Rho–Rho-kinase pathway in smooth muscle contraction and cytoskeletal reorganization of non-muscle cells

doi:10.1016/S0165-6147(00)01596-0

Trends in Pharmacological Sciences

Volume 22, Issue 1, 1 January 2001, Pages 32-39

https://doi.org/10.1016/S0165-6147(00)01596-0 Get rights and content

Abstract

Hypercontraction or abnormal contraction of vascular smooth muscle is a major cause of diseases such as hypertension and vasospasm of the coronary and cerebral arteries. A better understanding of the mechanism of regulation of smooth muscle contraction should lead to improved treatments for such diseases. Recent studies have revealed important roles for the small GTPase Rho and its effector, Rho-associated kinase (Rho kinase) in Ca²⁺-independent regulation of smooth muscle contraction. The Rho–Rho-kinase pathway modulates the level of phosphorylation of the myosin light chain of myosin II, mainly through inhibition of myosin phosphatase, and contributes to agonist-induced Ca²⁺-sensitization in smooth muscle contraction. Rho–Rho-kinase mechanisms also participate in a variety of the cellular functions of non-muscle cells, such as stress-fibre formation, cytokinesis and cell migration. This review summarizes the role of the Rho–Rho-kinase pathway in contractile processes of smooth muscle and in non-muscle cell functions, and the pathophysiological implications of this pathway.

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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Trends in Pharmacological Sciences

ReviewRho–Rho-kinase pathway in smooth muscle contraction and cytoskeletal reorganization of non-muscle cells

Abstract

Section snippets

Regulation of Rho activity

Rho-kinase and the myosin-binding subunit: specific effectors of Rho

Rho and Ca2+-sensitization

Concluding remarks

Acknowledgments

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Nature

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Review
Rho–Rho-kinase pathway in smooth muscle contraction and cytoskeletal reorganization of non-muscle cells

Rho and Ca²⁺-sensitization