Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Rho GTPases in cell biology

Nature volume 420, pages 629–635 (2002)Cite this article

Abstract

Rho GTPases are molecular switches that control a wide variety of signal transduction pathways in all eukaryotic cells. They are known principally for their pivotal role in regulating the actin cytoskeleton, but their ability to influence cell polarity, microtubule dynamics, membrane transport pathways and transcription factor activity is probably just as significant. Underlying this biological complexity is a simple biochemical idea, namely that by switching on a single GTPase, several distinct signalling pathways can be coordinately activated. With spatial and temporal activation of multiple switches factored in, it is not surprising to find Rho GTPases having such a prominent role in eukaryotic cell biology.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The Rho GTPase cycle.
Figure 2: Morphogenesis.
Figure 3: Movement.
Figure 4: Behaviour.

Similar content being viewed by others

References

  1. Ridley, A. J. & Hall, A. The small GTP-binding protein Rho regulates the assembly of focal adhesions and stress fibers in response to growth factors. Cell 70, 389–399 (1992)

    Article  CAS  Google Scholar 

  2. Ridley, A. J., Paterson, C. L., Johnston, C. L., Diekmann, D. & Hall, A. The small GTP-binding protein Rac regulates growth factor-induced membrane ruffling. Cell 70, 401–410 (1992)

    Article  CAS  Google Scholar 

  3. Nobes, C. D. & Hall, A. Rho, Rac and Cdc42 regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia and filopodia. Cell 81, 53–62 (1995)

    Article  CAS  Google Scholar 

  4. Kozma, R., Ahmed, S., Best, A. & Lim, L. The Ras-related protein Cdc42Hs and bradykinin promote formation of peripheral actin microspikes and filopodia in Swiss 3T3 fibroblasts. Mol. Cell. Biol. 15, 1942–1952 (1995)

    Article  CAS  Google Scholar 

  5. Pruyne, D. & Bretscher, A. Polarization of cell growth in yeast. I. Establishment and maintenance of polarity states. J. Cell Sci. 113, 365–375 (2000)

    CAS  PubMed  Google Scholar 

  6. Schmidt, A. & Hall, M. N. Signaling to the actin cytoskeleton. Annu. Rev. Cell Dev. Biol. 14, 305–338 (1998)

    Article  CAS  Google Scholar 

  7. Butty, A.-C. et al. A positive feedback loop stabilizes the guanine-exchange factor Cdc24 at sites of polarization. EMBO J. 21, 1565–1576 (2002)

    Article  CAS  Google Scholar 

  8. Kemphues, K. PARsing embryonic polarity. Cell 101, 345–348 (2000)

    Article  CAS  Google Scholar 

  9. Ohno, S. Intercellular juntions and cellular polarity: the PAR-aPKC complex, a conserved core cassette playing fundamental roles in cell polarity. Curr. Opin. Cell Biol. 13, 641–648 (2001)

    Article  CAS  Google Scholar 

  10. Gotta, M., Abraham, M. C. & Ahringer, J. CDC-42 controls early cell polarity and spindle orientation in C. elegans. Curr. Biol. 11, 482–488 (2001)

    Article  CAS  Google Scholar 

  11. Kay, A. J. & Hunter, C. P. CDC-42 regulates PAR protein localization and function to control cellular and embryonic polarity in C. elegans. Curr. Biol. 11, 474–481 (2001)

    Article  CAS  Google Scholar 

  12. Joberty, G., Petersen, C., Gao, L. & Macara, I. G. The cell-polarity protein Par6 links Par3 and atypical protein kinase C to Cdc42. Nature Cell Biol. 2, 531–539 (2000)

    Article  CAS  Google Scholar 

  13. Qiu, R.-G., Abo, A. & Martin, G. S. A human homolog of the C. elegans polarity determinant Par-6 links Rac and Cdc42 to PKCζ signaling and cell transformation. Curr. Biol. 10, 697–707 (2000)

    Article  CAS  Google Scholar 

  14. Lin, D. et al. A mammalian PAR-3-PAR-6 complex implicated in Cdc42/Rac1 and aPKC signalling and cell polarity. Nature Cell Biol. 2, 540–547 (2000)

    Article  CAS  Google Scholar 

  15. Van Aelst, L. & Symons, M. Role of Rho family GTPases in epithelial morphogenesis. Genes Dev. 16, 1032–1054 (2002)

    Article  CAS  Google Scholar 

  16. Vasioukhin, V., Bauer, C., Yin, M. & Fuchs, E. Directed actin polymerization is the driving force for epithelial cell-cell adhesion. Cell 100, 209–219 (2000)

    Article  CAS  Google Scholar 

  17. Raich, W. B., Agbunag, C. & Hardin, J. Rapid epithelial-sheet sealing in the Caenorhabditis elegans embryo requires cadherin-dependent filopodial priming. Curr. Biol. 9, 1139–1146 (1999)

    Article  CAS  Google Scholar 

  18. Jacinto, A., Martinez-Arias, A. & Martin, P. Mechanisms of epithelial fusion and repair. Nature Cell Biol. 3, E117–E123 (2001)

    Article  CAS  Google Scholar 

  19. Yamanaka, T. et al. PAR-6 regulates aPKC activity in a novel way and mediates cell-cell contact-induced formation of the epithelial junctional complex. Genes Cells 6, 721–731 (2001)

    Article  CAS  Google Scholar 

  20. Rojas, R., Ruiz, W. G., Leung, S. M., Jou, T. S. & Apodaca, G. Cdc42-dependent modulation of tight junctions and membrane protein traffic in polarized Madin-Darby canine kidney cells. Mol. Biol. Cell 12, 2257–2274 (2001)

    Article  CAS  Google Scholar 

  21. Gao, L., Joberty, G. & Macara, I. G. Assembly of epithelial tight junctions is negatively regulated by Par-6. Curr. Biol. 12, 221–225 (2002)

    Article  CAS  Google Scholar 

  22. Ebnet, K. et al. The cell polarity protein ASIP/PAR-3 directly associates with junctional adhesion molecule (JAM). EMBO J. 20, 3738–3748 (2001)

    Article  CAS  Google Scholar 

  23. O'Brien, L. E. et al. Rac1 orientates epithelial apical polarity through effects on basolateral laminin assembly. Nature Cell Biol. 3, 831–838 (2001)

    Article  CAS  Google Scholar 

  24. Kroschewski, R., Hall, A. & Mellman, I. Cdc42 controls secretory and endocytic transport to the basolateral plasma membrane of MDCK cells. Nature Cell Biol. 1, 8–13 (1999)

    Article  CAS  Google Scholar 

  25. Zhang, X. et al. Cdc42 interacts with the exocyst and regulates polarized secretion. J. Biol. Chem. 276, 46745–46750 (2001)

    Article  CAS  Google Scholar 

  26. Sugihara, K. et al. The exocyst complex binds the small GTPase RalA to mediate filopodia formation. Nature Cell Biol. 4, 73–78 (2001)

    Article  Google Scholar 

  27. Moskalenko, S. et al. The exocyst is a Ral effector complex. Nature Cell Biol. 4, 66–72 (2002)

    Article  CAS  Google Scholar 

  28. Luo, L. Rho GTPases in neuronal morphogenesis. Nature Rev. Neurosci. 1, 173–180 (2000)

    Article  ADS  CAS  Google Scholar 

  29. Lee, T., Winter, C., Marticke, S. S., Lee, A. & Luo, L. Essential role of Drosophila RhoA in the regulation of neuroblast proliferation and dendritic but not axonal morphogenesis. Neuron 25, 307–316 (2000)

    Article  CAS  Google Scholar 

  30. Ozdinler, P. H. & Erzurumlu, R. S. Regulation of neurotrophin-induced axonal responses via Rho GTPases. J. Comp. Neurol. 438, 377–387 (2001)

    Article  CAS  Google Scholar 

  31. Li, Z., Van Aelst, L. & Cline, H. T. Rho GTPases regulate distinct aspects of dendritic arbor growth in Xenopus central neurons in vivo. Nature Neurosci. 3, 217–225 (2000)

    Article  CAS  Google Scholar 

  32. Wong, W. T., Faulkner-Jones, B., Sanes, J. R. & Wong, R. O. Rapid dendritic remodeling in the developing retina: dependence on neurotransmission and reciprocal regulation by Rac and Rho. J. Neurosci. 20, 5024–5036 (2000)

    Article  CAS  Google Scholar 

  33. Ridley, A. Rho GTPases and cell migration. J. Cell Sci. 114, 2713–2722 (2001)

    CAS  PubMed  Google Scholar 

  34. Small, J. V., Stradal, T., Vignal, E. & Rottler, K. The lamellipodium: where motility begins. Trends Cell Biol. 12, 112–120 (2002)

    Article  CAS  Google Scholar 

  35. Condeelis, J. How is actin polymerization nucleated in vivo? Trends Cell Biol. 11, 288–293 (2001)

    Article  CAS  Google Scholar 

  36. Kraynov, V. S. et al. Localized Rac activation dynamics visualized in living cells. Science 290, 333–337 (2000)

    Article  ADS  CAS  Google Scholar 

  37. Gupta, T. & Schupbach, T. Two signals are better than one: border cell migration in Drosophila. Dev. Cell 1, 443–445 (2001)

    Article  CAS  Google Scholar 

  38. Duchek, P., Somogyi, K., Jekely, G., Beccari, S. & Rorth, P. Guidance of cell migration by the Drosophila PDGF/VEGF receptor. Cell 107, 17–26 (2001)

    Article  CAS  Google Scholar 

  39. Reddien, P. W. & Horvitz, H. R. CED-2/CrkII and CED-10/Rac control phagocytosis and cell migration in Caenorhabditis elegans. Nature Cell Biol. 2, 131–136 (2000)

    Article  CAS  Google Scholar 

  40. Albert, M. L., Kim, J. I. & Birge, R. B. αvβ5 integrin recruites the CrkII-Dock180-rac1 complex for phagocytosis of apoptotic cells. Nature Cell Biol. 2, 899–905 (2000)

    Article  CAS  Google Scholar 

  41. Worthylake, R. A., Lemoine, S., Watson, J. M. & Burridge, K. RhoA is required for monocyte tail retraction during transendothelial migration. J. Cell Biol. 154, 147–160 (2001)

    Article  CAS  Google Scholar 

  42. Allen, W. E., Zicha, D., Ridley, A. J. & Jones, G. E. A role for Cdc42 in macrophage chemotaxis. J. Cell Biol. 141, 1147–1157 (1998)

    Article  CAS  Google Scholar 

  43. Wittmann, T. & Waterman-Storer, C. M. Cell motility: can Rho GTPases and microtubules point the way? J. Cell Sci. 114, 3795–3803 (2001)

    CAS  PubMed  Google Scholar 

  44. Liu, B. P. & Strittmatter, S. M. Semaphorin-mediated axonal guidance via Rho-related G proteins. Curr. Opin. Cell Biol. 13, 619–626 (2001)

    Article  CAS  Google Scholar 

  45. Ng, J. et al. Rac GTPases control axon growth, guidance and branching. Nature 416, 442–447 (2002)

    Article  ADS  CAS  Google Scholar 

  46. Lundquist, E. A., Reddien, P. W., Hartwieg, E., Horvitz, H. R. & Bargmann, C. I. Three C. elegans Rac proteins and several alternative Rac regulators control axon guidance, cell migration and apoptotic cell phagocytosis. Development 128, 4475–4488 (2001)

    CAS  PubMed  Google Scholar 

  47. Brock, J., Midwinter, K., Lewis, J. & Martin, P. Healing of incisional wounds in the embryonic chick wing bud: characterization of the actin purse-string and demonstration of a requirement for Rho activation. J. Cell Biol. 135, 1097–1107 (1996)

    Article  CAS  Google Scholar 

  48. Lu, Y. & Settleman, J. The Drosophila Pkn protein kinase is a Rho/Rac effector _target required for dorsal closure during embryogenesis. Genes Dev. 13, 1168–1180 (1999)

    Article  CAS  Google Scholar 

  49. Stronach, B. E. & Perrimon, N. Stress signaling in Drosophila. Oncogene 18, 6172–6182 (1999)

    Article  CAS  Google Scholar 

  50. Knust, E. Drosophila morphogenesis: movements behind the edge. Curr. Biol. 7, R558–R561 (1997)

    Article  CAS  Google Scholar 

  51. Nobes, C. D. & Hall, A. Rho GTPases control polarity, protrusion and adhesion during cell movement. J. Cell Biol. 144, 1235–1244 (1999)

    Article  CAS  Google Scholar 

  52. Etienne-Manneville, S. & Hall, A. Integrin-mediated Cdc42 activation controls cell polarity in migrating astrocytes through PKCζ. Cell 106, 489–498 (2001)

    Article  CAS  Google Scholar 

  53. Palazzo, A. F. et al. Cdc42, dynein, and dynactin regulate MTOC reorientation independent of Rho-regulated microtubule stabilization. Curr. Biol. 11, 1536–1541 (2001)

    Article  CAS  Google Scholar 

  54. Ishizaki, T. et al. Coordination of microtubules and actin cytoskeleton by the Rho effector mDial. Nature Cell Biol. 3, 8–14 (2001)

    Article  CAS  Google Scholar 

  55. Ridely, A. J. Rho family proteins: coordinating cell responses. Trends Cell Biol. 11, 471–477 (2001)

    Article  Google Scholar 

  56. Fukata, Y., Amano, M. & Kaibuchi, K. Rho-Rho-kinase pathway in smooth muscle contraction and cytoskeletal reorganization of non-muscle cells. Trends Pharmacol. Sci. 22, 32–39 (2001)

    Article  CAS  Google Scholar 

  57. Sakurada, S., Okamoto, H., Takuwa, N., Sugimoto, N. & Takuwa, Y. Rho activation in excitatory agonist-stimulated vascular smooth muscle. Am. J. Physiol. Cell Physiol. 281, C571–C578 (2001)

    Article  CAS  Google Scholar 

  58. Uehata, M. et al. Calcium sensitization of smooth muscle mediated by Rho-associated protein kinase in hypertension. Nature 389, 990–994 (1997)

    Article  ADS  CAS  Google Scholar 

  59. van Nieuw Amerongen, G. P., van Delft, S., Vermeer, M. A., Collard, J. G. & van Hinsbergh, V. W. Activation of RhoA by thrombin in endothelial hypermeability: role of Rho kinase and protein tyrosine kinases. Circ. Res. 87, 335–340 (2000)

    Article  CAS  Google Scholar 

  60. Wojciak-Stothard, B., Potempa, S., Eichholtz, T. & Ridley, A. J. Rho and Rac but not Cdc42 regulate endothelial cell permeability. J. Cell Sci. 114, 1343–1355 (2001)

    CAS  PubMed  Google Scholar 

  61. Caron, E. & Hall, A. Identification of two distinct mechanisms of phagocytosis controlled by different Rho GTPases. Science 282, 1717–1721 (1998)

    Article  ADS  CAS  Google Scholar 

  62. Caron, E. Rac and roll over the corpses. Curr. Biol. 10, R489–R491 (2000)

    Article  CAS  Google Scholar 

  63. Bokoch, G. M. Regulation of cell function by Rho family GTPases. Immunol. Res. 21, 139–148 (2000)

    Article  ADS  CAS  Google Scholar 

  64. Nobes, C. & Marsh, M. Dendritic cells: new roles for Cdc42 and Rac in antigen uptake? Curr. Biol. 10, R739–R741 (2000)

    Article  CAS  Google Scholar 

  65. Aktories, K., Schmidt, G. & Just, I. Rho GTPases as _targets of bacterial protein toxins. Biol. Chem. 381, 421–426 (2000)

    Article  CAS  Google Scholar 

  66. Galan, J. E. Salmonella interactions with host cells: Type III secretion at work. Annu. Rev. Cell Dev. Biol. 17, 53–86 (2001)

    Article  CAS  Google Scholar 

  67. Cantrell, D. Lymphocyte signalling: a coordinating role for Vav? Curr. Biol. 8, R535–R538 (1998)

    Article  CAS  Google Scholar 

  68. Glassford, J. et al. Vav is required for cyclin D2 induction and proliferation of mouse B lymphocytes activated via the antigen receptor. J. Biol. Chem. 276, 41040–41048 (2001)

    Article  CAS  Google Scholar 

  69. Olson, M. F., Ashworth, A. & Hall, A. An essential role for Rho, Rac and CDC42 GTPases in cell cycle progression through G1. Science 269, 1270–1272 (1995)

    Article  ADS  CAS  Google Scholar 

  70. Welsh, C. F. et al. Timing of cyclin D1 expression within G1 phase is controlled by Rho. Nature Cell Biol. 3, 950–957 (2001)

    Article  CAS  Google Scholar 

  71. Olson, M. F., Paterson, H. F. & Marshall, C. J. Signals from Ras and Rho GTPases interact to regulate expression of p21Waf1/Cip1. Nature 394, 295–299 (1998)

    Article  ADS  CAS  Google Scholar 

  72. Mettouchi, A. et al. Integrin-specific activation of Rac controls progression through the G1 phase of the cell cycle. Mol. Cell 8, 115–127 (2001)

    Article  CAS  Google Scholar 

  73. Glotzer, M. Animal cell cytokinesis. Annu. Rev. Cell Dev. Biol. 17, 351–386 (2001)

    Article  CAS  Google Scholar 

  74. Stowers, L., Yelon, D., Berg, L. J. & Chant, J. Regulation of the polarization of T cells towards antigen-presenting cells by Ras-related GTPase CDC42. Proc. Natl Acad. Sci. USA 92, 5027–5031 (1995)

    Article  ADS  CAS  Google Scholar 

  75. Pinxteren, J. A., O'Sullivan, A. J., Larbi, K. Y., Tatham, P. E. R. & Gomperts, B. D. Thirty years of stimulus-secretion coupling: from Ca2+ to GTP in the regulation of exocytosis. Biochimie 82, 385–393 (2000)

    Article  CAS  Google Scholar 

  76. Chiang, S. H. et al. Insulin-stimulated GLUT4 translocation requires the CAP-dependent activation of TC10. Nature 410, 944–948 (2001)

    Article  ADS  CAS  Google Scholar 

  77. Kanzaki, M. & Pessin, J. E. Insulin-stimulated GLUT4 translocation in adipocytes is dependent upon cortical actin remodeling. J. Biol. Chem. 276, 42436–42444 (2001)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful for support from Cancer Research UK and the Medical Research Council. S.E.-M. is supported by an EMBO long-term fellowship.

Author information

Authors and Affiliations

  1. MRC Laboratory for Molecular Cell Biology and Cell Biology Unit, Cancer Research UK Oncogene and Signal Transduction Group, University College London, Gower Street, WC1E 6BT, London, UK

    Sandrine Etienne-Manneville & Alan Hall

  2. Department of Biochemistry and Molecular Biology, University College London, Gower Street, WC1E 6BT, London, UK

    Alan Hall

Authors
  1. Sandrine Etienne-Manneville
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alan Hall
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alan Hall.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Etienne-Manneville, S., Hall, A. Rho GTPases in cell biology. Nature 420, 629–635 (2002). https://doi.org/10.1038/nature01148

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature01148

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing
  NODES
Idea 1
idea 1
INTERN 1
twitter 1