Molecular Structures, Cellular Functions, and Physiological Roles of Rho Effectors
Rho GTPase is a regulator controlling the cytoskeleton in multiple contexts such as cell migration, adhesion, and cytokinesis. Upon binding to GTP, Rho exerts its functions through downstream Rho effectors such as ROCK/Rho-kinase/ROK, mDia, Citron, PKN, R
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Molecular Structures, Cellular Functions, and Physiological Roles of Rho Effectors Toshimasa Ishizaki and Shuh Narumiya
Abstract Rho GTPase is a regulator controlling the cytoskeleton in multiple contexts such as cell migration, adhesion, and cytokinesis. Upon binding to GTP, Rho exerts its functions through downstream Rho effectors such as ROCK/Rhokinase/ROK, mDia, Citron, PKN, Rhophilin, and Rhotekin. Our knowledge about the functions of Rho effectors has accumulated since their discoveries in the mid-1990s through in vitro studies using heterologous expression in cultured cells and in vivo studies using gene targeting strategy as well as pharmaceutical intervention. In this chapter, we summarize findings obtained by these studies and discuss their implications. Keywords Actin cytoskeleton • Rho • Rock (Rho-kinase) • mDia • PKN • Rhophilin • Rhotekin • In vitro functions
16.1
ROCK
16.1.1 Molecular Structure, Isoforms, Activity, and Activation Mechanism ROCK/Rho-kinase/ROK is the best characterized of the Rho effectors. It belongs to the AGC family of serine/threonine kinases (Ishizaki et al. 1996; Leung et al. 1995; Matsui et al. 1996; Nakagawa et al. 1996) and contains two members, ROCK1 (also T. Ishizaki Department of Pharmacology, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama, Yufu, Oita 879-5593, Japan S. Narumiya (*) Center for Innovation in Immunoregulative Technology and Therapeutics, Kyoto University Graduate School of Medicine, Kyoto, Shogoin Kawara-cho, Sakyo-ku, Kyoto 606-8507, Japan e-mail: [email protected] A. Wittinghofer (ed.), Ras Superfamily Small G Proteins: Biology and Mechanisms 1, DOI 10.1007/978-3-7091-1806-1_16, © Springer-Verlag Wien 2014
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referred to as Rho-kinaseβ/ROKβ) and ROCK2 (also referred to as Rho-kinaseα/ ROKα). ROCK1 and ROCK2 transcripts are ubiquitously but differentially expressed in tissues. ROCK1 is preferentially expressed in the lung, liver, spleen, kidney, and testis, whereas ROCK2 is most highly expressed in the brain and heart (Nakagawa et al. 1996). Both kinases are composed of the N-terminal kinase domain followed by the central coiled-coil domain containing a Rho-binding domain (RBD) and the C-terminal pleckstrin-homology (PH) domain with an internal cysteine-rich domain (Fig. 16.1). The two isoforms share 65 % overall homology and 92 % identity in the kinase domain (Ishizaki et al. 1996; Leung et al. 1995; Matsui et al. 1996; Nakagawa et al. 1996). The active form of Rho directly binds to the C-terminal region of the coiled-coil domain of ROCK, leading to activation of the catalytic activity of ROCK. Studies of structural analysis revealed that eliciting the kinase activity of ROCK requires both N- and C-terminal extension segments in addition to its core catalytic domain (Fig. 16.1). These segments contribute to dimer formation of ROCK, keeping its catalytic domain in an active conformation (Jacobs et al. 2006; Yamaguchi et al. 2006). Besides binding to the active form of Rho, ROCKs are activated
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