title: Integrin alpha3beta1 engagement disrupts intercellular adhesion.
abstract: During tissue morphogenesis and tumor invasion, epithelial cells must undergo intercellular rearrangement in which cells are repositioned with respect to one another and the surrounding mesenchymal extracellular matrix. Using three-dimensional aggregates of squamous epithelial cells, we show that such intercellular rearrangements can be triggered by activation of beta1 integrins after their ligation with extracellular matrices. On nonadherent substrates, multicellular aggregates (MCAs) formed rapidly via E-cadherin junctional complexes and over time became compacted spheroids exhibiting a more epithelial phenotype. After MCAs were replated on culture substrates, the spheroids collapsed to yield tightly arranged cell monolayers. Cell-cell contact induced rapid elevation in E-cadherin levels, which was due to an increase in the metabolic stability of junctional receptors. During MCA remodeling of cell-cell adhesions, and monolayer formation, their E-cadherin levels fell rapidly. Similar behavior was obtained regardless of which ECM ligand-collagen type I, fibronectin, or laminin 1-MCAs were seeded on. In contrast, when seeded onto a matrix elaborated by squamous epithelial cells, cells in the MCA attached, spread, lost cell-cell junctions, and dispersed. Analysis identified laminin 5 as the active ECM ligand in this matrix, and MCA dispersion required functional beta1 integrin and specifically alpha3beta1. Furthermore, substrate-immobilized anti-integrin antibody effectively reproduced the epithelial-mesenchymal-like transition induced by the laminin 5 matrix. During the early stages of aggregate rearrangement and collapse, cells on laminin 5 substrates, but not those on collagen I substrates, exhibited intense cortical arrays of F-actin, microspikes, and fascin accumulation at their peripheral surfaces. These results suggest that engagement of specific integrin-ligand pairs regulates cadherin junctional adhesions during events common to epithelial morphogenesis and tumor invasion.
authors.affiliation: Department of Stomatology, University of California at San Francisco, San Francisco, California, 94143-0512, USA.
authors.forename: K
authors.initials: K
authors.lastname: Kawano
authors.forename: S S
authors.initials: SS
authors.lastname: Kantak
authors.forename: M
authors.initials: M
authors.lastname: Murai
authors.forename: C C
authors.initials: CC
authors.lastname: Yao
authors.forename: R H
authors.initials: RH
authors.lastname: Kramer
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000378:metabolism / Q000494:pharmacology; D002449:Cell Aggregation / Q000502:physiology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003094:Collagen / Q000378:metabolism / Q000494:pharmacology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003720:Densitometry; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D019044:Image Cytometry; D039201:Integrin alpha3beta1; D016023:Integrins / Q000378:metabolism*; D007365:Intercellular Junctions / Q000378:metabolism; D007797:Laminin / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D008840:Microfilament Proteins / Q000378:metabolism; D010641:Phenotype; D011554:Pseudopodia / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D000097794:Kalinin
chemical_list: D000911:Antibodies, Monoclonal; D015820:Cadherins; D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D003094:Collagen; D017077:Culture Media, Conditioned; D003598:Cytoskeletal Proteins; D005353:Fibronectins; D039201:Integrin alpha3beta1; D016023:Integrins; D007797:Laminin; D008024:Ligands; D008840:Microfilament Proteins; D012333:RNA, Messenger; D000097794:Kalinin; C121346:laminin 1; C020324:fascin