WNK1 regulates phosphorylation of cation-chloride-coupled cotransporters via the STE20-related kinases, SPAK and OSR1
- PMID: 16263722
- DOI: 10.1074/jbc.M510042200
WNK1 regulates phosphorylation of cation-chloride-coupled cotransporters via the STE20-related kinases, SPAK and OSR1
Abstract
The WNK1 and WNK4 genes have been found to be mutated in some patients with hyperkalemia and hypertension caused by pseudohypoaldosteronism type II. The clue to the pathophysiology of pseudohypoaldosteronism type II was its striking therapeutic response to thiazide 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 have shown that WNK1 phosphorylates and regulates the STE20-related kinases, Ste20-related proline-alanine-rich kinase (SPAK) and oxidative stress response 1 (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 suggested 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.
Similar articles
-
The WNK-SPAK/OSR1 pathway: master regulator of cation-chloride cotransporters.Sci Signal. 2014 Jul 15;7(334):re3. doi: 10.1126/scisignal.2005365. Sci Signal. 2014. PMID: 25028718 Review.
-
Mechanism of regulation of renal ion transport by WNK kinases.Curr Opin Nephrol Hypertens. 2008 Sep;17(5):519-25. doi: 10.1097/MNH.0b013e32830dd580. Curr Opin Nephrol Hypertens. 2008. PMID: 18695394 Review.
-
Activation of the thiazide-sensitive Na+-Cl- cotransporter by the WNK-regulated kinases SPAK and OSR1.J Cell Sci. 2008 Mar 1;121(Pt 5):675-84. doi: 10.1242/jcs.025312. Epub 2008 Feb 12. J Cell Sci. 2008. PMID: 18270262
-
Functional interactions of the SPAK/OSR1 kinases with their upstream activator WNK1 and downstream substrate NKCC1.Biochem J. 2006 Jul 1;397(1):223-31. doi: 10.1042/BJ20060220. Biochem J. 2006. PMID: 16669787 Free PMC article.
-
The WNK1 and WNK4 protein kinases that are mutated in Gordon's hypertension syndrome phosphorylate and activate SPAK and OSR1 protein kinases.Biochem J. 2005 Oct 1;391(Pt 1):17-24. doi: 10.1042/BJ20051180. Biochem J. 2005. PMID: 16083423 Free PMC article.
Cited by
-
Magnesium in hypertension: mechanisms and clinical implications.Front Physiol. 2024 Apr 10;15:1363975. doi: 10.3389/fphys.2024.1363975. eCollection 2024. Front Physiol. 2024. PMID: 38665599 Free PMC article. Review.
-
SPAK inhibitor ZT-1a attenuates reactive astrogliosis and oligodendrocyte degeneration in a mouse model of vascular dementia.CNS Neurosci Ther. 2024 Mar;30(3):e14654. doi: 10.1111/cns.14654. CNS Neurosci Ther. 2024. PMID: 38433018 Free PMC article.
-
Unanticipated domain requirements for Drosophila Wnk kinase in vivo.PLoS Genet. 2023 Oct 11;19(10):e1010975. doi: 10.1371/journal.pgen.1010975. eCollection 2023 Oct. PLoS Genet. 2023. PMID: 37819975 Free PMC article.
-
NCC regulation by WNK signal cascade.Front Physiol. 2023 Jan 4;13:1081261. doi: 10.3389/fphys.2022.1081261. eCollection 2022. Front Physiol. 2023. PMID: 36685207 Free PMC article. Review.
-
Potassium Homeostasis and WNK Kinases in the Regulation of the Sodium-Chloride Cotransporter: Hyperaldosteronism and Its Metabolic Consequences.Kidney360. 2022 Nov 24;3(11):1823-1828. doi: 10.34067/KID.0005752022. eCollection 2022 Nov 24. Kidney360. 2022. PMID: 36514400 Free PMC article. No abstract available.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases