Rho GTPases and Cancer

Abstract

The Rho (Ras-homologous) family of proteins constitutes a major branch of the Ras superfamily of small GTPases, and is evolutionarily conserved across several phyla. Thus far, 25 members have been identified, and these may be divided into 6 subfamilies based on amino acid sequence identity, structural motifs, and biological function. These include the RhoA-related subfamily (RhoA, RhoB, RhoC), the Rac1-related subfamily (Rac1, Rac1b, Rac2, Rac3, and RhoG), and the Cdc42-related subfamily (Cdc42, G25 K, TC10, TCL, Wrch1, and Wrch-2; see Table 1). Rho proteins may be distinguished from other Ras superfamily members by the presence of a Rho-type GTPase domain, which shares 30% amino acid sequence identity with the small GTPase domain of Ras proteins. Members of the Rho GTPase family share 40–95% identity within their Rho-type GTPase domains (reviewed in Wennerberg and Der 2004). Like Ras proteins, most Rho GTPases function as molecular switches that cycle between an inactive GDP-bound state and an active GTP-bound state. The interconversion between the two states is mediated by interaction with regulatory proteins: guanine nucleotide-exchange factors (Rho-GEFs) accelerate the rate of GDP to GTP exchange, and thus promote the activity of Rho proteins, while GTPase-activating proteins (Rho-GAPs) stimulate the intrinsic GTPase activity of Rho proteins, resulting in their inactivation. An additional level of regulation is offered by Rho-GDP dissociation inhibitors (RhoGDIs), which sequester Rho proteins in the cytoplasm in an inactive state. Active GTP-bound Rho proteins are able to interact with a wide range of downstream effector proteins, through which they mediate diverse cellular functions (see Fig. 1). An additional determinant of Rho GTPase function is subcellular localization, which may be influenced by several factors, including post-translational isoprenoid modification and the presence of a C-terminal polybasic region