title: (Alpha)3(beta)1 integrin regulates epithelial cytoskeletal organization.
abstract: Epithelial cell morphology and cytoskeletal organization are determined by interactions, with both adjacent cells and the extracellular matrix, which are mediated by integrins and cadherins. Little is known, however, of the relative contributions of integrins and cadherins to maintaining the sub-cortical cytoskeleton characteristic of epithelial cells. Since most studies that utilize integrin-blocking antibodies result in a loss of both cell-cell adhesion and sub-cortical cytoskeletal organization, it has been difficult to distinguish whether integrins and cadherins both mediate cytoskeletal assembly in epithelial cells. Therefore, cells derived from kidney collecting ducts of (alpha)3(beta)1 integrin-deficient mice were used to examine the role of integrins in epithelial cell morphology and cytoskeletal organization. In primary cell culture, (alpha)3(beta)1 integrin-deficient kidney collecting duct cells maintain cadherin-mediated cell-cell adhesions but fail to form the sub-cortical cytoskeleton that is characteristic of epithelial cells, and instead assemble actin stress fibers. Moreover, the cell-cell junctions in mutant cells were irregular, rather than being uniformly oriented perpendicular to the culture substrate. These results demonstrated that integrins have an primary and essential function in establishing and maintaining the sub-cortical cytoskeleton that is characteristic of epithelial cells. To further study the role of (alpha)3(beta)1 integrin in establishing and maintaining cytoskeletal organization in tubular epithelial cells, we derived immortalized cell lines from wild-type and (alpha)3(beta)1 integrin-deficient kidney collecting ducts that duplicated the cytoskeletal and cadherin organization observed in primary cells. E-cadherin and (alpha)- and (beta)-catenin were complexed together in equal amounts in membranes of wild-type and (alpha)3(beta)1 integrin-deficient cells. However, association of the cadherin:catenin complex with (alpha)-actinin was greatly decreased in mutant cells, indicating that integrin-mediated assembly of the sub-cortical cytoskeleton is essential for subsequent association of the cytoskeleton with the cadherin:catenin complex. These results present direct evidence for integrin:cadherin cross-regulation in which cadherin function is dependent on the presence of an integrin.
authors.affiliation: Department of Medicine, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
authors.forename: J M
authors.initials: JM
authors.lastname: Symons
authors.forename: S L
authors.initials: SL
authors.lastname: Goldstein
authors.forename: A
authors.initials: A
authors.lastname: McDonald
authors.forename: J H
authors.initials: JH
authors.lastname: Miner
authors.forename: J A
authors.initials: JA
authors.lastname: Kreidberg
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D015820:Cadherins / Q000032:analysis; D002461:Cell Line, Transformed; D003598:Cytoskeletal Proteins / Q000032:analysis*; D003599:Cytoskeleton / Q000648:ultrastructure*; D018076:DNA, Complementary / Q000235:genetics; D051180:Desmoplakins; D004847:Epithelial Cells / Q000378:metabolism / Q000648:ultrastructure*; D006801:Humans; D039422:Integrin alpha3; D039201:Integrin alpha3beta1; D016023:Integrins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007365:Intercellular Junctions / Q000378:metabolism / Q000648:ultrastructure; D007685:Kidney Tubules, Collecting / Q000166:cytology / Q000378:metabolism; D007797:Laminin / Q000096:biosynthesis; D046911:Macromolecular Substances; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015534:Trans-Activators; D014513:Ureter / Q000166:cytology / Q000378:metabolism; D051178:alpha Catenin; D051176:beta Catenin
chemical_list: D015703:Antigens, CD; C495273:CTNNA1 protein, human; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D015820:Cadherins; C495272:Ctnna1 protein, mouse; D003598:Cytoskeletal Proteins; D018076:DNA, Complementary; D051180:Desmoplakins; D039422:Integrin alpha3; D039201:Integrin alpha3beta1; D016023:Integrins; D007797:Laminin; D046911:Macromolecular Substances; D015534:Trans-Activators; D051178:alpha Catenin; D051176:beta Catenin