Chemokine-induced monocyte transmigration requires cdc42-mediated cytoskeletal changes

The ras-related small GTPases of the rho family coordinate the assembly of complex cytoskeletal structures crucial for cell motility and polarization. Cdc42 controls filopodia formation in some cell types; however, other physiological functions, agonists and subsequent signaling cascades remain to be elucidated. Expression of cdc42 mutants in monocytic cells showed that CC chemokines regulate the rearrangement of the actin cytoskeleton via cdc42, i.e. formation of filopodia-like projections was induced by CC chemokines or dominant active cdc42, while dominant inactive cdc42 prevented its stimulation with CC chemokines. Both cdc42 mutants inhibited CC chemokine-induced monocyte migration across bare filters or across filters coated with endothelium, implicating cdc42 activity and its effector functions in chemotaxis. In contrast, cdc42 mutants did not affect the rho-dependent activation integrin avidity by CC chemokines. The chemokine-induced signaling pathways involved phosphoinositide 3-kinase upstream of cdc42, as shown by inhibition of cytoskeletal reorganization with wortmannin. These data identify CC chemokines as physiological agonists of cdc42 and reveal its functional importance in chemotaxis and extravasation of monocytes.