Cadherins are regulated by Ep-CAM via phosphaditylinositol-3 kinase.
The cross-signaling between (cell) adhesion molecules is nowadays a well-accepted phenomenon and includes orchestrated cellular changes and changes in the microenvironment. For example, Ep-CAM is an epithelial adhesion molecule that prevails in active proliferating tissue and is suppressed in a more differentiated state of the cell. E-cadherin adhesion complexes are typical for the advanced and terminal differentiated cell status. During normal proliferation, E-cadherin is not suppressed. We have demonstrated the effect of overexpression of Ep-CAM on E-cadherin, which probably affects the connection of cadherins and F-actin. Phosphatidylinositol 3-kinase (Pi3K) participates in various regulating mechanisms, for example in signaling to nuclei, vesicle transport, and cytoskeletal rearrangements. The effect of Ep-CAM on E-cadherin mediated junctions as well as the involvement of Pi3K in regulating adherens junctions, led us to investigate the potential interaction between Pi3K and Ep-CAM. Introduction of Ep-CAM in the epithelial cells caused abrogation of N-cadherin mediated cell-cell adhesion, which could be inhibited by Pi3K inhibitor LY294002. Moreover, the Pi3K subunit p85 was precipitated with Ep-CAM from cell lysates, and this complex showed kinase activity. The Pi3K activity shuttled from N-cadherin to Ep-CAM. From our results, we conclude that Ep-CAM cross signaling with N-cadherin involves Pi3K, resulting in the abrogation of the cadherin adhesion complexes in epithelial cells.
Winter
Manon J
MJ
Department of Pathology, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands. winterm1@wyeth.com
Cirulli
Vincenzo
V
Briaire-de Bruijn
Inge H
IH
Litvinov
Sergey V
SV
D000951:Antigens, Neoplasm / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D000071858:Epithelial Cell Adhesion Molecule; D006801:Humans; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011485:Protein Binding / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
D000951:Antigens, Neoplasm; D015820:Cadherins; D015815:Cell Adhesion Molecules; D002867:Chromones; D000071858:Epithelial Cell Adhesion Molecule; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; C499379:EPCAM protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one