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.

GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors

Key Points

  • Human Rho GTPases (of which there are 22 members) comprise a main branch of the Ras superfamily of small GTPases and GDP/GTP-regulated molecular switches. Rho GTPases are activated by the direct engagement of guanine nucleotide-exchange factors (GEFs), which catalyse the ejection of GTPase-bound GDP and the loading of GTP. In humans, the 70 Dbl-family proteins comprise the largest group of Rho GEFs.

  • Dbl-family proteins are characterized by a catalytic Dbl homology (DH) domain that is immediately adjacent to a regulatory C-terminal pleckstrin homology (PH) domain. DH domains engage the flexible switch regions of GTPases, which leads to their remodelling and the exchange of nucleotides. PH domains assist in this process by less well understood, and more varied, mechanisms.

  • In most scenarios, PH domains are thought to bind weakly to phosphoinositides to facilitate GDP/GTP exchange. The binding of phosphoinositides has been proposed to facilitate this exchange by causing allosteric changes within the DH–PH array. However, it is more likely that phosphoinositide binding functions to guide the precise subcellular localization of Dbl proteins, and to orientate DH–PH arrays at lipid bilayers to promote the productive engagement of membrane-bound GTPases.

  • Dbl proteins function to integrate diverse extracellular stimuli — for example, signals from heterotrimeric G-protein-coupled- or tyrosine-kinase-associated receptors that control the spatio-temporal activation of Rho GTPases. Regulatory mechanisms include the intramolecular autoinhibition of Dbl proteins, which can be relieved by various inputs — most notably, phosphorylation. It is likely that the flux of phosphoinositide levels regulates the exchange activity of Dbl proteins.

  • In addition to Dbl proteins, Dock-family human proteins (11 members), as well as bacterial proteins, expand the diversity of proteins that function as GEFs and activators of Rho GTPases.

  • The contribution of aberrant Rho-GTPase function to human disease is supported by the association of mutated Dbl-family proteins with cancer, developmental and neurological disorders. Furthermore, viral and bacterial pathogens manipulate Rho GEFs to facilitate their invasion and pathogenicity of human cells.

Abstract

Guanine nucleotide-exchange factors (GEFs) are directly responsible for the activation of Rho-family GTPases in response to diverse extracellular stimuli, and ultimately regulate numerous cellular responses such as proliferation, differentiation and movement. With 69 distinct homologues, Dbl-related GEFs represent the largest family of direct activators of Rho GTPases in humans, and they activate Rho GTPases within particular spatio-temporal contexts. The failure to do so can have significant consequences and is reflected in the aberrant function of Dbl-family GEFs in some human diseases.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Regulating Rho-GTPase activity.
Figure 2: The Dbl family.
Figure 3: Three-dimensional structures of DH–PH domains.
Figure 4: Key interactions viewed within the structure of Dbs–Cdc42.
Figure 5: Model of PH-domain-assisted guanine nucleotide exchange.
Figure 6: Rho GEFs as signalling nodes.
Figure 7: Mutation of Rho GEFs in human diseases.

Accession codes

Accessions

Protein Data Bank

References

  1. 1

    Van Aelst, L. & D'Souza-Schorey, C. Rho GTPases and signaling networks. Genes Dev. 11, 2295–2322 (1997).

    CAS  Article  Google Scholar 

  2. 2

    Bishop, A. L. & Hall, A. Rho GTPases and their effector proteins. Biochem. J. 348, 241–255 (2000).

    CAS  Article  Google Scholar 

  3. 3

    Kjoller, L. & Hall, A. Signaling to Rho GTPases. Exp. Cell Res. 253, 166–179 (1999).

    CAS  PubMed  Google Scholar 

  4. 4

    Sah, V. P., Seasholtz, T. M., Sagi, S. A. & Brown, J. H. The role of Rho in G protein-coupled receptor signal transduction. Annu. Rev. Pharmacol. Toxicol. 40, 459–489 (2000).

    CAS  Google Scholar 

  5. 5

    Evers, E. E. et al. Rho family proteins in cell adhesion and cell migration. Eur. J. Cancer 36, 1269–1274 (2000).

    CAS  Google Scholar 

  6. 6

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

    CAS  PubMed  Google Scholar 

  7. 7

    Etienne-Manneville, S. & Hall, A. Rho GTPases in cell biology. Nature 420, 629–635 (2002).

    CAS  Google Scholar 

  8. 8

    Raftopoulou, M. & Hall, A. Cell migration: Rho GTPases lead the way. Dev. Biol. 265, 23–32 (2004).

    CAS  PubMed  Google Scholar 

  9. 9

    Sahai, E. & Marshall, C. J. RHO-GTPases and cancer. Nature Rev. Cancer 2, 133–142 (2002).

    Google Scholar 

  10. 10

    Eva, A., Vecchio, G., Rao, C. D., Tronick, S. R. & Aaronson, S. A. The predicted DBL oncogene product defines a distinct class of transforming proteins. Proc. Natl Acad. Sci. USA 85, 2061–2065 (1988).

    CAS  PubMed  Google Scholar 

  11. 11

    Hart, M. J., Eva, A., Evans, T., Aaronson, S. A. & Cerione, R. A. Catalysis of guanine nucleotide exchange on the CDC42Hs protein by the dbl oncogene product. Nature 354, 311–314 (1991). Seminal paper showing the first direct activation of a Rho GTPase by a Dbl protein.

    CAS  PubMed  Google Scholar 

  12. 12

    Schmidt, A. & Hall, A. Guanine nucleotide exchange factors for Rho GTPases: turning on the switch. Genes Dev. 16, 1587–1609 (2002).

    CAS  Google Scholar 

  13. 13

    Worthylake, D. K., Rossman, K. L. & Sondek, J. Crystal structure of Rac1 in complex with the guanine nucleotide exchange region of Tiam1. Nature 408, 682–688 (2000). Original structure of a DH–PH-domain fragment bound to a nucleotide-depleted GTPase and used to define the mechanism of nucleotide exchange.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Liu, X. et al. NMR structure and mutagenesis of the N-terminal Dbl homology domain of the nucleotide exchange factor Trio. Cell 95, 269–277 (1998).

    CAS  PubMed  Google Scholar 

  15. 15

    Soisson, S. M., Nimnual, A. S., Uy, M., Bar-Sagi, D. & Kuriyan, J. Crystal structure of the Dbl and pleckstrin homology domains from the human Son of sevenless protein. Cell 95, 259–268 (1998). The first structure showing the interdomain arrangement of a DH domain and its associated PH domain.

    CAS  PubMed  Google Scholar 

  16. 16

    Aghazadeh, B. et al. Structure and mutagenesis of the Dbl homology domain. Nature Struct. Biol. 5, 1098–1107 (1998).

    CAS  PubMed  Google Scholar 

  17. 17

    Aghazadeh, B., Lowry, W. E., Huang, X. Y. & Rosen, M. K. Structural basis for relief of autoinhibition of the Dbl homology domain of proto-oncogene Vav by tyrosine phosphorylation. Cell 102, 625–633 (2000). This structure of Vav highlights the autoinhibition of the DH domain by steric exclusion, which is relieved on phosphorylation.

    CAS  Google Scholar 

  18. 18

    Rossman, K. L. et al. A crystallographic view of interactions between Dbs and Cdc42, PH domain-assisted guanine nucleotide exchange. EMBO J. 21, 1315–1326 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Snyder, J. T. et al. Structural basis for the selective activation of Rho GTPases by Dbl exchange factors. Nature Struct. Biol. 9, 468–475 (2002).

    CAS  PubMed  Google Scholar 

  20. 20

    Worthylake, D. K., Rossman, K. L. & Sondek, J. Crystal structure of the DH/PH fragment of Dbs without bound GTPase. Structure 12, 1078–1086 (2004).

    PubMed  Google Scholar 

  21. 21

    Skowronek, K. R., Guo, F., Zheng, Y. & Nassar, N. The C-terminal basic tail of RhoG assists the guanine nucleotide exchange factor Trio in binding to phospholipids. J. Biol. Chem. 279, 37895–37907 (2004).

    CAS  PubMed  Google Scholar 

  22. 22

    Kristelly, R., Gao, G. & Tesmer, J. J. Structural determinants of RhoA binding and nucleotide exchange in leukemia-associated RhoGEF. J. Biol. Chem. 279, 47352–47362 (2004).

    CAS  PubMed  Google Scholar 

  23. 23

    Sondermann, H., Soisson, S. M., Boykevisch, S., Yang, S. S., Bar-Sagi, D. & Kuriyan, J. Structural analysis of autoinhibition in the Ras activator Son of sevenless. Cell 119, 393–405 (2004).

    CAS  PubMed  Google Scholar 

  24. 24

    Boriack-Sjodin, P. A., Margarit, S. M., Bar-Sagi, D. & Kuriyan, J. The structural basis of the activation of Ras by Sos. Nature 394, 337–343 (1998).

    CAS  Google Scholar 

  25. 25

    Goldberg, J. Structural basis for activation of ARF GTPase, mechanisms of guanine nucleotide exchange and GTP-myristoyl switching. Cell 95, 237–248 (1998).

    CAS  PubMed  Google Scholar 

  26. 26

    Renault, L., Kuhlmann, J., Henkel, A. & Wittinghofer, A. Structural basis for guanine nucleotide exchange on Ran by the regulator of chromosome condensation (RCC1). Cell 105, 245–255 (2001).

    CAS  PubMed  Google Scholar 

  27. 27

    Shimizu, T. et al. An open conformation of switch I revealed by the crystal structure of a Mg2+-free form of RHOA complexed with GDP. Implications for the GDP/GTP exchange mechanism. J. Biol. Chem. 275, 18311–18317 (2000).

    CAS  PubMed  Google Scholar 

  28. 28

    Buchwald, G. et al. Structural basis for the reversible activation of a Rho protein by the bacterial toxin SopE. EMBO J. 21, 3286–3295 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Rossman, K. L. et al. Functional analysis of cdc42 residues required for guanine nucleotide exchange. J. Biol. Chem. 277, 50893–50898 (2002).

    CAS  PubMed  Google Scholar 

  30. 30

    Karnoub, A. E. et al. Molecular basis for Rac1 recognition by guanine nucleotide exchange factors. Nature Struct. Biol. 8, 1037–1041 (2001).

    CAS  PubMed  Google Scholar 

  31. 31

    Cheng, L. et al. RhoGEF specificity mutants implicate RhoA as a target for Dbs transforming activity. Mol. Cell. Biol. 22, 6895–6905 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Rossman, K. L. & Campbell, S. L. Bacterial expressed DH and DH/PH domains. Methods Enzymol. 325, 25–38 (2000).

    CAS  PubMed  Google Scholar 

  33. 33

    Rossman, K. L. et al. Multifunctional roles for the PH domain of Dbs in regulating Rho GTPase activation. J. Biol. Chem. 278, 18393–18400 (2003).

    CAS  PubMed  Google Scholar 

  34. 34

    Ron, D. et al. A region of proto-dbl essential for its transforming activity shows sequence similarity to a yeast cell cycle gene, CDC24, and the human breakpoint cluster gene, bcr. New Biol. 3, 372–379 (1991).

    CAS  PubMed  Google Scholar 

  35. 35

    Whitehead, I. P., Kirk, H., Tognon, C., Trigo-Gonzalez, G. & Kay, R. Expression cloning of lfc, a novel oncogene with structural similarities to guanine nucleotide exchange factors and to the regulatory region of protein kinase C. J. Biol. Chem. 271, 18388–18395 (1995).

    Google Scholar 

  36. 36

    Ferguson, K. M., Lemmon, M. A., Schlessinger, J. & Sigler, P. B. Structure of the high affinity complex of inositol trisphosphate with a phospholipase C pleckstrin homology domain. Cell 83, 1037–1046 (1995).

    CAS  PubMed  Google Scholar 

  37. 37

    Snyder, J. T. et al. Quantitative analysis of the effect of phosphoinositide interactions on the function of Dbl family proteins. J. Biol. Chem. 276, 45868–45875 (2001).

    CAS  PubMed  Google Scholar 

  38. 38

    Chen, R. H., Corbalan-Garcia, S. & Bar-Sagi, D. The role of the PH domain in the signal-dependent membrane targeting of Sos. EMBO J. 16, 1351–1359 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Baumeister, M. A. et al. Loss of phosphatidylinositol 3-phosphate binding by the C-terminal Tiam-1 pleckstrin homology domain prevents in vivo Rac1 activation without affecting membrane targeting. J. Biol. Chem. 278, 11457–11464 (2003).

    CAS  PubMed  Google Scholar 

  40. 40

    Stam, J. C. et al. Targeting of Tiam1 to the plasma membrane requires the cooperative function of the N-terminal pleckstrin homology domain and an adjacent protein interaction domain. J. Biol. Chem. 272, 28447–28454 (1997).

    CAS  PubMed  Google Scholar 

  41. 41

    Das, B. et al. Control of intramolecular interactions between the pleckstrin homology and Dbl homology domains of Vav and Sos1 regulates Rac binding. J. Biol. Chem. 275, 15074–15081 (2000).

    CAS  Google Scholar 

  42. 42

    Crompton, A. M. et al. Regulation of Tiam1 nucleotide exchange activity by pleckstrin domain binding ligands. J. Biol. Chem. 275, 25751–25759 (2000).

    CAS  PubMed  Google Scholar 

  43. 43

    Russo, C. et al. Modulation of oncogenic DBL activity by phosphoinositol phosphate binding to pleckstrin homology domain. J. Biol. Chem. 276, 19524–19531 (2001).

    CAS  PubMed  Google Scholar 

  44. 44

    Welch, H. C. et al. P-Rex1, a PtdIns(3,4,5)P3- and Gβγ-regulated guanine-nucleotide exchange factor for Rac. Cell 108, 809–821 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Kubiseski, T. J., Culotti, J. & Pawson, T. Functional analysis of the Caenorhabditis elegans UNC-73B PH domain demonstrates a role in activation of the Rac GTPase in vitro and axon guidance in vivo. Mol. Cell. Biol. 23, 6823–6835 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    Skowronek, K. R., Guo, F., Zheng, Y. & Nassar, N. The C-terminal basic tail of RhoG assists the guanine nucleotide exchange factor trio in binding to phospholipids. J. Biol. Chem. 279, 37895–37907 (2004).

    CAS  PubMed  Google Scholar 

  47. 47

    Vanni, C. et al. Phosphorylation-independent membrane relocalization of ezrin following association with Dbl in vivo. Oncogene 23, 4098–4106 (2004).

    CAS  PubMed  Google Scholar 

  48. 48

    Bellanger, J. M. et al. The Rac1- and RhoG-specific GEF domain of Trio targets filamin to remodel cytoskeletal actin. Nature Cell Biol. 2, 888–892 (2000).

    CAS  PubMed  Google Scholar 

  49. 49

    Seipel, K., O'Brien, S. P., Iannotti, E., Medley, Q. G. & Streuli, M. Tara, a novel F-actin binding protein, associates with the Trio guanine nucleotide exchange factor and regulates actin cytoskeletal organization. J. Cell Sci. 114, 389–399 (2001).

    CAS  PubMed  Google Scholar 

  50. 50

    Rumenapp, U., Freichel-Blomquist, A., Wittinghofer, B., Jakobs, K. H. & Wieland, T. A mammalian Rho-specific guanine-nucleotide exchange factor (p164-RhoGEF) without a pleckstrin homology domain. Biochem. J. 366, 721–728 (2002).

    PubMed  PubMed Central  Google Scholar 

  51. 51

    Takei, K., Slepnev, V. I., Haucke, V. & De Camilli, P. Functional partnership between amphiphysin and dynamin in clathrin-mediated endocytosis. Nature Cell Biol. 1, 33–39 (1999).

    CAS  PubMed  Google Scholar 

  52. 52

    Han, J. et al. Lck regulates Vav activation of members of the Rho family of GTPases. Mol. Cell. Biol. 17, 1346–1353 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Crespo, P., Schuebel, K. E., Ostrom, A. A., Gutkind, J. S. & Bustelo, X. R. Phosphotyrosine-dependent activation of Rac-1 GDP/GTP exchange by the vav proto-oncogene product. Nature 385, 169–172 (1997). Although it had been known for years that Vav was phosphorylated, this paper describes the first instance of the activation of the nucleotide-exchange potential of a Dbl protein by phosphorylation.

    CAS  Google Scholar 

  54. 54

    Fleming, I. N., Elliott, C. M., Buchanan, F. G., Downes, C. P. & Exton, J. H. Ca2+/calmodulin-dependent protein kinase II regulates Tiam1 by reversible protein phosphorylation. J. Biol. Chem. 274, 12753–12758 (1999).

    CAS  PubMed  Google Scholar 

  55. 55

    Fleming, I. N., Elliott, C. M., Collard, J. G. & Exton, J. H. Lysophosphatidic acid induces threonine phosphorylation of Tiam1 in Swiss 3T3 fibroblasts via activation of protein kinase C. J. Biol. Chem. 272, 33105–33110 (1997).

    CAS  PubMed  Google Scholar 

  56. 56

    Servitja, J. M., Marinissen, M. J., Sodhi, A., Bustelo, X. R. & Gutkind, J. S. Rac1 function is required for Src-induced transformation. Evidence of a role for Tiam1 and Vav2 in Rac activation by Src. J. Biol. Chem. 278, 34339–34346 (2003).

    CAS  PubMed  Google Scholar 

  57. 57

    Kiyono, M., Kaziro, Y. & Satoh, T. Induction of Rac-guanine nucleotide exchange activity of Ras-GRF1/CDC25(Mm) following phosphorylation by the nonreceptor tyrosine kinase Src. J. Biol. Chem. 275, 5441–5446 (2000).

    CAS  Google Scholar 

  58. 58

    Kesavapany, S. et al. p35/cyclin-dependent kinase 5 phosphorylation of ras guanine nucleotide releasing factor 2 (RasGRF2) mediates Rac-dependent extracellular signal-regulated kinase 1/2 activity, altering RasGRF2 and microtubule-associated protein 1b distribution in neurons. J. Neurosci. 24, 4421–4431 (2004).

    CAS  PubMed  Google Scholar 

  59. 59

    Schmidt, A. & Hall, A. The Rho exchange factor Net1 is regulated by nuclear sequestration. J. Biol. Chem. 277, 14581–14588 (2002).

    CAS  PubMed  Google Scholar 

  60. 60

    Tatsumoto, T., Xie, X., Blumenthal, R., Okamoto, I. & Miki, T. Human ECT2 is an exchange factor for Rho GTPases, phosphorylated in G2/M phases, and involved in cytokinesis. J. Cell Biol. 147, 921–928 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Krendel, M., Zenke, F. T. & Bokoch, G. M. Nucleotide exchange factor GEF-H1 mediates cross-talk between microtubules and the actin cytoskeleton. Nature Cell Biol. 4, 294–301 (2002).

    CAS  PubMed  Google Scholar 

  62. 62

    Matsuzawa, T., Kuwae, A., Yoshida, S., Sasakawa, C. & Abe, A. Enteropathogenic Escherichia coli activates the RhoA signaling pathway via the stimulation of GEF-H1. EMBO J. 23, 3570–3582 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Michiels, F. et al. 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. J. Cell Biol. 137, 387–398 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Buchanan, F. G., Elliot, C. M., Gibbs, M. & Exton, J. H. Translocation of the Rac1 guanine nucleotide exchange factor Tiam1 induced by platelet-derived growth factor and lysophosphatidic acid. J. Biol. Chem. 275, 9742–9748 (2000).

    CAS  PubMed  Google Scholar 

  65. 65

    Li, Z et al. Directional sensing requires Gβγ-mediated PAK1 and PIXα-dependent activation of Cdc42. Cell 114, 215–227 (2003). α-Pix is shown to coordinate PAK, Gβγ and Cdc42 in a molecular complex that is necessary for proper chemotaxis.

    CAS  Google Scholar 

  66. 66

    Obermeier, A. et al. PAK promotes morphological changes by acting upstream of Rac. EMBO J. 17, 4328–4339 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Zhao, Z. S., Manser, E., Loo, T. H. & Lim, L. Coupling of PAK-interacting exchange factor PIX to GIT1 promotes focal complex disassembly. Mol. Cell. Biol. 20, 6354–6363 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Park, H. S. et al. Sequential activation of phosphatidylinositol 3-kinase, βPix, Rac1, and Nox1 in growth factor-induced production of H2O2 . Mol. Cell. Biol. 24, 4384–4394 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Hussain, N. K. et al. Endocytic protein intersectin-l regulates actin assembly via Cdc42 and N-WASP. Nature Cell Biol. 3, 927–932 (2001).

    CAS  PubMed  Google Scholar 

  70. 70

    Buchsbaum, R. J., Connolly, B. A. & Feig, L. A. Interaction of Rac exchange factors Tiam1 and Ras-GRF1 with a scaffold for the p38 mitogen-activated protein kinase cascade. Mol. Cell. Biol. 22, 4073–4085 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Buchsbaum, R. J., Connolly, B. A. & Feig, L. A. Regulation of p70 S6 kinase by complex formation between the Rac guanine nucleotide exchange factor (Rac-GEF) Tiam1 and the scaffold spinophilin. J. Biol. Chem. 278, 18833–18841 (2003).

    CAS  PubMed  Google Scholar 

  72. 72

    Kozasa, T. et al. p115 RhoGEF, a GTPase activating protein for Gα12 and Gα13 . Science 280, 2109–2111 (1998).

    CAS  Google Scholar 

  73. 73

    Suzuki, N., Nakamura, S., Mano, H. & Kozasa, T. G Gα12 activates Rho GTPase through tyrosine-phosphorylated leukemia-associated RhoGEF. Proc. Natl Acad. Sci. USA 100, 733–738 (2003).

    CAS  PubMed  Google Scholar 

  74. 74

    Hart, M. J. et al. Direct stimulation of the guanine nucleotide exchange activity of p115 RhoGEF by Gα13 . Science 280, 2112–2114 (1998). This paper was the first to describe the important physiological link between GPCR-mediated activation of Gα 13 subunits and the activation of RhoA by p115-RhoGEF. Close homologues of p115-RhoGEF behave similarly.

    CAS  Google Scholar 

  75. 75

    Chen, Z., Singer, W. D., Wells, C. D., Sprang, S. R. & Sternweis, P. C. Mapping the Gα13 binding interface of the rgRGS domain of p115RhoGEF. J. Biol. Chem. 278, 9912–9919 (2003).

    CAS  PubMed  Google Scholar 

  76. 76

    Wells, C. D. et al. Mechanisms for reversible regulation between G13 and Rho exchange factors. J. Biol. Chem. 277, 1174–1181 (2002).

    CAS  PubMed  Google Scholar 

  77. 77

    Biddlecome, G. H., Berstein, G. & Ross, E. M. Regulation of phospholipase C-β1 by Gq and m1 muscarinic cholinergic receptor. J. Biol. Chem. 271, 7999–8007 (1996).

    CAS  PubMed  Google Scholar 

  78. 78

    Berstein, G. et al. Phospholipase C-β1 is a GTPase-activating protein for Gq/11, its physiologic regulator. Cell 70, 411–418 (1992).

    CAS  PubMed  Google Scholar 

  79. 79

    Zhong, H. et al. A spatial focusing model for G protein signals. Regulator of G protein signaling (RGS) protein-mediated kinetic scaffolding. J. Biol. Chem. 278, 7278–7284 (2003).

    CAS  PubMed  Google Scholar 

  80. 80

    Shamah, S. M. et al. EphA receptors regulate growth cone dynamics through the novel guanine nucleotide exchange factor ephexin. Cell 105, 233–244 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

    Ogita, H. et al. EphA4-mediated Rho activation via Vsm-RhoGEF expressed specifically in vascular smooth muscle cells. Circ. Res. 93, 23–31 (2003).

    CAS  PubMed  Google Scholar 

  82. 82

    Lambert, J. M. et al. Tiam1 mediates Ras activation of Rac by a PI(3)K-independent mechanism. Nature Cell Biol. 4, 621–625 (2002).

    CAS  Google Scholar 

  83. 83

    Innocenti, M. et al. Mechanisms through which Sos-1 coordinates the activation of Ras and Rac. J. Cell Biol. 156, 125–136 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Cheng, L., Mahon, G. M., Kostenko, E. V. & Whitehead, I. P. Pleckstrin homology domain-mediated activation of the Rho-specific guanine nucleotide exchange factor Dbs by Rac1. J. Biol. Chem. 279, 12786–12793 (2004).

    CAS  PubMed  Google Scholar 

  85. 85

    Curtis, C. et al. Scambio, a novel guanine nucleotide exchange factor for Rho. Mol. Cancer 3, 10 (2004).

    PubMed  PubMed Central  Google Scholar 

  86. 86

    Gulli, M. P. et al. Phosphorylation of the Cdc42 exchange factor Cdc24 by the PAK-like kinase Cla4 may regulate polarized growth in yeast. Mol. Cell 6, 1155–1167 (2000).

    CAS  Google Scholar 

  87. 87

    Shimada, Y., Gulli, M. P. & Peter, M. Nuclear sequestration of the exchange factor Cdc24 by Far1 regulates cell polarity during yeast mating. Nature Cell Biol. 2, 117–124 (2000).

    CAS  Google Scholar 

  88. 88

    Butty, A. C., Pryciak, P. M., Huang, L. S., Herskowitz, I. & Peter, M. The role of Far1p in linking the heterotrimeric G protein to polarity establishment proteins during yeast mating. Science 282, 1511–1516 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

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

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Shimada, Y., Wiget, P., Gulli, M. P., Bi, E. & Peter, M. The nucleotide exchange factor Cdc24p may be regulated by auto-inhibition. EMBO J. 23, 1051–1062 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    Wiget, P., Shimada, Y., Butty, A. C., Bi, E. & Peter, M. Site-specific regulation of the GEF Cdc24p by the scaffold protein Far1p during yeast mating. EMBO J. 23, 1063–1074 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    Bose, I. et al. Assembly of scaffold-mediated complexes containing Cdc42p, the exchange factor Cdc24p, and the effector Cla4p required for cell cycle-regulated phosphorylation of Cdc24p. J. Biol. Chem. 276, 7176–7186 (2001).

    CAS  Google Scholar 

  93. 93

    Boettner, B. & Van Aelst, L. The role of Rho GTPases in disease development. Gene 286, 155–174 (2002).

    CAS  PubMed  Google Scholar 

  94. 94

    Turner, M. et al. A requirement for the Rho-family GTP exchange factor Vav in positive and negative selection of thymocytes. Immunity 7, 451–460 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Doody, G. M. et al. Signal transduction through Vav-2 participates in humoral immune responses and B cell maturation. Nature Immunol. 2, 542–547 (2001).

    CAS  Google Scholar 

  96. 96

    Tedford, K. et al. Compensation between Vav-1 and Vav-2 in B cell development and antigen receptor signaling. Nature Immunol. 2, 548–555 (2001).

    CAS  Google Scholar 

  97. 97

    Fujikawa, K. et al. Vav1/2/3-null mice define an essential role for Vav family proteins in lymphocyte development and activation but a differential requirement in MAPK signaling in T and B cells. J. Exp. Med. 198, 1595–1608 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    O'Brien, S. P. et al. Skeletal muscle deformity and neuronal disorder in Trio exchange factor-deficient mouse embryos. Proc. Natl Acad. Sci. USA 97, 12074–12078 (2000).

    CAS  PubMed  Google Scholar 

  99. 99

    Advani, A. S. & Pendergast, A. M. Bcr–Abl variants: biological and clinical aspects. Leuk. Res. 26, 713–720 (2002).

    CAS  PubMed  Google Scholar 

  100. 100

    Kourlas, P. J. et al. Identification of a gene at 11q23 encoding a guanine nucleotide exchange factor: evidence for its fusion with MLL in acute myeloid leukemia. Proc. Natl Acad. Sci. USA 97, 2145–2150 (2000).

    CAS  PubMed  Google Scholar 

  101. 101

    Engers, R. et al. Tiam1 mutations in human renal-cell carcinomas. Int. J. Cancer 88, 369–376 (2000).

    CAS  PubMed  Google Scholar 

  102. 102

    Debily, M. A. et al. Expression and molecular characterization of alternative transcripts of the ARHGEF5/TIM oncogene specific for human breast cancer. Hum. Mol. Genet. 13, 323–334 (2004).

    CAS  PubMed  Google Scholar 

  103. 103

    Malliri, A. et al. Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours. Nature 417, 867–871 (2002). Showed the importance of Tiam1 in facilitating Ras-mediated tumour formation in Tiam1-deficient mice.

    CAS  PubMed  Google Scholar 

  104. 104

    Kawasaki, Y. et al. Asef, a link between the tumor suppressor APC and G-protein signaling. Science 289, 1194–1197 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    Kawasaki, Y., Sato, R. & Akiyama, T. Mutated APC and Asef are involved in the migration of colorectal tumour cells. Nature Cell Biol. 5, 211–215 (2003).

    CAS  PubMed  Google Scholar 

  106. 106

    Booden, M. A., Eckert, L. B., Der, C. J. & Trejo, J. Persistent signaling by dysregulated thrombin receptor trafficking promotes breast carcinoma cell invasion. Mol. Cell. Biol. 24, 1990–1999 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. 107

    Pasteris, N. G. et al. Isolation and characterization of the faciogenital dysplasia (Aarskog–Scott syndrome) gene, a putative Rho/Rac guanine nucleotide exchange factor. Cell 79, 669–678 (1994).

    CAS  PubMed  Google Scholar 

  108. 108

    Orrico, A. et al. Phenotypic and molecular characterisation of the Aarskog–Scott syndrome, a survey of the clinical variability in light of FGD1 mutation analysis in 46 patients. Eur. J. Hum. Genet. 12, 16–23 (2004).

    CAS  PubMed  Google Scholar 

  109. 109

    Hadano, S. et al. A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nature Genet. 29, 166–173 (2001).

    CAS  PubMed  Google Scholar 

  110. 110

    Eymard-Pierre, E. et al. Infantile-onset ascending hereditary spastic paralysis is associated with mutations in the alsin gene. Am. J. Hum. Genet. 71, 518–527 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111

    Gros-Louis, F. et al. An ALS2 gene mutation causes hereditary spastic paraplegia in a Pakistani kindred. Ann. Neurol. 53, 144–145 (2003).

    CAS  PubMed  Google Scholar 

  112. 112

    Mahana, W., Zhao, T. M., Teller, R., Robinson, M. A. & Kindt, T. J. Genes in the pX region of human T cell leukemia virus I influence Vav phosphorylation in T cells. Proc. Natl Acad. Sci. USA 95, 1782–1787 (1998).

    CAS  PubMed  Google Scholar 

  113. 113

    Fackler, O. T., Luo, W., Geyer, M., Alberts, A. S. & Peterlin, B. M. Activation of Vav by Nef induces cytoskeletal rearrangements and downstream effector functions. Mol. Cell 3, 729–739 (1999).

    CAS  PubMed  Google Scholar 

  114. 114

    Zhang, H. et al. Functional interaction between the cytoplasmic leucine-zipper domain of HIV-1 gp41 and p115-RhoGEF. Curr. Biol. 9, 1271–1274 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115

    Brugnera, E. et al. Unconventional Rac-GEF activity is mediated through the Dock180–ELMO complex. Nature Cell Biol. 4, 574–582 (2002). Provides biochemical evidence that Dock180, although lacking a DH domain, can have Rho GEF activity.

    CAS  Google Scholar 

  116. 116

    Namekata, K., Enokido, Y., Iwasawa, K. & Kimura, H. MOCA induces membrane spreading by activating Rac1. J. Biol. Chem. 279, 14331–14337 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Meller, N., Irani-Tehrani, M., Kiosses, W. B., Del Pozo, M. A. & Schwartz, M. A. Zizimin1, a novel Cdc42 activator, reveals a new GEF domain for Rho proteins. Nature Cell Biol. 4, 639–647 (2002).

    CAS  PubMed  Google Scholar 

  118. 118

    Shinohara, M. et al. SWAP-70 is a guanine-nucleotide-exchange factor that mediates signalling of membrane ruffling. Nature 416, 759–763 (2002).

    CAS  Google Scholar 

  119. 119

    Mavrakis, K. J., McKinlay, K. J., Jones, P. & Sablitzky, F. DEF6, a novel PH–DH-like domain protein, is an upstream activator of the Rho GTPases Rac1, Cdc42, and RhoA. Exp. Cell Res. 294, 335–344 (2004).

    CAS  PubMed  Google Scholar 

  120. 120

    Hardt, W. D., Chen, L. M., Schuebel, K. E., Bustelo, X. R. & Galan, J. E. S. typhimurium encodes an activator of Rho GTPases that induces membrane ruffling and nuclear responses in host cells. Cell 93, 815–826 (1998). Shows that bacteria possess unique proteins that function as RhoGEFs to facilitate their invasion of human host cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    Friebel, A. et al. SopE and SopE2 from Salmonella typhimurium activate different sets of RhoGTPases of the host cell. J. Biol. Chem. 276, 34035–34040 (2001).

    CAS  Google Scholar 

  122. 122

    Margarit, S. M. et al. Structural evidence for feedback activation by Ras·GTP of the Ras-specific nucleotide exchange factor SOS. Cell 112, 685–695 (2003).

    CAS  PubMed  Google Scholar 

  123. 123

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

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Kaartinen, V. et al. Abnormal function of astroglia lacking Abr and Bcr RacGAPs. Development 128, 4217–4227 (2001).

    CAS  PubMed  Google Scholar 

  125. 125

    Kaartinen, V., Nagy, A., Gonzalez-Gomez, I., Groffen, J. & Heisterkamp, N. Vestibular dysgenesis in mice lacking Abr and Bcr Cdc42/RacGAPs. Dev. Dyn. 223, 517–525 (2002).

    CAS  PubMed  Google Scholar 

  126. 126

    Voncken, J. W. et al. Increased neutrophil respiratory burst in bcr-null mutants. Cell 80, 719–728 (1995).

    CAS  PubMed  Google Scholar 

  127. 127

    Hirsch, E. et al. Defective dendrite elongation but normal fertility in mice lacking the Rho-like GTPase activator Dbl. Mol. Cell. Biol. 22, 3140–3148 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. 128

    Brambilla, R. et al. A role for the Ras signalling pathway in synaptic transmission and long-term memory. Nature 390, 281–286 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 129

    Giese, K. P. et al. Hippocampus-dependent learning and memory is impaired in mice lacking the Ras-guanine-nucleotide releasing factor 1 (Ras-GRF1). Neuropharm. 41, 791–800 (2001).

    CAS  Google Scholar 

  130. 130

    Font de Mora, J. et al. Ras-GRF1 signaling is required for normal β-cell development and glucose homeostasis. EMBO J. 22, 3039–3049 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131

    Fernandez-Medarde, A. et al. Targeted disruption of Ras-Grf2 shows its dispensability for mouse growth and development. Mol. Cell. Biol. 22, 2498–2504 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132

    Wang, D. Z. et al. Mutation in Sos1 dominantly enhances a weak allele of the EGFR, demonstrating a requirement for Sos1 in EGFR signaling and development. Genes Dev. 11, 309–320 (1997).

    CAS  PubMed  Google Scholar 

  133. 133

    Qian, X. et al. The Sos1 and Sos2 Ras-specific exchange factors: differences in placental expression and signaling properties. EMBO J. 19, 642–654 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. 134

    Esteban, L. M. et al. Ras-guanine nucleotide exchange factor sos2 is dispensable for mouse growth and development. Mol. Cell. Biol. 20, 6410–6413 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135

    Zhang, R., Alt, F. W., Davidson, L., Orkin, S. H. & Swat, W. Defective signalling through the T- and B-cell antigen receptors in lymphoid cells lacking the vav proto-oncogene. Nature 374, 470–473 (1995).

    CAS  Google Scholar 

  136. 136

    Tarakhovsky, A. et al. Defective antigen receptor-mediated proliferation of B and T cells in the absence of Vav. Nature 374, 467–470 (1995).

    CAS  Google Scholar 

  137. 137

    Fischer, K. D. et al. Defective T-cell receptor signalling and positive selection of Vav-deficient CD4+ CD8+ thymocytes. Nature 374, 474–477 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to apologize for not being able to cite original work of many colleagues due to space constraints. Our studies are supported by grants to C.J.D. and to J.S from the National Institutes of Health. K.L.R. was supported by a fellowship from the National Cancer Institute.

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Channing J. Der or John Sondek.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

Entrez

SopE

SopE2

Interpro

Bar domain

DH domain

PH domain

Saccharomyces genome database

Cdc24

Cdc25

Swiss-Prot

Cdc42

Dbl

Dbs

ITSN-L

LARG

Miro1

p115-RhoGEF

PDZ-RhoGEF

α-Pix

β-Pix

Rac1

Ras

Rcc1

RhoA

RhoBTB1

RhoD

RhoE

RhoF

RhoG

RhoH

RhoV

Sos1

Tara

Tiam1

Trio

Vav1

FURTHER INFORMATION

SMART database

Protein Data Bank

Glossary

G-PROTEIN-COUPLED RECEPTOR

A seven-helix membrane-spanning cell-surface receptor that signals through heterotrimeric GTP-binding and -hydrolysing G proteins to stimulate or inhibit the activity of a downstream enzyme.

PHAGOCYTOSIS

An actin-dependent process by which cells engulf external particulate material by extension and fusion of pseudopods.

CYTOKINESIS

The separation of a cell into two, which is marked by ingression of the cleavage 'furrow' between two segregated masses of genomic DNA.

PLECKSTRIN HOMOLOGY (PH) DOMAIN

A sequence of 100 amino acids that is present in many signalling molecules and that binds to lipid products of phosphatidylinositol 3-kinase. Pleckstrin is a protein of unknown function that was originally identified in platelets. It is a principal substrate of protein kinase C.

SWITCH REGIONS

Regions of nucleotide-binding proteins that have different conformations in the triphosphate-bound, compared to the diphosphate-bound, state.

α-HELIX

An element of protein secondary structure in which hydrogen bonds that lie along the backbone of a single polypeptide cause the chain to form a right-handed helix.

310 HELIX

A tighter, less stable helix than the α-helix, with three residues per turn, which form hydrogen-bonded loops of 10 atoms.

HOMOLOGY MODELLING

Prediction of the tertiary structure of an unknown protein using a known three-dimensional structure of a homologous protein.

CLEAVAGE FURROW

An invagination of the plasma membrane in the division plane of an animal cell that contains a contractile ring, and that leads to scission of the daughter cells.

CHEMOTAXIS

A type of migration that is stimulated by a gradient of a chemical stimulant or chemoattractant.

SCAFFOLD

A protein that functions as a support to assemble a multiprotein complex.

SRC-HOMOLOGY-3 (SH3) DOMAIN

A protein module of 80 amino acids that is present in a range of proteins and that was first identified in the protein kinase Src. SH3 domains interact with proline-rich sequences that usually contain a PXXXPXR motif (where X is any amino acid).

PDZ DOMAIN

(Postsynaptic-density protein of 95 kDa, Discs large and Zona occludens-1). A region that is present in several scaffolding proteins and that is named after the founding members of this protein family. PDZ domains bind to specific short amino-acid sequences that are found in several proteins at, or outside, junctions.

HETEROTRIMERIC G PROTEIN

A complex of three proteins (Gα, Gβ and Gγ). Whereas Gβ and Gγ form a tight complex, Gα is part of the complex in its inactive, GDP-bound, form but dissociates in its active, GTP-bound, form. Both Gα and Gβγ can transmit downstream signals after activation.

GROWTH CONE

Motile tip of the axon or dendrite of a growing nerve cell, which spreads out into a large cone-shaped appendage.

BUD SITES

Cell-wall sites where the yeast S. cerevisiae undergoes reproduction by initiation of budding.

MATING PROJECTION

A specialized structure that is formed by vegetative S. cerevisiae to initiate polarized cell growth, and to allow polarized mating cells to signal to one another.

DOMINANT NEGATIVE

A defective protein that retains interaction capabilities and so distorts or competes with normal proteins.

EXPRESSION-LIBRARY SCREENS

A genome-wide cloning strategy that uses a biological gain-of-function (for example, uncontrolled growth) to isolate and identify genes with specific cellular activities.

C2 DOMAIN

Better known as Ca2+-dependent phospholipid-binding domains in proteins such as conventional protein kinase C isoforms and synaptotagmin. The C2 domain is another modular signalling domain that can induce membrane–protein, or protein–protein, interactions, after binding several Ca2+ ions. There are C2 domains that do not bind Ca2+ but constitutively bind to a membrane, others that might be involved in Ca2+-independent protein–protein interactions, and some that might bind inositol polyphosphates.

ARMADILLO (ARM) ARRAY

The armadillo repeat is an 40-amino-acid-long tandemly repeated sequence motif that was first identified in the Drosophila melanogaster segment polarity gene armadillo.

SQUAMOUS CELL CARCINOMA

A carcinoma that develops from the layers of thin, flat squamous cells of the epithelium.

CALPONIN-HOMOLOGY DOMAIN

A protein domain, which is often found tandemly arrayed, that functions in the binding of actin.

CYTOPATHICITY

The ability of certain viruses to cause degenerative changes in their host cells as a consequence of viral invasion and multiplication. This might include changes in cell morphology, cell lysis, cell death and altered cell–cell interactions.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Rossman, K., Der, C. & Sondek, J. GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors. Nat Rev Mol Cell Biol 6, 167–180 (2005). https://doi.org/10.1038/nrm1587

Download citation

Further reading

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