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A SYK/SHC1 pathway regulates the amount of CFTR in the plasma membrane

2020-12Journal article Restricted access
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dc.contributor.authorLoureiro, Cláudia Almeida
dc.contributor.authorPinto, Francisco R.
dc.contributor.authorBarros, Patrícia
dc.contributor.authorMatos, Paulo
dc.contributor.authorJordan, Peter
dc.date.accessioned2021-03-06T15:27:39Z
dc.date.available2021-03-06T15:27:39Z
dc.date.issued2020-12
dc.description.abstractMutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause the recessive genetic disease cystic fibrosis, where the chloride transport across the apical membrane of epithelial cells mediated by the CFTR protein is impaired. CFTR protein trafficking to the plasma membrane (PM) is the result of a complex interplay between the secretory and membrane recycling pathways that control the number of channels present at the membrane. In addition, the ion transport activity of CFTR at the PM is modulated through post-translational protein modifications. Previously we described that spleen tyrosine kinase (SYK) phosphorylates a specific tyrosine residue in the nucleotide-binding domain 1 domain and this modification can regulate the PM abundance of CFTR. Here we identified the underlying biochemical mechanism using peptide pull-down assays followed by mass spectrometry. We identified in bronchial epithelial cells that the adaptor protein SHC1 recognizes tyrosine-phosphorylated CFTR through its phosphotyrosine-binding domain and that the formation of a complex between SHC1 and CFTR is induced at the PM in the presence of activated SYK. The depletion of endogenous SHC1 expression was sufficient to promote an increase in CFTR at the PM of these cells. The results identify a SYK/SHC1 pathway that regulates the PM levels of CFTR channels, contributing to a better understanding of how CFTR-mediated chloride secretion is regulated.pt_PT
dc.description.sponsorshipThis work was supported by Fundação para a Ciência e Tecnologia (FCT), Portugal, through Grants PTDC/BIACEL/28408/2017 to PJ and UID/MULTI/04046/2019 to the research unit BioISI, and fellowship SFRH/BD/52488/2014 from the BioSYS Ph.D. programme PD65-2012 to CAL and SFRH/BPD/94322/2013 to PB.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationCell Mol Life Sci. 2020 Dec;77(23):4997-5015. doi: 10.1007/s00018-020-03448-4. Epub 2020 Jan 23.pt_PT
dc.identifier.doi10.1007/s00018-020-03448-4pt_PT
dc.identifier.issn1420-682X
dc.identifier.urihttp://hdl.handle.net/10400.18/7343
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherSpringer/ Birkhäuser Verlagpt_PT
dc.relationPTDC/BIACEL/28408/2017pt_PT
dc.relationSFRH/BD/52488/2014pt_PT
dc.relation.publisherversionhttps://link.springer.com/article/10.1007/s00018-020-03448-4pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/pt_PT
dc.subjectCell Membranept_PT
dc.subjectChloridespt_PT
dc.subjectCystic Fibrosis Transmembrane Conductance Regulatorpt_PT
dc.subjectEpithelial Cellspt_PT
dc.subjectLungpt_PT
dc.subjectPhosphopeptidespt_PT
dc.subjectPhosphorylationpt_PT
dc.subjectPhosphotyrosinept_PT
dc.subjectProtein Domainspt_PT
dc.subjectProtein Interaction Mapspt_PT
dc.subjectProtein Kinase Inhibitorspt_PT
dc.subjectSrc Homology 2 Domain-Containing, Transforming Protein 1pt_PT
dc.subjectSyk Kinasept_PT
dc.subjectSignal Transductionpt_PT
dc.subjectVias de Transdução de Sinal e Patologias Associadaspt_PT
dc.titleA SYK/SHC1 pathway regulates the amount of CFTR in the plasma membranept_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876/UID%2FMulti%2F04046%2F2013/PT (2019)
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBPD%2F94322%2F2013/PT
oaire.citation.endPage5015pt_PT
oaire.citation.issue23pt_PT
oaire.citation.startPage4997pt_PT
oaire.citation.titleCellular and Molecular Life Sciencespt_PT
oaire.citation.volume77pt_PT
oaire.fundingStream5876
oaire.fundingStreamSFRH
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.embargofctAcesso de acordo com política editorial da revista.pt_PT
rcaap.rightsembargoedAccesspt_PT
rcaap.typearticlept_PT
relation.isProjectOfPublication0dbd968f-ea65-4a2a-9b40-008aff7adbeb
relation.isProjectOfPublicationda7b5837-d061-46f4-ad5d-7f9016ece954
relation.isProjectOfPublication.latestForDiscovery0dbd968f-ea65-4a2a-9b40-008aff7adbeb

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