[Rho-mediated signal transduction and its physiological roles]

Rho is a member of the Ras-related family of small molecular weight GTP-binding proteins, and Rho works as a molecular switch by shuttling between the GDP-bound inactive form and the GTP-bound active form. Rho is involved in cell motility, cell adhesion, and cytokinesis through the reorganization of the actin cytoskeleton. In addition to this, Rho also regulates Ras-induced transformation, transcriptional activation and cell cycle progression. These actions through the Rho signaling are mediated by downstream Rho effectors. Several putative Rho effectors including ROCK and mDia have been isolated on the basis of their selective binding to the GTP-bound form of Rho. Among them, the ROCK family of Rho-associated serine/threonine protein kinases inactivates myosin phosphatase and actin depolymerizing factor (cofilin/Destrin) to induce stabilization of filamentous actin and increase in the actomyosin-based contractility. mDia binds profilin likely to promote actin polymerization. Thus, these effectors are supposed to work in organization of the actin cytoskeleton. Furthermore, analyses using a ROCK specific inhibitor Y-27632 have suggested that the Rho-ROCK pathway works in contractions of vascular smooth muscles and is involved in malignant cell transformation and tumor invasion and metastasis.