Off the beaten paths: Alternative and crosstalk regulation of Rho GTPases

FASEB Journal

Volumn 26, Issue 2, 2012, Pages 469-479

  Boulter, Etienne ^a   Estrach, Soline ^a   Garcia Mata, Rafael ^b   Féral, Chloé C ^a  

^a INSERM   (France)

^b UNIVERSITY OF NORTH CAROLINA   (United States)

Author keywords

Isoprenylation; Phosphorylation; Post translational modification; RhoGEF; SUMOylation

Indexed keywords

GUANINE NUCLEOTIDE EXCHANGE FACTOR; GUANOSINE TRIPHOSPHATASE ACTIVATING PROTEIN; RHO FACTOR; RHO GUANINE NUCLEOTIDE BINDING PROTEIN;

ENZYME REGULATION; GENE SWITCHING; HUMAN; LIPID MEMBRANE; PRIORITY JOURNAL; PROTEIN DEGRADATION; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; PROTEIN PROCESSING; REVIEW; SIGNAL TRANSDUCTION;

ANIMALS; GUANOSINE DIPHOSPHATE; GUANOSINE TRIPHOSPHATE; HUMANS; MEMBRANE LIPIDS; MODELS, BIOLOGICAL; PHOSPHORYLATION; PROTEIN CONFORMATION; PROTEIN PROCESSING, POST-TRANSLATIONAL; PROTEOLYSIS; REACTIVE OXYGEN SPECIES; RHO GTP-BINDING PROTEINS; SIGNAL TRANSDUCTION;

EID: 84856531511     PISSN: 08926638     EISSN: 15306860     Source Type: Journal    
DOI: 10.1096/fj.11-192252     Document Type: Review

References (88)

1. Jaffe, A. B., and Hall, A. (2005) Rho GTPases: biochemistry and biology. Annu. Rev. Cell Dev. Biol. 21, 247-269 (Pubitemid 41740635)
2. Wherlock, M., and Mellor, H. (2002) The Rho GTPase family: a Racs to Wrchs story. J. Cell Sci. 115, 239-240 (Pubitemid 34145173)
3. Cherfils, J., and Chardin, P. (1999) GEFs: structural basis for their activation of small GTP-binding proteins. Trends Biochem. Sci. 24, 306-311 (Pubitemid 29366804)
4. Garcia-Mata, R., Boulter, E., and Burridge, K. (2011) The 'invisible hand': regulation of RHO GTPases by RHOGDIs. Nat. Rev. Mol. Cell. Biol. 12, 493-504
5. Rossman, K. L., Der, C. J., and Sondek, J. (2005) GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors. Nat. Rev. Mol. Cell. Biol. 6, 167-180 (Pubitemid 40215811)
6. Boquet, P., and Lemichez, E. (2003) Bacterial virulence factors targeting Rho GTPases: parasitism or symbiosis? Trends Cell Biol. 13, 238-246 (Pubitemid 36556008)
7. Aktories, K. (2011) Bacterial protein toxins that modify host regulatory GTPases. Nat. Rev. Microbiol. 9, 487-498
8. Visvikis, O., Maddugoda, M. P., and Lemichez, E. (2010) Direct modifications of Rho proteins: deconstructing GTPase regulation. Biol. Cell 102, 377-389
9. Hancock, J. F., Cadwallader, K., and Marshall, C. J. (1991) Methylation and proteolysis are essential for efficient membrane binding of prenylated p21K-ras(B). EMBO J. 10, 641-646 (Pubitemid 21905518)
10. Hancock, J. F., Cadwallader, K., Paterson, H., and Marshall, C. J. (1991) A CAAX or a CAAL motif and a second signal are sufficient for plasma membrane targeting of ras proteins. EMBO J. 10, 4033-4039 (Pubitemid 21905433)
11. Hancock, J. F., Magee, A. I., Childs, J. E., and Marshall, C. J. (1989) All ras proteins are polyisoprenylated but only some are palmitoylated. Cell 57, 1167-1177 (Pubitemid 19169813)
12. Hancock, J. F., Paterson, H., and Marshall, C. J. (1990) A polybasic domain or palmitoylation is required in addition to the CAAX motif to localize p21ras to the plasma membrane. Cell 63, 133-139
13. Casey, P. J., Solski, P. A., Der, C. J., and Buss, J. E. (1989) p21ras is modified by a farnesyl isoprenoid. Proc. Natl. Acad. Sci. U. S. A. 86, 8323-8327 (Pubitemid 19286052)
14. Katayama, M., Kawata, M., Yoshida, Y., Horiuchi, H., Yamamoto, T., Matsuura, Y., and Takai, Y. (1991) The posttranslationally modified C-terminal structure of bovine aortic smooth muscle rhoA p21. J. Biol. Chem. 266, 12639-12645 (Pubitemid 21907143)
15. Adamson, P., Marshall, C. J., Hall, A., and Tilbrook, P. A. (1992) Post-translational modifications of p21rho proteins. J. Biol. Chem. 267, 20033-20038
16. Berzat, A. C., Buss, J. E., Chenette, E. J., Weinbaum, C. A., Shutes, A., Der, C. J., Minden, A., and Cox, A. D. (2005) Transforming activity of the Rho family GTPase, Wrch-1, a Wnt-regulated Cdc42 homolog, is dependent on a novel carboxyl-terminal palmitoylation motif. J. Biol. Chem. 280, 33055-33065 (Pubitemid 41368355)
17. Chenette, E. J., Abo, A., and Der, C. J. (2005) Critical and distinct roles of amino- and carboxyl-terminal sequences in regulation of the biological activity of the Chp atypical Rho GTPase. J. Biol. Chem. 280, 13784-13792 (Pubitemid 40517275)
18. Michaelson, D., Silletti, J., Murphy, G., D'Eustachio, P., Rush, M., and Philips, M. R. (2001) Differential localization of Rho GTPases in live cells: regulation by hypervariable regions and RhoGDI binding. J. Cell Biol. 152, 111-126 (Pubitemid 32102441)
19. Roberts, P. J., Mitin, N., Keller, P. J., Chenette, E. J., Madigan, J. P., Currin, R. O., Cox, A. D., Wilson, O., Kirschmeier, P., and Der, C. J. (2008) Rho family GTPase modification and dependence on CAAX motif-signaled posttranslational modification. J. Biol. Chem. 283, 25150-25163
20. Lane, K. T., and Beese, L. S. (2006) Thematic review series: lipid posttranslational modifications. Structural biology of protein farnesyltransferase and geranylgeranyltransferase type I. J. Lipid Res. 47, 681-699
21. Cushman, I., and Casey, P. J. (2009) Role of isoprenylcysteine carboxylmethyltransferase-catalyzed methylation in Rho function and migration. J. Biol. Chem. 284, 27964-27973
22. Willingham, M. C., Pastan, I., Shih, T. Y., and Scolnick, E. M. (1980) Localization of the src gene product of the Harvey strain of MSV to plasma membrane of transformed cells by electron microscopic immunocytochemistry. Cell 19, 1005-1014 (Pubitemid 10155234)
23. Adamson, P., Paterson, H. F., and Hall, A. (1992) Intracellular localization of the P21rho proteins. J. Cell Biol. 119, 617-627
24. Bokoch, G. M., Bohl, B. P., and Chuang, T. H. (1994) Guanine nucleotide exchange regulates membrane translocation of Rac/Rho GTP-binding proteins. J. Biol. Chem. 269, 31674-31679 (Pubitemid 24379533)
25. Quinn, M. T., Evans, T., Loetterle, L. R., Jesaitis, A. J., and Bokoch, G. M. (1993) Translocation of Rac correlates with NADPH oxidase activation. Evidence for equimolar translocation of oxidase components. J. Biol. Chem. 268, 20983-20987 (Pubitemid 23292279)
26. del Pozo, M. A., Alderson, N. B., Kiosses, W. B., Chiang, H. H., Anderson, R. G., and Schwartz, M. A. (2004) Integrins regulate Rac targeting by internalization of membrane domains. Science 303, 839-842 (Pubitemid 38174662)
27. Del Pozo, M. A., Kiosses, W. B., Alderson, N. B., Meller, N., Hahn, K. M., and Schwartz, M. A. (2002) Integrins regulate GTP-Rac localized effector interactions through dissociation of Rho-GDI. Nat. Cell Biol. 4, 232-239 (Pubitemid 34218197)
28. Del Pozo, M. A., Price, L. S., Alderson, N. B., Ren, X. D., and Schwartz, M. A. (2000) Adhesion to the extracellular matrix regulates the coupling of the small GTPase Rac to its effector PAK. EMBO J. 19, 2008-2014 (Pubitemid 30237576)
29. Boulter, E., Garcia-Mata, R., Guilluy, C., Dubash, A., Rossi, G., Brennwald, P. J., and Burridge, K. (2010) Regulation of Rho GTPase crosstalk, degradation and activity by RhoGDI1. Nat. Cell Biol. 12, 477-483
30. Boulter, E., and Garcia-Mata, R. (2010) RhoGDI: a rheostat for the Rho switch. Small GTPases 1, 65-68
31. Leventis, R., and Silvius, J. R. (1998) Lipid-binding characteristics of the polybasic carboxy-terminal sequence of K-ras4B. Biochemistry 37, 7640-7648 (Pubitemid 28235248)
32. Yeung, T., Gilbert, G. E., Shi, J., Silvius, J., Kapus, A., and Grinstein, S. (2008) Membrane phosphatidylserine regulates surface charge and protein localization. Science 319, 210-213
33. Yeung, T., Terebiznik, M., Yu, L., Silvius, J., Abidi, W. M., Philips, M., Levine, T., Kapus, A., and Grinstein, S. (2006) Receptor activation alters inner surface potential during phagocytosis. Science 313, 347-351 (Pubitemid 44480958)
34. Prior, I. A., Harding, A., Yan, J., Sluimer, J., Parton, R. G., and Hancock, J. F. (2001) GTP-dependent segregation of H-ras from lipid rafts is required for biological activity. Nat. Cell Biol. 3, 368 -375
35. Roy, S., Luetterforst, R., Harding, A., Apolloni, A., Etheridge, M., Stang, E., Rolls, B., Hancock, J. F., and Parton, R. G. (1999) Dominant-negative caveolin inhibits H-Ras function by disrupting cholesterol-rich plasma membrane domains. Nat. Cell Biol. 1, 98-105 (Pubitemid 129501951)
36. Fairn, G. D., Hermansson, M., Somerharju, P., and Grinstein, S. (2011) Phosphatidylserine is polarized and required for proper Cdc42 localization and for development of cell polarity. [E-pub ahead of print] Nat Cell Biol. doi: 10.1038/ncb2351
37. Heo, W. D., Inoue, T., Park, W. S., Kim, M. L., Park, B. O., Wandless, T. J., and Meyer, T. (2006) PI(3,4,5)P3 and PI(4,5)P2 lipids target proteins with polybasic clusters to the plasma membrane. Science 314, 1458-1461 (Pubitemid 44871952)
38. Lang, P., Gesbert, F., Delespine-Carmagnat, M., Stancou, R., Pouchelet, M., and Bertoglio, J. (1996) Protein kinase A phosphorylation of RhoA mediates the morphological and functional effects of cyclic AMP in cytotoxic lymphocytes. EMBO J. 15, 510-519 (Pubitemid 26044564)
39. Sauzeau, V., Le Jeune, H., Cario-Toumaniantz, C., Smolenski, A., Lohmann, S. M., Bertoglio, J., Chardin, P., Pacaud, P., and Loirand, G. (2000) Cyclic GMP-dependent protein kinase signaling pathway inhibits RhoA-induced Ca2+ sensitization of contraction in vascular smooth muscle. J. Biol. Chem. 275, 21722-21729
40. Savoia, C., Tabet, F., Yao, G., Schiffrin, E. L., and Touyz, R. M. (2005) Negative regulation of RhoA/Rho kinase by angiotensin II type 2 receptor in vascular smooth muscle cells: role in angiotensin II-induced vasodilation in stroke-prone spontaneously hypertensive rats. J. Hypertens. 23, 1037-1045 (Pubitemid 40637923)
41. Hoffman, G. R., Nassar, N., and Cerione, R. A. (2000) Structure of the Rho family GTP-binding protein Cdc42 in complex with the multifunctional regulator RhoGDI. Cell 100, 345-356 (Pubitemid 30353090)
42. Ellerbroek, S. M., Wennerberg, K., and Burridge, K. (2003) Serine phosphorylation negatively regulates RhoA in vivo. J. Biol. Chem. 278, 19023-19031 (Pubitemid 36799287)
43. Tkachenko, E., Sabouri-Ghomi, M., Pertz, O., Kim, C., Gutierrez, E., Machacek, M., Groisman, A., Danuser, G., and Ginsberg, M. H. (2011) Protein kinase A governs a RhoA-RhoGDI protrusion-retraction pacemaker in migrating cells. Nat. Cell Biol. 13, 660-667
44. Forget, M. A., Desrosiers, R. R., Gingras, D., and Beliveau, R. (2002) Phosphorylation states of Cdc42 and RhoA regulate their interactions with Rho GDP dissociation inhibitor and their extraction from biological membranes. Biochem. J. 361, 243-254 (Pubitemid 34174491)
45. Tillement, V., Lajoie-Mazenc, I., Casanova, A., Froment, C., Penary, M., Tovar, D., Marquez, R., Monsarrat, B., Favre, G., and Pradines, A. (2008) Phosphorylation of RhoB by CK1 impedes actin stress fiber organization and epidermal growth factor receptor stabilization. Exp. Cell Res. 314, 2811-2821
46. Riento, K., Totty, N., Villalonga, P., Garg, R., Guasch, R., and Ridley, A. J. (2005) RhoE function is regulated by ROCK I-mediated phosphorylation. EMBO J. 24, 1170-1180 (Pubitemid 40516600)
47. Alan, J. K., Berzat, A. C., Dewar, B. J., Graves, L. M., and Cox, A. D. (2010) Regulation of the Rho family small GTPase Wrch-1/RhoU by C-terminal tyrosine phosphorylation requires Src. Mol. Cell. Biol. 30, 4324-4338
48. Kwon, T., Kwon, D. Y., Chun, J., Kim, J. H., and Kang, S. S. (2000) Akt protein kinase inhibits Rac1-GTP binding through phosphorylation at serine 71 of Rac1. J. Biol. Chem. 275, 423- 428
49. Tu, S., Wu, W. J., Wang, J., and Cerione, R. A. (2003) Epidermal growth factor-dependent regulation of Cdc42 is mediated by the Src tyrosine kinase. J. Biol. Chem. 278, 49293-49300
50. Sorg, I., Goehring, U. M., Aktories, K., and Schmidt, G. (2001) Recombinant Yersinia YopT leads to uncoupling of RhoA-effector interaction. Infect. Immun. 69, 7535-7543 (Pubitemid 33089239)
51. Heo, J., and Campbell, S. L. (2005) Mechanism of redox-mediated guanine nucleotide exchange on redox-active Rho GTPases. J. Biol. Chem. 280, 31003-31010 (Pubitemid 41291833)
52. Heo, J., Raines, K. W., Mocanu, V., and Campbell, S. L. (2006) Redox regulation of RhoA. Biochemistry 45, 14481-14489 (Pubitemid 44865203)
53. Castillo-Lluva, S., Tatham, M. H., Jones, R. C., Jaffray, E. G., Edmondson, R. D., Hay, R. T., and Malliri, A. (2010) SUMOylation of the GTPase Rac1 is required for optimal cell migration. Nat. Cell Biol. 12, 1078-1085
54. Kovacic, H. N., Irani, K., and Goldschmidt-Clermont, P. J. (2001) Redox regulation of human Rac1 stability by the proteasome in human aortic endothelial cells. J. Biol. Chem. 276, 45856-45861
55. Doye, A., Mettouchi, A., Bossis, G., Clement, R., Buisson-Touati, C., Flatau, G., Gagnoux, L., Piechaczyk, M., Boquet, P., and Lemichez, E. (2002) CNF1 exploits the ubiquitin-proteasome machinery to restrict Rho GTPase activation for bacterial host cell invasion. Cell 111, 553-564 (Pubitemid 35356560)
56. Wang, H. R., Zhang, Y., Ozdamar, B., Ogunjimi, A. A., Alexandrova, E., Thomsen, G. H., and Wrana, J. L. (2003) Regulation of cell polarity and protrusion formation by targeting RhoA for degradation. Science 302, 1775-1779 (Pubitemid 37505743)
57. Chen, Y., Yang, Z., Meng, M., Zhao, Y., Dong, N., Yan, H., Liu, L., Ding, M., Peng, H. B., and Shao, F. (2009) Cullin mediates degradation of RhoA through evolutionarily conserved BTB adaptors to control actin cytoskeleton structure and cell movement. Mol. Cell 35, 841-855
58. Ozdamar, B., Bose, R., Barrios-Rodiles, M., Wang, H. R., Zhang, Y., and Wrana, J. L. (2005) Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity. Science 307, 1603-1609 (Pubitemid 40354739)
59. Sahai, E., Garcia-Medina, R., Pouyssegur, J., and Vial, E. (2007) Smurf1 regulates tumor cell plasticity and motility through degradation of RhoA leading to localized inhibition of contractility. J. Cell Biol. 176, 35-42 (Pubitemid 46041678)
60. Boyer, L., Turchi, L., Desnues, B., Doye, A., Ponzio, G., Mege, J. L., Yamashita, M., Zhang, Y. E., Bertoglio, J., Flatau, G., Boquet, P., and Lemichez, E. (2006) CNF1-induced ubiquitylation and proteasome destruction of activated RhoA is impaired in Smurf1-/- cells. Mol. Biol. Cell 17, 2489-2497 (Pubitemid 43825488)
61. Schwamborn, J. C., Muller, M., Becker, A. H., and Puschel, A. W. (2007) Ubiquitination of the GTPase Rap1B by the ubiquitin ligase Smurf2 is required for the establishment of neuronal polarity. EMBO J. 26, 1410-1422 (Pubitemid 46398703)
62. Cheng, P. L., Lu, H., Shelly, M., Gao, H., and Poo, M. M. (2011) Phosphorylation of e3 ligase smurf1 switches its substrate preference in support of axon development. Neuron 69, 231-243
63. Asanuma, K., Yanagida-Asanuma, E., Faul, C., Tomino, Y., Kim, K., and Mundel, P. (2006) Synaptopodin orchestrates actin organization and cell motility via regulation of RhoA signalling. Nat. Cell Biol. 8, 485-491
64. Zimmerman, E. S., Schulman, B. A., and Zheng, N. (2010) Structural assembly of cullin-RING ubiquitin ligase complexes. Curr. Opin. Struct. Biol. 20, 714-721
65. Wilkins, A., Ping, Q., and Carpenter, C. L. (2004) RhoBTB2 is a substrate of the mammalian Cul3 ubiquitin ligase complex. Genes Dev. 18, 856-861 (Pubitemid 38529655)
66. Aspenstrom, P., Fransson, A., and Saras, J. (2004) Rho GTPases have diverse effects on the organization of the actin filament system. Biochem. J. 377, 327-337 (Pubitemid 38142188)
67. Nethe, M., Anthony, E. C., Fernandez-Borja, M., Dee, R., Geerts, D., Hensbergen, P. J., Deelder, A. M., Schmidt, G., and Hordijk, P. L. (2010) Focal-adhesion targeting links caveolin-1 to a Rac1-degradation pathway. J. Cell Sci. 123, 1948-1958
68. del Pozo, M. A., Balasubramanian, N., Alderson, N. B., Kiosses, W. B., Grande-Garcia, A., Anderson, R. G., and Schwartz, M. A. (2005) Phospho-caveolin-1 mediates integrin-regulated membrane domain internalization. Nat. Cell Biol. 7, 901-908 (Pubitemid 41486291)
69. Stevens, E. V., Banet, N., Onesto, C., Plachco, A., Alan, J. K., Nikolaishvili-Feinberg, N., Midkiff, B. R., Kuan, P., Liu, J., Miller, C. R., Vigil, D., Graves, L. M., and Der, C. J. (2011) RhoGDI2 antagonizes ovarian carcinoma growth, invasion and metastasis. Small GTPases 2, 202-210
70. Stamatakis, K., Cernuda-Morollon, E., Hernandez-Perera, O., and Perez-Sala, D. (2002) Isoprenylation of RhoB is necessary for its degradation. A novel determinant in the complex regulation of RhoB expression by the mevalonate pathway. J. Biol. Chem. 277, 49389-49396 (Pubitemid 36014371)
71. Haklai, R., Weisz, M. G., Elad, G., Paz, A., Marciano, D., Egozi, Y., Ben-Baruch, G., and Kloog, Y. (1998) Dislodgment and accelerated degradation of Ras. Biochemistry 37, 1306-1314
72. Guilluy, C., Garcia-Mata, R., and Burridge, K. (2011) Rho protein crosstalk: another social network? [E-pub ahead of print] Trends Cell Biol. doi: 10.1016/j.tcb.2011.08.002
73. Ridley, A. J., Paterson, H. F., Johnston, C. L., Diekmann, D., and Hall, A. (1992) The small GTP-binding protein rac regulates growth factor-induced membrane ruffling. Cell 70, 401-410
74. Rottner, K., Hall, A., and Small, J. V. (1999) Interplay between Rac and Rho in the control of substrate contact dynamics. Curr. Biol. 9, 640-648 (Pubitemid 29291944)
75. Ridley, A. J., Schwartz, M. A., Burridge, K., Firtel, R. A., Ginsberg, M. H., Borisy, G., Parsons, J. T., and Horwitz, A. R. (2003) Cell migration: integrating signals from front to back. Science 302, 1704-1709 (Pubitemid 37505725)
76. Pertz, O., Hodgson, L., Klemke, R. L., and Hahn, K. M. (2006) Spatiotemporal dynamics of RhoA activity in migrating cells. Nature 440, 1069-1072
77. Machacek, M., Hodgson, L., Welch, C., Elliott, H., Pertz, O., Nalbant, P., Abell, A., Johnson, G. L., Hahn, K. M., and Danuser, G. (2009) Coordination of Rho GTPase activities during cell protrusion. Nature 461, 99-103
78. Nimnual, A. S., Taylor, L. J., and Bar-Sagi, D. (2003) Redox-dependent downregulation of Rho by Rac. Nat. Cell Biol. 5, 236-241 (Pubitemid 36322251)
79. Wennerberg, K., Forget, M. A., Ellerbroek, S. M., Arthur, W. T., Burridge, K., Settleman, J., Der, C. J., and Hansen, S. H. (2003) Rnd proteins function as RhoA antagonists by activating p190 RhoGAP. Curr. Biol. 13, 1106-1115 (Pubitemid 36815258)
80. Rosenfeldt, H., Castellone, M. D., Randazzo, P. A., and Gutkind, J. S. (2006) Rac inhibits thrombin-induced Rho activation: evidence of a Pak-dependent GTPase crosstalk. J. Mol. Signal. 1, 8
81. Ohta, Y., Hartwig, J. H., and Stossel, T. P. (2006) FilGAP, a Rho- and ROCK-regulated GAP for Rac binds filamin A to control actin remodelling. Nat. Cell Biol. 8, 803-814 (Pubitemid 44151583)
82. Katoh, H., and Negishi, M. (2003) RhoG activates Rac1 by direct interaction with the Dock180-binding protein Elmo. Nature 424, 461-464 (Pubitemid 36917498)
83. Benink, H. A., and Bement, W. M. (2005) Concentric zones of active RhoA and Cdc42 around single cell wounds. J. Cell Biol. 168, 429-439 (Pubitemid 40205065)
84. Bellanger, J. M., Lazaro, J. B., Diriong, S., Fernandez, A., Lamb, N., and Debant, A. (1998) The two guanine nucleotide exchange factor domains of Trio link the Rac1 and the RhoA pathways in vivo. Oncogene 16, 147-152 (Pubitemid 28045100)
85. Krugmann, S., Williams, R., Stephens, L., and Hawkins, P. T. (2004) ARAP3 is a PI3K- and rap-regulated GAP for RhoA. Curr. Biol. 14, 1380-1384 (Pubitemid 39081641)
86. Frank, S. R., Adelstein, M. R., and Hansen, S. H. (2006) GIT2 represses Crk- and Rac1-regulated cell spreading and Cdc42-mediated focal adhesion turnover. EMBO J. 25, 1848-1859
87. Albertinazzi, C., Za, L., Paris, S., and de Curtis, I. (2003) ADP-ribosylation factor 6 and a functional PIX/p95-APP1 complex are required for Rac1B-mediated neurite outgrowth. Mol. Biol. Cell. 14, 1295-1307 (Pubitemid 36547401)
88. Lambert, J. M., Lambert, Q. T., Reuther, G. W., Malliri, A., Siderovski, D. P., Sondek, J., Collard, J. G., and Der, C. J. (2002) Tiam1 mediates Ras activation of Rac by a PI(3)K-independent mechanism. Nat. Cell Biol. 4, 621-625