関: Rho-associated kinase

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the 18th letter of the Roman alphabet (同)r
the 17th letter of the Greek alphabet
an enzyme that catalyzes the conversion of a proenzyme to an active enzyme
the basic unit of money in Papua New Guinea

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resistance / 17歳以下父兄同伴映画の表示 / rook
ロウ(ギリシア語アルファベットの17番目Ρ,ρ;英語のR,rに相当)
rhodiumの化学記号

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2012/10/26 17:18:24」(JST)

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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 mainly involved 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.^[1]^[2]

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).^[3] 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. ^[1]^[2]^[4]

Function

Fig.1 Role and Regulation of ROCK

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 organisation and contractility as follows:^[2]

Amount of actin filaments

ROCK inhibits the depolymerisation 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.^[2]^[5]

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 fibres, 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]^[6]

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.^[7]^[8] 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.^[2]^[9]^[10]^[11]^[12]^[13]

ROCKs also seem to antagonize the insulin signaling pathway resulting in a reduction of cell size and influence cell fate.^[2]
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 regulates also MLC phosphorylation and actomyosin contractility which regulate membrane blebbing.^[2]
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.^[2]
ROCKs regulate cell-cell adhesion: Loss of ROCK activity seems to lead to loss of tight junction integrity in endothelial cells. However 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.^[2]

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).

Homologues

The two mouse ROCK isoforms ROCK1 and ROCK2 have high homology. They have 65% amino acid sequences in common and 92% homology within their kinase domains. ^[1] ^[4]

ROCKs are homologous to other metazoan kinases such as myotonic dystrophy kinase (DMPK), DMPK-related cell division control protein 42 (Cdc42)-binding kinases (MRCK) and citron kinase. All of theses kinases are composed of a N-terminal kinase domain, a coiled-coil structure and other functional motifs at the C-terminus ^[2]

Regulation

ROCK is a downstream effector molecule of the Rho GTPase Rho which increases ROCK kinase activity when bound to it.

Autoinhibition

ROCK activity is regulated by the disruption of an intramolecular autoinhibition. The structure of ROCK proteins generally consists of an N-terminal kinase domain, a coiled-coiled region and a PH domain containing a cystein-rich domain (CRD) at the C-terminal. A Rho-binding domain (RBD) is located in close proximity just in front of the PH domain.

The kinase activity is inhibited by the intramolecular binding between the C-terminal cluster of RBD domain and the PH domain to the N-terminal kinase domain of ROCK. Thus the kinase activity is off when ROCK is intramoleculary folded. The kinase activity is switched on when Rho-GTP binds to the Rho-binding domain of ROCK, disrupting the autoinhibitory interaction within ROCK, which liberates the kinase domain because ROCK is then no longer intramolecularly folded.^[2]

Other regulators

It has also been shown that Rho is not the only activator of ROCK. ROCK can also be regulated by lipids, in particular arachidonic acid, and protein oligomerization which induces N-terminal transphosphorylation.^[2]

Disease

Recent research has shown that ROCK signaling plays an important role in many diseases including diabetes, neurodegenerative diseases, pulmonary hypertension^[14] and cancer. It has been shown to be involved in causing tissue thickening and stiffening around tumours in a mouse model of skin cancer, principally by increasing the amount of collagen in the tissue around the tumour.^[15]

Researchers are developing ROCK inhibitors for treating disease. For example, such drugs could potentially prevent cancer from spreading by blocking cell migration, stopping cancer cells from spreading into neighbouring tissue.^[1]

References

^ ^a ^b ^c ^d Hahmann C, Schroeter T (2010). "Rho-kinase inhibitors as therapeutics: from pan inhibition to isoform selectivity". Cell Mol Life Sci 67 (2): 171–7. doi:10.1007/s00018-009-0189-x. PMID 19907920.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m Riento K, Ridley AJ (2003). "Rocks: multifunctional kinases in cell behaviours". Nat Rev Mol Cell Biol 4 (6): 446–56. doi:10.1038/nrm1128. PMID 12778124.
^ Leung T, Chen XQ, Manser E, Lim L (October 1996). "The p160 RhoA-binding kinase ROK alpha is a member of a kinase family and is involved in the reorganization of the cytoskeleton". Mol. Cell. Biol. 16 (10): 5313–27. PMC 231530. PMID 8816443. //www.ncbi.nlm.nih.gov/pmc/articles/PMC231530/.
^ ^a ^b Nakagawa O, Fujisawa K, Ishizaki T, Saito Y, Nakao K, Narumiya S (August 1996). "ROCK-I and ROCK-II, two isoforms of Rho-associated coiled-coil forming protein serine/threonine kinase in mice". FEBS Lett. 392 (2): 189–93. doi:10.1016/0014-5793(96)00811-3. PMID 8772201.
^ Maekawa M, Ishizaki T, Boku S, et al. (August 1999). "Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase". Science 285 (5429): 895–8. doi:10.1126/science.285.5429.895. PMID 10436159.
^ Wang Y, Zheng XR, Riddick N, et al. (February 2009). "ROCK Isoform Regulation of Myosin Phosphatase and Contractility in Vascular Smooth Muscle Cells". Circ. Res. 104 (4): 531–40. doi:10.1161/CIRCRESAHA.108.188524. PMC 2649695. PMID 19131646. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2649695/.
^ Li Z, Dong X, Dong X, et al. (April 2005). "Regulation of PTEN by Rho small GTPases". Nat. Cell Biol. 7 (4): 399–404. doi:10.1038/ncb1236. PMID 15793569.
^ "Entrez Gene: PTEN phosphatase and tensin homolog (mutated in multiple advanced cancers 1)". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5728.
^ Gao SY, Li CY, Chen J, et al. (2004). "Rho-ROCK signal pathway regulates microtubule-based process formation of cultured podocytes--inhibition of ROCK promoted process elongation". Nephron Exp. Nephrol. 97 (2): e49–61. doi:10.1159/000078406. PMID 15218323.
^ Drechsel DN, Hyman AA, Hall A, Glotzer M (January 1997). "A requirement for Rho and Cdc42 during cytokinesis in Xenopus embryos". Curr. Biol. 7 (1): 12–23. doi:10.1016/S0960-9822(06)00023-6. PMID 8999996.
^ Kosako H, Yoshida T, Matsumura F, Ishizaki T, Narumiya S, Inagaki M (December 2000). "Rho-kinase/ROCK is involved in cytokinesis through the phosphorylation of myosin light chain and not ezrin/radixin/moesin proteins at the cleavage furrow". Oncogene 19 (52): 6059–64. doi:10.1038/sj.onc.1203987. PMID 11146558.
^ Yasui Y, Amano M, Nagata K, et al. (November 1998). "Roles of Rho-associated Kinase in Cytokinesis; Mutations in Rho-associated Kinase Phosphorylation Sites Impair Cytokinetic Segregation of Glial Filaments". J. Cell Biol. 143 (5): 1249–58. doi:10.1083/jcb.143.5.1249. PMC 2133074. PMID 9832553. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2133074/.
^ Piekny AJ, Mains PE (June 2002). "Rho-binding kinase (LET-502) and myosin phosphatase (MEL-11) regulate cytokinesis in the early Caenorhabditis elegans embryo". J. Cell. Sci. 115 (Pt 11): 2271–82. PMID 12006612.
^ Dahal BK, Kosanovic D et al. (2010). "Therapeutic efficacy of azaindole-1 in experimental pulmonary hypertension". European Respiratory Journal 36(4):808-18 (4): 808–18. doi:10.1183/09031936.00140309. PMID 20530035. http://erj.ersjournals.com/content/36/4/808.abstract.
^ Samuel, MS.; Lopez, JI.; McGhee, EJ.; Croft, DR.; Strachan, D.; Timpson, P.; Munro, J.; Schröder, E. et al. (Jun 2011). "Actomyosin-mediated cellular tension drives increased tissue stiffness and β-catenin activation to induce interfollicular epidermal hyperplasia and tumor growth". Cancer Cell 19 (6): 776–91. doi:10.1016/j.ccr.2011.05.008. PMC 3115541. PMID 21665151. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3115541/.

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English Journal

Gene variations of ROCKs and risk of ischaemic stroke: the Women's Genome Health Study.

Zee RY, Wang QM1, Chasman DI2, Ridker PM2, Liao JK3.Author information 1‡Spaulding Rehabilitation Hospital and Harvard Medical School, Boston, MA 02129, U.S.A.2*Division of Preventive Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, U.S.A.3§Cardiology Section, University of Chicago, Chicago, IL 60637, U.S.A.AbstractRecent animal and human studies have demonstrated the importance of the ROCK (RhoA/Rho-associated kinase) pathway in IsST (ischaemic stroke). Whether the genetic variation within ROCK-associated genes modulates the risk of IsST remains elusive. The association between 66 tSNPs [tagging SNPs (single nucleotide polymorphisms)] of three ROCK-associated genes [ROCK1, ROCK2 and ARHGEF10 (Rho guanine-nucleotide-exchange factor 10)] and the incidence of IsST was investigated in 23294 Caucasian female participants of the prospective WGHS (Women's Genome Health Study). All were free of known cancer and cardiovascular disease at baseline. During a 15-year follow-up period, 323 participants developed their first ever IsST. Multivariable Cox regression analysis was performed to investigate the relationship between genotypes and risk of IsST assuming an additive genetic model. Haplotype-block analysis was also performed. A total of ten tSNPs were associated with the risk of IsST (three in ARHGEF10 and seven in ROCK1; P<0.050). Further investigation using the haplotype-block analysis revealed a similar significant association of pre-specified haplotypes of ROCK1 with the risk of IsST (P=0.005). If corroborated in other large prospective studies, the findings of the present study suggest that genetic variation within the ROCK-associated pathway gene loci examined, and in particular ROCK1 gene variation, may influence the risk of IsST.
Clinical science (London, England : 1979).Clin Sci (Lond).2014 Jun 1;126(12):829-35. doi: 10.1042/CS20130652.
Recent animal and human studies have demonstrated the importance of the ROCK (RhoA/Rho-associated kinase) pathway in IsST (ischaemic stroke). Whether the genetic variation within ROCK-associated genes modulates the risk of IsST remains elusive. The association between 66 tSNPs [tagging SNPs (single
PMID 24351102

The role of valvular endothelial cell paracrine signaling and matrix elasticity on valvular interstitial cell activation.

Gould ST1, Matherly EE1, Smith JN1, Heistad DD2, Anseth KS3.Author information 1Department of Chemical and Biological Engineering, The BioFrontiers Institute, Boulder, CO 80303, USA.2Departments of Internal Medicine and Pharmacology, University of Iowa Health Care, Iowa City, IA 52242, USA.3Department of Chemical and Biological Engineering, The BioFrontiers Institute, Boulder, CO 80303, USA; Howard Hughes Medical Institute University of Colorado, Boulder, CO 80303, USA. Electronic address: Kristi.Anseth@Colorado.edu.AbstractThe effects of valvular endothelial cell (VlvEC) paracrine signaling on VIC phenotype and nodule formation were tested using a co-culture platform with physiologically relevant matrix elasticities and diffusion distance. 100 μm thin poly(ethylene glycol) (PEG) hydrogels of 3-27 kPa Young's moduli were fabricated in transwell inserts. VICs were cultured on the gels, as VIC phenotype is known to change significantly within this range, while VlvECs lined the underside of the membrane. Co-culture with VlvECs significantly reduced VIC activation to the myofibroblast phenotype on all gels with the largest percent decrease on the 3 kPa gels (∼70%), while stiffer gels resulted in approximately 20-30% decrease. Additionally, VlvECs significantly reduced αSMA protein expression (∼2 fold lower) on both 3 and 27 kPa gels, as well as the number (∼2 fold lower) of nodules formed on the 27 kPa gels. Effects of VlvECs were prevented when nitric oxide (NO) release was inhibited with l-NAME, suggesting that VlvEC produced NO inhibits VIC activation. Withdrawal of l-NAME after 3, 5, and 7 days with restoration of VlvEC NO production for 2 additional days led to a partial reversal of VIC activation (∼25% decrease). A potential mechanism by which VlvEC produced NO reduced VIC activation was studied by inhibiting initial and mid-stage cGMP pathway molecules. Inhibition of soluble guanylyl cyclase (sGC) with ODQ or protein kinase G (PKG) with RBrcGMP or stimulation of Rho kinase (ROCK) with LPA, abolished VlvEC effects on VIC activation. This work contributes substantially to the understanding of the valve endothelium's role in preventing VIC functions associated with aortic valve stenosis initiation and progression.
Biomaterials.Biomaterials.2014 Apr;35(11):3596-606. doi: 10.1016/j.biomaterials.2014.01.005. Epub 2014 Jan 24.
The effects of valvular endothelial cell (VlvEC) paracrine signaling on VIC phenotype and nodule formation were tested using a co-culture platform with physiologically relevant matrix elasticities and diffusion distance. 100 μm thin poly(ethylene glycol) (PEG) hydrogels of 3-27 kPa Young's moduli
PMID 24462357

PLEKHG2/FLJ00018, a Rho family-specific guanine nucleotide exchange factor, is tyrosine phosphorylated via the EphB2/cSrc signaling pathway.

Sato K1, Suzuki T2, Yamaguchi Y3, Kitade Y4, Nagase T3, Ueda H5.Author information 1United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Yanagido, Gifu 501-1193, Japan.2Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, Yanagido, Gifu 501-1193, Japan.3Kazusa DNA Research Institute, Kisarazu, Chiba 292-0818, Japan.4United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Yanagido, Gifu 501-1193, Japan; Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, Yanagido, Gifu 501-1193, Japan.5United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Yanagido, Gifu 501-1193, Japan; Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, Yanagido, Gifu 501-1193, Japan. Electronic address: hueda@gifu-u.ac.jp.AbstractPLEKHG2/FLJ00018, a Rho family-specific guanine nucleotide exchange factor (RhoGEF), is activated by heterotrimeric GTP-binding protein (G protein) Gβγ subunits, and in turn activates the small G protein Rac and Cdc42, which have been shown to mediate signaling pathways leading to actin cytoskeletal reorganization. In the present study, we show that co-expression of the constitutively active mutant of cSrc, a non-receptor tyrosine kinase, and PLEKHG2 induced the tyrosine phosphorylation of PLEKHG2 in HEK293 cells. Through deletion and base substitution mutagenesis we have identified Tyr489 of PLEKHG2 as the site phosphorylated by cSrc. Furthermore, using a high-throughput src homology 2 (SH2) domain binding assay, the SH2 domain of ABL1 and the PI 3-kinse regulator subunit (PIK3R3) were identified as candidates for the binding partner of tyrosine-phosphorylated PLEKHG2. The interaction between PLEKHG2 and the full-length of PIK3R3, but not ABL1, occurs in a tyrosine-phosphorylation-dependent manner. Furthermore, PLEKHG2 is tyrosine phosphorylated at Tyr489 by ephrinB2 receptor signaling via cSrc. Investigation of the physiological function of tyrosine phosphorylation at Tyr489 in PLEKHG2 remains a subject for future studies.
Cellular signalling.Cell Signal.2014 Apr;26(4):691-6. doi: 10.1016/j.cellsig.2013.12.006. Epub 2013 Dec 27.
PLEKHG2/FLJ00018, a Rho family-specific guanine nucleotide exchange factor (RhoGEF), is activated by heterotrimeric GTP-binding protein (G protein) Gβγ subunits, and in turn activates the small G protein Rac and Cdc42, which have been shown to mediate signaling pathways leading to actin cytoskelet
PMID 24378532

Japanese Journal

Circadian Variation of Rho-Kinase Activity in Circulating Leukocytes of Patients With Vasospastic Angina

Nihei Taro,Takahashi Jun,Tsuburaya Ryuji [他]
Circulation journal : official journal of the Japanese Circulation Society 78(5), 1183-1190, 2014-05
NAID 40020045511

次世代治療 Rhoキナーゼ阻害薬 : 肺動脈性肺高血圧症におけるRhoキナーゼ経路の役割 (特集肺高血圧症の薬物治療の最前線)

福本義弘
日本薬理学雑誌 = Folia pharmacologica Japonica : くすりとからだ : ファーマコロジカ 143(4), 178-181, 2014-04
NAID 40020052225

Potent Vasodilatory Effect of Fasudil on Radial Artery Graft in Coronary Artery Bypass Operations

Watanabe Go,Yamaguchi Shojiro,Takagi Takeshi,Tomita Shigeyuki,Tuan Pham Minh
Annals of Thoracic Surgery 97(3), 845-850, 2014-03
… We evaluated the usefulness of fasudil, a Rho kinase inhibitor, in dilating the RA graft and increasing graft free flow (GFF) compared with the conventional graft-dilating agents papaverine and verapamil-nitroglycerin (VG). …
NAID 120005368226

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★リンクテーブル★

リンク元	「Rho-associated kinase」「Rhoキナーゼ」「Rho-キナーゼ」
関連記事	「R」「kinase」「Rh」

「Rho-associated kinase」

Rho-associated, coiled-coil containing protein kinase 2
Identifiers
Symbol	ROCK2
Entrez	9475
HUGO	10252
OMIM	604002
RefSeq	NM_004850
UniProt	O75116
Other data

Rho-associated, coiled-coil containing protein kinase 1
Identifiers
Symbol	ROCK1
Entrez	6093
HUGO	10251
OMIM	601702
RefSeq	NM_005406
UniProt	Q13464
Other data

ROCK
	Crystal structure of human ROCK I
Identifiers
Symbol	Rho-associated protein kinase
Alt. symbols	Rho-associated, coiled-coil containing protein kinase
Entrez	579202
Other data
EC number	2.7.11.1