Small GTPases of the Rho family and cell transformation.

Abstract

The Rho GTPases form a distinct subgroup of the Ras superfamily of low molecular weight GTP binding proteins. These proteins are implicated in signal transduction leading to changes in membrane structures and cytoskeletal reorganisation associated with changes in cell shape. Like other Ras-related proteins, Rho GTPases are thought to adopt either an active GTP-bound conformational state or an inactive GDP-bound state. Although cycling between these states is controlled by several regulatory proteins, mutations in Rho proteins can favour a specific status: an asparagine substitution in Rho at a position homologous to Ras threonine 17leads to a drop in its affinity for GTP. This mutated protein acts as an inhibitor by sequestering positive regulatory factors, thereby preventing activation of the endogenous Rho GTPase. Conversely, substitutions of residues similar to those found in oncogenic Ras proteins (e.g. G12V or Q61L) leads to constitutively active Rho proteins, due to a reduced GTP hydrolysis. Once loaded with GTP, the GTPase gains the ability to bind cognate effector downstream targets, which converts the input signal into a specific set of activations.