RBCC Red Blood Cell Collection

RHOA (ARH12, ARHA, RHO12) [Confidence: high (present in two of the MS resources)]
Transforming protein RhoA (Rho cDNA clone 12; h12; Flags: Precursor)

UniProt P61586
ID RHOA_HUMAN Reviewed; 193 AA.
AC P61586; P06749; Q53HM4; Q5U024; Q9UDJ0; Q9UEJ4;
DT 01-JAN-1988, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-JAN-1988, sequence version 1.
DT 22-JAN-2014, entry version 125.
DE RecName: Full=Transforming protein RhoA;
DE AltName: Full=Rho cDNA clone 12;
DE Short=h12;
DE Flags: Precursor;
GN Name=RHOA; Synonyms=ARH12, ARHA, RHO12;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=3822842; DOI=10.1093/nar/15.4.1869;
RA Yeramian P., Chardin P., Madaule P., Tavitian A.;
RT "Nucleotide sequence of human rho cDNA clone 12.";
RL Nucleic Acids Res. 15:1869-1869(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Retina;
RX PubMed=7835413; DOI=10.1006/exer.1994.1102;
RA Fagan K.P., Oliveira L., Pittler S.J.;
RT "Sequence of rho small GTP-binding protein cDNAs from human retina and
RT identification of novel 5' end cloning artifacts.";
RL Exp. Eye Res. 59:235-237(1994).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RA Puhl H.L. III, Ikeda S.R., Aronstam R.S.;
RT "cDNA clones of human proteins involved in signal transduction
RT sequenced by the Guthrie cDNA resource center (www.cdna.org).";
RL Submitted (APR-2002) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Adipose tissue;
RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y.,
RA Tanaka A., Yokoyama S.;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Esophageal carcinoma;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16641997; DOI=10.1038/nature04728;
RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R.,
RA Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R.,
RA Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V.,
RA Hume J., Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R.,
RA Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Wei S.,
RA Wheeler D.A., Wright M.W., Worley K.C., Yuan Y., Zhang Z., Adams C.Q.,
RA Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clendenning J., Clerc-Blankenburg K.P., Chen R., Chen Z., Davis C.,
RA Delgado O., Dinh H.H., Dong W., Draper H., Ernst S., Fu G.,
RA Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., Hao B.,
RA Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., Jackson L.R.,
RA Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., Liu J.,
RA Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Palmeiri A.,
RA Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J.,
RA Zhang X., Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H.,
RA Reinhardt R., Naylor S.L., Yang H., Olson M., Weinstock G.,
RA Gibbs R.A.;
RT "The DNA sequence, annotation and analysis of human chromosome 3.";
RL Nature 440:1194-1198(2006).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain, and Colon;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [9]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 5-193.
RC TISSUE=Mammary cancer;
RX PubMed=8039707; DOI=10.1016/0378-1119(94)90382-4;
RA Moscow J.A., He R., Gudas J.M., Cowan K.H.;
RT "Utilization of multiple polyadenylation signals in the human RHOA
RT protooncogene.";
RL Gene 144:229-236(1994).
RN [10]
RP PROTEIN SEQUENCE OF 28-39; 45-57; 78-86; 130-144; 146-162 AND 165-184,
RP AND ADP-RIBOSYLATION AT ASN-41.
RC TISSUE=Platelet;
RX PubMed=1328215;
RA Nemoto Y., Namba T., Teru-uchi T., Ushikubi F., Morii N., Narumiya S.;
RT "A rho gene product in human blood platelets. I. Identification of the
RT platelet substrate for botulinum C3 ADP-ribosyltransferase as rhoA
RT protein.";
RL J. Biol. Chem. 267:20916-20920(1992).
RN [11]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 137-193.
RX PubMed=1556108;
RA Moscow J.A., Morrow C.S., He R., Mullenbach G.T., Cowan K.H.;
RT "Structure and function of the 5'-flanking sequence of the human
RT cytosolic selenium-dependent glutathione peroxidase gene (hgpx1).";
RL J. Biol. Chem. 267:5949-5958(1992).
RN [12]
RP INTERACTION WITH ROCK1.
RX PubMed=8617235;
RA Ishizaki T., Maekawa M., Fujisawa K., Okawa K., Iwamatsu A.,
RA Fujita A., Watanabe N., Saito Y., Kakizuka A., Morii N., Narumiya S.;
RT "The small GTP-binding protein Rho binds to and activates a 160 kDa
RT Ser/Thr protein kinase homologous to myotonic dystrophy kinase.";
RL EMBO J. 15:1885-1893(1996).
RN [13]
RP INTERACTION WITH ROCK2.
RX PubMed=8641286;
RA Matsui T., Amano M., Yamamoto T., Chihara K., Nakafuku M., Ito M.,
RA Nakano T., Okawa K., Iwamatsu A., Kaibuchi K.;
RT "Rho-associated kinase, a novel serine/threonine kinase, as a putative
RT target for small GTP binding protein Rho.";
RL EMBO J. 15:2208-2216(1996).
RN [14]
RP FUNCTION.
RX PubMed=8910519; DOI=10.1074/jbc.271.46.28772;
RA Quilliam L.A., Lambert Q.T., Mickelson-Young L.A., Westwick J.K.,
RA Sparks A.B., Kay B.K., Jenkins N.A., Gilbert D.J., Copeland N.G.,
RA Der C.J.;
RT "Isolation of a NCK-associated kinase, PRK2, an SH3-binding protein
RT and potential effector of Rho protein signaling.";
RL J. Biol. Chem. 271:28772-28776(1996).
RN [15]
RP FUNCTION, AND INTERACTION WITH PKN2.
RX PubMed=9121475;
RA Vincent S., Settleman J.;
RT "The PRK2 kinase is a potential effector target of both Rho and Rac
RT GTPases and regulates actin cytoskeletal organization.";
RL Mol. Cell. Biol. 17:2247-2256(1997).
RN [16]
RP INTERACTION WITH ARHGEF2.
RX PubMed=9857026; DOI=10.1074/jbc.273.52.34954;
RA Ren Y., Li R., Zheng Y., Busch H.;
RT "Cloning and characterization of GEF-H1, a microtubule-associated
RT guanine nucleotide exchange factor for Rac and Rho GTPases.";
RL J. Biol. Chem. 273:34954-34960(1998).
RN [17]
RP INTERACTION WITH DGKQ, AND MUTAGENESIS OF TYR-34.
RX PubMed=10066731; DOI=10.1074/jbc.274.11.6820;
RA Houssa B., de Widt J., Kranenburg O., Moolenaar W.H.,
RA van Blitterswijk W.J.;
RT "Diacylglycerol kinase theta binds to and is negatively regulated by
RT active RhoA.";
RL J. Biol. Chem. 274:6820-6822(1999).
RN [18]
RP INTERACTION WITH HRSV PROTEIN F.
RX PubMed=10438814;
RA Pastey M.K., Crowe J.E. Jr., Graham B.S.;
RT "RhoA interacts with the fusion glycoprotein of respiratory syncytial
RT virus and facilitates virus-induced syncytium formation.";
RL J. Virol. 73:7262-7270(1999).
RN [19]
RP INTERACTION WITH RTKN.
RX PubMed=10940294; DOI=10.1074/jbc.M000465200;
RA Reynaud C., Fabre S., Jalinot P.;
RT "The PDZ protein TIP-1 interacts with the Rho effector rhotekin and is
RT involved in Rho signaling to the serum response element.";
RL J. Biol. Chem. 275:33962-33968(2000).
RN [20]
RP PHOSPHORYLATION AT SER-188 BY PRKG1.
RX PubMed=11162591; DOI=10.1006/bbrc.2000.4194;
RA Sawada N., Itoh H., Yamashita J., Doi K., Inoue M., Masatsugu K.,
RA Fukunaga Y., Sakaguchi S., Sone M., Yamahara K., Yurugi T., Nakao K.;
RT "cGMP-dependent protein kinase phosphorylates and inactivates RhoA.";
RL Biochem. Biophys. Res. Commun. 280:798-805(2001).
RN [21]
RP INTERACTION WITH AKAP13.
RX PubMed=11696353; DOI=10.1016/S0014-5793(01)02995-7;
RA Klussmann E., Edemir B., Pepperle B., Tamma G., Henn V.,
RA Klauschenz E., Hundsrucker C., Maric K., Rosenthal W.;
RT "Ht31: the first protein kinase A anchoring protein to integrate
RT protein kinase A and Rho signaling.";
RL FEBS Lett. 507:264-268(2001).
RN [22]
RP INTERACTION WITH ARHGEF3.
RX PubMed=12221096; DOI=10.1074/jbc.M207401200;
RA Arthur W.T., Ellerbroek S.M., Der C.J., Burridge K., Wennerberg K.;
RT "XPLN, a guanine nucleotide exchange factor for RhoA and RhoB, but not
RT RhoC.";
RL J. Biol. Chem. 277:42964-42972(2002).
RN [23]
RP INTERACTION WITH YERSINIA PESTIS YOPT, AND CLEAVAGE.
RX PubMed=12062101; DOI=10.1016/S0092-8674(02)00766-3;
RA Shao F., Merritt P.M., Bao Z., Innes R.W., Dixon J.E.;
RT "A Yersinia effector and a Pseudomonas avirulence protein define a
RT family of cysteine proteases functioning in bacterial pathogenesis.";
RL Cell 109:575-588(2002).
RN [24]
RP FUNCTION, AND INTERACTION WITH PLCE1.
RX PubMed=12900402; DOI=10.1074/jbc.M306904200;
RA Wing M.R., Snyder J.T., Sondek J., Harden T.K.;
RT "Direct activation of phospholipase C-epsilon by Rho.";
RL J. Biol. Chem. 278:41253-41258(2003).
RN [25]
RP INTERACTION WITH YERSINIA PSEUDOTUBERCULOSIS YOPT, CLEAVAGE, AND
RP MUTAGENESIS OF LEU-193.
RX PubMed=12538863; DOI=10.1073/pnas.252770599;
RA Shao F., Vacratsis P.O., Bao Z., Bowers K.E., Fierke C.A., Dixon J.E.;
RT "Biochemical characterization of the Yersinia YopT protease: cleavage
RT site and recognition elements in Rho GTPases.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:904-909(2003).
RN [26]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=16103226; DOI=10.1083/jcb.200501097;
RA Yuce O., Piekny A., Glotzer M.;
RT "An ECT2-centralspindlin complex regulates the localization and
RT function of RhoA.";
RL J. Cell Biol. 170:571-582(2005).
RN [27]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=16236794; DOI=10.1091/mbc.E05-06-0569;
RA Kamijo K., Ohara N., Abe M., Uchimura T., Hosoya H., Lee J.S.,
RA Miki T.;
RT "Dissecting the role of Rho-mediated signaling in contractile ring
RT formation.";
RL Mol. Biol. Cell 17:43-55(2006).
RN [28]
RP INTERACTION WITH PKP4, AND SUBCELLULAR LOCATION.
RX PubMed=17115030; DOI=10.1038/ncb1504;
RA Wolf A., Keil R., Gotzl O., Mun A., Schwarze K., Lederer M.,
RA Huttelmaier S., Hatzfeld M.;
RT "The armadillo protein p0071 regulates Rho signalling during
RT cytokinesis.";
RL Nat. Cell Biol. 8:1432-1440(2006).
RN [29]
RP FUNCTION.
RX PubMed=19934221; DOI=10.1242/jcs.053728;
RA Bristow J.M., Sellers M.H., Majumdar D., Anderson B., Hu L.,
RA Webb D.J.;
RT "The Rho-family GEF Asef2 activates Rac to modulate adhesion and actin
RT dynamics and thereby regulate cell migration.";
RL J. Cell Sci. 122:4535-4546(2009).
RN [30]
RP AMPYLATION AT TYR-34, AND MUTAGENESIS OF TYR-34.
RX PubMed=19362538; DOI=10.1016/j.molcel.2009.03.008;
RA Worby C.A., Mattoo S., Kruger R.P., Corbeil L.B., Koller A.,
RA Mendez J.C., Zekarias B., Lazar C., Dixon J.E.;
RT "The fic domain: regulation of cell signaling by adenylylation.";
RL Mol. Cell 34:93-103(2009).
RN [31]
RP UBIQUITINATION.
RX PubMed=19782033; DOI=10.1016/j.molcel.2009.09.004;
RA Chen Y., Yang Z., Meng M., Zhao Y., Dong N., Yan H., Liu L., Ding M.,
RA Peng H.B., Shao F.;
RT "Cullin mediates degradation of RhoA through evolutionarily conserved
RT BTB adaptors to control actin cytoskeleton structure and cell
RT movement.";
RL Mol. Cell 35:841-855(2009).
RN [32]
RP AMPYLATION AT THR-37.
RX PubMed=19039103; DOI=10.1126/science.1166382;
RA Yarbrough M.L., Li Y., Kinch L.N., Grishin N.V., Ball H.L., Orth K.;
RT "AMPylation of Rho GTPases by Vibrio VopS disrupts effector binding
RT and downstream signaling.";
RL Science 323:269-272(2009).
RN [33]
RP MUTAGENESIS OF GLY-14.
RX PubMed=19948726; DOI=10.1074/jbc.M109.088427;
RA Chatterjee A., Wang L., Armstrong D.L., Rossie S.;
RT "Activated Rac1 GTPase translocates protein phosphatase 5 to the cell
RT membrane and stimulates phosphatase activity in vitro.";
RL J. Biol. Chem. 285:3872-3882(2010).
RN [34]
RP INTERACTION WITH ARHGDIA.
RX PubMed=20400958; DOI=10.1038/ncb2049;
RA Boulter E., Garcia-Mata R., Guilluy C., Dubash A., Rossi G.,
RA Brennwald P.J., Burridge K.;
RT "Regulation of Rho GTPase crosstalk, degradation and activity by
RT RhoGDI1.";
RL Nat. Cell Biol. 12:477-483(2010).
RN [35]
RP FUNCTION.
RX PubMed=20937854; DOI=10.1073/pnas.1000975107;
RA Zaoui K., Benseddik K., Daou P., Salaun D., Badache A.;
RT "ErbB2 receptor controls microtubule capture by recruiting ACF7 to the
RT plasma membrane of migrating cells.";
RL Proc. Natl. Acad. Sci. U.S.A. 107:18517-18522(2010).
RN [36]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [37]
RP ENZYME REGULATION.
RX PubMed=21565175; DOI=10.1016/j.bbrc.2011.04.116;
RA Naji L., Pacholsky D., Aspenstrom P.;
RT "ARHGAP30 is a Wrch-1-interacting protein involved in actin dynamics
RT and cell adhesion.";
RL Biochem. Biophys. Res. Commun. 409:96-102(2011).
RN [38]
RP INTERACTION WITH GNB2L1.
RX PubMed=20499158; DOI=10.1007/s10549-010-0955-3;
RA Cao X.X., Xu J.D., Xu J.W., Liu X.L., Cheng Y.Y., Li Q.Q., Xu Z.D.,
RA Liu X.P.;
RT "RACK1 promotes breast carcinoma migration/metastasis via activation
RT of the RhoA/Rho kinase pathway.";
RL Breast Cancer Res. Treat. 126:555-563(2011).
RN [39]
RP FUNCTION, AND INTERACTION WITH PKN2.
RX PubMed=20974804; DOI=10.1128/MCB.01001-10;
RA Wallace S.W., Magalhaes A., Hall A.;
RT "The Rho target PRK2 regulates apical junction formation in human
RT bronchial epithelial cells.";
RL Mol. Cell. Biol. 31:81-91(2011).
RN [40]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS).
RX PubMed=9302995; DOI=10.1038/nsb0997-699;
RA Wei Y., Zhang Y., Derewenda U., Liu X., Minor W., Nakamoto R.K.,
RA Somlyo A.V., Somlyo A.P., Derewenda Z.S.;
RT "Crystal structure of RhoA-GDP and its functional implications.";
RL Nat. Struct. Biol. 4:699-703(1997).
RN [41]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 4-181 OF MUTANT VAL-14.
RX PubMed=9545299; DOI=10.1074/jbc.273.16.9656;
RA Ihara K., Muraguchi S., Kato M., Shimizu T., Shirakawa M., Kuroda S.,
RA Kaibuchi K., Hakoshima T.;
RT "Crystal structure of human RhoA in a dominantly active form complexed
RT with a GTP analogue.";
RL J. Biol. Chem. 273:9656-9666(1998).
RN [42]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 1-181 IN COMPLEX WITH PRKCL1.
RX PubMed=10388627; DOI=10.1006/jsbi.1999.4114;
RA Maesaki R., Shimizu T., Ihara K., Kuroda S., Kaibuchi K.,
RA Hakoshima T.;
RT "Biochemical and crystallographic characterization of a Rho effector
RT domain of the protein serine/threonine kinase N in a complex with
RT RhoA.";
RL J. Struct. Biol. 126:166-170(1999).
RN [43]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 3-180 IN COMPLEX WITH GDP.
RX PubMed=10748207; DOI=10.1074/jbc.M910274199;
RA Shimizu T., Ihara K., Maesaki R., Kuroda S., Kaibuchi K.,
RA Hakoshima T.;
RT "An open conformation of switch I revealed by the crystal structure of
RT a Mg2+-free form of RHOA complexed with GDP. Implications for the
RT GDP/GTP exchange mechanism.";
RL J. Biol. Chem. 275:18311-18317(2000).
RN [44]
RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS).
RX PubMed=11927263; DOI=10.1016/S1074-5521(02)00112-6;
RA Graham D.L., Lowe P.N., Grime G.W., Marsh M., Rittinger K.,
RA Smerdon S.J., Gamblin S.J., Eccleston J.F.;
RT "MgF(3)(-) as a transition state analog of phosphoryl transfer.";
RL Chem. Biol. 9:375-381(2002).
RN [45]
RP X-RAY CRYSTALLOGRAPHY (2.81 ANGSTROMS) IN COMPLEX WITH MCF2.
RX PubMed=12006984; DOI=10.1038/nsb796;
RA Snyder J.T., Worthylake D.K., Rossman K.L., Betts L., Pruitt W.M.,
RA Siderovski D.P., Der C.J., Sondek J.;
RT "Structural basis for the selective activation of Rho GTPases by Dbl
RT exchange factors.";
RL Nat. Struct. Biol. 9:468-475(2002).
RN [46]
RP X-RAY CRYSTALLOGRAPHY (1.5 ANGSTROMS) OF MUTANT LEU-63 IN COMPLEX WITH
RP A GTP ANALOG AND MG(2+).
RX PubMed=12777804; DOI=10.1107/S0907444903005390;
RA Longenecker K., Read P., Lin S.-K., Somlyo A.P., Nakamoto R.K.,
RA Derewenda Z.S.;
RT "Structure of a constitutively activated RhoA mutant (Q63L) at 1.55 A
RT resolution.";
RL Acta Crystallogr. D 59:876-880(2003).
CC -!- FUNCTION: Regulates a signal transduction pathway linking plasma
CC membrane receptors to the assembly of focal adhesions and actin
CC stress fibers. Involved in a microtubule-dependent signal that is
CC required for the myosin contractile ring formation during cell
CC cycle cytokinesis. Plays an essential role in cleavage furrow
CC formation. Required for the apical junction formation of
CC keratinocyte cell-cell adhesion. Serves as a target for the yopT
CC cysteine peptidase from Yersinia pestis, vector of the plague, and
CC Yersinia pseudotuberculosis, which causes gastrointestinal
CC disorders. Stimulates PKN2 kinase activity. May be an activator of
CC PLCE1. Activated by ARHGEF2, which promotes the exchange of GDP
CC for GTP. Essential for the SPATA13-mediated regulation of cell
CC migration and adhesion assembly and disassembly. The MEMO1-RHOA-
CC DIAPH1 signaling pathway plays an important role in ERBB2-
CC dependent stabilization of microtubules at the cell cortex. It
CC controls the localization of APC and CLASP2 to the cell membrane,
CC via the regulation of GSK3B activity. In turn, membrane-bound APC
CC allows the localization of the MACF1 to the cell membrane, which
CC is required for microtubule capture and stabilization.
CC -!- COFACTOR: Magnesium.
CC -!- ENZYME REGULATION: GTP hydrolysis is stimulated by ARHGAP30.
CC -!- SUBUNIT: Interacts with ARHGEF28 (By similarity). Binds PRKCL1,
CC ROCK1 and ROCK2. Interacts with ARHGEF2, ARHGEF3, NET1 and RTKN.
CC Interacts with PLCE1 and AKAP13. Interacts (in the constitutively
CC activated, GTP-bound form) with DGKQ. Interacts with human
CC respiratory syncytial virus (HRSV) protein F; this interaction
CC facilitates virus-induced syncytium formation. Interacts with
CC GNB2L1/RACK1; enhances RHOA activation. Interacts with PKP4; the
CC interaction is detected at the midbody. Interacts (GTP-bound form
CC preferentially) with PKN2; the interaction stimulates
CC autophosphorylation and phosphorylation of PKN2. Interacts with
CC ARHGDIA; this interaction inactivates and stabilizes RHOA.
CC Interacts with ARHGDIB.
CC -!- INTERACTION:
CC Q15109:AGER; NbExp=2; IntAct=EBI-446668, EBI-1646426;
CC Q07960:ARHGAP1; NbExp=2; IntAct=EBI-446668, EBI-602762;
CC P52565:ARHGDIA; NbExp=2; IntAct=EBI-446668, EBI-712693;
CC O15085:ARHGEF11; NbExp=6; IntAct=EBI-446668, EBI-311099;
CC Q9NZN5:ARHGEF12; NbExp=2; IntAct=EBI-446668, EBI-821440;
CC Q8IW93:ARHGEF19; NbExp=2; IntAct=EBI-446668, EBI-7799822;
CC Q9Y4D1:DAAM1; NbExp=4; IntAct=EBI-446668, EBI-2817289;
CC O60610:DIAPH1; NbExp=3; IntAct=EBI-446668, EBI-3959709;
CC O08808:Diaph1 (xeno); NbExp=3; IntAct=EBI-446668, EBI-1026445;
CC Q6PDM6:Mcf2l (xeno); NbExp=3; IntAct=EBI-446668, EBI-602149;
CC P19338:NCL; NbExp=3; IntAct=EBI-446668, EBI-346967;
CC Q9Z0S9:Rabac1 (xeno); NbExp=3; IntAct=EBI-446668, EBI-476965;
CC Q13464:ROCK1; NbExp=4; IntAct=EBI-446668, EBI-876651;
CC Q9BST9:RTKN; NbExp=5; IntAct=EBI-446668, EBI-446694;
CC Q8C6B2:Rtkn (xeno); NbExp=3; IntAct=EBI-446668, EBI-1162441;
CC Q15796:SMAD2; NbExp=2; IntAct=EBI-446668, EBI-1040141;
CC Q9HCE7:SMURF1; NbExp=2; IntAct=EBI-446668, EBI-976466;
CC -!- SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor; Cytoplasmic
CC side. Cytoplasm, cytoskeleton. Cleavage furrow. Cytoplasm, cell
CC cortex. Midbody. Cell projection, lamellipodium (By similarity).
CC Note=Localized to cell-cell contacts in calcium-treated
CC keratinocytes (By similarity). Translocates to the equatorial
CC region before furrow formation in a ECT2-dependent manner.
CC Localizes to the equatorial cell cortex (at the site of the
CC presumptive furrow) in early anaphase in a activated form and in a
CC myosin- and actin-independent manner.
CC -!- DOMAIN: The basic-rich region is essential for yopT recognition
CC and cleavage.
CC -!- PTM: Substrate for botulinum ADP-ribosyltransferase.
CC -!- PTM: Cleaved by yopT protease when the cell is infected by some
CC Yersinia pathogens. This removes the lipid attachment, and leads
CC to its displacement from plasma membrane and to subsequent
CC cytoskeleton cleavage.
CC -!- PTM: AMPylation at Tyr-34 and Thr-37 are mediated by bacterial
CC enzymes in case of infection by H.somnus and V.parahaemolyticus,
CC respectively. AMPylation occurs in the effector region and leads
CC to inactivation of the GTPase activity by preventing the
CC interaction with downstream effectors, thereby inhibiting actin
CC assembly in infected cells. It is unclear whether some human
CC enzyme mediates AMPylation; FICD has such ability in vitro but
CC additional experiments remain to be done to confirm results in
CC vivo.
CC -!- PTM: Phosphorylation by PRKG1 at Ser-188 inactivates RHOA
CC signaling.
CC -!- PTM: Ubiquitinated by the BCR(BACURD1) and BCR(BACURD2) E3
CC ubiquitin ligase complexes, leading to its degradation by the
CC proteasome, thereby regulating the actin cytoskeleton and cell
CC migration.
CC -!- SIMILARITY: Belongs to the small GTPase superfamily. Rho family.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/RHOAID42107ch3p21.html";
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DR EMBL; X05026; CAA28690.1; -; mRNA.
DR EMBL; L25080; AAC33178.1; -; mRNA.
DR EMBL; AF498970; AAM21117.1; -; mRNA.
DR EMBL; BT019870; AAV38673.1; -; mRNA.
DR EMBL; AK222556; BAD96276.1; -; mRNA.
DR EMBL; BX647063; CAE46190.1; -; mRNA.
DR EMBL; AC104452; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC121247; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC137114; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC001360; AAH01360.1; -; mRNA.
DR EMBL; BC005976; AAH05976.1; -; mRNA.
DR EMBL; L09159; AAA50612.1; -; mRNA.
DR EMBL; M83094; AAA67539.1; -; Genomic_DNA.
DR PIR; A26675; TVHU12.
DR RefSeq; NP_001655.1; NM_001664.2.
DR UniGene; Hs.247077; -.
DR PDB; 1A2B; X-ray; 2.40 A; A=1-181.
DR PDB; 1CC0; X-ray; 5.00 A; A/C=1-190.
DR PDB; 1CXZ; X-ray; 2.20 A; A=1-181.
DR PDB; 1DPF; X-ray; 2.00 A; A=1-180.
DR PDB; 1FTN; X-ray; 2.10 A; A=1-193.
DR PDB; 1KMQ; X-ray; 1.55 A; A=4-181.
DR PDB; 1LB1; X-ray; 2.81 A; B/D/F/H=1-189.
DR PDB; 1OW3; X-ray; 1.80 A; B=1-193.
DR PDB; 1S1C; X-ray; 2.60 A; A/B=1-181.
DR PDB; 1TX4; X-ray; 1.65 A; B=3-179.
DR PDB; 1X86; X-ray; 3.22 A; B/D/F/H=1-193.
DR PDB; 1XCG; X-ray; 2.50 A; B/F=3-180.
DR PDB; 2RGN; X-ray; 3.50 A; C/F=1-193.
DR PDB; 3KZ1; X-ray; 2.70 A; E/F=1-181.
DR PDB; 3LW8; X-ray; 1.85 A; A/B/C/D=2-181.
DR PDB; 3LWN; X-ray; 2.28 A; A/B=2-181.
DR PDB; 3LXR; X-ray; 1.68 A; A=2-181.
DR PDB; 3MSX; X-ray; 1.65 A; A=1-180.
DR PDB; 3T06; X-ray; 2.84 A; B/F=3-180.
DR PDBsum; 1A2B; -.
DR PDBsum; 1CC0; -.
DR PDBsum; 1CXZ; -.
DR PDBsum; 1DPF; -.
DR PDBsum; 1FTN; -.
DR PDBsum; 1KMQ; -.
DR PDBsum; 1LB1; -.
DR PDBsum; 1OW3; -.
DR PDBsum; 1S1C; -.
DR PDBsum; 1TX4; -.
DR PDBsum; 1X86; -.
DR PDBsum; 1XCG; -.
DR PDBsum; 2RGN; -.
DR PDBsum; 3KZ1; -.
DR PDBsum; 3LW8; -.
DR PDBsum; 3LWN; -.
DR PDBsum; 3LXR; -.
DR PDBsum; 3MSX; -.
DR PDBsum; 3T06; -.
DR ProteinModelPortal; P61586; -.
DR SMR; P61586; 2-181.
DR DIP; DIP-29642N; -.
DR IntAct; P61586; 42.
DR MINT; MINT-4999683; -.
DR STRING; 9606.ENSP00000400175; -.
DR BindingDB; P61586; -.
DR ChEMBL; CHEMBL6052; -.
DR DrugBank; DB01076; Atorvastatin.
DR DrugBank; DB00641; Simvastatin.
DR PhosphoSite; P61586; -.
DR DMDM; 47606458; -.
DR PaxDb; P61586; -.
DR PeptideAtlas; P61586; -.
DR PRIDE; P61586; -.
DR DNASU; 387; -.
DR Ensembl; ENST00000418115; ENSP00000400175; ENSG00000067560.
DR GeneID; 387; -.
DR KEGG; hsa:387; -.
DR UCSC; uc003cwu.3; human.
DR CTD; 387; -.
DR GeneCards; GC03M049371; -.
DR HGNC; HGNC:667; RHOA.
DR HPA; CAB005052; -.
DR MIM; 165390; gene.
DR neXtProt; NX_P61586; -.
DR PharmGKB; PA134865095; -.
DR eggNOG; COG1100; -.
DR HOGENOM; HOG000233974; -.
DR HOVERGEN; HBG009351; -.
DR InParanoid; P61586; -.
DR KO; K04513; -.
DR OMA; RNDPHTI; -.
DR OrthoDB; EOG73FQPD; -.
DR Reactome; REACT_111045; Developmental Biology.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_604; Hemostasis.
DR SignaLink; P61586; -.
DR ChiTaRS; RHOA; human.
DR EvolutionaryTrace; P61586; -.
DR GeneWiki; RHOA; -.
DR GenomeRNAi; 387; -.
DR NextBio; 1611; -.
DR PMAP-CutDB; P61586; -.
DR PRO; PR:P61586; -.
DR ArrayExpress; P61586; -.
DR Bgee; P61586; -.
DR CleanEx; HS_RHOA; -.
DR Genevestigator; P61586; -.
DR GO; GO:0043296; C:apical junction complex; IDA:UniProtKB.
DR GO; GO:0030424; C:axon; IEA:Ensembl.
DR GO; GO:0005938; C:cell cortex; IDA:UniProtKB.
DR GO; GO:0032154; C:cleavage furrow; IEA:UniProtKB-SubCell.
DR GO; GO:0005856; C:cytoskeleton; IEA:UniProtKB-SubCell.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0030027; C:lamellipodium; ISS:UniProtKB.
DR GO; GO:0030496; C:midbody; IEA:UniProtKB-SubCell.
DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0032587; C:ruffle membrane; IEA:Ensembl.
DR GO; GO:0005525; F:GTP binding; IEA:UniProtKB-KW.
DR GO; GO:0003924; F:GTPase activity; TAS:UniProtKB.
DR GO; GO:0030036; P:actin cytoskeleton organization; TAS:UniProtKB.
DR GO; GO:0030521; P:androgen receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0043297; P:apical junction assembly; IMP:UniProtKB.
DR GO; GO:0007411; P:axon guidance; TAS:Reactome.
DR GO; GO:0007160; P:cell-matrix adhesion; IEA:Ensembl.
DR GO; GO:0036089; P:cleavage furrow formation; IDA:UniProtKB.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0050771; P:negative regulation of axonogenesis; TAS:Reactome.
DR GO; GO:0043124; P:negative regulation of I-kappaB kinase/NF-kappaB cascade; IEA:Ensembl.
DR GO; GO:0033144; P:negative regulation of intracellular steroid hormone receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0045665; P:negative regulation of neuron differentiation; IEA:Ensembl.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; TAS:Reactome.
DR GO; GO:0043931; P:ossification involved in bone maturation; ISS:BHF-UCL.
DR GO; GO:0048015; P:phosphatidylinositol-mediated signaling; TAS:Reactome.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0030838; P:positive regulation of actin filament polymerization; IEA:Ensembl.
DR GO; GO:0050772; P:positive regulation of axonogenesis; TAS:Reactome.
DR GO; GO:0045785; P:positive regulation of cell adhesion; IEA:Ensembl.
DR GO; GO:0030307; P:positive regulation of cell growth; IEA:Ensembl.
DR GO; GO:0030335; P:positive regulation of cell migration; IEA:Ensembl.
DR GO; GO:0043280; P:positive regulation of cysteine-type endopeptidase activity involved in apoptotic process; IEA:Ensembl.
DR GO; GO:0032467; P:positive regulation of cytokinesis; IMP:UniProtKB.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB cascade; IEP:UniProtKB.
DR GO; GO:0043525; P:positive regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0045666; P:positive regulation of neuron differentiation; IMP:MGI.
DR GO; GO:0042346; P:positive regulation of NF-kappaB import into nucleus; NAS:UniProtKB.
DR GO; GO:0071803; P:positive regulation of podosome assembly; IEA:Ensembl.
DR GO; GO:0051496; P:positive regulation of stress fiber assembly; IDA:MGI.
DR GO; GO:0045727; P:positive regulation of translation; IEA:Ensembl.
DR GO; GO:0045907; P:positive regulation of vasoconstriction; IEA:Ensembl.
DR GO; GO:0051924; P:regulation of calcium ion transport; IEA:Ensembl.
DR GO; GO:0030334; P:regulation of cell migration; IMP:UniProtKB.
DR GO; GO:0050773; P:regulation of dendrite development; IEA:Ensembl.
DR GO; GO:0033688; P:regulation of osteoblast proliferation; ISS:BHF-UCL.
DR GO; GO:0051056; P:regulation of small GTPase mediated signal transduction; TAS:Reactome.
DR GO; GO:0006357; P:regulation of transcription from RNA polymerase II promoter; IEA:Ensembl.
DR GO; GO:0043200; P:response to amino acid stimulus; IEA:Ensembl.
DR GO; GO:0042493; P:response to drug; IEA:Ensembl.
DR GO; GO:0045471; P:response to ethanol; IEA:Ensembl.
DR GO; GO:0051384; P:response to glucocorticoid stimulus; IEA:Ensembl.
DR GO; GO:0009749; P:response to glucose stimulus; IEA:Ensembl.
DR GO; GO:0001666; P:response to hypoxia; IEA:Ensembl.
DR GO; GO:0009612; P:response to mechanical stimulus; IEA:Ensembl.
DR GO; GO:0007266; P:Rho protein signal transduction; TAS:UniProtKB.
DR GO; GO:0007519; P:skeletal muscle tissue development; IEA:Ensembl.
DR GO; GO:0090307; P:spindle assembly involved in mitosis; IMP:BHF-UCL.
DR GO; GO:0043149; P:stress fiber assembly; IEA:Ensembl.
DR GO; GO:0031098; P:stress-activated protein kinase signaling cascade; IEA:Ensembl.
DR GO; GO:0061383; P:trabecula morphogenesis; ISS:BHF-UCL.
DR GO; GO:0007179; P:transforming growth factor beta receptor signaling pathway; TAS:Reactome.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR005225; Small_GTP-bd_dom.
DR InterPro; IPR001806; Small_GTPase.
DR InterPro; IPR003578; Small_GTPase_Rho.
DR Pfam; PF00071; Ras; 1.
DR PRINTS; PR00449; RASTRNSFRMNG.
DR SMART; SM00174; RHO; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR TIGRFAMs; TIGR00231; small_GTP; 1.
DR PROSITE; PS51420; RHO; 1.
PE 1: Evidence at protein level;
KW 3D-structure; ADP-ribosylation; Cell cycle; Cell division;
KW Cell membrane; Cell projection; Complete proteome; Cytoplasm;
KW Cytoskeleton; Direct protein sequencing; GTP-binding;
KW Host-virus interaction; Lipoprotein; Magnesium; Membrane; Methylation;
KW Nucleotide-binding; Phosphoprotein; Prenylation; Proto-oncogene;
KW Reference proteome; Ubl conjugation.
FT CHAIN 1 190 Transforming protein RhoA.
FT /FTId=PRO_0000030411.
FT PROPEP 191 193 Removed in mature form.
FT /FTId=PRO_0000030412.
FT NP_BIND 12 19 GTP.
FT NP_BIND 59 63 GTP (By similarity).
FT NP_BIND 117 120 GTP.
FT MOTIF 34 42 Effector region (Potential).
FT COMPBIAS 182 187 Arg/Lys-rich (basic).
FT SITE 189 190 Cleavage; by yopT.
FT MOD_RES 34 34 O-AMP-tyrosine; by Haemophilus IbpA.
FT MOD_RES 37 37 O-AMP-threonine; by Vibrio VopS.
FT MOD_RES 41 41 ADP-ribosylasparagine; by botulinum toxin
FT (Probable).
FT MOD_RES 188 188 Phosphoserine; by PKG/PRKG1.
FT MOD_RES 190 190 Cysteine methyl ester.
FT LIPID 190 190 S-geranylgeranyl cysteine.
FT MUTAGEN 14 14 G->V: Causes constitutive activation.
FT MUTAGEN 34 34 Y->A: Abolishes interaction with DGKQ.
FT MUTAGEN 34 34 Y->F: Abolishes AMPylation by Haemophilus
FT IbpA.
FT MUTAGEN 63 63 Q->L: Causes constitutive activation.
FT MUTAGEN 193 193 L->M: Converts geranyl-geranylation to
FT farnesylation; does not prevent the
FT cleavage by yopT.
FT CONFLICT 23 23 I -> T (in Ref. 5; BAD96276).
FT STRAND 5 13
FT TURN 15 17
FT HELIX 18 27
FT STRAND 38 48
FT STRAND 51 60
FT HELIX 64 66
FT TURN 67 69
FT HELIX 70 73
FT STRAND 78 85
FT HELIX 89 97
FT HELIX 99 106
FT STRAND 112 117
FT HELIX 119 121
FT HELIX 125 133
FT HELIX 141 150
FT STRAND 154 158
FT TURN 161 163
FT HELIX 167 179
SQ SEQUENCE 193 AA; 21768 MW; C4DA2DC31FF858BC CRC64;
MAAIRKKLVI VGDGACGKTC LLIVFSKDQF PEVYVPTVFE NYVADIEVDG KQVELALWDT
AGQEDYDRLR PLSYPDTDVI LMCFSIDSPD SLENIPEKWT PEVKHFCPNV PIILVGNKKD
LRNDEHTRRE LAKMKQEPVK PEEGRDMANR IGAFGYMECS AKTKDGVREV FEMATRAALQ
ARRGKKKSGC LVL
//

MIM 165390
*RECORD*
*FIELD* NO
165390
*FIELD* TI
*165390 RAS HOMOLOG GENE FAMILY, MEMBER A; RHOA
;;APLYSIA RAS-RELATED HOMOLOG 12; ARH12;;
read moreARHA;;
ONCOGENE RHO H12; RHOH12; RHO12
*FIELD* TX
The human ARH genes (sometimes called 'Rho' genes) share several
properties with the RAS gene family (see 190020).

MAPPING

Cannizzaro et al. (1990) mapped 1 member of the ARH family, the H12
(RHOA) gene, to chromosome 3p21 by in situ hybridization. Kiss et al.
(1997) assigned the RHOA gene to chromosome 3p21.3 by fluorescence in
situ hybridization and by PCR study of somatic cell hybrids.

BIOCHEMICAL FEATURES

Maesaki et al. (1999) reported the 2.2-angstrom crystal structure of
RhoA bound to an effector domain of protein kinase PRKCL1 (601302). The
structure revealed the antiparallel coiled-coil finger (ACC finger) fold
of the effector domain that binds to the Rho specificity-determining
regions containing switch I, beta strands B2 and B3, and the C-terminal
alpha helix A5, predominantly by specific hydrogen bonds. The ACC finger
fold is distinct from those for other small G proteins and provides
evidence for the diverse ways of effector recognition. Sequence analysis
based on the structure suggested that the ACC finger fold is widespread
in Rho effector proteins.

Lutz et al. (2007) determined the crystal structure of the G-alpha-q
(600998)-p63RhoGEF (610215)-RhoA complex, detailing the interactions of
G-alpha-q with the Dbl and pleckstrin homology (DH and PH) domains of
p63RhoGEF. These interactions involved the effector-binding site and the
C-terminal region of G-alpha-q and appeared to relieve autoinhibition of
the catalytic DH domain by the PH domain. Trio (601893), Duet (604605),
and p63RhoGEF were shown to constitute a family of G-alpha-q effectors
that appear to activate RhoA both in vitro and in intact cells. Lutz et
al. (2007) proposed that this structure represents the crux of an
ancient signal transduction pathway that is expected to be important in
an array of physiologic processes.

GENE FUNCTION

The small guanosine triphosphatase (GTP) Rho regulates remodeling of the
actin cytoskeleton during cell morphogenesis and motility. In their
Figure 3C, Maekawa et al. (1999) diagrammed proposed signaling pathways
for Rho-induced remodeling of the actin cytoskeleton. They demonstrated
that active Rho signals to its downstream effector ROCK1 (601702), which
phosphorylates and activates LIM kinase (see 601329). LIM kinase, in
turn, phosphorylates cofilin (601442), inhibiting its
actin-depolymerizing activity.

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 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.

Sin et al. (2002) used in vivo time-lapse imaging of optic tectal cells
in Xenopus laevis tadpoles to demonstrate that enhanced visual activity
driven by a light stimulus promotes dendritic arbor growth. The
stimulus-induced dendritic arbor growth requires glutamate receptor (see
138249)-mediated synaptic transmission, decreased RhoA activity, and
increased RAC (see 602048) and CDC42 (116952) activity. Sin et al.
(2002) concluded that their results delineated a role for Rho GTPases in
the structural plasticity driven by visual stimulation in vivo.

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.

Wang et al. (2003) found that atypical protein kinase C-zeta (PKC2;
176982), an effector of the Cdc42/Rac1-PAR6 (607484) polarity complex,
recruited Smurf1 (605568) to cellular protrusions, where it controlled
the local level of RhoA. Smurf1 thus links the polarity complex to
degradation of RhoA in lamellipodia and filopodia to prevent RhoA
signaling during dynamic membrane movements.

Using mouse brain endothelial cells, Crose et al. (2009) showed that
Ccm2 (607929) interacted with the RhoA ubiquitin ligase Smurf1. Ccm2
directed Smurf1 to the cell periphery, which led to local degradation of
RhoA. Knockdown of Ccm2 resulted in RhoA stability and cytoskeletal
changes leading to monolayer permeability, decreased tubule formation,
and reduced cell migration. Crose et al. (2009) concluded that CCM2
contributes to endothelial cell integrity by regulating SMURF1-directed
RHOA degradation.

Borikova et al. (2010) showed that knockdown of Ccm1 (KRIT1; 604214),
Ccm2, or Ccm3 (603285) in mouse embryonic endothelial cells induced RhoA
overexpression and persistent RhoA activity at the cell edge, as well as
in the cytoplasm and nucleus. RhoA activation was especially pronounced
following Ccm1 knockdown. Knockdown of Ccm1, Ccm2, or Ccm3 inhibited
formation of vessel-like tubes and invasion of extracellular matrix.
Knockdown or inhibition of Rock2 countered these effects and was
associated with inhibition of RhoA-stimulated phosphorylation of myosin
light chain-2 (MLC2; see 160781). Borikova et al. (2010) concluded that
the protein complex made up of CCM1, CCM2, and CCM3 regulates RhoA
activation and cytoskeletal dynamics.

In human coronary artery vascular smooth muscle cells, UPA (PLAU;
191840) stimulates cell migration via a UPA receptor (UPAR, or PLAUR;
173391) signaling complex containing TYK2 (176941) and
phosphatidylinositol 3-kinase (PI3K; see 601232). Kiian et al. (2003)
showed that association of TYK2 and PI3K with active GTP-bound forms of
both RHOA and RAC1, but not CDC42, as well as phosphorylation of myosin
light chain (see 160781), are downstream events required for
UPA/UPAR-directed migration.

Wu et al. (2005) showed that transcripts for RhoA, a small GTPase that
regulates the actin cytoskeleton, are localized in developing axons and
growth cones, and that this localization is mediated by an axonal
targeting element located in the RhoA 3-prime untranslated region.
Sema3A (603961) induces intraaxonal translation of RhoA mRNA, and this
local translation of RhoA is necessary and sufficient for
Sema3A-mediated growth cone collapse. Wu et al. (2005) concluded that
their studies indicate that local RhoA translation regulates the
neuronal cytoskeleton and identify a new mechanism for the regulation of
RhoA signaling.

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
(601702) 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.

Pertz et al. (2006) used a fluorescent biosensor, based on a novel
design preserving reversible membrane interactions, to visualize the
spatiotemporal dynamics of RhoA activity during cell migration. In
randomly migrating cells, RhoA activity is concentrated in a sharp band
directly at the edge of protrusions. It is observed sporadically in
retracting tails, and is low in the cell body. RhoA activity is also
associated with peripheral ruffles and pinocytic vesicles, but not with
dorsal ruffles induced by platelet-derived growth factor (PDGF; see
173430). In contrast to randomly migrating cells, PDGF-induced membrane
protrusions have low RhoA activity, potentially because PDGF strongly
activates Rac, which had been shown to antagonize RhoA activity. Pertz
et al. (2006) concluded that different extracellular cues induce
distinct patterns of RhoA signaling during membrane protrusion.

Yoshida et al. (2006) found that in S. cerevisiae the small GTP-binding
protein RhoA stimulates type 2 myosin contractility and formin (FMN1;
136535)-dependent assembly of the cytokinetic actin contractile ring.
Yoshida et al. (2006) found that budding yeast Polo-like kinase Cdc5
(see 602868) controls the targeting and activation of RhoA at the
division site via Rho1 guanine nucleotide exchange factors. Yoshida et
al. (2006) concluded that this role of Cdc5 (Polo-like kinase) in
regulating Rho1 is likely to be relevant to cytokinesis and asymmetric
cell division in other organisms.

Canman et al. (2008) noted that, during cytokinesis, RhoA orchestrates
contractile ring assembly and constriction. RhoA signaling is controlled
by the central spindle, a set of microtubule bundles that forms between
the separating chromosomes. Centralspindlin is a protein complex
consisting of kinesin-6 ZEN4 (KIF23; 605064) and the Rho
GTPase-activating protein CYK4 (RACGAP1; 604980) and is required for
central spindle assembly and cytokinesis in C. elegans. Canman et al.
(2008) found that 2 separation-of-function mutations in the GAP domain
of CYK4 lead to cytokinesis defects that mimic centralspindlin loss of
function. These defects could be rescued by depletion of RAC or its
effectors, but not by depletion of RhoA. Canman et al. (2008) concluded
that inactivation of RAC by CYK4 functions in parallel with RhoA
activation to drive contractile ring constriction during cytokinesis.

Machacek et al. (2009) examined GTPase coordination in mouse embryonic
fibroblasts both through simultaneous visualization of 2 GTPase
biosensors and using a 'computational multiplexing' approach capable of
defining the relationships between multiple protein activities
visualized in separate experiments. They found that RhoA is activated at
the cell edge synchronous with edge advancement, whereas Cdc42 (116952)
and Rac1 (602048) are activated 2 microns behind the edge with a delay
of 40 seconds. This indicates that Rac1 and RhoA operate
antagonistically through spatial separation and precise timing, and that
RhoA has a role in the initial events of protrusion, whereas Rac1 and
Cdc42 activate pathways implicated in reinforcement and stabilization of
newly expanded protrusions.

Wu et al. (2009) developed an approach to produce genetically encoded
photoactivatable derivatives of Rac1, a key GTPase regulating actin
cytoskeletal dynamics in metazoan cells. Rac1 mutants were fused to the
photoreactive LOV (light oxygen voltage) domain from phototropin,
sterically blocking Rac1 interactions until irradiation unwound a helix
linking LOV to Rac1. Photoactivatable Rac1 (PA-Rac1) could be reversibly
and repeatedly activated using 458- or 473-nm light to generate
precisely localized cell protrusions and ruffling. Localized Rac
activation or inactivation was sufficient to produce cell motility and
control the direction of cell movement. Myosin was involved in Rac
control of directionality but not in Rac-induced protrusion, whereas PAK
was required for Rac-induced protrusion. PA-Rac1 was used to elucidate
Rac regulation of RhoA in cell motility. Rac and Rho coordinate
cytoskeletal behaviors with seconds and submicrometer precision. Rac was
shown to inhibit RhoA in mouse embryonic fibroblasts, with inhibition
modulated at protrusions and ruffles. A PA-Rac crystal structure and
modeling revealed LOV-Rac interactions that will facilitate extension of
this photoactivation approach to other proteins.

In studies in vascular smooth muscle cells (VSMC), Guilluy et al. (2010)
demonstrated that ARHGEF1 (601855) is specifically responsible for
angiotensin receptor-1 (AGTR1; 106165)-mediated RHOA activation through
a mechanism involving the phosphorylation of tyr738 in ARHGEF1 by JAK2
(147796). Guilluy et al. (2010) generated mice lacking Arhgef1 in VSMCs
and found that the mutant mice were protected against angiotensin II
(see 106150)-dependent hypertension without alteration in baseline blood
pressure or the response to other vasoactive factors. Guilluy et al.
(2010) concluded that control of RHOA signaling through ARHGEF1 is
central to the development of angiotensin II-dependent hypertension.

Murakoshi et al. (2011) used 2-photon fluorescence lifetime imaging
microscopy to monitor the activity of 2 Rho GTPases, RhoA and Cdc42, in
single dendritic spines undergoing structural plasticity associated with
long-term potentiation in CA1 pyramidal neurons in cultured slices of
rat hippocampus. When long-term volume increase was induced in a single
spine using 2-photon glutamate uncaging, RhoA and Cdc42 were rapidly
activated in the stimulated spine. These activities decayed over about 5
minutes, and were then followed by a phase of persistent activation
lasting more than half an hour. Although active RhoA and Cdc42 were
similarly mobile, their activity patterns were different. RhoA
activation diffused out of the stimulated spine and spread over about 5
microns along the dendrite. In contrast, Cdc42 activation was restricted
to the stimulated spine, and exhibited a steep gradient at the spine
necks. Inhibition of the Rho-Rock pathway preferentially inhibited the
initial spine growth, whereas the inhibition of the Cdc42-Pak pathway
blocked the maintenance of sustained structural plasticity. RhoA and
Cdc42 activation depended on calcium ion/calmodulin-dependent kinase
(CaMKII). Thus, Murakoshi et al. (2011) concluded that RhoA and Cdc42
relay transient CaMKII activation to synapse-specific, long-term
signaling required for spine structural plasticity.

ANIMAL MODEL

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.

*FIELD* RF
1. 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.

2. Borikova, A. L.; Dibble, C. F.; Sciaky, N.; Welch, C. M.; Abell,
A. N.; Bencharit, S.; Johnson, G. L.: Rho kinase inhibition rescues
the endothelial cell cerebral cavernous malformation phenotype. J.
Biol. Chem. 285: 11760-11764, 2010.

3. Canman, J. C.; Lewellyn, L.; Laband, K.; Smerdon, S. J.; Desai,
A.; Bowerman, B.; Oegema, K.: Inhibition of Rac by the GAP activity
of centralspindlin is essential for cytokinesis. Science 322: 1543-1546,
2008.

4. Cannizzaro, L. A.; Madaule, P.; Hecht, F.; Axel, R.; Croce, C.
M.; Huebner, K.: Chromosome localization of human ARH genes, a ras-related
gene family. Genomics 6: 197-203, 1990.

5. Crose, L. E. S.; Hilder, T. L.; Sciaky, N.; Johnson, G. L.: Cerebral
cavernous malformation 2 protein promotes Smad ubiquitin regulatory
factor 1-mediated RhoA degradation in endothelial cells. J. Biol.
Chem. 284: 13301-13305, 2009.

6. Guilluy, C.; Bregeon, J.; Toumaniantz, G.; Rolli-Derkinderen, M.;
Retailleau, K.; Loufrani, L.; Henrion, D.; Scalbert, E.; Bril, A.;
Torres, R. M.; Offermanns, S.; Pacaud, P.; Loirand, G.: The Rho exchange
factor Arhgef1 mediates the effects of angiotensin II on vascular
tone and blood pressure. Nature Med. 16: 183-190, 2010.

7. Kiian, I.; Tkachuk, N.; Haller, H.; Dumler, I.: Urokinase-induced
migration of human vascular smooth muscle cells requires coupling
of the small GTPase RhoA and Rac1 to the Tyk2/PI3-K signalling pathway. Thromb.
Haemost. 89: 904-914, 2003.

8. Kiss, C.; Li, J.; Szeles, A.; Gizatullin, R. Z.; Kashuba, V. I.;
Lushnikova, T.; Protopopov, A. I.; Kelve, M.; Kiss, H.; Kholodnyuk,
I. D.; Imreh, S.; Klein, G.; Zabarovsky, E. R.: Assignment of the
ARHA and GPX1 genes to human chromosome bands 3p21.3 by in situ hybridization
and with somatic cell hybrids. Cytogenet. Cell Genet. 79: 228-230,
1997.

9. Lutz, S.; Shankaranarayanan, A.; Coco, C.; Ridilla, M.; Nance,
M. R.; Vettel, C.; Baltus, D.; Evelyn, C. R.; Neubig, R. R.; Wieland,
T.; Tesmer, J. J. G.: Structure of G-alpha(q)-p63RhoGEF-RhoA complex
reveals a pathway for the activation of RhoA by GPCRs. Science 318:
1923-1927, 2007.

10. Machacek, M.; Hodgson, L.; Welch, C.; Elliott, H.; Pertz, O.;
Nalbant, P.; Abell, A.; Johnson, G. L.; Hahn, K. M.; Danuser, G.:
Coordination of Rho GTPase activities during cell protrusion. Nature 461:
99-103, 2009.

11. 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.

12. Maesaki, R.; Ihara, K.; Shimizu, T.; Kuroda, S.; Kaibuchi, K.;
Hakoshima, T.: The structural basis of Rho effector recognition revealed
by the crystal structure of human RhoA complexed with the effector
domain of PKN/PRK1. Molec. Cell 4: 793-803, 1999.

13. Murakoshi, H.; Wang, H.; Yasuda, R.: Local, persistent activation
of Rho GTPases during plasticity of single dendritic spines. Nature 472:
100-104, 2011.

14. 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.

15. Pertz, O.; Hodgson, L.; Klemke, R. L.; Hahn, K. M.: Spatiotemporal
dynamics of RhoA activity in migrating cells. Nature 440: 1069-1072,
2006.

16. 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.

17. Sin, W. C.; Haas, K.; Ruthazer, E. S.; Cline, H. T.: Dendrite
growth increased by visual activity requires NMDA receptor and Rho
GTPases. Nature 419: 475-480, 2002.

18. 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.

19. Wang, H.-R.; Zhang, Y.; Ozdamar, B.; Ogunjimi, A. A.; Alexandrova,
E.; Thomsen, G. H.; Wrana, J. L.: Regulation of cell polarity and
protrusion formation by targeting RhoA for degradation. Science 302:
1775-1779, 2003.

20. Wu, K. Y.; Hengst, U.; Cox, L. J.; Macosko, E. Z.; Jeromin, A.;
Urquhart, E. R.; Jaffrey, S. R.: Local translation of RhoA regulates
growth cone collapse. (Letter) Nature 436: 1020-1024, 2005.

21. Wu, Y. I.; Frey, D.; Lungu, O. I.; Jaehrig, A.; Schlichting, I.;
Kuhlman, B.; Hahn, K. M.: A genetically encoded photoactivatable
Rac controls the motility of living cells. Nature 461: 104-108,
2009.

22. Yoshida, S.; Kono, K.; Lowery, D. M.; Bartolini, S.; Yaffe, M.
B.; Ohya, Y.; Pellman, D.: Polo-like kinase Cdc5 controls the local
activation of Rho1 to promote cytokinesis. Science 313: 108-111,
2006.

23. 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.

*FIELD* CN
Ada Hamosh - updated: 5/9/2011
Patricia A. Hartz - updated: 12/20/2010
Marla J. F. O'Neill - updated: 3/11/2010
Ada Hamosh - updated: 10/13/2009
Ada Hamosh - updated: 12/22/2008
Ada Hamosh - updated: 2/11/2008
Ada Hamosh - updated: 8/7/2006
Ada Hamosh - updated: 8/1/2006
Ada Hamosh - updated: 4/18/2006
Ada Hamosh - updated: 9/15/2005
Patricia A. Hartz - updated: 2/18/2005
Patricia A. Hartz - updated: 10/27/2004
Ada Hamosh - updated: 12/30/2003
Ada Hamosh - updated: 12/3/2003
Jane Kelly - updated: 6/19/2001
Stylianos E. Antonarakis - updated: 1/4/2000
Ada Hamosh - updated: 8/5/1999
Victor A. McKusick - updated: 5/28/1998

*FIELD* CD
Victor A. McKusick: 10/27/1989

*FIELD* ED
terry: 08/08/2012
alopez: 5/10/2011
terry: 5/9/2011
mgross: 1/5/2011
terry: 12/20/2010
wwang: 4/2/2010
wwang: 3/15/2010
terry: 3/11/2010
alopez: 10/22/2009
terry: 10/13/2009
wwang: 12/23/2008
terry: 12/22/2008
alopez: 2/14/2008
terry: 2/11/2008
alopez: 4/4/2007
alopez: 8/9/2006
terry: 8/7/2006
alopez: 8/3/2006
terry: 8/1/2006
alopez: 4/21/2006
terry: 4/18/2006
alopez: 9/16/2005
terry: 9/15/2005
alopez: 9/15/2005
terry: 9/12/2005
mgross: 2/18/2005
mgross: 10/27/2004
alopez: 12/30/2003
terry: 12/30/2003
alopez: 12/8/2003
terry: 12/3/2003
alopez: 11/19/2002
terry: 11/18/2002
carol: 8/10/2001
mcapotos: 6/20/2001
mcapotos: 6/19/2001
mgross: 1/4/2000
alopez: 8/5/1999
alopez: 8/3/1998
terry: 6/1/1998
terry: 5/28/1998
mark: 10/17/1997
mark: 4/1/1996
supermim: 3/16/1992
carol: 6/18/1990
carol: 6/13/1990
supermim: 3/20/1990
supermim: 2/8/1990
ddp: 10/27/1989