Integrin-mediated adhesion regulates cell polarity and membrane protrusionthrough the Rho family of GTPases

Integrin-mediated adhesion is a critical regulator of cell migration. Here we demonstrate that integrin-mediated adhesion to high fibronectin concentr ations induces a stop signal for cell migration by inhibiting cell polariza tion and protrusion. On fibronectin, the stop signal is generated through a lpha5 beta1 integrin-mediated signaling to the Rho family of GTPases. Speci fically, Cdc42 and Rac1 activation exhibits a biphasic dependence on fibron ectin concentration that parallels optimum cell polarization and protrusion . In contrast, RhoA activity increases with increasing substratum concentra tion. We find that cross talk between Cdc42 and Rac1 is required for substr atum-stimulated protrusion, whereas RhoA activity is inhibitory. We also sh ow that Cdc42 activity is inhibited by Rac1 activation, suggesting that Rac 1 activity may down-regulate Cdc42 activity and promote the formation of st abilized rather than transient protrusion. Furthermore, expression of RhoA down-regulates Cdc42 and Rac1 activity, providing a mechanism whereby RhoA may inhibit cell polarization and protrusion. These findings implicate adhe sion-dependent signaling as a mechanism to stop cell migration by regulatin g cell polarity and protrusion via the Rho family of GTPases.