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      Rho-Kinase/ROCK: A Key Regulator of the Cytoskeleton and Cell Polarity

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          Abstract

          Rho-associated kinase (Rho-kinase/ROCK/ROK) is an effector of the small GTPase Rho and belongs to the AGC family of kinases. Rho-kinase has pleiotropic functions including the regulation of cellular contraction, motility, morphology, polarity, cell division, and gene expression. Pharmacological analyses have revealed that Rho-kinase is involved in a wide range of diseases such as vasospasm, pulmonary hypertension, nerve injury, and glaucoma, and is therefore considered to be a potential therapeutic target. This review focuses on the structure, function, and modes of activation and action of Rho-kinase.

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          Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase.

          M. Maekawa, T Ishizaki, S Boku … (1999)
          The actin cytoskeleton undergoes extensive remodeling during cell morphogenesis and motility. The small guanosine triphosphatase Rho regulates such remodeling, but the underlying mechanisms of this regulation remain unclear. Cofilin exhibits actin-depolymerizing activity that is inhibited as a result of its phosphorylation by LIM-kinase. Cofilin was phosphorylated in N1E-115 neuroblastoma cells during lysophosphatidic acid-induced, Rho-mediated neurite retraction. This phosphorylation was sensitive to Y-27632, a specific inhibitor of the Rho-associated kinase ROCK. ROCK, which is a downstream effector of Rho, did not phosphorylate cofilin directly but phosphorylated LIM-kinase, which in turn was activated to phosphorylate cofilin. Overexpression of LIM-kinase in HeLa cells induced the formation of actin stress fibers in a Y-27632-sensitive manner. These results indicate that phosphorylation of LIM-kinase by ROCK and consequently increased phosphorylation of cofilin by LIM-kinase contribute to Rho-induced reorganization of the actin cytoskeleton.
          Article 0 comments Cited 340 times – based on 0 reviews     Review now
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            Phosphorylation and activation of myosin by Rho-associated kinase (Rho-kinase).

            Megumi K. Kimura, K Chihara, Kori Matsuura … (1996)
            The small GTPase Rho is implicated in physiological functions associated with actin-myosin filaments such as cytokinesis, cell motility, and smooth muscle contraction. We have recently identified and molecularly cloned Rho-associated serine/threonine kinase (Rho-kinase), which is activated by GTP Rho (Matsui, T., Amano, M., Yamamoto, T., Chihara, K., Nakafuku, M., Ito, M., Nakano, T., Okawa, K., Iwamatsu, A., and Kaibuchi, K. (1996) EMBO J. 15, 2208-2216). Here we found that Rho-kinase stoichiometrically phosphorylated myosin light chain (MLC). Peptide mapping and phosphoamino acid analyses revealed that the primary phosphorylation site of MLC by Rho-kinase was Ser-19, which is the site phosphorylated by MLC kinase. Rho-kinase phosphorylated recombinant MLC, whereas it failed to phosphorylate recombinant MLC, which contained Ala substituted for both Thr-18 and Ser-19. We also found that the phosphorylation of MLC by Rho-kinase resulted in the facilitation of the actin activation of myosin ATPase. Thus, it is likely that once Rho is activated, then it can interact with Rho-kinase and activate it. The activated Rho-kinase subsequently phosphorylates MLC. This may partly account for the mechanism by which Rho regulates cytokinesis, cell motility, or smooth muscle contraction.
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              Rho GTPases Control Polarity, Protrusion, and Adhesion during Cell Movement

              Catherine Nobes, Alan Hall (1999)
              Cell movement is essential during embryogenesis to establish tissue patterns and to drive morphogenetic pathways and in the adult for tissue repair and to direct cells to sites of infection. Animal cells move by crawling and the driving force is derived primarily from the coordinated assembly and disassembly of actin filaments. The small GTPases, Rho, Rac, and Cdc42, regulate the organization of actin filaments and we have analyzed their contributions to the movement of primary embryo fibroblasts in an in vitro wound healing assay. Rac is essential for the protrusion of lamellipodia and for forward movement. Cdc42 is required to maintain cell polarity, which includes the localization of lamellipodial activity to the leading edge and the reorientation of the Golgi apparatus in the direction of movement. Rho is required to maintain cell adhesion during movement, but stress fibers and focal adhesions are not required. Finally, Ras regulates focal adhesion and stress fiber turnover and this is essential for cell movement. We conclude that the signal transduction pathways controlled by the four small GTPases, Rho, Rac, Cdc42, and Ras, cooperate to promote cell movement.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cytoskeleton (Hoboken)
                Journal ID (publisher-id): cm
                Title: Cytoskeleton (Hoboken, N.j.)
                Publisher: John Wiley & Sons, Inc.
                ISSN (Print): 1949-3584
                ISSN (Electronic): 1949-3592
                Publication date (Print): September 2010
                Publication date (Electronic): 10 August 2010
                Volume: 67
                Issue: 9
                Pages: 545-554
                Affiliations
                [1 ]simpleDepartment of Cell Pharmacology, Graduate School of Medicine, Nagoya University 65 Tsurumai, Showa-ku, Nagoya 466-8550, Japan
                [2 ]simpleDepartment of Tissue Morphogenesis, Max-Planck-Institute for Molecular Biomedicine Roentgenstrasse 20 48149 Muenster, Germany
                [3 ]simpleJapan Science and Technology Agency CREST, 4-1-8, Honcho, Kawaguchi 332-0012, Japan
                Author notes
                *Address correspondence to: Kozo Kaibuchi, Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, 65 Tsurumai, Showa-ku, Nagoya 466-8550, Japan or Japan Science and Technology Agency, CREST, 4-1-8, Honcho, Kawaguchi 332-0012, Japan. E-mail: kaibuchi@ 123456med.nagoya-u.ac.jp

                Monitoring Editor: Pekka Lappalainen

                Article
                DOI: 10.1002/cm.20472
                PMC ID: 3038199
                PubMed ID: 20803696
                SO-VID: ee2bbbcc-46bd-4c67-98ce-79a8e54b8d7b
                Copyright © Copyright © 2010 Wiley-Liss, Inc., A Wiley Company
                License:

                Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

                History
                Date received : 24 February 2010
                Date revision received : 07 July 2010
                Date accepted : 13 July 2010
                Categories
                Subject: Review Article

                ScienceOpen disciplines: Cell biology
                Keywords: rho,kinase,polarity,actomyosin,cytoskeleton
                Data availability:
                ScienceOpen disciplines: Cell biology
                Keywords: rho, kinase, polarity, actomyosin, cytoskeleton

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