Regulation of epithelial migration by epithelial cell adhesion molecule requires its Claudin-7 interaction domain.

Abstract

Epithelial cell adhesion molecule (EpCAM) is a glycoprotein on the surface of epithelial cells that is essential for intestinal epithelial integrity and expressed at high levels in many epithelial derived cancers and circulating tumor cells. Here we show the effect of EpCAM levels on migration of Madin-Darby-Canine Kidney (MDCK) epithelial cells. MDCK cells depleted of EpCAM show increased activation of extracellular signal-regulated kinase (ERK) and of myosin, and increased cell spreading and epithelial sheet migration into a gap. In contrast, over-expression of EpCAM inhibits ERK and myosin activation, and slows epithelial sheet migration. Loss of EpCAM is rescued by EpCAM-YFP mutated in the extracellular domain required for cis-dimerization whereas EpCAM-YFP with a mutation that inhibits Claudin-7 interaction cannot rescue increased ERK, myosin activation, and increased migration in EpCAM-depleted cells. In summary, these results indicate that interaction of EpCAM and Claudin-7 at the cell surface negatively regulates epithelial migration by inhibiting ERK and actomyosin contractility.