Abstract
The With No lysine [K] (WNK)-Ste20-related proline/alanine-rich kinase (SPAK)/oxidative stress-responsive kinase 1 (OSR1) pathway has been reported to be a crucial signaling pathway for triggering pseudohypoaldosteronism type II (PHAII), an autosomal dominant hereditary disease that is characterized by hypertension. However, the molecular mechanism(s) by which the WNK-SPAK/OSR1 pathway is regulated remain unclear. In this report, we identified WNK4 as an interacting partner of a recently identified MAP3K, apoptosis signal-regulating kinase 3 (ASK3). We found that WNK4 is phosphorylated in an ASK3 kinase activity-dependent manner. By exploring the ASK3-dependent phosphorylation sites, we identified Ser575 as a novel phosphorylation site in WNK4 by LC-MS/MS analysis. ASK3-dependent WNK4 Ser575 phosphorylation was mediated by the p38MAPK-MAPK-activated protein kinase (MK) pathway. Osmotic stress, as well as hypotonic low-chloride stimulation, increased WNK4 Ser575 phosphorylation via the p38MAPK-MK pathway. ASK3 was required for the p38MAPK activation induced by hypotonic stimulation but was not required for that induced by hypertonic stimulation or hypotonic low-chloride stimulation. Our results suggest that the p38MAPK-MK pathway might regulate WNK4 in an osmotic stress-dependent manner but its upstream regulators might be divergent depending on the types of osmotic stimuli.
Highlights
With no lysine [K] (WNK) kinases, which consist of WNK1, WNK2, WNK3 and WNK4, comprise a unique kinase family characterized by their irregular positioning of the lysine residue that is required for ATP binding1,2
We revealed that the osmotic stress induces WNK4 Ser575 phosphorylation via the p38MAPK-MK pathway and ASK3 is required for the hypotonic stimulation-dependent p38MAPK activation, which leads to WNK4 Ser575 phosphorylation
We propose a model in which the p38MAPK-MK pathway might be involved in the regulation of WNK4 in response to osmotic stress (Fig. 7)
Summary
With no lysine [K] (WNK) kinases, which consist of WNK1, WNK2, WNK3 and WNK4, comprise a unique kinase family characterized by their irregular positioning of the lysine residue that is required for ATP binding. WNK1 and WNK4 were reported to be responsible for pseudohypoaldosteronism type II (PHAII), which is an autosomal dominant hereditary disease characterized by hypertension, hyperkalemia and metabolic acidosis. WNK1 and WNK4 were reported to be responsible for pseudohypoaldosteronism type II (PHAII), which is an autosomal dominant hereditary disease characterized by hypertension, hyperkalemia and metabolic acidosis3 As this hypertension is effectively cured by treatment with thiazide diuretics, hyperactivation of the Na-Cl cotransporter (NCC), the target of thiazide diuretics, is thought to be the main cause of PHAII hypertensive symptoms. The Ser575 phosphorylation was induced by the osmotic stress via the p38MAPK-MK pathway, and ASK3 was required for the hypotonic stress-induced WNK4 Ser575 phosphorylation From these results, we propose a potential model in which WNK4 might be regulated by the stress-activated MAPK signaling pathway
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