Regulation of the nucleotide state of the Rho GTPases is accomplished by the action of three major classes of proteins: guanine nucleotide exchange factors, guanine nucleotide dissociation inhibitors and GTPase activating proteins (GAPs)

Members of the Rho family of small GTPases, which includes the Rho, Rac and Cdc42 proteins, function as critical regulators of actin cytoskeleton organization. As such, these proteins mediate a variety of cellular processes, including migration, adhesion and shape change (Hall, 1998; Van Aelst and D’Souza-Schorey, 1997). These cellular functions of the Rho GTPases have recently been linked to several of the morphogenetic events associated with normal embryonic development in mammals and in other multicellular organisms (Settleman, 1999). Like the Ras GTPases, Rho proteins cycle between a GDP-bound inactive form and a GTP-bound active form in a tightly regulated manner (Nobes and Hall, 1994). Regulation of the nucleotide state of the Rho GTPases is accomplished by the action of three major classes of proteins: guanine nucleotide exchange factors, guanine nucleotide dissociation inhibitors and GTPase activating proteins (GAPs). GAPs function by stimulating the relatively weak intrinsic GTP hydrolyzing activity of their substrate GTPases, thereby inactivating them. Among the numerous RhoGAPs that have been described, p190 RhoGAP, together with a closely related protein, p190-B, accounts for a substantial fraction of the total Rho inhibitory activity in cultured cells (Burbelo et al., 1995; Settleman et al., 1992a; Vincent and Settleman, 1999), and both proteins are widely expressed in adult mammalian tissues (Burbelo et al., 1998; Settleman et al., 1992a). P190 RhoGAP was first identified as the major binding partner of p120 RasGAP in Src-transformed cells (Ellis et al., 1990). Thus, p190 RhoGAP may integrate signals transduced by the Ras and Rho family GTPases. P190 RhoGAP contains an aminoterminal GTPase domain (Foster et al., 1994) and a carboxyterminal RhoGAP domain that preferentially interacts with the Rho GTPase (Settleman et al., 1992b). Although the precise role of the GTPase domain of p190 RhoGAP has not been established, it appears to regulate the ability of p190 RhoGAP to function as a Rho regulator in cultured cells (Tatsis et al., 1998). Evidence for a role for p190 RhoGAP in regulating the actin cytoskeleton comes from several studies with cultured 4891 Development 127, 4891-4903 (2000) Printed in Great Britain © The Company of Biologists Limited 2000 DEV9730