Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Am J Physiol Renal Physiol
2013 Dec 15;30512:F1687-96. doi: 10.1152/ajprenal.00211.2013.
Show Gene links
Show Anatomy links
Regulation of NKCC2 activity by inhibitory SPAK isoforms: KS-SPAK is a more potent inhibitor than SPAK2.
Park HJ
,
Curry JN
,
McCormick JA
.
???displayArticle.abstract???
The cation cotransporters Na(+)-K(+)-2Cl(-) cotransporter 1 and 2 (NKCC1 and NKCC2) and Na(+)-Cl cotransporter (NCC) are phosphorylated and activated by the kinases Ste20-related proline alanine-rich kinase (SPAK) and oxidative stress-responsive kinase (OSR1), and their targeted disruption in mice causes phenotypes resembling the human disorders Bartter syndrome and Gitelman syndrome, reflecting reduced NKCC2 and NCC activity, respectively. We previously cloned a kinase-inactive kidney-specific SPAK isoform, kidney-specific (KS)-SPAK, which lacks the majority of the kinase domain present in full-length SPAK. Another putative inactive SPAK isoform, SPAK2, which only lacks the initial portion of the kinase domain, is also highly expressed in kidney. The functional relevance of inactive SPAK isoforms is unclear. Here, we tested whether KS-SPAK and SPAK2 differentially affect cation cotransporter activity. While KS-SPAK and SPAK2 both strongly inhibited NKCC1 activity, SPAK2 was a much weaker inhibitor of NKCC2 activity. Removal of the catalytic loop from SPAK2 resulted in an inhibitory effect on NKCC2 similar to that of KS-SPAK. Full-length SPAK is phosphorylated and activated by members of the with-no-lysine[K] (WNK) kinase family. Mutation of a WNK phosphorylation in KS-SPAK did not alter its ability to inhibit NKCC2 activity. In contrast, we found that residues involved in KS-SPAK interactions with cation cotransporters are required for it to inhibit cotransporter activity. Finally, both KS-SPAK and SPAK2 associated with NKCC2, as demonstrated by coimmunoprecipitation. Together, these data identify the structural basis for the differential effects of KS-SPAK and SPAK2 on cation cotransporter activity that may be physiologically important.
Anselmo,
WNK1 and OSR1 regulate the Na+, K+, 2Cl- cotransporter in HeLa cells.
2006, Pubmed
Anselmo,
WNK1 and OSR1 regulate the Na+, K+, 2Cl- cotransporter in HeLa cells.
2006,
Pubmed
Dowd,
PASK (proline-alanine-rich STE20-related kinase), a regulatory kinase of the Na-K-Cl cotransporter (NKCC1).
2003,
Pubmed
Flatman,
Cotransporters, WNKs and hypertension: an update.
2008,
Pubmed
,
Xenbase
Gagnon,
On the substrate recognition and negative regulation of SPAK, a kinase modulating Na+-K+-2Cl- cotransport activity.
2010,
Pubmed
,
Xenbase
Gagnon,
Molecular physiology of SPAK and OSR1: two Ste20-related protein kinases regulating ion transport.
2012,
Pubmed
Gamba,
Molecular physiology and pathophysiology of electroneutral cation-chloride cotransporters.
2005,
Pubmed
Gamba,
Regulation of NKCC2 activity by SPAK truncated isoforms.
2014,
Pubmed
Giménez,
Regulatory phosphorylation sites in the NH2 terminus of the renal Na-K-Cl cotransporter (NKCC2).
2005,
Pubmed
,
Xenbase
Grimm,
SPAK isoforms and OSR1 regulate sodium-chloride co-transporters in a nephron-specific manner.
2012,
Pubmed
Hannemann,
Phosphorylation and transport in the Na-K-2Cl cotransporters, NKCC1 and NKCC2A, compared in HEK-293 cells.
2011,
Pubmed
Lenertz,
Properties of WNK1 and implications for other family members.
2005,
Pubmed
Lin,
Impaired phosphorylation of Na(+)-K(+)-2Cl(-) cotransporter by oxidative stress-responsive kinase-1 deficiency manifests hypotension and Bartter-like syndrome.
2011,
Pubmed
McCormick,
The WNKs: atypical protein kinases with pleiotropic actions.
2011,
Pubmed
McCormick,
A SPAK isoform switch modulates renal salt transport and blood pressure.
2011,
Pubmed
Moriguchi,
WNK1 regulates phosphorylation of cation-chloride-coupled cotransporters via the STE20-related kinases, SPAK and OSR1.
2005,
Pubmed
Nguyen,
Effects of K+-deficient diets with and without NaCl supplementation on Na+, K+, and H2O transporters' abundance along the nephron.
2012,
Pubmed
Piechotta,
Cation chloride cotransporters interact with the stress-related kinases Ste20-related proline-alanine-rich kinase (SPAK) and oxidative stress response 1 (OSR1).
2002,
Pubmed
Ponce-Coria,
Regulation of NKCC2 by a chloride-sensing mechanism involving the WNK3 and SPAK kinases.
2008,
Pubmed
,
Xenbase
Rafiqi,
Role of the WNK-activated SPAK kinase in regulating blood pressure.
2010,
Pubmed
Richardson,
Activation of the thiazide-sensitive Na+-Cl- cotransporter by the WNK-regulated kinases SPAK and OSR1.
2008,
Pubmed
Richardson,
The regulation of salt transport and blood pressure by the WNK-SPAK/OSR1 signalling pathway.
2008,
Pubmed
Richardson,
Regulation of the NKCC2 ion cotransporter by SPAK-OSR1-dependent and -independent pathways.
2011,
Pubmed
Saritas,
SPAK differentially mediates vasopressin effects on sodium cotransporters.
2013,
Pubmed
Seyberth,
Bartter- and Gitelman-like syndromes: salt-losing tubulopathies with loop or DCT defects.
2011,
Pubmed
Shetlar,
Characterization of a Na(+)-K(+)-2Cl- cotransport system in oocytes from Xenopus laevis.
1990,
Pubmed
,
Xenbase
Vitari,
Functional interactions of the SPAK/OSR1 kinases with their upstream activator WNK1 and downstream substrate NKCC1.
2006,
Pubmed
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
Won,
Recruitment interactions can override catalytic interactions in determining the functional identity of a protein kinase.
2011,
Pubmed
Yang,
SPAK-knockout mice manifest Gitelman syndrome and impaired vasoconstriction.
2010,
Pubmed
Zagórska,
Regulation of activity and localization of the WNK1 protein kinase by hyperosmotic stress.
2007,
Pubmed
