| http://purl.uniprot.org/citations/24393035 | http://www.w3.org/1999/02/22-rdf-syntax-ns#type | http://purl.uniprot.org/core/Journal_Citation |
| http://purl.uniprot.org/citations/24393035 | http://www.w3.org/2000/01/rdf-schema#comment | "Precise homoeostasis of the intracellular concentration of Cl-is achieved via the co-ordinated activities of the Cl-influx and efflux. We demonstrate that the WNK (WNK lysine-deficient protein kinase)-activated SPAK (SPS1-related proline/alanine-rich kinase)/OSR1 (oxidative stress-responsive kinase 1) known to directly phosphorylate and stimulate the N[K]CCs (Na+-K+ ion co-transporters), also promote inhibition of the KCCs (K+-Cl-co-transporters) by directly phosphorylating a recently described C-terminal threonine residue conserved in all KCC isoforms [Site-2 (Thr1048)]. First, we demonstrate that SPAK and OSR1, in the presence of the MO25 regulatory subunit, robustly phosphorylates all KCC isoforms at Site-2 in vitro. Secondly, STOCK1S-50699, a WNK pathway inhibitor, suppresses SPAK/OSR1 activation and KCC3A Site-2 phosphorylation with similar efficiency. Thirdly, in ES (embryonic stem) cells lacking SPAK/OSR1 activity, endogenous phosphorylation of KCC isoforms at Site-2 is abolished and these cells display elevated basal activity of 86Rb+ uptake that was not markedly stimulated further by hypotonic high K+ conditions, consistent with KCC3A activation. Fourthly, a tight correlation exists between SPAK/OSR1 activity and the magnitude of KCC3A Site-2 phosphorylation. Lastly, a Site-2 alanine KCC3A mutant preventing SPAK/OSR1 phosphorylation exhibits increased activity. We also observe that KCCs are directly phosphorylated by SPAK/OSR1, at a novel Site-3 (Thr5 in KCC1/KCC3 and Thr6 in KCC2/KCC4), and a previously recognized KCC3-specific residue, Site-4 (Ser96). These data demonstrate that the WNK-regulated SPAK/OSR1 kinases directly phosphorylate the N[K]CCs and KCCs, promoting their stimulation and inhibition respectively. Given these reciprocal actions with anticipated net effects of increasing Cl-influx, we propose that the targeting of WNK-SPAK/OSR1 with kinase inhibitors might be a novel potent strategy to enhance cellular Cl-extrusion, with potential implications for the therapeutic modulation of epithelial and neuronal ion transport in human disease states."xsd:string |
| http://purl.uniprot.org/citations/24393035 | http://purl.org/dc/terms/identifier | "doi:10.1042/bj20131478"xsd:string |
| http://purl.uniprot.org/citations/24393035 | http://purl.uniprot.org/core/author | "Alessi D.R."xsd:string |
| http://purl.uniprot.org/citations/24393035 | http://purl.uniprot.org/core/author | "Gourlay R."xsd:string |
| http://purl.uniprot.org/citations/24393035 | http://purl.uniprot.org/core/author | "Zhang J."xsd:string |
| http://purl.uniprot.org/citations/24393035 | http://purl.uniprot.org/core/author | "Campbell D.G."xsd:string |
| http://purl.uniprot.org/citations/24393035 | http://purl.uniprot.org/core/author | "Deak M."xsd:string |
| http://purl.uniprot.org/citations/24393035 | http://purl.uniprot.org/core/author | "Kahle K.T."xsd:string |
| http://purl.uniprot.org/citations/24393035 | http://purl.uniprot.org/core/author | "Macartney T.J."xsd:string |
| http://purl.uniprot.org/citations/24393035 | http://purl.uniprot.org/core/author | "de Los Heros P."xsd:string |
| http://purl.uniprot.org/citations/24393035 | http://purl.uniprot.org/core/date | "2014"xsd:gYear |
| http://purl.uniprot.org/citations/24393035 | http://purl.uniprot.org/core/name | "Biochem J"xsd:string |
| http://purl.uniprot.org/citations/24393035 | http://purl.uniprot.org/core/pages | "559-573"xsd:string |
| http://purl.uniprot.org/citations/24393035 | http://purl.uniprot.org/core/title | "The WNK-regulated SPAK/OSR1 kinases directly phosphorylate and inhibit the K+-Cl- co-transporters."xsd:string |
| http://purl.uniprot.org/citations/24393035 | http://purl.uniprot.org/core/volume | "458"xsd:string |
| http://purl.uniprot.org/citations/24393035 | http://www.w3.org/2004/02/skos/core#exactMatch | http://purl.uniprot.org/pubmed/24393035 |
| http://purl.uniprot.org/citations/24393035 | http://xmlns.com/foaf/0.1/primaryTopicOf | https://pubmed.ncbi.nlm.nih.gov/24393035 |
| http://purl.uniprot.org/uniprot/Q9Y376#attribution-27F07FCBB01470ED638FE9D0B5DAF679 | http://purl.uniprot.org/core/source | http://purl.uniprot.org/citations/24393035 |
| http://purl.uniprot.org/uniprot/Q9Y376#attribution-66E6FEDA1D953E5F150964594D6A3948 | http://purl.uniprot.org/core/source | http://purl.uniprot.org/citations/24393035 |
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| http://purl.uniprot.org/uniprot/O95747#attribution-27F07FCBB01470ED638FE9D0B5DAF679 | http://purl.uniprot.org/core/source | http://purl.uniprot.org/citations/24393035 |
| http://purl.uniprot.org/uniprot/Q9Y666#attribution-201383B467620CA14FA90771DFC2CAAA | http://purl.uniprot.org/core/source | http://purl.uniprot.org/citations/24393035 |
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| http://purl.uniprot.org/uniprot/Q9UHW9#attribution-27F07FCBB01470ED638FE9D0B5DAF679 | http://purl.uniprot.org/core/source | http://purl.uniprot.org/citations/24393035 |