RHO - GTPases and cancer

Nature Reviews Cancer

Volumn 2, Issue 2, 2002, Pages 133-142

  Sahai, Erik ^a   Marshall, Christopher J ^a  

^a INSTITUTE OF CANCER RESEARCH   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

CYCLIN D1; CYCLIN DEPENDENT KINASE; GUANOSINE DIPHOSPHATE; GUANOSINE TRIPHOSPHATASE; GUANOSINE TRIPHOSPHATE; PROTEIN P21; PROTEIN P27; RHO GUANINE NUCLEOTIDE BINDING PROTEIN; UNCLASSIFIED DRUG;

APOPTOSIS; CANCER GROWTH; CARCINOGENESIS; CELL MOTILITY; EXTRACELLULAR MATRIX; HUMAN; HYDROLYSIS; MALIGNANT TRANSFORMATION; METASTASIS; NONHUMAN; ONCOGENE RAS; PRIORITY JOURNAL; PROGNOSIS; PROTEIN BINDING; PROTEIN DEGRADATION; PROTEIN FUNCTION; REVIEW; ANIMAL; CANCER INVASION; CELL CYCLE; DRUG DESIGN; ENZYMOLOGY; GENETICS; METABOLISM; NEOPLASM; PATHOLOGY; SIGNAL TRANSDUCTION;

ANIMALS; APOPTOSIS; CELL CYCLE; DRUG DESIGN; HUMANS; NEOPLASM INVASIVENESS; NEOPLASM METASTASIS; NEOPLASMS; RHO GTP-BINDING PROTEINS; SIGNAL TRANSDUCTION;

EID: 0036488510     PISSN: 1474175X     EISSN: None     Source Type: Journal    
DOI: 10.1038/nrc725     Document Type: Review

References (140)

1. Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860-921 (2001).
2. Bishop, A. L. & Hall, A. Rho GTPases and their effector proteins. Biochem. J. 348, 241-255 (2000).
3. Hall, A. Rho GTPases and the actin cytoskeleton. Science 279, 509-514 (1998).
4. Van Aelst, L. & D'Souza-Schorey, C. Rho GTPases and signaling networks. Genes Dev. 11, 2295-2322 (1997).
5. Qiu, R. G., Chen, J., McCormick, F. & Symons, M. A role for Rho in Ras transformation. Proc. Natl Acad. Sci. USA 92, 11781-11785 (1995). One of the first reports to indicate involvement of a RHO-family member in RAS-mediated transformation (see also references 6 and 10).
6. Qiu, R. G., Chen, J., Kirn, D., McCormick, F. & Symons, M. An essential role for Rac in Ras transformation. Nature 374, 457-459 (1995).
7. Qiu, R. G., Abo, A., McCormick, F. & Symons, M. Cdc42 regulates anchorage-independent growth and is necessary for Ras transformation. Mol. Cell. Biol. 17, 3449-3458 (1997).
8. Roux, P., Gauthier-Rouviere, C., Doucet-Brutin, S. & Fort, P. The small GTPases Cdc42Hs, Rac1 and RhoG delineate Raf-independent pathways that cooperate to transform NIH3T3 cells. Curr. Biol. 7, 629-637 (1997).
9. Murphy, G. A. et al. Cellular functions of TC10, a Rho family GTPase: regulation of morphology, signal transduction and cell growth. Oncogene 18, 3831-3845 (1999).
10. Khosravi-Far, R., Solski, P. A., Clark, G. J., Kinch, M. S. & Der, C. J. Activation of Rac1, RhoA, and mitogen-activated protein kinases is required for Ras transformation. Mol. Cell. Biol. 15, 6443-6453 (1995).
11. Ingram, D. A. et al. Hyperactivation of p21(Ras) and the hematopoietic-specific Rho GTPase, Rac2, cooperate to alter the proliferation of neurofibromin-deficient mast cells in vivo and in vitro. J. Exp. Med. 194, 57-69 (2001). Genetic manipulation of mice shows the importance of Rac2 in proliferation of mast cells with hyperactive Ras.
12. Koudas, 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).
13. Kin, Y., Li, G., Shibuya, M. & Maru, Y. The DBL homology domain of BCR is not a simple spacer in p210 BCR-ABL of the Philadelphia chromosome J. Biol. Chem. 276, 39462-39468 (2001).
14. Reuther, G. W. et al. Leukemia-associated Rho guanine nucleotide exchange factor, a Dbl family protein found mutated in leukemia, causes transformation by activation of, RhoA. J. Biol. Chem. 276, 27145-27151 (2001).
15. Preudhomme, C. et al. Nonrandom 4p13 rearrangements of the RhoH/TTF gene, encoding a GTP-binding protein, in non-Hodgkin's lymphoma and multiple myeloma. Oncogene 19, 2023-2032 (2000).
16. Pasqualucci, L. et al. Hypermutation of multiple protooncogenes in B-cell diffuse large-cell lymphomas. Nature 412, 341-346 (2001).
17. Kamai, T., Arai, K., Tsujii, T., Honda, M. & Yoshida, K. Overexpression of RhoA mRNA is associated with advanced stage in testicular germ cell tumour. BJU Int. 87, 227-231 (2001),
18. Fritz, G., Just, I. & Kaina, B. Rho GTPases are overexpressed in human tumors Int. J. Cancer 81, 682-687 (1999).
19. Suwa, H. et al. Overexpression of the RhoC gene correlates with progression of ductal adenocarcinoma of the pancreas. Br. J. Cancer 77, 147-152 (1998).
20. van Golen, K. L., Wu, Z. F. Qiao, X. T., Bao, L. W. & Merajver, S. D. RhoC GTPase, a novel transforming oncogene for human mammary epithelial cells that partially recapitulates the inflammatory breast cancer phenotype. Cancer Res 68, 5832-5838 (2000).
21. Schnelzer, A. et al. Rac1 in human breast cancer: overexpression, mutation analysis, and characterization of a new isoform, Rac1b. Oncogene 19, 3013-3020 (2000). Intriguing paper showing that the splice variant of RAC1 that is highly expressed in breast and colon cancer has an increased GDP-GTP exchange rate (see also reference 22). An increased GDP-GTP exchange rate can promote transformation of fibroblasts (see reference 33).
22. Jordan, P., Brazao, R., Boavida, M. G., Gespach, C. & Chastre, E. Cloning of a novel human Rac1b splice variant with increased expression in colorectal tumors. Oncogene 18, 6835-6839 (1999).
23. Zondag, G. C. et al. Oncogenic Ras downregulates Rac activity, which leads to increased Rho activity and epithelial-mesenchymal transition. J. Cell. Biol. 149, 775-782 (2000).
24. Royal, I., Lamarche-Vane, N., Lamorte, L., Kaibuchi, K. & Park, M. Activation of CDC42, RAC, PAK, and Rho-kinase in response to hepatocyte growth factor differentially regulates epithelial cell colony spreading and dissociation. Mol. Biol. Cell 11, 1709-1725 (2000).
25. Fukata, M. et al. Involvement of IQGAP1, an effector of Rac1 and Cdc42 GTPases, in cell-cell dissociation during cell scattering. Mol. Cell. Biol. 21, 2165-2183 (2001).
26. Bhowmick, N. A. et al. Transforming growth factor-β1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism. Mol. Biol. Cell. 12, 27-36 (2001).
27. Liu, A. X., Rane, N., Liu, J. P. & Prendergast, G. C. 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. Biol. 21, 6906-6912 (2001).
28. Habas, R., Kato, Y. & He, X. Wnt/Frizzled activation of Rho regulates vertebrate gastrulation and requires a novel formin homology protein Daam1. Cell 107, 843-854 (2001).
29. Kawasaki, Y. et al. Asef, a link between the tumor suppressor APC and G-protein signaling. Science 289, 1194-1197 (2000).
30. Tao, W., Pennica, D., Xu, L., Kalejta, R. F. & Levine, A. J. Wrch-1, a novel member of the Rho gene family that is regulated by Wnt-1. Genes Dev. 15, 1796-1807 (2001).
31. Baron, M., O'Leary, V., Evans, D. A., Hicks, M. & Hudson, K Multiple roles of the Dcdc42 GTPase during wing development in Drosophila melanogaster. Mol. Gen. Genet. 264, 98-104 (2000).
32. Winter, C. G. et al Drosophila Rho-associated kinase (Drok) links Frizzied-mediated planar cell polarity signaling to the actin cytoskeleton. Cell. 105, 81-91 (2001).
33. Lin, R., Bagrodia, S., Cerione, R. & Manor, D. A novel Cdc42Hs mutant induces cellular transformation. Curr. Biol. 7, 794-797 (1997).
34. Ridley, A. J., Paterson, H. F., Johnston, C. L., Diekmann, D. & Hall, A. The small GTP-binding protein RAC regulates growth factor-induced membrane ruffling. Cell 70, 401-410 (1992).
35. Nobes, C. D. & Hall, A. Rho, RAC, and CDC42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia. Cell 81, 53-62 (1995).
36. Sahai, E., Olson, M. F. & Marshall, C. J. Cross-talk between Ras and Rho signalling pathways in transformation favours proliferation and increased motility. EMBO J. 20, 755-766 (2001).
37. Mira, J. P., Benard, V., Groffen, J., Sanders, L. C. & Knaus, U. G. Endogenous, hyperactive Rac3 controls proliferation of breast cancer cells by a p21-activated kinase-dependent pathway, Proc. Natl Acad. Sci. USA 97, 185-189 (2000).
38. Clark, E. A., Golub, T. R., Lander, E. S. & Hynes, R. O. Genomic analysis of metastasis reveals an essential role for RhoC. Nature 406, 532-535 (2000). RHOC is required in vivo for the metastasis of melanoma cells. RHOC mRNA is upregulated in melanoma cell lines that are selected for high metastatic potential.
39. Ridley, A., J. Rho GTPases and cell migration. J. Cell Sci. 114, 2713-2722 (2001).
40. Iteh, K. et al. An essential part for Rho-associated kinase in the transcellular invasion of tumor cells. Nature Med. 5, 221-225 (1999). RHOA-ROCK signalling can promote dissemination of tumour cells, and this can be blocked using a pharmacological inhibitor of ROCK in vivo.
41. Murata, T. et al. Inhibitory effect of Y-27632, a ROCK inhibitor, on progression of rat liver fibrosis in association with inactivation of hepatic stellate cells. J. Hepatol. 35, 474-481 (2001).
42. Somlyo, A. V. et al. Rho-kinase inhibitor retards migration and in vivo dissemination of human prostate cancer cells. Biochem. Biophys. Res Commun. 269, 652-659 (2000).
43. Guasch, R. M., Scambler, P., Jones, G. E. & Ridley, A. J. RhoE regulates actin cytoskeleton organization and cell migration. Mol. Cell. Biol. 18, 4761-4771 (1998).
44. Nobes, C. D. et al. A new member of the Rho family, Rnd1, promotes disassembly of actin filament structures and loss of cell adhesion. J. Cell Biol. 141, 187-197 (1998).
45. Hansen, S. H. et al. Induced expression of Rnd3 is associated with transformation of polarized epithelial cells by the Raf-MEK-extracellular signal-regulated kinase pathway. Mol. Cell. Biol. 20, 9364-9375 (2000).
46. O'Brien, L. E. et al. Rac1 orientates epithelial apical polanty through effects on basolateral laminin assembly. Nature Cell Biol. 3, 831-838 (2001).
47. Kim, S. K. Cell polarity: new PARtners for Cdc42 and Rac. Nature Cell Biol. 2, E143-E145 (2000).
48. Braga, V. M., Betson, M., Li, X. & Lamarche-Vane, N. Activation of the small GTPase Rac is sufficient to disrupt cadherin-dependent cell-cell adhesion in normal human keratinocytes. Mol. Biol. Cell 11, 3703-3721 (2000).
49. Quinlan, M. P. Rac regulates the stability of the adherens junction and its components, thus affecting epithelial cell differentiation and transformation. Oncogene 18, 6434-6442 (1999).
50. Sander, E. E. et al. Matrix-dependent Tiam1/Rac signaling in epithelial cells promotes either cell-cell adhesion or cell migration and is regulated by phosphatidylinositol 3-kinase J. Cell Biol. 143, 1385-1398 (1998).
51. Matsui, T. et al. Rho-kinase phosphorylates COOH-terminal threonines of ezrin/radixin/moesin (ERM) proteins and regulates their head-to-tail association. J. Cell Biol. 140, 647-657 (1998).
52. Shaw, R. J. et al. The Nf2 tumor suppressor, merlin, functions in Rac-dependent signaling. Dev. Cell 1, 63-72 (2001). Shows how a link between RAC and the tumour suppressor NF2 might promote proliferation and cell motility. This link might be important in tumorigenesis (see also reference 58).
53. Xiao, G. H., Beeser, A., Chernoff, J. & Testa, J. R. p21-activated kinase links Rac/Cdc42 signaling to Merlin. J. Biol. Chem. 21, 21 (2001).
54. Khanna, C. et al. Metastasis-associated differences in gene expression in a murine model of osteosarcoma. Cancer Res. 61, 3750-3759 (2001).
55. Akisawa, N., Nishimori, I., Iwamura, T. Onishi, S. & Hollingsworth, M. A. High levels of ezrin expressed by human pancreatic adenocarcinoma cell lines with high metastatic potential. Biochem. Biophys. Res. Commun. 258, 395-400 (1999).
56. Clarke, G., Ryan, E., O'Keane, J. C., Crowe, J. & Mathuna, P. M. Mortality association of enhanced CD44v6 expression is not mediated through occult lymphatic spread in stage II colorectal cancer. J. Gastroenterol. Hepatol. 15, 1028-1031 (2000).
57. Harada, N. et al. Introduction of antisense CD44S cDNA down-regulates expression of overall CD44 isoforms and inhibits tumor growth and metastasis in highly metastatic colon carcinoma cells. Int. J. Cancer 91, 67-75 (2001).
58. McClatchey, A. I. et al. Mice heterozygous for a mutation at the Nf2 tumor suppressor locus develop a range of highly metastatic tumors. Genes Dev. 12, 1121-1133 (1998).
59. Zhuge, Y. & Xu, J. Rac1 mediates type I collagen-dependent MMP-2 activation: role in cell invasion across collagen barrier. J. Biol. Chem. 276, 16248-16256 (2001).
60. Engers, R., Springer, E., Michiels, F., Collard, J. G. & Gabbert, H. E. Rac affects invasion of human renal cell carcinomas by upregulating TIMP-1 and TIMP-2 expression. J. Biol. Chem. 10, 10 (2001).
61. Kheradmand, F., Werner, E., Tremble, P., Symons, M. & Werb, Z. Role of Rac1 and oxygen radicals in collagenase-1 expression induced by cell shape change. Science 280, 898-902 (1998).
62. Matsumoto, Y. et al. Small GTP-binding protein, Rho, both increased and decreased cellular motility, activation of matrix metalloproteinase 2 and invasion of human osteosarcoma cells. Jpn. J. Cancer Res. 92, 429-438 (2001).
63. 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).
64. Adamson, P., Etienne, S., Couraud, P. O., Calder, V. & Greenwood, J. Lymphocyte migration through brain endothelial cell monolayers involves signaling through endothelial ICAM-1 via a Rho-dependent pathway. J. Immunol. 162, 2964-2973 (1999).
65. van Golen, K. L., Wu, Z. F., Qiao, X. T., Bao, L. & Merajver, S. D. RhoC GTPase overexpression modulates induction of angiogenic factors in breast cells. Neoplasia 2, 418-425 (2000).
66. Soede, R. D. M. et al. Stromal cell-derived factor-1-induced LFA-1 activation during in vivo migration of T cell hybridoma cells requires Gq/11, RhoA, and myosin, as well as Gi and Cdc42. J. Immunol. 166, 4293-4301 (2001).
67. Pines, J. The cell cycle kinases. Semin. Cancer Biol. 5, 305-313 (1994).
68. Sherr, C. J. & Roberts, J. M. CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 13, 1501-1512 (1999).
69. Robles, A. I. et al. Reduced skin tumor development in cyclin D1-deficient mice highlights the oncogenic Ras pathway in vivo. Genes Dev. 12, 2469-2474 (1998).
70. Shaulian, E. & Karin, M. AP-1 in cell proliferation and survival. Oncogene 20, 2390-2400 (2001).
71. Albanese, C. et al. Transforming p21 Ras mutants and c-Ets-2 activate the cyclin D1 promoter through distinguishable regions. J. Biol. Chem. 270, 23589-23597 (1995).
72. Hinz, M. et al. NF-κB function in growth control: regulation of cyclin D1 expression and G0/G1-to-S-phase transition. Mol. Cell. Biol. 19, 2690-2698 (1999)
73. Vojtek, A. B. & Cooper, J. A. Rho family members: activators of MAP kinase cascades. Cell 82, 527-529 (1995).
74. Westwick, J. K. et al. Rac regulation of transformation, gene expression, and actin organization by multiple, PAK-independent pathways. Mol. Cell. Biol. 17, 1324-1335 (1997).
75. Marinissen, M. J., Chiariello, M. & Gutkind, J. S. Regulation of gene expression by the small GTPase Rho through the ERK6 (p38-7γ) MAP kinase pathway. Genes Dev. 15, 535-553 (2001).
76. Hill, C. S., Wynne, J. & Treisman, R. The Rho family GTPases RhoA, Rac1, and CDC42Hs regulate transcriptional activation by SRF. Cell 81, 1159-1170 (1995).
77. Benbow, U. & Brinckerhoff, C. E. The AP-1 site and MMP gene regulation: what is all the fuss about? Matrix Biol. 15, 519-526 (1997).
78. Frost, J. A. et al. Cross-cascade activation of ERKs and ternary complex factors by Rho family proteins. EMBO J. 16, 6426-6438 (1997).
79. Welsh, C. F. et al. Timing of cyclin D1 expression within G1 phase is controlled by Rho. Nature Cell Biol. 3, 950-957 (2001).
80. King, A. J. et al. The protein kinase Pak3 positively regulares regulates Raf-1 activity through phosphorylation of serine 338. Nature 396, 180-183 (1998).
81. Narumiya, S., Ishizaki, T. & Watanabe, N. Rho effectors and reorganization of actin cytoskeleton FEBS Lett. 410, 68-72 (1997).
82. Danen, E. H. & Yamada, K. M. Fibronectin, integnns, and growth control. J. Cell Physiol. 189, 1-13 (2001).
83. Assoian, R. K. & Schwartz, M. A. Coordinate signaling by integrins and receptor tyrosine kinases in the regulation of G1 phase cell-cycle progression. Curr. Opin. Genet. Dev. 11, 48-53 (2001).
84. Joneson, T. & Bar-Sagi, D. Suppression of Ras-induced apoptosis by the Rac GTPase. Mol. Cell. Biol. 19, 5892-5901 (1999).
85. Joyce, D. et al. Integration of Rac-dependent regulation of cyclin D1 transcription through a nuclear factor-κB-dependent pathway. J. Biol. Chem. 274, 25245-25249 (1999).
86. Cammarano, M. S. & Minden, A. Dbl and the Rho GTPases activate NFκB by IκB kinase (IKK)-dependent and IKK-independent pathways. J. Biol. Chem. 276, 25876-25882 (2001).
87. Frost, J. A. et al. Stimulation of NFκB activity by multiple signaling pathways requires PAK1. J. Biol. Chem. 275, 19693-19699 (2000).
88. 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).
89. Lallena, M. J. Diaz-Meco, M. T., Bren, G., Paya, C. V. & Moscat, J. Activation of IκB kinase-β by protein kinase C isoforms. Mol. Cell. Biol. 19, 2180-2188 (1999).
90. Qiu, R. G., Abo, A. & Steven Martin, G. 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).
91. Murphy, G. A. et al. Signaling mediated by the closely related mammalian Rho family GTPases TC10 and Cdc42 suggests distinct functional pathways. Cell Growth Differ. 12, 157-167 (2001).
92. Sonenshein, G. E. Rel/NF-κB transcription factors and the control of apoptosis. Semin. Cancer Biol. 8, 113-119 (1997).
93. Mettouchi, A. et al. Integrin-specific activation of Rac controls progression through the G(1) phase of the cell cycle. Mol. Cell 8, 115-127 (2001). RAC1 acts downstream of a physical cue - integrin engagement - to upregulate cyclin D1 in a transcription-independent manner.
94. WAF1 is demonstrated in the context of oncogenic RAS signalling (see also reference 112).
95. Sahai, E., Ishizaki, T., Narumiya, S. & Treisman, R. Transformation mediated by RhoA requires activity of ROCK kinases. Curr. Biol. 9, 136-145 (1999).
96. Tran Quang, C., Gautreau, A., Arpin, M. & Treisman, R. Ezrin function is required for ROCK-mediated fibroblast transformation by the Net and Dbl oncogenes. EMBO J. 19, 4565-4576 (2000).
97. Adnane, J., Bizouarn, F. A., Qian, Y., Hamilton, A. D. & Sebti, S. M. p21(WAF1/CIP1) is upregulated by the geranylgeranyltransferase I inhibitor GGTI-298 through a transforming growth factor-β- and Sp1-responsive element: involvement of the small GTPase RhoA. Mol. Cell. Biol. 18, 6962-6970 (1998).
98. Hirai, A. et al. Geranylgeranylated rho small GTPase(s) are essential for the degradation of p27Kip1 and facililate the progression from G1 to S phase in growth-stimulated rat FRTL-5 cells. J. Biol. Chem. 272, 13-16 (1997).
99. Weber, J. D., Hu, W., Jefcoat, S. C. Jr, Raben, D. M. & Baldassare, J. J. Ras-stimulated extracellular signal-related kinase 1 and RhoA actvities coordinate platelet-derived growth factor-induced G1 progression through the independent regulation of cyclin D1 and p27. J. Biol. Chem. 272, 32966-32971 (1997).
100. Tanaka, T. et al. Activation of cyclin-dependent kinase 2 (Cdk2) in growth-stimulated rat astrocytes. Geranylgeranylated Rho small GTPase(s) are essential for the induction of cyclin E gene expression J. Biol. Chem. 273, 26772-26778 (1998).
101. Ghosh, P. M., Moyer, M. L., Mott, G. E. & Kreisberg, J. I., Effect of cyclin E overexpression on lovastatin-induced G1 arrest and RhoA inactivation in NIH3T3 cells. J. Cell Biochem. 74, 532-543 (1999).
102. Chiariello, M., Marinissen, M. J. & Gutkind, J. S. Regulation of c-myc expression by PDGP through Rho GTPases. Nature Cell Biol. 3, 580-586 (2001).
103. Gampel, A., Parker, P. J., & Mellor, H. Regulation of epidermal growth factor receptor traffic by the small GTPase RhoB. Curr Biol. 9, 955-958 (1999).
104. Wu, W. J., Erickson, J. W., Lin, R. & Cerione, R. A. The γ-subunit of the coatomer complex binds Cdc42 to mediate transformation. Nature 405, 800-804 (2000).
105. Lamaze, C., Chuang, T. H., Terlecky, L. J., Bokoch, G. M. & Schmid, S. L. Regulation of receptor-mediated endocytosis by 1Rho and Rac. Nature 382, 177-179 (1996).
106. Murphy, C. et al. Endosome dynamics regulated by a Rho protein. Nature 384, 427-432 (1996).
107. Malecz, N. et al. Synaptojanin 2, a novel Rac1 effector that regulates clathrin-mediated endocytosis. Curr. Biol. 10, 1383-1386 (2000).
108. Hotta, K., Tanaka, K., Mino, A., Kohno, H. & Takai, Y. Interaction of the Rho family small G proteins with kinectin, an anchoring protein of kinesin motor. Biochem. Biophys. Res. Commun. 225, 69-74 (1996).
109. Vignal, E., Blangy, A., Martin, M., Gauthier-Rouviere, C. & Fort, P. Kinectin is a key effector of RhoG microtubule-dependent cellular activity. Mol. Cell. Biol. 21, 8022-8034 (2001).
110. Gachet, Y., Tournier, S., Millar, J. B. & Hyams, J. S. A MAP kinase-dependent actin checkpoint ensures proper spindle orientation in fission yeast. Nature 412, 352-355 (2001).
111. Ren, X. D., Kiosses, W. B. & Schwartz, M. A. Regulation of the small GTP-binding protein Rho by cell adhesion and the cytoskeleton. EMBO J. 18, 578-585 (1999).
112. Noren, N. K., Niessen, C. M., Gumbiner, B. M. & Burridge, K. Cadherin engagement regulates Rho family GTPases. J. Biol. Chem. 16, 16 (2001).
113. WAF1 and promote proliferation (see also reference 93).
114. Coleman, M. L. & Olson, M. F. Rho GTPase signalling pathways in the morphological changes associated with apoptosis. Cell Death Differ. (in the press).
115. Pervaiz, S., Cao, J., Chao, O. S., Chin, Y. Y. & Clement, M. V. Activation of the RacGTPase inhibits apoptosis in human tumor cells. Oncogene 20, 6263-6268 (2001).
116. Coniglio, S. J., Jou, T. S. & Symons, M. Rac1 protects epithelial cells against anoikis. J. Biol. Chem. 276, 28113-28120 (2001).
117. Tang, Y., Zhou, H., Chen, A., Pittman, R. N. & Field, J. The Akt proto-oncogene links Ras to Pak and cell survival signals. J. Biol. Chem. 275, 9106-9109 (2000).
118. Schurmann, A. et al. p21-activated kinase 1 phosphorylates the death agonist bad and protects cells from apoptosis. Mol. Cell. Biol. 20, 453-461 (2000).
119. L expression while mediating survival and actin function in primary mast cells. Immunity 12, 557-568 (2000).
120. Costello, P. S., Cleverley, S. C., Galandrini, R., Henning, S. W. & Cantrell, D. A. The GTPase Rho controls a p53-dependent survival checkpoint during thymopoiesis. J. Exp. Med. 192, 77-85 (2000).
121. Liu, A., Cerniglia, G. J., Bernhard, E. J. & Prendergast, G. C. RhoB is required to mediate apoptosis in neoplastically transformed cells after DNA damage. Proc. Natl Acad. Sci. USA 98, 6192-6197 (2001).
122. Prendergast, G. C. Actin' up: RhoB in cancer and apoptosis. Nature Rev. Cancer 1, 162-168 (2001).
123. Subauste, M. C. et al. Rho family proteins modulate rapid apoptosis induced by cytotoxic T lymphocytes and Fas. J. Biol. Chem. 275, 9725-9733 (2000).
124. Brenner, B. et al. Fas- or ceramide-induced apoptosis is mediated by a Rac1-regulated activation of Jun N-terminal kinase/p38 kinases and GADD153. J. Biol. Chem. 272, 22173-22181 (1997).
125. Sebti, S. M. & Hamilton, A. D. Inhibition of Rho GTPases using protein geranylgeranyltransferase I inhibitors. Methods Enzymol. 325, 381-388 (2000).
126. Vastrik, I., Eickholt, B. J., Walsh, F. S., Ridley, A. & Doherty, P. Sema3A-induced growth-cone collapse is mediated by Rac1 amino acids 17-32. Curr. Biol. 9, 991-998 (1999).
127. Chardin, P. & McCormick, F. Brefeldin A: the advantage of being uncompetitive. Cell 97, 153-155 (1999).
128. Du, W. & Prendergaet, G. C. Geranylgeranylated RhoB mediates suppression of human tumor cell growth by farnesyltransferase inhibitors. Cancer Res. 59, 5492-5496 (1999).
129. Liu, A., Du, W., Liu, J. P., Jessell, T. M. & Prendergast, G. C. RhoB alteration is necessary for apoptotic and antineoplastic responses to farnesyltransferase inhibitors. Mol. Cell. Biol. 20, 6105-6113 (2000).
130. Pollack, I. F., Bredel, M., Erff, M., Hamilton, A. D. & Sebti, S. M. Inhibition of Ras and related guanosine triphosphate-dependent proteins as a therapeutic strategy for blocking malignant glioma growth: II. Preclinical studies in a nude mouse model. Neurosurgery 45, 1208-1214; discussion 1214-1205 (1999).
131. Sun, J., Qian, Y., Hamilton, A. D. & Sebti, S. M. Both farnesyltransferase and geranylgeranyltransferase I inhibitors are required for inhibition of oncogenic K-Ras prenylation but each alone is sufficient to suppress human tumor growth in nude mouse xenografts. Oncogene 16, 1467-1473 (1998).
132. Ishizaki, T. et al. Coordination of microtubules and the actin cytoskeleton by the Rho effector mDia1. Nature Cell Biol. 3, 8-14 (2001).
133. Ellis, S. & Mellor, H. The novel Rho-family GTPase rif regulates coordinated actin-based membrane rearrangements. Curr. Biol. 10, 1387-1390 (2000).
134. Aronheim, A. et al Chp, a homologue of the GTPase Cdc42Hs, activates the JNK pathway and is implicated in reorganizing the actin cytoskeleton. Curr. Biol. 8, 1125-1128 (1998).
135. Vignal, E. et al. Characterization of TCL, a new GTPase of the Rho family related to TC10 and Cdc42. J. Biol. Chem. 275, 36457-36464 (2000).
136. Neudauer, C. L., Joberty, G. & Macara, I. G. PIST: a novel PDZ/coiled-coil domain binding partner for the Rho-family GTPase TC10. Biochem. Biophys. Res. Commun. 280, 541-547 (2001).
137. Chiang, S. H. et al. Insulin-stimulated GLUT4 translocation requires the CAP-dependent activation of TC10. Nature 410, 944-948 (2001).
138. Abraham, M. T. et al. Motility-related proteins as markers for head and neck squamous cell cancer. Laryngoscope 111, 1285-1289 (2001).
139. van Golen, K. L. et al. A novel putative low-affinity insulin-like growth factor-binding protein, LIBC (lost in inflammatory breast cancer), and RhoC GTPase correlate with the inflammatory breast cancer phenotype. Clin. Cancer Res. 5, 2511-2519 (1999).
140. Engers, R. et al. Tiam1 mutations in human renal-cell carcinomas. Int. J. Cancer 88, 369-376 (2000).