Abstract
Rho-associated kinases ROCK1 and ROCK2 are serine/threonine kinases that are downstream targets of the small GTPases RhoA, RhoB, and RhoC. ROCKs are involved in diverse cellular activities including actin cytoskeleton organization, cell adhesion and motility, proliferation and apoptosis, remodeling of the extracellular matrix and smooth muscle cell contraction. The role of ROCK1 and ROCK2 has long been considered to be similar; however, it is now clear that they do not always have the same functions. Moreover, depending on their subcellular localization, activation, and other environmental factors, ROCK signaling can have different effects on cellular function. With respect to the heart, findings in isoform-specific knockout mice argue for a role of ROCK1 and ROCK2 in the pathogenesis of cardiac fibrosis and cardiac hypertrophy, respectively. Increased ROCK activity could play a pivotal role in processes leading to cardiovascular diseases such as hypertension, pulmonary hypertension, angina pectoris, vasospastic angina, heart failure, and stroke, and thus ROCK activity is a potential new biomarker for heart disease. Pharmacological ROCK inhibition reduces the enhanced ROCK activity in patients, accompanied with a measurable improvement in medical condition. In this review, we focus on recent findings regarding ROCK signaling in the pathogenesis of cardiovascular disease, with a special focus on differences between ROCK1 and ROCK2 function.
Highlights
ROCK in the Cardiovascular System(Wen et al, 2008). ROCK1 and ROCK2 have the highest amino acid homology between their kinase domain (92%), and are most divergent within their coiled-coil domains with 55% homology
Rho-associated kinases ROCK1 and ROCK2 are serine/threonine kinases that are downstream targets of the small GTPases RhoA, RhoB, and RhoC
The function of both kinases has long been considered to be similar, it has become evident that in addition to common functions, they have different targets. Depending on their subcellular localization, activation and other environmental factors, ROCK signaling might lead to different effects on cellular function
Summary
(Wen et al, 2008). ROCK1 and ROCK2 have the highest amino acid homology between their kinase domain (92%), and are most divergent within their coiled-coil domains with 55% homology. The PH-C1 domains of ROCK1 and ROCK2 seem to have differential binding preferences for membrane lipids: the PH-C1 domain of ROCK2 was demonstrated to bind strongly to phosphatidylinositol (3,4,5)-trisphosphate and phosphatidylinositol (4,5)-bisphosphate, whereas the one of ROCK1 did not (Yoneda et al, 2005) This might partly explain why ROCK1 and ROCK2 were described to have distinct subcellular distributions, which vary, depending on the cell type and method. In human and mouse skeletal muscle a unique splice variant of ROCK2 was detected, named ROCK2m. This variant contains an insertion of 57 amino acids following the RBD, and is progressively expressed during myogenic differentiation together with ROCK2. Whether ROCK2m is differentially regulated, or has a different function to ROCK2 is not clear so far (Pelosi et al, 2007)
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