Rap1 Regulates E-cadherin-mediated Cell-Cell Adhesion*
- Leo S. Price‡§,
- Amra Hajdo-Milasinovic¶,
- Jun Zhao‡∥,
- Fried J. T. Zwartkruis‡**,
- John G. Collard¶ and
- Johannes L. Bos‡
- ‡Department of Physiological Chemistry and the Centre for Biomedical Genetics, University Medical Centre Utrecht, Universiteitsweg 100, 3584 CG Utrecht, and the ¶Division of Cell Biology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
- ↵§ Supported by the Dutch Cancer Society. To whom correspondence should be addressed: Dept. of Physiological Chemistry, Stratenum Bldg., University Medical Centre Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands. Tel.: 31-30-253-9482; Fax: 31-30-253-9035; E-mail: .
The small GTPase Rap is best characterized as a critical regulator of integrin-mediated cell adhesion, although its mechanism of action is not understood. Rap also influences the properties of other cell-surface receptors and biological processes, although whether these are a consequence of effects on integrins is not clear. We show here that Rap also plays an important role in the regulation of cadherin-mediated cell-cell adhesion in epithelial cells. Expression of constitutively active Rap1A restored cadherin-mediated cell-cell contacts in mesenchymal Ras-transformed Madin-Darby canine kidney cells, resulting in reversion to an epithelial phenotype. Activation of endogenous Rap via the Rap exchange factor Epac1 also antagonized hepatocyte growth factor-induced disruption of adherens junctions. Inhibition of Rap signaling resulted in disruption of epithelial cell-cell contacts. Rap activity was required for adhesion of cells to recombinant E-cadherin extracellular domains, i.e. in the absence of integrin-mediated adhesion. These findings suggest that Rap signaling positively contributes to cadherin-mediated adhesion and that this occurs independently of effects on integrin-mediated adhesion. Our results imply that Rap may function in a broader manner to regulate the function of cell-surface adhesion receptors.
- Received May 3, 2004.
- Revision received May 27, 2004.
- The American Society for Biochemistry and Molecular Biology, Inc.