Rme-6, a Novel Regulator for EGFR Trafficking and Signaling

Abstract

The Epidermal Growth Factor Receptor (EGFR) is a key regulator for critical cellular processes including proliferation, migration, and apoptosis. Dysregulation of EGFR trafficking and signaling plays a crucial role in cancer development and contributes significantly to resistance to chemotherapy. This thesis examines the novel regulatory role of Rme-6, a Rab5 guanine nucleotide exchange factor (GEF), in modulating EGFR signaling by influencing its endocytic flux, a key determinant in the spatial and temporal dynamics of EGFR-mediated signaling pathways. Through a series of molecular and cellular experiments, I demonstrate that Rme-6 critically influences EGFR endocytic trafficking. Specifically, loss of Rme-6 results in increased accumulation of EGFR in APPL1-positive endosomes. This accumulation alters the downstream signaling fate of ERK1/2 by modulating its nuclear translocation. I have shown that Rme-6 has a positive effect on ERK1/2 signaling, while its disruption leads to aberrant ERK1/2 activity. This change in ERK1/2 signaling correlates with altered cell proliferation rates, suggesting a potential mechanism for cancer progression. Additionally, I reveal that Rme-6 may act as a scaffold for CK2 to phosphorylate ERK1/2 on its SPS motif, which is essential for its nuclear translocation and activation of transcription factors such as c-Fos. This phosphorylation impacts gene expression and subsequent cell fate decisions. This research not only advances our understanding of the molecular dynamics of EGFR signaling but also proposes Rme-6 as a potential therapeutic target in cancers characterized by dysregulated EGFR signaling pathways.