Guanine nucleotide exchange factors for Rho GTPases: turning on the switch

Abstract

Rho GTPases control many aspects of cell behavior through the regulation of multiple signal transduction pathways (Van Aelst and D’Souza-Schorey 1997; Hall 1998). Rho, Rac, and Cdc42 were first recognized in the early 1990s for their unique ability to induce specific filamentous actin structures in fibroblasts; stress fibers, lamellipodia/membrane ruffles, and filopodia, respectively (Hall 1998). Over the intervening years, evidence has accumulated to show that in all eukaryotic cells, Rho GTPases are involved in most, if not all, actin-dependent processes such as those involved in migration, adhesion, morphogenesis, axon guidance, and phagocytosis (Kaibuchi et al. 1999; Chimini and Chavrier 2000; Luo 2000). In addition to their well-established roles in controlling the actin cytoskeleton, Rho GTPases regulate the microtubule cytoskeleton, cell polarity, gene expression, cell cycle progression, and membrane transport pathways (Van Aelst and D’Souza-Schorey 1997; Daub et al. 2001; Etienne-Manneville and Hall 2001). With such a prominent role in so many aspects of cell biology, it is not surprising that they are themselves highly regulated. Like all GTPases, Rho proteins act as binary switches by cycling between an inactive (GDP-bound) and an active (GTP-bound) conformational state (Fig. 1; Van Aelst and D’Souza-Schorey 1997). The cell controls this switch by regulating the interconversion and accessibility of these two forms in a variety of ways. Guanine nucleotide exchange factors (GEFs) stimulate the exchange of GDP for GTP to generate the activated form, which is then capable of recognizing downstream targets, or effector proteins. GTPase activating proteins (GAPs) accelerate the intrinsic GTPase activity of Rho family members to inactivate the switch. Finally, guanine nucleotide dissociation inhibitors (GDIs) interact with the prenylated, GDP-bound form to control cycling between membranes and cytosol. In theory, activation of a Rho GTPase could occur through stimulation of a GEF or inhibition of a GAP. In practice, however, all the evidence points to GEFs being the critical mediators of Rho GTPase activation, and this paper reviews our present understanding of how they do this. Structural features