Rho family of GTPases

The Rho family of GTPases is a family of small (~21 kDa) signaling G proteins, and is a subfamily of the Ras superfamily. The members of the Rho GTPase family have been shown to regulate many aspects of intracellular actin dynamics, and are found in all eukaryotic kingdoms, including yeasts and some plants. Three members of the family have been studied in detail: Cdc42, Rac1, and RhoA. All G proteins are 'molecular switches', and Rho proteins play a role in organelle development, cytoskeletal dynamics, cell movement, and other common cellular functions. The Rho family of GTPases is a family of small (~21 kDa) signaling G proteins, and is a subfamily of the Ras superfamily. The members of the Rho GTPase family have been shown to regulate many aspects of intracellular actin dynamics, and are found in all eukaryotic kingdoms, including yeasts and some plants. Three members of the family have been studied in detail: Cdc42, Rac1, and RhoA. All G proteins are 'molecular switches', and Rho proteins play a role in organelle development, cytoskeletal dynamics, cell movement, and other common cellular functions. Identification of the Rho family of GTPases began in the mid-1980s. The first identified Rho member was RhoA, isolated serendipitously in 1985 from a low stringency cDNA screening. Rac1 and Rac2 were identified next, in 1989 followed by Cdc42 in 1990. Eight additional mammalian Rho members were identified from biological screenings until the late 1990s, a turning point in biology where availability of complete genome sequences allowed full identification of gene families. All eukaryote cells contain Rho GTPase (ranging from 6 in yeast to 20 in mammals). In mammals, the Rho family is thus made of 20 members distributed in 8 subfamilies: Rho, Rnd, RhoD/F, RhoH, Rac, Cdc42, RhoU/V and RhoBTB. As early as 1990, Paterson et al. began expressing activated Rho protein in Swiss 3T3 fibroblasts. By the mid-1990s, Rho proteins had been observed to affect the formation of cellular projections ('processes') in fibroblasts. In a 1998 review article, Alan Hall compiled evidence showing that not only do fibroblasts form processes upon Rho activation, but so do virtually all eukaryotic cells. A 2006 review article by Bement et al. explored the significance of spatial zones of Rho activation. The Rho family of GTPases belong to the Ras superfamily of proteins, which consists of over 150 varieties in mammals. Rho proteins sometimes denote some members of the Rho family (RhoA, RhoB, and RhoC), and sometimes refers to all members of the family. This article is about the family as a whole. In mammals, the Rho family contains 20 members. Almost all research involves the three most common members of the Rho family: Cdc42, Rac1 and RhoA. These 20 mammalian members are subdivided in the Rac subfamily (Rac1, Rac2, Rac3, and RhoG), Cdc42 subfamily (Cdc42, TC10/RhoQ, TCL/RhoJ), the RhoUV family (RhoV/Chp and RhoU/Wrch-1/), RhoA subfamlly (RhoA, RhoB, and RhoC), the Rnd subfamily (Rnd1/Rho6, Rnd2/RhoN and Rnd3/RhoE), the RhoD subfamily (RhoD and RhoF/Rif), RhoBTB (RhoBTB1&2) and RhoH/TTF. Three general classes of regulators of Rho protein signaling have been identified: guanine nucleotide exchange factor (GEFs), GTPase-activating proteins (GAPs) and guanine nucleotide dissociation inhibitors (GDIs). GEFs activate Rho proteins by catalyzing the exchange of GDP for GTP. GAPs control the ability of the GTPase to hydrolyze GTP to GDP, controlling the natural rate of movement from the active conformation to the inactive conformation. GDI proteins form a large complex with the Rho protein, helping to prevent diffusion within the membrane and into the cytosol and thus acting as an anchor and allowing tight spatial control of Rho activation. In human, 82 GEF (71 Dbl-like and 11 DOCK-like ) control positively the activity of Rho members, while 66 GAP proteins control it negatively.