Rho GTPases and the actin cytoskeleton

The actin cytoskeleton mediates a variety of essential biological functions in all eukaryotic cells. In addition to providing a structural framework around which cell shape and polarity are defined, its dynamic properties provide the driving force for cells to move and to divide. Understanding the biochemical mechanisms that control the organization of actin is thus a major goal of contemporary cell biology, with implications for health and disease. Members of the Rho family of small guanosine triphosphatases have emerged as key regulators of the actin cytoskeleton, and furthermore, through their interaction with multiple target proteins, they ensure coordinated control of other cellular activities such as gene transcription and adhesion. The story begins back in the early 1990s with the analysis of Rho, then a newly described member of the Ras superfamily of small guanosine triphosphatases (GTPases). In Swiss 3T3 fibroblasts, it was shown that Rho can be activated by the addition of extracellular ligands [for example, lysophos-phatidic acid] and that Rho activation leads to the assembly of contractile actin-myosin filaments (stress fibers) and of associated focal adhesion complexes (Fig. 1, C and D) (1). It was concluded that Rho acts as a molecular switch to control a signal trans-duction pathway that links membrane re-ceptors to the cytoskeleton. Rac, the next member of the Rho family to be analyzed, could be activated by a distinct set of ago-nists (for example, platelet-derived growth factor or insulin), leading to the assembly of a meshwork of actin filaments at the cell periphery to produce lamellipodia and membrane ruffles (Fig. 1E) (2). More re-cently, activation of Cdc42, a third member of the Rho subfamily, was shown to induce actin-rich surface protrusions called filopo-dia (Fig. 1G) (3, 4). As with Rho, the cytoskeletal changes induced by Rac and Cdc42 are also associated with distinct, in-tegrin-based adhesion complexes (Fig. 1, F and H) (3). Moreover, there is significant cross-talk between GTPases of the Ras an