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Papers In Press, published online ahead of print October 31, 2005
Department of Molecular Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 101-0062
Corresponding Author: shibuya.mcb{at}mri.tmd.ac.jp
The WNK1 and WNK4 genes have been found to be mutated in some patients with hyperkalemia and hypertension caused by pseudohypoaldosteronism type II (PHA II). The clue to the pathophysiology of PHAII was its striking therapeutic response to thiaziede diuretics, which are known to block the sodium-chloride cotransporter (NCC). Although this suggests a role for WNK1 in hypertension, the precise molecular mechanisms are largely unknown. Here we show that WNK1 phosphorylates and regulates the STE20-related kinases, SPAK and OSR1. WNK1 was observed to phosphorylate the evolutionary conserved serine residue located outside the kinase domains of SPAK and OSR1, and mutation of the OSR1 serine residue caused enhanced OSR1 kinase activity. In addition, hypotonic stress was shown to activate SPAK and OSR1 and induce phosphorylation of the conserved OSR1 serine residue, suggesting that WNK1 may be an activator of the SPAK and OSR1 kinases. Moreover, SPAK and OSR1 were found to directly phosphorylate the N-terminal regulatory regions of cation-chloride-coupled cotransporters including NKCC1, NKCC2 and NCC. Phosphorylation of NCC was induced by hypotonic stress in cells. These results suggest that WNK1 and SPAK/OSR1 mediate the hypotonic stress signaling pathway to the transporters, and may provide insights into the mechanisms by which WNK1 regulates ion balance.
J. Biol. Chem, 10.1074/jbc.M510042200
Submitted on September 13, 2005
Revised on October 27, 2005
Accepted on October 28, 2005
WNK1 regulates phosphorylation of cation-chloride-coupled cotransporters via the STE20-related kinases, SPAK and OSR1
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