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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, CAN, V1a, OSR1, ROMK
Papers on WNK4
Generation of WNK1 knockout cell lines by CRISPR/Cas-mediated genome editing.
Subramanya et al., Pittsburgh, United States. In Am J Physiol Renal Physiol, 04 Jan 2015
Both cell lines exhibited reduced endogenous WNK4 protein abundance, indicating that WNK1 is required for WNK4 stability.
Angiotensin II signaling via protein kinase C phosphorylates Kelch-like 3, preventing WNK4 degradation.
Lifton et al., Tokyo, Japan. In Proc Natl Acad Sci U S A, 28 Nov 2014
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 targets WNKs for degradation-cause constitutively increased renal salt reabsorption and impaired K(+) secretion, resulting in hypertension and hyperkalemia.
WNK1 Activates Large-Conductance Ca2+-Activated K+ Channels through Modulation of ERK1/2 Signaling.
Cai et al., Harbin, China. In J Am Soc Nephrol, Sep 2014
We previously showed that WNK4 inhibits renal large-conductance Ca(2+)-activated K(+) (BK) channel activity by enhancing its degradation through a lysosomal pathway.
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.
Mechanism of salt-sensitive hypertension: focus on adrenal and sympathetic nervous systems.
Fujita, Tokyo, Japan. In J Am Soc Nephrol, Jun 2014
Furthermore, these studies point to crucial roles for the Rac1-mineralocorticoid receptor-NCC/ENaC and the renal β-adrenergic stimulant-glucocorticoid receptor-WNK4-NCC pathways in certain rodent models of salt-sensitive hypertension.
Interacting influence of diuretics and diet on BK channel-regulated K homeostasis.
Sansom et al., Omaha, United States. In Curr Opin Pharmacol, Apr 2014
In distal nephron cells, membrane BK-α expression is inhibited by WNK4 in in vitro expression systems, indicating a role in the hyperkalemic phenotype in patients with familial hyperkalemic hypertension type 2 (FHHt2).
Molecular insights from dysregulation of the thiazide-sensitive WNK/SPAK/NCC pathway in the kidney: Gordon syndrome and thiazide-induced hyponatraemia.
O'Shaughnessy et al., Nottingham, United Kingdom. In Clin Exp Pharmacol Physiol, Dec 2013
with-no-lysine(K) kinase 1 (WNK1), WNK4, kelch-like family member 3 (KLHL3) and cullin 3 (CUL3)] can cause the phenotype of GS.
Comprehensive assessment of the association of WNK4 polymorphisms with hypertension: evidence from a meta-analysis.
Zheng et al., Hangzhou, China. In Sci Rep, Dec 2013
The relationship between with-no-lysine [K] kinase 4 (WNK4) gene polymorphisms and hypertension has been widely investigated, However, the studies yielded contradictory results.
Mineralocorticoid receptor phosphorylation regulates ligand binding and renal response to volume depletion and hyperkalemia.
Lifton et al., New Haven, United States. In Cell Metab, Dec 2013
In volume depletion, angiotensin II and WNK4 signaling decrease MR(S843-P) levels, whereas hyperkalemia increases MR(S843-P).
Effects of angiotensin II on kinase-mediated sodium and potassium transport in the distal nephron.
Hoorn et al., Rotterdam, Netherlands. In Curr Opin Nephrol Hypertens, 2013
RECENT FINDINGS: Ang II can activate the sodium chloride cotransporter (NCC) through phosphorylation by Ste20-related, proline-alanine rich kinase (SPAK), an effect that is independent of aldosterone but dependent on with no lysine kinase 4 (WNK4).
11Beta-hydroxylase deficiency and other syndromes of mineralocorticoid excess as a rare cause of endocrine hypertension.
Koch et al., Jackson, United States. In Horm Metab Res, 2012
Apart from primary aldosteronism, mineralocorticoid excess can be caused by congenital adrenal hyperplasia (CAH) due to mutations of the 11beta-hydroxylase and 17alpha-hydroxylase genes, by inactivating mutations of the glucocorticoid receptor gene (Chrousos syndrome), endogenous hypercortisolism (Cushing's syndrome), by mutations of the 11beta-hydroxysteroid dehydrogenase type 2 gene (apparent mineralocorticoid excess/AME) or licorice/carbenoxolone intake, mutations of the epithelial sodium channel genes (Liddle syndrome), mutations of the mineralocorticoid receptor gene (Geller syndrome), and by mutations in the WNK1, WNK4, KLHL3, CUL3 genes (pseudohypoaldosteronism type 2 or Gordon syndrome).
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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