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Gene Review

Rac1  -  RAS-related C3 botulinum substrate 1

Mus musculus

Synonyms: AL023026, D5Ertd559e, Ras-related C3 botulinum toxin substrate 1, p21-Rac1
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Disease relevance of Rac1


High impact information on Rac1

  • YpkA inhibits nucleotide exchange in Rac1 and RhoA, and mutations that disrupt the YpkA-GTPase interface abolish this activity in vitro and impair in vivo YpkA-induced cytoskeletal disruption [6].
  • Here we solve the crystal structure of a YpkA-Rac1 complex and find that YpkA possesses a Rac1 binding domain that mimics host guanidine nucleotide dissociation inhibitors (GDIs) of the Rho GTPases [6].
  • Activation requires an intact effector domain and isoprenylation of Cdc42 and Rac1 [7].
  • Here we investigate the role of Rac1 in cell transformation and show that Rat1 fibroblasts expressing activated Val-12 Rac1 (Rac1 with valine at residue 12) display all the hallmarks of malignant transformation [8].
  • In a focus-forming assay in NIH3T3 fibroblasts to measure the efficiency of transformation, we found that dominant-negative Asn-17 Rac1 inhibited focus formation by oncogenic Ras, but not by RafCAAX, a Raf kinase targeted to the plasma membrane by virtue of the addition of a carboxyterminal localization signal from K-Ras [8].

Chemical compound and disease context of Rac1


Biological context of Rac1

  • In addition, a Rac1/2 or Vav1/3 deficiency blocks Arp2/3 recruitment and actin polymerization at the complement-induced phagosome, indicating that these proteins regulate early steps in phagocytosis [14].
  • The LIM protein Ajuba influences p130Cas localization and Rac1 activity during cell migration [15].
  • Interestingly, distinct morphological phenotypes were observed; suppression of Rac1 activity caused loss of the leading process, whereas repression of JNK activity did not, suggesting the complexity of the signaling cascade [16].
  • Rac1 is the small GTPase responsible for regulating the neutrophil chemotaxis compass [17].
  • Although a body of literature has implicated the Rho family members Rac1 and Rac2 in multiple hematopoietic-cell functions, the role of Cdc42 in hematopoiesis remains unclear [18].

Anatomical context of Rac1

  • The scaffold protein, linker for activation of T cells (LAT), and Rac1 (a target of Vav activity) were constitutively present in GEMs [19].
  • The mechanisms through which the small GTPases Rac1 and Cdc42 regulate the formation of membrane ruffles, lamellipodia, and filopodia are currently unknown [20].
  • The Tiam1 gene encodes an activator of Rac1, and similarly to constitutively activated (V12)Rac1, overexpression of Tiam1 in fibroblasts induces the formation of membrane ruffles [21].
  • Mutations that render RhoA, Cdc42hs, or Rac1, either constitutively active or dominant negative abrogated binding to RhoGDI alpha and redirected expression to both PMs and internal membranes [22].
  • We demonstrate here that although Rac1 null neutrophils display normal chemokinesis, they are unable to migrate toward the source of the chemoattractant [17].

Associations of Rac1 with chemical compounds


Physical interactions of Rac1


Co-localisations of Rac1


Regulatory relationships of Rac1

  • Our results obtained from gene-targeted primary MEFs indicate that Rac1 is essential not only for lamellipodia induction but also for the RhoA-regulated actin stress fiber and focal adhesion complex formation and that Rac1 is involved in cell survival regulation through anoikis-dependent as well as -independent mechanisms [35].
  • Furthermore, these results suggest that although both Cdc42Hs and Rac1 can activate p38 in situ, the effects of Cdc42Hs and Rac1 on cell cycle progression are, in fact, quite distinct [36].
  • MOCA induces membrane spreading by activating Rac1 [37].
  • We report here that dominant negative forms of Rac1 and Cdc42Hs inhibit the expression of the muscle-specific genes myogenin, troponin T, and myosin heavy chain in L6 and C2 myoblasts [38].
  • Cortactin redistributes from the cytoplasm into membrane ruffles as a result of growth factor-induced Rac1 activation, and this translocation is blocked by expression of dominant negative Rac1N17 [39].
  • These data show a specific requirement for Rac1 function in cells expressing oncogenic K-ras [40].

Other interactions of Rac1

  • Although overexpressed Cdc42hs and Rac2 were observed predominantly on endomembrane, Rac1 was predominantly at the PM [22].
  • In addition, like Vav and Rac1, we found that Vav2 activated the Jun NH(2)-terminal kinase cascade and also caused the formation of lamellipodia and membrane ruffles in NIH 3T3 cells [41].
  • Oncogenic activity of Tiam1 and Rac1 in NIH3T3 cells [42].
  • MYC-Csl induced cell spreading and lamellipodia formation in C2C12 cells at the expense of filopodia, suggestive of modulation of Rac1 activity [43].
  • Combined with PK inhibitors and genetic mutants of Rac1 and JNK in PK activity assays, Western blotting analyses, and IL-1 enzyme-linked immunosorbent assay, the role of individual PKs in the regulation of proIL-1/IL-1 was extensively dissected [44].
  • We conclude that PI3K/p110alpha mediates growth factor-dependent ROS production by recruiting p47(phox) and Rac-1 to the cell membrane, thereby assembling the active Nox complex [45].

Analytical, diagnostic and therapeutic context of Rac1


  1. CD44 interaction with tiam1 promotes Rac1 signaling and hyaluronic acid-mediated breast tumor cell migration. Bourguignon, L.Y., Zhu, H., Shao, L., Chen, Y.W. J. Biol. Chem. (2000) [Pubmed]
  2. Rac1/Cdc42 and RhoA GTPases antagonistically regulate chondrocyte proliferation, hypertrophy, and apoptosis. Wang, G., Beier, F. J. Bone Miner. Res. (2005) [Pubmed]
  3. Roles of STEF/Tiam1, guanine nucleotide exchange factors for Rac1, in regulation of growth cone morphology. Matsuo, N., Terao, M., Nabeshima, Y., Hoshino, M. Mol. Cell. Neurosci. (2003) [Pubmed]
  4. Light-Induced photoreceptor degeneration in the mouse involves activation of the small GTPase Rac1. Belmonte, M.A., Santos, M.F., Kihara, A.H., Yan, C.Y., Hamassaki, D.E. Invest. Ophthalmol. Vis. Sci. (2006) [Pubmed]
  5. Adaptor molecule Crk is required for sustained phosphorylation of Grb2-associated binder 1 and hepatocyte growth factor-induced cell motility of human synovial sarcoma cell lines. Watanabe, T., Tsuda, M., Makino, Y., Ichihara, S., Sawa, H., Minami, A., Mochizuki, N., Nagashima, K., Tanaka, S. Mol. Cancer Res. (2006) [Pubmed]
  6. Yersinia virulence depends on mimicry of host rho-family nucleotide dissociation inhibitors. Prehna, G., Ivanov, M.I., Bliska, J.B., Stebbins, C.E. Cell (2006) [Pubmed]
  7. The 70 kDa S6 kinase complexes with and is activated by the Rho family G proteins Cdc42 and Rac1. Chou, M.M., Blenis, J. Cell (1996) [Pubmed]
  8. An essential role for Rac in Ras transformation. Qiu, R.G., Chen, J., Kirn, D., McCormick, F., Symons, M. Nature (1995) [Pubmed]
  9. Ankyrin-Tiam1 interaction promotes Rac1 signaling and metastatic breast tumor cell invasion and migration. Bourguignon, L.Y., Zhu, H., Shao, L., Chen, Y.W. J. Cell Biol. (2000) [Pubmed]
  10. Guanosine triphosphatase activation occurs downstream of calcineurin in cardiac hypertrophy*. Richardson, K.E., Tannous, P., Berenji, K., Nolan, B., Bayless, K.J., Davis, G.E., Rothermel, B.A., Hill, J.A. J. Investig. Med. (2005) [Pubmed]
  11. Proteomic analysis of Rac1 transgenic mice displaying dilated cardiomyopathy reveals an increase in creatine kinase M-chain protein abundance. Buscemi, N., Doherty-Kirby, A., Sussman, M.A., Lajoie, G., Van Eyk, J.E. Mol. Cell. Biochem. (2003) [Pubmed]
  12. The role of Rac1 in maintaining malignant phenotype of mouse skin tumor cells. Kwei, K.A., Finch, J.S., Ranger-Moore, J., Bowden, G.T. Cancer Lett. (2006) [Pubmed]
  13. Role of Rac1 in a bleomycin-induced scleroderma model using fibroblast-specific Rac1-knockout mice. Liu, S., Kapoor, M., Shi-wen, X., Kennedy, L., Denton, C.P., Glogauer, M., Abraham, D.J., Leask, A. Arthritis Rheum. (2008) [Pubmed]
  14. Requirements for Vav guanine nucleotide exchange factors and Rho GTPases in FcgammaR- and complement-mediated phagocytosis. Hall, A.B., Gakidis, M.A., Glogauer, M., Wilsbacher, J.L., Gao, S., Swat, W., Brugge, J.S. Immunity (2006) [Pubmed]
  15. The LIM protein Ajuba influences p130Cas localization and Rac1 activity during cell migration. Pratt, S.J., Epple, H., Ward, M., Feng, Y., Braga, V.M., Longmore, G.D. J. Cell Biol. (2005) [Pubmed]
  16. The in vivo roles of STEF/Tiam1, Rac1 and JNK in cortical neuronal migration. Kawauchi, T., Chihama, K., Nabeshima, Y., Hoshino, M. EMBO J. (2003) [Pubmed]
  17. Rac1 is the small GTPase responsible for regulating the neutrophil chemotaxis compass. Sun, C.X., Downey, G.P., Zhu, F., Koh, A.L., Thang, H., Glogauer, M. Blood (2004) [Pubmed]
  18. Genetic deletion of Cdc42GAP reveals a role of Cdc42 in erythropoiesis and hematopoietic stem/progenitor cell survival, adhesion, and engraftment. Wang, L., Yang, L., Filippi, M.D., Williams, D.A., Zheng, Y. Blood (2006) [Pubmed]
  19. The Src homology 2 domain of Vav is required for its compartmentation to the plasma membrane and activation of c-Jun NH(2)-terminal kinase 1. Arudchandran, R., Brown, M.J., Peirce, M.J., Song, J.S., Zhang, J., Siraganian, R.P., Blank, U., Rivera, J. J. Exp. Med. (2000) [Pubmed]
  20. Localization of p21-activated kinase 1 (PAK1) to pinocytic vesicles and cortical actin structures in stimulated cells. Dharmawardhane, S., Sanders, L.C., Martin, S.S., Daniels, R.H., Bokoch, G.M. J. Cell Biol. (1997) [Pubmed]
  21. Regulated membrane localization of Tiam1, mediated by the NH2-terminal pleckstrin homology domain, is required for Rac-dependent membrane ruffling and C-Jun NH2-terminal kinase activation. Michiels, F., Stam, J.C., Hordijk, P.L., van der Kammen, R.A., Ruuls-Van Stalle, L., Feltkamp, C.A., Collard, J.G. J. Cell Biol. (1997) [Pubmed]
  22. Differential localization of Rho GTPases in live cells: regulation by hypervariable regions and RhoGDI binding. Michaelson, D., Silletti, J., Murphy, G., D'Eustachio, P., Rush, M., Philips, M.R. J. Cell Biol. (2001) [Pubmed]
  23. Regulation of neurite outgrowth in N1E-115 cells through PDZ-mediated recruitment of diacylglycerol kinase zeta. Yakubchyk, Y., Abramovici, H., Maillet, J.C., Daher, E., Obagi, C., Parks, R.J., Topham, M.K., Gee, S.H. Mol. Cell. Biol. (2005) [Pubmed]
  24. The monomeric G-proteins Rac1 and/or Cdc42 are required for the inhibition of voltage-dependent calcium current by bradykinin. Wilk-Blaszczak, M.A., Singer, W.D., Quill, T., Miller, B., Frost, J.A., Sternweis, P.C., Belardetti, F. J. Neurosci. (1997) [Pubmed]
  25. p19Arf-p53 tumor suppressor pathway regulates cell motility by suppression of phosphoinositide 3-kinase and Rac1 GTPase activities. Guo, F., Gao, Y., Wang, L., Zheng, Y. J. Biol. Chem. (2003) [Pubmed]
  26. Isoform-specific membrane targeting mechanism of Rac during Fc gamma R-mediated phagocytosis: positive charge-dependent and independent targeting mechanism of Rac to the phagosome. Ueyama, T., Eto, M., Kami, K., Tatsuno, T., Kobayashi, T., Shirai, Y., Lennartz, M.R., Takeya, R., Sumimoto, H., Saito, N. J. Immunol. (2005) [Pubmed]
  27. G alpha 13 signals via p115RhoGEF cascades regulating JNK1 and primitive endoderm formation. Lee, Y.N., Malbon, C.C., Wang, H.Y. J. Biol. Chem. (2004) [Pubmed]
  28. B cell antigen receptor-induced Rac1 activation and Rac1-dependent spreading are impaired in transitional immature B cells due to levels of membrane cholesterol. Brezski, R.J., Monroe, J.G. J. Immunol. (2007) [Pubmed]
  29. Binding of laminin alpha1-chain LG4-5 domain to alpha-dystroglycan causes tyrosine phosphorylation of syntrophin to initiate Rac1 signaling. Zhou, Y.W., Thomason, D.B., Gullberg, D., Jarrett, H.W. Biochemistry (2006) [Pubmed]
  30. Skeletal muscle signaling pathway through the dystrophin glycoprotein complex and Rac1. Oak, S.A., Zhou, Y.W., Jarrett, H.W. J. Biol. Chem. (2003) [Pubmed]
  31. An activating mutant of Rac1 that fails to interact with Rho GDP-dissociation inhibitor stimulates membrane ruffling in mammalian cells. Gandhi, P.N., Gibson, R.M., Tong, X., Miyoshi, J., Takai, Y., Konieczkowski, M., Sedor, J.R., Wilson-Delfosse, A.L. Biochem. J. (2004) [Pubmed]
  32. Signaling from G protein-coupled receptors to c-Jun kinase involves beta gamma subunits of heterotrimeric G proteins acting on a Ras and Rac1-dependent pathway. Coso, O.A., Teramoto, H., Simonds, W.F., Gutkind, J.S. J. Biol. Chem. (1996) [Pubmed]
  33. Examination of the coordinate effects of Pseudomonas aeruginosa ExoS on Rac1. Rocha, C.L., Rucks, E.A., Vincent, D.M., Olson, J.C. Infect. Immun. (2005) [Pubmed]
  34. Epidermal growth factor-induced mobilization of a ganglioside-specific sialidase (NEU3) to membrane ruffles. Yamaguchi, K., Hata, K., Wada, T., Moriya, S., Miyagi, T. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  35. Genetic deletion of Rac1 GTPase reveals its critical role in actin stress fiber formation and focal adhesion complex assembly. Guo, F., Debidda, M., Yang, L., Williams, D.A., Zheng, Y. J. Biol. Chem. (2006) [Pubmed]
  36. Cdc42Hs, but not Rac1, inhibits serum-stimulated cell cycle progression at G1/S through a mechanism requiring p38/RK. Molnár, A., Theodoras, A.M., Zon, L.I., Kyriakis, J.M. J. Biol. Chem. (1997) [Pubmed]
  37. MOCA induces membrane spreading by activating Rac1. Namekata, K., Enokido, Y., Iwasawa, K., Kimura, H. J. Biol. Chem. (2004) [Pubmed]
  38. Critical activities of Rac1 and Cdc42Hs in skeletal myogenesis: antagonistic effects of JNK and p38 pathways. Meriane, M., Roux, P., Primig, M., Fort, P., Gauthier-Rouvière, C. Mol. Biol. Cell (2000) [Pubmed]
  39. Translocation of cortactin to the cell periphery is mediated by the small GTPase Rac1. Weed, S.A., Du, Y., Parsons, J.T. J. Cell. Sci. (1998) [Pubmed]
  40. Requirement for Rac1 in a K-ras induced lung cancer in the mouse. Kissil, J.L., Walmsley, M.J., Hanlon, L., Haigis, K.M., Bender Kim, C.F., Sweet-Cordero, A., Eckman, M.S., Tuveson, D.A., Capobianco, A.J., Tybulewicz, V.L., Jacks, T. Cancer Res. (2007) [Pubmed]
  41. Vav2 is an activator of Cdc42, Rac1, and RhoA. Abe, K., Rossman, K.L., Liu, B., Ritola, K.D., Chiang, D., Campbell, S.L., Burridge, K., Der, C.J. J. Biol. Chem. (2000) [Pubmed]
  42. Oncogenic activity of Tiam1 and Rac1 in NIH3T3 cells. van Leeuwen, F.N., van der Kammen, R.A., Habets, G.G., Collard, J.G. Oncogene (1995) [Pubmed]
  43. Muscle costameric protein, Chisel/Smpx, associates with focal adhesion complexes and modulates cell spreading in vitro via a Rac1/p38 pathway. Schindeler, A., Lavulo, L., Harvey, R.P. Exp. Cell Res. (2005) [Pubmed]
  44. Ligands of macrophage scavenger receptor induce cytokine expression via differential modulation of protein kinase signaling pathways. Hsu, H.Y., Chiu, S.L., Wen, M.H., Chen, K.Y., Hua, K.F. J. Biol. Chem. (2001) [Pubmed]
  45. Phosphatidylinositol 3-kinase-dependent membrane recruitment of Rac-1 and p47phox is critical for alpha-platelet-derived growth factor receptor-induced production of reactive oxygen species. Bäumer, A.T., Ten Freyhaus, H., Sauer, H., Wartenberg, M., Kappert, K., Schnabel, P., Konkol, C., Hescheler, J., Vantler, M., Rosenkranz, S. J. Biol. Chem. (2008) [Pubmed]
  46. Association of RhoGDIalpha with Rac1 GTPase mediates free radical production during myocardial hypertrophy. Custodis, F., Eberl, M., Kilter, H., Böhm, M., Laufs, U. Cardiovasc. Res. (2006) [Pubmed]
  47. Critical roles for Rac1 and Rac2 GTPases in B cell development and signaling. Walmsley, M.J., Ooi, S.K., Reynolds, L.F., Smith, S.H., Ruf, S., Mathiot, A., Vanes, L., Williams, D.A., Cancro, M.P., Tybulewicz, V.L. Science (2003) [Pubmed]
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