Function and regulation of Rnd proteins

Key Points The three Rnd proteins appeared late in evolution (in vertebrates) and are Rho-family proteins with unusual biochemical properties. They do not cycle between GDP (inactive) and GTP (active) states, but are constitutively active (GTP bound). Because Rnd proteins are constitutively active and do not cycle, they are regulated by other mechanisms, including expression levels, localization, phosphorylation and degradation. Rnd proteins have effects antagonistic to Rho, and they inhibit the formation of contractile acto-myosin cables (stress fibres). Rnd proteins are expressed in neurons where they participate in the extension of growth cones. Rnd proteins are involved in axon guidance and interact with plexins (the semaphorin receptors) to modulate downstream pathways. Rnd proteins are also involved in fibroblast-growth-factor-receptor-1 signalling. Rnd3 overexpression blocks cell-cycle progression, and Rnd3 protein expression is frequently decreased in prostate and breast cancer. However, increased expression of Rnd3 has also been observed in cancers with a constitutively active Ras–Raf pathway. Additional studies are required to understand the basis for these apparent discrepancies. Further studies in animal models are needed to investigate the roles of Rnd proteins in brain development, and a more precise understanding of the functions of Rnd partners is required. A role in axonal regeneration of injured nerve cells is another exciting possibility. The Rnd proteins, which form a distinct sub-group of the Rho family of small GTP-binding proteins, have been shown to regulate the organization of the actin cytoskeleton in several tissues. In the brain, they participate in neurite extension, whereas in smooth muscle, they modulate contractility. Recent evidence has shown that Rnd3 (RhoE) is also involved in the regulation of cell-cycle progression and transformation, indicating that these proteins might have other, as yet unexplored roles.