Regulation of cytoskeleton and cell adhesions by small GTPases and their targets

The small GTPases are implicated in the regulation of cytoskeletons and cell adhesions. We previously identified AF-6 as a Ras target. Rho-kinase as a Rho target and IQGAP as a Cdc42 and Racl target. AF-6 accumulated at cell cell contact sites at where occludin and ZO-1. tight junction markers, were localized. AF-6 directly interacted with ZO-1 and activated Ras inhibited this interaction, suggesting that Ras acting through AF-6 can regulate cell cell adhesion via the occludin/ZO-1 pathway. Microinjection of the dominant active form of Rho kinase into serum-starved Swiss 3T3 cells induced the formation of stress fibers and focal adhesions, whereas microinjection of the dominant negative form inhibited the LPA-induced formation of stress fibers and focal adhesion. Thus, Rho-kinase appears to mediate signals from Rho and to induce the formation of stress fibers and focal adhesions. IQGAP1 accumulated at cell-cell contact sites at where cadherin and catenins were localized. IQGAP1 interacted with E-cadherin and catenins in vivo and in vitro. Beta-catenin inhibitedd the binding of IQGAP1 to E-cadhehn, suggesting that IQGAP1 and beta-catenin compete for the interaction with E-cadherin. Overexpression of IQGAPl in KB cells resulted in disruption of cell-cell and cell-substratum adhesions, and dominant active Cdc42 rescued this IQGAPl effect. These observations suggest that Cdc42/Racl acting through IQGAPl can regulate cell cell adhesion via the cadherin/catenin pathway.