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RAS and RHO GTPases in G1-phase cell-cycle regulation

Nature Reviews Molecular Cell Biology volume 5, pages 355–366 (2004)Cite this article

Key Points

  • H-RAS, N-RAS and K-RAS GTPases promote cell-cycle progression through the RAF–MEK–ERK/MAPK, RAL and PI3K signalling pathways. Additional RAS-family members, including E-RAS, R-RAS, TC21 and RAL proteins, also promote cell-cycle progression and proliferation using these RAS-regulated pathways.

  • The principal function of RAS in G1–S-phase progression is to inactivate the retinoblastoma (RB) protein and thereby relieve cells from its growth-inhibitory effects — cells without RB no longer require RAS activity.

  • Cyclin-D1 induction is one of the key events required for RB phosphorylation and consequent G1-phase progression. Growth-factor-induced transcription of the cyclin-D1 gene, stabilization of the cyclin-D1 protein and formation of complexes containing cyclin D1 and cyclin-dependent kinase (CDK)4 or CDK6 is regulated primarily through RAS-dependent pathways.

  • Mitogen-induced downregulation of the CDK inhibitor p27KIP1 is mediated by RAS through transcriptional and post-transcriptional mechanisms. Mitogens also signal through RAS to elevate p21CIP1 to moderate levels that allow p21CIP1 to promote the assembly, nuclear retention and stability of cyclin-D1–CDK complexes.

  • Similar to RAS proteins, RHO GTPases contribute to cell-cycle progression by influencing the levels of cyclin D1 and of the CDK inhibitors p27KIP1 and p21CIP1.

  • Mitogenic stimulation leads to enhanced rates of mRNA translation and synthesis of proteins that are required for cell growth and G1-phase progression. RAS and RHO signalling pathways are intimately involved in transducing mitogenic signals to the translational apparatus.

  • RAS effector pathways converge on the tuberous sclerosis (TSC) complex, an inhibitor of the RAS-related RAS homologue enriched in brain (RHEB) GTPase. Inhibition of the TSC complex by these signalling pathways allows RHEB to activate the master translation regulator, target of rapamycin (TOR). Elevated protein translation promotes cell growth and proliferation.

Abstract

As RAS mutations are among the most frequent alterations in human cancers, RAS proteins and their signalling pathways have been studied intensively. Here, we outline the contributions of H-RAS, N-RAS and K-RAS to cell-cycle progression and cell growth. We also summarize recent results that indicate how other members of the RAS-GTPase subfamily — including E-RAS, RHEB, R-RAS, TC21 and RAL, as well as RHO GTPases — promote proliferation by regulating the transcription, translation and degradation of key cell-cycle components.

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Figure 1: RAS- and RHO-GTPase families.
Figure 2: The eukaryotic cell cycle.
Figure 3: RAS effects on cell-cycle components.
Figure 4: RAS effector pathways.
Figure 5: Regulation of translation by the target of rapamycin.
Figure 6: Regulation of TOR/S6K/4E-BP1 by the TSC–RHEB pathway.

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References

  1. Sherr, C. J. The Pezcoller lecture: cancer cell cycles revisited. Cancer Res. 60, 3689–3695 (2000).

    CAS  PubMed  Google Scholar 

  2. Mulcahy, L. S., Smith, M. R. & Stacey, D. W. Requirement for ras proto-oncogene function during serum-stimulated growth of NIH 3T3 cells. Nature 313, 241–243 (1985). First demonstration of the essential role of RAS in mitogen-induced proliferation.

    Article  CAS  PubMed  Google Scholar 

  3. Stacey, D. W., Feig, L. A. & Gibbs, J. B. Dominant inhibitory Ras mutants selectively inhibit the activity of either cellular or oncogenic Ras. Mol. Cell. Biol. 11, 4053–4064 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Feramisco, J. R., Gross, M., Kamata, T., Rosenberg, M. & Sweet, R. W. Microinjection of the oncogene form of the human H-ras (T-24) protein results in rapid proliferation of quiescent cells. Cell 38, 109–117 (1984). Showed that the introduction of recombinant RAS protein is sufficient for the induction of proliferation.

    Article  CAS  PubMed  Google Scholar 

  5. Mittnacht, S., Paterson, H., Olson, M. F. & Marshall, C. J. Ras signalling is required for inactivation of the tumour suppressor pRb cell-cycle control protein. Curr. Biol. 7, 219–221 (1997).

    Article  CAS  PubMed  Google Scholar 

  6. Peeper, D. S. et al. Ras signalling linked to the cell-cycle machinery by the retinoblastoma protein. Nature 386, 177–181 (1997). Along with reference 5, provides genetic evidence that inactivation of the retinoblastoma protein is a key function of RAS in cell-cycle regulation.

    Article  CAS  PubMed  Google Scholar 

  7. D'Abaco, G. M., Hooper, S., Paterson, H. & Marshall, C. J. Loss of Rb overrides the requirement for ERK activity for cell proliferation. J. Cell Sci. 115, 4607–4616 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Filmus, J. et al. Induction of cyclin D1 overexpression by activated ras. Oncogene 9, 3627–3633 (1994).

    CAS  PubMed  Google Scholar 

  9. Hitomi, M. & Stacey, D. W. Cellular ras and cyclin D1 are required during different cell cycle periods in cycling NIH 3T3 cells. Mol. Cell. Biol. 19, 4623–4632 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Aktas, H., Cai, H. & Cooper, G. M. Ras links growth factor signaling to the cell cycle machinery via regulation of cyclin D1 and the Cdk inhibitor p27KIP1. Mol. Cell. Biol. 17, 3850–3857 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Albanese, C. et al. Transforming p21ras mutants and c-Ets-2 activate the cyclin D1 promoter through distinguishable regions. J. Biol. Chem. 270, 23589–23597 (1995).

    Article  CAS  PubMed  Google Scholar 

  12. Lavoie, J. N., L'Allemain, G., Brunet, A., Muller, R. & Pouyssegur, J. Cyclin D1 expression is regulated positively by the p42/p44MAPK and negatively by the p38/HOGMAPK pathway. J. Biol. Chem. 271, 20608–20616 (1996).

    Article  CAS  PubMed  Google Scholar 

  13. Winston, J. T., Coats, S. R., Wang, Y. Z. & Pledger, W. J. Regulation of the cell cycle machinery by oncogenic ras. Oncogene 12, 127–134 (1996).

    CAS  PubMed  Google Scholar 

  14. Treinies, I., Paterson, H. F., Hooper, S., Wilson, R. & Marshall, C. J. Activated MEK stimulates expression of AP-1 components independently of phosphatidylinositol 3-kinase (PI3-kinase) but requires a PI3-kinase signal to stimulate DNA synthesis. Mol. Cell. Biol. 19, 321–329 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Balmanno, K. & Cook, S. J. Sustained MAP kinase activation is required for the expression of cyclin D1, p21Cip1 and a subset of AP-1 proteins in CCL39 cells. Oncogene 18, 3085–3097 (1999).

    Article  CAS  PubMed  Google Scholar 

  16. Suzuki, T. et al. Phosphorylation of three regulatory serines of Tob by Erk1 and Erk2 is required for Ras-mediated cell proliferation and transformation. Genes Dev. 16, 1356–1370 (2002).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Gille, H. & Downward, J. Multiple ras effector pathways contribute to G(1) cell cycle progression. J. Biol. Chem. 274, 22033–22040 (1999).

    Article  CAS  PubMed  Google Scholar 

  18. Diehl, J. A., Cheng, M., Roussel, M. F. & Sherr, C. J. Glycogen synthase kinase-3β regulates cyclin D1 proteolysis and subcellular localization. Genes Dev. 12, 3499–3511 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Muise-Helmericks, R. C. et al. Cyclin D expression is controlled post-transcriptionally via a phosphatidylinositol 3-kinase/Akt-dependent pathway. J. Biol. Chem. 273, 29864–29872 (1998).

    Article  CAS  PubMed  Google Scholar 

  20. Yu, Q., Geng, Y. & Sicinski, P. Specific protection against breast cancers by cyclin D1 ablation. Nature 411, 1017–1021 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Takuwa, N. & Takuwa, Y. Ras activity late in G1 phase required for p27kip1 downregulation, passage through the restriction point, and entry into S phase in growth factor-stimulated NIH 3T3 fibroblasts. Mol. Cell. Biol. 17, 5348–5358 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Weber, J. D., Hu, W., Jefcoat, S. C. Jr., Raben, D. M. & Baldassare, J. J. Ras-stimulated extracellular signal-related kinase 1 and RhoA activities coordinate platelet-derived growth factor-induced G1 progression through the independent regulation of cyclin D1 and p27. J. Biol. Chem. 272, 32966–32971 (1997).

    Article  CAS  PubMed  Google Scholar 

  23. Delmas, C. et al. The p42/p44 mitogen-activated protein kinase activation triggers p27Kip1 degradation independently of CDK2/cyclin E in NIH 3T3 cells. J. Biol. Chem. 276, 34958–34965 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Rivard, N., Boucher, M. J., Asselin, C. & L'Allemain, G. MAP kinase cascade is required for p27 downregulation and S phase entry in fibroblasts and epithelial cells. Am. J. Physiol. 277, C652–C664 (1999).

    Article  CAS  PubMed  Google Scholar 

  25. Vlach, J., Hennecke, S. & Amati, B. Phosphorylation-dependent degradation of the cyclin-dependent kinase inhibitor p27. EMBO J. 16, 5334–5344 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sheaff, R. J., Groudine, M., Gordon, M., Roberts, J. M. & Clurman, B. E. Cyclin E-CDK2 is a regulator of p27Kip1. Genes Dev. 11, 1464–1478 (1997).

    CAS  PubMed  Google Scholar 

  27. Malek, N. P. et al. A mouse knock-in model exposes sequential proteolytic pathways that regulate p27Kip1 in G1 and S phase. Nature 413, 323–327 (2001).

    Article  CAS  PubMed  Google Scholar 

  28. Mamillapalli, R. et al. PTEN regulates the ubiquitin-dependent degradation of the CDK inhibitor p27KIP1 through the ubiquitin E3 ligase SCFSKP2. Curr. Biol. 11, 263–267 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. Medema, R. H., Kops, G. J., Bos, J. L. & Burgering, B. M. AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1. Nature 404, 782–787 (2000). Showed that RAS-induced transcriptional repression of p27KIP1 occurs through the effects of AKT/PKB on forkhead transcription factors.

    Article  CAS  PubMed  Google Scholar 

  30. Kops, G. J. et al. Direct control of the Forkhead transcription factor AFX by protein kinase B. Nature 398, 630–634 (1999).

    Article  CAS  PubMed  Google Scholar 

  31. de Ruiter, N. D., Burgering, B. M. & Bos, J. L. Regulation of the Forkhead transcription factor AFX by Ral-dependent phosphorylation of threonines 447 and 451. Mol. Cell. Biol. 21, 8225–8235 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Liu, Y., Martindale, J. L., Gorospe, M. & Holbrook, N. J. Regulation of p21WAF1/CIP1 expression through mitogen-activated protein kinase signaling pathway. Cancer Res. 56, 31–35 (1996).

    CAS  PubMed  Google Scholar 

  33. Bottazzi, M. E., Zhu, X., Bohmer, R. M. & Assoian, R. K. Regulation of p21cip1 expression by growth factors and the extracellular matrix reveals a role for transient ERK activity in G1 phase. J. Cell Biol. 146, 1255–1264 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. LaBaer, J. et al. New functional activities for the p21 family of CDK inhibitors. Genes Dev. 11, 847–862 (1997).

    Article  CAS  PubMed  Google Scholar 

  35. Cheng, M. et al. The p21Cip1 and p27Kip1 CDK 'inhibitors' are essential activators of cyclin D-dependent kinases in murine fibroblasts. EMBO J. 18, 1571–1583 (1999). Along with reference 34, describes the function of p21 and p27 as assembly factors for cyclin–CDK complexes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Alt, J. R., Gladden, A. B. & Diehl, J. A. p21Cip1 Promotes cyclin D1 nuclear accumulation via direct inhibition of nuclear export. J. Biol. Chem. 277, 8517–8523 (2002).

    Article  CAS  PubMed  Google Scholar 

  37. Rajasekhar, V. K. et al. Oncogenic Ras and Akt signaling contribute to glioblastoma formation by differential recruitment of existing mRNAs to polysomes. Mol. Cell 12, 889–901 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Hidalgo, M. & Rowinsky, E. K. The rapamycin-sensitive signal transduction pathway as a target for cancer therapy. Oncogene 19, 6680–6686 (2000).

    Article  CAS  PubMed  Google Scholar 

  39. Hashemolhosseini, S. et al. Rapamycin inhibition of the G1 to S transition is mediated by effects on cyclin D1 mRNA and protein stability. J. Biol. Chem. 273, 14424–14429 (1998).

    Article  CAS  PubMed  Google Scholar 

  40. Kawamata, S., Sakaida, H., Hori, T., Maeda, M. & Uchiyama, T. The upregulation of p27Kip1 by rapamycin results in G1 arrest in exponentially growing T-cell lines. Blood 91, 561–569 (1998).

    Article  CAS  PubMed  Google Scholar 

  41. Nelsen, C. J., Rickheim, D. G., Tucker, M. M., Hansen, L. K. & Albrecht, J. H. Evidence that cyclin D1 mediates both growth and proliferation downstream of TOR in hepatocytes. J. Biol. Chem. 278, 3656–3663 (2003).

    Article  CAS  PubMed  Google Scholar 

  42. Nourse, J. et al. Interleukin-2-mediated elimination of the p27Kip1 cyclin-dependent kinase inhibitor prevented by rapamycin. Nature 372, 570–573 (1994).

    Article  CAS  PubMed  Google Scholar 

  43. Jiang, H., Coleman, J., Miskimins, R. & Miskimins, W. K. Expression of constitutively active 4EBP-1 enhances p27Kip1 expression and inhibits proliferation of MCF7 breast cancer cells. Cancer Cell Int. 3, 2 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Rousseau, D., Kaspar, R., Rosenwald, I., Gehrke, L. & Sonenberg, N. Translation initiation of ornithine decarboxylase and nucleocytoplasmic transport of cyclin D1 mRNA are increased in cells overexpressing eukaryotic initiation factor 4E. Proc. Natl Acad. Sci. USA 93, 1065–1070 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Lane, H. A., Fernandez, A., Lamb, N. J. & Thomas, G. p70S6K function is essential for G1 progression. Nature 363, 170–172 (1993). Demonstrated the crucial role of S6K, and therefore of the regulation of protein translation, in cell-cycle progression.

    Article  CAS  PubMed  Google Scholar 

  46. Dufner, A. & Thomas, G. Ribosomal S6 kinase signaling and the control of translation. Exp. Cell Res. 253, 100–109 (1999).

    Article  CAS  PubMed  Google Scholar 

  47. Kleijn, M., Scheper, G. C., Voorma, H. O. & Thomas, A. A. Regulation of translation initiation factors by signal transduction. Eur. J. Biochem. 253, 531–544 (1998).

    Article  CAS  PubMed  Google Scholar 

  48. Gao, X. & Pan, D. TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth. Genes Dev. 15, 1383–1392 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Potter, C. J., Huang, H. & Xu, T. Drosophila Tsc1 functions with Tsc2 to antagonize insulin signaling in regulating cell growth, cell proliferation, and organ size. Cell 105, 357–368 (2001).

    Article  CAS  PubMed  Google Scholar 

  50. Tapon, N., Ito, N., Dickson, B. J., Treisman, J. E. & Hariharan, I. K. The Drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation. Cell 105, 345–355 (2001). Together with references 48 and 49, revealed the roles of TSC1 and TSC2 in cell growth and proliferation.

    Article  CAS  PubMed  Google Scholar 

  51. Gao, X. et al. Tsc tumour suppressor proteins antagonize amino-acid–TOR signalling. Nature Cell Biol. 4, 699–704 (2002).

    Article  CAS  PubMed  Google Scholar 

  52. Goncharova, E. A. et al. Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation. A role for the TSC2 tumor suppressor gene in pulmonary lymphangioleiomyomatosis (LAM). J. Biol. Chem. 277, 30958–30967 (2002).

    Article  CAS  PubMed  Google Scholar 

  53. Inoki, K., Li, Y., Zhu, T., Wu, J. & Guan, K. L. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nature Cell Biol. 4, 648–657 (2002).

    Article  CAS  PubMed  Google Scholar 

  54. Jaeschke, A. et al. Tuberous sclerosis complex tumor suppressor-mediated S6 kinase inhibition by phosphatidylinositide-3-OH kinase is mTOR independent. J. Cell Biol. 159, 217–224 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Tee, A. R. et al. Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling. Proc. Natl Acad. Sci. USA 99, 13571–13576 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Manning, B. D., Tee, A. R., Logsdon, M. N., Blenis, J. & Cantley, L. C. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol. Cell 10, 151–162 (2002). References 51–56, published in quick succession, establish the involvement of the TSC complex in the regulation of S6K through TOR.

    Article  CAS  PubMed  Google Scholar 

  57. Soucek, T., Yeung, R. S. & Hengstschlager, M. Inactivation of the cyclin-dependent kinase inhibitor p27 upon loss of the tuberous sclerosis complex gene-2. Proc. Natl Acad. Sci. USA 95, 15653–15658 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ito, N. & Rubin, G. M. gigas, a Drosophila homolog of tuberous sclerosis gene product-2, regulates the cell cycle. Cell 96, 529–539 (1999).

    Article  CAS  PubMed  Google Scholar 

  59. Benvenuto, G. et al. The tuberous sclerosis-1 (TSC1) gene product hamartin suppresses cell growth and augments the expression of the TSC2 product tuberin by inhibiting its ubiquitination. Oncogene 19, 6306–6316 (2000).

    Article  CAS  PubMed  Google Scholar 

  60. Herbert, T. P., Tee, A. R. & Proud, C. G. The extracellular signal-regulated kinase pathway regulates the phosphorylation of 4E-BP1 at multiple sites. J. Biol. Chem. 277, 11591–11596 (2002).

    Article  CAS  PubMed  Google Scholar 

  61. von Manteuffel, S. R., Gingras, A. C., Ming, X. F., Sonenberg, N. & Thomas, G. 4E-BP1 phosphorylation is mediated by the FRAP-p70s6k pathway and is independent of mitogen-activated protein kinase. Proc. Natl Acad. Sci. USA 93, 4076–4080 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Lin, T. A., Kong, X., Saltiel, A. R., Blackshear, P. J. & Lawrence, J. C. Jr. Control of PHAS-I by insulin in 3T3-L1 adipocytes. Synthesis, degradation, and phosphorylation by a rapamycin-sensitive and mitogen-activated protein kinase-independent pathway. J. Biol. Chem. 270, 18531–18538 (1995).

    Article  CAS  PubMed  Google Scholar 

  63. Rolli-Derkinderen, M. et al. ERK and p38 inhibit the expression of 4E-BP1 repressor of translation through induction of Egr-1. J. Biol. Chem. 278, 18859–18867 (2003).

    Article  CAS  PubMed  Google Scholar 

  64. Ming, X. F. et al. Activation of p70/p85 S6 kinase by a pathway independent of p21ras. Nature 371, 426–429 (1994).

    Article  CAS  PubMed  Google Scholar 

  65. Lehman, J. A., Calvo, V. & Gomez-Cambronero, J. Mechanism of ribosomal p70S6 kinase activation by granulocyte macrophage colony-stimulating factor in neutrophils: cooperation of a MEK-related, THR421/SER424 kinase and a rapamycin-sensitive, m-TOR-related THR389 kinase. J. Biol. Chem. 278, 28130–28138 (2003).

    Article  CAS  PubMed  Google Scholar 

  66. Martin, K. A., Schalm, S. S., Romanelli, A., Keon, K. L. & Blenis, J. Ribosomal S6 kinase 2 inhibition by a potent C-terminal repressor domain is relieved by mitogen-activated protein-extracellular signal-regulated kinase kinase-regulated phosphorylation. J. Biol. Chem. 276, 7892–7898 (2001).

    Article  CAS  PubMed  Google Scholar 

  67. Tee, A. R., Anjum, R. & Blenis, J. Inactivation of the tuberous sclerosis complex-1 and-2 gene products occurs by phosphoinositide 3-kinase (PI3K)/Akt-dependent and-independent phosphorylation of tuberin. J. Biol. Chem. 278, 37288–37296 (2003).

    Article  CAS  PubMed  Google Scholar 

  68. Basu, T. N. et al. Aberrant regulation of ras proteins in malignant tumour cells from type 1 neurofibromatosis patients. Nature 356, 713–715 (1992).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  70. The European Chromosome 16 Tuberous Sclerosis Consortium. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 75, 1305–1315 (1993).

  71. Wienecke, R., Konig, A. & DeClue, J. E. Identification of tuberin, the tuberous sclerosis-2 product. Tuberin possesses specific Rap1GAP activity. J. Biol. Chem. 270, 16409–16414 (1995).

    Article  CAS  PubMed  Google Scholar 

  72. Xiao, G. H., Shoarinejad, F., Jin, F., Golemis, E. A. & Yeung, R. S. The tuberous sclerosis 2 gene product, tuberin, functions as a Rab5 GTPase activating protein (GAP) in modulating endocytosis. J. Biol. Chem. 272, 6097–6100 (1997).

    Article  CAS  PubMed  Google Scholar 

  73. Castro, A. F., Rebhun, J. F., Clark, G. G. & Quilliam, L. A. Rheb binds TSC2 and promotes S6 kinase activation in a rapamycin- and farnesylation-dependent manner. J. Biol. Chem. 278, 32493–32496 (2003).

    Article  CAS  PubMed  Google Scholar 

  74. Garami, A. et al. Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Mol. Cell 11, 1457–1466 (2003).

    Article  CAS  PubMed  Google Scholar 

  75. Zhang, Y. et al. Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nature Cell Biol. 5, 578–581 (2003).

    Article  CAS  PubMed  Google Scholar 

  76. Saucedo, L. J. et al. Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nature Cell Biol. 5, 566–571 (2003).

    Article  CAS  PubMed  Google Scholar 

  77. Stocker, H. et al. Rheb is an essential regulator of S6K in controlling cell growth in Drosophila. Nature Cell Biol. 5, 559–566 (2003). References 74–77 put RHEB into the pathway of TOR–S6K regulation by the TSC complex.

    Article  CAS  PubMed  Google Scholar 

  78. Yee, W. M. & Worley, P. F. Rheb interacts with Raf-1 kinase and may function to integrate growth factor- and protein kinase A-dependent signals. Mol. Cell. Biol. 17, 921–933 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Gromov, P. S., Madsen, P. & Tomerup, N., Celis, J. E. A novel approach for expression cloning of small GTPases: identification, tissue distribution and chromosome mapping of the human homolog of rheb. FEBS Lett. 377, 221–226 (1995).

    Article  CAS  PubMed  Google Scholar 

  80. Mach, K. E., Furge, K. A. & Albright, C. F. Loss of Rhb1, a Rheb-related GTPase in fission yeast, causes growth arrest with a terminal phenotype similar to that caused by nitrogen starvation. Genetics 155, 611–622 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Patel, P. H. et al. Drosophila Rheb GTPase is required for cell cycle progression and cell growth. J. Cell Sci. 116, 3601–3610 (2003).

    Article  CAS  PubMed  Google Scholar 

  82. Tee, A. R., Manning, B. D., Roux, P. P., Cantley, L. C. & Blenis, J. Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr. Biol. 13, 1259–1268 (2003).

    Article  CAS  PubMed  Google Scholar 

  83. Inoki, K., Li, Y., Xu, T. & Guan, K. L. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev. 17, 1829–1834 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Dan, H. C. et al. Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin. J. Biol. Chem. 277, 35364–35370 (2002).

    Article  CAS  PubMed  Google Scholar 

  85. Zhang, H., Stallock, J. P., Ng, J. C., Reinhard, C. & Neufeld, T. P. Regulation of cellular growth by the Drosophila target of rapamycin dTOR. Genes Dev. 14, 2712–2724 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Mak, B. C., Takemaru, K., Kenerson, H. L., Moon, R. T. & Yeung, R. S. The tuberin–hamartin complex negatively regulates β-catenin signaling activity. J. Biol. Chem. 278, 5947–5951 (2003).

    Article  CAS  PubMed  Google Scholar 

  87. Urano, T., Emkey, R. & Feig, L. A. Ral-GTPases mediate a distinct downstream signaling pathway from Ras that facilitates cellular transformation. EMBO J. 15, 810–816 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. White, M. A., Vale, T., Camonis, J. H., Schaefer, E. & Wigler, M. H. A role for the Ral guanine nucleotide dissociation stimulator in mediating Ras-induced transformation. J. Biol. Chem. 271, 16439–16442 (1996). Along with reference 87, this paper revealed the crucial contribution of RAL in RAS signalling that leads to cell proliferation.

    Article  CAS  PubMed  Google Scholar 

  89. Rosario, M., Paterson, H. F. & Marshall, C. J. Activation of the Ral and phosphatidylinositol 3′ kinase signaling pathways by the ras-related protein TC21. Mol. Cell. Biol. 21, 3750–3762 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Henry, D. O. et al. Ral GTPases contribute to regulation of cyclin D1 through activation of NF-κB. Mol. Cell. Biol. 20, 8084–8092 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Chien, Y. & White, M. A. RAL GTPases are linchpin modulators of human tumour-cell proliferation and survival. EMBO Rep. 4, 800–806 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Self, A. J., Caron, E., Paterson, H. F. & Hall, A. Analysis of R-Ras signalling pathways. J. Cell Sci. 114, 1357–1366 (2001).

    Article  CAS  PubMed  Google Scholar 

  93. Rosario, M., Paterson, H. F. & Marshall, C. J. Activation of the Raf/MAP kinase cascade by the Ras-related protein TC21 is required for the TC21-mediated transformation of NIH 3T3 cells. EMBO J. 18, 1270–1279 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Marte, B. M., Rodriguez-Viciana, P., Wennstrom, S., Warne, P. H. & Downward, J. R-Ras can activate the phosphoinositide 3-kinase but not the MAP kinase arm of the Ras effector pathways. Curr. Biol. 7, 63–70 (1997).

    Article  CAS  PubMed  Google Scholar 

  95. Kimmelman, A. C., Osada, M. & Chan, A. M. R-Ras3, a brain-specific Ras-related protein, activates Akt and promotes cell survival in PC12 cells. Oncogene 19, 2014–2022 (2000).

    Article  CAS  PubMed  Google Scholar 

  96. Graham, S. M. et al. Aberrant function of the Ras-related protein TC21/R-Ras2 triggers malignant transformation. Mol. Cell. Biol. 14, 4108–4115 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Yamamoto, M. et al. ADP-ribosylation of the rhoA gene product by botulinum C3 exoenzyme causes Swiss 3T3 cells to accumulate in the G1 phase of the cell cycle. Oncogene 8, 1449–1455 (1993).

    CAS  PubMed  Google Scholar 

  98. Olson, M. F., Ashworth, A. & Hall, A. An essential role for Rho, Rac, and Cdc42 GTPases in cell cycle progression through G1. Science 269, 1270–1272 (1995). Along with reference 97, demonstrates the essential role of Rho GTPases in cell proliferation.

    Article  CAS  PubMed  Google Scholar 

  99. Olson, M. F., Paterson, H. F. & Marshall, C. J. Signals from Ras and Rho GTPases interact to regulate expression of p21Waf1/Cip1. Nature 394, 295–299 (1998). Showed that Rho contributes to RAS-induced cell-cycle progression through repression of p21CIP1.

    Article  CAS  PubMed  Google Scholar 

  100. Lloyd, A. C. et al. Cooperating oncogenes converge to regulate cyclin/cdk complexes. Genes Dev. 11, 663–677 (1997).

    Article  CAS  PubMed  Google Scholar 

  101. Pumiglia, K. M. & Decker, S. J. Cell cycle arrest mediated by the MEK/mitogen-activated protein kinase pathway. Proc. Natl Acad. Sci. USA 94, 448–452 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Sewing, A., Wiseman, B., Lloyd, A. C. & Land, H. High-intensity Raf signal causes cell cycle arrest mediated by p21Cip1. Mol. Cell. Biol. 17, 5588–5597 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Woods, D. et al. Raf-induced proliferation or cell cycle arrest is determined by the level of Raf activity with arrest mediated by p21Cip1. Mol. Cell. Biol. 17, 5598–5611 (1997). References 100–103 showed that the intensity of signalling through the Raf–MEK–ERK/MAPK pathway determines whether cells proliferate or undergo p21-mediated cell-cycle arrest.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Auer, K. L. et al. Prolonged activation of the mitogen-activated protein kinase pathway promotes DNA synthesis in primary hepatocytes from p21Cip-1/WAF1-null mice, but not in hepatocytes from p16INK4a-null mice. Biochem. J. 336, 551–560 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Zuckerbraun, B. S., Shapiro, R. A., Billiar, T. R. & Tzeng, E. RhoA influences the nuclear localization of extracellular signal-regulated kinases to modulate p21Waf/Cip1 expression. Circulation 108, 876–881 (2003).

    Article  CAS  PubMed  Google Scholar 

  106. Lai, J. M., Wu, S., Huang, D. Y. & Chang, Z. F. Cytosolic retention of phosphorylated extracellular signal-regulated kinase and a Rho-associated kinase-mediated signal impair expression of p21(Cip1/Waf1) in phorbol 12-myristate-13-acetate-induced apoptotic cells. Mol. Cell. Biol. 22, 7581–7592 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Sahai, E., Ishizaki, T., Narumiya, S. & Treisman, R. Transformation mediated by RhoA requires activity of ROCK kinases. Curr. Biol. 9, 136–145 (1999).

    Article  CAS  PubMed  Google Scholar 

  108. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Roovers, K. & Assoian, R. K. Effects of rho kinase and actin stress fibers on sustained extracellular signal-regulated kinase activity and activation of G(1) phase cyclin-dependent kinases. Mol. Cell. Biol. 23, 4283–4294 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Noren, N. K., Niessen, C. M., Gumbiner, B. M. & Burridge, K. Cadherin engagement regulates Rho family GTPases. J. Biol. Chem. 276, 33305–33308 (2001).

    Article  CAS  PubMed  Google Scholar 

  111. Bao, W., Thullberg, M., Zhang, H., Onischenko, A. & Stromblad, S. Cell attachment to the extracellular matrix induces proteasomal degradation of p21CIP1 via Cdc42/Rac1 signaling. Mol. Cell. Biol. 22, 4587–4597 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Hirai, A. et al. Geranylgeranylated rho small GTPase(s) are essential for the degradation of p27Kip1 and facilitate the progression from G1 to S phase in growth-stimulated rat FRTL-5 cells. J. Biol. Chem. 272, 13–16 (1997).

    Article  CAS  PubMed  Google Scholar 

  113. Laufs, U., Marra, D., Node, K. & Liao, J. K. 3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors attenuate vascular smooth muscle proliferation by preventing rho GTPase-induced down-regulation of p27(Kip1). J. Biol. Chem. 274, 21926–21931 (1999).

    Article  CAS  PubMed  Google Scholar 

  114. Hu, Z. Y., Madamanchi, N. R. & Rao, G. N. cAMP inhibits linoleic acid-induced growth by antagonizing p27kip1 depletion, but not interfering with the extracellular signal-regulated kinase or AP-1 activities. Biochim. Biophys. Acta 1405, 139–146 (1998).

    Article  CAS  PubMed  Google Scholar 

  115. Hu, W., Bellone, C. J. & Baldassare, J. J. RhoA stimulates p27Kip degradation through its regulation of cyclin E/CDK2 activity. J. Biol. Chem. 274, 3396–3401 (1999).

    Article  CAS  PubMed  Google Scholar 

  116. Adnane, J., Bizouarn, F. A., Qian, Y., Hamilton, A. D. & Sebti, S. M. p21WAF1/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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. 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).

    Article  CAS  PubMed  Google Scholar 

  118. Vidal, A., Millard, S. S., Miller, J. P. & Koff, A. Rho activity can alter the translation of p27 mRNA and is important for RasV12-induced transformation in a manner dependent on p27 status. J. Biol. Chem. 277, 16433–16440 (2002).

    Article  CAS  PubMed  Google Scholar 

  119. Roovers, K., Davey, G., Zhu, X., Bottazzi, M. E. & Assoian, R. K. α5β1 integrin controls cyclin D1 expression by sustaining mitogen-activated protein kinase activity in growth factor-treated cells. Mol. Biol. Cell 10, 3197–3204 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Welsh, C. F. et al. Timing of cyclin D1 expression within G1 phase is controlled by Rho. Nature Cell Biol. 3, 950–957 (2001). Along with references 119 and 133, this paper revealed the contribution of integrin signalling through Rho GTPases to the elevation of cyclin-D1 levels.

    Article  CAS  PubMed  Google Scholar 

  121. Roovers, K., Klein, E. A., Castagnino, P. & Assoian, R. K. Nuclear translocation of LIM kinase mediates Rho–Rho kinase regulation of cyclin D1 expression. Dev. Cell 5, 273–284 (2003).

    Article  CAS  PubMed  Google Scholar 

  122. 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).

    Article  CAS  PubMed  Google Scholar 

  123. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Gjoerup, O., Lukas, J., Bartek, J. & Willumsen, B. M. Rac and Cdc42 are potent stimulators of E2F-dependent transcription capable of promoting retinoblastoma susceptibility gene product hyperphosphorylation. J. Biol. Chem. 273, 18812–18818 (1998).

    Article  CAS  PubMed  Google Scholar 

  125. Page, K. et al. Characterization of a Rac1 signaling pathway to cyclin D(1) expression in airway smooth muscle cells. J. Biol. Chem. 274, 22065–22071 (1999).

    Article  CAS  PubMed  Google Scholar 

  126. 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).

    Article  CAS  PubMed  Google Scholar 

  127. 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).

    Article  CAS  PubMed  Google Scholar 

  128. 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).

    CAS  PubMed  Google Scholar 

  129. Romanelli, A., Martin, K. A., Toker, A. & Blenis, J. p70 S6 kinase is regulated by protein kinase Cζ and participates in a phosphoinositide 3-kinase-regulated signalling complex. Mol. Cell. Biol. 19, 2921–2928 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Chou, M. M. & Blenis, J. The 70 kDa S6 kinase complexes with and is activated by the Rho family G proteins Cdc42 and Rac1. Cell 85, 573–583 (1996).

    Article  CAS  PubMed  Google Scholar 

  131. Lambert, J. M., Karnoub, A. E., Graves, L. M., Campbell, S. L. & Der, C. J. Role of MLK3-mediated activation of p70 S6 kinase in Rac1 transformation. J. Biol. Chem. 277, 4770–4777 (2002).

    Article  CAS  PubMed  Google Scholar 

  132. Chou, M. M., Masuda-Robens, J. M. & Gupta, M. L. Cdc42 promotes G1 progression through p70S6k-mediated induction of cyclin E expression. J. Biol. Chem. 278, 35241–35247 (2003).

    Article  CAS  PubMed  Google Scholar 

  133. 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).

    Article  CAS  PubMed  Google Scholar 

  134. Miyoshi, J., Kagimoto, M., Soeda, E. & Sakaki, Y. The human c-Ha-ras2 is a processed pseudogene inactivated by numerous base substitutions. Nucleic Acids Res. 12, 1821–1828 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Takahashi, K., Mitsui, K. & Yamanaka, S. Role of ERas in promoting tumour-like properties in mouse embryonic stem cells. Nature 423, 541–545 (2003).

    Article  CAS  PubMed  Google Scholar 

  136. Jirmanova, L., Afanassieff, M., Gobert-Gosse, S., Markossian, S. & Savatier, P. Differential contributions of ERK and PI3-kinase to the regulation of cyclin D1 expression and to the control of the G1/S transition in mouse embryonic stem cells. Oncogene 21, 5515–5528 (2002).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We apologize to our colleagues whose work could not be cited because of space restrictions. Work in the Olson laboratory is supported by the American Cancer Society and the National Institutes of Health. Research in the Marshall laboratory is supported by Cancer Research UK.

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Authors and Affiliations

  1. Abramson Family Cancer Research Institute, BRB II/III, 421 Curie Boulevard, University of Pennsylvania, Philadelphia, 19104-6160, Pennsylvania, USA

    Mathew L. Coleman & Michael F. Olson

  2. The Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK

    Christopher J. Marshall

Authors
  1. Mathew L. Coleman
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  2. Christopher J. Marshall
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Correspondence to Michael F. Olson.

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Related links

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DATABASES

LocusLink

CDC42

CHP

E-RAS

H-RAS

K-RAS

M-RAS

N-RAS

RAC1

RAC2

RAC3

RALA

RALB

RAP1A

RAP1B

RAP2A

RAP2B

RAP2C

RHEB

RHEBL1

RHOA

RHOB

RHOBTB1

RHOBTB2

RHOBTB3

RHOC

RHOD

RHOE

RHOG

RHOH

RIF

RIT1

RIT2

RND1

RND2

R-RAS

TC10

TC21

TCL

WRCH1

FURTHER INFORMATION

MultAlin multiple sequence alignment program

Glossary

QUIESCENT

The state of a cell that has exited the cell cycle and is in the G0 ('resting') phase.

DOMINANT-NEGATIVE

A protein containing a mutation that adversely affects the function of the corresponding, normal wild-type protein within the same cell. For small GTPases, dominant-negatives are inactive proteins with a reduced affinity for GTP that inhibit the wild-type proteins by binding and sequestering guanine-nucleotide-exchange factors.

AP-1 SITE

The palindromic DNA sequence TGACTCA, which serves as a binding site for transcription-factor complexes formed from heterodimers of FOS- and JUN-family proteins.

PROTEASOME

A large multisubunit protease complex that selectively degrades multi-ubiquitylated proteins. It contains a 20S particle that incorporates the catalytic activity, and two regulatory 19S particles.

FORKHEAD TRANSCRIPTION-FACTOR FAMILY

A family consisting of more than 40 members, which belong to the winged-helix class of DNA-binding proteins and are involved in diverse cellular functions, including glucose metabolism, apoptosis and cell-cycle regulation.

F-BOX

A domain found in the F-box family of proteins that binds and recruits protein substrates to SKP1/CUL1/F-box protein (SCF) E3 ubiquitin ligases. F-box proteins mediate the interaction between the substrate and the ubiquitin ligase, which results in substrate ubiquitylation and degradation by the proteasome.

E3 UBIQUITIN LIGASE

The final enzyme complex in the ubiquitin-conjugation pathway. E3 enzymes transfer ubiquitin from previous components of the pathway to the substrate protein to form a covalently linked ubiquitin–substrate conjugate, which is then degraded by the proteasome.

POLYSOME

Or polyribosome; two or more ribosomes attached to different points on the same strand of mRNA.

TOP TRACTS

Terminal oligopyrimidine (TOP) tract. An uninterrupted sequence of 4–20 pyrimidines that is typically found in the 5′-untranslated region of messenger RNAs that encode components of the mammalian translational apparatus.

GTPase-ACTIVATING PROTEIN

(GAP). A protein that stimulates the intrinsic ability of a GTPase to hydrolyse GTP to GDP. Therefore, GAPs negatively regulate GTPases by converting them from active (GTP-bound) to inactive (GDP-bound).

EPISTASIS

A genetic interaction between two alleles. Epistatic analysis studies the genetic interaction between gene products in a signalling pathway. By determining the phenotypes of single and double mutants, the functional order of the components can be inferred.

RNA INTERFERENCE

The use of double-stranded RNAs, with sequences that precisely match a given gene, to 'knock down' the expression of that gene by directing RNA-degrading enzymes to destroy the encoded mRNA transcript.

T-LOOP

A structural loop that is highly conserved in the catalytic domains of protein kinases. Phosphorylation of this transactivation loop is often required for full catalytic activity.

FARNESYLATION

A post-translational modification in which a farnesyl group (a hydrophobic group of three isoprene units) is conjugated to proteins, such as RAS GTPases, that contain a carboxy-terminal CAAX motif. Farnesylation promotes attachment of the modified proteins to membranes.

STRESS FIBRES

A component of the actin cytoskeleton that consists of contractile bundles of actin and myosin II, which terminate in adhesion plaques that link the actin cytoskeleton to the cell surface. Stress fibres are involved in cell adhesion and the generation of tensile force.

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Coleman, M., Marshall, C. & Olson, M. RAS and RHO GTPases in G1-phase cell-cycle regulation. Nat Rev Mol Cell Biol 5, 355–366 (2004). https://doi.org/10.1038/nrm1365

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