Alternative titles; symbols
HGNC Approved Gene Symbol: ROCK1
Cytogenetic location: 18q11.1 Genomic coordinates (GRCh38): 18:20,946,906-21,111,813 (from NCBI)
The protein serine/threonine kinase ROCK1 is a downstream effector for the small GTPase Rho (RHOA; 165390). ROCK1 is involved in a wide range of physiologic and pathologic processes that require remodeling of the actin cytoskeleton and the formation of actomyosin bundles, including cell contractility and migration (summary by Shimizu et al., 2005).
The small GTPase Rho regulates formation of focal adhesions and stress fibers of fibroblasts, as well as adhesion and aggregation of platelets and lymphocytes by shuttling between the inactive GDP-bound form and the active GTP-bound form. Rho is also essential in cytokinesis and plays a role in transcriptional activation by serum response factor (600589). Ishizaki et al. (1996) identified the protein serine/threonine kinase ROCK1, which they called p160-ROCK, that is activated when bound to the GTP-bound form of Rho.
Fujisawa et al. (1996) reported that the full-length 1,354-amino acid human ROCK1 protein has an N-terminal kinase domain, followed by a 600-amino acid alpha-helical region, a pleckstrin (PLEK; 173570) homology domain, and a C-terminal cysteine-rich region. The alpha-helical region includes a cysteine-rich zinc finger. Fujisawa et al. (1996) localized the Rho-binding domain of ROCK1 to residues 934 to 1015, near the C-terminal end of the alpha-helical region.
By X-gal staining of Rock1 +/- mouse embryos, Shimizu et al. (2005) found widespread Rock1 expression, with staining detected in skin, heart, aorta, umbilical blood vessels, and dorsal root ganglia.
Hartz (2014) mapped the ROCK1 gene to chromosome 18q11.1 based on an alignment of the ROCK1 sequence (GenBank AB208965) and the genomic sequence (GRCh37).
Maekawa et al. (1999) demonstrated that ROCK1 phosphorylates and activates LIM kinase (see 601329) which, in turn, phosphorylates cofilin (601442), inhibiting its actin-depolymerizing activity. They diagrammed proposed signaling pathways for Rho-induced remodeling of the actin cytoskeleton in their Figure 3C.
Bito et al. (2000) found that up- and downregulation of Rock1 in cultured mouse cerebellar granule neurons during the first day in vitro affected axon numbers and growth cone size. Inhibition of endogenous Rock1 was sufficient to initiate formation of axonal processes and to facilitate axonal maturation during early stages of axonogenesis, with little effect on axon elongation. Rock1 also negatively controlled the size and motility of growth cones at the tip of extending axons.
Anderson and SundarRaj (2001) noted that increased expression of ROCK1 is associated with limbal to corneal epithelial transition on the ocular surface. In a study of the expression of ROCK1 during the cell cycle of the corneal epithelium, they found that levels of ROCK1 were significantly lower in the G1 phase than in the S and G0 phases. Downregulation of ROCK1 during the G1 phase is due in part to the decreased levels of its mRNA. The authors concluded that ROCK1 may have a role in the progression of the cell cycle in the corneal epithelial cells as they migrate centripetally from the limbus across the corneal surface.
Nakamura et al. (2001) studied the role of Rho in the migration of corneal epithelial cells in rabbit. They detected both ROCK1 and ROCK2 (604002) in the corneal epithelium at protein and mRNA levels. They found that exoenzyme C3, a Rho inhibitor, inhibits corneal epithelial migration in a dose-dependent manner and prevents the stimulatory effect of the Rho activator lysophosphatidic acid (LPA). Both cytochalasin B, an inhibitor of actin filament assembly, and ML7, an inhibitor of myosin light chain kinase, also prevent LPA stimulation of epithelial migration. The authors suggested that Rho mediates corneal epithelial migration in response to external stimuli by regulating the organization of the actin cytoskeleton.
Rao et al. (2001) investigated the role of Rho kinase in the modulation of aqueous humor outflow facility. The treatment of human trabecular meshwork and canal of Schlemm cells with a Rho kinase-specific inhibitor led to significant but reversible changes in cell shape and decreased actin stress fibers, focal adhesions, and protein phosphotyrosine staining. Based on the Rho kinase inhibitor-induced changes in myosin light chain (see 160780) phosphorylation and actomyosin organization, the authors suggested that cellular relaxation and loss of cell-substratum adhesions in the human trabecular meshwork and canal of Schlemm cells could result in either increased paracellular fluid flow across the canal of Schlemm or altered flow pathway through the juxtacanalicular tissue, thereby lowering resistance to outflow. They suggested Rho kinase as a potential target for the development of drugs to modulate intraocular pressure in glaucoma patients.
Tsuji et al. (2002) found that treatment of serum-starved Swiss 3T3 fibroblasts with specific inhibitors of the Rho downstream effectors Rock and Dia1 (602121) suppressed formation of LPA-induced stress fibers and focal adhesions. Inhibition of Rock, but not Dia1, also induced membrane ruffles and focal complexes. Rock activation resulted in tyrosine phosphorylation of focal adhesion kinase (FAK, or PTK2; 600758) and paxillin (PXN; 602505), whereas DIA1 activation resulted in phosphorylation of Cas (BCAR1; 602941), followed by activation of Rac (RAC1; 602048). In addition, Rock antagonized Rac activation.
Using immunofluorescence analysis, electron microscopy, and RNA interference, Chevrier et al. (2002) found that ROCK was required for centrosome positioning during the cell cycle in bovine kidney and HeLa cells. ROCK predominantly bound to the mother centriole and an intercentriolar linker. Inhibition of ROCK provoked centrosome splitting in G1 and abnormal movement of the mother centriole, which is normally motionless at the cell center during G1. ROCK inhibition after anaphase triggered migration of the mother centriole to the midbody, followed by completion of cell division. Chevrier et al. (2002) concluded that ROCK is required for centrosome positioning and centrosome-dependent exit from mitosis.
Lamprecht et al. (2002) noted that the p190 RhoGAP (ARHGAP35; 605277)-ROCK pathway regulates dendrite and axon morphology during neural development. They found that Rock played a role in memory formation in rats. Following fear conditioning, Rock became associated with Grb2 (108355) in the lateral amygdala. RasGAP (RASA1; 139150) and Shc (SHC1; 600560) also associated in the Grb2 complex following fear conditioning. Inhibition of Rock during fear conditioning impaired long-term, but not short-term, memory.
Zhou et al. (2003) found that Rho and its effector Rock1 preferentially regulated the amount of A-beta(42), a highly amyloidogenic, 42-residue amyloid beta (104760) peptide, produced in vitro and that only those NSAIDs (nonsteroidal antiinflammatory drugs) effective as Rho inhibitors lowered A-beta(42). Administration of a selective Rock inhibitor also preferentially lowered brain levels of A-beta(42) in a transgenic mouse model of Alzheimer disease (104300). Thus, Zhou et al. (2003) concluded that the Rho-Rock pathway may regulate amyloid precursor protein processing, and a subset of NSAIDs can reduce A-beta(42) through inhibition of Rho activity.
RhoA signaling plays a critical role in many cellular processes, including cell migration. Valderrama et al. (2006) showed that the vaccinia F11L protein interacts directly with RhoA, inhibiting its signaling by blocking the interaction with its downstream effectors ROCK and mammalian Dia (300108). RNA interference-mediated depletion of F11L during infection resulted in the absence of vaccinia-induced cell motility and inhibition of viral morphogenesis. Disruption of the RhoA binding site in F11L, which resembles that of ROCK, led to an identical phenotype. Thus, Valderrama et al. (2006) concluded that inhibition of RhoA signaling is required for both vaccinia morphogenesis and virus-induced cell motility.
In 3-dimensional matrices, cancer cells move with a rounded, amoeboid morphology that is controlled by ROCK1-dependent contraction of actomyosin. Using human cancer cell lines, Pinner and Sahai (2008) showed that PDK1 (PDPK1; 605213) was required for phosphorylation of myosin light chain and cell motility, both on deformable gels and in vivo. Depletion of PDK1 via RNA interference altered the localization of ROCK1 and reduced its ability to drive cortical actomyosin contraction. This form of ROCK1 regulation did not require PDK1 kinase activity. Instead, PDK1 competed directly with RHOE (RND3; 602924) for binding to ROCK1 and opposed inhibition of ROCK1 by RHOE.
Vemula et al. (2010) found that Rock1 -/- mouse macrophages and neutrophils exhibited increased migration in vitro. Rock1 -/- bone marrow-derived macrophages (BMMs) showed increased adhesion on a fibronectin (see 135600) fragment. Flow cytometric analysis revealed that Rock1 -/- BMMs had elevated F-actin compared with controls. Rock1 deficiency was associated with reduced receptor-mediated Pten (601728) activation via serine and threonine phosphorylation, accumulation of phosphatidylinositol 3-phosphate, and elevated downstream Pten targets. Vemula et al. (2010) concluded that ROCK1 is a physiologic regulator of PTEN that represses excessive recruitment of macrophages and neutrophils during acute inflammation.
Using knockdown and overexpression studies, Chun et al. (2012) found that Rock1 was necessary and sufficient to control insulin (INS; 176730)-induced Glut4 (SLC2A4; 138190) translocation and glucose transport in 3T3-L1 mouse adipocytes and L6 rat myoblasts. The amount of Rock1, but not Rock2, increased in the low-density microsome fraction of adipocytes and myoblasts following insulin stimulation. Overexpression of Rock1 significantly increased basal and insulin-stimulated glucose transport in 3T3-L1 adipocytes, and inhibition of actin polymerization abrogated this effect.
Bivalacqua et al. (2004) studied the contribution of RhoA/Rho kinase signaling to erectile dysfunction in streptozotocin (STZ) diabetic rats. Rho kinase and eNOS (163729) colocalized in the endothelium of corpus cavernosum, and RhoA and Rho kinase abundance and Mypt1 (602021) phosphorylation were elevated in STZ diabetic rat penis. In addition, eNOS protein expression, cavernosal constitutive NOS activity, and cGMP levels were reduced in STZ diabetic rat penis. Bivalacqua et al. (2004) introduced a dominant-negative RhoA mutant and found that erectile responses in the STZ diabetic rats improved to values similar to controls.
Shimizu et al. (2005) obtained Rock1 -/- mice at the expected mendelian ratio. Rock1 -/- mice showed variable severity of eyes open at birth and failure of ventral body wall closure. The latter resulted in omphalocele, which included liver and small intestine in some Rock1 -/- mice. Many Rock1 -/- newborns succumbed to cannibalism of the omphalocele by the mother in her process of clearing the placenta and umbilicus. Surviving Rock1 -/- adults had no other organ or tissue abnormalities, were fertile and apparently healthy, and displayed normal wound healing. However, some developed an apparent secondary proliferative inflammation of the eyelid. Rock1 +/- mice appeared normal. Eyelids of Rock1 -/- mice showed reduced Egf (131530)-induced phosphorylation of myosin light chain (Mlc) in keratinocytes and absence of thick actomyosin bundles connecting keratinocytes at the leading edge of the closing eyelid. In wildtype mice, these structures contracted like a purse string, resulting in eyelid closure prior to birth. The failure of umbilical ring closure in Rock1 -/- mice was also due to absence of Mlc phosphorylation and failure of actomyosin assembly in epithelial cells of the umbilical ring. The eyelid and umbilical ring defects in Rock1 -/- mice appeared superficially similar, but they had distinct elements of upstream signaling, and the severity of the phenotypes was not correlated.
Rikitake et al. (2005) obtained reduced numbers of Rock1 -/- mice at birth, and some Rock1 -/- pups that were recovered showed defects in eyelid closure and omphalocele. Rock1 +/- mice appeared normal and showed normal cardiac structure and function and agonist-induced hypertrophy. However, Rock1 +/- hearts exhibited resistance to agonist-induced perivascular fibrosis and reduced expression of fibrosis markers. Rock1 +/- hearts were also resistant to fibrosis due to transaortic constriction or myocardial infarction.
Lee et al. (2009) found no detectable anatomic abnormalities in Rock1 +/- or Rock1 -/- mice of mixed genetic background. Although Rock1 -/- mice exhibited normal glucose tolerance at 16 to 18 weeks of age, they showed insulin resistance and increased glucose-induced insulin secretion. Insulin signaling was impaired in Rock1 -/- skeletal muscle.
Impaired leptin (LEP; 164160) signaling in the hypothalamus causes hyperphagia, which promotes adiposity and weight gain. Huang et al. (2012) found that mice with targeted Rock1 deletion in either Pomc (176830)- or Agrp (602311)-expressing hypothalamic neurons displayed obesity and impaired leptin sensitivity. Deletion of Rock1 in arcuate nucleus enhanced food intake, resulting in severe obesity. Rock1 regulated feeding behavior and adiposity by targeting Jak2 (147796) in the leptin receptor (LEPR; 601007) signaling pathway.
Anderson, S. C., SundarRaj, N. Regulation of a Rho-associated kinase expression during the corneal epithelial cell cycle. Invest. Ophthal. Vis. Sci. 42: 933-940, 2001. [PubMed: 11274069]
Bito, H., Furuyashiki, T., Ishihara, H., Shibasaki, Y., Ohashi, K., Mizuno, K., Maekawa, M., Ishizaki, T., Narumiya, S. A critical role for a Rho-associated kinase, p160ROCK, in determining axon outgrowth in mammalian CNS neurons. Neuron 26: 431-441, 2000. [PubMed: 10839361] [Full Text: https://doi.org/10.1016/s0896-6273(00)81175-7]
Bivalacqua, T. J., Champion, H. C., Usta, M. F., Cellek, S., Chitaley, K., Webb, R. C., Lewis, R. L., Mills, T. M., Hellstrom, W. J. G., Kadowitz, P. J. RhoA/Rho-kinase suppresses endothelial nitric oxide synthase in the penis: a mechanism for diabetes-associated erectile dysfunction. Proc. Nat. Acad. Sci. 101: 9121-9126, 2004. [PubMed: 15184671] [Full Text: https://doi.org/10.1073/pnas.0400520101]
Chevrier, V., Piel, M., Collomb, N., Saoudi, Y., Frank, R., Paintrand, M., Narumiya, S., Bornens, M., Job, D. The Rho-associated protein kinase p160ROCK is required for centrosome positioning. J. Cell Biol. 157: 807-817, 2002. [PubMed: 12034773] [Full Text: https://doi.org/10.1083/jcb.200203034]
Chun, K.-H., Araki, K., Jee, Y., Lee, D.-H., Oh, B.-C., Huang, H., Park, K. S., Lee, S. W., Zabolotny, J. M., Kim, Y.-B. Regulation of glucose transport by ROCK1 differs from that of ROCK2 and is controlled by actin polymerization. Endocrinology 153: 1649-1662, 2012. [PubMed: 22355071] [Full Text: https://doi.org/10.1210/en.2011-1036]
Fujisawa, K., Fujita, A., Ishizaki, T., Saito, Y., Narumiya, S. Identification of the Rho-binding domain of p160-ROCK, a Rho-associated coiled-coil containing protein kinase. J. Biol. Chem. 271: 23022-23028, 1996. [PubMed: 8798490] [Full Text: https://doi.org/10.1074/jbc.271.38.23022]
Hartz, P. A. Personal Communication. Baltimore, Md. 3/21/2014.
Huang, H., Kong, D., Byun, K. H., Ye, C., Koda, S., Lee, D. H., Oh, B.-C., Lee, S. W., Lee, B., Zabolotny, J. M., Kim, M. S., Bjorbaek, C., Lowell, B. B., Kim, Y.-B. Rho-kinase regulates energy balance by targeting hypothalamic leptin receptor signaling. Nature Neurosci. 15: 1391-1398, 2012. [PubMed: 22941110] [Full Text: https://doi.org/10.1038/nn.3207]
Ishizaki, T., Maekawa, M., Fujisawa, K., Okawa, K., Iwamatsu, A., Fujita, A., Watanabe, N., Saito, Y., Kakisuka, A., Morii, N., Narumiya, S. 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, 1996. [PubMed: 8617235]
Lamprecht, R., Farb, C. R., LeDoux, J. E. Fear memory formation involves p190 RhoGAP and ROCK proteins through a GRB2-mediated complex. Neuron 36: 727-738, 2002. [PubMed: 12441060] [Full Text: https://doi.org/10.1016/s0896-6273(02)01047-4]
Lee, D. H., Shi, J., Jeoung, N. H., Kim, M. S., Zabolotny, J. M., Lee, S. W., White, M. F., Wei, L., Kim, Y.-B. Targeted disruption of ROCK1 causes insulin resistance in vivo. J. Biol. Chem. 284: 11776-11780, 2009. [PubMed: 19276091] [Full Text: https://doi.org/10.1074/jbc.C900014200]
Maekawa, M., Ishizaki, T., Boku, S., Watanabe, N., Fujita, A., Iwamatsu, A., Obinata, T., Ohashi, K., Mizuno, K., Narumiya, S. Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. Science 285: 895-898, 1999. [PubMed: 10436159] [Full Text: https://doi.org/10.1126/science.285.5429.895]
Nakamura, M., Nagano, T., Chikama, T., Nishida, T. Role of the small GTP-binding protein Rho in epithelial cell migration in the rabbit cornea. Invest. Ophthal. Vis. Sci. 42: 941-947, 2001. [PubMed: 11274070]
Pinner, S., Sahai, E. PDK1 regulates cancer cell motility by antagonising inhibition of ROCK1 by RhoE. Nature Cell Biol. 10: 127-137, 2008. Note: Erratum: Nature Cell Biol. 10: 370 only, 2008. [PubMed: 18204440] [Full Text: https://doi.org/10.1038/ncb1675]
Rao, P. V., Deng, P.-F., Kumar, J., Epstein, D. L. Modulation of aqueous humor outflow facility by the Rho kinase-specific inhibitor Y-27632. Invest. Ophthal. Vis. Sci. 42: 1029-1037, 2001. Note: Erratum: Invest. Ophthal. Vis. Sci. 42: 1690 only, 2001. [PubMed: 11274082]
Rikitake, Y., Oyama, N., Wang, C.-Y. C., Noma, K., Satoh, M., Kim, H.-H., Liao, J. K. Decreased perivascular fibrosis but not cardiac hypertrophy in ROCK1 +/- haploinsufficient mice. Circulation 112: 2959-2965, 2005. [PubMed: 16260635] [Full Text: https://doi.org/10.1161/CIRCULATIONAHA.105.584623]
Shimizu, Y., Thumkeo, D., Keel, J., Ishizaki, T., Oshima, H., Oshima, M., Noda, Y., Matsumura, F., Taketo, M. M., Narumiya, S. ROCK-I regulates closure of the eyelids and ventral body wall by inducing assembly of actomyosin bundles. J. Cell Biol. 168: 941-953, 2005. [PubMed: 15753128] [Full Text: https://doi.org/10.1083/jcb.200411179]
Tsuji, T., Ishizaki, T., Okamoto, M., Higashida, C., Kimura, K., Furuyashiki, T., Arakawa, Y., Birge, R. B., Nakamoto, T., Hirai, H., Narumiya, S. ROCK and mDia1 antagonize in Rho-dependent Rac activation in Swiss 3T3 fibroblasts. J. Cell Biol. 157: 819-830, 2002. [PubMed: 12021256] [Full Text: https://doi.org/10.1083/jcb.200112107]
Valderrama, F., Cordeiro, J. V., Schleich, S., Frischknecht, F., Way, M. Vaccinia virus-induced cell motility requires F11L-mediated inhibition of RhoA signaling. Science 311: 377-381, 2006. [PubMed: 16424340] [Full Text: https://doi.org/10.1126/science.1122411]
Vemula, S., Shi, J., Hanneman, P., Wei, L., Kapur, R. ROCK1 functions as a suppressor of inflammatory cell migration by regulating PTEN phosphorylation and stability. Blood 115: 1785-1796, 2010. [PubMed: 20008297] [Full Text: https://doi.org/10.1182/blood-2009-08-237222]
Zhou, Y., Su, Y., Li, B., Liu, F., Ryder, J. W., Wu, X., Gonzalez-DeWhitt, P. A., Gelfanova, V., Hale, J. E., May, P. C., Paul, S. M., Ni, B. Nonsteroidal anti-inflammatory drugs can lower amyloidogenic A-beta(42) by inhibiting Rho. Science 302: 1215-1217, 2003. [PubMed: 14615541] [Full Text: https://doi.org/10.1126/science.1090154]