 and WNK4 inhibit ROMK activity...