Intravesicular epidermal growth factor receptor subject to retrograde trafficking drives epidermal growth factor-dependent migration

Sabrina Maisel, Derrick Broka, Joyce Schroeder

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

The Epidermal Growth Factor Receptor (EGFR) is frequently mutated and overexpressed in metastatic cancer. Although EGFR is a transmembrane tyrosine kinase localized to the basolateral membrane in normal epithelium, it is frequently found intracellularly localized in transformed cells. We have previously demonstrated the epithelial adaptor protein mucin 1 (MUC1) alters trafficking of EGFR, inhibiting its degradation and promoting its translocation to the nucleus, where it can directly modulate gene transcription. Here, we demonstrate that MUC1 promotes the retention of EGF-bound EGFR in Early Endosome Antigen1 (EEA1)-positive vesicles while preventing its trafficking to the lysosome. These events result in the accumulation of endosomal vesicles harboring active receptor throughout the cell and a reorganization of the actin cytoskeleton. EGF-dependent cell migration and filopodia formation is reliant upon this altered trafficking, and can be prevented by blocking retrograde trafficking. Together, these results indicate that intracellular EGFR may play an essential role in cancer metastasis and a potential mechanism for the failure of therapeutic antibodies in EGFR-driven metastatic breast cancer.

Original languageEnglish (US)
Pages (from-to)6463-6477
Number of pages15
JournalOncotarget
Volume9
Issue number5
DOIs
StatePublished - Jan 1 2018

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Keywords

  • Cetuximab
  • Epidermal growth factor receptor
  • Migration
  • MUC1
  • Retrograde trafficking

ASJC Scopus subject areas

  • Oncology

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