title: Clustering of integrin α5 at the lateral membrane restores epithelial polarity in invasive colorectal cancer cells.
abstract: 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.
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN 37232.
authors.forename: Alina
authors.initials: A
authors.lastname: Starchenko
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232.
authors.forename: Ramona
authors.initials: R
authors.lastname: Graves-Deal
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232.
authors.forename: Yu-Ping
authors.initials: YP
authors.lastname: Yang
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232.
authors.forename: Cunxi
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232.
authors.forename: Roy
authors.initials: R
authors.lastname: Zent
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232.
authors.forename: Bhuminder
authors.initials: B
authors.lastname: Singh
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232 robert.coffey@vanderbilt.edu.|Veterans Affairs Medical Center, Nashville, TN 37212.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Coffey
mesh_terms: D000906:Antibodies; D015820:Cadherins; D002448:Cell Adhesion / Q000502:physiology; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D016764:Cell Polarity / Q000502:physiology; D015179:Colorectal Neoplasms / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000502:physiology; D005109:Extracellular Matrix / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D039482:Integrin alpha5 / Q000378:metabolism / Q000502:physiology; D039081:Integrin alpha5beta1 / Q000378:metabolism* / Q000502:physiology; D019012:Integrin beta1 / Q000378:metabolism; D008565:Membrane Proteins; D008566:Membranes / Q000378:metabolism
chemical_list: D000906:Antibodies; D015820:Cadherins; D005353:Fibronectins; D039482:Integrin alpha5; D039081:Integrin alpha5beta1; D019012:Integrin beta1; D008565:Membrane Proteins