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Molecular Structures, Cellular Functions, and Physiological Roles of Rho Effectors

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Ras Superfamily Small G Proteins: Biology and Mechanisms 1

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Abstract

Rho GTPase is a regulator controlling the cytoskeleton in multiple contexts such as cell migration, adhesion, and cytokinesis. Upon binding to GTP, Rho exerts its functions through downstream Rho effectors such as ROCK/Rho-kinase/ROK, mDia, Citron, PKN, Rhophilin, and Rhotekin. Our knowledge about the functions of Rho effectors has accumulated since their discoveries in the mid-1990s through in vitro studies using heterologous expression in cultured cells and in vivo studies using gene targeting strategy as well as pharmaceutical intervention. In this chapter, we summarize findings obtained by these studies and discuss their implications.

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References

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

    PubMed  CAS  Google Scholar 

  • Amano M, Mukai H, Ono Y, Chihara K, Matsui T, Hamajima Y, Okawa K, Iwamatsu A, Kaibuchi K (1996b) Identification of a putative target for Rho as the serine-threonine kinase protein kinase N. Science 271:648–650

    PubMed  CAS  Google Scholar 

  • Arakawa Y, Bito H, Furuyashiki T, Tsuji T, Takemoto-Kimura S, Kimura K, Nozaki K, Hashimoto N, Narumiya S (2003) Control of axon elongation via an SDF-1alpha/Rho/mDia pathway in cultured cerebellar granule neurons. J Cell Biol 161:381–391

    PubMed  CAS  PubMed Central  Google Scholar 

  • Arimura N, Inagaki N, Chihara K, Ménager C, Nakamura N, Amano M, Iwamatsu A, Goshima Y, Kaibuchi K (2000) Phosphorylation of collapsin response mediator protein-2 by Rho-kinase. Evidence for two separate signaling pathways for growth cone collapse. J Biol Chem 275:23973–23980

    PubMed  CAS  Google Scholar 

  • Baarlink C, Wang H, Grosse R (2013) Nuclear actin network assembly by formins regulates the SRF coactivator MAL. Science 340:864–867

    PubMed  CAS  Google Scholar 

  • Balendran A, Biondi RM, Cheung PC, Casamayor A, Deak M, Alessi DR (2000) A 3-phosphoinositide-dependent protein kinase-1 (PDK1) docking site is required for the phosphorylation of protein kinase Czeta (PKCzeta) and PKC-related kinase 2 by PDK1. J Biol Chem 275:20806–20813

    PubMed  CAS  Google Scholar 

  • Bartolini F, Gundersen GG (2010) Formins and microtubules. Biochim Biophys Acta 1803:164–173

    PubMed  CAS  PubMed Central  Google Scholar 

  • Bartolini F, Moseley JB, Schmoranzer J, Cassimeris L, Goode BL, Gundersen GG (2008) The formin mDia2 stabilizes microtubules independently of its actin nucleation activity. J Cell Biol 181:523–536

    PubMed  CAS  PubMed Central  Google Scholar 

  • Bassi ZI, Verbrugghe KJ, Capalbo L, Gregory S, Montembault E, Glover DM, D’Avino PP (2011) Sticky/Citron kinase maintains proper RhoA localization at the cleavage site during cytokinesis. J Cell Biol 195:595–603

    PubMed  CAS  PubMed Central  Google Scholar 

  • Bassi ZI, Audusseau M, Riparbelli MG, Callaini G, D’Avino PP (2013) Citron kinase controls a molecular network required for midbody formation in cytokinesis. Proc Natl Acad Sci USA 110:9782–9787

    PubMed  CAS  PubMed Central  Google Scholar 

  • Begum N, Sandu OA, Ito M, Lohmann SM, Smolenski A (2002) Active Rho kinase (ROK-α) associates with insulin receptor substrate-1 and inhibits signaling in vascular smooth muscle cells. J Biol Chem 277:6214–6222

    PubMed  CAS  Google Scholar 

  • Behrends J, Clément S, Pajak B, Pohl V, Maenhaut C, Dumont JE, Schurmans S (2005) Normal thyroid structure and function in rhophilin 2-deficient mice. Mol Cell Biol 25:2846–2852

    PubMed  CAS  PubMed Central  Google Scholar 

  • Beli P, Mascheroni D, Xu D, Innocenti M (2008) WAVE and Arp2/3 jointly inhibit filopodium formation by entering into a complex with mDia2. Nat Cell Biol 10:849–857

    PubMed  CAS  Google Scholar 

  • Biondi RM, Cheung PC, Casamayor A, Deak M, Currie RA, Alessi DR (2000) Identification of a pocket in the PDK1 kinase domain that interacts with PIF and the C-terminal residues of PKA. EMBO J 19:979–988

    PubMed  CAS  PubMed Central  Google Scholar 

  • Bione S, Sala C, Manzini C, Arrigo G, Zuffardi O, Banfi S, Borsani G, Jonveaux P, Philippe C, Zuccotti M, Ballabio A, Toniolo D (1998) A human homologue of the Drosophila melanogaster diaphanous gene is disrupted in a patient with premature ovarian failure: evidence for conserved function in oogenesis and implications for human sterility. Am J Hum Genet 62:533–541

    PubMed  CAS  PubMed Central  Google Scholar 

  • Bito H, Furuyashiki T, Ishihara H, Shibasaki Y, Ohashi K, Mizuno K, Maekawa M, Ishizaki T, Narumiya S (2000) A critical role for a Rho-associated kinase, p160ROCK, in determining axon outgrowth in mammalian CNS neurons. Neuron 26:431–441

    PubMed  CAS  Google Scholar 

  • Bourguignon LY, Gilad E, Peyrollier K, Brightman A, Swanson RA (2007) Hyaluronan-CD44 interaction stimulates Rac1 signaling and PKN gamma kinase activation leading to cytoskeleton function and cell migration in astrocytes. J Neurochem 101:1002–1017

    PubMed  CAS  Google Scholar 

  • Brandt DT, Marion S, Griffiths G, Watanabe T, Kaibuchi K, Grosse R (2007) Dia1 and IQGAP1 interact in cell migration and phagocytic cup formation. J Cell Biol 178:193–200

    PubMed  CAS  PubMed Central  Google Scholar 

  • Calautti E, Grossi M, Mammucari C, Aoyama Y, Pirro M, Ono Y, Li J, Dotto GP (2002) Fyn tyrosine kinase is a downstream mediator of Rho/PRK2 function in keratinocyte cell-cell adhesion. J Cell Biol 156:137–148

    PubMed  CAS  PubMed Central  Google Scholar 

  • Camera P, da Silva JS, Griffiths G, Giuffrida MG, Ferrara L, Schubert V, Imarisio S, Silengo L, Dotti CG, Di Cunto F (2003) Citron-N is a neuronal Rho-associated protein involved in Golgi organization through actin cytoskeleton regulation. Nat Cell Biol 5:1071–1078

    PubMed  CAS  Google Scholar 

  • Camera P, Schubert V, Pellegrino M, Berto G, Vercelli A, Muzzi P, Hirsch E, Altruda F, Dotti CG, Di Cunto F (2008) The RhoA-associated protein Citron-N controls dendritic spine maintenance by interacting with spine-associated Golgi compartments. EMBO Rep 9:384–389

    PubMed  CAS  PubMed Central  Google Scholar 

  • Chan CC, Khodarahmi K, Liu J, Sutherland D, Oschipok LW, Steeves JD, Tetzlaff W (2005) Dose-dependent beneficial and detrimental effects of ROCK inhibitor Y27632 on axonal sprouting and functional recovery after rat spinal cord injury. Exp Neurol 196:352–364

    PubMed  CAS  Google Scholar 

  • Chellaiah MA, Biswas RS, Rittling SR, Denhardt DT, Hruska KA (2003) Rho-dependent Rho kinase activation increases CD44 surface expression and bone resorption in osteoclasts. J Biol Chem 278:29086–29097

    PubMed  CAS  Google Scholar 

  • Cheng L, Zhang J, Ahmad S, Rozier L, Yu H, Deng H, Mao Y (2010) Aurora B regulates formin mDia3 in achieving metaphase chromosome alignment. Dev Cell 20:342–352

    Google Scholar 

  • Chihara K, Amano M, Nakamura N, Yano T, Shibata M, Tokui T, Ichikawa H, Ikebe R, Ikebe M, Kaibuchi K (1997) Cytoskeletal rearrangements and transcriptional activation of c-fos serum response element by Rho-kinase. J Biol Chem 272:25121–25127

    PubMed  CAS  Google Scholar 

  • Chitaley K, Wingard CJ, Clinton Webb R, Branam H, Stopper VS, Lewis RW, Mills TM (2001) Antagonism of Rho-kinase stimulates rat penile erection via a nitric oxide-independent pathway. Nat Med 7:119–122

    PubMed  CAS  Google Scholar 

  • Coleman MP, Perry VH (2002) Axon pathology in neurological disease: a neglected therapeutic target. Trends Neurosci 25:532–537

    PubMed  CAS  Google Scholar 

  • Coleman ML, Sahai EA, Yeo M, Bosch M, Dewar A, Olson MF (2001) Membrane blebbing during apoptosis results from caspase-mediated activation of ROCK I. Nat Cell Biol 3:339–345

    PubMed  CAS  Google Scholar 

  • Collier FM, Gregorio-King CC, Gough TJ, Talbot CD, Walder K, Kirkland MA (2004) Identification and characterization of a lymphocytic Rho-GTPase effector: rhotekin-2. Biochem Biophys Res Commun 324:1360–1369

    PubMed  CAS  Google Scholar 

  • Copp AJ, Greene ND, Murdoch JN (2003) The genetic basis of mammalian neurulation. Nat Rev Genet 4:784–793

    PubMed  Google Scholar 

  • Dergham P, Ellezam B, Essagian C, Avedissian H, Lubell WD, McKerracher L (2002) Rho signaling pathway targeted to promote spinal cord repair. J Neurosci 22:6570–6577

    PubMed  CAS  Google Scholar 

  • Dettori R, Sonzogni S, Meyer L, Lopez-Garcia LA, Morrice NA, Zeuzem S, Engel M, Piiper A, Neimanis S, Frödin M, Biondi RM (2009) Regulation of the interaction between protein kinase C-related protein kinase 2 (PRK2) and its upstream kinase, 3-phosphoinositide-dependent protein kinase 1 (PDK1). J Biol Chem 284:30318–30327

    PubMed  CAS  PubMed Central  Google Scholar 

  • DeWard AD, Leali K, West RA, Prendergast GC, Alberts AS (2009) Loss of RhoB expression enhances the myelodysplastic phenotype of mammalian diaphanous-related Formin mDia1 knockout mice. PLoS One 4:e7102

    PubMed  PubMed Central  Google Scholar 

  • Di Cunto F, Calautti E, Hsiao J, Ong L, Topley G, Turco E, Dotto GP (1998) Citron rho-interacting kinase, a novel tissue-specific ser/thr kinase encompassing the Rho-Rac-binding protein Citron. J Biol Chem 273:29706–29711

    PubMed  Google Scholar 

  • Di Cunto F, Imarisio S, Hirsch E, Broccoli V, Bulfone A, Migheli A, Atzori C, Turco E, Triolo R, Dotto GP, Silengo L, Altruda F (2000) Defective neurogenesis in citron kinase knockout mice by altered cytokinesis and massive apoptosis. Neuron 28:115–127

    PubMed  Google Scholar 

  • Di Cunto F, Imarisio S, Camera P, Boitani C, Altruda F, Silengo L (2002) Essential role of citron kinase in cytokinesis of spermatogenic precursors. J Cell Sci 115:4819–4826

    PubMed  Google Scholar 

  • Duffy P, Schmandke A, Schmandke A, Sigworth J, Narumiya S, Cafferty WB, Strittmatter SM (2009) Rho-associated kinase II (ROCKII) limits axonal growth after trauma within the adult mouse spinal cord. J Neurosci 29:15266–15276

    PubMed  CAS  PubMed Central  Google Scholar 

  • DuFort CC, Paszek MJ, Weaver VM (2011) Balancing forces: architectural control of mechanotransduction. Nat Rev Mol Cell Biol 12:308–319

    PubMed  CAS  PubMed Central  Google Scholar 

  • Echard A, Hickson GR, Foley E, O’Farrell PH (2004) Terminal cytokinesis events uncovered after an RNAi screen. Curr Biol 14:1685–1693

    PubMed  CAS  PubMed Central  Google Scholar 

  • Eiraku M, Takata N, Ishibashi H, Kawada M, Sakakura E, Okuda S, Sekiguchi K, Adachi T, Sasai Y (2011) Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature 472:51–56

    PubMed  CAS  Google Scholar 

  • Eisenmann KM, West RA, Hildebrand D, Kitchen SM, Peng J, Sigler R, Zhang J, Siminovitch KA, Alberts AS (2007) T cell responses in mammalian diaphanous-related formin mDia1 knock-out mice. J Biol Chem 282:25152–25158

    PubMed  CAS  Google Scholar 

  • Eisenmann KM, Dykema KJ, Matheson SF, Kent NF, DeWard AD, West RA, Tibes R, Furge KA, Alberts AS (2009) 5q- myelodysplastic syndromes: chromosome 5q genes direct a tumor-suppression network sensing actin dynamics. Oncogene 28:3429–3441

    PubMed  CAS  Google Scholar 

  • Eto M, Barandier C, Rathgeb L, Kozai T, Joch H, Yang Z, Luscher TF (2001) Thrombin suppresses endothelial nitric oxide synthase and upregulates endothelin-converting enzyme-1 expression by distinct pathways: role of Rho/ROCK and mitogen-activated protein kinase. Circ Res 89:583–590

    PubMed  CAS  Google Scholar 

  • Fournier AE, Takizawa BT, Strittmatter SM (2003) Rho kinase inhibition enhances axonal regeneration in the injured CNS. J Neurosci 23:1416–1423

    PubMed  CAS  Google Scholar 

  • Fujita A, Nakamura K, Kato T, Watanabe N, Ishizaki T, Kimura K, Mizoguchi A, Narumiya S (2000) Ropporin, a sperm-specific binding protein of rhophilin, that is localized in the fibrous sheath of sperm flagella. J Cell Sci 113:103–112

    PubMed  CAS  Google Scholar 

  • Furukawa N, Ongusaha P, Jahng WJ, Araki K, Choi CS, Kim HJ, Lee YH, Kaibuchi K, Kahn BB, Masuzaki H, Kim JK, Lee SW, Kim YB (2005) Role of Rho-kinase in regulation of insulin action and glucose homeostasis. Cell Metab 2:119–129

    PubMed  CAS  Google Scholar 

  • Furuyashiki T, Fujisawa K, Fujita A, Madaule P, Uchino S, Mishina M, Bito H, Narumiya S (1999) Citron, a Rho-target, interacts with PSD-95/SAP-90 at glutamatergic synapses in the thalamus. J Neurosci 19:109–118

    PubMed  CAS  Google Scholar 

  • Gaggioli C, Hooper S, Hidalgo-Carcedo C, Grosse R, Marshall JF, Harrington K, Sahai E (2007) Fibroblast-led collective invasion of carcinoma cells with differing roles for rhogtpases in leading and following cells. Nat Cell Biol 9:1392–1400

    PubMed  CAS  Google Scholar 

  • Gai M, Camera P, Dema A, Bianchi F, Berto G, Scarpa E, Germena G, Di Cunto F (2011) Citron kinase controls abscission through RhoA and anillin. Mol Biol Cell 22:3768–3778

    PubMed  CAS  PubMed Central  Google Scholar 

  • Gaillard J, Ramabhadran V, Neumanne E, Gurel P, Blanchoin L, Vantard M, Higgs HN (2011) Differential interactions of the formins INF2, mDia1, and mDia2 with microtubules. Mol Biol Cell 22:4575–4587

    PubMed  CAS  PubMed Central  Google Scholar 

  • Gasman S, Kalaidzidis Y, Zerial M (2003) RhoD regulates endosome dynamics through Diaphanous-related Formin and Src tyrosine kinase. Nat Cell Biol 5:195–204

    PubMed  CAS  Google Scholar 

  • Genda T, Sakamoto M, Ichida T, Asakura H, Kojiro M, Narumiya S, Hirohashi S (1999) Cell motility mediated by rho and Rho-associated protein kinase plays a critical role in intrahepatic metastasis of human hepatocellular carcinoma. Hepatology 30:1027–1036

    PubMed  CAS  Google Scholar 

  • Geron E, Schejter ED, Shilo BZ (2013) Directing exocrine secretory vesicles to the apical membrane by actin cables generated by the formin mDia1. Proc Natl Acad Sci USA 110:10652–10657

    PubMed  CAS  PubMed Central  Google Scholar 

  • Goh WI, Ahmed S (2012) mDia1-3 in mammalian filopodia. Commun Integr Biol 5:340–344

    PubMed  CAS  PubMed Central  Google Scholar 

  • Haigo SL, Hildebrand JD, Harland RM, Wallingford JB (2003) Shroom induces apical constriction and is required for hingepoint formation during neural tube closure. Curr Biol 13:2125–2137

    PubMed  CAS  Google Scholar 

  • Hara M, Takayasu M, Watanabe K, Noda A, Takagi T, Suzuki Y, Yoshida J (2000) Protein kinase inhibition by fasudil hydrochloride promotes neurological recovery after spinal cord injury in rats. J Neurosurg 93:94–101

    PubMed  CAS  Google Scholar 

  • Harmey D, Stenbeck G, Nobes CD, Lax AJ, Grigoriadis AE (2004) Regulation of osteoblast differentiation by Pasteurella multocida toxin (PMT): a role for Rho GTPase in bone formation. J Bone Miner Res 19:661–670

    PubMed  CAS  Google Scholar 

  • Heasman SJ, Carlin LM, Cox S, Ng T, Ridley AJ (2010) Coordinated RhoA signaling at the leading edge and uropod is required for T cell transendothelial migration. J Cell Biol 190:553–563

    PubMed  CAS  PubMed Central  Google Scholar 

  • Higashida C, Kiuchi T, Akiba Y, Mizuno H, Maruoka M, Narumiya S, Mizuno K, Watanabe N (2013) F- and G-actin homeostasis regulates mechanosensitive actin nucleation by formins. Nat Cell Biol 15:395–405

    PubMed  CAS  Google Scholar 

  • Hildebrand JD (2005) Shroom regulates epithelial cell shape via the apical positioning of an actomyosin network. J Cell Sci 118:5191–5203

    PubMed  CAS  Google Scholar 

  • Hildebrand JD, Soriano P (1999) Shroom, a PDZ domain-containing actin-binding protein, is required for neural tube morphogenesis in mice. Cell 99:485–497

    PubMed  CAS  Google Scholar 

  • Hirose M, Ishizaki T, Watanabe N, Uehata M, Kranenburg O, Moolenaar WH, Matsumura F, Maekawa M, Bito H, Narumiya S (1998) Molecular dissection of the Rho-associated protein kinase (p160ROCK)-regulated neurite remodeling in neuroblastoma N1E-115 cells. J Cell Biol 141:1625–1636

    PubMed  CAS  PubMed Central  Google Scholar 

  • Honjo M, Inatani M, Kido N, Sawamura T, Yue BY, Honda Y, Tanihara H (2001a) Effects of protein kinase inhibitor, HA1077, on intraocular pressure and outflow facility in rabbit eyes. Arch Ophthalmol 119:1171–1178

    PubMed  CAS  Google Scholar 

  • Honjo M, Tanihara H, Inatani M, Kido N, Sawamura T, Yue BY, Narumiya S, Honda Y (2001b) Effects of rho-associated protein kinase inhibitor Y-27632 on intraocular pressure and outflow facility. Invest Ophthalmol Vis Sci 42:137–144

    PubMed  CAS  Google Scholar 

  • Ishizaki T, Maekawa M, Fujisawa K, Okawa K, Iwamatsu A, Fujita A, Watanabe N, Saito Y, Kakizuka A, Morii N, Narumiya S (1996) The small GTP-binding protein Rho binds to and activates a 160 kDa Ser/Thr protein kinase homologous to myotonic dystrophy kinase. EMBO J 15:1885–1893

    PubMed  CAS  PubMed Central  Google Scholar 

  • Ishizaki T, Morishima Y, Okamoto M, Furuyashiki T, Kato T, Narumiya S (2001) Coordination of microtubules and the actin cytoskeleton by the Rho effector mDia1. Nat Cell Biol 3:8–14

    PubMed  CAS  Google Scholar 

  • Itoh K, Yoshioka K, Akedo H, Uehata M, Ishizaki T, Narumiya S (1999) An essential part for Rho-associated kinase in the transcellular invasion of tumor cells. Nat Med 5:221–225

    PubMed  CAS  Google Scholar 

  • Jacobs M, Hayakawa K, Swenson L, Bellon S, Fleming M, Taslimi P, Doran J (2006) The structure of dimeric ROCK I reveals the mechanism for ligand selectivity. J Biol Chem 281:260–268

    PubMed  CAS  Google Scholar 

  • Jégou A, Carlier MF, Romet-Lemonne G (2013) Formin mDia1 senses and generates mechanical forces on actin filaments. Nat Commun 4:1883

    PubMed  Google Scholar 

  • Ji P, Jayapal SR, Lodish HF (2008) Enucleation of cultured mouse fetal erythroblasts requires Rac GTPases and mDia2. Nat Cell Biol 10:314–321

    PubMed  CAS  Google Scholar 

  • Juliano R (2009) SCAI blocks MAL-evolent effects on cancer cell invasion. Nat Cell Biol 11:540–542

    PubMed  CAS  Google Scholar 

  • Kamijo H, Matsumura Y, Thumkeo D, Koike S, Masu M, Shimizu Y, Ishizaki T, Narumiya S (2011) Impaired vascular remodeling in the yolk sac of embryos deficient in ROCK-I and ROCK-II. Genes Cells 16:1012–1021

    PubMed  CAS  Google Scholar 

  • Kanda T, Wakino S, Homma K, Yoshioka K, Takematsu S, Hasegawa K, Takamatsu I, Sugano N, Hayashi K, Saruta T (2006) Rho-kinase as a molecular target for insulin resistance and hypertension. FASEB J 20:169–171

    PubMed  CAS  Google Scholar 

  • Kaneko T, Amano M, Maeda A, Goto H, Takahashi K, Ito M, Kaibuchi K (2000) Identification of calponin as a novel substrate of Rho-kinase. Biochem Biophys Res Commun 273:110–116

    PubMed  CAS  Google Scholar 

  • Karlsson R, Pedersen ED, Wang Z, Brakebusch C (2009) Rho GTPase function in tumorigenesis. Biochim Biophys Acta 1796:91–98

    PubMed  CAS  Google Scholar 

  • Katayama K, Melendez J, Baumann JM, Leslie JR, Chauhan BK, Nemkul N, Lang RA, Kuan CY, Zheng Y, Yoshida Y (2011) Loss of RhoA in neural progenitor cells causes the disruption of adherens junctions and hyperproliferation. Proc Natl Acad Sci USA 108:7607–7612

    PubMed  CAS  PubMed Central  Google Scholar 

  • Katayama K, Leslie JR, Lang RA, Zheng Y, Yoshida YJ (2012) Left-right locomotor circuitry depends on RhoA-driven organization of the neuroepithelium in the developing spinal cord. J Neurosci 32:10396–10407

    PubMed  CAS  PubMed Central  Google Scholar 

  • Kimura K, Ito M, Amano M, Chihara K, Fukata Y, Nakafuku M, Yamamori B, Feng J, Nakano T, Okawa K, Iwamatsu A, Kaibuchi K (1996) Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science 273:245–248

    PubMed  CAS  Google Scholar 

  • Kimura K, Fukata Y, Matsuoka Y, Bennett V, Matsuura Y, Okawa K, Iwamatsu A, Kaibuchi K (1998) Regulation of the association of adducin with actin filaments by Rho-associated kinase (Rho-kinase) and myosin phosphatase. J Biol Chem 273:5542–5548

    PubMed  CAS  Google Scholar 

  • Kitagawa M, Mukai H, Shibata H, Ono Y (1995) Purification and characterization of a fatty acid-activated protein kinase (PKN) from rat testis. Biochem J 310:657–664

    PubMed  CAS  PubMed Central  Google Scholar 

  • Koh H, Lee KH, Kim D, Kim S, Kim JW, Chung J (2000) Inhibition of Akt and its anti-apoptotic activities by tumor necrosis factor-induced protein kinase C-related kinase 2 (PRK2) cleavage. J Biol Chem 275:34451–34458

    PubMed  CAS  Google Scholar 

  • Kumar MS, Hancock DC, Molina-Arcas M, Steckel M, East P, Diefenbacher M, Armenteros-Monterroso E, Lassailly F, Matthews N, Nye E, Stamp G, Behrens A, Downward J (2012) The GATA2 transcriptional network is requisite for RAS oncogene-driven non-small cell lung cancer. Cell 149:642–655

    PubMed  CAS  Google Scholar 

  • Lachmann S, Jevons A, De Rycker M, Casamassima A, Radtke S, Collazos A, Parker PJ (2011) Regulatory domain selectivity in the cell-type specific PKN-dependence of cell migration. PLoS One 6:e21732

    PubMed  CAS  PubMed Central  Google Scholar 

  • Lahoz A, Hall A (2008) DLC1: a significant GAP in the cancer genome. Genes Dev 22:1724–1730

    PubMed  CAS  PubMed Central  Google Scholar 

  • Lee DH, Shi J, Jeoung NH, Kim MS, Zabolotny JM, Lee SW, White MF, Wei L, Kim YB (2009) Targeted Disruption of ROCK1 Causes Insulin Resistance in Vivo. J Biol Chem 284:11776–11780

    PubMed  CAS  PubMed Central  Google Scholar 

  • Leenders F, Möpert K, Schmiedeknecht A, Santel A, Czauderna F, Aleku M, Penschuck S, Dames S, Sternberger M, Röhl T, Wellmann A, Arnold W, Giese K, Kaufmann J, Klippel A (2004) PKN3 is required for malignant prostate cell growth downstream of activated PI 3-kinase. EMBO J 23:3303–3313

    PubMed  CAS  PubMed Central  Google Scholar 

  • Lehmann M, Fournier A, Selles-Navarro I, Dergham P, Sebok A, Leclerc N, Tigyi G, McKerracher L (1999) Inactivation of Rho signaling pathway promotes CNS axon regeneration. J Neurosci 19:7537–7547

    PubMed  CAS  Google Scholar 

  • Leung T, Manser E, Tan L, Lim L (1995) A novel serine/threonine kinase binding the Ras-related RhoA GTPase which translocates the kinase to peripheral membranes. J Biol Chem 270:29051–29054

    PubMed  CAS  Google Scholar 

  • Lim WG, Zhu Y, Wang CH, Tan BJ, Armstrong JS, Dokland T, Yang H, Zhu YZ, Teo TS, Duan W (2005) The last five amino acid residues at the C-terminus of PRK1/PKN is essential for full lipid responsiveness. Cell Signal 17:1084–1097

    PubMed  CAS  Google Scholar 

  • Liu CA, Wang MJ, Chi CW, Wu CW, Chen JY (2004) Rho/Rhotekin-mediated NF-kappaB activation confers resistance to apoptosis. Oncogene 23:8731–8742

    PubMed  CAS  Google Scholar 

  • Loomis RJ, Holmes DA, Elms A, Solski PA, Der CJ, Su L (2006) Citron kinase, a RhoA effector, enhances HIV-1 virion production by modulating exocytosis. Traffic 7:1643–1653

    PubMed  CAS  Google Scholar 

  • Lu Y, Settleman J (1999) The Drosophila Pkn protein kinase is a Rho/Rac effector target required for dorsal closure during embryogenesis. Genes Dev 13:1168–1180

    PubMed  CAS  PubMed Central  Google Scholar 

  • Lynch ED, Lee MK, Morrow JE, Welcsh PL, León PE, King MC (1997) Nonsyndromic deafness DFNA1 associated with mutation of a human homolog of the Drosophila gene diaphanous. Science 278:1315–1318

    PubMed  CAS  Google Scholar 

  • Madaule P, Furuyashiki T, Reid T, Ishizaki T, Watanabe G, Morii N, Narumiya S (1995) A novel partner for the GTP-bound forms of rho and rac. FEBS Lett 377:243–248

    PubMed  CAS  Google Scholar 

  • Madaule P, Eda M, Watanabe N, Fujisawa K, Matsuoka T, Bito H, Ishizaki T, Narumiya S (1998) Role of citron kinase as a target of the small GTPase Rho in cytokinesis. Nature 394:491–494

    PubMed  CAS  Google Scholar 

  • Maekawa M, Ishizaki T, Boku S, Watanabe N, Fujita A, Iwamatsu A, Obinata T, Ohashi K, Mizuno K, Narumiya S (1999) Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. Science 285:895–898

    PubMed  CAS  Google Scholar 

  • Matsui T, Amano M, 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 small GTP binding protein Rho. EMBO J 15:2208–2216

    PubMed  CAS  PubMed Central  Google Scholar 

  • Matsui T, Maeda M, Doi Y, Yonemura S, Amano M, Kaibuchi K, Tsukita S, Tsukita S (1998) Rho-kinase phosphorylates COOH-terminal threonines of ezrin/radixin/moesin (ERM) proteins and regulates their head-to-tail association. J Cell Biol 140:647–657

    PubMed  CAS  PubMed Central  Google Scholar 

  • Metzger E, Muller JM, Ferrari S, Buettner R, Schule R (2003) A novel inducible transactivation domain in the androgen receptor: implications for PRK in prostate cancer. EMBO J 22:270–280

    PubMed  CAS  PubMed Central  Google Scholar 

  • Miki T, Okawa K, Sekimoto T, Yoneda Y, Watanabe S, Ishizaki T, Narumiya S (2009) mDia2 shuttles between the nucleus and the cytoplasm through the importin-{alpha}/{beta}- and CRM1-mediated nuclear transport mechanism. J Biol Chem 284:5753–5762

    PubMed  CAS  Google Scholar 

  • Misaki K, Mukai H, Yoshinaga C, Oishi K, Isagawa T, Takahashi M, Ohsumi K, Kishimoto T, Ono Y (2001) PKN delays mitotic timing by inhibition of Cdc25C: possible involvement of PKN in the regulation of cell division. Proc Natl Acad Sci USA 98:125–129

    PubMed  CAS  PubMed Central  Google Scholar 

  • Mukai H (2003) The structure and function of PKN, a protein kinase having a catalytic domain homologous to that of PKC. J Biochem 133:17–27

    PubMed  CAS  Google Scholar 

  • Mukai H, Kitagawa M, Shibata H, Takanaga H, Mori K, Shimakawa M, Miyahara M, Hirao K, Ono Y (1994) Activation of PKN, a novel 120-kDa protein kinase with leucine zipper-like sequences, by unsaturated fatty acids and by limited proteolysis. Biochem Biophys Res Commun 204:348–356

    PubMed  CAS  Google Scholar 

  • Nagumo H, Ikenoya M, Sakurada K, Furuya K, Ikuhara T, Hiraoka H, Sasaki Y (2001) Rho-associated kinase phosphorylates MARCKS in human neuronal cells. Biochem Biophys Res Commun 280:605–609

    PubMed  CAS  Google Scholar 

  • Naim V, Imarisio S, Di Cunto F, Gatti M, Bonaccorsi S (2004) Drosophila citron kinase is required for the final steps of cytokinesis. Mol Biol Cell 15:5053–5063

    PubMed  CAS  PubMed Central  Google Scholar 

  • Nakagawa O, Fujisawa K, Ishizaki T, Saito Y, Nakao K, Narumiya S (1996) ROCK-I and ROCK-II, two isoforms of Rho-associated coiled-coil forming protein serine/threonine kinase in mice. FEBS Lett 392:189–193

    PubMed  CAS  Google Scholar 

  • Nakamura K, Fujita A, Murata T, Watanabe G, Mori C, Fujita J, Watanabe N, Ishizaki T, Yoshida O, Narumiya S (1999) Rhophilin, a small GTPase Rho-binding protein, is abundantly expressed in the mouse testis and localized in the principal piece of the sperm tail. FEBS Lett 445:9–13

    PubMed  CAS  Google Scholar 

  • Nakayama M, Goto TM, Sugimoto M, Nishimura T, Shinagawa T, Ohno S, Amano M, Kaibuchi K (2008) Rho-kinase phosphorylates PAR-3 and disrupts PAR complex formation. Dev Cell 14:205–215

    PubMed  CAS  Google Scholar 

  • Narumiya S, Ishizaki T, Uehata M (2000) Use and properties of ROCK-specific inhibitor Y-27632. Methods Enzymol 325:273–284

    PubMed  CAS  Google Scholar 

  • Niederöst B, Oertle T, Fritsche J, McKinney RA, Bandtlow CE (2002) Nogo-A and myelin-associated glycoprotein mediate neurite growth inhibition by antagonistic regulation of RhoA and Rac1. J Neurosci 22:10368–10376

    PubMed  Google Scholar 

  • Nishimura T, Takeichi M (2008) Shroom3-mediated recruitment of Rho kinases to the apical cell junctions regulates epithelial and neuroepithelial planar remodeling. Development 135:1493–1502

    PubMed  CAS  Google Scholar 

  • Nishimura T, Honda H, Takeichi M (2012) Planar cell polarity links axes of spatial dynamics in neural-tube closure. Cell 149:1084–1097

    PubMed  CAS  Google Scholar 

  • Ohgushi M, Sasai Y (2011) Lonely death dance of human pluripotent stem cells: ROCKing between metastable cell states. Trends Cell Biol 21:274–282

    PubMed  CAS  Google Scholar 

  • Olson MF (2008) Applications for ROCK kinase inhibition. Curr Opin Cell Biol 20:242–248

    PubMed  CAS  PubMed Central  Google Scholar 

  • Palmer RH, Dekker LV, Woscholski R, Le Good JA, Gigg R, Parker PJ (1995) Activation of PRK1 by phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate. A comparison with protein kinase C isotypes. J Biol Chem 270:22412–22416

    PubMed  CAS  Google Scholar 

  • Paul AS, Pollard TD (2009) Review of the mechanism of processive actin filament elongation by formins. Cell Motil Cytoskeleton 66:606–617

    PubMed  CAS  PubMed Central  Google Scholar 

  • Peck JW, Oberst M, Bouker KB, Bowden E, Burbelo PD (2002) The RhoA-binding protein, rhophilin-2, regulates actin cytoskeleton organization. J Biol Chem 277:43924–43932

    PubMed  CAS  Google Scholar 

  • Pellegrin S, Mellor H (2005) The Rho family GTPase Rif induces filopodia through mDia2. Curr Biol 15:129–133

    PubMed  CAS  Google Scholar 

  • Peng J, Kitchen SM, West RA, Sigler R, Eisenmann KM, Alberts AS (2007) Myeloproliferative defects following targeting of the Drf1 gene encoding the mammalian diaphanous related formin mDia1. Cancer Res 67:7565–7571

    PubMed  CAS  Google Scholar 

  • Qiu R, Chen GJ, McCormick F, Symons M (1995) A role for Rho in Ras transformation. Proc Natl Acad Sci USA 92:11781–11785

    PubMed  CAS  PubMed Central  Google Scholar 

  • Raff MC, Whitmore AV, Finn JT (2002) Axonal self-destruction and neurodegeneration. Science 296:868–871

    PubMed  CAS  Google Scholar 

  • Rajasekaran M, White S, Baquir A, Wilkes N (2005) Rho-kinase inhibition improves erectile function in aging male Brown-Norway rats. J Androl 26:182–188

    PubMed  CAS  Google Scholar 

  • Rao PV, Deng PF, Kumar J, Epstein DL (2001) Modulation of aqueous humor outflow facility by the Rho kinase-specific inhibitor Y-27632. Invest Ophthalmol Vis Sci 42:1029–1037

    PubMed  CAS  Google Scholar 

  • Reid T, Furuyashiki T, Ishizaki T, Watanabe G, Watanabe N, Fujisawa K, Morii N, Madaule P, Narumiya S (1996) Rhotekin, a new putative target for Rho bearing homology to a serine/threonine kinase, PKN, and rhophilin in the rho-binding domain. J Biol Chem 271:13556–13560

    PubMed  CAS  Google Scholar 

  • Rikitake Y, Kim HH, Huang Z, Seto M, Yano K, Asano T, Moskowitz MA, Liao JK (2005) Inhibition of Rho kinase (ROCK) leads to increased cerebral blood flow and stroke protection. Stroke 36:2251–2257

    PubMed  CAS  PubMed Central  Google Scholar 

  • Riveline D, Zamir E, Balaban NQ, Schwarz US, Ishizaki T, Narumiya S, Kam Z, Geiger B, Bershadsky AD (2001) Focal contacts as mechanosensors: externally applied local mechanical force induces growth of focal contacts by an mDia1-dependent and ROCK-independent mechanism. J Cell Biol 153:1175–1186

    PubMed  CAS  PubMed Central  Google Scholar 

  • Rossman KL, Der CJ, Sondek J (2005) GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors. Nat Rev Mol Cell Biol 6:167–180

    PubMed  CAS  Google Scholar 

  • Sahai E, Marshall CJ (2002) ROCK and Dia have opposing effects on adherens junctions downstream of Rho. Nat Cell Biol 4:408–415

    PubMed  CAS  Google Scholar 

  • Sahai E, Marshall CJ (2003a) Differing modes of tumour cell invasion have distinct requirements for Rho/ROCK signalling and extracellular proteolysis. Nat Cell Biol 5:711–719

    PubMed  CAS  Google Scholar 

  • Sahai E, Marshall CJ (2003b) RHO-GTPases and cancer. Nat Rev Cancer 2:133–142

    Google Scholar 

  • Sahai E, Ishizaki T, Narumiya S, Treisman R (1999) Transformation mediated by RhoA requires activity of ROCK kinases. Curr Biol 11:136–145

    Google Scholar 

  • Sakamoto S, Ishizaki T, Okawa K, Watanabe S, Arakawa T, Watanabe N, Narumiya S (2012a) Liprin-α controls stress fiber formation by binding to mDia and regulating its membrane localization. J Cell Sci 125:108–120

    PubMed  CAS  Google Scholar 

  • Sakamoto S, Narumiya S, Ishizaki T (2012b) A new role of multi scaffold protein Liprin-α: Liprin-α suppresses Rho-mDia mediated stress fiber formation. Bioarchitecture 2:43–49

    PubMed  PubMed Central  Google Scholar 

  • Sakata D, Taniguchi H, Yasuda S, Adachi-Morishima A, Hamazaki Y, Nakayama R, Miki T, Minato N, Narumiya S (2007) Impaired T lymphocyte trafficking in mice deficient in an actin-nucleating protein, mDia1. J Exp Med 204:2031–2038

    PubMed  CAS  PubMed Central  Google Scholar 

  • Samuel MS, Munro J, Bryson S, Forrow S, Stevenson D, Olson MF (2009) Tissue selective expression of conditionally-regulated ROCK by gene targeting to a defined locus. Genesis 47:440–446

    PubMed  CAS  Google Scholar 

  • Samuel MS, Lopez JI, McGhee EJ, Croft DR, Strachan D, Timpson P, Munro J, Schröder E, Zhou J, Brunton VG, Barker N, Clevers H, Sansom OJ, Anderson KI, Weaver VM, Olson MF (2011) Actomyosin-mediated cellular tension drives increased tissue stiffness and β-catenin activation to induce epidermal hyperplasia and tumor growth. Cancer Cell 19:776–791

    PubMed  CAS  PubMed Central  Google Scholar 

  • Sanz-Moreno V, Gaggioli C, Yeo M, Albrengues J, Wallberg F, Viros A, Hooper S, Mitter R, Feral CC, Cook M, Larkin J, Marais R, Meneguzzi G, Sahai E, Marshall CJ (2011) Rock and jak1 signaling cooperate to control actomyosin contractility in tumor cells and stroma. Cancer Cell 20:229–245

    PubMed  CAS  Google Scholar 

  • Sarkisian MR, Li W, Di Cunto F, D’Mello SR, LoTurco JJ (2002) Citron-kinase, a protein essential to cytokinesis in neuronal progenitors, is deleted in the flathead mutant rat. J Neurosci 22:RC217

    PubMed  Google Scholar 

  • Satoh K, Fukumoto Y, Shimokawa H (2011) Rho-kinase: important new therapeutic target in cardiovascular diseases. Am J Physiol Heart Circ Physiol 301:H287–H296

    PubMed  CAS  Google Scholar 

  • Schmandke A, Schmandke A, Strittmatter SM (2007) ROCK and Rho: biochemistry and neuronal functions of Rho-associated protein kinases. Neuroscientist 13:454–456

    PubMed  CAS  PubMed Central  Google Scholar 

  • Schoen CJ, Emery SB, Thorne MC, Ammana HR, Sliwerska E, Arnett J, Hortsch M, Hannan F, Burmeister M, Lesperance MM (2010) Increased activity of Diaphanous homolog 3 (DIAPH3)/diaphanous causes hearing defects in humans with auditory neuropathy and in Drosophila. Proc Natl Acad Sci USA 107:13396–13401

    PubMed  CAS  PubMed Central  Google Scholar 

  • Schoen CJ, Burmeister M, Lesperance MM (2013) Diaphanous homolog 3 (Diap3) overexpression causes progressive hearing loss and inner hair cell defects in a transgenic mouse model of human deafness. PLoS One 8:e56520

    PubMed  CAS  PubMed Central  Google Scholar 

  • Sebbagh M, Renvoizé C, Hamelin J, Riché N, Bertoglio J, Bréard J (2001) Caspase-3-mediated cleavage of ROCK I induces MLC phosphorylation and apoptotic membrane blebbing. Nat Cell Biol 3:346–352

    PubMed  CAS  Google Scholar 

  • Sebbagh M, Hamelin J, Bertoglio J, Solary E, Bréard J (2005) Direct cleavage of ROCK II by granzyme B induces target cell membrane blebbing in a caspase-independent manner. J Exp Med 201:465–471

    PubMed  CAS  PubMed Central  Google Scholar 

  • Serres MP, Kossatz U, Chi Y, Roberts JM, Malek NP, Besson A (2012) p27(Kip1) controls cytokinesis via the regulation of citron kinase activation. J Clin Invest 122:844–858

    PubMed  CAS  PubMed Central  Google Scholar 

  • Shimizu Y, Thumkeo D, Keel J, Ishizaki T, Oshima H, Oshima M, Noda Y, Matsumura F, Taketo MM, Narumiya S (2005) ROCK-I regulates closure of the eyelids and ventral body wall by inducing assembly of actomyosin bundles. J Cell Biol 168:941–953

    PubMed  CAS  PubMed Central  Google Scholar 

  • Shinohara R, Thumkeo D, Kamijo H, Kaneko N, Sawamoto K, Watanabe K, Takebayashi H, Kiyonari H, Ishizaki T, Furuyashiki T, Narumiya S (2012) A role for mDia, a Rho-regulated actin nucleator, in tangential migration of interneuron precursors. Nat Neurosci 15:373–380

    PubMed  CAS  Google Scholar 

  • Somlyo AP, Wu X, Walker LA, Somlyo AV (1994) Pharmacomechanical coupling: the role of calcium, G-proteins, kinases and phosphatases. Rev Physiol Biochem Pharmacol 134:201–234

    Google Scholar 

  • Standaert M, Bandyopadhyay G, Galloway L, Ono Y, Mukai H, Farese R (1998) Comparative effects of GTPgammaS and insulin on the activation of Rho, phosphatidylinositol 3-kinase, and protein kinase N in rat adipocytes. Relationship to glucose transport. J Biol Chem 273:7470–7477

    PubMed  CAS  Google Scholar 

  • Steuve S, Devosse T, Lauwers E, Vanderwinden JM, André B, Courtoy PJ, Pirson I (2006) Rhophilin-2 is targeted to late-endosomal structures of the vesicular machinery in the presence of activated RhoB. Exp Cell Res 312:3981–3989

    PubMed  CAS  Google Scholar 

  • Suzuki Y, Shibuya M, Satoh S, Sugimoto Y, Takakura K (2007) A postmarketing surveillance study of fasudil treatment after aneurysmal subarachnoid hemorrhage. Surg Neurol 68:126–131, discussion 131-132

    PubMed  Google Scholar 

  • Takahashi M, Mukai H, Toshimori M, Miyamoto M, Ono Y (1998) Proteolytic activation of PKN by caspase-3 or related protease during apoptosis. Proc Natl Acad Sci USA 95:11566–11571

    PubMed  CAS  PubMed Central  Google Scholar 

  • Takemoto M, Sun J, Hiroki J, Shimokawa H, Liao JK (2002) Rho-kinase mediates hypoxia-induced downregulation of endothelial nitric oxide synthase. Circulation 106:57–62

    PubMed  CAS  Google Scholar 

  • Tanaka H, Yamashita T, Yachi K, Fujiwara T, Yoshikawa H, Tohyama M (2004) Cytoplasmic p21(Cip1/WAF1) enhances axonal regeneration and functional recovery after spinal cord injury in rats. Neuroscience 127:155–164

    PubMed  CAS  Google Scholar 

  • Tanizaki H, Egawa G, Inaba K, Honda T, Nakajima S, Moniaga CS, Otsuka A, Ishizaki T, Tomura M, Watanabe T, Miyachi Y, Narumiya S, Okada T, Kabashima K (2010) Rho-mDia1 pathway is required for adhesion, migration, and T-cell stimulation in dendritic cells. Blood 116:5875–5884

    PubMed  CAS  Google Scholar 

  • Teixeira CE, Ying Z, Webb RC (2005) Proerectile effects of the Rho-kinase inhibitor (S)-(+)-2-methyl-1-[(4-methyl-5-isoquinolinyl)sulfonyl]homopiperazine (H-1152) in the rat penis. J Pharmacol Exp Ther 315:155–162

    PubMed  CAS  Google Scholar 

  • Thumkeo D, Keel J, Ishizaki T, Hirose M, Nonomura K, Oshima H, Oshima M, Taketo MM, Narumiya S (2003) Targeted disruption of the mouse rho-associated kinase 2 gene results in intrauterine growth retardation and fetal death. Mol Cell Biol 23:5043–5055

    PubMed  CAS  PubMed Central  Google Scholar 

  • Thumkeo D, Shimizu Y, Sakamoto S, Yamada S, Narumiya S (2005) ROCK-I and ROCK-II cooperatively regulate closure of eyelid and ventral body wall in mouse embryo. Genes Cells 10:825–834

    PubMed  CAS  Google Scholar 

  • Thumkeo D, Shinohara R, Watanabe K, Takebayashi H, Toyoda Y, Tohyama K, Ishizaki T, Furuyashiki T, Narumiya S (2011) Deficiency of mDia, an actin nucleator, disrupts integrity of neuroepithelium and causes periventricular dysplasia. PLoS One 6:e25465

    PubMed  CAS  PubMed Central  Google Scholar 

  • Thurston SF, Kulacz WA, Shaikh S, Lee JM, Copeland JW (2012) The ability to induce microtubule acetylation is a general feature of formin proteins. PLoS One 7:e48041

    PubMed  CAS  PubMed Central  Google Scholar 

  • Tian B, Kaufman PL (2005) Effects of the Rho kinase inhibitor Y-27632 and the phosphatase inhibitor calyculin A on outflow facility in monkeys. Exp Eye Res 80:215–225

    PubMed  CAS  Google Scholar 

  • Tokushige H, Inatani M, Nemoto S, Sakaki H, Katayama K, Uehata M, Tanihara H (2007) Effects of topical administration of y-39983, a selective rho-associated protein kinase inhibitor, on ocular tissues in rabbits and monkeys. Invest Ophthalmol Vis Sci 48:3216–3222

    PubMed  Google Scholar 

  • Tominaga T, Ishizaki T, Narumiya S, Barber DL (1998) p160ROCK mediates RhoA activation of Na-H exchange. EMBO J 17:4712–4722

    PubMed  CAS  PubMed Central  Google Scholar 

  • Torbett NE, Casamassima A, Parker PJ (2003) Hyperosmotic-induced protein kinase N 1 activation in a vesicular compartment is dependent upon Rac1 and 3-phosphoinositide-dependent kinase 1. J Biol Chem 278:2344–32351

    Google Scholar 

  • Toyoda Y, Shinohara R, Thumkeo D, Kamijo H, Nishimaru H, Hioki H, Kaneko T, Ishizaki T, Furuyashiki T, Narumiya S (2013) EphA4-dependent axon retraction and midline localization of Ephrin-B3 are disrupted in the spinal cord of mice lacking mDia1 and mDia3 in combination. Genes Cells 18:873–885

    PubMed  CAS  Google Scholar 

  • Tsuji T, Ishizaki T, Okamoto M, Higashida C, Kimura K, Furuyashiki T, Arakawa Y, Birge RB, Nakamoto T, Hirai H, Narumiya S (2002) ROCK and mDia1 antagonize in Rho-dependent Rac activation in Swiss 3T3 fibroblasts. J Cell Biol 157:819–830

    PubMed  CAS  PubMed Central  Google Scholar 

  • Uehata M, Ishizaki T, Satoh H, Ono T, Kawahara T, Morishita T, Tamakawa H, Yamagami K, Inui J, Maekawa M, Narumiya S (1997) Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature 389:990–994

    PubMed  CAS  Google Scholar 

  • Wahl S, Barth H, Ciossek T, Aktories K, Mueller BK (2000) Ephrin-A5 induces collapse of growth cones by activating Rho and Rho kinase. J Cell Biol 149:263–270

    PubMed  CAS  PubMed Central  Google Scholar 

  • Waki M, Yoshida Y, Oka T, Azuma M (2001) Reduction of intraocular pressure by topical administration of an inhibitor of the Rho-associated protein kinase. Curr Eye Res 22:470–474

    PubMed  CAS  Google Scholar 

  • Wallar BJ, Deward AD, Resau JH, Alberts AS (2006) RhoB and the mammalian Diaphanous-related formin mDia2 in endosome trafficking. Exp Cell Res 313:560–571

    PubMed  Google Scholar 

  • Watanabe G, Saito Y, Madaule P, Ishizaki T, Fujisawa K, Morii N, Mukai H, Ono Y, Kakizuka A, Narumiya S (1996) Protein kinase N (PKN) and PKN-related protein rhophilin as targets of small GTPase Rho. Science 271:645–648

    PubMed  CAS  Google Scholar 

  • Watanabe N, Madaule P, Reid T, Ishizaki T, Watanabe G, Kakizuka A, Saito Y, Nakao K, Jockusch BM, Narumiya S (1997) p140mDia, a mammalian homolog of Drosophila diaphanous, is a target protein for Rho small GTPase and is a ligand for profilin. EMBO J 16:3044–3056

    PubMed  CAS  PubMed Central  Google Scholar 

  • Watanabe N, Kato T, Fujita A, Ishizaki T, Narumiya S (1999) Cooperation between mDia1 and ROCK in Rho-induced actin reorganization. Nat Cell Biol 1:136–143

    PubMed  CAS  Google Scholar 

  • Watanabe K, Ueno M, Kamiya D, Nishiyama A, Matsumura M, Wataya T, Takahashi JB, Nishikawa S, Nishikawa S, Muguruma K, Sasai Y (2007) A ROCK inhibitor permits survival of dissociated human embryonic stem cells. Nat Biotechnol 25:681–686

    PubMed  CAS  Google Scholar 

  • Watanabe S, Ando Y, Yasuda S, Hosoya H, Watanabe N, Ishizaki T, Narumiya S (2008) mDia2 induces the actin scaffold for the contractile ring and stabilizes its position during cytokinesis in NIH 3T3 cells. Mol Biol Cell 19:2328–2338

    PubMed  CAS  PubMed Central  Google Scholar 

  • Watanabe S, Okawa K, Miki T, Sakamoto S, Morinaga T, Segawa K, Arakawa T, Kinoshita M, Ishizaki T, Narumiya S (2010) Rho and anillin-dependent control of mDia2 localization and function in cytokinesis. Mol Biol Cell 21:3193–3204

    PubMed  CAS  PubMed Central  Google Scholar 

  • Watanabe S, De Zan T, Ishizaki T, Narumiya S (2013a) Citron kinase mediates transition from constriction to abscission through its coiled-coil domain. J Cell Sci 126:1773–1784

    PubMed  CAS  Google Scholar 

  • Watanabe S, De Zan T, Ishizaki T, Yasuda S, Kamijo H, Yamada D, Aoki T, Kiyonari H, Kaneko H, Shimizu R, Yamamoto M, Goshima G, Narumiya S (2013b) Loss of a Rho-Regulated Actin Nucleator, mDia2, Impairs Cytokinesis during Mouse Fetal Erythropoiesis. Cell Rep 5:926–932

    PubMed  CAS  Google Scholar 

  • Wei L, Roberts W, Wang L, Yamada M, Zhang S, Zhao Z, Rivkees SA, Schwartz RJ, Imanaka-Yoshida K (2001) Rho kinases play an obligatory role in vertebrate embryonic organogenesis. Development 128:2953–2962

    PubMed  CAS  Google Scholar 

  • Wen Y, Eng CH, Schmoranzer J, Cabrera-Poch N, Morris EJ, Chen M, Wallar BJ, Alberts AS, Gundersen GG (2004) EB1 and APC bind to mDia to stabilize microtubules downstream of Rho and promote cell migration. Nat Cell Biol 6:820–830

    PubMed  CAS  Google Scholar 

  • Wheeler AP, Ridley AJ (2004) Why three Rho proteins? RhoA, RhoB, RhoC, and cell motility. Exp Cell Res 301:43–49

    PubMed  CAS  Google Scholar 

  • Whitlock NA, Harrison B, Mixon T, Yu XQ, Wilson A, Gerhardt B, Eberhart DE, Abuin A, Rice DS (2009) Decreased intraocular pressure in mice following either pharmacological or genetic inhibition of ROCK. J Ocul Pharmacol Ther 25:187–194

    PubMed  CAS  Google Scholar 

  • Wick MJ, Dong LQ, Riojas RA, Ramos FJ, Liu F (2000) Mechanism of phosphorylation of protein kinase B/Akt by a constitutively active 3-phosphoinositide-dependent protein kinase-1. J Biol Chem 275:40400–40406

    PubMed  CAS  Google Scholar 

  • Wingard CJ, Johnson JA, Holmes A, Prikosh A (2003) Improved erectile function after Rho-kinase inhibition in a rat castrate model of erectile dysfunction. Am J Physiol Regul Integr Comp Physiol 284:R1572–R1579

    PubMed  CAS  Google Scholar 

  • Wolfrum S, Dendorfer A, Rikitake Y, Stalker TJ, Gong Y, Scalia R, Dominiak P, Liao JK (2004) Inhibition of Rho-kinase leads to rapid activation of phosphatidylinositol 3-kinase/protein kinase Akt and cardiovascular protection. Arterioscler Thromb Vasc Biol 24:1842–1847

    PubMed  CAS  PubMed Central  Google Scholar 

  • Xue W, Krasnitz A, Lucito R, Sordella R, Vanaelst L, Cordon-Cardo C, Singer S, Kuehnel F, Wigler M, Powers S, Zender L, Lowe SW (2008) DLC1 is a chromosome 8p tumor suppressor whose loss promotes hepatocellular carcinoma. Genes Dev 22:1439–1444

    PubMed  CAS  PubMed Central  Google Scholar 

  • Yamaguchi H, Miwa Y, Kasa M, Kitano K, Amano M, Kaibuchi K, Hakoshima T (2006) Structural basis for induced-fit binding of Rho-kinase to the inhibitor Y-27632. J Biochem 140:305–311

    PubMed  CAS  Google Scholar 

  • Yamana N, Arakawa Y, Nishino T, Kurokawa K, Tanji M, Itoh RE, Monypenny J, Ishizaki T, Bito H, Nozaki K, Hashimoto N, Matsuda M, Narumiya S (2006) The Rho-mDia1 pathway regulates cell polarity and focal adhesion turnover in migrating cells through mobilizing Apc and c-Src. Mol Cell Biol 26:6844–6858

    PubMed  CAS  PubMed Central  Google Scholar 

  • Yamashiro S, Totsukawa G, Yamakita Y, Sasaki Y, Madaule P, Ishizaki T, Narumiya S, Matsumura F (2003) Citron kinase, a Rho-dependent kinase, induces di-phosphorylation of regulatory light chain of myosin II. Mol Biol Cell 14:1745–1756

    PubMed  CAS  PubMed Central  Google Scholar 

  • Yamashita T, Higuchi H, Tohyama M (2002) The p75 receptor transduces the signal from myelin-associated glycoprotein to Rho. J Cell Biol 157:565–570

    PubMed  CAS  PubMed Central  Google Scholar 

  • Yang C, Czech L, Gerboth S, Kojima S, Scita G, Svitkina T (2007) Novel roles of formin mDia2 in lamellipodia and filopodia formation in motile cells. PLoS Biol 5:e317

    PubMed  PubMed Central  Google Scholar 

  • Yasuda S, Oceguera-Yanez F, Kato T, Okamoto M, Yonemura S, Terada Y, Ishizaki T, Narumiya S (2004) Cdc42 and mDia3 regulate microtubule attachment to kinetochores. Nature 428:767–771

    PubMed  CAS  Google Scholar 

  • Yasui T, Sakakibara-Yada K, Nishimura T, Morita K, Tada S, Mosialos G, Kieff E, Kikutani H (2012) Protein kinase N1, a cell inhibitor of Akt kinase, has a central role in quality control of germinal center formation. Proc Natl Acad Sci USA 109:21022–21027

    PubMed  CAS  PubMed Central  Google Scholar 

  • Yoneda A, Multhaupt HA, Couchman JR (2005) The Rho kinases I and II regulate different aspects of myosin II activity. J Cell Biol 170:443–453

    PubMed  CAS  PubMed Central  Google Scholar 

  • Yoneda A, Ushakov D, Multhaupt HA, Couchman JR (2007) Fibronectin matrix assembly requires distinct contributions from Rho kinases I and -II. Mol Biol Cell 18:66–75

    PubMed  CAS  PubMed Central  Google Scholar 

  • Zhang W, Vazquez L, Apperson M, Kennedy MB (1999) Citron binds to PSD-95 at glutamatergic synapses on inhibitory neurons in the hippocampus. J Neurosci 19:96–108

    PubMed  CAS  Google Scholar 

  • Zhou Z, Meng Y, Asrar S, Todorovski Z, Jia Z (2009) A critical role of rho-kinase ROCK2 in the regulation of spine and synaptic function. Neuropharmacology 56:81–89

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacology, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama, Yufu, Oita, 879-5593, Japan

    Toshimasa Ishizaki

  2. Center for Innovation in Immunoregulative Technology and Therapeutics, Kyoto University Graduate School of Medicine, Kyoto, Shogoin Kawara-cho, Sakyo-ku, Kyoto, 606-8507, Japan

    Shuh Narumiya

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  1. Max-Planck-Institute of Molecular Physiology, Dortmund, Nordrhein-Westfalen, Germany

    Alfred Wittinghofer

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Ishizaki, T., Narumiya, S. (2014). Molecular Structures, Cellular Functions, and Physiological Roles of Rho Effectors. In: Wittinghofer, A. (eds) Ras Superfamily Small G Proteins: Biology and Mechanisms 1. Springer, Vienna. https://doi.org/10.1007/978-3-7091-1806-1_16

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