Rho-associated kinase

Bito H, Ishihara H, Shibasaki Y, Ohashi K, Mizuno K, Maekawa M, Ishizaki T, Narumiya S. A critical role for a Rho-associated kinase, pl60ROCK, in determining axon outgrowth in mammalian CNS neurons. Neuron 2000 26 431-441. 

Ca2+ entry, Ca2+-uptake into the SR by SERCA, Ca2+ extrusion from the cell and dephosphorylation of the myosin light chains. The t ype 1 phosphatase, myosin light chain phosphatase (MLCP) dephosphorylates myosin. As with MLCK its activity is physiologically regulated, e.g. its activity is decreased following phosphorylation via Rho associated kinase (Somlyo Somlyo 2000). In the uterus we have found a small but significant reduction of force, but not Ca2+ when Rho-associated kinase is inhibited (Kupittayanant et al 2001b). 

Kupittayanant S, Burdyga TV, Wray S 2001 The effects of inhibiting Rho-associated kinase with Y-27632 on force and intracellular calcium in human myometrium. Pfliiger s Arch 443 112-114... 

Amano M, Ito M, Kimura K, Fukata Y, CMhara K, Nakano T, Matsuura Y, Kaibuchi K (1996) Phosphorylation and activation of myosin by Rho-associated kinase (Rho-kinase). J Biol Chem 271 20246-20249... 

Ohashi K, Nagata K, Maekawa M, IshizaM T, Narumiya S, Mizuno K (2000) Rho-associated kinase ROCK activates LlM-kinase 1 by phosphorylation at threonine 508 within the activation loop. J Biol Chem 275 3577-3582... 

The interaction between RhoA and its key effector Rho-associated kinase (ROK or ROCK) is decreased upon RhoA phosphorylation, as shown by pull-down assays [71], and RhoA phosphorylation is also inversely correlated with signaling to its downstream effector phosphoh-pase D (PLD) [76,81]. However, not all effects of RhoA phosphorylation can be attributed to increased binding to RhoGDI leading to decreased signaling. RhoA expressed in bacteria (i.e., nonprenylated) and phosphorylated in vitro bound less efficiently to its downstream effector ROK in vitro than did nonphosphorylated RhoA [65]. Since this was done without any RhoGDI present, there must be something intrinsic about RhoA phosphorylation that affects RhoA interactions with at least some of its... 

Kikuchi A, Kuroda S, Sasaki T et al. (1992) Functional interactions of stimulatory and inhibitory GDP/GTP exchange proteins and their common substrate small GTP-binding protein. In J. Biol. Chem. 26iJ-. 14611-5 Kimura K, Ito M, Amano M etal. (1996) Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). In Science 273 245-8 Koch G, Norgauer J, Aktories K (1994) ADP-ribosylation of Rho by Clostridium limosum exoenzyme affects basal but not N-formyl-peptide-stimulated actin... 

Fig. 10.1 The network of LPA and SIP signaling through Gprotein-coupled receptors. Each LPA and SI Preceptor couples to their specific class of Gproteins. Ligand binding activates or inhibits downstream second messenger molecules, and the most prominent cellular effects are illustrated. Rock, Rho-associated kinase SRF, serum response factor IPS, inositol 1,4,5-trisphosphate PLC, phospholipase C DAG, diacylglycerol PKC, protein kinase C MAPK, mitogen-activated protein kinase PI3K, phosphoinositol 3-kinase DAG, diacylglycerol...

The pattern of activation and possible cross-talk between protein kinase C and Rho associated kinase dependent inhibition of the activity of MLCP is unknown. It appears that neither pathway can fully account for the GTP-dependent increase in Ca + sensitivity since neither inhibitors of protein kinase C including peptide inhibitors of atypical protein kinase C (Gailly et al. 1997) nor inactivation of Rho with exoenzyme C3 (Itagaki et al. 1995, Otto et al. 1996) completely inhibited the GTPyS-induced increase in Ca +-sensitivity.The different signalling pathways may be differently expressed and/or activated in different types of smooth muscle (e.g. intestinal versus arterial smooth muscle) and may also vary from species to species. 

Prior to the discovery of the role of RhoA and Rho-associated kinases, several other kinases, including protein kinase Cs (PKCs), tyrosine kinases and MAP kinase, have been implicated in Ca " -sensitization, based largely on the effects of agents that activate or inhibit them. 

Kowarski D, Shuman H, Somlyo AP, Somlyo AV (1985) Calcium release by noradrenaline from central sarcoplasmic reticulum in rabbit main pulmonary artery smooth muscle. J Physiol (London) 366 153-175 Kureishi Y, Kobayashi S, Amano M, Kimura K, Kanaide H, Nakano T, Kaibuchi K, Ito M. (1997) Rho-associated kinase directly induces smooth muscle contraction through myosin light chain phosphorylation. J Biol Chem 272 12257-12260 LaBelle EF, Murray BM (1990) Differences in inositol phosphate production in rat tail artery and thoracic artery. J Cell Physiol 144 391-400 LaBelle EF, Polydk E (1996) Phospholipase C p2 in vascular smooth muscle. J Cell Physiol 169 358-363... 

Matsui T, Amano M, Yamamoto T, Chihara K, Nakafuku M, Ito M, Nakano T, Okawa K, Iwamatsu A, Kaibuchi K. (1996) Rho-associated kinase, a novel serine/threonine kinase, as a putative target for the small GTP binding protein Rho. EMBO J 15 2208-2216... 

Wilson DP, Susnjar M, Kiss E, Sutherland C, Walsh MP (2005) Thromboxane A2-induced contraction of rat caudal arterial smooth muscle involves activation of Ca entry and Ca sensitization rho-associated kinase-mediated phosphorylation of MYPTl at Thr-855, but not Thr-697. Biochem J 389 763 774... 

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