Differential modulation of cadherin-mediated cell-cell adhesion by platelet endothelial cell adhesion molecule-1 isoforms through activation of extracellular regulated kinases.
The role of platelet endothelial cell adhesion molecule-1 (PECAM-1) in endothelial cell-cell interactions and its contribution to cadherin-mediated cell adhesion are poorly understood. Such studies have been difficult because all known endothelial cells express PECAM-1. We have used Madin-Darby canine kidney (MDCK) cells as a model system in which to evaluate the role of PECAM-1 isoforms that differ in their cytoplasmic domains in cell-cell interactions. MDCK cells lack endogenous PECAM-1 but form cell-cell junctions similar to those of endothelial cells, in which PECAM-1 is concentrated. MDCK cells were transfected with two isoforms of murine PECAM-1, Delta15 and Delta14&15, the predominant isoforms expressed in vivo. Expression of the Delta15 isoform resulted in apparent dedifferentiation of MDCK cells concomitant with the loss of adherens junctions, down-regulation of E-cadherin, alpha- and beta-catenin expression, and sustained activation of extracellular regulated kinases. The Delta15 isoform was not concentrated at cell-cell contacts. In contrast, the Delta14&15 isoform localized to sites of cell-cell contact and had no effect on MDCK cell morphology, cadherin/catenin expression, or extracellular regulated kinase activity. Thus, the presence of exon 14 in the cytoplasmic domain of PECAM-1 has dramatic effects on the ability of cells to maintain adherens junctions and an epithelial phenotype. Therefore, changes in the expression of exon 14 containing PECAM-1 isoforms, which we have observed during development, may have profound functional consequences.
Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA.
N
N
Sheibani
C M
CM
Sorenson
W A
WA
Frazier
D000818:Animals; D015820:Cadherins / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D005419:Flavonoids / Q000494:pharmacology; D007365:Intercellular Junctions / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D016297:Mutagenesis, Site-Directed; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators; D014162:Transfection; D051176:beta Catenin
D015820:Cadherins; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D020033:Protein Isoforms; D015534:Trans-Activators; D051176:beta Catenin; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one