Clustering of integrin alpha 5 at the lateral membrane restores epithelial polarity in invasive colorectal cancer cells

摘要

Apicobasolateral polarity is a fundamental property of epithelial cells, and its loss is a hallmark of cancer. Integrin-mediated contact with the extracellular matrix defines the basal surface, setting in motion E-cadherin-mediated cell-cell contact, which establishes apicobasolateral polarity. Role(s) for lateral integrins in this polarization process and the consequences of their disruption are incompletely understood. We show that addition of an integrin beta 1-activating monoclonal antibody, P4G11, to invasive colorectal cancer cells in three-dimensional type 1 collagen reverts the invasive phenotype and restores apicobasolateral polarity. P4G11 induces clustering of integrin alpha 5 beta 1 at lateral, intercellular surfaces. This leads to deposition and polymerization of fibronectin and recruitment of paxillin to sites of lateral integrin alpha 5 beta 1 clustering and is followed by tight junction formation, as determined by ZO-1 localization. Inducible elimination of integrin alpha 5 abrogates the epithelial-organizing effects of P4G11. In addition, polymerization of fibronectin is required for the effects of P4G11, and addition of polymerized superfibronectin is sufficient to induce tight junction formation and apicobasolateral polarization. In the normal human colon, we show that integrin alpha 5 localizes to the lateral membrane of terminally differentiated colonocytes and that integrin alpha 5 staining may be reduced in colorectal cancer. Thus we propose a novel role for integrin alpha 5 beta 1 in regulating epithelial morphogenesis.