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This study has identified specific WNK4 that are involved in opening TRPV4, using a selective screen of short interfering ribonucleic acid (siRNA) SMARTpools, which individually targeted all human kinases, in human embryonic kidney 293 (HEK293) cells that stably express inducible TRPV4.
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Kidney-specific WNK1 isoform is a potent activator of WNK4 and NCC-mediated sodium/chloride transport.
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tacrolimus increases levels of KLHL3(S433-P), resulting in increased levels of WNK4, phosphorylated SPAK, and Na-Cl cotransporter.These findings demonstrate that KLHL3(S433-P) is a calcineurin substrate and implicate increased KLHL3 phosphorylation in tacrolimus-induced pathologies.
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5 WNK4 sites (S47, S64, S1169, S1180, S1196) are phosphorylated downstream of AngII signaling in cultured cells and in vitro by PKC and PKA. Phosphorylation at S64 and S1196 promoted phosphorylation of the WNK4 kinase T-loop at S332 (required for kinase activation) and increased phosphorylation of SPAK. Volume depletion induced phosphorylation of these sites in vivo, predominantly in the distal convoluted tubule.
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Modulation of WNK4 activity by [Cl]i can account for its dual role on the NCC, and this has important physiological implications regarding the regulation of extracellular potassium concentration.
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This study provides substantial new insights into the role of phosphorylation of KLHL3 in regulating the interaction with WNK4
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The distribution of allele frequency and genotype of WNK4 gene Ala589Ser polymorphism showed significant differences between essential hypertension subjects, with or without type 2 diabetes mellitus, and normotensive subjects.
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Data indicate that WNK lysine deficient protein kinase 4 protein (WNK4) was degraded not only by proteasomes but also by atypical protein kinase C scaffold protein p62 (p62)-kelch-like 3 protein (KLHL3)-mediated selective autophagy.
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this meta-analysis suggested that WNK4 G1155942T and C6749T gene polymorphisms may contribute to the susceptibility and development of hypertension.
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Akt and PKA phosphorylated KLHL3 at S433, and phosphorylation of KLHL3 by PKA inhibited WNK4 degradation.
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WNK4 is a substrate of SFKs and the association of c-Src and PTP-1D with WNK4 at Tyr(1092) and Tyr(1143) plays an important role in modulating the inhibitory effect of WNK4 on ROMK
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WNK4 inhibits SNARE formation of syntaxin 13 with VAMP2.
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Regulation of WNK4 by CUL3 and its relationship to blood pressure regulation and electrolyte homeostasis. [Review]
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WNK4 inhibits Large-conductance, Ca(2 )-activated K( ) channel activity, in part, by increasing channel degradation through an ubiquitin-dependent pathway.
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analysis of how mutations of KLHL3 show less ability to ubiquitinate WNK4 because of KLHL3's low stability and/or decreased binding to CUL3 or WNK4
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WNK4 inhibits ENaC channel activity independently of Nedd4-2-mediated ENaC ubiquitination.
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KLHL3 is a substrate adaptor for WNK4 in a ubiquitin E3 ligase complex
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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.
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The Exon 8 G1155942T polymorphism in WNK4 gene was associated with hypertension in the Kazakhs ethnic group in Xinjiang, and the T allele might be the risk factor for essential hypertension.
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R1185C mutation disrupts a CaM binding site at the WNK4 COOH-terminal region and alters the phosphorylation of WNK4 by SGK1.