Epithelial Membrane Protein 2 and [beta]1 integrin signaling regulate APC-mediated processes

Adenomatous Polyposis Coli (APC) plays a critical role in cell motility, maintenance of apical-basal polarity, and epithelial morphogenesis. We previously demonstrated that APC loss in Madin Darby Canine Kidney (MDCK) cells increases cyst size and inverts polarity independent of Wnt signaling, and upregulates the tetraspan protein, Epithelial Membrane Protein 2 (EMP2). Herein, we show that APC loss increases [beta]1 integrin expression and migration of MDCK cells. Through 3D in vitro model systems and 2D migration analysis, we have depicted the molecular mechanism(s) by which APC influences polarity and cell motility. EMP2 knockdown in APC shRNA cells revealed that APC regulates apical-basal polarity and cyst size through EMP2. Chemical inhibition of [beta]1 integrin and its signaling components, FAK and Src, indicated that APC controls cyst size and migration, but not polarity, through [beta]1 integrin and its downstream targets. Combined, the current studies have identified two distinct and novel mechanisms required for APC to regulate polarity, cyst size, and cell migration independent of Wnt signaling. * [beta]1 integrin is upregulated in APC knockdown MDCK cells. * APC loss increases cell motility during wound-healing assays. * EMP2 regulates APC-mediated cyst size and apical polarity, but has no impact on migration. * [beta]1 integrin signaling mediates cyst size and migration due to APC loss, with no effect on polarity.