title: Rap1 regulates E-cadherin-mediated cell-cell adhesion.
abstract: 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.
authors.affiliation: Department of Physiological Chemistry and the Centre for Biomedical Genetics, University Medical Centre Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands. l.s.price@med.uu.nl
authors.forename: Leo S
authors.initials: LS
authors.lastname: Price
authors.forename: Amra
authors.initials: A
authors.lastname: Hajdo-Milasinovic
authors.forename: Jun
authors.initials: J
authors.lastname: Zhao
authors.forename: Fried J T
authors.initials: FJ
authors.lastname: Zwartkruis
authors.forename: John G
authors.initials: JG
authors.lastname: Collard
authors.forename: Johannes L
authors.initials: JL
authors.lastname: Bos
mesh_terms: D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology; D002450:Cell Communication / Q000502:physiology*; D002461:Cell Line, Transformed; D004285:Dogs; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics; D015398:Signal Transduction; D020827:rap1 GTP-Binding Proteins / Q000502:physiology*
chemical_list: D015820:Cadherins; D020662:Guanine Nucleotide Exchange Factors; D011994:Recombinant Proteins; D020827:rap1 GTP-Binding Proteins