WNK4

WNK4
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2V3S, 4CH9, 4CHB
Identifiers
Aliases	WNK4, PHA2B, PRKWNK lysine deficient protein kinase 4
External IDs	MGI: 1917097 HomoloGene: 13020 GeneCards: WNK4
Gene ontology Molecular function • transferase activity • nucleotide binding • protein kinase activity • kinase activity • protein binding • chloride channel inhibitor activity • ATP binding • protein serine/threonine kinase activity Cellular component • cytoplasm • bicellular tight junction • cell junction • cytosol Biological process • protein localization • distal tubule morphogenesis • regulation of cellular process • ion homeostasis • phosphorylation • ion transport • chloride transport • renal sodium ion absorption • negative regulation of pancreatic juice secretion • intracellular signal transduction • regulation of ion homeostasis • protein phosphorylation • positive regulation of ion transmembrane transporter activity Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	65266	69847
Ensembl	ENSG00000126562	ENSMUSG00000035112
UniProt	Q96J92	Q80UE6
RefSeq (mRNA)	NM_032387 NM_001321299	NM_175638
RefSeq (protein)	NP_115763.2	NP_783569.1
Location (UCSC)	Chr 17: 42.78 – 42.8 Mb	Chr 11: 101.26 – 101.28 Mb
PubMed search	[1]	[2]
Wikidata

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Serine/threonine-protein kinase WNK4 also known as WNK lysine deficient protein kinase 4 or WNK4, is an enzyme that in humans is encoded by the WNK4 gene.^[3]

Function

The WNK4 gene encodes a serine-threonine kinase expressed in distal nephron.^[3] Its primary role in renal physiology is as a molecular switch between the angiontensin II–aldosterone mediated volume retention and the aldosterone mediated potassium wasting. This is achieved by regulating the sodium-chloride symporter (NCC), that is uniquely expressed in the distal nephron and is sensitive to thiazide type diuretics.^[4]

Under basal conditions (low circulating Ang II and low Aldosterone), WNK4 will inhibit NCC function. It has been proposed that in the event of hyperkalemia and an increased secretion of aldosterone (which will upregulate both ENac and ROMK), this inhibition of NCC, will allow an increase in the arrival of sodium to the distal nephron (rich in ENaC and ROMK) which will allow the exchange of sodium for potassium ions, thereby reducing plasma potassium levels, without increasing sodium chloride retention (which is always accompanied by volume expansion). Furthermore, it has been proposed that in the presence of AngII the WNK4 mediated NCC inhibition will be suppressed thereby increasing sodium-chloride reabsorption in the distal convoluted tubule. This along with the concomitant increase in passive water reabsortion due to the increased salt load in the distal convluted tubule cells will ultimately increase circulating volume.^[5]

References

1. "Human PubMed Reference:".
2. "Mouse PubMed Reference:".
3. "Entrez Gene: WNK4 WNK lysine deficient protein kinase 4".
4. San-Cristobal P, de los Heros P, Ponce-Coria J, Moreno E, Gamba G (2008). "WNK kinases, renal ion transport and hypertension". Am. J. Nephrol. 28 (5): 860–70. doi:10.1159/000139639. PMC 2820349. PMID 18547946.
5. San-Cristobal P, Pacheco-Alvarez D, Richardson C, Ring AM, Vazquez N, Rafiqi FH, Chari D, Kahle KT, Leng Q, Bobadilla NA, Hebert SC, Alessi DR, Lifton RP, Gamba G (March 2009). "Angiotensin II signaling increases activity of the renal Na-Cl cotransporter through a WNK4-SPAK-dependent pathway". Proc. Natl. Acad. Sci. U.S.A. 106 (11): 4384–9. doi:10.1073/pnas.0813238106. PMC 2647339. PMID 19240212.

Further reading

• Subramanya AR, Yang CL, McCormick JA, Ellison DH (2006). "WNK kinases regulate sodium chloride and potassium transport by the aldosterone-sensitive distal nephron.". Kidney Int. 70 (4): 630–4. doi:10.1038/sj.ki.5001634. PMID 16820787.
• Peng JB, Warnock DG (2007). "WNK4-mediated regulation of renal ion transport proteins.". Am. J. Physiol. Renal Physiol. 293 (4): F961–73. doi:10.1152/ajprenal.00192.2007. PMID 17634397.
• Bonaldo MF, Lennon G, Soares MB (1997). "Normalization and subtraction: two approaches to facilitate gene discovery.". Genome Res. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID 8889548.
• Wilson FH, Disse-Nicodème S, Choate KA, et al. (2001). "Human hypertension caused by mutations in WNK kinases.". Science. 293 (5532): 1107–12. doi:10.1126/science.1062844. PMID 11498583.
• Veríssimo F, Jordan P (2001). "WNK kinases, a novel protein kinase subfamily in multi-cellular organisms.". Oncogene. 20 (39): 5562–9. doi:10.1038/sj.onc.1204726. PMID 11571656.
• Wilson FH, Kahle KT, Sabath E, et al. (2003). "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. 100 (2): 680–4. doi:10.1073/pnas.242735399. PMC 141056. PMID 12515852.
• Erlich PM, Cui J, Chazaro I, et al. (2003). "Genetic variants of WNK4 in whites and African Americans with hypertension.". Hypertension. 41 (6): 1191–5. doi:10.1161/01.HYP.0000070025.30572.91. PMID 12719438.
• Piechotta K, Garbarini N, England R, Delpire E (2004). "Characterization of the interaction of the stress kinase SPAK with the Na⁺-K⁺-2Cl⁻ cotransporter in the nervous system: evidence for a scaffolding role of the kinase.". J. Biol. Chem. 278 (52): 52848–56. doi:10.1074/jbc.M309436200. PMID 14563843.
• Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs.". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
• Kahle KT, Gimenez I, Hassan H, et al. (2004). "WNK4 regulates apical and basolateral Cl⁻ flux in extrarenal epithelia.". Proc. Natl. Acad. Sci. U.S.A. 101 (7): 2064–9. doi:10.1073/pnas.0308434100. PMC 357052. PMID 14769928.
• Yamauchi K, Rai T, Kobayashi K, et al. (2004). "Disease-causing mutant WNK4 increases paracellular chloride permeability and phosphorylates claudins.". Proc. Natl. Acad. Sci. U.S.A. 101 (13): 4690–4. doi:10.1073/pnas.0306924101. PMC 384808. PMID 15070779.
• Kamide K, Takiuchi S, Tanaka C, et al. (2004). "Three novel missense mutations of WNK4, a kinase mutated in inherited hypertension, in Japanese hypertensives: implication of clinical phenotypes.". Am. J. Hypertens. 17 (5 Pt 1): 446–9. doi:10.1016/j.amjhyper.2003.12.020. PMID 15110905.
• Mayan H, Munter G, Shaharabany M, et al. (2004). "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. 89 (8): 4025–30. doi:10.1210/jc.2004-0037. PMID 15292344.
• Fu Y, Subramanya A, Rozansky D, Cohen DM (2006). "WNK kinases influence TRPV4 channel function and localization.". Am. J. Physiol. Renal Physiol. 290 (6): F1305–14. doi:10.1152/ajprenal.00391.2005. PMID 16403833.
• Cai H, Cebotaru V, Wang YH, et al. (2006). "WNK4 kinase regulates surface expression of the human sodium chloride cotransporter in mammalian cells.". Kidney Int. 69 (12): 2162–70. doi:10.1038/sj.ki.5000333. PMID 16688122.
• Jiang Y, Ferguson WB, Peng JB (2007). "WNK4 enhances TRPV5-mediated calcium transport: potential role in hypercalciuria of familial hyperkalemic hypertension caused by gene mutation of WNK4.". Am. J. Physiol. Renal Physiol. 292 (2): F545–54. doi:10.1152/ajprenal.00187.2006. PMID 17018846.
• Ring AM, Leng Q, Rinehart J, et al. (2007). "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. 104 (10): 4025–9. doi:10.1073/pnas.0611728104. PMC 1803763. PMID 17360471.

External links

• GeneReviews/NCBI/NIH/UW entry on Pseudohypoaldosteronism Type II