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FEBS Lett
2013 Jun 19;58712:1717-22. doi: 10.1016/j.febslet.2013.04.032.
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Disease-causing mutations in KLHL3 impair its effect on WNK4 degradation.
Wu G, Peng JB.
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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. We determined whether WNK4 or its effector is regulated by KLHL3 in Xenopus oocytes. KLHL3 inhibited the positive effect of WNK4 on Na(+)-Cl(-) cotransporter (NCC) by decreasing WNK4 protein abundance without decreasing that of NCC and the downstream kinase OSR1 directly. Ubiquitination and degradation of WNK4 were induced by KLHL3. The effect of KLHL3 on WNK4 degradation was blocked by a dominant negative form of cullin 3. All five PHAII mutations of KLHL3 tested disrupted the regulation on WNK4. We conclude that KLHL3 is a substrate adaptor for WNK4 in a ubiquitin E3 ligase complex.
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23665031 ???displayArticle.pmcLink???PMC3697765 ???displayArticle.link???FEBS Lett ???displayArticle.grants???[+]
Boyden,
Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.
2012, Pubmed
Boyden,
Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities.
2012,
Pubmed Castañeda-Bueno,
Activation of the renal Na+:Cl- cotransporter by angiotensin II is a WNK4-dependent process.
2012,
Pubmed
,
Xenbase Furukawa,
Targeting of protein ubiquitination by BTB-Cullin 3-Roc1 ubiquitin ligases.
2003,
Pubmed Gordon,
Hypertension and severe hyperkalaemia associated with suppression of renin and aldosterone and completely reversed by dietary sodium restriction.
1970,
Pubmed Hossain Khan,
Phosphorylation of Na-Cl cotransporter by OSR1 and SPAK kinases regulates its ubiquitination.
2012,
Pubmed Jiang,
WNK4 enhances TRPV5-mediated calcium transport: potential role in hypercalciuria of familial hyperkalemic hypertension caused by gene mutation of WNK4.
2007,
Pubmed
,
Xenbase Kigoshi,
Ubiquitin ligase activity of Cul3-KLHL7 protein is attenuated by autosomal dominant retinitis pigmentosa causative mutation.
2011,
Pubmed Lalioti,
Wnk4 controls blood pressure and potassium homeostasis via regulation of mass and activity of the distal convoluted tubule.
2006,
Pubmed Louis-Dit-Picard,
KLHL3 mutations cause familial hyperkalemic hypertension by impairing ion transport in the distal nephron.
2012,
Pubmed Na,
Disease-causing mutations in the acidic motif of WNK4 impair the sensitivity of WNK4 kinase to calcium ions.
2012,
Pubmed Na,
Disease-causing R1185C mutation of WNK4 disrupts a regulatory mechanism involving calmodulin binding and SGK1 phosphorylation sites.
2013,
Pubmed
,
Xenbase Ohta,
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.
2013,
Pubmed PAVER,
HYPERTENSION AND HYPERPOTASSAEMIA WITHOUT RENAL DISEASE IN A YOUNG MALE.
1964,
Pubmed Richardson,
Activation of the thiazide-sensitive Na+-Cl- cotransporter by the WNK-regulated kinases SPAK and OSR1.
2008,
Pubmed Ring,
An SGK1 site in WNK4 regulates Na+ channel and K+ channel activity and has implications for aldosterone signaling and K+ homeostasis.
2007,
Pubmed
,
Xenbase Rondou,
BTB Protein KLHL12 targets the dopamine D4 receptor for ubiquitination by a Cul3-based E3 ligase.
2008,
Pubmed Rozansky,
Aldosterone mediates activation of the thiazide-sensitive Na-Cl cotransporter through an SGK1 and WNK4 signaling pathway.
2009,
Pubmed
,
Xenbase San-Cristobal,
WNK3 and WNK4 amino-terminal domain defines their effect on the renal Na+-Cl- cotransporter.
2008,
Pubmed
,
Xenbase San-Cristobal,
Angiotensin II signaling increases activity of the renal Na-Cl cotransporter through a WNK4-SPAK-dependent pathway.
2009,
Pubmed
,
Xenbase Subramanya,
WNK4 diverts the thiazide-sensitive NaCl cotransporter to the lysosome and stimulates AP-3 interaction.
2009,
Pubmed
,
Xenbase Vitari,
The WNK1 and WNK4 protein kinases that are mutated in Gordon's hypertension syndrome phosphorylate and activate SPAK and OSR1 protein kinases.
2005,
Pubmed Wakabayashi,
Impaired KLHL3-mediated ubiquitination of WNK4 causes human hypertension.
2013,
Pubmed Wilson,
Human hypertension caused by mutations in WNK kinases.
2001,
Pubmed Wilson,
Molecular pathogenesis of inherited hypertension with hyperkalemia: the Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4.
2003,
Pubmed
,
Xenbase Yang,
Molecular pathogenesis of pseudohypoaldosteronism type II: generation and analysis of a Wnk4(D561A/+) knockin mouse model.
2007,
Pubmed Yang,
WNK kinases regulate thiazide-sensitive Na-Cl cotransport.
2003,
Pubmed
,
Xenbase Zhang,
Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex.
2004,
Pubmed Zhang,
Down-regulation of intestinal apical calcium entry channel TRPV6 by ubiquitin E3 ligase Nedd4-2.
2010,
Pubmed
,
Xenbase Zhou,
WNK4 enhances the degradation of NCC through a sortilin-mediated lysosomal pathway.
2010,
Pubmed Zimmerman,
Structural assembly of cullin-RING ubiquitin ligase complexes.
2010,
Pubmed
