TNF-α-Driven Changes in Polarized EGF Receptor Trafficking Facilitate Phosphatidylinositol 3-Kinase/Protein Kinase B Signaling From the Apical Surface of MDCK Epithelial Cells.

This manuscript describes a novel unconventional secretory pathway that facilitates EGF receptor (EGFR) signaling from apical membranes in polarized epithelial cells responding to immune cell mediators. Epithelial tissues provide a physical barrier between our bodies and the external environment and share an intimate relationship with circulating and local immune cells. Our studies describe an unexpected connection between the proinflammatory cytokine tumor necrosis factor-alpha (TNF-α) and EGFR typically localized to basolateral membranes in polarized epithelial cells. These two molecules sit atop complex biological networks with a long history of shared investigative interest from the vantage point of signaling pathway interactions. We have discovered that TNF-α alters the functional landscape of fully polarized epithelial cells by changing the speed and direction of EGFR secretion. Our results show apical EGFR delivery occurs within minutes of de novo synthesis likely via a direct route from the endoplasmic reticulum without passage through the Golgi complex. Additionally, our studies have revealed that apical cellular compartmentalization constitutes an important mechanism to specify EGFR signaling via phosphatidylinositol-4,5-bisphosphate 3-kinase/protein-kinase-B pathways. Our study paves the way for a better understanding of how inflammatory cytokines fine-tune local homeostatic and inflammatory responses by altering the spatial organization of epithelial cell signaling systems.