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Proc Natl Acad Sci U S A
2006 Feb 07;1036:1976-81. doi: 10.1073/pnas.0510947103.
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WNK3 bypasses the tonicity requirement for K-Cl cotransporter activation via a phosphatase-dependent pathway.
de Los Heros P
,
Kahle KT
,
Rinehart J
,
Bobadilla NA
,
Vázquez N
,
San Cristobal P
,
Mount DB
,
Lifton RP
,
Hebert SC
,
Gamba G
.
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SLC12A cation/Cl- cotransporters are mutated in human disease, are targets of diuretics, and are collectively involved in the regulation of cell volume, neuronal excitability, and blood pressure. This gene family has two major branches with different physiological functions and inverse regulation: K-Cl cotransporters (KCC1-KCC4) mediate cellular Cl- efflux, are inhibited by phosphorylation, and are activated by dephosphorylation; Na-(K)-Cl cotransporters (NCC and NKCC1/2) mediate cellular Cl- influx and are activated by phosphorylation. A single kinase/phosphatase pathway is thought to coordinate the activities of these cotransporters in a given cell; however, the mechanisms involved are as yet unknown. We previously demonstrated that WNK3, a paralog of serine-threonine kinases mutated in hereditary hypertension, is coexpressed with several cation/Cl- cotransporters and regulates their activity. Here, we show that WNK3 completely prevents the cell swelling-induced activation of KCC1-KCC4 in Xenopus oocytes. In contrast, catalytically inactive WNK3 abolishes the cell shrinkage-induced inhibition of KCC1-KCC4, resulting in a >100-fold stimulation of K-Cl cotransport during conditions in which transport is normally inactive. This activation is completely abolished by calyculin A and cyclosporine A, inhibitors of protein phosphatase 1 and 2B, respectively. Wild-type WNK3 activates Na-(K)-Cl cotransporters by increasing their phosphorylation, and catalytically inactive kinase inhibits Na-(K)-Cl cotransporters by decreasing their phosphorylation, such that our data suggest that WNK3 is a crucial component of the kinase/phosphatase signaling pathway that coordinately regulates the Cl- influx and efflux branches of the SLC12A cotransporter family.
Adragna,
Regulation of K-Cl cotransport: from function to genes.
2004, Pubmed
Adragna,
Regulation of K-Cl cotransport: from function to genes.
2004,
Pubmed
Bollen,
Combinatorial control of protein phosphatase-1.
2001,
Pubmed
Cohen,
Protein phosphatase 1--targeted in many directions.
2002,
Pubmed
Connor,
Importance of the beta12-beta13 loop in protein phosphatase-1 catalytic subunit for inhibition by toxins and mammalian protein inhibitors.
1999,
Pubmed
Darman,
Modulation of ion transport by direct targeting of protein phosphatase type 1 to the Na-K-Cl cotransporter.
2001,
Pubmed
Darman,
A regulatory locus of phosphorylation in the N terminus of the Na-K-Cl cotransporter, NKCC1.
2002,
Pubmed
Dumont,
Oogenesis in Xenopus laevis (Daudin). I. Stages of oocyte development in laboratory maintained animals.
1972,
Pubmed
,
Xenbase
Flatman,
Regulation of Na-K-2Cl cotransport by phosphorylation and protein-protein interactions.
2002,
Pubmed
Gagnon,
Volume sensitivity of cation-Cl- cotransporters is modulated by the interaction of two kinases: Ste20-related proline-alanine-rich kinase and WNK4.
2006,
Pubmed
,
Xenbase
Gamba,
WNK lies upstream of kinases involved in regulation of ion transporters.
2005,
Pubmed
Gamba,
Molecular physiology and pathophysiology of electroneutral cation-chloride cotransporters.
2005,
Pubmed
Gamba,
Role of WNK kinases in regulating tubular salt and potassium transport and in the development of hypertension.
2005,
Pubmed
Giménez,
Short-term stimulation of the renal Na-K-Cl cotransporter (NKCC2) by vasopressin involves phosphorylation and membrane translocation of the protein.
2003,
Pubmed
Haas,
The Na-K-Cl cotransporter of secretory epithelia.
2000,
Pubmed
Hebert,
Molecular physiology of cation-coupled Cl- cotransport: the SLC12 family.
2004,
Pubmed
Jennings,
Okadaic acid inhibition of KCl cotransport. Evidence that protein dephosphorylation is necessary for activation of transport by either cell swelling or N-ethylmaleimide.
1991,
Pubmed
Kahle,
WNK3 modulates transport of Cl- in and out of cells: implications for control of cell volume and neuronal excitability.
2005,
Pubmed
,
Xenbase
Kahle,
WNK4 regulates the balance between renal NaCl reabsorption and K+ secretion.
2003,
Pubmed
,
Xenbase
Kahle,
Paracellular Cl- permeability is regulated by WNK4 kinase: insight into normal physiology and hypertension.
2004,
Pubmed
Lauf,
Erythrocyte K-Cl cotransport: properties and regulation.
1992,
Pubmed
Lauf,
K-Cl cotransport: properties and molecular mechanism.
2000,
Pubmed
,
Xenbase
Lytle,
A volume-sensitive protein kinase regulates the Na-K-2Cl cotransporter in duck red blood cells.
1998,
Pubmed
Lytle,
Coordinate modulation of Na-K-2Cl cotransport and K-Cl cotransport by cell volume and chloride.
2002,
Pubmed
Lytle,
Activation of the avian erythrocyte Na-K-Cl cotransport protein by cell shrinkage, cAMP, fluoride, and calyculin-A involves phosphorylation at common sites.
1997,
Pubmed
Mercado,
Functional comparison of the K+-Cl- cotransporters KCC1 and KCC4.
2000,
Pubmed
,
Xenbase
Mercado,
NH2-terminal heterogeneity in the KCC3 K+-Cl- cotransporter.
2005,
Pubmed
,
Xenbase
Mount,
Cloning and characterization of KCC3 and KCC4, new members of the cation-chloride cotransporter gene family.
1999,
Pubmed
,
Xenbase
Payne,
Functional characterization of the neuronal-specific K-Cl cotransporter: implications for [K+]o regulation.
1997,
Pubmed
Rinehart,
WNK3 kinase is a positive regulator of NKCC2 and NCC, renal cation-Cl- cotransporters required for normal blood pressure homeostasis.
2005,
Pubmed
,
Xenbase
Song,
Molecular, functional, and genomic characterization of human KCC2, the neuronal K-Cl cotransporter.
2002,
Pubmed
,
Xenbase
Starke,
K-Cl cotransport in rabbit red cells: further evidence for regulation by protein phosphatase type 1.
1993,
Pubmed
Strange,
Dependence of KCC2 K-Cl cotransporter activity on a conserved carboxy terminus tyrosine residue.
2000,
Pubmed
,
Xenbase
Vitari,
The WNK1 and WNK4 protein kinases that are mutated in Gordon's hypertension syndrome phosphorylate and activate SPAK and OSR1 protein kinases.
2005,
Pubmed
Wilson,
Human hypertension caused by mutations in WNK kinases.
2001,
Pubmed
Wilson,
Molecular pathogenesis of inherited hypertension with hyperkalemia: the Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4.
2003,
Pubmed
,
Xenbase
Xu,
WNK1 activates SGK1 to regulate the epithelial sodium channel.
2005,
Pubmed
Xu,
WNK1 activates SGK1 by a phosphatidylinositol 3-kinase-dependent and non-catalytic mechanism.
2005,
Pubmed
,
Xenbase
Xu,
Regulation of WNK1 by an autoinhibitory domain and autophosphorylation.
2002,
Pubmed
Yang,
WNK kinases regulate thiazide-sensitive Na-Cl cotransport.
2003,
Pubmed
,
Xenbase
Yang,
Mechanisms of WNK1 and WNK4 interaction in the regulation of thiazide-sensitive NaCl cotransport.
2005,
Pubmed
