Loss of EGF receptor polarity enables homeostatic imbalance in epithelial-cell models.

The polarized distribution of membrane proteins into apical and basolateral domains provides the basis for specialized functions of epithelial tissues. The EGF receptor (EGFR) plays important roles in embryonic development, adult-epithelial tissue homeostasis, and growth and survival of many carcinomas. Typically targeted to basolateral domains, there is also considerable evidence of EGFR sorting plasticity but very limited knowledge regarding domain-specific EGFR substrates. Here we have investigated effects of selective EGFR mistargeting because of inactive-basolateral sorting signals on epithelial-cell homeostatic responses to growth-induced stress in MDCK cell models. Aberrant EGFR localization was associated with multilayer formation, anchorage-independent growth, and upregulated expression of the intermediate filament-protein vimentin characteristically seen in cells undergoing epithelial-to-mesenchymal transition. EGFRs were selectively retained following their internalization from apical membranes, and a signaling pathway involving the signaling adaptor Gab1 protein and extracellular signal-regulated kinase ERK5 had an essential role integrating multiple responses to growth-induced stress. Our studies highlight the potential importance of cellular machinery specifying EGFR polarity in epithelial pathologies associated with homeostatic imbalance.