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Rho-associated protein kinase (ROCK) is a kinase belonging to the AGC (PKA/ PKG/PKC) family of serine-threonine kinases. It is involved mainly in regulating the shape and movement of cells by acting on the cytoskeleton. ROCKs (ROCK1 and ROCK2) occur in mammals (human, rat, mouse, cow), zebrafish, Xenopus, invertebrates (C. elegans, Mosquito, Drosophila) and chicken. Human ROCK1 has a molecular mass of 158 kDa and is a major downstream effector of the small GTPase RhoA. Mammalian ROCK consists of a kinase domain, a coiled-coil region and a Pleckstrin homology (PH) domain, which reduces the kinase activity of ROCKs by an autoinhibitory intramolecular fold if RhoA-GTP is not present. Rat ROCKs were discovered as the first effectors of Rho and they induce the formation of stress fibers and focal adhesions by phosphorylating MLC (myosin light chain). Due to this phosphorylation, the actin binding of myosin II and, thus, the contractility increases. Two mouse ROCK isoforms ROCK1 and ROCK2 have been identified. ROCK1 is mainly expressed in the lung, liver, spleen, kidney and testis. However, ROCK2 is distributed mostly in the brain and heart. 〔〔 ==Function== ROCK plays a role in a wide range of different cellular phenomena, as ROCK is a downstream effector protein of the small GTPase Rho, which is one of the major regulators of the cytoskeleton. 1. ROCK is a key regulator of actin organization and thus a regulator of cell migration as follows: Different substrates can be phosphorylated by ROCKs, including LIM kinase, myosin light chain (MLC) and MLC phosphatase. These substrates, once phosphorylated, regulate actin filament organization and contractility as follows:〔 *Amount of actin filaments ROCK inhibits the depolymerization of actin filaments indirectly: ROCK phosphorylates and activates LIM kinase, which in turn phosphorylates ADF/cofilin, thereby inactivating its actin-depolymerization activity. This results in the stabilization of actin filaments and an increase in their numbers. Thus, over time actin monomers that are needed to continue actin polymerization for migration become limited. The increased stable actin filaments and the loss of actin monomers contribute to a reduction of cell migration.〔 *Cellular contractility ROCK also regulates cell migration by promoting cellular contraction and thus cell-substratum contacts. ROCK increases the activity of the motor protein myosin II by two different mechanisms: : *Firstly, phosphorylation of the myosin light chain (MLC) increases the myosin II ATPase activity. Thus several bundled and active myosins, which are asynchronously active on several actin filaments, move actin filaments against each other, resulting in the net shortenting of actin fibres. : *Secondly, ROCK inactivates MLC phosphatase, leading to increased levels of phosphorylated MLC. Thus in both cases, ROCK activation by Rho induces the formation of actin stress fibers, actin filament bundles of opposing polarity, containing myosin II, tropomyosin, caldesmon and MLC-kinase, and consequently of focal contacts, which are immature integrin-based adhesion points with the extracellular substrate.〔 2. Other functions and targets *RhoA-GTP stimulates the phospholipid phosphatase activity of PTEN (phosphatase and tensin homologue), a human tumor suppressor protein. This stimulation seems to depend on ROCK. In this way, PTEN is important to prevent uncontrolled cell division as is exhibited in cancer cells. *ROCK plays an important role in cell cycle control, it seems to inhibit the premature separation of the two centrioles in G1, and is proposed to be required for contraction of the cleavage furrow, which is necessary for the completion of cytokinesis.〔 *ROCKs also seem to antagonize the insulin signaling pathway, resulting in a reduction of cell size and influence cell fate.〔 *ROCKS play a role in membrane blebbing, a morphological change seen in cells committed to apoptosis. The pro-apoptotic protease, caspase 3, activates ROCK kinase activity by cleaving the C-terminal PH domain. As a result, the autoinhibitory intramolecular fold of ROCK is abolished. ROCK also regulates MLC phosphorylation and actomyosin contractility, which regulate membrane blebbing.〔 *ROCKs contribute to neurite retraction by inducing growth cone collapse by activating actomyosin contractility. It is also possible that phosphorylation of collapsin response mediator protein-2 (CRMP2) by ROCK inhibits CRPM2 function of promoting axon outgrowth, resulting in growth cone collapse.〔 *ROCKs regulate cell-cell adhesion: Loss of ROCK activity seems to lead to loss of tight junction integrity in endothelial cells. In epithelial cells inhibition of ROCK seems to decrease tight junction integrity. Active ROCK in these cells seems to stimulate the disruption of E-Cadherin-mediated cell-cell contacts by activating actomyosin contractility.〔 3. Other ROCK targets *NHE1 (a sodium hydrogen exchanger, involved in focal adhesions and actin organisation) *intermediate filament proteins: Vimentin, GFAP (glial fibrillaric acidic protein), NF-L (neurofilament L protein) *F-actin binding proteins: Adducin, EF-1&alpha (elongation factor, translation co-factor), MARCKS (myristylated alanine-rich C kinase substrate), Caponin (unknown function), and ERM (involved in linkage of the actin cytoskelton to the plasma membrane). 抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』 ■ウィキペディアで「Rho-associated protein kinase」の詳細全文を読む スポンサード リンク
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