ROCK and Rho: Biochemistry and Neuronal Functions of Rho-Associated Protein Kinases

Abstract

Rho-associated protein kinases (ROCKs) play key roles in mediating the control of the actin cytoskeleton by Rho family GTPases in response to extracellular signals. Such signaling pathways contribute to diverse neuronal functions from cell migration to axonal guidance to dendritic spine morphology to axonal regeneration to cell survival. In this review, the authors summarize biochemical knowledge of ROCK function and categorize neuronal ROCK-dependent signaling pathways. Further study of ROCK signal transduction mechanisms and specificities will enhance our understanding of brain development, plasticity, and repair. The ROCK pathway also provides a potential site for therapeutic intervention to promote neuronal regeneration and to limit degeneration. KeywordsRho GTPase; Cytoskeleton; Rho-associated kinase; Signal transduction; Axonal outgrowthThe cytoplasmic Rho family of GTPases plays a critical role in regulating actin microfilament dynamics. The control of cell shape and cell migration by Rho GTPases has attracted intense interest from the fields of cancer biology and cardiovascular medicine. More recently, it has become clear that Rho family proteins and their intracellular effectors participate in a range of neuronal functions from axonal growth to neuronal differentiation to neuronal survival to regeneration.The Rho-associated kinases (ROCKs) are principal mediators of RhoA activity, especially in the nervous system, and are the focus of this review. We explore current knowledge regarding the downstream targets and functions of ROCKs. In addition, we summarize known transduction mechanisms from extracellular neuronal signals to ROCK. By analyzing the upstream receptors, effectors, and mediators of Rho GTPase-related neuronal morphogenesis, we group these pathways functionally and biochemically. Rho-GTPasesBy sequence homology, the Ras-superfamily of GTPases can be subdivided into 9 families: Ras, Rab, Arf, Ran, Rad, Rheb, Rag, Rit and Rho (Blumenstein 2004 RhoA (Structure and Posttranslational Modification)Here, we focus on RhoA, a small GTPase of about 24 kDa (Kamai and others 2004) that has been extensively studied. This protein's CAAX-box is composed of the amino acids cysteine (C), leucine (L), valine (V), and leucine (L). Mutation of the X-amino acid of a ras peptide to leucine (Seabra and others 1991), as well as the examination of a variety of small guanine nucleotide binding proteins in which X = leucine or phenylalanine (Kawata and others 1990; Maltese and others 1990; Buss and others 1991; Yamane and others 1991; Leung and others 2007), revealed that these amino acids specify prenylation with geranylgeranyl by protein geranylgeranyltransferase type 1. In Rho family proteins where X = serine, methionine, glutamine, or alanine, prenylation is catalyzed by protein farnesyl transferase to add a farnesyl group. As predicted by its sequence, RhoA is modified by a thioether linkage of C20 geranylgeranyl to the COOH-terminal cysteine residue ( Figure 2.Although the two ROCK isoforms share 65%...

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