Disease relevance of WNK1

• Mutations in WNK1 and WNK4 cause a familial form of hypertension by undefined mechanisms [1].
• Intronic deletions with increased expression of a ubiquitous long WNK1 transcript cause pseudohypoaldosteronism type 2 (PHA II), characterized by hypertension and hyperkalemia [2].
• The WNK1 and WNK4 genes have been found to be mutated in some patients with hyperkalemia and hypertension caused by pseudohypoaldosteronism type II [3].
• We showed that WNK1 is activated by hypertonic stress in kidney epithelial cells and in breast and colon cancer cell lines [4].
• Pseudohypoaldosteronism type II (PHAII), an autosomal dominant disorder characterized by hypertension, hyperkalemia, and hyperchloremic acidosis, is reportedly due to mutations in WNK1 and WNK4 kinase genes [5].

High impact information on WNK1

• A WNK in the kidney controls blood pressure [6].
• WNK1 is cytoplasmic, whereas WNK4 localizes to tight junctions [7].
• Human hypertension caused by mutations in WNK kinases [7].
• These findings suggest that phosphorylation of Syts by WNK1 can regulate Ca2+ sensing and the subsequent Ca2+-dependent interactions mediated by Syt C2 domains [1].
• Endogenous WNK1 and Syt2 coimmunoprecipitate and colocalize on a subset of secretory granules in INS-1 cells [1].

Chemical compound and disease context of WNK1

• Mutations in the human genes encoding WNK1 [with no K (lysine) protein kinase-1] and the related protein kinase WNK4 are the cause of Gordon's hypertension syndrome [8].
• Mutations in the genes encoding two family members, WNK1 and WNK4, cause a chloride-dependent, thiazide-sensitive inherited syndrome of hypertension and hyperkalemia [9].
• Because TRPV4 and WNK kinases are coexpressed in the distal nephron in vivo and because there is a tendency toward hypercalcemia in TRPV4-/- mice, we speculate that this pathway may impact systemic Ca2+ balance [10].
• Kinases of the WNK family influence expression and function of the thiazide-sensitive Na+-Cl- cotransporter, and monogenic human hypertension has been linked to mutations in the gene coding for WNK4 [10].

Biological context of WNK1

• Here, we report that long WNK1 inhibited ROMK1 by stimulating its endocytosis [2].
• Rat WNK1 is 85% identical to a splice variant lacking exons 11 and 12 of the described human kinase which we have called human WNK1 [11].
• Two of these genes, WNK1 and WNK4 located in human chromosomes 12 and 17, respectively, are responsible for PHA-II [12].
• Association of WNK1 gene polymorphisms and haplotypes with ambulatory blood pressure in the general population [13].
• The WNK1 and WNK4 genes, which encode proteins in the WNK family of serine-threonine kinases, are involved in renal electrolyte homeostasis [13].

Anatomical context of WNK1

• Depletion of WNK1 from HeLa cells by using small interfering RNA reduces OSR1 kinase activity [14].
• The results of co-expressing WNK1 with ROMK in Xenopus oocytes are reported for the first time [15].
• The goal of this study was to determine the effect of aldosterone, the main hormonal regulator of Na(+) homeostasis, on the transcription of WNK1 isoforms in renal target cells, by using an unique mouse cortical collecting duct cell line that stably expresses functional mineralocorticoid receptors [16].
• Similarly, coexpression of KS-WNK1 and the epithelial Na(+) channel in Fischer rat thyroid epithelial cells also stimulates Na(+) current, suggesting that KS-WNK1 affects the subcellular location or activity but not the expression of epithelial Na(+) channel [16].
• Whereas small interfering RNA-induced loss of WNK1 protein did not significantly affect insulin-stimulated glucose transport in 3T3-L1 adipocytes, it significantly enhanced insulin-stimulated thymidine incorporation by about 2-fold [17].

Associations of WNK1 with chemical compounds

• Phosphorylation by WNK1 increases the amount of Ca2+ required for Syt2 binding to phospholipid vesicles; mutation of threonine 202, a WNK1 phosphorylation site, partially prevents this change [1].
• The same amino acid alteration was recently described for rat WNK1 (with no K=lysine) in which another nearby lysine residue was shown to confer kinase activity to the protein [11].
• Mutation of Ser325 in OSR1 to alanine or glutamic acid did not affect the basal activity of OSR1 or its ability to be activated by WNK1 [8].
• WNK kinases are a recently discovered class of serine-threonine kinases that are distinctive because of the substitution of cysteine for lysine in subdomain II of the catalytic domain [18].
• The kidney-specific WNK1 isoform is induced by aldosterone and stimulates epithelial sodium channel-mediated Na+ transport [16].

Physical interactions of WNK1

• Moreover, both MEKK2 and MEKK3 coimmunoprecipitated with endogenous WNK1 from cell lysates [19].

Enzymatic interactions of WNK1

• However, WNK1 phosphorylated both WNK4 and WNK2 [4].
• We establish that an intact CCT domain is required for WNK1 to efficiently phosphorylate and activate OSR1 [20].

Co-localisations of WNK1

• Here, we report that WNK1 co-localizes with CFTR protein in pulmonary epithelial cells [21].

Regulatory relationships of WNK1

• Moreover, IGF1-induced phosphorylation of endogenous WNK1 did not occur in PDK1-/- ES (embryonic stem) cells, in which PKB is not activated [22].
• Gain-of-function WNK1 mutations would be expected to inhibit WNK4 activity, thereby activating NCC, contributing to the PHAII phenotype [23].
• WNK1 expression also induced phosphorylation of endogenous claudin-4 in MDCKII cells, as well as over-expressed claudin-4 [5].
• WNK1 activates SGK1 to regulate the epithelial sodium channel [24].
• WNK kinases influence TRPV4 channel function and localization [10].

Other interactions of WNK1

• The predicted WNK3 protein has a similar structural organization to the other human WNK kinases [25].
• Together, these findings emphasize that the molecular mechanisms that underpin WNK1 regulation of ROMK expression are distinct from those that affect NCCT expression [15].
• The effect of the related kinase WNK1 on TRPV4 function and surface expression was similar to that of WNK4 [10].
• Overexpression of human WNK1 increases paracellular chloride permeability and phosphorylation of claudin-4 in MDCKII cells [5].
• Increased channel activity induced by WNK1 depends on SGK1 and the E3 ubiquitin ligase Nedd4-2 [24].

Analytical, diagnostic and therapeutic context of WNK1

• Gel filtration suggested that WNK1 exists as a tetramer, and yeast two-hybrid data showed that the N terminus of WNK1 (residues 1-222) interacts with residues 481-660, which includes the WNK1 autoinhibitory domain and a C-terminal coiled-coil domain [4].
• Through the analysis of enzyme fragments and sequence alignments, we have identified an autoinhibitory domain of WNK1 [26].
• In immunoprecipitation experiments, we were unable to detect direct interaction between TRPV4 and either WNK kinase [10].
• Here we report the effects of dissolved metal complexes of Fe(III), Al(III), and Cr(III) on the step velocities of the [100] face of KH2PO4 (KDP) as observed with atomic force microscopy [27].

References