RBCC Red Blood Cell Collection

RAC1 (TC25) [Confidence: high (present in two of the MS resources)]
Ras-related C3 botulinum toxin substrate 1 (Cell migration-inducing gene 5 protein; Ras-like protein TC25; p21-Rac1; Flags: Precursor)

hRBCD IPI00010271
IPI00010271 Splice isoform A of P15154 Ras-related C3 botulinum toxin substrate 1 Splice isoform A of P15154 Ras-related C3 botulinum toxin substrate 1 membrane n/a n/a 2 n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a membrane bound splice isoform A and B found at its expected molecular weight found at molecular weight

UniProt P63000
ID RAC1_HUMAN Reviewed; 192 AA.
AC P63000; O95501; P15154; Q3Y4D3; Q5JAA8; Q9BTB4;
DT 31-AUG-2004, integrated into UniProtKB/Swiss-Prot.
read moreDT 31-AUG-2004, sequence version 1.
DT 22-JAN-2014, entry version 130.
DE RecName: Full=Ras-related C3 botulinum toxin substrate 1;
DE AltName: Full=Cell migration-inducing gene 5 protein;
DE AltName: Full=Ras-like protein TC25;
DE AltName: Full=p21-Rac1;
DE Flags: Precursor;
GN Name=RAC1; Synonyms=TC25; ORFNames=MIG5;
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] (ISOFORM A).
RX PubMed=2674130;
RA Didsbury J., Weber R.F., Bokoch G.M., Evans T., Snyderman R.;
RT "Rac, a novel ras-related family of proteins that are botulinum toxin
RT substrates.";
RL J. Biol. Chem. 264:16378-16382(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM A).
RX PubMed=2108320;
RA Drivas G.T., Shih A., Coutavas E., Rush M.G., D'Eustachio P.;
RT "Characterization of four novel ras-like genes expressed in a human
RT teratocarcinoma cell line.";
RL Mol. Cell. Biol. 10:1793-1798(1990).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS A AND B).
RX PubMed=11062023; DOI=10.1006/bbrc.2000.3743;
RA Matos P., Skaug J., Marques B., Beck S., Verissimo F., Gespach C.,
RA Boavida M.G., Scherer S.W., Jordan P.;
RT "Small GTPase Rac1: structure, localization, and expression of the
RT human gene.";
RL Biochem. Biophys. Res. Commun. 277:741-751(2000).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS A AND B).
RC TISSUE=Colon, and Skin;
RX PubMed=10597294; DOI=10.1038/sj.onc.1203233;
RA Jordan P., Brazao R., Boavida M.G., Gespach C., Chastre E.;
RT "Cloning of a novel human Rac1b splice variant with increased
RT expression in colorectal tumors.";
RL Oncogene 18:6835-6839(1999).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM B).
RA Schnelzer A., Knaus U., Prechtel D., Dehne K., Harbeck N., Gerhard M.,
RA Schmitt M., Lengyel E.;
RT "Mutations and altered expression of Rac1 in human breast cancer --
RT characterization of a new Rac1 isoform, Rac1ins.";
RL Submitted (MAR-1999) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM A).
RA Kim J.W.;
RT "Identification of a human migration-inducing gene.";
RL Submitted (APR-2003) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM A), AND VARIANT
RP ILE-135.
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 [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM A).
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 (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG NIEHS SNPs program;
RL Submitted (AUG-2005) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12853948; DOI=10.1038/nature01782;
RA Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H.,
RA Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R.,
RA Wylie K., Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H.,
RA Sun H., Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A.,
RA Vanbrunt A., Nguyen C., Du F., Lamar B., Courtney L., Kalicki J.,
RA Ozersky P., Bielicki L., Scott K., Holmes A., Harkins R., Harris A.,
RA Strong C.M., Hou S., Tomlinson C., Dauphin-Kohlberg S.,
RA Kozlowicz-Reilly A., Leonard S., Rohlfing T., Rock S.M.,
RA Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., Strowmatt C.,
RA Latreille P., Miller N., Johnson D., Murray J., Woessner J.P.,
RA Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., Spieth J.,
RA Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., Cook L.L.,
RA Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., Mardis E.R.,
RA Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E.,
RA Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K.,
RA Simms E., Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S.,
RA Baertsch R.A., Brent M.R., Keibler E., Flicek P., Bork P., Suyama M.,
RA Bailey J.A., Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R.,
RA Eddy S.R., McPherson J.D., Olson M.V., Eichler E.E., Green E.D.,
RA Waterston R.H., Wilson R.K.;
RT "The DNA sequence of human chromosome 7.";
RL Nature 424:157-164(2003).
RN [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM A).
RC TISSUE=Pancreas, and Skin;
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 [12]
RP ISOPRENYLATION AT CYS-189.
RX PubMed=1903399;
RA Kinsella B.T., Erdman R.A., Maltese W.A.;
RT "Carboxyl-terminal isoprenylation of ras-related GTP-binding proteins
RT encoded by rac1, rac2, and ralA.";
RL J. Biol. Chem. 266:9786-9794(1991).
RN [13]
RP FUNCTION.
RX PubMed=1643658; DOI=10.1016/0092-8674(92)90164-8;
RA Ridley A.J., Paterson H.F., Johnston C.L., Diekmann D., Hall A.;
RT "The small GTP-binding protein rac regulates growth factor-induced
RT membrane ruffling.";
RL Cell 70:401-410(1992).
RN [14]
RP INTERACTION WITH RALBP1.
RX PubMed=7673236; DOI=10.1074/jbc.270.38.22473;
RA Jullien-Flores V., Dorseuil O., Romero F., Letourneur F.,
RA Saragosti S., Berger R., Tavitian A., Gacon G., Camonis J.H.;
RT "Bridging Ral GTPase to Rho pathways. RLIP76, a Ral effector with
RT CDC42/Rac GTPase-activating protein activity.";
RL J. Biol. Chem. 270:22473-22477(1995).
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 DOCK2.
RX PubMed=10559471; DOI=10.1016/S0167-4889(99)00133-0;
RA Nishihara H., Kobayashi S., Hashimoto Y., Ohba F., Mochizuki N.,
RA Kurata T., Nagashima K., Matsuda M.;
RT "Non-adherent cell-specific expression of DOCK2, a member of the human
RT CDM-family proteins.";
RL Biochim. Biophys. Acta 1452:179-187(1999).
RN [18]
RP INTERACTION WITH PARD6A, AND MUTAGENESIS OF GLN-61.
RX PubMed=10954424;
RA Johansson A.-S., Driessens M., Aspenstroem P.;
RT "The mammalian homologue of the Caenorhabditis elegans polarity
RT protein PAR-6 is a binding partner for the Rho GTPases Cdc42 and
RT Rac1.";
RL J. Cell Sci. 113:3267-3275(2000).
RN [19]
RP INTERACTION WITH BAIAP2.
RX PubMed=11130076; DOI=10.1038/35047107;
RA Miki H., Yamaguchi H., Suetsugu S., Takenawa T.;
RT "IRSp53 is an essential intermediate between Rac and WAVE in the
RT regulation of membrane ruffling.";
RL Nature 408:732-735(2000).
RN [20]
RP INTERACTION WITH PLXNB1.
RX PubMed=11035813; DOI=10.1073/pnas.220421797;
RA Vikis H.G., Li W., He Z., Guan K.-L.;
RT "The semaphorin receptor plexin-B1 specifically interacts with active
RT Rac in a ligand-dependent manner.";
RL Proc. Natl. Acad. Sci. U.S.A. 97:12457-12462(2000).
RN [21]
RP INTERACTION WITH PARD6A; PARD6B AND PARD6G; PRKCI AND PRKCZ, AND
RP MUTAGENESIS OF GLY-12 AND THR-17.
RX PubMed=11260256; DOI=10.1046/j.1365-2443.2001.00404.x;
RA Noda Y., Takeya R., Ohno S., Naito S., Ito T., Sumimoto H.;
RT "Human homologues of the Caenorhabditis elegans cell polarity protein
RT PAR6 as an adaptor that links the small GTPases Rac and Cdc42 to
RT atypical protein kinase C.";
RL Genes Cells 6:107-119(2001).
RN [22]
RP ACTIVATION BY PREX1.
RX PubMed=11955434; DOI=10.1016/S0092-8674(02)00663-3;
RA Welch H.C.E., Coadwell W.J., Ellson C.D., Ferguson G.J., Andrews S.R.,
RA Erdjument-Bromage H., Tempst P., Hawkins P.T., Stephens L.R.;
RT "P-Rex1, a PtdIns(3,4,5)P3- and Gbetagamma-regulated guanine-
RT nucleotide exchange factor for Rac.";
RL Cell 108:809-821(2002).
RN [23]
RP INTERACTION WITH ITGB1BP1.
RX PubMed=11807099; DOI=10.1083/jcb.200108030;
RA Degani S., Balzac F., Brancaccio M., Guazzone S., Retta S.F.,
RA Silengo L., Eva A., Tarone G.;
RT "The integrin cytoplasmic domain-associated protein ICAP-1 binds and
RT regulates Rho family GTPases during cell spreading.";
RL J. Cell Biol. 156:377-387(2002).
RN [24]
RP SUBUNIT OF A COMPLEX CONTAINING ELMO1 AND DOCK1.
RX PubMed=12134158; DOI=10.1038/ncb824;
RA Brugnera E., Haney L., Grimsley C., Lu M., Walk S.F.,
RA Tosello-Trampont A.-C., Macara I.G., Madhani H., Fink G.R.,
RA Ravichandran K.S.;
RT "Unconventional Rac-GEF activity is mediated through the Dock180-ELMO
RT complex.";
RL Nat. Cell Biol. 4:574-582(2002).
RN [25]
RP INTERACTION WITH NOXA1.
RX PubMed=12716910; DOI=10.1074/jbc.M212856200;
RA Takeya R., Ueno N., Kami K., Taura M., Kohjima M., Izaki T., Nunoi H.,
RA Sumimoto H.;
RT "Novel human homologues of p47phox and p67phox participate in
RT activation of superoxide-producing NADPH oxidases.";
RL J. Biol. Chem. 278:25234-25246(2003).
RN [26]
RP INTERACTION WITH USP6.
RX PubMed=12612085; DOI=10.1128/MCB.23.6.2151-2161.2003;
RA Masuda-Robens J.M., Kutney S.N., Qi H., Chou M.M.;
RT "The TRE17 oncogene encodes a component of a novel effector pathway
RT for Rho GTPases Cdc42 and Rac1 and stimulates actin remodeling.";
RL Mol. Cell. Biol. 23:2151-2161(2003).
RN [27]
RP INTERACTION WITH DSCAM.
RX PubMed=15169762; DOI=10.1074/jbc.M401878200;
RA Li W., Guan K.L.;
RT "The Down syndrome cell adhesion molecule (DSCAM) interacts with and
RT activates Pak.";
RL J. Biol. Chem. 279:32824-32831(2004).
RN [28]
RP INTERACTION WITH S100A8 AND CALPROTECTIN.
RX PubMed=15642721; DOI=10.1096/fj.04-2377fje;
RA Kerkhoff C., Nacken W., Benedyk M., Dagher M.C., Sopalla C.,
RA Doussiere J.;
RT "The arachidonic acid-binding protein S100A8/A9 promotes NADPH oxidase
RT activation by interaction with p67phox and Rac-2.";
RL FASEB J. 19:467-469(2005).
RN [29]
RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS], AND MASS SPECTROMETRY.
RC TISSUE=Melanoma;
RX PubMed=17081065; DOI=10.1021/pr060363j;
RA Chi A., Valencia J.C., Hu Z.-Z., Watabe H., Yamaguchi H.,
RA Mangini N.J., Huang H., Canfield V.A., Cheng K.C., Yang F., Abe R.,
RA Yamagishi S., Shabanowitz J., Hearing V.J., Wu C., Appella E.,
RA Hunt D.F.;
RT "Proteomic and bioinformatic characterization of the biogenesis and
RT function of melanosomes.";
RL J. Proteome Res. 5:3135-3144(2006).
RN [30]
RP INTERACTION WITH DOCK7.
RX PubMed=16982419; DOI=10.1016/j.neuron.2006.07.020;
RA Watabe-Uchida M., John K.A., Janas J.A., Newey S.E., Van Aelst L.;
RT "The Rac activator DOCK7 regulates neuronal polarity through local
RT phosphorylation of stathmin/Op18.";
RL Neuron 51:727-739(2006).
RN [31]
RP INTERACTION WITH DEF6, AND DOMAIN.
RX PubMed=17121847; DOI=10.1074/jbc.M605153200;
RA Oka T., Ihara S., Fukui Y.;
RT "Cooperation of DEF6 with activated Rac in regulating cell
RT morphology.";
RL J. Biol. Chem. 282:2011-2018(2007).
RN [32]
RP INTERACTION WITH BAIAP2L1.
RX PubMed=17430976; DOI=10.1242/jcs.001776;
RA Millard T.H., Dawson J., Machesky L.M.;
RT "Characterisation of IRTKS, a novel IRSp53/MIM family actin regulator
RT with distinct filament bundling properties.";
RL J. Cell Sci. 120:1663-1672(2007).
RN [33]
RP INTERACTION WITH SPATA13.
RX PubMed=17145773; DOI=10.1128/MCB.01608-06;
RA Hamann M.J., Lubking C.M., Luchini D.N., Billadeau D.D.;
RT "Asef2 functions as a Cdc42 exchange factor and is stimulated by the
RT release of an autoinhibitory module from a concealed C-terminal
RT activation element.";
RL Mol. Cell. Biol. 27:1380-1393(2007).
RN [34]
RP UBIQUITINATION AT LYS-147.
RX PubMed=18093184; DOI=10.1111/j.1742-4658.2007.06209.x;
RA Visvikis O., Lores P., Boyer L., Chardin P., Lemichez E., Gacon G.;
RT "Activated Rac1, but not the tumorigenic variant Rac1b, is
RT ubiquitinated on Lys 147 through a JNK-regulated process.";
RL FEBS J. 275:386-396(2008).
RN [35]
RP FUNCTION, AND MUTAGENESIS OF GLY-12 AND THR-17.
RX PubMed=19029984; DOI=10.1038/nm.1879;
RA Shibata S., Nagase M., Yoshida S., Kawarazaki W., Kurihara H.,
RA Tanaka H., Miyoshi J., Takai Y., Fujita T.;
RT "Modification of mineralocorticoid receptor function by Rac1 GTPase:
RT implication in proteinuric kidney disease.";
RL Nat. Med. 14:1370-1376(2008).
RN [36]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-71 (ISOFORM B), AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [37]
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 [38]
RP INTERACTION WITH UNKL.
RX PubMed=20148946; DOI=10.1111/j.1742-4658.2010.07575.x;
RA Lores P., Visvikis O., Luna R., Lemichez E., Gacon G.;
RT "The SWI/SNF protein BAF60b is ubiquitinated through a signalling
RT process involving Rac GTPase and the RING finger protein Unkempt.";
RL FEBS J. 277:1453-1464(2010).
RN [39]
RP FUNCTION, AND INTERACTION WITH ITGB4.
RX PubMed=19403692; DOI=10.1091/mbc.E09-01-0051;
RA Hamill K.J., Hopkinson S.B., DeBiase P., Jones J.C.;
RT "BPAG1e maintains keratinocyte polarity through beta4 integrin-
RT mediated modulation of Rac1 and cofilin activities.";
RL Mol. Biol. Cell 20:2954-2962(2009).
RN [40]
RP AMPYLATION AT TYR-32, MASS SPECTROMETRY, AND MUTAGENESIS OF TYR-32.
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 [41]
RP AMPYLATION AT THR-35, MASS SPECTROMETRY, AND MUTAGENESIS OF THR-35.
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 [42]
RP INTERACTION WITH TBC1D2.
RX PubMed=20116244; DOI=10.1016/j.cub.2009.12.053;
RA Frasa M.A., Maximiano F.C., Smolarczyk K., Francis R.E., Betson M.E.,
RA Lozano E., Goldenring J., Seabra M.C., Rak A., Ahmadian M.R.,
RA Braga V.M.;
RT "Armus is a Rac1 effector that inactivates Rab7 and regulates E-
RT cadherin degradation.";
RL Curr. Biol. 20:198-208(2010).
RN [43]
RP FUNCTION.
RX PubMed=20696765; DOI=10.1074/jbc.M110.120451;
RA Li X., Lee A.Y.;
RT "Semaphorin 5A and plexin-B3 inhibit human glioma cell motility
RT through RhoGDIalpha-mediated inactivation of Rac1 GTPase.";
RL J. Biol. Chem. 285:32436-32445(2010).
RN [44]
RP FUNCTION, INTERACTION WITH PPP5C, SUBCELLULAR LOCATION, AND
RP MUTAGENESIS OF THR-17; GLY-30; THR-35 AND GLN-61.
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 [45]
RP INTERACTION WITH ARHGEF16.
RX PubMed=20679435; DOI=10.1083/jcb.201005141;
RA Hiramoto-Yamaki N., Takeuchi S., Ueda S., Harada K., Fujimoto S.,
RA Negishi M., Katoh H.;
RT "Ephexin4 and EphA2 mediate cell migration through a RhoG-dependent
RT mechanism.";
RL J. Cell Biol. 190:461-477(2010).
RN [46]
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 [47]
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 [48]
RP UBIQUITINATION.
RX PubMed=22036506; DOI=10.1016/j.devcel.2011.08.015;
RA Torrino S., Visvikis O., Doye A., Boyer L., Stefani C., Munro P.,
RA Bertoglio J., Gacon G., Mettouchi A., Lemichez E.;
RT "The E3 ubiquitin-ligase HACE1 catalyzes the ubiquitylation of active
RT Rac1.";
RL Dev. Cell 21:959-965(2011).
RN [49]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH PACSIN2.
RX PubMed=21693584; DOI=10.1242/jcs.080630;
RA de Kreuk B.J., Nethe M., Fernandez-Borja M., Anthony E.C.,
RA Hensbergen P.J., Deelder A.M., Plomann M., Hordijk P.L.;
RT "The F-BAR domain protein PACSIN2 associates with Rac1 and regulates
RT cell spreading and migration.";
RL J. Cell Sci. 124:2375-2388(2011).
RN [50]
RP 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 [51]
RP INTERACTION WITH FARP1.
RX PubMed=23209303; DOI=10.1083/jcb.201205041;
RA Cheadle L., Biederer T.;
RT "The novel synaptogenic protein Farp1 links postsynaptic cytoskeletal
RT dynamics and transsynaptic organization.";
RL J. Cell Biol. 199:985-1001(2012).
RN [52]
RP INTERACTION WITH ARHGDIA.
RX PubMed=23434736; DOI=10.1136/jmedgenet-2012-101442;
RA Gupta I.R., Baldwin C., Auguste D., Ha K.C., El Andalousi J.,
RA Fahiminiya S., Bitzan M., Bernard C., Akbari M.R., Narod S.A.,
RA Rosenblatt D.S., Majewski J., Takano T.;
RT "ARHGDIA: a novel gene implicated in nephrotic syndrome.";
RL J. Med. Genet. 50:330-338(2013).
RN [53]
RP FUNCTION.
RX PubMed=23633677; DOI=10.1126/scisignal.2003627;
RA Borroni E.M., Cancellieri C., Vacchini A., Benureau Y., Lagane B.,
RA Bachelerie F., Arenzana-Seisdedos F., Mizuno K., Mantovani A.,
RA Bonecchi R., Locati M.;
RT "Beta-arrestin-dependent activation of the cofilin pathway is required
RT for the scavenging activity of the atypical chemokine receptor D6.";
RL Sci. Signal. 6:RA30-RA30(2013).
RN [54]
RP INTERACTION WITH FARP2.
RX PubMed=23375260; DOI=10.1016/j.str.2013.01.001;
RA He X., Kuo Y.C., Rosche T.J., Zhang X.;
RT "Structural basis for autoinhibition of the guanine nucleotide
RT exchange factor FARP2.";
RL Structure 21:355-364(2013).
RN [55]
RP X-RAY CRYSTALLOGRAPHY (1.38 ANGSTROMS) OF 1-184 IN COMPLEX WITH GTP
RP ANALOG.
RX PubMed=9033596; DOI=10.1038/nsb0297-147;
RA Hirshberg M., Stockley R.W., Dodson G., Webb M.R.;
RT "The crystal structure of human rac1, a member of the rho-family
RT complexed with a GTP analogue.";
RL Nat. Struct. Biol. 4:147-152(1997).
RN [56]
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF MUTANT LEU-61 IN COMPLEX WITH
RP GTP AND NCF2.
RX PubMed=11090627;
RA Lapouge K., Smith S.J., Walker P.A., Gamblin S.J., Smerdon S.J.,
RA Rittinger K.;
RT "Structure of the TPR domain of p67phox in complex with Rac.GTP.";
RL Mol. Cell 6:899-907(2000).
RN [57]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 1-177 IN COMPLEX WITH TIAM1.
RX PubMed=11130063; DOI=10.1038/35047014;
RA Worthylake D.K., Rossman K.L., Sondek J.;
RT "Crystal structure of Rac1 in complex with the guanine nucleotide
RT exchange region of Tiam1.";
RL Nature 408:682-688(2000).
RN [58]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 1-184 IN COMPLEX WITH
RP SALMONELLA SPTP.
RX PubMed=11163217; DOI=10.1016/S1097-2765(00)00141-6;
RA Stebbins C.E., Galan J.E.;
RT "Modulation of host signaling by a bacterial mimic: structure of the
RT Salmonella effector SptP bound to Rac1.";
RL Mol. Cell 6:1449-1460(2000).
RN [59]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 1-176 IN COMPLEX WITH GTP
RP ANALOG AND P.AERUGINOSA EXOS.
RX PubMed=11135665; DOI=10.1038/83007;
RA Wuertele M., Wolf E., Pederson K.J., Buchwald G., Ahmadian M.R.,
RA Barbieri J.T., Wittinghofer A.;
RT "How the Pseudomonas aeruginosa ExoS toxin downregulates Rac.";
RL Nat. Struct. Biol. 8:23-26(2001).
RN [60]
RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) IN COMPLEX WITH ARHGDIA.
RX PubMed=11513578; DOI=10.1021/bi010288k;
RA Grizot S., Faure J., Fieschi F., Vignais P.V., Dagher M.-C.,
RA Pebay-Peyroula E.;
RT "Crystal structure of the Rac1-RhoGDI complex involved in NADPH
RT oxidase activation.";
RL Biochemistry 40:10007-10013(2001).
RN [61]
RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) IN COMPLEX WITH GTP ANALOG AND
RP ARFIP2.
RX PubMed=11346801; DOI=10.1038/35075620;
RA Tarricone C., Xiao B., Justin N., Walker P.A., Rittinger K.,
RA Gamblin S.J., Smerdon S.J.;
RT "The structural basis of Arfaptin-mediated cross-talk between Rac and
RT Arf signalling pathways.";
RL Nature 411:215-219(2001).
RN [62]
RP X-RAY CRYSTALLOGRAPHY (1.75 ANGSTROMS) OF ISOFORM B, AND
RP CHARACTERIZATION (ISOFORM B).
RX PubMed=14625275; DOI=10.1074/jbc.M310281200;
RA Fiegen D., Haeusler L.C., Blumenstein L., Herbrand U., Dvorsky R.,
RA Vetter I.R., Ahmadian M.R.;
RT "Alternative splicing of Rac1 generates Rac1b, a self-activating
RT GTPase.";
RL J. Biol. Chem. 279:4743-4749(2004).
RN [63]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 1-184 IN COMPLEX WITH
RP Y.PSEUDOTUBERCULOSIS YPKA.
RX PubMed=16959567; DOI=10.1016/j.cell.2006.06.056;
RA Prehna G., Ivanov M.I., Bliska J.B., Stebbins C.E.;
RT "Yersinia virulence depends on mimicry of host Rho-family nucleotide
RT dissociation inhibitors.";
RL Cell 126:869-880(2006).
RN [64]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 1-177 IN COMPLEX WITH GTP
RP ANALOG AND PLCB2, AND MUTAGENESIS OF PHE-37; TRP-56; LEU-67 AND
RP LEU-70.
RX PubMed=17115053; DOI=10.1038/nsmb1175;
RA Jezyk M.R., Snyder J.T., Gershberg S., Worthylake D.K., Harden T.K.,
RA Sondek J.;
RT "Crystal structure of Rac1 bound to its effector phospholipase C-
RT beta2.";
RL Nat. Struct. Mol. Biol. 13:1135-1140(2006).
RN [65]
RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 1-177 IN COMPLEX WITH DOCK2.
RX PubMed=21613211; DOI=10.1074/jbc.M111.236455;
RA Kulkarni K., Yang J., Zhang Z., Barford D.;
RT "Multiple factors confer specific Cdc42 and Rac protein activation by
RT dedicator of cytokinesis (DOCK) nucleotide exchange factors.";
RL J. Biol. Chem. 286:25341-25351(2011).
CC -!- FUNCTION: Plasma membrane-associated small GTPase which cycles
CC between active GTP-bound and inactive GDP-bound states. In its
CC active state, binds to a variety of effector proteins to regulate
CC cellular responses such as secretory processes, phagocytosis of
CC apoptotic cells, epithelial cell polarization and growth-factor
CC induced formation of membrane ruffles. Rac1 p21/rho GDI
CC heterodimer is the active component of the cytosolic factor sigma
CC 1, which is involved in stimulation of the NADPH oxidase activity
CC in macrophages. Essential for the SPATA13-mediated regulation of
CC cell migration and adhesion assembly and disassembly. Stimulates
CC PKN2 kinase activity. In concert with RAB7A, plays a role in
CC regulating the formation of RBs (ruffled borders) in osteoclasts.
CC In glioma cells, promotes cell migration and invasion. In
CC podocytes, promotes nuclear shuttling of NR3C2; this modulation is
CC required for a proper kidney functioning. Required for atypical
CC chemokine receptor ACKR2-induced LIMK1-PAK1-dependent
CC phosphorylation of cofilin (CFL1) and for up-regulation of ACKR2
CC from endosomal compartment to cell membrane, increasing its
CC efficiency in chemokine uptake and degradation.
CC -!- FUNCTION: Isoform B has an accelerated GEF-independent GDP/GTP
CC exchange and an impaired GTP hydrolysis, which is restored
CC partially by GTPase-activating proteins. It is able to bind to the
CC GTPase-binding domain of PAK but not full-length PAK in a GTP-
CC dependent manner, suggesting that the insertion does not
CC completely abolish effector interaction.
CC -!- ENZYME REGULATION: Regulated by guanine nucleotide exchange
CC factors (GEFs) which promote the exchange of bound GDP for free
CC GTP, GTPase activating proteins (GAPs) which increase the GTP
CC hydrolysis activity, and GDP dissociation inhibitors which inhibit
CC the dissociation of the nucleotide from the GTPase. GTP hydrolysis
CC is stimulated by ARHGAP30.
CC -!- SUBUNIT: Interacts with NISCH. Interacts with PIP5K1A. Interacts
CC with the GTP-bound form of RAB7A. Interacts with SRGAP2. Interacts
CC with CYFIP1/SRA-1. Interacts with PLXNB3. Interacts with ARHGDIA;
CC the interaction is induced by SEMA5A, mediated through PLXNB3 and
CC inactivates and stabilizes RAC1. Interacts (GTP-bound form
CC preferentially) with PKN2 (via the REM repeats); the interaction
CC stimulates autophosphorylation and phosphorylation of PKN2.
CC Interacts with the GEF proteins PREX1, RASGRF2, FARP1, FARP2,
CC DOCK1, DOCK2 and DOCK7, which promote the exchange between GDP and
CC GTP, and therefore activate it. Interacts with PARD6A, PARD6B and
CC PARD6G in a GTP-dependent manner. Part of a quaternary complex
CC containing PARD3, some PARD6 protein (PARD6A, PARD6B or PARD6G)
CC and some atypical PKC protein (PRKCI or PRKCZ), which plays a
CC central role in epithelial cell polarization. Found in a trimeric
CC complex composed of DOCK1 and ELMO1, which plays a central role in
CC phagocytosis of apoptotic cells. Interacts with RALBP1 via its
CC effector domain. Interacts with PLXNB1. Probably found in a
CC ternary complex composed of DSCAM, PAK1 and RAC1. Interacts with
CC DSCAM; the interaction requires PAK1. Part of a complex with
CC MAP2K3, MAP3K3, CCM2 and DEF6. Interacts with BAIAP2, BAIAP2L1 and
CC DEF6. Interacts with Y.pseudotuberculosis YPKA and PLCB2.
CC Interacts with NOXA1. Interacts with ARHGEF2. Interacts with
CC TBC1D2. Interacts with UNKL. Interacts with USP6. Interacts with
CC SPATA13. Interacts with ARHGEF16; mediates activation of RAC1 by
CC EPHA2. Interacts with ITGB4. Interacts with S100A8 and
CC calprotectin (S100A8/9). Interacts with PACSIN2. Interacts with
CC ITGB1BP1. Interacts (when active) with PPP5C (via TPR repeats);
CC activates PPP5C phosphatase activity and translocates PPP5C to the
CC cell membrane.
CC -!- INTERACTION:
CC P53365:ARFIP2; NbExp=9; IntAct=EBI-413628, EBI-638194;
CC P52565:ARHGDIA; NbExp=6; IntAct=EBI-413628, EBI-712693;
CC Q14155:ARHGEF7; NbExp=7; IntAct=EBI-413628, EBI-717515;
CC Q9UQB8:BAIAP2; NbExp=4; IntAct=EBI-413628, EBI-525456;
CC Q13490:BIRC2; NbExp=2; IntAct=EBI-413628, EBI-514538;
CC P52757:CHN2; NbExp=4; IntAct=EBI-413628, EBI-714925;
CC Q14185:DOCK1; NbExp=10; IntAct=EBI-413628, EBI-446740;
CC Q92608:DOCK2; NbExp=3; IntAct=EBI-413628, EBI-448771;
CC O75369:FLNB; NbExp=2; IntAct=EBI-413628, EBI-352089;
CC Q5S007:LRRK2; NbExp=5; IntAct=EBI-413628, EBI-5323863;
CC Q01968:OCRL; NbExp=3; IntAct=EBI-413628, EBI-6148898;
CC Q13153:PAK1; NbExp=15; IntAct=EBI-413628, EBI-1307;
CC Q13177:PAK2; NbExp=4; IntAct=EBI-413628, EBI-1045887;
CC O75914:PAK3; NbExp=2; IntAct=EBI-413628, EBI-3389553;
CC Q9NPB6:PARD6A; NbExp=2; IntAct=EBI-413628, EBI-81876;
CC Q9BYG5:PARD6B; NbExp=3; IntAct=EBI-413628, EBI-295391;
CC Q9BYG4:PARD6G; NbExp=2; IntAct=EBI-413628, EBI-295417;
CC P19174:PLCG1; NbExp=7; IntAct=EBI-413628, EBI-79387;
CC P41743:PRKCI; NbExp=3; IntAct=EBI-413628, EBI-286199;
CC Q01105:SET; NbExp=8; IntAct=EBI-413628, EBI-1053182;
CC Q7Z6J0:SH3RF1; NbExp=2; IntAct=EBI-413628, EBI-311339;
CC Q8TEJ3:SH3RF3; NbExp=6; IntAct=EBI-413628, EBI-7975674;
CC Q9H9P5:UNKL; NbExp=2; IntAct=EBI-413628, EBI-7797561;
CC P15498:VAV1; NbExp=2; IntAct=EBI-413628, EBI-625518;
CC P98170:XIAP; NbExp=3; IntAct=EBI-413628, EBI-517127;
CC -!- SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor; Cytoplasmic
CC side (By similarity). Melanosome. Cytoplasm (By similarity).
CC Note=Inner surface of plasma membrane possibly with attachment
CC requiring prenylation of the C-terminal cysteine (By similarity).
CC Identified by mass spectrometry in melanosome fractions from stage
CC I to stage IV. Found in the ruffled border (a late endosomal-like
CC compartment in the plasma membrane) of bone-resorbing osteoclasts
CC (By similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=A; Synonyms=Rac1A;
CC IsoId=P63000-1, P15154-1;
CC Sequence=Displayed;
CC Name=B; Synonyms=Rac1B, Rac1ins;
CC IsoId=P63000-2, P15154-2;
CC Sequence=VSP_005710;
CC Note=Contains a phosphoserine at position 71;
CC -!- TISSUE SPECIFICITY: Isoform B is predominantly identified in skin
CC and epithelial tissues from the intestinal tract. Its expression
CC is elevated in colorectal tumors at various stages of neoplastic
CC progression, as compared to their respective adjacent tissues.
CC -!- DOMAIN: The effector region mediates interaction with DEF6.
CC -!- PTM: AMPylation at Tyr-32 and Thr-35 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: GTP-bound active form is ubiquitinated by HACE1, leading to
CC its degradation by the proteasome.
CC -!- SIMILARITY: Belongs to the small GTPase superfamily. Rho family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAZ80485.1; Type=Erroneous initiation; Note=Translation N-terminally extended;
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/rac1/";
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DR EMBL; M29870; AAA36537.1; -; mRNA.
DR EMBL; M31467; AAA36544.1; -; mRNA.
DR EMBL; AJ132694; CAA10732.1; -; mRNA.
DR EMBL; AJ132695; CAB53579.5; -; Genomic_DNA.
DR EMBL; AJ132695; CAA10733.6; -; Genomic_DNA.
DR EMBL; AF136373; AAD30547.1; -; mRNA.
DR EMBL; AY279384; AAQ16632.1; -; mRNA.
DR EMBL; AF498964; AAM21111.1; -; mRNA.
DR EMBL; BT007121; AAP35785.1; -; mRNA.
DR EMBL; DQ165078; AAZ80485.1; ALT_INIT; Genomic_DNA.
DR EMBL; AC009412; AAS07511.1; -; Genomic_DNA.
DR EMBL; AC009412; AAS07512.1; -; Genomic_DNA.
DR EMBL; BC004247; AAH04247.1; -; mRNA.
DR EMBL; BC050687; AAH50687.1; -; mRNA.
DR EMBL; BC107748; AAI07749.1; -; mRNA.
DR PIR; A34788; TVHUC1.
DR RefSeq; NP_008839.2; NM_006908.4.
DR RefSeq; NP_061485.1; NM_018890.3.
DR UniGene; Hs.413812; -.
DR PDB; 1E96; X-ray; 2.40 A; A=2-192.
DR PDB; 1FOE; X-ray; 2.80 A; B/D/F/H=1-177.
DR PDB; 1G4U; X-ray; 2.30 A; R=1-184.
DR PDB; 1HE1; X-ray; 2.00 A; C/D=2-176.
DR PDB; 1HH4; X-ray; 2.70 A; A/B=2-192.
DR PDB; 1I4D; X-ray; 2.50 A; D=1-192.
DR PDB; 1I4L; X-ray; 2.70 A; D=1-192.
DR PDB; 1I4T; X-ray; 2.60 A; D=1-192.
DR PDB; 1MH1; X-ray; 1.38 A; A=2-184.
DR PDB; 1RYF; X-ray; 1.75 A; A/B=1-182.
DR PDB; 1RYH; X-ray; 1.75 A; A/B=1-182.
DR PDB; 2FJU; X-ray; 2.20 A; A=1-177.
DR PDB; 2H7V; X-ray; 2.60 A; A/B=1-184.
DR PDB; 2NZ8; X-ray; 2.00 A; A=1-177.
DR PDB; 2P2L; X-ray; 1.90 A; A/B/C=1-184.
DR PDB; 2RMK; NMR; -; A=1-192.
DR PDB; 2VRW; X-ray; 1.85 A; A=1-184.
DR PDB; 2WKP; X-ray; 1.90 A; A=4-180.
DR PDB; 2WKQ; X-ray; 1.60 A; A=4-180.
DR PDB; 2WKR; X-ray; 2.20 A; A=4-180.
DR PDB; 2YIN; X-ray; 2.70 A; C/D=1-177.
DR PDB; 3B13; X-ray; 3.01 A; B/D=1-177.
DR PDB; 3BJI; X-ray; 2.60 A; C/D=1-177.
DR PDB; 3RYT; X-ray; 3.58 A; C=1-177.
DR PDB; 3SBD; X-ray; 2.10 A; A/B=2-177.
DR PDB; 3SBE; X-ray; 2.60 A; A=2-177.
DR PDB; 3SU8; X-ray; 3.20 A; A=1-177.
DR PDB; 3SUA; X-ray; 4.39 A; A/B/C=1-177.
DR PDB; 3TH5; X-ray; 2.30 A; A/B=2-177.
DR PDB; 4GZL; X-ray; 2.00 A; A/B=2-177.
DR PDB; 4GZM; X-ray; 2.80 A; A/B=2-177.
DR PDBsum; 1E96; -.
DR PDBsum; 1FOE; -.
DR PDBsum; 1G4U; -.
DR PDBsum; 1HE1; -.
DR PDBsum; 1HH4; -.
DR PDBsum; 1I4D; -.
DR PDBsum; 1I4L; -.
DR PDBsum; 1I4T; -.
DR PDBsum; 1MH1; -.
DR PDBsum; 1RYF; -.
DR PDBsum; 1RYH; -.
DR PDBsum; 2FJU; -.
DR PDBsum; 2H7V; -.
DR PDBsum; 2NZ8; -.
DR PDBsum; 2P2L; -.
DR PDBsum; 2RMK; -.
DR PDBsum; 2VRW; -.
DR PDBsum; 2WKP; -.
DR PDBsum; 2WKQ; -.
DR PDBsum; 2WKR; -.
DR PDBsum; 2YIN; -.
DR PDBsum; 3B13; -.
DR PDBsum; 3BJI; -.
DR PDBsum; 3RYT; -.
DR PDBsum; 3SBD; -.
DR PDBsum; 3SBE; -.
DR PDBsum; 3SU8; -.
DR PDBsum; 3SUA; -.
DR PDBsum; 3TH5; -.
DR PDBsum; 4GZL; -.
DR PDBsum; 4GZM; -.
DR DisProt; DP00408; -.
DR ProteinModelPortal; P63000; -.
DR SMR; P63000; 1-177.
DR DIP; DIP-29260N; -.
DR IntAct; P63000; 91.
DR MINT; MINT-4999291; -.
DR STRING; 9606.ENSP00000348461; -.
DR BindingDB; P63000; -.
DR ChEMBL; CHEMBL6094; -.
DR DrugBank; DB00175; Pravastatin.
DR DrugBank; DB00641; Simvastatin.
DR PhosphoSite; P63000; -.
DR DMDM; 51702787; -.
DR PaxDb; P63000; -.
DR PRIDE; P63000; -.
DR DNASU; 5879; -.
DR Ensembl; ENST00000348035; ENSP00000258737; ENSG00000136238.
DR Ensembl; ENST00000356142; ENSP00000348461; ENSG00000136238.
DR GeneID; 5879; -.
DR KEGG; hsa:5879; -.
DR UCSC; uc003spx.3; human.
DR CTD; 5879; -.
DR GeneCards; GC07P006380; -.
DR H-InvDB; HIX0031500; -.
DR HGNC; HGNC:9801; RAC1.
DR HPA; CAB035994; -.
DR MIM; 602048; gene.
DR neXtProt; NX_P63000; -.
DR PharmGKB; PA34162; -.
DR eggNOG; COG1100; -.
DR HOGENOM; HOG000233974; -.
DR HOVERGEN; HBG009351; -.
DR KO; K04392; -.
DR OMA; NERRMQP; -.
DR OrthoDB; EOG764747; -.
DR Reactome; REACT_111045; Developmental Biology.
DR Reactome; REACT_111102; Signal Transduction.
DR Reactome; REACT_111155; Cell-Cell communication.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_604; Hemostasis.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; P63000; -.
DR ChiTaRS; RAC1; human.
DR EvolutionaryTrace; P63000; -.
DR GeneWiki; RAC1; -.
DR GenomeRNAi; 5879; -.
DR NextBio; 22846; -.
DR PMAP-CutDB; P63000; -.
DR PRO; PR:P63000; -.
DR ArrayExpress; P63000; -.
DR Bgee; P63000; -.
DR CleanEx; HS_RAC1; -.
DR Genevestigator; P63000; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0019897; C:extrinsic to plasma membrane; IEA:Ensembl.
DR GO; GO:0000139; C:Golgi membrane; IEA:Ensembl.
DR GO; GO:0030027; C:lamellipodium; IEA:Ensembl.
DR GO; GO:0042470; C:melanosome; IEA:UniProtKB-SubCell.
DR GO; GO:0001891; C:phagocytic cup; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0032587; C:ruffle membrane; IEA:Ensembl.
DR GO; GO:0005802; C:trans-Golgi network; IDA:FlyBase.
DR GO; GO:0005525; F:GTP binding; IDA:UniProtKB.
DR GO; GO:0003924; F:GTPase activity; TAS:UniProtKB.
DR GO; GO:0030041; P:actin filament polymerization; TAS:UniProtKB.
DR GO; GO:0048532; P:anatomical structure arrangement; IEA:Ensembl.
DR GO; GO:0097190; P:apoptotic signaling pathway; TAS:Reactome.
DR GO; GO:0002093; P:auditory receptor cell morphogenesis; IEA:Ensembl.
DR GO; GO:0007411; P:axon guidance; TAS:Reactome.
DR GO; GO:0045453; P:bone resorption; IEA:Ensembl.
DR GO; GO:0048870; P:cell motility; IDA:UniProtKB.
DR GO; GO:0008283; P:cell proliferation; IEA:Ensembl.
DR GO; GO:0045216; P:cell-cell junction organization; IEA:Ensembl.
DR GO; GO:0007160; P:cell-matrix adhesion; NAS:BHF-UCL.
DR GO; GO:0021799; P:cerebral cortex radially oriented cell migration; IEA:Ensembl.
DR GO; GO:0090103; P:cochlea morphogenesis; IEA:Ensembl.
DR GO; GO:0048813; P:dendrite morphogenesis; IEA:Ensembl.
DR GO; GO:0071542; P:dopaminergic neuron differentiation; IEA:Ensembl.
DR GO; GO:0021831; P:embryonic olfactory bulb interneuron precursor migration; IEA:Ensembl.
DR GO; GO:0043652; P:engulfment of apoptotic cell; IEA:Ensembl.
DR GO; GO:0003382; P:epithelial cell morphogenesis; IEA:Ensembl.
DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome.
DR GO; GO:0038096; P:Fc-gamma receptor signaling pathway involved in phagocytosis; TAS:Reactome.
DR GO; GO:0006972; P:hyperosmotic response; IEA:Ensembl.
DR GO; GO:0006954; P:inflammatory response; TAS:ProtInc.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0035556; P:intracellular signal transduction; TAS:ProtInc.
DR GO; GO:0030032; P:lamellipodium assembly; IMP:UniProtKB.
DR GO; GO:0051668; P:localization within membrane; IMP:BHF-UCL.
DR GO; GO:0002551; P:mast cell chemotaxis; IEA:Ensembl.
DR GO; GO:0032707; P:negative regulation of interleukin-23 production; IDA:BHF-UCL.
DR GO; GO:0048261; P:negative regulation of receptor-mediated endocytosis; TAS:UniProtKB.
DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; 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:0043065; P:positive regulation of apoptotic process; TAS:Reactome.
DR GO; GO:0045740; P:positive regulation of DNA replication; IEA:Ensembl.
DR GO; GO:0010592; P:positive regulation of lamellipodium assembly; IDA:MGI.
DR GO; GO:0043552; P:positive regulation of phosphatidylinositol 3-kinase activity; IEA:Ensembl.
DR GO; GO:0001934; P:positive regulation of protein phosphorylation; IMP:UniProtKB.
DR GO; GO:0035025; P:positive regulation of Rho protein signal transduction; TAS:UniProtKB.
DR GO; GO:0030334; P:regulation of cell migration; IMP:UniProtKB.
DR GO; GO:0050690; P:regulation of defense response to virus by virus; TAS:Reactome.
DR GO; GO:0010310; P:regulation of hydrogen peroxide metabolic process; TAS:BHF-UCL.
DR GO; GO:0060263; P:regulation of respiratory burst; IDA:BHF-UCL.
DR GO; GO:0097178; P:ruffle assembly; IEA:Ensembl.
DR GO; GO:0031529; P:ruffle organization; TAS:UniProtKB.
DR GO; GO:0007264; P:small GTPase mediated signal transduction; IEA:Ensembl.
DR GO; GO:0034446; P:substrate adhesion-dependent cell spreading; IEA:Ensembl.
DR GO; GO:0031295; P:T cell costimulation; TAS:Reactome.
DR GO; GO:0016032; P:viral process; TAS:Reactome.
DR GO; GO:0060071; P:Wnt receptor signaling pathway, planar cell polarity pathway; IEA:Ensembl.
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; Alternative splicing; Cell membrane;
KW Complete proteome; Cytoplasm; GTP-binding; Isopeptide bond;
KW Lipoprotein; Membrane; Methylation; Nucleotide-binding;
KW Phosphoprotein; Polymorphism; Prenylation; Reference proteome;
KW Ubl conjugation.
FT CHAIN 1 189 Ras-related C3 botulinum toxin substrate
FT 1.
FT /FTId=PRO_0000042036.
FT PROPEP 190 192 Removed in mature form (By similarity).
FT /FTId=PRO_0000042037.
FT NP_BIND 10 17 GTP (By similarity).
FT NP_BIND 57 61 GTP (By similarity).
FT NP_BIND 115 118 GTP (By similarity).
FT MOTIF 32 40 Effector region (Potential).
FT MOD_RES 32 32 O-AMP-tyrosine; by Haemophilus IbpA.
FT MOD_RES 35 35 O-AMP-threonine; by Vibrio VopS.
FT MOD_RES 39 39 ADP-ribosylasparagine; by botulinum toxin
FT (By similarity).
FT MOD_RES 189 189 Cysteine methyl ester.
FT LIPID 189 189 S-geranylgeranyl cysteine.
FT CROSSLNK 147 147 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin).
FT VAR_SEQ 75 75 T -> TVGETYGKDITSRGKDKPIA (in isoform B).
FT /FTId=VSP_005710.
FT VARIANT 26 26 N -> D (in dbSNP:rs5830).
FT /FTId=VAR_014540.
FT VARIANT 28 28 F -> L (in dbSNP:rs5832).
FT /FTId=VAR_014541.
FT VARIANT 59 59 A -> T (in dbSNP:rs5837).
FT /FTId=VAR_014542.
FT VARIANT 63 63 D -> G (in dbSNP:rs5831).
FT /FTId=VAR_014543.
FT VARIANT 93 93 V -> G (in dbSNP:rs5826).
FT /FTId=VAR_014545.
FT VARIANT 93 93 V -> I (in dbSNP:rs5825).
FT /FTId=VAR_014544.
FT VARIANT 108 108 T -> I (in dbSNP:rs5838).
FT /FTId=VAR_014546.
FT VARIANT 130 130 K -> R (in dbSNP:rs5828).
FT /FTId=VAR_014547.
FT VARIANT 133 133 K -> E (in dbSNP:rs5835).
FT /FTId=VAR_014548.
FT VARIANT 135 135 T -> I (in dbSNP:rs11540455).
FT /FTId=VAR_033303.
FT VARIANT 180 180 P -> S (in dbSNP:rs16063).
FT /FTId=VAR_014549.
FT VARIANT 182 182 V -> E (in dbSNP:rs5836).
FT /FTId=VAR_014550.
FT MUTAGEN 12 12 G->V: Constitutively active. Interacts
FT with PARD6 proteins. Increases nuclear
FT localization and up-regulates
FT transcriptional activity of NR3C2.
FT MUTAGEN 17 17 T->N: Constitutively inactivated.
FT Abolishes interaction with PARD6
FT proteins. No effect on NR3C2
FT transcriptional activity. No interaction
FT with PPP5C. Doesn't activate PPP5C
FT phosphatase activity and translocate
FT PPP5C to the plasma membrane.
FT MUTAGEN 30 30 G->V: No interaction with PPP5C; when
FT associated with L-61. Translocates to the
FT plasma membrane; also when associated
FT with L-61.
FT MUTAGEN 32 32 Y->F: Abolishes AMPylation by Haemophilus
FT IbpA.
FT MUTAGEN 35 35 T->A: Abolishes AMPylation by Vibrio
FT VopS.
FT MUTAGEN 35 35 T->S: No interaction with PPP5C; when
FT associated with L-61. Translocates to the
FT plasma membrane; also when associated
FT with L-61.
FT MUTAGEN 37 37 F->A: Strongly reduced interaction with
FT PLCB2.
FT MUTAGEN 56 56 W->A: Strongly reduced interaction with
FT PLCB2.
FT MUTAGEN 61 61 Q->L: Constitutively active. Interacts
FT with PARD6 proteins. Interacts with
FT PPP5C, activates its phosphatase activity
FT and translocates PPP5C to the plasma
FT membrane. No interaction with PPP5C; when
FT associated with V-30 or S-35.
FT Translocates to the plasma membrane; also
FT when associated with V-30 or S-35.
FT MUTAGEN 67 67 L->A: Strongly reduced interaction with
FT PLCB2.
FT MUTAGEN 70 70 L->A: Strongly reduced interaction with
FT PLCB2.
FT CONFLICT 192 192 Missing (in Ref. 2; AAA36544).
FT STRAND 2 9
FT HELIX 12 14
FT HELIX 16 25
FT STRAND 31 36
FT STRAND 39 46
FT STRAND 49 56
FT HELIX 62 64
FT TURN 65 67
FT HELIX 68 71
FT STRAND 76 83
FT HELIX 87 95
FT HELIX 97 104
FT STRAND 106 108
FT STRAND 110 115
FT HELIX 117 120
FT HELIX 123 131
FT HELIX 139 148
FT STRAND 152 156
FT TURN 159 161
FT HELIX 165 176
SQ SEQUENCE 192 AA; 21450 MW; ACEDF83A45E5EA67 CRC64;
MQAIKCVVVG DGAVGKTCLL ISYTTNAFPG EYIPTVFDNY SANVMVDGKP VNLGLWDTAG
QEDYDRLRPL SYPQTDVFLI CFSLVSPASF ENVRAKWYPE VRHHCPNTPI ILVGTKLDLR
DDKDTIEKLK EKKLTPITYP QGLAMAKEIG AVKYLECSAL TQRGLKTVFD EAIRAVLCPP
PVKKRKRKCL LL
//

MIM 602048
*RECORD*
*FIELD* NO
602048
*FIELD* TI
*602048 RAS-RELATED C3 BOTULINUM TOXIN SUBSTRATE 1; RAC1
;;RHO FAMILY, SMALL GTP-BINDING PROTEIN RAC1;;
read moreCED10, C. ELEGANS, HOMOLOG OF
*FIELD* TX

GENE FAMILY

Members of the RAS superfamily of small GTP-binding proteins (see
190020) appear to regulate a diverse array of cellular events, including
the control of cell growth, cytoskeletal reorganization, and the
activation of protein kinases.

CLONING

Didsbury et al. (1989) identified 2 human cDNAs, called RAC1 and RAC2
(602049) by them, that are 92% identical and share 58% and 26 to 30%
amino acid identity with human RHOS and RAS, respectively. The 2 genes
encode the C-terminal consensus sequence (CXXX-COOH), which localizes
RAS to the inner plasma membrane, and the residues gly12 and ala59, at
which sites mutations elicit transforming potential to RAS. The authors
detected RAC1 mRNA in brain and liver tissue and in HL-60 cells
differentiating to neutrophil-like morphology. Using transfection
experiments, Didsbury et al. (1989) showed that RAC1 and RAC2 are
substrates for ADP-ribosylation by the C3 component of botulinum toxin.
Drivas et al. (1990) cloned 4 RAS-like sequences, 1 of which, TC25,
appears to be identical to RAC1. See also RAC3 (602050).

Matos et al. (2000) isolated the RAC1 gene from genomic DNA. Northern
blot analysis demonstrated expression of 1.2- and 2.5-kb transcripts in
all 12 tissues studied, with the strongest expression in heart,
placenta, and kidney. The 2 transcripts were expressed in
tissue-specific ratios, and multiple polyadenylation sites were found.
By RT-PCR, Matos et al. (2000) found alternative splicing within the
coding region of RAC1; a second gene product with an additional 57
nucleotides, which corresponded to RAC1B, a splice variant previously
described by Jordan et al. (1999). Matos et al. (2000) showed that RAC1B
is a constitutively active mutant which induces the formation of
lamellipodia in fibroblasts.

GENE STRUCTURE

Matos et al. (2000) demonstrated that the RAC1 gene is 29 kb long and
contains 7 exons. The RAC1 promoter lacks both a TATA box and CCAAT box,
contains a CpG island surrounding the transcription initiation sites,
and is GC rich, all characteristics of a housekeeping gene.

MAPPING

By FISH and inclusion within a mapped clone, Matos et al. (2000) mapped
the RAC1 gene to 7p22 near PMS2 (600259). They also found a processed
RAC1 pseudogene at Xq26.2-q27.2.

GENE FUNCTION

By screening rat brain cytosol for proteins that interacted with Ras
(HRAS; 190020)-related GTPases, or p21 proteins, of the Rho (RHOA;
165390) subfamily, Manser et al. (1994) identified 3 proteins,
designated PAKs (see PAK1; 602590) that interacted with the GTP-bound
forms of human CDC42 and RAC1, but not RHOA.

To identify the effector pathways that mediate the activities induced by
RAC, Joneson et al. (1996) isolated mutant RAC proteins that could
discriminate among the RAC targets PAK and POR1 (601638) in the yeast
2-hybrid system. PAK proteins are a family of highly conserved
serine/threonine kinases that are activated by interaction with RAC1
(Manser et al., 1994). POR1 interacts with RAC1 and appears to function
in RAC-induced membrane ruffling which is apparently induced by actin
polymerization (Van Aelst et al., 1996). Joneson et al. (1996) reported
that 1 mutant of activated human RAC protein was defective in its
binding to PAK3 (300142) and failed to stimulate PAK and JNK (see
601158) activity. This mutant did bind to POR1 and it induced membrane
ruffling and transformation. A second RAC mutant, which bound PAK but
not POR1, induced JNK activation but was defective in inducing membrane
ruffling and transformation. The authors concluded that the effects of
RAC on the JNK cascade and on actin polymerization and cell
proliferation are mediated by distinct effector functions that diverge
at the level of RAC itself. No RAC mutants were isolated that separated
the ability of RAC to induce membrane ruffling and to stimulate cell
proliferation. These results led Joneson et al. (1996) to conclude that
RAC-mediated pathways leading to actin polymerization and proliferation
are interdependent.

RAC1 appears to function in the regulation of actin filaments at the
plasma membrane, resulting in the production of lamellipodia and
ruffles, the generation of reactive oxygen species in phagocytic and
nonphagocytic cells, and activation of the family of stress-activated
protein kinases (JNKs/SAPKs). Moore et al. (1997) transiently expressed
a dominant-negative form of RAC1 in rat fibroblasts and found that it
resulted in cytostatic growth arrest. Cell cycle analysis demonstrated
that cells expressing the transgene accumulated in G2/M. The results
suggested that RAC1 is required for cell proliferation and provided the
first demonstration in mammalian cells of a role for small GTP-binding
proteins in the G2/M transition.

Integrin-mediated reorganization of cell shape leads to an altered
cellular phenotype. Kheradmand et al. (1998) found that disruption of
the actin cytoskeleton, initiated by binding of soluble antibody to
alpha-5 (135620)/beta-1 (135630) integrin, led to increased expression
of the collagenase-1 gene (120355) in rabbit synovial fibroblasts.
Activation of RAC1, which is downstream of the integrin, was necessary
for this process, and expression of activated RAC1 was sufficient to
increase expression of collagenase-1. RAC1 activation generated reactive
oxygen species that were essential for nuclear factor kappa-B
(164011)-dependent transcriptional regulation of interleukin-1-alpha
(147760), which, in an autocrine manner, induced collagenase-1 gene
expression. Remodeling of the extracellular matrix and consequent
alterations of integrin-mediated adhesion and cytoarchitecture are
central to development, wound healing, inflammation, and malignant
disease. Kheradmand et al. (1998) stated that the resulting activation
of RAC1 may lead to altered gene regulation and alterations in cellular
morphogenesis, migration, and invasion.

The signal transducers and activators of transcription (STAT)
transcription factors become phosphorylated on tyrosine and translocate
to the nucleus after stimulation of cells with growth factors or
cytokines. Simon et al. (2000) showed that the RAC1 guanosine
triphosphatase can bind to and regulate STAT3 (102582) activity.
Dominant-negative RAC1 inhibited STAT3 activation by growth factors,
whereas activated RAC1 stimulated STAT3 phosphorylation on both tyrosine
and serine residues. Moreover, activated RAC1 formed a complex with
STAT3 in mammalian cells. Yeast 2-hybrid analysis indicated that STAT3
binds directly to active but not inactive RAC1 and that the interaction
occurs via the effector domain. Simon et al. (2000) concluded that RAC1
may serve as an alternative mechanism for targeting STAT3 to tyrosine
kinase signaling complexes.

Epidermal growth factor receptor (EGFR; 131550) signaling involves small
GTPases of the Rho family, and EGFR trafficking involves small GTPases
of the Rab family. Lanzetti et al. (2000) reported that the EPS8
(600206) protein connects these signaling pathways. EPS8 is a substrate
of EGFR that is held in a complex with SOS1 (182530) by the adaptor
protein E3B1 (SSH3BP1; 603050), thereby mediating activation of RAC.
Through its SH3 domain, EPS8 interacts with RNTRE (605405). Lanzetti et
al. (2000) showed that RNTRE is a RAB5 (179512) GTPase-activating
protein whose activity is regulated by EGFR. By entering in a complex
with EPS8, RNTRE acts on RAB5 and inhibits internalization of the EGFR.
Furthermore, RNTRE diverts EPS8 from its RAC-activating function,
resulting in the attenuation of RAC signaling. Thus, depending on its
state of association with E3B1 or RNTRE, EPS8 participates in both EGFR
signaling through RAC and EGFR trafficking through RAB5.

Neural Wiskott-Aldrich syndrome protein (N-WASP; 605056) functions in
several intracellular events including filopodium formation, vesicle
transport, and movement of viruses, by stimulating rapid actin
polymerization through the ARP2/3 complex. N-WASP is regulated by the
direct binding of CDC42 (116952), which exposes the domain in N-WASP
that activates the ARP2/3 complex. A WASP-related protein, WAVE/SCAR
(see 605875), functions in RAC-induced membrane ruffling; however, RAC
does not bind directly to WAVE, raising the question of how WAVE is
regulated by RAC. Miki et al. (2000) demonstrated that IRSP53 (605475),
a substrate for insulin receptor with unknown function, is the 'missing
link' between RAC and WAVE2. Activated RAC binds to the N terminus of
IRSP53, and the C-terminal SH3 domain of IRSP53 binds to WAVE2 to form a
trimolecular complex. From studies of ectopic expression, Miki et al.
(2000) found that IRSP53 is essential for RAC to induce membrane
ruffling, probably because it recruits WAVE2, which stimulates actin
polymerization mediated by the ARP2/3 complex.

Rhodopsin (RHO; 180380) is essential for photoreceptor morphogenesis;
photoreceptors lacking rhodopsin degenerate in humans, mice, and
Drosophila. Chang and Ready (2000) reported that transgenic expression
of a dominant-active Drosophila Rho guanosine triphosphatase, Rac1,
rescued photoreceptor morphogenesis in rhodopsin null mutants.
Expression of dominant-negative Rac1 resulted in a phenotype similar to
that seen in rhodopsin null mutants. Rac1 was localized in a
specialization of the photoreceptor cortical actin cytoskeleton, which
was lost in rhodopsin null mutants. Thus, rhodopsin appears to organize
the actin cytoskeleton through RAC1, contributing a structural support
essential for photoreceptor morphogenesis.

Studying rat hippocampal neurons in culture, Hernandez-Deviez et al.
(2002) determined that dendritic arbor development is regulated by
complex interactions of ARNO (602488), ARF6 (600464), and RAC1.
Activation of ARNO and ARF6 resulted in signaling through RAC1 that
suppressed dendritic branching.

Eden et al. (2002) reported a mechanism by which RAC1 and the adaptor
protein NCK (600508) activate actin nucleation through WAVE1 (605035).
WAVE1 exists in a heterotetrameric complex that includes orthologs of
human PIR121 (606323), NAP125 (NCKAP1; 604891), and HSPC300 (611183).
Whereas recombinant WAVE1 is constitutively active, the WAVE1 complex is
inactive. Eden et al. (2002) proposed that Rac1 and Nck cause
dissociation of the WAVE1 complex, which releases active WAVE1-HSPC300
and leads to actin nucleation. Eden et al. (2002) also determined that
ABI2 (606442) interacts with WAVE1 and appears to remain associated with
the NAP125-PIR121 subcomplex upon dissociation of the WAVE1 complex.

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 (165390)
activity, and increased RAC 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.

Katoh and Negishi (2003) demonstrated that RHO G (179505) interacts
directly with ELMO2 (606421) in a GTP-dependent manner and forms a
ternary complex with DOCK180 (601403) to induce activation of RAC1. The
RHO G-ELMO2-DOCK180 pathway is required for activation of RAC1 and cell
spreading mediated by integrin, as well as for neurite outgrowth induced
by nerve growth factor. Katoh and Negishi (2003) concluded that RHO G
activates RAC1 through ELMO and DOCK180 to control cell morphology.

RAC phosphorylates merlin (NF2; 607379) via PAK activation (Xiao et al.,
2002; Kissil et al., 2002). Kaempchen et al. (2003) hypothesized that
merlin deficiency might cause an activation of RAC and its dependent
signaling pathways, in particular the protumorigenic JNK (601158)
pathway. The authors documented enhanced activation of RAC1 in primary
human schwannoma cells, found both RAC and its effector PAK1 (602590) at
the membrane where they colocalized, and described increased levels of
phosphorylated JNK in the nucleus of these cells. The authors concluded
that merlin regulates RAC activation, and suggested that this may
important for human schwannoma cell dedifferentiation.

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.

Faucherre et al. (2003) demonstrated interaction of the RhoGAP domain of
OCRL1 (300535), the phosphatidylinositol 4,5-bisphosphate-5-phosphatase
mutant in Lowe oculocerebrorenal syndrome (309000), with the Rho GTPase
Rac. Activated Rac GTPase associated with the OCRL1 RhoGAP domain in
vitro and coimmunoprecipitated with endogenous OCRL1. OCRL1 RhoGAP
exhibited a significant interaction with GDP-bound Rac in vitro.
Immunofluorescence studies and Golgi perturbation assays demonstrated
that a fraction of endogenous Rac colocalized with OCRL1 and
gamma-adaptin (603533) in the trans-Golgi network. The authors concluded
that OCRL1 is a bifunctional protein which, in addition to its PIP2
5-phosphatase activity, binds to Rac GTPase.

By yeast 2-hybrid analysis of a mouse T-cell cDNA library, Uhlik et al.
(2003) showed that a C-terminal fragment of mouse Osm (CCM2; 607929)
interacted with Mekk3 (MAP3K3; 602539), a p38 (MAPK14; 600289) activator
that responds to sorbitol-induced hyperosmotic conditions. Mekk3 and Osm
colocalized in the cytoplasmic compartment of cotransfected cells, and
the Mekk3-Osm complex was recruited to Rac1- and cytoskeletal
actin-containing membrane ruffles in response to sorbitol treatment.
Protein interaction assays showed that Osm interacted directly with the
Mekk3 substrate Mkk3 (MAP2K3; 602315), with actin, and with both GDP-
and GTP-loaded Rac1. Uhlik et al. (2003) concluded that the
RAC1-OSM-MEKK3-MKK3 complex is required for regulation of p38 activity
in response to osmotic shock.

By electroporating genes into chicken presomitic mesenchymal cells,
Nakaya et al. (2004) demonstrated that Cdc42 and Rac1 play different
roles in mesenchymal-epithelial transition. Different levels of Cdc42
appeared to affect the binary decision between epithelial and
mesenchymal states. Proper levels of Rac1 were also necessary for
somitic epithelialization, since cells with either activated or
inhibited Rac1 failed to undergo correct epithelialization.

By yeast 2-hybrid analysis and in vitro binding assays, Malecz et al.
(2000) showed that a 56-amino acid domain in the C terminus of human
SYNJ2 (609410) interacted with RAC1. Expression of constitutively active
RAC1 caused the translocation of SYNJ2 from the cytoplasm to the plasma
membrane. Both activated RAC1 and a membrane-targeted version of SYNJ2
inhibited endocytosis of EGFR and transferrin receptor (TFRC; 190010), a
process that depends on polyphosphoinositides.

Chuang et al. (2004) found that small interfering RNA-mediated depletion
of RAC1 or SYNJ2 in 2 human glioblastoma cell lines inhibited migration
of the cells through 3-dimensional gel and rat brain slices, and it
inhibited cell migration on glioma-derived extracellular matrix.
Depletion of RAC1 or SYNJ2 inhibited formation of lamellipodia and
invadopodia, specialized membrane structures involved in extracellular
matrix degradation. Chuang et al. (2004) concluded that SYNJ2 and RAC1
contribute to cell invasion and migration by regulating the formation of
invadopodia and lamellipodia.

RAC1 stimulates actin remodeling at the cell periphery, leading to
lamellipodia formation. Steffen et al. (2004) found that Sra1 (CYFIP1;
606322) and Nap1 (NCKAP1) interacted with Wave2 and Abi1 (SSH3BP1) in
resting mouse melanoma cells or following Rac1 activation.
Microinjection of constitutively active RAC1 resulted in translocation
of Sra1, Nap1, Wave2, and Abi1 to the tips of membrane protrusions.
Moreover, removal of SRA1 or NAP1 by RNA interference in human or mouse
cells abrogated formation of RAC1-dependent lamellipodia. Microinjection
of active RAC1 failed to restore lamellipodia protrusion in cells
lacking either SRA1 or NAP1. Steffen et al. (2004) concluded that SRA1
and NAP1 are essential components of a WAVE2- and ABI1-containing
complex linking RAC1 to site-directed actin assembly.

Radisky et al. (2005) found that exposure of mouse mammary epithelial
cells to MMP3 (185250) induces the expression of an alternatively
spliced form of RAC1, which causes an increase in cellular reactive
oxygen species. The reactive oxygen species stimulated the expression of
the transcription factor Snail (see 604238) and epithelial-mesenchymal
transition, and caused oxidative damage to DNA and genomic instability.
Radisky et al. (2005) concluded that these findings identified a pathway
in which a component of the breast tumor microenvironment alters
cellular structure in culture and tissue structure in vivo, leading to
malignant transformation.

Kinchen et al. (2005) showed that in C. elegans, CED1 (see 107770), CED6
(see 608165), and CED7 (see 601615) are required for actin
reorganization around the apoptotic cell corpse, and that CED1 and CED6
colocalize with each other and with actin around the dead cell.
Furthermore, Kinchen et al. (2005) found that the CED10(Rac) GTPase acts
genetically downstream of these proteins to mediate corpse removal,
functionally linking the 2 engulfment pathways and identifying the CED1,
CED6, and CED7 signaling module as upstream regulators of Rac
activation.

Yeung et al. (2006) devised genetically encoded probes to assess surface
potential in intact cells. These probes revealed marked, localized
alterations in the change of the inner surface of the plasma membrane of
macrophages during the course of phagocytosis. Hydrolysis of
phosphoinositides and displacement of phosphatidylserine accounted for
the change in surface potential at the phagosomal cup. Signaling
molecules such as KRAS (190070), RAC1, and c-SRC (190090) that are
targeted to the membrane by electrostatic interactions were rapidly
released from membrane subdomains where the surface charge was altered
by lipid remodeling during phagocytosis.

Using a fluorescent probe that binds to Rac-GTP, Halet and Carroll
(2007) found that Rac-GTP was polarized in the cortex overlying the
meiotic spindle in mouse oocytes. Polarization of Rac activation
occurred during spindle migration and was promoted by the proximity of
chromatin to the cortex. Inhibition of Rac during oocyte maturation
caused a permanent block at prometaphase I and spindle elongation. In
metaphase II-arrested oocytes, Rac inhibition caused the spindle to
detach from the cortex and prevented polar body emission after
activation. Halet and Carroll (2007) concluded that RAC-GTP plays a
major role in oocyte meiosis via the regulation of spindle stability and
anchoring to the cortex.

Using human and other mammalian cells, Guo et al. (2007) showed that RAC
used PAK to directly activate transmembrane guanylyl cyclases (e.g.,
GUCY2E; 601138), leading to increased cellular cGMP levels. This
RAC-cGMP signaling pathway was involved in platelet-derived growth
factor (PDGF; see 173430)-induced fibroblast cell migration and
lamellipodium formation.

Harraz et al. (2008) demonstrated that SOD1 (147450) directly regulated
cellular NOX2 (300481) production of reactive oxygen species by binding
RAC1 and inhibiting RAC1 GTPase activity. Oxidation of RAC1 uncoupled
SOD1 binding in a reversible fashion, suggesting a model of redox
sensing.

Park et al. (2007) identified brain-specific angiogenesis inhibitor-1
(BAI1; 602682) as a receptor upstream of ELMO (606420) and as a receptor
that can bind phosphatidylserine on apoptotic cells. BAI1 is a
7-transmembrane protein belonging to the adhesion-type G protein-coupled
receptor family with an extended extracellular region. Park et al.
(2007) showed that BAI1 functions as an engulfment receptor in both the
recognition and subsequent internalization of apoptotic cells. Through
multiple lines of investigation, Park et al. (2007) identified
phosphatidylserine, a key 'eat-me' signal exposed on apoptotic cells, as
a ligand for BAI1. The thrombospondin type 1 (188060) repeats within the
extracellular region of BAI1 mediate direct binding to
phosphatidylserine. As with intracellular signaling, BAI1 forms a
trimeric complex with ELMO and Dock180 (601403), and functional studies
suggested that BAI1 cooperates with ELMO/Dock180/Rac to promote maximal
engulfment of apoptotic cells. Last, Park et al. (2007) found that
decreased BAI1 expression or interference with BAI1 function inhibited
the engulfment of apoptotic targets ex vivo and in vivo. Thus, Park et
al. (2007) concluded that BAI1 is a phosphatidylserine recognition
receptor that can directly recruit a Rac-GEF complex to mediate the
uptake of apoptotic cells.

Shibata et al. (2008) showed that a constitutively active RAC1 mutant
potentiated aldosterone-induced mineralocorticoid receptor (NR3C2;
600983) nuclear accumulation and transcriptional activity in HEK293
cells transfected with human constructs. In cultured rat podocytes,
activated RAC1 facilitated mineralocorticoid receptor nuclear
accumulation via PAK (see 602590) phosphorylation. Shibata et al. (2008)
found that mice lacking Rho GDP-dissociation inhibitor-alpha (ARHGDIA;
601925) developed progressive renal disease characterized by heavy
albuminuria and podocyte damage. These renal changes were associated
with increased Rac1 and mineralocorticoid receptor signaling in the
kidney without alteration in systemic aldosterone status. Pharmacologic
intervention with a Rac-specific small molecule inhibitor diminished
mineralocorticoid receptor overactivity and renal damage. Furthermore,
mineralocorticoid receptor blockade suppressed albuminuria and
histologic changes in Arhgdia -/- mice. Shibata et al. (2008) concluded
that RAC1 modulates mineralocorticoid receptor activity, and that
activation of the RAC1-mineralocorticoid receptor pathway has a major
role in the pathogenesis of renal damage.

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 (165390) is
activated at the cell edge synchronous with edge advancement, whereas
Cdc42 (116952) and Rac1 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.

Juncadella et al. (2013) showed that airway epithelial cells efficiently
engulf apoptotic epithelial cells and secrete antiinflammatory
cytokines, dependent upon intracellular signaling by the small GTPase
RAC1. Inducible deletion of Rac1 expression specifically in airway
epithelial cells in a mouse model resulted in defective engulfment by
epithelial cells and aberrant antiinflammatory cytokine production.
Intranasal priming and challenge of these mice with house dust mite
extract or ovalbumin as allergens led to exacerbated inflammation,
augmented Th2 cytokines and airway hyperresponsiveness, with decreased
Il10 (124092) in bronchial lavages. Rac1-deficient epithelial cells
produced much higher Il33 (608678) upon allergen or apoptotic cell
encounter, with increased numbers of nuocyte-like cells. Administration
of exogenous Il10 'rescued' the airway inflammation phenotype in
Rac1-deficient mice, with decreased Il33. Collectively, these genetic
and functional studies suggested a role for RAC1-dependent engulfment by
airway epithelial cells and in establishing the antiinflammatory
environment, and that defects in cell clearance in the airway could
contribute to inflammatory responses towards common allergens.

Keestra et al. (2013) demonstrated that NOD1 (605980) senses cytosolic
microbial products by monitoring the activation state of small Rho
GTPases. Activation of RAC1 and CDC42 (116952) by bacterial delivery or
ectopic expression of SopE, a virulence factor of the enteric pathogen
Salmonella, triggered the NOD1 signaling pathway with consequent RIP2
(603455)-mediated induction of NF-kappa-B (see 164011)-dependent
inflammatory responses. Similarly, activation of the NOD1 signaling
pathway by peptidoglycan required RAC1 activity. Furthermore, Keestra et
al. (2013) showed that constitutively active forms of RAC1, CDC42, and
RHOA (165390) activated the NOD1 signaling pathway.

ANIMAL MODEL

Gu et al. (2003) generated mice with a conditional deficiency in Rac1 in
order to avoid the embryonic lethality observed in homozygous
Rac1-deficient mice. Rac1-deficient hemopoietic stem cells (HSCs), but
not Rac2-deficient HSCs, failed to engraft in the marrow of irradiated
recipient mice. Deletion of both Rac1 and Rac2 resulted in a massive
egress of HSCs into the peripheral blood circulation. Rac2, but not
Rac1, regulated superoxide production and directed migration in
neutrophils. Gu et al. (2003) concluded that the 2 GTPases play distinct
roles in actin organization, cell survival, and proliferation in
neutrophils and HSCs, possibly due to the subcellular localization of
each protein.

Walmsley et al. (2003) generated mice with a conditional Rac1 deficiency
specifically in the B-cell lineage. In the absence of both Rac1 and
Rac2, B-cell development was almost completely blocked. Both GTPases
were required to transduce B-cell receptor (BCR) signals leading to
proliferation, survival, and the upregulation of Baffr (TNFRSF13C;
606269), the B-cell-activating receptor for BAFF (TNFSF13B; 603969),
which is required for B-cell development and maintenance.

Using 2-photon video microscopy and lymph node cells from Rac1- and
Rac2-deficient mice, Benvenuti et al. (2004) showed that dendrites of
mature dendritic cells, under the control of Rac1 and Rac2, but not Rho
itself, contact and then entrap naive T cells.

Aznar Benitah et al. (2005) generated mice with a conditional deletion
of Rac1 in adult epidermis. Deletion of Rac1 stimulated stem cells to
divide and undergo terminal differentiation, leading to failure to
maintain the interfollicular epidermis, hair follicles, and sebaceous
glands. Rac1 exerts its effects in the epidermis by negatively
regulating c-Myc (190080) through phosphorylation of p21-activated
kinase-2 (PAK2; 605022). The dorsal skin of the conditionally deleted
Rac1 mice showed 3 to 6 distinct phenotypes, designated early, middle,
and late. After 3 to 5 days (early), there was thickening of the
interfollicular epidermis (IFE) with increased numbers of living and
cornified cell layers, and the infundibulum, at the junction between the
IFE and hair follicle, was expanded. After 7 to 9 days (middle), there
was disorganization and decreased cellularity of the IFE basal layer,
together with cell enlargement. Sebaceous glands were also enlarged and
disorganized. After 11 to 15 days, the late phenotype developed: partial
or complete loss of viable IFE cell layers, diminution of the hair
follicle bulb, and degeneration of the infundibulum into cysts. Aznar
Benitah et al. (2005) concluded that a pleiotropic regulator of cell
adhesion and the cytoskeleton plays a critical role in controlling exit
from the stem cell niche and proposed that Rac and Myc represent a
global stem cell regulatory axis.

Satoh et al. (2006) generated mice with a temporal and specific deletion
of cardiomyocyte Rac1. Compared to wildtype or heterozygous mice, the
hearts of homozygous mutant mice showed decreased gp91-phox (CYBB;
300481) and p67-phox (NCF2; 608515) interaction, NADPH oxidase activity,
and myocardial oxidative stress in response to angiotensin II (see
106150) stimulation, which correlated with decreased myocardial
hypertrophy. Satoh et al. (2006) concluded that RAC1 is critical for the
hypertrophic response in the heart.

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22. Kinchen, J. M.; Cabello, J.; Klingele, D.; Wong, K.; Feichtinger,
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25. Machacek, M.; Hodgson, L.; Welch, C.; Elliott, H.; Pertz, O.;
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29. Miki, H.; Yamaguchi, H.; Suetsugu, S.; Takenawa, T.: IRSp53 is
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30. Moore, K. A.; Sethi, R.; Doanes, A. M.; Johnson, T. M.; Pracyk,
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32. Park, D.; Tosello-Trampont, A.-C.; Elliott, M. R.; Lu, M.; Haney,
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*FIELD* CN
Ada Hamosh - updated: 05/06/2013
Ada Hamosh - updated: 2/20/2013
Matthew B. Gross - updated: 5/10/2011
Matthew B. Gross - updated: 5/6/2010
Ada Hamosh - updated: 10/13/2009
Patricia A. Hartz - updated: 2/24/2009
Patricia A. Hartz - updated: 12/19/2008
Ada Hamosh - updated: 4/22/2008
Cassandra L. Kniffin - updated: 2/29/2008
Patricia A. Hartz - updated: 7/9/2007
Ada Hamosh - updated: 11/28/2006
Marla J. F. O'Neill - updated: 6/23/2006
Patricia A. Hartz - updated: 3/2/2006
Ada Hamosh - updated: 2/1/2006
George E. Tiller - updated: 9/12/2005
Ada Hamosh - updated: 8/15/2005
Ada Hamosh - updated: 8/3/2005
Patricia A. Hartz - updated: 6/13/2005
George E. Tiller - updated: 3/10/2005
Patricia A. Hartz - updated: 2/18/2005
Patricia A. Hartz - updated: 10/7/2004
Paul J. Converse - updated: 9/14/2004
Paul J. Converse - updated: 10/24/2003
Ada Hamosh - updated: 7/24/2003
Cassandra L. Kniffin - updated: 2/5/2003
Ada Hamosh - updated: 9/13/2002
Ada Hamosh - updated: 12/18/2000
Ada Hamosh - updated: 12/14/2000
Joanna S. Amberger - updated: 12/6/2000
Ada Hamosh - updated: 11/15/2000
Ada Hamosh - updated: 10/20/2000
Victor A. McKusick - updated: 5/5/1998
Victor A. McKusick - updated: 10/14/1997

*FIELD* CD
Moyra Smith: 11/18/1996

*FIELD* ED
alopez: 05/06/2013
alopez: 2/22/2013
terry: 2/20/2013
alopez: 11/26/2012
alopez: 6/21/2011
terry: 6/10/2011
terry: 5/25/2011
mgross: 5/10/2011
wwang: 5/14/2010
mgross: 5/6/2010
alopez: 10/22/2009
terry: 10/13/2009
mgross: 2/24/2009
mgross: 1/5/2009
terry: 12/19/2008
alopez: 5/9/2008
terry: 4/22/2008
wwang: 3/19/2008
ckniffin: 2/29/2008
wwang: 9/21/2007
alopez: 9/18/2007
terry: 7/9/2007
alopez: 12/7/2006
terry: 11/28/2006
wwang: 6/26/2006
terry: 6/23/2006
mgross: 3/2/2006
alopez: 2/2/2006
terry: 2/1/2006
alopez: 10/20/2005
terry: 9/12/2005
alopez: 8/18/2005
terry: 8/15/2005
alopez: 8/4/2005
terry: 8/3/2005
mgross: 6/13/2005
alopez: 3/10/2005
mgross: 2/18/2005
terry: 2/2/2005
mgross: 10/7/2004
mgross: 9/14/2004
mgross: 10/24/2003
tkritzer: 7/25/2003
terry: 7/24/2003
carol: 2/14/2003
ckniffin: 2/5/2003
alopez: 11/19/2002
terry: 11/18/2002
alopez: 9/16/2002
tkritzer: 9/13/2002
joanna: 4/24/2001
alopez: 4/18/2001
mgross: 12/18/2000
carol: 12/14/2000
terry: 12/7/2000
joanna: 12/6/2000
mgross: 11/15/2000
alopez: 10/20/2000
dkim: 9/11/1998
alopez: 8/31/1998
alopez: 5/7/1998
terry: 5/5/1998
alopez: 5/4/1998
mark: 11/25/1997
dholmes: 11/5/1997
mark: 10/14/1997