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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
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Orientador(es)
Resumo(s)
Plasma 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.
Highlights: -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.
Highlights: -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.
Descrição
Palavras-chave
CFTR Idebenone MAPK Signaling SHC-1. Plasma Membrane Vias de Transdução de Sinal e Patologias Associadas
Contexto Educativo
Citação
Biochem Biophys Res Commun. 2026 Jun 11:817:153757. doi: 10.1016/j.bbrc.2026.153757. Epub 2026 Apr 13
Editora
Elsevier