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Gene Review

RAC1  -  ras-related C3 botulinum toxin substrate 1...

Homo sapiens

Synonyms: Cell migration-inducing gene 5 protein, MIG5, Rac-1, Ras-like protein TC25, Ras-related C3 botulinum toxin substrate 1, ...
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Disease relevance of RAC1

  • When applied to human prostate cancer PC-3 cells, it was able to inhibit the proliferation, anchorage-independent growth and invasion phenotypes that require the endogenous Rac1 activity [1].
  • In this study, we showed that c-Abl-PKCdelta-Rac1-p38 MAPK signaling is required for the conformational changes of Bak and Bax during ionizing radiation-induced apoptotic cell death in human non-small cell lung cancer cells [2].
  • Surprisingly, pertussis toxin and overexpression of the free Gbetagamma-specific sequestering minigene hbetaARK1(495) also inhibit EGLT-mediated CDC42 and Rac1 activation completely [3].
  • The roles of Rac1 and TIRAP in LPS activation of HIV replication is not known [4].
  • To further define the relevance of activation of the Rac1/p38 MAP kinase pathway in the induction of arsenic-dependent antileukemic effects, studies were performed using bone marrows from patients with chronic myelogenous leukemia [5].
  • These results suggest that Rac1 plays a major role in colorectal adenocarcinoma progression [6].

Psychiatry related information on RAC1

  • The biological mechanisms underlying the mental retardation associated with mutation of the ARHGEF6 gene, a Rac1/Cdc42 exchange factor, are still unknown, although defects in the plasticity of synaptic networks have been postulated [7].

High impact information on RAC1

  • The effector IpgB2 stimulates cellular responses analogous to GTP-active RhoA, whereas IpgB1 and Map function as the active forms of Rac1 and Cdc42, respectively [8].
  • Indeed, expression of constitutively active forms of Rho1 or Rac1 in adult flies results in ethanol resistance similar to that observed in whir mutants [9].
  • Here we describe the solution structure of the N-terminal DH domain of Trio that catalyzes nucleotide exchange for Rac1 [10].
  • Taken together, these findings strongly support a critical role for Rac1 and Cdc42 in controlling the JNK signaling pathway [11].
  • Mechanism of regulation of WAVE1-induced actin nucleation by Rac1 and Nck [12].

Chemical compound and disease context of RAC1


Biological context of RAC1


Anatomical context of RAC1

  • EGF redistributes beta2-chimaerin to promote its association with the small GTPase Rac1 at the plasma membrane, as determined by FRET [22].
  • We identified three proteins in neutrophil cytosol of molecular size 65, 62 and 68 kDa which interact in a GTP-dependent manner with rac1 and CDC42Hs, but not with rho [23].
  • The interaction with beta-Pix is nucleotide independent and is necessary and sufficient for Rac1 recruitment to membrane ruffles and to focal adhesions [24].
  • DOCK2 associates with CrkL and regulates Rac1 in human leukemia cell lines [25].
  • We examined the activation of Rho family small G proteins and the regulation of MAPKs through Rac1 in cardiac myocytes [26].

Associations of RAC1 with chemical compounds

  • This relocalization and association with Rac1 were impaired by disruption of the beta2-chimaerin C1 domain as well as by PLCgamma1 RNAi, thus defining beta2-chimaerin as a novel DAG effector [22].
  • The chemical compound NSC23766 was identified by a structure-based virtual screening of compounds that fit into a surface groove of Rac1 known to be critical for GEF specification [1].
  • We also found that CrkL-induced activation of small guanine triphosphatase (GTPase) Rac1 was significantly inhibited by the DOCK2-dCS mutant in 293T cells [25].
  • In human neutrophils, beta2 integrin engagement mediated a decrease in GTP-bound Rac1 and Rac2 [27].
  • Phosphoinositide 3-kinase also bound to Rac1 and Cdc42Hs, and these interactions were GTP-dependent [28].
  • We propose a novel mechanism in which alpha6beta4 integrin signaling via Rac1, 14-3-3 proteins, and SSH family members regulates cofilin activation, cell polarity, and matrix assembly, leading to specific epidermal cell migration behavior [29].

Physical interactions of RAC1

  • Rac1 interacted directly with p67phox in a GTP-dependent manner [30].
  • Here we have characterized the interaction of Rac1 with a panel of mammalian GAPs and putative effectors by measuring the kinetic and binding parameters involved and made comparisons with similar interactions for Cdc42 and RhoA [31].
  • TPR domain mutants of NOXA1 that interfere with Rac1 binding were ineffective in supporting Nox1-dependent ROS generation [32].
  • The formation of E-lams was dependent on fibronectin-binding integrins and normally regulated Rac1, and expression of either dominant-negative or constitutively active forms of Rac1 prevented E-lam formation [33].
  • CYFIP1/2 are proteins of unknown function, but CYFIP1 has recently been shown to interact with the small GTPase Rac1, which is implicated in development and maintenance of neuronal structures [34].

Enzymatic interactions of RAC1

  • The Rac1-specific guanine nucleotide exchange factor Vav is heavily phosphorylated on tyrosine residues upon CD5 costimulation, which is a prerequisite for its activation [35].
  • We demonstrated that FAK tyrosine-phosphorylated betaPIX and thereby increased its binding to Rac1 [36].

Co-localisations of RAC1


Regulatory relationships of RAC1

  • RhoG is a member of the Rho family of GTPases that activates Rac1 and Cdc42 through a microtubule-dependent pathway [39].
  • Interaction of Rac1 with GTPase-activating proteins and putative effectors. A comparison with Cdc42 and RhoA [31].
  • Nox1-dependent reactive oxygen generation is regulated by Rac1 [32].
  • The binding of HA to keratinocytes promotes PKNgamma kinase recruitment into a complex with CD44 and subsequently stimulates Rac1-mediated PKNgamma kinase activity [40].
  • Herceptin blocked basal and TGF-beta-stimulated Rac1 activity but did not repress TGF-beta-stimulated transcriptional reporter activity [41].
  • Rac1 was activated in infected cells and accumulated with F-actin in a PI3K-independent manner at bacterial entry sites [42].

Other interactions of RAC1

  • The Rho family of small GTPases (RhoA, Rac1 and Cdc42) controls signal-transduction pathways that influence many aspects of cell behaviour, including cytoskeletal dynamics [21].
  • These results constitute the first report of a Syk --> PI3K --> Rac1 --> Akt signal cascade controlled by IL-2 that mediates NK cell survival [43].
  • The present studies demonstrate that Nox1, a homolog of the phagocyte NADPH-oxidase component gp91(phox), is activated by Rac1 [32].
  • Rac3 differs from Rac1/2 at its carboxyl-terminal end, a domain associated with subcellular localization and binding to specific cellular regulators [44].
  • A 68-kDa kinase and NADPH oxidase component p67phox are targets for Cdc42Hs and Rac1 in neutrophils [45].

Analytical, diagnostic and therapeutic context of RAC1

  • In the present study, we found that alphav integrin ligation activated small GTPase Rac1 preferentially, and dominant negative Rac1 inhibited alphav integrin-mediated p38 MAPK activation [46].
  • VSMC microinjection with antibodies to either Rho or Rac1 decreased uPA-stimulated cell migration, indicating the involvement of both GTPases in the migration process [47].
  • Immunofluorescence experiments demonstrated clear colocalization of PKG and Rac1 in membrane ruffles and dynamic membrane regions supporting a functional interaction [48].
  • The GC-rich gene promoter shows characteristics of a housekeeping gene and Northern blot studies revealed ubiquitous expression of two rac1 transcripts, 1.2 and 2.5 kb in size [49].
  • The dissociation constant (K(d)) for interaction between actin and p47(phox) was estimated to be 0.45 microM by surface plasmon resonance, and that between actin and rac1 or rac2 was 1.7 or 4.6 microM, respectively [50].


  1. Rational design and characterization of a Rac GTPase-specific small molecule inhibitor. Gao, Y., Dickerson, J.B., Guo, F., Zheng, J., Zheng, Y. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  2. Activation of Bak and Bax through c-abl-protein kinase Cdelta-p38 MAPK signaling in response to ionizing radiation in human non-small cell lung cancer cells. Choi, S.Y., Kim, M.J., Kang, C.M., Bae, S., Cho, C.K., Soh, J.W., Kim, J.H., Kang, S., Chung, H.Y., Lee, Y.S., Lee, S.J. J. Biol. Chem. (2006) [Pubmed]
  3. Flt-1-mediated down-regulation of endothelial cell proliferation through pertussis toxin-sensitive G proteins, beta gamma subunits, small GTPase CDC42, and partly by Rac-1. Zeng, H., Zhao, D., Mukhopadhyay, D. J. Biol. Chem. (2002) [Pubmed]
  4. Rac1 and Toll-IL-1 receptor domain-containing adapter protein mediate Toll-like receptor 4 induction of HIV-long terminal repeat. Equils, O., Madak, Z., Liu, C., Michelsen, K.S., Bulut, Y., Lu, D. J. Immunol. (2004) [Pubmed]
  5. Activation of Rac1 and the p38 mitogen-activated protein kinase pathway in response to arsenic trioxide. Verma, A., Mohindru, M., Deb, D.K., Sassano, A., Kambhampati, S., Ravandi, F., Minucci, S., Kalvakolanu, D.V., Platanias, L.C. J. Biol. Chem. (2002) [Pubmed]
  6. A critical role for Rac1 in tumor progression of human colorectal adenocarcinoma cells. Espina, C., Céspedes, M.V., García-Cabezas, M.A., Gómez del Pulgar, M.T., Boluda, A., Oroz, L.G., Benitah, S.A., Cejas, P., Nistal, M., Mangues, R., Lacal, J.C. Am. J. Pathol. (2008) [Pubmed]
  7. Sequential implication of the mental retardation proteins ARHGEF6 and PAK3 in spine morphogenesis. Nod??-Langlois, R., Muller, D., Boda, B. J. Cell. Sci. (2006) [Pubmed]
  8. Identification of a bacterial type III effector family with G protein mimicry functions. Alto, N.M., Shao, F., Lazar, C.S., Brost, R.L., Chua, G., Mattoo, S., McMahon, S.A., Ghosh, P., Hughes, T.R., Boone, C., Dixon, J.E. Cell (2006) [Pubmed]
  9. Distinct Behavioral Responses to Ethanol Are Regulated by Alternate RhoGAP18B Isoforms. Rothenfluh, A., Threlkeld, R.J., Bainton, R.J., Tsai, L.T., Lasek, A.W., Heberlein, U. Cell (2006) [Pubmed]
  10. NMR structure and mutagenesis of the N-terminal Dbl homology domain of the nucleotide exchange factor Trio. Liu, X., Wang, H., Eberstadt, M., Schnuchel, A., Olejniczak, E.T., Meadows, R.P., Schkeryantz, J.M., Janowick, D.A., Harlan, J.E., Harris, E.A., Staunton, D.E., Fesik, S.W. Cell (1998) [Pubmed]
  11. The small GTP-binding proteins Rac1 and Cdc42 regulate the activity of the JNK/SAPK signaling pathway. Coso, O.A., Chiariello, M., Yu, J.C., Teramoto, H., Crespo, P., Xu, N., Miki, T., Gutkind, J.S. Cell (1995) [Pubmed]
  12. Mechanism of regulation of WAVE1-induced actin nucleation by Rac1 and Nck. Eden, S., Rohatgi, R., Podtelejnikov, A.V., Mann, M., Kirschner, M.W. Nature (2002) [Pubmed]
  13. HIF-1alpha mRNA and protein upregulation involves Rho GTPase expression during hypoxia in renal cell carcinoma. Turcotte, S., Desrosiers, R.R., Béliveau, R. J. Cell. Sci. (2003) [Pubmed]
  14. Requirement of Rho-family GTPases in the invasion of Type 1-piliated uropathogenic Escherichia coli. Martinez, J.J., Hultgren, S.J. Cell. Microbiol. (2002) [Pubmed]
  15. Rac1-NADPH oxidase-regulated generation of reactive oxygen species mediates glutamate-induced apoptosis in SH-SY5Y human neuroblastoma cells. Nikolova, S., Lee, Y.S., Lee, Y.S., Kim, J.A. Free Radic. Res. (2005) [Pubmed]
  16. Phosphatidylinositol 3-kinase, Cdc42, and Rac1 act downstream of Ras in integrin-dependent neurite outgrowth in N1E-115 neuroblastoma cells. Sarner, S., Kozma, R., Ahmed, S., Lim, L. Mol. Cell. Biol. (2000) [Pubmed]
  17. Targeted mutation of serine 697 in the Ret tyrosine kinase causes migration defect of enteric neural crest cells. Asai, N., Fukuda, T., Wu, Z., Enomoto, A., Pachnis, V., Takahashi, M., Costantini, F. Development (2006) [Pubmed]
  18. Characterization of small GTPases Cdc42 and Rac and the relationship between Cdc42 and actin cytoskeleton in vegetative and ectomycorrhizal hyphae of Suillus bovinus. Gorfer, M., Tarkka, M.T., Hanif, M., Pardo, A.G., Laitiainen, E., Raudaskoski, M. Mol. Plant Microbe Interact. (2001) [Pubmed]
  19. Matos P, Oliveira C, Velho S, Gonçalves V, et al. (2008). B-RafV600E cooperates with alternative spliced Rac1b to sustain colorectal cancer cell survival. Gastroenterology, 135, 899-906. WikiGenes. Publication
  20. Endotoxin induces toll-like receptor 4 expression in vascular smooth muscle cells via NADPH oxidase activation and mitogen-activated protein kinase signaling pathways. Lin, F.Y., Chen, Y.H., Tasi, J.S., Chen, J.W., Yang, T.L., Wang, H.J., Li, C.Y., Chen, Y.L., Lin, S.J. Arterioscler. Thromb. Vasc. Biol. (2006) [Pubmed]
  21. Synaptopodin orchestrates actin organization and cell motility via regulation of RhoA signalling. Asanuma, K., Yanagida-Asanuma, E., Faul, C., Tomino, Y., Kim, K., Mundel, P. Nat. Cell Biol. (2006) [Pubmed]
  22. Phospholipase Cgamma/diacylglycerol-dependent activation of beta2-chimaerin restricts EGF-induced Rac signaling. Wang, H., Yang, C., Leskow, F.C., Sun, J., Canagarajah, B., Hurley, J.H., Kazanietz, M.G. EMBO J. (2006) [Pubmed]
  23. A novel serine kinase activated by rac1/CDC42Hs-dependent autophosphorylation is related to PAK65 and STE20. Martin, G.A., Bollag, G., McCormick, F., Abo, A. EMBO J. (1995) [Pubmed]
  24. Targeting and activation of Rac1 are mediated by the exchange factor beta-Pix. ten Klooster, J.P., Jaffer, Z.M., Chernoff, J., Hordijk, P.L. J. Cell Biol. (2006) [Pubmed]
  25. DOCK2 associates with CrkL and regulates Rac1 in human leukemia cell lines. Nishihara, H., Maeda, M., Oda, A., Tsuda, M., Sawa, H., Nagashima, K., Tanaka, S. Blood (2002) [Pubmed]
  26. Regulation of mitogen-activated protein kinases in cardiac myocytes through the small G protein Rac1. Clerk, A., Pham, F.H., Fuller, S.J., Sahai, E., Aktories, K., Marais, R., Marshall, C., Sugden, P.H. Mol. Cell. Biol. (2001) [Pubmed]
  27. Down-regulation of Rac activity during beta 2 integrin-mediated adhesion of human neutrophils. Dib, K., Melander, F., Axelsson, L., Dagher, M.C., Aspenström, P., Andersson, T. J. Biol. Chem. (2003) [Pubmed]
  28. Rho family GTPases bind to phosphoinositide kinases. Tolias, K.F., Cantley, L.C., Carpenter, C.L. J. Biol. Chem. (1995) [Pubmed]
  29. The slingshot family of phosphatases mediates Rac1 regulation of cofilin phosphorylation, laminin-332 organization, and motility behavior of keratinocytes. Kligys, K., Claiborne, J.N., DeBiase, P.J., Hopkinson, S.B., Wu, Y., Mizuno, K., Jones, J.C. J. Biol. Chem. (2007) [Pubmed]
  30. Interaction of Rac with p67phox and regulation of phagocytic NADPH oxidase activity. Diekmann, D., Abo, A., Johnston, C., Segal, A.W., Hall, A. Science (1994) [Pubmed]
  31. Interaction of Rac1 with GTPase-activating proteins and putative effectors. A comparison with Cdc42 and RhoA. Zhang, B., Chernoff, J., Zheng, Y. J. Biol. Chem. (1998) [Pubmed]
  32. Nox1-dependent reactive oxygen generation is regulated by Rac1. Cheng, G., Diebold, B.A., Hughes, Y., Lambeth, J.D. J. Biol. Chem. (2006) [Pubmed]
  33. Glycogen synthase kinase-3 regulates cytoskeleton and translocation of Rac1 in long cellular extensions of human keratinocytes. Koivisto, L., Häkkinen, L., Matsumoto, K., McCulloch, C.A., Yamada, K.M., Larjava, H. Exp. Cell Res. (2004) [Pubmed]
  34. A highly conserved protein family interacting with the fragile X mental retardation protein (FMRP) and displaying selective interactions with FMRP-related proteins FXR1P and FXR2P. Schenck, A., Bardoni, B., Moro, A., Bagni, C., Mandel, J.L. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  35. Signaling through CD5 activates a pathway involving phosphatidylinositol 3-kinase, Vav, and Rac1 in human mature T lymphocytes. Gringhuis, S.I., de Leij, L.F., Coffer, P.J., Vellenga, E. Mol. Cell. Biol. (1998) [Pubmed]
  36. FAK Potentiates Rac1 Activation and Localization to Matrix Adhesion Sites: A Role for betaPIX. Chang, F., Lemmon, C.A., Park, D., Romer, L.H. Mol. Biol. Cell (2007) [Pubmed]
  37. ARF6 requirement for Rac ruffling suggests a role for membrane trafficking in cortical actin rearrangements. Radhakrishna, H., Al-Awar, O., Khachikian, Z., Donaldson, J.G. J. Cell. Sci. (1999) [Pubmed]
  38. AIF-1 is an actin-polymerizing and Rac1-activating protein that promotes vascular smooth muscle cell migration. Autieri, M.V., Kelemen, S.E., Wendt, K.W. Circ. Res. (2003) [Pubmed]
  39. Kinectin is a key effector of RhoG microtubule-dependent cellular activity. Vignal, E., Blangy, A., Martin, M., Gauthier-Rouvière, C., Fort, P. Mol. Cell. Biol. (2001) [Pubmed]
  40. Hyaluronan-CD44 interaction with Rac1-dependent protein kinase N-gamma promotes phospholipase Cgamma1 activation, Ca(2+) signaling, and cortactin-cytoskeleton function leading to keratinocyte adhesion and differentiation. Bourguignon, L.Y., Singleton, P.A., Diedrich, F. J. Biol. Chem. (2004) [Pubmed]
  41. Overexpression of HER2 (erbB2) in human breast epithelial cells unmasks transforming growth factor beta-induced cell motility. Ueda, Y., Wang, S., Dumont, N., Yi, J.Y., Koh, Y., Arteaga, C.L. J. Biol. Chem. (2004) [Pubmed]
  42. Invasion of endothelial cells by tissue-invasive M3 type group A streptococci requires Src kinase and activation of Rac1 by a phosphatidylinositol 3-kinase-independent mechanism. Nerlich, A., Rohde, M., Talay, S.R., Genth, H., Just, I., Chhatwal, G.S. J. Biol. Chem. (2009) [Pubmed]
  43. Regulation of Akt-dependent cell survival by Syk and Rac. Jiang, K., Zhong, B., Ritchey, C., Gilvary, D.L., Hong-Geller, E., Wei, S., Djeu, J.Y. Blood (2003) [Pubmed]
  44. Characterization of RAC3, a novel member of the Rho family. Haataja, L., Groffen, J., Heisterkamp, N. J. Biol. Chem. (1997) [Pubmed]
  45. A 68-kDa kinase and NADPH oxidase component p67phox are targets for Cdc42Hs and Rac1 in neutrophils. Prigmore, E., Ahmed, S., Best, A., Kozma, R., Manser, E., Segal, A.W., Lim, L. J. Biol. Chem. (1995) [Pubmed]
  46. Rac1-MKK3-p38-MAPKAPK2 pathway promotes urokinase plasminogen activator mRNA stability in invasive breast cancer cells. Han, Q., Leng, J., Bian, D., Mahanivong, C., Carpenter, K.A., Pan, Z.K., Han, J., Huang, S. J. Biol. Chem. (2002) [Pubmed]
  47. Urokinase-induced migration of human vascular smooth muscle cells requires coupling of the small GTPases RhoA and Rac1 to the Tyk2/PI3-K signalling pathway. Kiian, I., Tkachuk, N., Haller, H., Dumler, I. Thromb. Haemost. (2003) [Pubmed]
  48. Activation of the small GTPase Rac1 by cGMP-dependent protein kinase. Hou, Y., Ye, R.D., Browning, D.D. Cell. Signal. (2004) [Pubmed]
  49. Small GTPase Rac1: structure, localization, and expression of the human gene. Matos, P., Skaug, J., Marques, B., Beck, S., Veríssimo, F., Gespach, C., Boavida, M.G., Scherer, S.W., Jordan, P. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  50. Direct interaction of actin with p47(phox) of neutrophil NADPH oxidase. Tamura, M., Kai, T., Tsunawaki, S., Lambeth, J.D., Kameda, K. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
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