Delay of EGF-Stimulated EGFR Degradation in Myotonic Dystrophy Type 1 (DM1)

Eva Alegre-Cortés, Alberto Giménez-Bejarano, Elisabet Uribe-Carretero, Marta Paredes-Barquero, André R.A. Marques, Mafalda Lopes-da-Silva, Otília V. Vieira, Saray Canales-Cortés, Pedro J. Camello, Guadalupe Martínez-Chacón, Ana Aiastui, Roberto Fernández-Torrón, Adolfo López de Munain, Patricia Gomez-Suaga, Mireia Niso-Santano, Rosa A. González-Polo, José M. Fuentes, Sokhna M.S. Yakhine-Diop

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Abstract

Myotonic dystrophy type 1 (DM1) is an autosomal dominant disease caused by a CTG repeat expansion in the 3′ untranslated region of the dystrophia myotonica protein kinase gene. AKT dephosphorylation and autophagy are associated with DM1. Autophagy has been widely studied in DM1, although the endocytic pathway has not. AKT has a critical role in endocytosis, and its phosphorylation is mediated by the activation of tyrosine kinase receptors, such as epidermal growth factor receptor (EGFR). EGF-activated EGFR triggers the internalization and degradation of ligand–receptor complexes that serve as a PI3K/AKT signaling platform. Here, we used primary fibroblasts from healthy subjects and DM1 patients. DM1-derived fibroblasts showed increased autophagy flux, with enlarged endosomes and lysosomes. Thereafter, cells were stimulated with a high concentration of EGF to promote EGFR internalization and degradation. Interestingly, EGF binding to EGFR was reduced in DM1 cells and EGFR internalization was also slowed during the early steps of endocytosis. However, EGF-activated EGFR enhanced AKT and ERK1/2 phosphorylation levels in the DM1-derived fibroblasts. Therefore, there was a delay in EGF-stimulated EGFR endocytosis in DM1 cells; this alteration might be due to the decrease in the binding of EGF to EGFR, and not to a decrease in AKT phosphorylation.

Original languageEnglish
Article number3018
JournalCells
Volume11
Issue number19
DOIs
Publication statusPublished - Oct 2022

Keywords

  • AKT
  • autophagy
  • DMPK
  • endosomes
  • LBPA
  • lysosomes
  • muscle atrophy

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