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Dissecting the impact of SHC-1 inhibitors in enhancing the plasma membrane abundance of the CFTR channel across epithelial cell models

2026-06-11Artigo científico Acesso aberto
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datacite.subject.fosCiências Médicas::Ciências da Saúde
datacite.subject.sdg03:Saúde de Qualidade
dc.contributor.authorBarros, Patricia
dc.contributor.authorPereira, Mariana F.L.
dc.contributor.authorTomilov, Alexey
dc.contributor.authorCortopassi, Gino
dc.contributor.authorJordan, Peter
dc.contributor.authorMatos, Paulo
dc.date.accessioned2026-10-01T11:08:44Z
dc.date.available2026-10-01T11:08:44Z
dc.date.issued2026-06-11
dc.description.abstractPlasma membrane (PM) ion transport depends on tightly regulated trafficking and activation of ion channels. For the cystic fibrosis transmembrane conductance regulator (CFTR), dysregulation caused by tobacco smoke or chronic inflammation contributes to diseases such as chronic obstructive pulmonary disease (COPD). We previously showed that phosphorylation of CFTR at tyrosine 512 (Y512) by spleen tyrosine kinase promotes its internalization via the MAPK/SHC-1 pathway in CFBE airway cells. Here, we investigated whether this mechanism is conserved in other epithelial models and whether inhibition of SHC-1 increased CFTR abundance at the PM. CFTR surface levels were assessed in CFBE, 16HBE, and Caco-2 cells using biotinylation and immunoblotting after treatment with MEK inhibitor selumetinib, SHC-1 inhibitor idebenone (IDE), or its novel inhibitor 110#3. MAPK activity was evaluated by ERK phosphorylation. We found that MAPK/SHC-1-dependent CFTR internalization was conserved in 16HBE and Caco-2 cells. In CFBE cells, treatment with IDE or 110#3 increased PM CFTR levels, but also unrelated PM proteins (GLUT1 and E-cadherin). No significant effects were observed in 16HBE or Caco-2 cells. These findings suggest CFBE cells may not fully recapitulate endogenous CFTR trafficking and raise the possibility that selective SHC-1/pY512-CFTR inhibitors may modulate CFTR trafficking in COPD and other CFTR-related diseases.eng
dc.description.abstractHighlights: -MAPK/SHC-1–dependent CFTR internalization is conserved across epithelial models. -SHC-1 inhibitors boost PM CFTR in CFBE cells but also elevate unrelated PM proteins. -16HBE cells may more accurately model endogenous CFTR trafficking fidelity.eng
dc.description.sponsorshipWork supported by UID/04046/2025 - Biosystems and Integrative Sciences Institute Centre grant from FCT, Portugal.
dc.identifier.citationBiochem Biophys Res Commun. 2026 Jun 11:817:153757. doi: 10.1016/j.bbrc.2026.153757. Epub 2026 Apr 13
dc.identifier.doi10.1016/j.bbrc.2026.153757
dc.identifier.issn0006-291X
dc.identifier.pmid41990453
dc.identifier.urihttp://hdl.handle.net/10400.18/11362
dc.language.isoeng
dc.peerreviewedyes
dc.publisherElsevier
dc.relationUID/04046/2025
dc.relation.hasversionhttps://www.sciencedirect.com/science/article/pii/S0006291X26005218?via%3Dihub
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectCFTR
dc.subjectIdebenone
dc.subjectMAPK Signaling
dc.subjectSHC-1.
dc.subjectPlasma Membrane
dc.subjectVias de Transdução de Sinal e Patologias Associadas
dc.titleDissecting the impact of SHC-1 inhibitors in enhancing the plasma membrane abundance of the CFTR channel across epithelial cell modelseng
dc.typejournal article
dcterms.referenceshttps://ars.els-cdn.com/content/image/1-s2.0-S0006291X26005218-mmc1.pdf
dspace.entity.typePublication
oaire.citation.startPage153757
oaire.citation.titleBiochemical and Biophysical Research Communications
oaire.citation.volume817
oaire.versionhttp://purl.org/coar/version/c_970fb48d4fbd8a85

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