Rho-associated coiled-coil containing kinases (ROCK): structure, regulation, and functions

Abstract

Rho-associated coiled-coil containing kinases (ROCK) were originally identified as effectors of the RhoA small GTPase. (1)(-) (5) They belong to the AGC family of serine/threonine kinases (6) and play vital roles in facilitating actomyosin cytoskeleton contractility downstream of RhoA and RhoC activation. Since their discovery, ROCK kinases have been extensively studied, unveiling their manifold functions in processes including cell contraction, migration, apoptosis, survival, and proliferation. Two mammalian ROCK homologs have been identified, ROCK1 (also called ROCK I, ROKβ, Rho-kinase β, or p160ROCK) and ROCK2 (also known as ROCK II, ROKα, or Rho kinase), hereafter collectively referred to as ROCK. In this review, we will focus on the structure, regulation, and functions of ROCK.

Keywords: ROCK; Rho; actin; cytoskeleton; kinase; myosin; phosphorylation; signal transduction.

Figures

Figure 1. ROCK functional domains. Protein domains and their indicated positions were taken from the National Center for Biotechnology Information (NCBI; http://www.ncbi.nlm.nih.gov/protein) for human ROCK1 (NP_005397.1) and ROCK2 (NP_004841.2)

Figure 2. Modes of ROCK activation. In the inactive state, the carboxyl terminal of ROCK acts as an auto-inhibitory region. Binding of active Rho-GTP to the Rho binding domain (RBD) disrupts the negative regulation, thus activating the kinase. ROCK proteins may also be activated in a Rho-independent manner by removal of the inhibitory carboxyl terminal of ROCK1 and ROCK2 by caspase 3 or granzyme B mediated cleavage, respectively.

Figure 3. Tissue distribution of ROCK1 and ROCK2 determined from expressed sequence tags (EST). Relative expression levels were derived from the Tissue-specific Gene Expression and Regulation (TiGer) database (http://bioinfo.wilmer.jhu.edu/tiger). The expression levels were normalized with tissue-library size. Each value for a gene in a tissue is a ratio of observed ESTs to the expected one in this tissue. The expected number of ESTs is the product of total ESTs of the gene and the fraction of total ESTs in the tissue among all ESTs in 30 tissues. To depict tissue expression profiles, the normalized expression levels were graphed as percentages from only those tissues having values > 0.