Clustering of integrin α5 at the lateral membrane restores epithelial polarity in invasive colorectal cancer cells.

Starchenko A, Graves-Deal R, Yang YP, Li C, Zent R, Singh B, Coffey RJ
Mol Biol Cell. 2017 28 (10): 1288-1300

PMID: 28356422 · PMCID: PMC5426844 · DOI:10.1091/mbc.E16-12-0852

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 β1-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 α5β1 at lateral, intercellular surfaces. This leads to deposition and polymerization of fibronectin and recruitment of paxillin to sites of lateral integrin α5β1 clustering and is followed by tight junction formation, as determined by ZO-1 localization. Inducible elimination of integrin α5 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 α5 localizes to the lateral membrane of terminally differentiated colonocytes and that integrin α5 staining may be reduced in colorectal cancer. Thus we propose a novel role for integrin α5β1 in regulating epithelial morphogenesis.

© 2017 Starchenko et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).

MeSH Terms (16)

Antibodies Cadherins Cell Adhesion Cell Culture Techniques Cell Line, Tumor Cell Polarity Colorectal Neoplasms Epithelial Cells Extracellular Matrix Fibronectins Humans Integrin alpha5 Integrin alpha5beta1 Integrin beta1 Membrane Proteins Membranes

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