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WNK lysine deficient protein kinase 4

This gene encodes a member of the WNK family of serine-threonine protein kinases. The kinase is part of the tight junction complex in kidney cells, and regulates the balance between NaCl reabsorption and K(+) secretion. The kinase regulates the activities of several types of ion channels, cotransporters, and exchangers involved in electrolyte flux in epithelial cells. Mutations in this gene result in pseudohypoaldosteronism type IIB.[provided by RefSeq, Sep 2009] (from NCBI)
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Top mentioned proteins: SPAK, V1a, CAN, OSR1, PAK1
Papers on WNK4
Involvement of selective autophagy mediated by p62/SQSTM1 in KLHL3-dependent WNK4 degradation.
Uchida et al., Tokyo, Japan. In Biochem J, 15 Dec 2015
We reported that kelch-like protein 3 (KLHL3)-Cullin3 E3 ligase ubiquitinates with-no-lysine kinase 4 (WNK4) and that impaired WNK4 ubiquitination causes pseudohypoaldosteronism type II, a hereditary hypertensive disease.
Impaired degradation of WNK by Akt and PKA phosphorylation of KLHL3.
Sohara et al., Tokyo, Japan. In Biochem Biophys Res Commun, 13 Dec 2015
Mutations in with-no-lysine kinase (WNK) 1, WNK4, Kelch-like 3 (KLHL3), and Cullin3 result in an inherited hypertensive disease, pseudohypoaldosteronism type II.
Generation and analysis of knock-in mice carrying pseudohypoaldosteronism type II-causing mutations in the cullin 3 gene.
Uchida et al., Tokyo, Japan. In Biol Open, 21 Nov 2015
Cul3 and KLHL3 form an E3 ligase complex that ubiquitinates and reduces the expression level of WNK4.
Unique chloride-sensing properties of WNK4 permit the distal nephron to modulate potassium homeostasis.
Ellison et al., Portland, United States. In Kidney Int, 30 Oct 2015
Kinase assay studies showed that chloride inhibits WNK4 kinase activity at lower concentrations than it inhibits activity of WNK1 or WNK3.
Kelch-like 3/Cullin 3 ubiquitin ligase complex and WNK signaling in salt-sensitive hypertension and electrolyte disorder.
Uchida et al., Tokyo, Japan. In Nephrol Dial Transplant, Aug 2015
Mutations in with-no-lysine kinase 1 (WNK1) and WNK4 genes are reported to cause PHAII.
Revisiting the NaCl cotransporter regulation by with-no-lysine kinases.
Gamba et al., Mexico. In Am J Physiol Cell Physiol, Jun 2015
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 complex.
Periodic hypokalaemic polymyopathy in Burmese and closely related cats: a review including the latest genetic data.
Gandolfi et al., Sydney, Australia. In J Feline Med Surg, May 2015
RECENT ADVANCES AND FUTURE PROSPECTS: 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.
Renal mechanisms of salt-sensitive hypertension: contribution of two steroid receptor-associated pathways.
Fujita et al., Tokyo, Japan. In Am J Physiol Renal Physiol, Apr 2015
β2-Adrenergic stimulation due to increased renal sympathetic activity in obesity- and salt-induced hypertension suppresses histone deacetylase 8 activity via cAMP/PKA signaling, increasing the accessibility of GRs to the negative GR response element in the WNK4 promoter.
Regulation of blood pressure and renal electrolyte balance by Cullin-RING ligases.
Uchida, Tokyo, Japan. In Curr Opin Nephrol Hypertens, Sep 2014
The PHAII-causing mutations in WNK4, KLHL3, and Cullin-3 result in the decreased ubiquitination and increased abundance of WNK4 in the kidney, thereby activating the thiazide-sensitive NaCl cotransporter and causing PHAII.
Calcineurin inhibitors and hypertension: a role for pharmacogenetics?
Hoorn et al., Rotterdam, Netherlands. In Pharmacogenomics, Jun 2014
Recent data indicate that enzymes and transporters involved in CNI pharmacokinetics and pharmacodynamics, including CYP3A5, ABCB1, WNK4 and SPAK, are also associated with salt-sensitive hypertension.
Mineralocorticoid receptor phosphorylation regulates ligand binding and renal response to volume depletion and hyperkalemia.
Lifton et al., New Haven, United States. In Cell Metab, 2013
In volume depletion, angiotensin II and WNK4 signaling decrease MR(S843-P) levels, whereas hyperkalemia increases MR(S843-P).
Activation of the renal Na+:Cl- cotransporter by angiotensin II is a WNK4-dependent process.
Gamba et al., Mexico. In Proc Natl Acad Sci U S A, 2012
Activation of the renal Na+:Cl- cotransporter by angiotensin II is a WNK4-dependent process.
KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron.
Jeunemaitre et al., Paris, France. In Nat Genet, 2012
Familial hyperkalemic hypertension (FHHt) is a Mendelian form of arterial hypertension that is partially explained by mutations in WNK1 and WNK4 that lead to increased activity of the Na(+)-Cl(-) cotransporter (NCC) in the distal nephron.
Disease-causing mutations in the acidic motif of WNK4 impair the sensitivity of WNK4 kinase to calcium ions.
Peng et al., Birmingham, United States. In Biochem Biophys Res Commun, 2012
these results suggest that these PHAII-causing mutations disrupt a Ca(2+)-sensing mechanism around the acidic motif necessary for the regulation of WNK4 kinase activity by Ca(2+) ions.
WNK4 inhibits NCC protein expression through MAPK ERK1/2 signaling pathway.
Cai et al., Atlanta, United States. In Am J Physiol Renal Physiol, 2012
data suggest that WNK4 inhibits NCC protein through activating the MAPK ERK1/2 signaling pathway.
Antagonistic regulation of cystic fibrosis transmembrane conductance regulator cell surface expression by protein kinases WNK4 and spleen tyrosine kinase.
Jordan et al., Lisbon, Portugal. In Mol Cell Biol, 2011
Results show that Tyr512 phosphorylation is a novel signal regulating the prevalence of CFTR at the cell surface and that WNK4 and Syk perform an antagonistic role in this process.
The calcineurin inhibitor tacrolimus activates the renal sodium chloride cotransporter to cause hypertension.
Ellison et al., Portland, United States. In Nat Med, 2011
In wild-type mice, the CNI tacrolimus caused salt-sensitive hypertension and increased the abundance of phosphorylated NCC and the NCC-regulatory kinases WNK3, WNK4 and SPAK.
Hypertension associated polymorphisms in WNK1/WNK4 are not associated with hydrochlorothiazide response.
Hui et al., Beijing, China. In Clin Biochem, 2011
hypertension associated polymorphisms in WNK1 and WNK4 may not be predictors for antihypertensive response to diuretics.
Renal nerves, WNK4, glucocorticoids, and salt transport.
Brooks et al., Portland, United States. In Cell Metab, 2011
A study in Nature Medicine (Mu et al., 2011) shows that dietary salt excess, coupled with β-adrenergic stimulation, increases arterial pressure via glucocorticoid receptors and WNK4, suggesting interactions between these systems in the pathogenesis of hypertension.
Epigenetic modulation of the renal β-adrenergic-WNK4 pathway in salt-sensitive hypertension.
Fujita et al., Tokyo, Japan. In Nat Med, 2011
salt loading suppressed renal WNK4 expression, activated the Na(+)-Cl(-) cotransporter and induced salt-dependent hypertension
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