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.
Highlights
Epidermal Growth Factor Receptor (EGFR), a receptor tyrosine kinase and member of the ERBB family, is overexpressed in cancers including glioblastoma, head and neck, bladder, non-small cell lung, and breast [1, 2]
We have previously demonstrated that mucin 1 (MUC1) promotes EGFR-dependent breast cancer by inhibiting the degradation of EGFR and promoting its trafficking to the nucleus [18, 20]
To elucidate how MUC1 is altering trafficking, we investigated the effects of MUC1 expression on the canonical trafficking patterns of EGFR
Summary
Epidermal Growth Factor Receptor (EGFR), a receptor tyrosine kinase and member of the ERBB family, is overexpressed in cancers including glioblastoma, head and neck, bladder, non-small cell lung, and breast [1, 2]. EGFR regulates a variety of cellular processes, including survival, growth, migration, and adhesion [3]. EGFR primarily undergoes clathrin-mediated endocytosis where it maintains interactions with proteins such as Grb post-internalization, allowing for prolonged signal transduction from within endosomes [6, 7]. EGFR can meet other fates, including recycling to the cell surface and retrotranslocation to the mitochondria and nucleus [9,10,11]. Nuclear EGFR has been shown to traffic via retrotranslocation pathways to be delivered to the nucleus from the cell surface, similar to other proteins which have been shown to modulate downstream signal transduction from within endosomes while trafficking internally [14, 15]. Intracellular and nuclear EGFR is strongly correlated with poor therapeutic responses and metastatic progression in breast cancer, resulting in a 3.4 times greater mortality risk [16, 17]
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