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Tyrosine phosphorylation modulates cell surface expression of chloride cotransporters NKCC2 and KCC3

2019-05-28Journal article Restricted access
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dc.contributor.authorLoureiro, Cláudia Almeida
dc.contributor.authorBarros, Patrícia
dc.contributor.authorMatos, Paulo
dc.contributor.authorJordan, Peter
dc.date.accessioned2019-07-18T17:36:16Z
dc.date.available2020-05-01T00:30:16Z
dc.date.issued2019-05-28
dc.description.abstractCellular chloride transport has a fundamental role in cell volume regulation and renal salt handling. Cellular chloride entry or exit are mediated at the plasma membrane by cotransporter proteins of the solute carrier 12 family. For example, NKCC2 resorbs chloride with sodium and potassium ions at the apical membrane of epithelial cells in the kidney, whereas KCC3 releases chloride with potassium ions at the basolateral membrane. Their ion transport activity is regulated by protein phosphorylation in response to signaling pathways. An additional regulatory mechanism concerns the amount of cotransporter molecules inserted into the plasma membrane. Here we describe that tyrosine phosphorylation of NKCC2 and KCC3 regulates their plasma membrane expression levels. We identified that spleen tyrosine kinase (SYK) phosphorylates a specific N-terminal tyrosine residue in each cotransporter. Experimental depletion of endogenous SYK or pharmacological inhibition of its kinase activity increased the abundance of NKCC2 at the plasma membrane of human embryonic kidney cells. In contrast, overexpression of a constitutively active SYK mutant decreased NKCC2 membrane abundance. Intriguingly, the same experimental approaches revealed the opposite effect on KCC3 abundance at the plasma membrane, compatible with the known antagonistic roles of NKCC and KCC cotransporters in cell volume regulation. Thus, we identified a novel pathway modulating the cell surface expression of NKCC2 and KCC3 and show that this same pathway has opposite functional outcomes for these two cotransporters. The findings have several biomedical implications considering the role of these cotransporters in regulating blood pressure and cell volume.pt_PT
dc.description.abstractHighlights: Protein kinase SYK phosphorylates NKCC2 and KCC3 at an N-terminal tyrosine residue; Cellular SYK activity modulates the expression of NKCC2 and KCC3 at the cell surface; SYK activity modulates cell surface expression of NKCC2 and KCC3 in opposite ways; SYK-modulated cell surface expression of NKCC2 contributes to cell-volume regulation.pt_PT
dc.description.sponsorshipThis work was supported by Fundação para a Ciência e Tecnologia (FCT) [grants PTDC/SAU-ORG/119782/2010 and PTDC/BIA-CEL/28408/2017 to PJ, grant UID/MULTI/04046/2019 to the research unit BioISI, and fellowship SFRH/BD/52488/2014 from the BioSYS PhD programme PD65-2012 to CAL]. The authors acknowledge the following colleagues for providing reagents used in this study: K. Mutig, Charité, Berlin, Germany; Maria J. Valente, REQUIMTE, Porto, Portugal; Dimitar G. Efremov, ICGEB, Rome, Italy.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationArch Biochem Biophys. 2019 Jul 15;669:61-70. doi:10.1016/j.abb.2019.05.022. Epub 2019 May 28pt_PT
dc.identifier.doi10.1016/j.abb.2019.05.022pt_PT
dc.identifier.issn0003-9861
dc.identifier.urihttp://hdl.handle.net/10400.18/6443
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherElsevierpt_PT
dc.relationFCT PTDC/SAU-ORG/119782/2010pt_PT
dc.relationFCT PTDC/BIA-CEL/28408/2017pt_PT
dc.relationFCT UID/MULTI/04046/2019pt_PT
dc.relation.publisherversionhttps://www.sciencedirect.com/science/article/abs/pii/S0003986119300669?via%3Dihubpt_PT
dc.subjectChloride cotransportpt_PT
dc.subjectProtein Phosphorylationpt_PT
dc.subjectSYKpt_PT
dc.subjectPhosphotyrosinept_PT
dc.subjectSHC1pt_PT
dc.subjectKCC3pt_PT
dc.subjectMembrane Trafficpt_PT
dc.subjectNKCC2pt_PT
dc.subjectVias de Transdução de Sinal e Patologias Associadaspt_PT
dc.titleTyrosine phosphorylation modulates cell surface expression of chloride cotransporters NKCC2 and KCC3pt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage70pt_PT
oaire.citation.startPage61pt_PT
oaire.citation.titleArchives of Biochemistry and Biophysicspt_PT
oaire.citation.volume669pt_PT
rcaap.embargofctDe acordo com política editorial da revista.pt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT

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