Overexpression of the integrin-linked kinase mesenchymally transforms mammary epithelial cells

Signals generated by the interaction of pi integrins with laminin in the ba sement membrane contribute to mammary epithelial cell morphogenesis and dif ferentiation. The integrin-linked kinase (ILK) is one of the signaling moie ties that associates with the cytoplasmic domain of pr integrin subunits wi th some specificity. Forced expression of a dominant negative, kinase-dead form of ILK subtly altered mouse mammary epithelial cell morphogenesis but it did not prevent differentiative milk protein expression. In contrast, fo rced overexpression of wild-type ILK strongly inhibited both morphogenesis and differentiation. Overexpression of wild-type ILK also caused the cells to lose the cell-cell adhesion molecule E-cadherin, become invasive, reorga nize cortical actin into cytoplasmic stress fibers, and switch from an epit helial cytokeratin to a mesenchymal vimentin intermediate filament phenotyp e, Forced expression of E-cadherin in the latter mesenchymal cells rescued epithelial cytokeratin expression and it partially restored the ability of the cells to differentiate and undergo morphogenesis, These data demonstrat e that ILK, which responds to interactions between cells and the extracellu lar matrix, induces a mesenchymal transformation in mammary epithelial cell s, at least in part, by disrupting cell-cell junctions.