The Small GTPase Rho: Cellular Functions and Signal Transduction

Rho, a Ras homologue of small GTPase, is present from yeast to mammals. It shuttles between the active GTP-bound form and the inactive GDP-bound form and works as a switch in stimulus-evoked cell adhesion and motility, enhancement of contractile responses, and cytokinesis. In these actions, Rho directs the reorganization of the actin cytoskeleton at a specific time and at a specific site in the cell. It also activates serum response factor possibly via a kinase cascade and mediates a growth signal to nuclei. Two signalling processes are known to lead to Rho activation: one is activation of certain types of G-protein-coupled receptors such as lysophosphatidic acid receptor, and the other is activation of other small GTPases including Ras, CDC42, and Rac. Molecules catalyzing the GDP-GTP exchange of Rho, Rho guanine nucleotide exchange factors (Rho GEF), and those catalyzing the acceleration of GTP hydrolysis, Rho GTPase activating proteins (Rho GAP), were identified as Dbl- and Bcr-containing molecules, respectively. In addition, a molecule inhibiting guanine nucleotide exchange of Rho, Rho guanine nucleotide dissociation inhibitor (Rho-GDI), was isolated and characterized. More recently, putative Rho targets possibly mediating various Rho actions have been identified by their selective interaction with GTP-bound Rho. They include lipid kinases such as phosphatidyl-inositol-5-kinase and protein serine/threonine kinases such as PKN and p160ROCK. A model of the molecular mechanism of action of Rho constructed on the basis of these findings is presented. There are, however, still many unclarified links between cell stimulation, Rho activation and final Rho actions.