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© The Rockefeller University Press, 0021-9525/1998//1385 $5.00
The Journal of Cell Biology, Volume 143, Number 5, , 1998 1385-1398

Article

Matrix-dependent Tiam1/Rac Signaling in Epithelial Cells Promotes Either Cell–Cell Adhesion or Cell Migration and Is Regulated by Phosphatidylinositol 3-Kinase



Eva E. Sander, Sanne van Delft, Jean P. ten Klooster, Tim Reid, Rob A. van der Kammen, Frits Michiels, and John G. Collard

The Netherlands Cancer Institute, Division of Cell Biology, 1066 CX Amsterdam, The Netherlands

We previously demonstrated that both Tiam1, an activator of Rac, and constitutively active V12Rac promote E-cadherin–mediated cell–cell adhesion in epithelial Madin Darby canine kidney (MDCK) cells. Moreover, Tiam1 and V12Rac inhibit invasion of Ras-transformed, fibroblastoid MDCK-f3 cells by restoring E-cadherin–mediated cell–cell adhesion. Here we show that the Tiam1/Rac-induced cellular response is dependent on the cell substrate. On fibronectin and laminin 1, Tiam1/Rac signaling inhibits migration of MDCK-f3 cells by restoring E-cadherin–mediated cell– cell adhesion. On different collagens, however, expression of Tiam1 and V12Rac promotes motile behavior, under conditions that prevent formation of E-cadherin adhesions. In nonmotile cells, Tiam1 is present in adherens junctions, whereas Tiam1 localizes to lamellae of migrating cells. The level of Rac activation by Tiam1, as determined by binding to a glutathione-S-transferase– PAK protein, is similar on fibronectin or collagen I, suggesting that rather the localization of the Tiam1/Rac signaling complex determines the substrate-dependent cellular responses. Rac activation by Tiam1 requires PI3-kinase activity. Moreover, Tiam1- but not V12Rac-induced migration as well as E-cadherin–mediated cell– cell adhesion are dependent on PI3-kinase, indicating that PI3-kinase acts upstream of Tiam1 and Rac.

Key Words: cell migration • E-cadherin adhesion • PI3-kinase • Rac signaling • Tiam1

Abbreviations used in this paper: GEF, guanine nucleotide exchange factor; GST, glutathione-S-transferase; HGF, hepatocyte growth factor; o/n, overnight; PAK-CD, PAK-CRIB domain; PH domain, Pleckstrin homology domain; PI3-kinase, phosphatidylinositol 3-kinase; Tiam1, T-lymphoma invasion and metastasis gene 1.


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