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Vol. 10, Issue 1, 9-22, January 1999
and
*MRC-Laboratory for Molecular Cell Biology;
Cadherins are cell-cell adhesion receptors whose adhesive function
requires their association with the actin cytoskeleton via proteins
called catenins. The small guanosine triphosphatases (GTPases), Rho and
Rac, are intracellular proteins that regulate the formation of distinct
actin structures in different cell types. In keratinocytes and in other
epithelial cells, Rho and Rac activities are required for E-cadherin
function. Here we show that the regulation of cadherin adhesiveness by
the small GTPases is influenced by the maturation status of the
junction and the cellular context. E-cadherin localization was
disrupted in mature keratinocyte junctions after inhibition of Rho and
Rac. However, an incubation of 2 h was required after GTPase
inhibition, when compared with newly established E-cadherin contacts
(30 min). Regarding other cadherin receptors, P-cadherin was
effectively removed from mature keratinocytes junctions by blocking Rho
or Rac. In contrast, VE-cadherin localization at endothelial junctions
was independent of Rho/Rac activity. We demontrate that the
insensitivity of VE-cadherin to inhibition of Rho and Rac was not due
to the maturation status of endothelial junction, but rather the
cellular background: when transfected into CHO cells, the localization
of VE-cadherin was perturbed by inhibition of Rho proteins. Our results
suggest that the same stimuli may have different activity in regulating
the paracellular activity in endothelial and epithelial cells. In
addition, we uncovered possible roles for the small GTPases during the
establishment of E-cadherin-dependent contacts. In keratinocytes, Rac
activation by itself cannot promote accumulation of actin at the cell
periphery in the absence of cadherin-dependent contacts. Moreover,
neither Rho nor Rac activation was sufficient to redistribute cadherin molecules to cell borders, indicating that redistribution results mostly from the homophilic binding of the receptors. Our results point
out the complexity of the regulation of cadherin-mediated adhesion by
the small GTPases, Rho and Rac.
Department of Biochemistry and Molecular Biology,
Department of Molecular Medicine, University College
London, WC1E 6BT, London, United Kingdom; and
§Laboratory
of Vascular Biology, Istituto de Richerche Farmacologiche "Mario
Negri," Milano, Italy 20.157; and
¶Universitá
degli studi dell'Insubria, Facoltá di Medicina e Chirurgia,
Varese, Italy
Corresponding author.
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