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YES1 Kinase Mediates the Membrane Removal of Rescued F508del-CFTR in Airway Cells by Promoting MAPK Pathway Activation via SHC1

2023-06-06Journal article Open access
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dc.contributor.authorBarros, Patrícia
dc.contributor.authorMatos, Ana M.
dc.contributor.authorMatos, Paulo
dc.contributor.authorJordan, Peter
dc.date.accessioned2024-02-14T11:01:30Z
dc.date.available2024-02-14T11:01:30Z
dc.date.issued2023-06-06
dc.description(This article belongs to the Section Molecular Biology)pt_PT
dc.description.abstractRecent developments in CFTR modulator drugs have had a significant transformational effect on the treatment of individuals with Cystic Fibrosis (CF) who carry the most frequent F508del- CFTR mutation in at least one allele. However, the clinical effects of these revolutionary drugs remain limited by their inability to fully restore the plasma membrane (PM) stability of the rescued mutant channels. Here, we shed new light on the molecular mechanisms behind the reduced half-life of rescued F508del-CFTR at the PM of airway cells. We describe that YES1 protein kinase is enriched in F508del-CFTR protein PM complexes, and that its interaction with rescued channels is mediated and dependent on the adaptor protein YAP1. Moreover, we show that interference with this complex, either by depletion of one of these components or inhibiting YES1 activity, is sufficient to significantly improve the abundance and stability of modulator-rescued F508del-CFTR at the surface of airway cells. In addition, we found that this effect was mediated by a decreased phosphorylation of the scaffold protein SHC1, a key regulator of MAPK pathway activity. In fact, we showed that depletion of SHC1 or inhibition of MAPK pathway signaling was sufficient to improve rescued F508del-CFTR surface levels, whereas an ectopic increase in pathway activation downstream of SHC1, through the use of a constitutively active H-RAS protein, abrogated the stabilizing effect of YES1 inhibition on rescued F508del-CFTR. Taken together, our findings not only provide new mechanistic insights into the regulation of modulator-rescued F508del-CFTR membrane stability, but also open exciting new avenues to be further explored in CF research and treatment.pt_PT
dc.description.sponsorshipFunding: This work was supported by the Grant PTDC/BIA-CEL/28408/2017 (to PJ and PM) and Center Grant UID/MULTI/04046/2019 to BioISI from the Portuguese Fundação para a Ciência e a Tecnologia.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationBiomolecules. 2023 Jun 6;13(6):949. doi: 10.3390/biom13060949pt_PT
dc.identifier.doi10.3390/biom13060949pt_PT
dc.identifier.issn2218-273X
dc.identifier.urihttp://hdl.handle.net/10400.18/9104
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherMDPIpt_PT
dc.relationBiosystems & Integrative Sciences Institute
dc.relation.publisherversionhttps://www.mdpi.com/2218-273X/13/6/949pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectCystic Fibrosispt_PT
dc.subjectSignalingpt_PT
dc.subjectMAPKpt_PT
dc.subjectSHC1pt_PT
dc.subjectYESpt_PT
dc.subjectF508del-CFTRpt_PT
dc.subjectMAPK Pathwaypt_PT
dc.subjectPlasma Membrane Half-lifept_PT
dc.subjectFibrose Quísticapt_PT
dc.subjectVias de Transdução de Sinal e Patologias Associadaspt_PT
dc.titleYES1 Kinase Mediates the Membrane Removal of Rescued F508del-CFTR in Airway Cells by Promoting MAPK Pathway Activation via SHC1pt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleBiosystems & Integrative Sciences Institute
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FBIA-CEL%2F28408%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID%2FMulti%2F04046%2F2019/PT
oaire.citation.issue6pt_PT
oaire.citation.startPage949pt_PT
oaire.citation.titleBiomoleculespt_PT
oaire.citation.volume13pt_PT
oaire.fundingStream3599-PPCDT
oaire.fundingStream6817 - DCRRNI ID
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.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isProjectOfPublication710163b5-23b3-4080-82a2-3b5d7a1ff579
relation.isProjectOfPublication35168786-8dfc-4a00-9759-dab3669fe1ae
relation.isProjectOfPublication.latestForDiscovery710163b5-23b3-4080-82a2-3b5d7a1ff579

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