Review Article | Published:

Mammalian Rho GTPases: new insights into their functions from in vivo studies

Nature Reviews Molecular Cell Biology volume 9, pages 690701 (2008) | Download Citation

Abstract

Rho GTPases are key regulators of cytoskeletal dynamics and affect many cellular processes, including cell polarity, migration, vesicle trafficking and cytokinesis. These proteins are conserved from plants and yeast to mammals, and function by interacting with and stimulating various downstream targets, including actin nucleators, protein kinases and phospholipases. The roles of Rho GTPases have been extensively studied in different mammalian cell types using mainly dominant negative and constitutively active mutants. The recent availability of knockout mice for several members of the Rho family reveals new information about their roles in signalling to the cytoskeleton and in development.

Key points

  • There are 20 members of the Rho GTPase family in mammals; all eukaryotes have several Rho GTPases.

  • Rho GTPases regulate cytoskeletal dynamics, cell polarity, cell migration, cell-cycle progression, vesicle trafficking and cytokinesis.

  • Most studies into the function of Rho GTPases in mammalian systems have used cultured cells that express constitutively active and/or dominant-negative mutants.

  • Knockout mice for five Rho GTPases — RhoB, RhoC, RAC2, RAC3 and RhoH — are viable and fertile, allowing studies of their functions in vivo and in cells purified from tissues. So far, these studies have mostly shown that each of these GTPases has a similar role in vivo to that predicted from in vitro studies.

  • Knockout mice for Rac1 and Cdc42 die early in embryogenesis, and hence conditional knockout alleles have been generated to study their function.

  • The effects of knocking out Rac1 or Cdc42 have been investigated in multiple tissues and cell types in mice, from haematopoietic cells to neurons, glial cells, and epithelial cells; these studies have revealed novel functions for RAC1 and CDC42 that had not been predicted from in vitro analysis of cell lines.

  • In some cases, knockout of Rac1 or Cdc42 gives a different phenotype to expression of dominant negative RAC1 or dominant-negative CDC42; for example, dominant-negative CDC42 inhibits filopodium extension, but CDC42-null fibroblastoid cells can still make filopodia. However, CDC42-null neurons have a reduced number of filopodia. These results suggest that CDC42 contribution to filopodium extension is cell-type-specific.

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References

  1. 1.

    & Rho GTPases: biochemistry and biology. Annu. Rev. Cell Dev. Biol. 21, 247–269 (2005).

  2. 2.

    , & Taking Rho GTPases to the next level: the cellular functions of atypical Rho GTPases. Exp. Cell Res. 313, 3673–3679 (2007).

  3. 3.

    Function and regulation of Rnd proteins. Nature Rev. Mol. Cell Biol. 7, 54–62 (2006).

  4. 4.

    , , & Evolution of the Rho family of ras-like GTPases in eukaryotes. Mol. Biol. Evol. 24, 203–216 (2007).

  5. 5.

    Cdc42 — the centre of polarity. J. Cell Sci. 117, 1291–1300 (2004).

  6. 6.

    , , & Functional analysis of Cdc42 in actin filament assembly, epithelial morphogenesis, and cell signaling during Drosophila development. Dev. Biol. 221, 181–194 (2000).

  7. 7.

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

  8. 8.

    et al. Cdc42 is required for PIP2-induced actin polymerization and early development but not for cell viability. Curr. Biol. 10, 758–765 (2000).

  9. 9.

    & Filopodia: the fingers that do the walking. Sci. STKE 2007, re5 (2007).

  10. 10.

    , , & Distinct cellular effects and interactions of the Rho-family GTPase TC10. Curr. Biol. 8, 1151–1160 (1998).

  11. 11.

    , , , & Wrch-1, a novel member of the Rho gene family that is regulated by Wnt-1. Genes Dev. 15, 1796–1807 (2001).

  12. 12.

    , & Rho GTPases have diverse effects on the organization of the actin filament system. Biochem. J. 377, 327–337 (2004).

  13. 13.

    et al. Cdc42 regulates cofilin during the establishment of neuronal polarity. J. Neurosci. 27, 13117–13129 (2007). Describes the effect of conditional CDC42 deletion in the brain, and makes the surprising observation that loss of CDC42 leads to a decrease in cofilin activity.

  14. 14.

    , & Gene targeting of Cdc42 and Cdc42GAP affirms the critical involvement of Cdc42 in filopodia induction, directed migration, and proliferation in primary mouse embryonic fibroblasts. Mol. Biol. Cell 17, 4675–4685 (2006).

  15. 15.

    et al. Cdc42 is not essential for filopodium formation, directed migration, cell polarization, and mitosis in fibroblastoid cells. Mol. Biol. Cell 16, 4473–4484 (2005).

  16. 16.

    et al. N-WASP deficiency reveals distinct pathways for cell surface projections and microbial actin-based motility. Nature Cell Biol. 3, 897–904 (2001).

  17. 17.

    , , , & Disruption of the Diaphanous-related formin Drf1 gene encoding mDia1 reveals a role for Drf3 as an effector for Cdc42. Curr. Biol. 13, 534–545 (2003).

  18. 18.

    & Membrane curvature: the power of bananas, zeppelins and boomerangs. Curr. Biol. 17, R455–R457 (2007).

  19. 19.

    Do filopodia enable the growth cone to find its way? Sci. STKE 2003, pe20 (2003).

  20. 20.

    , & The role of the Rho GTPases in neuronal development. Genes Dev. 19, 1–49 (2005).

  21. 21.

    , , , & Cdc42 participates in the regulation of ADF/cofilin and retinal growth cone filopodia by brain derived neurotrophic factor. J. Neurobiol. 66, 103–114 (2006).

  22. 22.

    , , , & Brain-derived neurotrophic factor regulation of retinal growth cone filopodial dynamics is mediated through actin depolymerizing factor/cofilin. J. Neurosci. 24, 10741–10749 (2004).

  23. 23.

    , & The cofilin pathway in breast cancer invasion and metastasis. Nature Rev. Cancer 7, 429–440 (2007).

  24. 24.

    & Rho GTPases regulate axon growth through convergent and divergent signaling pathways. Neuron 44, 779–793 (2004).

  25. 25.

    & Mechanisms of axon ensheathment and myelin growth. Nature Rev. Neurosci. 6, 683–690 (2005).

  26. 26.

    et al. Cdc42 and Rac1 signaling are both required for and act synergistically in the correct formation of myelin sheaths in the CNS. J. Neurosci. 26, 10110–10119 (2006). Describes how targeted deletion of CDC42 or RAC1 in oligodendrocytes reduces their ability to form myelin sheaths.

  27. 27.

    et al. Essential and distinct roles for cdc42 and rac1 in the regulation of Schwann cell biology during peripheral nervous system development. J. Cell Biol. 177, 1051–1061 (2007).

  28. 28.

    , , & Chemokine-induced monocyte transmigration requires cdc42-mediated cytoskeletal changes. Eur. J. Immunol. 28, 2245–2251 (1998).

  29. 29.

    , , & A role for Cdc42 in macrophage chemotaxis. J. Cell Biol. 141, 1147–1157 (1998).

  30. 30.

    , , , & Rho GTPases control migration and polarization of adhesion molecules and cytoskeletal ERM components in T lymphocytes. Eur. J. Immunol. 29, 3609–3620 (1999).

  31. 31.

    & Rho GTPases control polarity, protrusion, and adhesion during cell movement. J. Cell Biol. 144, 1235–1244 (1999).

  32. 32.

    et al. Live imaging of wound inflammation in Drosophila embryos reveals key roles for small GTPases during in vivo cell migration. J. Cell Biol. 168, 567–573 (2005).

  33. 33.

    et al. Rho GTPase Cdc42 coordinates hematopoietic stem cell quiescence and niche interaction in the bone marrow. Proc. Natl Acad. Sci. USA 104, 5091–5096 (2007).

  34. 34.

    et al. Rac and Cdc42 play distinct roles in regulating PI(3, 4, 5)P3 and polarity during neutrophil chemotaxis. J. Cell Biol. 160, 375–385 (2003).

  35. 35.

    et al. Cdc42 is crucial for the establishment of epithelial polarity during early mammalian development. Dev. Dyn. 236, 2767–2778 (2007). Describes the earliest effects of CDC42 deletion during embryogenesis, including defects in cell polarity and cell–cell adhesion. These correlate with CDC42-mediated changes in polarity proteins such as aPKC and GSK3β.

  36. 36.

    , , , & Rho GTPase CDC42 regulates directionality and random movement via distinct MAPK pathways in neutrophils. Blood 108, 4205–4213 (2006).

  37. 37.

    et al. Rac and Cdc42 GTPases control hematopoietic stem cell shape, adhesion, migration, and mobilization. Proc. Natl Acad. Sci. USA 98, 5614–5618 (2001).

  38. 38.

    & The PAR proteins: fundamental players in animal cell polarization. Dev. Cell 13, 609–622 (2007).

  39. 39.

    & Cdc42 regulates GSK-3β and adenomatous polyposis coli to control cell polarity. Nature 421, 753–756 (2003).

  40. 40.

    et al. The Par–Tiam1 complex controls persistent migration by stabilizing microtubule-dependent front-rear polarity. Curr. Biol. 17, 1623–1634 (2007).

  41. 41.

    , & Nuclear movement regulated by Cdc42, MRCK, myosin, and actin flow establishes MTOC polarization in migrating cells. Cell 121, 451–463 (2005).

  42. 42.

    , , & Genome-wide analysis identifies a general requirement for polarity proteins in endocytic traffic. Nature Cell Biol. 9, 1066–1073 (2007).

  43. 43.

    Parsing the polarity code. Nature Rev. Mol. Cell Biol. 5, 220–231 (2004).

  44. 44.

    & Rho GTPases in cell biology. Nature 420, 629–635 (2002).

  45. 45.

    et al. PTEN-mediated apical segregation of phosphoinositides controls epithelial morphogenesis through Cdc42. Cell 128, 383–397 (2007).

  46. 46.

    et al. Cdc42 controls progenitor cell differentiation and β-catenin turnover in skin. Genes Dev. 20, 571–585 (2006). The first demonstration that CDC42 is essential for the formation of hair follicles in the skin, a process which is dependent on β-catenin.

  47. 47.

    , & Cdc42 expression in keratinocytes is required for the maintenance of the basement membrane in skin. Matrix Biol. 25, 466–474 (2006).

  48. 48.

    et al. The Rho-GTPase cdc42 regulates neural progenitor fate at the apical surface. Nature Neurosci. 9, 1099–1107 (2006). Describes how CDC42 is essential for polarized cell divisions in the mouse telencephalon, leading to a change in cell fate.

  49. 49.

    et al. Cdc42 deficiency causes Sonic hedgehog-independent holoprosencephaly. Proc. Natl Acad. Sci. USA 103, 16520–16525 (2006).

  50. 50.

    et al. Cdc42 critically regulates the balance between myelopoiesis and erythropoiesis. Blood 110, 3853–3861 (2007). Describes the effect of CDC42 on cell fate in the haematopoietic system: loss of CDC42 leads to inhibition of erythropoiesis and hyperproliferation of myeloid cells.

  51. 51.

    & RhoG activates Rac1 by direct interaction with the Dock180-binding protein Elmo. Nature 424, 461–464 (2003).

  52. 52.

    , , , & rac, a novel ras-related family of proteins that are botulinum toxin substrates. J. Biol. Chem. 264, 16378–16382 (1989).

  53. 53.

    , , & A member of the ras gene superfamily is expressed specifically in T, B and myeloid hemopoietic cells. Oncogene 5, 769–772 (1990).

  54. 54.

    , & Characterization of RAC3, a novel member of the Rho family. J. Biol. Chem. 272, 20384–20388 (1997).

  55. 55.

    , , & Differential distribution of Rac1 and Rac3 GTPases in the developing mouse brain: implications for a role of Rac3 in Purkinje cell differentiation. Eur. J. Neurosci. 18, 2417–2424 (2003).

  56. 56.

    et al. Generation and characterization of Rac3 knockout mice. Mol. Cell. Biol. 25, 5763–5776 (2005).

  57. 57.

    , & Growth-regulated expression of rhoG, a new member of the ras homolog gene family. Mol. Cell. Biol. 12, 3138–3148 (1992).

  58. 58.

    et al. Rac1 is required for the formation of three germ layers during gastrulation. Oncogene 17, 3427–3433 (1998).

  59. 59.

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

  60. 60.

    , , , & Rac1-deficient macrophages exhibit defects in cell spreading and membrane ruffling but not migration. J. Cell Sci. 117, 1259–1268 (2004).

  61. 61.

    et al. β1 integrin activates Rac1 in Schwann cells to generate radial lamellae during axonal sorting and myelination. J. Cell Biol. 177, 1063–1075 (2007).

  62. 62.

    et al. An essential role for Rac1 in endothelial cell function and vascular development. FASEB J. 22, 1829–1838 (2008).

  63. 63.

    et al. Rac1 is essential for platelet lamellipodia formation and aggregate stability under flow. J. Biol. Chem. 280, 39474–39484 (2005).

  64. 64.

    et al. Rac1 is the small GTPase responsible for regulating the neutrophil chemotaxis compass. Blood 104, 3758–3765 (2004).

  65. 65.

    et al. Deficiency of the hematopoietic cell-specific Rho family GTPase Rac2 is characterized by abnormalities in neutrophil function and host defense. Immunity 10, 183–196 (1999).

  66. 66.

    et al. Hematopoietic cell regulation by Rac1 and Rac2 guanosine triphosphatases. Science 302, 445–449 (2003).

  67. 67.

    et al. Rac2-deficient murine macrophages have selective defects in superoxide production and phagocytosis of opsonized particles. J. Immunol. 173, 5971–5979 (2004).

  68. 68.

    et al. Rac1 and Rac2 regulate macrophage morphology but are not essential for migration. J. Cell Sci. 119, 2749–2757 (2006).

  69. 69.

    et al. RhoG regulates the neutrophil NADPH oxidase. J. Immunol. 176, 5314–5320 (2006).

  70. 70.

    & The WASP–WAVE protein network: connecting the membrane to the cytoskeleton. Nature Rev. Mol. Cell Biol. 8, 37–48 (2007).

  71. 71.

    , & Rac1 and Rac2 differentially regulate actin free barbed end formation downstream of the fMLP receptor. J. Cell Biol. 179, 239–245 (2007). Describes the different roles for RAC1 and RAC2 in stimulating actin polymerization in neutrophils.

  72. 72.

    et al. Chemoattractant-stimulated Rac activation in wild-type and Rac2-deficient murine neutrophils: preferential activation of Rac2 and Rac2 gene dosage effect on neutrophil functions. J. Immunol. 169, 5043–5051 (2002).

  73. 73.

    et al. Rac GTPases regulate the morphology and deformability of the erythrocyte cytoskeleton. Blood 108, 3637–3645 (2006). Provides the first evidence that RAC1 and RAC2 are essential for the correct assembly of the membrane-associated cytoskeleton in erythrocytes.

  74. 74.

    Rho GTPases and their regulators in neuronal functions and development. Neurosignals 15, 228–237 (2006).

  75. 75.

    , , & Distinct morphogenetic functions of similar small GTPases: Drosophila Drac1 is involved in axonal outgrowth and myoblast fusion. Genes Dev. 8, 1787–1802 (1994).

  76. 76.

    , & Regulation of dendritic growth and remodeling by Rho, Rac, and Cdc42. Neuron 19, 625–634 (1997).

  77. 77.

    et al. Rac1 controls the formation of midline commissures and the competency of tangential migration in ventral telencephalic neurons. J. Neurosci. 27, 3884–3893 (2007). Describes the effect of RAC1 deletion in neurons, and indicates that RAC1 is not essential for axon outgrowth but does affect axon guidance, and has variable effects on neuron migration, depending on the site in the brain.

  78. 78.

    et al. Trio mediates netrin-1-induced Rac1 activation in axon outgrowth and guidance. Mol. Cell. Biol. 28, 2314–2323 (2008).

  79. 79.

    et al. The human Rho-GEF trio and its target GTPase RhoG are involved in the NGF pathway, leading to neurite outgrowth. Curr. Biol. 12, 307–312 (2002).

  80. 80.

    , , & Kalirin Dbl-homology guanine nucleotide exchange factor 1 domain initiates new axon outgrowths via RhoG-mediated mechanisms. J. Neurosci. 22, 6980–6990 (2002).

  81. 81.

    , , , & Overexpression of a neural-specific rho family GTPase, cRac1B, selectively induces enhanced neuritogenesis and neurite branching in primary neurons. J. Cell Biol. 142, 815–825 (1998).

  82. 82.

    et al. Hyperactivity and novelty-induced hyperreactivity in mice lacking Rac3. Behav. Brain Res. 186, 246–255 (2008).

  83. 83.

    Functions of Rac GTPases during neuronal development. Dev. Neurosci. 30, 47–58 (2008).

  84. 84.

    et al. Differential effects of the Rac GTPase on Purkinje cell axons and dendritic trunks and spines. Nature 379, 837–840 (1996).

  85. 85.

    , , , & Normal levels of Rac1 are important for dendritic but not axonal development in hippocampal neurons. Biol. Cell 99, 455–464 (2007).

  86. 86.

    et al. Vav1 and Rac control chemokine-promoted T lymphocyte adhesion mediated by the integrin α4β1. Mol. Biol. Cell 16, 3223–3235 (2005).

  87. 87.

    , & Rac regulates integrin-mediated spreading and increased adhesion of T lymphocytes. Mol. Cell. Biol. 18, 3936–3946 (1998).

  88. 88.

    , & Rac2 specificity in macrophage integrin signaling: potential role for Syk kinase. J. Biol. Chem. 278, 41661–41669 (2003).

  89. 89.

    , , , & Genetic deletion of Rac1 GTPase reveals its critical role in actin stress fiber formation and focal adhesion complex assembly. J. Biol. Chem. 281, 18652–18659 (2006).

  90. 90.

    et al. Rac1 deletion in mouse neutrophils has selective effects on neutrophil functions. J. Immunol. 170, 5652–5657 (2003).

  91. 91.

    , , , & Rac2-deficient hematopoietic stem cells show defective interaction with the hematopoietic microenvironment and long-term engraftment failure. Stem Cells 23, 335–346 (2005).

  92. 92.

    et al. Rac GTPases differentially integrate signals regulating hematopoietic stem cell localization. Nature Med. 11, 886–891 (2005). Describes an important function for RAC1 but not for RAC2 in the engraftment of haematopoietic stem cells into the bone marrow.

  93. 93.

    & Function of Rho family proteins in actin dynamics during phagocytosis and engulfment. Nature Cell Biol. 2, E191–E196 (2000).

  94. 94.

    , & Actin dynamics during phagocytosis. Semin. Immunol. 13, 347–355 (2001).

  95. 95.

    , , & Involvement of the Arp2/3 complex in phagocytosis mediated by FcγR or CR3. Nature Cell Biol. 2, 246–248 (2000).

  96. 96.

    & Phagocytosis of microbes: complexity in action. Annu. Rev. Immunol. 20, 825–852 (2002).

  97. 97.

    & Clearance of apoptotic cells by phagocytes. Cell Death Differ. 15, 243–250 (2008).

  98. 98.

    , , , & Opposite effects of rho family GTPases on engulfment of apoptotic cells by macrophages. J. Biol. Chem. 281, 8836–8842 (2006).

  99. 99.

    et al. Phagocytosis of apoptotic cells is regulated by a UNC-73/TRIO-MIG-2/RhoG signaling module and armadillo repeats of CED-12/ELMO. Curr. Biol. 14, 2208–2216 (2004).

  100. 100.

    , , & The role of Rac1 and Rac2 in bacterial killing. Cell. Immunol. 235, 92–97 (2005). Demonstrates that RAC1 and RAC2 have different roles in bacterial phagocytosis and in the activation of NADPH oxidase.

  101. 101.

    et al. Dominant negative mutation of the hematopoietic-specific Rho GTPase, Rac2, is associated with a human phagocyte immunodeficiency. Blood 96, 1646–1654 (2000).

  102. 102.

    & Cdc42, Rac1, and Rac2 display distinct patterns of activation during phagocytosis. Mol. Biol. Cell 15, 3509–3519 (2004).

  103. 103.

    et al. Requirements for Vav guanine nucleotide exchange factors and Rho GTPases in FcγR- and complement-mediated phagocytosis. Immunity 24, 305–316 (2006).

  104. 104.

    How human neutrophils kill and degrade microbes: an integrated view. Immunol. Rev. 219, 88–102 (2007).

  105. 105.

    Regulation of neutrophil function by Rac GTPases. Curr. Opin. Hematol. 10, 8–15 (2003).

  106. 106.

    & Rac2 is an essential regulator of neutrophil nicotinamide adenine dinucleotide phosphate oxidase activation in response to specific signaling pathways. J. Immunol. 166, 1223–1232 (2001).

  107. 107.

    et al. Rac2 is critical for neutrophil primary granule exocytosis. Blood 104, 832–839 (2004).

  108. 108.

    et al. Requirement of Rac1 in the development of cardiac hypertrophy. Proc. Natl Acad. Sci. USA 103, 7432–7437 (2006).

  109. 109.

    et al. Identifying the relative contributions of Rac1 and Rac2 to osteoclastogenesis. J. Bone Miner. Res. 23, 260–270 (2008).

  110. 110.

    , & Rac1 GTPase regulates cell genomic stability and senescence. J. Biol. Chem. 281, 38519–38528 (2006).

  111. 111.

    Reactive oxygen species in tumor progression. Front. Biosci. 10, 1881–1896 (2005).

  112. 112.

    & Why three Rho proteins? RhoA, RhoB, RhoC, and cell motility. Exp. Cell Res. 301, 43–49 (2004).

  113. 113.

    et al. RhoB-dependent modulation of postendocytic traffic in polarized Madin–Darby canine kidney cells. Traffic 8, 932–949 (2007).

  114. 114.

    , , & RhoB is dispensable for mouse development, but it modifies susceptibility to tumor formation as well as cell adhesion and growth factor signaling in transformed cells. Mol. Cell. Biol. 21, 6906–6912 (2001).

  115. 115.

    et al. RhoC is dispensable for embryogenesis and tumor initiation but essential for metastasis. Genes Dev. 19, 1974–1979 (2005).

  116. 116.

    & Regulation of endocytic traffic by rho family GTPases. Trends Cell Biol. 10, 85–88 (2000).

  117. 117.

    Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking. Trends Cell Biol. 16, 522–529 (2006).

  118. 118.

    , , & Farnesyltransferase inhibitors disrupt EGF receptor traffic through modulation of the RhoB GTPase. J. Cell Sci. 117, 3221–3231 (2004).

  119. 119.

    , & Regulation of epidermal growth factor receptor traffic by the small GTPase rhoB. Curr. Biol. 9, 955–958 (1999).

  120. 120.

    , , & RhoB regulates PDGFR-β trafficking and signaling in vascular smooth muscle cells. Arterioscler Thromb. Vasc Biol. 27, 2597–2605 (2007).

  121. 121.

    , & Not just a sink: endosomes in control of signal transduction. Curr. Opin. Cell Biol. 16, 400–406 (2004).

  122. 122.

    , , , & RhoB controls Akt trafficking and stage-specific survival of endothelial cells during vascular development. Genes Dev. 17, 2721–2732 (2003).

  123. 123.

    & RhoB in cancer suppression. Histol. Histopathol. 21, 213–218 (2006).

  124. 124.

    & Rho GTPases in cancer cell biology. FEBS Lett. 582, 2093–2101 (2008).

  125. 125.

    et al. RhoB, not RhoA, represses the transcription of the transforming growth factor β type II receptor by a mechanism involving activator protein 1. J. Biol. Chem. 277, 8500–8507 (2002).

  126. 126.

    , , , & RhoC induces differential expression of genes involved in invasion and metastasis in MCF10A breast cells. Breast Cancer Res. Treat 84, 3–12 (2004).

  127. 127.

    , , & Genomic analysis of metastasis reveals an essential role for RhoC. Nature 406, 532–535 (2000).

  128. 128.

    , , & RhoC GTPase is required for PC-3 prostate cancer cell invasion but not motility. Oncogene 25, 2285–2296 (2006).

  129. 129.

    et al. RhoC is essential for the metastasis of gastric cancer. J. Mol. Med. 85, 1149–1156 (2007).

  130. 130.

    , & Functional analysis of the contribution of RhoA and RhoC GTPases to invasive breast carcinoma. Cancer Res. 64, 8694–8701 (2004).

  131. 131.

    , & Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature 449, 682–688 (2007).

  132. 132.

    & ROCK and Dia have opposing effects on adherens junctions downstream of Rho. Nature Cell Biol. 4, 408–415 (2002).

  133. 133.

    et al. Conditional ROCK activation in vivo induces tumor cell dissemination and angiogenesis. Cancer Res. 64, 8994–9001 (2004).

  134. 134.

    et al. RhoH GTPase recruits and activates Zap70 required for T cell receptor signaling and thymocyte development. Nature Immunol. 7, 1182–1190 (2006). The first paper to show that RhoH is required for T-cell development and contributes to signalling by the T-cell receptor by associating with ZAP70.

  135. 135.

    et al. TTF, a gene encoding a novel small G protein, fuses to the lymphoma-associated LAZ3 gene by t(3;4) chromosomal translocation. Oncogene 10, 2171–2178 (1995).

  136. 136.

    et al. The hematopoiesis-specific GTP-binding protein RhoH is GTPase deficient and modulates activities of other Rho GTPases by an inhibitory function. Mol. Cell. Biol. 22, 1158–1171 (2002).

  137. 137.

    et al. Structural features of hematopoiesis-specific RhoH/ARHH gene: high diversity of 5′-UTR in different hematopoietic lineages suggests a complex post-transcriptional regulation. Gene 343, 55–68 (2004).

  138. 138.

    , , & RhoH, a hematopoietic-specific Rho GTPase, regulates proliferation, survival, migration, and engraftment of hematopoietic progenitor cells. Blood 105, 1467–1475 (2005).

  139. 139.

    et al. RhoH is important for positive thymocyte selection and T-cell receptor signaling. Blood 109, 2346–2355 (2007).

  140. 140.

    , , & Cross-talk between RhoH and Rac1 in regulation of actin cytoskeleton and chemotaxis of hematopoietic progenitor cells. Blood 111, 2597–2605 (2008).

  141. 141.

    , , , & RhoH is required to maintain the integrin LFA-1 in a nonadhesive state on lymphocytes. Nature Immunol. 5, 961–967 (2004).

  142. 142.

    et al. Rap1 is a potent activation signal for leukocyte function-associated antigen 1 distinct from protein kinase C and phosphatidylinositol-3-OH kinase. Mol. Cell. Biol. 20, 1956–1969 (2000).

  143. 143.

    & Positive and negative regulation of T-cell activation through kinases and phosphatases. Biochem. J. 371, 15–27 (2003).

  144. 144.

    , & GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors. Nature Rev. Mol. Cell Biol. 6, 167–180 (2005).

  145. 145.

    & Catching a GEF by its tail. Trends Cell Biol. 17, 36–43 (2007).

  146. 146.

    Tools of the trade: use of dominant-inhibitory mutants of Ras-family GTPases. Nature Cell Biol. 1, E25–E27 (1999).

  147. 147.

    & Current knowledge of the large RhoGAP family of proteins. Biol. Cell 99, 67–86 (2007).

  148. 148.

    & Cell type-specific functions of Rho GTPases revealed by gene targeting in mice. Trends Cell Biol. 17, 58–64 (2007).

  149. 149.

    & RhoGDI: multiple functions in the regulation of Rho family GTPase activities. Biochem. J. 390, 1–9 (2005).

  150. 150.

    & The many faces of actin: matching assembly factors with cellular structures. Nature Cell Biol. 9, 1110–1121 (2007).

  151. 151.

    TCR signaling: another Abl-bodied kinase joins the cascade. Curr. Biol. 14, R562–R564 (2004).

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Acknowledgements

We apologize to all those authors in the field whose papers we could not cite because of space limitations. We thank members of our laboratory for discussions. Work in our laboratory is supported by the Medical Research Council UK, Cancer Research UK and the European Commission Network of Excellence, MAIN.

Author information

Affiliations

  1. King's College London, Randall Division of Cell and Molecular Biophysics, Guy's Campus, London, SE1 1UL, UK  sarah.heasman@kcl.ac.uk  anne.ridley@kcl.ac.uk

    • Sarah J. Heasman
    •  & Anne J. Ridley

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Supplementary information

Glossary

Formins

A family of proteins that bind to the barbed end of actin filaments and regulate actin dynamics.

Actin-filament severing

The disruption of interactions between neighbouring actin molecules in actin filaments such that the filament is cut in two. Actin-filament severing proteins include gelsolin and villin.

Glial cells

Non-neuronal cells of the nervous system that provide support and nutrition for neurons. They also form myelin and contribute to axon guidance.

Myelin

Multiple layers of plasma membrane made by glial cells that wrap around axons and electrically insulate them. Myelin contains high levels of glycolipids and myelin-specific proteins.

Embryoid bodies

Aggregates of embryonic stem cells that are used to model the early steps of peri-implantation embryonic development, including establishment of epithelial polarity.

Barbed ends

The fast-growing ends of actin filaments, so-called because of their appearance in electron micrographs following binding of a fragment of myosin.

Capping proteins

Proteins that bind to the ends of actin filaments and prevent actin polymerization.

Spectrins

A family of large, mostly α-helical proteins that form a plasma-membrane-associated lattice that consists of spectrin tetramers and short actin filaments.

Phagocytic cup

Plasma membrane extension around a particle that is in the process of being engulfed by phagocytosis.

Farnesyl transferase

An enzyme that adds a 15-carbon isoprenoid called a farnesyl group to a Cys residue near the C terminus of a number of proteins, including several Rho GTPases. Other Rho GTPases, such as RhoA and RAC1, are modified by the addition of a 20-carbon geranylgeranyl group.

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DOI

https://doi.org/10.1038/nrm2476

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