Mouse proximal tubular cell-cell adhesion inhibits apoptosis by a cadherin-dependent mechanism

Adhesion of epithelial cells to matrix is known to inhibit apoptosis. However, the role of cell-cell adhesion in mediating cell survival remains uncertain. Primary cultures of mouse proximal tubular (MPT) cells were used to examine the role of cell-cell adhesion in promoting survival. When MPT cells were deprived of both cell-matrix and cell-cell adhesion, they died by apoptosis. However, when incubated in agarose-coated culture dishes (to prevent cell-matrix adhesion) and at high cell density (to allow cell-cell interactions), MPT cells adhered to one another and remained viable. Expression of E-cadherin among suspended, aggregating cells increased with time. A His-Ala-Val (HAV)-containing peptide that inhibits homophilic E-cadherin binding prevented cell-cell aggregation and promoted apoptosis of MPT cells in suspension. By contrast, inhibition of potential beta(1)-integrin-mediated interactions between cells in suspension did not prevent either aggregation or survival of suspended cells. Aggregation of cells in suspension activated phosphatidylinositol 3-kinase (PI3K), an event that was markedly reduced by the presence of the HAV peptide. LY-294002, an inhibitor of PI3K, also inhibited survival of suspended cells. In summary, we provide novel evidence that MPT cells, when deprived of normal cell-matrix interactions, can adhere to one another in a cadherin-dependent fashion and remain viable. Survival of aggregated cells depends on activation of PI3K.