Trends in Pharmacological Sciences
ReviewRho–Rho-kinase pathway in smooth muscle contraction and cytoskeletal reorganization of non-muscle cells
Section snippets
Regulation of Rho activity
At least ten members of the Rho family of GTPases are present in mammals: Rho (isoforms A–E, and G), Rac (isoforms 1 and 2), Cdc42 and TC10. Rho, Rac1 and Cdc42 have been the most intensively characterized 14. The effector domains of RhoA, RhoB and RhoC (collectively referred to here as Rho) have the same amino acid sequence, and these GTPases appear to have similar cellular functions. Most of the functions of Rho described below are based on studies of RhoA. Like other GTP-binding proteins,
Rho-kinase and the myosin-binding subunit: specific effectors of Rho
Rho is involved in the regulation of stress-fibre and focal-adhesion formation, cell morphology, cell aggregation, cadherin-mediated cell–cell adhesion, cell motility, cytokinesis, membrane ruffling, neurite retraction, microvilli formation and smooth muscle contraction 18., 19., 20.. Several proteins have been identified as effectors of Rho, including protein kinase N [PKN (PRK1)], Rho-kinase, the myosin-binding subunit (MBS) of myosin phosphatase, rhophilin, rhotekin, citron, p140 mDia and
Rho and Ca2+-sensitization
The role of Rho in agonist-induced Ca2+-sensitization in smooth muscle has been elucidated. Thus, the Ca2+-sensitizing effect of agonists or GTPγS (a non-hydrolysable GTP analogue) are blocked completely by inhibitory toxins specific for Rho, such as Clostridium botulinum C3 and Staphylococcal toxin EDIN (epidermal differentiation inhibitor) 8., 9., and the introduction of GTPγS–Rho or the constitutively active form of Rho into permeabilized smooth muscle cells induces Ca2+-sensitization 8., 9.
Concluding remarks
The discovery of Rho effectors has contributed to an understanding of the signalling pathway in which Rho regulates a diverse array of cellular functions. It is now known that the Rho–Rho-kinase pathway is essential for smooth muscle contraction. In addition, this pathway is involved in cytokinesis, cell morphology, cell migration and invasion via the phosphorylation of various proteins. By using probes that specifically inhibit the activity of Rho-kinase, it has been shown that, in animal
Acknowledgments
Owing to constraints in the number of references that can be cited, we are unable to cite many studies of our colleagues, who have made important contributions to this field. We would like to thank M. Ito, A. Iwamatsu, M. Inagaki, N. Inagaki, M. Ikebe, M. Shibata, Y. Matsuura, H. Shimokawa, F. Matsumura, K. Katoh, K. Fujiwara and T. Nakamura for their collaboration. The work in our laboratory was supported by grants-in-aid for scientific research from the Ministry of Education, Science, and
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