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Ras oncogenes: split personalities

Key Points

  • Oncogenic mutations of Ras, which are found in human tumours, tumour cell lines and in carcinogen-induced experimental tumours, cause the hyper-activation of the Ras proteins.

  • Ras proteins are GTPases that shuttle between the inactive GDP-bound and the active GTP-bound states. This nucleotide switching is regulated by guanine nucleotide exchange factors (GEFs), which favour the accumulation of RasGTP, and GTPase-activating proteins (GAPs), which facilitate GTP hydrolysis. Oncogenic mutations of Ras proteins are GAP-insensitive and are chronically active.

  • Active GTP-bound Ras proteins activate signalling pathways by engaging partners called effectors. These effectors initiate a cascade of signal transduction events that control processes, such as gene expression, cell-cycle progression, membrane trafficking, motility and survival.

  • De-regulated Ras signalling causes a series of congenital developmental disorders collectively known as cardio-facio-cutaneous syndromes. These diseases include neurofibromatosis type-1, Costello and Noonan syndromes, and are characterized by the accumulation of sporadic tumours, as well as skeletal, cardiac and visual abnormalities.

  • The enzymes involved in the post-translational processing of Ras have been attractive drug targets for cancer therapy. Among them are the farnesyltransferase inhibitors (FTIs), which inhibit the critical farnesylation reaction.

Abstract

Extensive research on the Ras proteins and their functions in cell physiology over the past 30 years has led to numerous insights that have revealed the involvement of Ras not only in tumorigenesis but also in many developmental disorders. Despite great strides in our understanding of the molecular and cellular mechanisms of action of the Ras proteins, the expanding roster of their downstream effectors and the complexity of the signalling cascades that they regulate indicate that much remains to be learnt.

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Figure 1: The Ras family of small GTPases.
Figure 2: C-terminal processing of Ras proteins.
Figure 3: Recycling of Ras proteins.
Figure 4: Anatomy of Ras regulation.
Figure 5: Ras signalling networks.

References

  1. DeFeo, D. et al. Analysis of two divergent rat genomic clones homologous to the transforming gene of Harvey murine sarcoma virus. Proc. Natl Acad. Sci. USA 78, 3328–3332 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Ellis, R. W., DeFeo, D., Furth, M. E. & Scolnick, E. M. Mouse cells contain two distinct ras gene mRNA species that can be translated into a p21 onc protein. Mol. Cell. Biol. 2, 1339–1345 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Chang, E. H., Gonda, M. A., Ellis, R. W., Scolnick, E. M. & Lowy, D. R. Human genome contains four genes homologous to transforming genes of Harvey and Kirsten murine sarcoma viruses. Proc. Natl Acad. Sci. USA 79, 4848–4852 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Stehelin, D., Varmus, H. E., Bishop, J. M. & Vogt, P. K. DNA related to the transforming gene(s) of avian sarcoma viruses is present in normal avian DNA. Nature 260, 170–173 (1976).

    CAS  PubMed  Google Scholar 

  5. Parada, L. F., Tabin, C. J., Shih, C. & Weinberg, R. A. Human EJ bladder carcinoma oncogene is homologue of Harvey sarcoma virus ras gene. Nature 297, 474–478 (1982).

    CAS  PubMed  Google Scholar 

  6. Der, C. J., Krontiris, T. G. & Cooper, G. M. Transforming genes of human bladder and lung carcinoma cell lines are homologous to the ras genes of Harvey and Kirsten sarcoma viruses. Proc. Natl Acad. Sci. USA 79, 3637–3640 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Santos, E., Tronick, S. R., Aaronson, S. A., Pulciani, S. & Barbacid, M. T24 human bladder carcinoma oncogene is an activated form of the normal human homologue of BALB- and Harvey-MSV transforming genes. Nature 298, 343–347 (1982).

    CAS  PubMed  Google Scholar 

  8. Tabin, C. J. et al. Mechanism of activation of a human oncogene. Nature 300, 143–149 (1982).

    CAS  PubMed  Google Scholar 

  9. Reddy, E. P., Reynolds, R. K., Santos, E. & Barbacid, M. A point mutation is responsible for the acquisition of transforming properties by the T24 human bladder carcinoma oncogene. Nature 300, 149–152 (1982).

    CAS  PubMed  Google Scholar 

  10. Taparowsky, E. et al. Activation of the T24 bladder carcinoma transforming gene is linked to a single amino acid change. Nature 300, 762–765 (1982).

    CAS  PubMed  Google Scholar 

  11. Capon, D. J., Chen, E. Y., Levinson, A. D., Seeburg, P. H. & Goeddel, D. V. Complete nucleotide sequences of the T24 human bladder carcinoma oncogene and its normal homologue. Nature 302, 33–37 (1983). References 6–11 established that oncogenic activation of Ras is caused by point mutations of the endogenous gene.

    CAS  PubMed  Google Scholar 

  12. Shimizu, K. et al. Three human transforming genes are related to the viral ras oncogenes. Proc. Natl Acad. Sci. USA 80, 2112–2116 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Hall, A., Marshall, C. J., Spurr, N. K. & Weiss, R. A. Identification of transforming gene in two human sarcoma cell lines as a new member of the ras gene family located on chromosome 1. Nature 303, 396–400 (1983).

    CAS  PubMed  Google Scholar 

  14. Taparowsky, E., Shimizu, K., Goldfarb, M. & Wigler, M. Structure and activation of the human N-ras gene. Cell 34, 581–586 (1983).

    CAS  PubMed  Google Scholar 

  15. Murray, M. J. et al. The HL-60 transforming sequence: a ras oncogene coexisting with altered myc genes in hematopoietic tumors. Cell 33, 749–757 (1983).

    CAS  PubMed  Google Scholar 

  16. Newbold, R. F. & Overell, R. W. Fibroblast immortality is a prerequisite for transformation by EJ c-Ha-ras oncogene. Nature 304, 648–651 (1983).

    CAS  PubMed  Google Scholar 

  17. Land, H., Parada, L. F. & Weinberg, R. A. Tumorigenic conversion of primary embryo fibroblasts requires at least two cooperating oncogenes. Nature 304, 596–602 (1983).

    CAS  PubMed  Google Scholar 

  18. Ruley, H. E. Adenovirus early region 1A enables viral and cellular transforming genes to transform primary cells in culture. Nature 304, 602–606 (1983). References 16–18 proposed the notion that multiple pathways are required for cellular transformation.

    CAS  PubMed  Google Scholar 

  19. Rhim, J. S. et al. Neoplastic transformation of human epidermal keratinocytes by AD12-SV40 and Kirsten sarcoma viruses. Science 227, 1250–1252 (1985).

    CAS  PubMed  Google Scholar 

  20. Yoakum, G. H. et al. Transformation of human bronchial epithelial cells transfected by Harvey ras oncogene. Science 227, 1174–1179 (1985).

    CAS  PubMed  Google Scholar 

  21. Yancopoulos, G. D. et al. N-myc can cooperate with ras to transform normal cells in culture. Proc. Natl Acad. Sci. USA 82, 5455–5459 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Santos, E. et al. Malignant activation of a K-ras oncogene in lung carcinoma but not in normal tissue of the same patient. Science 223, 661–664 (1984).

    CAS  PubMed  Google Scholar 

  23. Nakano, H. et al. Isolation of transforming sequences of two human lung carcinomas: structural and functional analysis of the activated c-K-ras oncogenes. Proc. Natl Acad. Sci. USA 81, 71–75 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Hirai, H. et al. Activation of the c-K-ras oncogene in a human pancreas carcinoma. Biochem. Biophys. Res. Commun. 127, 168–174 (1985).

    CAS  PubMed  Google Scholar 

  25. Hand, P. H. et al. Monoclonal antibodies of predefined specificity detect activated ras gene expression in human mammary and colon carcinomas. Proc. Natl Acad. Sci. USA 81, 5227–5231 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Fujita, J. et al. Ha-ras oncogenes are activated by somatic alterations in human urinary tract tumours. Nature 309, 464–466 (1984).

    CAS  PubMed  Google Scholar 

  27. Gambke, C., Signer, E. & Moroni, C. Activation of N-ras gene in bone marrow cells from a patient with acute myeloblastic leukaemia. Nature 307, 476–478 (1984).

    CAS  PubMed  Google Scholar 

  28. Gambke, C., Hall, A. & Moroni, C. Activation of an N-ras gene in acute myeloblastic leukemia through somatic mutation in the first exon. Proc. Natl Acad. Sci. USA 82, 879–882 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Bos, J. L. et al. Amino-acid substitutions at codon 13 of the N-ras oncogene in human acute myeloid leukaemia. Nature 315, 726–730 (1985).

    CAS  PubMed  Google Scholar 

  30. Janssen, J. W., Steenvoorden, A. C., Collard, J. G. & Nusse, R. Oncogene activation in human myeloid leukemia. Cancer Res. 45, 3262–3267 (1985).

    CAS  PubMed  Google Scholar 

  31. Sklar, M. D. & Kitchingman, G. R. Isolation of activated ras transforming genes from two patients with Hodgkin's disease. Int. J. Radiat. Oncol. Biol. Phys. 11, 49–55 (1985).

    CAS  PubMed  Google Scholar 

  32. Padua, R. A., Barrass, N. C. & Currie, G. A. Activation of N-ras in a human melanoma cell line. Mol. Cell. Biol. 5, 582–585 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Sukumar, S., Notario, V., Martin-Zanca, D. & Barbacid, M. Induction of mammary carcinomas in rats by nitroso-methylurea involves malignant activation of H-ras-1 locus by single point mutations. Nature 306, 658–661 (1983).

    CAS  PubMed  Google Scholar 

  34. Balmain, A. & Pragnell, I. B. Mouse skin carcinomas induced in vivo by chemical carcinogens have a transforming Harvey-ras oncogene. Nature 303, 72–74 (1983).

    CAS  PubMed  Google Scholar 

  35. Balmain, A., Ramsden, M., Bowden, G. T. & Smith, J. Activation of the mouse cellular Harvey-ras gene in chemically induced benign skin papillomas. Nature 307, 658–660 (1984). References 33–35 indicated that chemical carcinogenesis caused mutations of ras sequences.

    CAS  PubMed  Google Scholar 

  36. Guerrero, I., Calzada, P., Mayer, A. & Pellicer, A. A molecular approach to leukemogenesis: mouse lymphomas contain an activated c-ras oncogene. Proc. Natl Acad. Sci. USA 81, 202–205 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Guerrero, I., Villasante, A., Corces, V. & Pellicer, A. Activation of a c-K-ras oncogene by somatic mutation in mouse lymphomas induced by γ radiation. Science 225, 1159–1162 (1984).

    CAS  PubMed  Google Scholar 

  38. Mizuki, K., Nose, K., Okamoto, H., Tsuchida, N. & Hayashi, K. Amplification of c-Ki-ras gene and aberrant expression of c-myc in WI-38 cells transformed in vitro by γ-irradiation. Biochem. Biophys. Res. Commun. 128, 1037–1043 (1985).

    CAS  PubMed  Google Scholar 

  39. Shih, T. Y., Papageorge, A. G., Stokes, P. E., Weeks, M. O. & Scolnick, E. M. Guanine nucleotide-binding and autophosphorylating activities associated with the p21src protein of Harvey murine sarcoma virus. Nature 287, 686–691 (1980).

    CAS  PubMed  Google Scholar 

  40. Gilman, A. G. G proteins: transducers of receptor-generated signals. Annu. Rev. Biochem. 56, 615–649 (1987).

    CAS  PubMed  Google Scholar 

  41. McGrath, J. P., Capon, D. J., Goeddel, D. V. & Levinson, A. D. Comparative biochemical properties of normal and activated human ras p21 protein. Nature 310, 644–649 (1984).

    CAS  PubMed  Google Scholar 

  42. Gibbs, J. B., Sigal, I. S., Poe, M. & Scolnick, E. M. Intrinsic GTPase activity distinguishes normal and oncogenic ras p21 molecules. Proc. Natl Acad. Sci. USA 81, 5704–5708 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Sweet, R. W. et al. The product of ras is a GTPase and the T24 oncogenic mutant is deficient in this activity. Nature 311, 273–275 (1984).

    CAS  PubMed  Google Scholar 

  44. Clark, R., Wong, G., Arnheim, N., Nitecki, D. & McCormick, F. Antibodies specific for amino acid 12 of the ras oncogene product inhibit GTP binding. Proc. Natl Acad. Sci. USA 82, 5280–5284 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Der, C. J., Finkel, T. & Cooper, G. M. Biological and biochemical properties of human rasH genes mutated at codon 61. Cell 44, 167–176 (1986).

    CAS  PubMed  Google Scholar 

  46. Trahey, M. & McCormick, F. A cytoplasmic protein stimulates normal N-ras p21 GTPase, but does not affect oncogenic mutants. Science 238, 542–545 (1987). References 41–46 established that oncogenic mutation of ras affects its nucleotide cycle.

    CAS  PubMed  Google Scholar 

  47. Shih, T. Y. et al. Identification of a precursor in the biosynthesis of the p21 transforming protein of harvey murine sarcoma virus. J. Virol. 42, 253–261 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Sefton, B. M., Trowbridge, I. S., Cooper, J. A. & Scolnick, E. M. The transforming proteins of Rous sarcoma virus, Harvey sarcoma virus and Abelson virus contain tightly bound lipid. Cell 31, 465–474 (1982).

    CAS  PubMed  Google Scholar 

  49. Willumsen, B. M., Christensen, A., Hubbert, N. L., Papageorge, A. G. & Lowy, D. R. The p21 ras C-terminus is required for transformation and membrane association. Nature 310, 583–586 (1984).

    CAS  PubMed  Google Scholar 

  50. Willumsen, B. M., Norris, K., Papageorge, A. G., Hubbert, N. L. & Lowy, D. R. Harvey murine sarcoma virus p21 ras protein: biological and biochemical significance of the cysteine nearest the carboxy terminus. EMBO J. 3, 2581–2585 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Srivastava, S. K., Lacal, J. C., Reynolds, S. H. & Aaronson, S. A. Antibody of predetermined specificity to a carboxy-terminal region of H-ras gene products inhibits their guanine nucleotide-binding function. Mol. Cell. Biol. 5, 3316–3319 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Casey, P. J., Solski, P. A., Der, C. J. & Buss, J. E. p21ras is modified by a farnesyl isoprenoid. Proc. Natl Acad. Sci. USA 86, 8323–8327 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Schafer, W. R. et al. Genetic and pharmacological suppression of oncogenic mutations in ras genes of yeast and humans. Science 245, 379–385 (1989).

    CAS  PubMed  Google Scholar 

  54. Reiss, Y., Goldstein, J. L., Seabra, M. C., Casey, P. J. & Brown, M. S. Inhibition of purified p21ras farnesyl:protein transferase by Cys-AAX tetrapeptides. Cell 62, 81–88 (1990).

    CAS  PubMed  Google Scholar 

  55. Schaber, M. D. et al. Polyisoprenylation of Ras in vitro by a farnesyl-protein transferase. J. Biol. Chem. 265, 14701–14704 (1990).

    CAS  PubMed  Google Scholar 

  56. Schafer, W. R. et al. Enzymatic coupling of cholesterol intermediates to a mating pheromone precursor and to the ras protein. Science 249, 1133–1139 (1990).

    CAS  PubMed  Google Scholar 

  57. Hancock, J. F., Paterson, H. & Marshall, C. J. A polybasic domain or palmitoylation is required in addition to the CAAX motif to localize p21ras to the plasma membrane. Cell 63, 133–139 (1990).

    CAS  PubMed  Google Scholar 

  58. Kamata, T. & Feramisco, J. R. Epidermal growth factor stimulates guanine nucleotide binding activity and phosphorylation of ras oncogene proteins. Nature 310, 147–150 (1984).

    CAS  PubMed  Google Scholar 

  59. 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).

    CAS  PubMed  Google Scholar 

  60. Hagag, N., Halegoua, S. & Viola, M. Inhibition of growth factor-induced differentiation of PC12 cells by microinjection of antibody to ras p21. Nature 319, 680–682 (1986).

    CAS  PubMed  Google Scholar 

  61. Campisi, J., Gray, H. E., Pardee, A. B., Dean, M. & Sonenshein, G. E. Cell-cycle control of c-myc but not c-ras expression is lost following chemical transformation. Cell 36, 241–247 (1984).

    CAS  PubMed  Google Scholar 

  62. Samid, D., Schaff, Z., Chang, E. H. & Friedman, R. M. Interferon-induced modulation of human ras oncogene expression. Prog. Clin. Biol. Res. 192, 265–268 (1985).

    CAS  PubMed  Google Scholar 

  63. Emanoil-Ravier, R. et al. Interferon-mediated regulation of myc and Ki-ras oncogene expression in long-term-treated murine viral transformed cells. J. Interferon Res. 5, 613–619 (1985).

    CAS  PubMed  Google Scholar 

  64. Samid, D., Chang, E. H. & Friedman, R. M. Development of transformed phenotype induced by a human ras oncogene is inhibited by interferon. Biochem. Biophys. Res. Commun. 126, 509–516 (1985).

    CAS  PubMed  Google Scholar 

  65. Korn, L. J., Siebel, C. W., McCormick, F. & Roth, R. A. Ras p21 as a potential mediator of insulin action in Xenopus oocytes. Science 236, 840–843 (1987).

    CAS  PubMed  Google Scholar 

  66. Hurley, J. B., Simon, M. I., Teplow, D. B., Robishaw, J. D. & Gilman, A. G. Homologies between signal transducing G proteins and ras gene products. Science 226, 860–862 (1984).

    CAS  PubMed  Google Scholar 

  67. Gibbs, J. B., Schaber, M. D., Allard, W. J., Sigal, I. S. & Scolnick, E. M. Purification of ras GTPase activating protein from bovine brain. Proc. Natl Acad. Sci. USA 85, 5026–5030 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Vogel, U. S. et al. Cloning of bovine GAP and its interaction with oncogenic ras p21. Nature 335, 90–93 (1988).

    CAS  PubMed  Google Scholar 

  69. Trahey, M. et al. Molecular cloning of two types of GAP complementary DNA from human placenta. Science 242, 1697–1700 (1988).

    CAS  PubMed  Google Scholar 

  70. Molloy, C. J. et al. PDGF induction of tyrosine phosphorylation of GTPase activating protein. Nature 342, 711–714 (1989).

    CAS  PubMed  Google Scholar 

  71. Xu, G. F. et al. The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell 62, 599–608 (1990).

    CAS  PubMed  Google Scholar 

  72. Ballester, R. et al. The NF1 locus encodes a protein functionally related to mammalian GAP and yeast IRA proteins. Cell 63, 851–859 (1990).

    CAS  PubMed  Google Scholar 

  73. Martin, G. A. et al. The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21. Cell 63, 843–849 (1990).

    CAS  PubMed  Google Scholar 

  74. Wallace, M. R. et al. Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science 249, 181–186 (1990).

    CAS  PubMed  Google Scholar 

  75. Robinson, L. C., Gibbs, J. B., Marshall, M. S., Sigal, I. S. & Tatchell, K. CDC25: a component of the RAS-adenylate cyclase pathway in Saccharomyces cerevisiae. Science 235, 1218–1221 (1987).

    CAS  PubMed  Google Scholar 

  76. Broek, D. et al. The S. cerevisiae CDC25 gene product regulates the RAS/adenylate cyclase pathway. Cell 48, 789–799 (1987).

    CAS  PubMed  Google Scholar 

  77. Wolfman, A. & Macara, I. G. A cytosolic protein catalyzes the release of GDP from p21ras. Science 248, 67–69 (1990).

    CAS  PubMed  Google Scholar 

  78. Downward, J., Riehl, R., Wu, L. & Weinberg, R. A. Identification of a nucleotide exchange-promoting activity for p21ras. Proc. Natl Acad. Sci. USA 87, 5998–6002 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. West, M., Kung, H. F. & Kamata, T. A novel membrane factor stimulates guanine nucleotide exchange reaction of ras proteins. FEBS Lett. 259, 245–248 (1990).

    CAS  PubMed  Google Scholar 

  80. Wei, W. et al. Identification of a mammalian gene structurally and functionally related to the CDC25 gene of Saccharomyces cerevisiae. Proc. Natl Acad. Sci. USA 89, 7100–7104 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Shou, C., Farnsworth, C. L., Neel, B. G. & Feig, L. A. Molecular cloning of cDNAs encoding a guanine-nucleotide-releasing factor for Ras p21. Nature 358, 351–354 (1992).

    CAS  PubMed  Google Scholar 

  82. Bowtell, D., Fu, P., Simon, M. & Senior, P. Identification of murine homologues of the Drosophila son of sevenless gene: potential activators of ras. Proc. Natl Acad. Sci. USA 89, 6511–6515 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Gale, N. W., Kaplan, S., Lowenstein, E. J., Schlessinger, J. & Bar-Sagi, D. Grb2 mediates the EGF-dependent activation of guanine nucleotide exchange on Ras. Nature 363, 88–92 (1993).

    CAS  PubMed  Google Scholar 

  84. Li, N. et al. Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling. Nature 363, 85–88 (1993).

    CAS  PubMed  Google Scholar 

  85. Rozakis-Adcock, M., Fernley, R., Wade, J., Pawson, T. & Bowtell, D. The SH2 and SH3 domains of mammalian Grb2 couple the EGF receptor to the Ras activator mSos1. Nature 363, 83–85 (1993).

    CAS  PubMed  Google Scholar 

  86. Egan, S. E. et al. Association of Sos Ras exchange protein with Grb2 is implicated in tyrosine kinase signal transduction and transformation. Nature 363, 45–51 (1993).

    CAS  PubMed  Google Scholar 

  87. Buday, L. & Downward, J. Epidermal growth factor regulates p21ras through the formation of a complex of receptor, Grb2 adapter protein, and Sos nucleotide exchange factor. Cell 73, 611–620 (1993).

    CAS  PubMed  Google Scholar 

  88. Bernards, A. GAPs galore! A survey of putative Ras superfamily GTPase activating proteins in man and Drosophila. Biochim. Biophys. Acta 1603, 47–82 (2003).

    CAS  PubMed  Google Scholar 

  89. Geyer, M. & Wittinghofer, A. GEFs, GAPs, GDIs and effectors: taking a closer (3D) look at the regulation of Ras-related GTP-binding proteins. Curr. Opin. Struct. Biol. 7, 786–792 (1997).

    CAS  PubMed  Google Scholar 

  90. Tucker, J. et al. Expression of p21 proteins in Escherichia coli and stereochemistry of the nucleotide-binding site. EMBO J. 5, 1351–1358 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Itoh, H. et al. Molecular cloning and sequence determination of cDNAs for α subunits of the guanine nucleotide-binding proteins Gs, Gi, and Go from rat brain. Proc. Natl Acad. Sci. USA 83, 3776–3780 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Clanton, D. J., Hattori, S. & Shih, T. Y. Mutations of the ras gene product p21 that abolish guanine nucleotide binding. Proc. Natl Acad. Sci. USA 83, 5076–5080 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Der, C. J., Pan, B. T. & Cooper, G. M. rasH mutants deficient in GTP binding. Mol. Cell. Biol. 6, 3291–3294 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Lacal, J. C., Anderson, P. S. & Aaronson, S. A. Deletion mutants of Harvey ras p21 protein reveal the absolute requirement of at least two distant regions for GTP-binding and transforming activities. EMBO J. 5, 679–687 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Sigal, I. S., Gibbs, J. B., D'Alonzo, J. S. & Scolnick, E. M. Identification of effector residues and a neutralizing epitope of Ha-ras-encoded p21. Proc. Natl Acad. Sci. USA 83, 4725–4729 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Stone, J. C., Vass, W. C., Willumsen, B. M. & Lowy, D. R. p21-ras effector domain mutants constructed by “cassette” mutagenesis. Mol. Cell. Biol. 8, 3565–3569 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Pai, E. F. et al. Structure of the guanine-nucleotide-binding domain of the Ha-ras oncogene product p21 in the triphosphate conformation. Nature 341, 209–214 (1989).

    CAS  PubMed  Google Scholar 

  98. Brunger, A. T. et al. Crystal structure of an active form of RAS protein, a complex of a GTP analog and the HRAS p21 catalytic domain. Proc. Natl Acad. Sci. USA 87, 4849–4853 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Milburn, M. V. et al. Molecular switch for signal transduction: structural differences between active and inactive forms of protooncogenic ras proteins. Science 247, 939–945 (1990).

    CAS  PubMed  Google Scholar 

  100. Schlichting, I. et al. Time-resolved X-ray crystallographic study of the conformational change in Ha-Ras p21 protein on GTP hydrolysis. Nature 345, 309–315 (1990).

    CAS  PubMed  Google Scholar 

  101. Tong, L. A. et al. Structural differences between a ras oncogene protein and the normal protein. Nature 337, 90–93 (1989).

    CAS  PubMed  Google Scholar 

  102. Krengel, U. et al. Three-dimensional structures of H-ras p21 mutants: molecular basis for their inability to function as signal switch molecules. Cell 62, 539–548 (1990).

    CAS  PubMed  Google Scholar 

  103. Scheffzek, K. et al. The Ras–RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants. Science 277, 333–338 (1997).

    CAS  PubMed  Google Scholar 

  104. 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). References 97–104 described the structural details of Ras activation.

    CAS  PubMed  Google Scholar 

  105. Bar-Sagi, D. & Feramisco, J. R. Induction of membrane ruffling and fluid-phase pinocytosis in quiescent fibroblasts by ras proteins. Science 233, 1061–1068 (1986).

    CAS  PubMed  Google Scholar 

  106. Backer, J. M. & Weinstein, I. B. p21 ras proteins and guanine nucleotides modulate the phosphorylation of 36- and 17-kilodalton mitochondria-associated proteins. Proc. Natl Acad. Sci. USA 83, 6357–6361 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Hegde, A. N. & Das, M. R. ras proteins enhance the phosphorylation of a 38 kDa protein (p38) in rat liver plasma membrane. FEBS Lett. 217, 74–80 (1987).

    CAS  PubMed  Google Scholar 

  108. Lacal, J. C. et al. Rapid stimulation of diacylglycerol production in Xenopus oocytes by microinjection of H-ras p21. Science 238, 533–536 (1987).

    CAS  PubMed  Google Scholar 

  109. Lacal, J. C., Moscat, J. & Aaronson, S. A. Novel source of 1,2-diacylglycerol elevated in cells transformed by Ha-ras oncogene. Nature 330, 269–272 (1987).

    CAS  PubMed  Google Scholar 

  110. Wolfman, A. & Macara, I. G. Elevated levels of diacylglycerol and decreased phorbol ester sensitivity in ras-transformed fibroblasts. Nature 325, 359–361 (1987).

    CAS  PubMed  Google Scholar 

  111. Fleischman, L. F., Chahwala, S. B. & Cantley, L. ras-transformed cells: altered levels of phosphatidylinositol-4,5-bisphosphate and catabolites. Science 231, 407–410 (1986).

    CAS  PubMed  Google Scholar 

  112. Lacal, J. C., Fleming, T. P., Warren, B. S., Blumberg, P. M. & Aaronson, S. A. Involvement of functional protein kinase C in the mitogenic response to the H-ras oncogene product. Mol. Cell. Biol. 7, 4146–4149 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Huang, M. et al. Enhancement of inositol phospholipid metabolism and activation of protein kinase C in ras-transformed rat fibroblasts. J. Biol. Chem. 263, 17975–17980 (1988).

    CAS  PubMed  Google Scholar 

  114. Fukami, K. et al. Antibody to phosphatidylinositol 4,5-bisphosphate inhibits oncogene-induced mitogenesis. Proc. Natl Acad. Sci. USA 85, 9057–9061 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Moodie, S. A., Willumsen, B. M., Weber, M. J. & Wolfman, A. Complexes of Ras.GTP with Raf-1 and mitogen-activated protein kinase kinase. Science 260, 1658–1661 (1993).

    CAS  PubMed  Google Scholar 

  116. Warne, P. H., Viciana, P. R. & Downward, J. Direct interaction of Ras and the amino-terminal region of Raf-1 in vitro. Nature 364, 352–355 (1993).

    CAS  PubMed  Google Scholar 

  117. Zhang, X. F. et al. Normal and oncogenic p21ras proteins bind to the amino-terminal regulatory domain of c-Raf-1. Nature 364, 308–313 (1993).

    CAS  PubMed  Google Scholar 

  118. Vojtek, A. B., Hollenberg, S. M. & Cooper, J. A. Mammalian Ras interacts directly with the serine/threonine kinase Raf. Cell 74, 205–214 (1993). References 115–118 described the physical and functional coupling of Ras to the Raf–MAPK effector pathway.

    CAS  PubMed  Google Scholar 

  119. Wood, K. W., Sarnecki, C., Roberts, T. M. & Blenis, J. ras mediates nerve growth factor receptor modulation of three signal-transducing protein kinases: MAP kinase, Raf-1, and RSK. Cell 68, 1041–1050 (1992).

    CAS  PubMed  Google Scholar 

  120. Leevers, S. J. & Marshall, C. J. Activation of extracellular signal-regulated kinase, ERK2, by p21ras oncoprotein. EMBO J. 11, 569–574 (1992).

    CAS  Google Scholar 

  121. Leevers, S. J., Paterson, H. F. & Marshall, C. J. Requirement for Ras in Raf activation is overcome by targeting Raf to the plasma membrane. Nature 369, 411–414 (1994).

    CAS  PubMed  Google Scholar 

  122. Stokoe, D., Macdonald, S. G., Cadwallader, K., Symons, M. & Hancock, J. F. Activation of Raf as a result of recruitment to the plasma membrane. Science 264, 1463–1467 (1994).

    CAS  PubMed  Google Scholar 

  123. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. White, M. A. et al. Multiple Ras functions can contribute to mammalian cell transformation. Cell 80, 533–541 (1995).

    CAS  PubMed  Google Scholar 

  125. Rajagopalan, H. et al. Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature 418, 934 (2002).

    CAS  PubMed  Google Scholar 

  126. Rodriguez-Viciana, P. et al. Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 370, 527–532 (1994).

    CAS  PubMed  Google Scholar 

  127. Hofer, F., Fields, S., Schneider, C. & Martin, G. S. Activated Ras interacts with the Ral guanine nucleotide dissociation stimulator. Proc. Natl Acad. Sci. USA 91, 11089–11093 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. Kikuchi, A., Demo, S. D., Ye, Z. H., Chen, Y. W. & Williams, L. T. ralGDS family members interact with the effector loop of ras p21. Mol. Cell. Biol. 14, 7483–7491 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Spaargaren, M. & Bischoff, J. R. Identification of the guanine nucleotide dissociation stimulator for Ral as a putative effector molecule of R-ras, H-ras, K-ras, and Rap. Proc. Natl Acad. Sci. USA 91, 12609–12613 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Rodriguez-Viciana, P. et al. Role of phosphoinositide 3-OH kinase in cell transformation and control of the actin cytoskeleton by Ras. Cell 89, 457–467 (1997).

    CAS  PubMed  Google Scholar 

  131. Marte, B. M. & Downward, J. PKB/Akt: connecting phosphoinositide 3-kinase to cell survival and beyond. Trends Biochem. Sci. 22, 355–358 (1997).

    CAS  PubMed  Google Scholar 

  132. Khwaja, A., Rodriguez-Viciana, P., Wennstrom, S., Warne, P. H. & Downward, J. Matrix adhesion and Ras transformation both activate a phosphoinositide 3-OH kinase and protein kinase B/Akt cellular survival pathway. EMBO J. 16, 2783–2793 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Mayo, M. W. et al. Requirement of NF-κB activation to suppress p53-independent apoptosis induced by oncogenic Ras. Science 278, 1812–1815 (1997).

    CAS  PubMed  Google Scholar 

  134. 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).

    CAS  PubMed  Google Scholar 

  135. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Hamad, N. M. et al. Distinct requirements for Ras oncogenesis in human versus mouse cells. Genes Dev. 16, 2045–2057 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Kelley, G. G., Reks, S. E., Ondrako, J. M. & Smrcka, A. V. Phospholipase Cɛ: a novel Ras effector. EMBO J. 20, 743–754 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Song, C. et al. Regulation of a novel human phospholipase, C, PLCɛ, through membrane targeting by Ras. J. Biol. Chem. 276, 2752–2757 (2001).

    CAS  PubMed  Google Scholar 

  140. Lopez, I., Mak, E. C., Ding, J., Hamm, H. E. & Lomasney, J. W. A novel bifunctional phospholipase C that is regulated by Gα12 and stimulates the Ras/mitogen-activated protein kinase pathway. J. Biol. Chem. 276, 2758–2765 (2001).

    CAS  PubMed  Google Scholar 

  141. 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  PubMed  Google Scholar 

  142. Malliri, A. et al. Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours. Nature 417, 867–871 (2002).

    CAS  PubMed  Google Scholar 

  143. Bai, Y. et al. Crucial role of phospholipase Cɛ in chemical carcinogen-induced skin tumor development. Cancer Res. 64, 8808–8810 (2004).

    CAS  PubMed  Google Scholar 

  144. Gupta, S. et al. Binding of Ras to phosphoinositide 3-kinase p110α is required for Ras-driven tumorigenesis in mice. Cell 129, 957–968 (2007).

    CAS  PubMed  Google Scholar 

  145. Gonzalez-Garcia, A. et al. RalGDS is required for tumor formation in a model of skin carcinogenesis. Cancer Cell 7, 219–226 (2005).

    CAS  PubMed  Google Scholar 

  146. Kuriyama, M. et al. Identification of AF-6 and canoe as putative targets for Ras. J. Biol. Chem. 271, 607–610 (1996).

    CAS  PubMed  Google Scholar 

  147. Ponting, C. P. & Benjamin, D. R. A novel family of Ras-binding domains. Trends Biochem. Sci. 21, 422–425 (1996).

    CAS  Google Scholar 

  148. Mandai, K. et al. Afadin: A novel actin filament-binding protein with one PDZ domain localized at cadherin-based cell-to-cell adherens junction. J. Cell Biol. 139, 517–528 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Han, L. & Colicelli, J. A human protein selected for interference with Ras function interacts directly with Ras and competes with Raf1. Mol. Cell. Biol. 15, 1318–1323 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Tall, G. G., Barbieri, M. A., Stahl, P. D. & Horazdovsky, B. F. Ras-activated endocytosis is mediated by the Rab5 guanine nucleotide exchange activity of RIN1. Dev. Cell 1, 73–82 (2001).

    CAS  PubMed  Google Scholar 

  151. Milstein, M. et al. RIN1 is a breast tumor suppressor gene. Cancer Res. 67, 11510–11516 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Vavvas, D., Li, X., Avruch, J. & Zhang, X. F. Identification of Nore1 as a potential Ras effector. J. Biol. Chem. 273, 5439–5442 (1998).

    CAS  PubMed  Google Scholar 

  153. Khokhlatchev, A. et al. Identification of a novel Ras-regulated proapoptotic pathway. Curr. Biol. 12, 253–265 (2002).

    CAS  PubMed  Google Scholar 

  154. Vos, M. D., Martinez, A., Ellis, C. A., Vallecorsa, T. & Clark, G. J. The pro-apoptotic Ras effector Nore1 may serve as a Ras-regulated tumor suppressor in the lung. J. Biol. Chem. 278, 21938–21943 (2003).

    CAS  PubMed  Google Scholar 

  155. Vos, M. D. et al. RASSF2 is a novel K-Ras-specific effector and potential tumor suppressor. J. Biol. Chem. 278, 28045–28051 (2003).

    CAS  PubMed  Google Scholar 

  156. Tommasi, S. et al. Tumor susceptibility of Rassf1a knockout mice. Cancer Res. 65, 92–98 (2005).

    CAS  PubMed  Google Scholar 

  157. Leon, J., Guerrero, I. & Pellicer, A. Differential expression of the ras gene family in mice. Mol. Cell. Biol. 7, 1535–1540 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Johnson, L. et al. K-ras is an essential gene in the mouse with partial functional overlap with N-ras. Genes Dev. 11, 2468–2481 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Koera, K. et al. K-ras is essential for the development of the mouse embryo. Oncogene 15, 1151–1159 (1997).

    CAS  PubMed  Google Scholar 

  160. Esteban, L. M. et al. Targeted genomic disruption of H-ras and N-ras, individually or in combination, reveals the dispensability of both loci for mouse growth and development. Mol. Cell. Biol. 21, 1444–1452 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Umanoff, H., Edelmann, W., Pellicer, A. & Kucherlapati, R. The murine N-ras gene is not essential for growth and development. Proc. Natl Acad. Sci. USA 92, 1709–1713 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Potenza, N. et al. Replacement of K-Ras with H-Ras supports normal embryonic development despite inducing cardiovascular pathology in adult mice. EMBO Rep. 6, 432–437 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Fiorucci, G. & Hall, A. All three human ras genes are expressed in a wide range of tissues. Biochim. Biophys. Acta 950, 81–83 (1988).

    CAS  PubMed  Google Scholar 

  164. Bivona, T. G. et al. PKC regulates a farnesyl-electrostatic switch on K-Ras that promotes its association with Bcl-XL on mitochondria and induces apoptosis. Mol. Cell 21, 481–493 (2006).

    CAS  PubMed  Google Scholar 

  165. Chiu, V. K. et al. Ras signalling on the endoplasmic reticulum and the Golgi. Nature Cell Biol. 4, 343–350 (2002).

    CAS  PubMed  Google Scholar 

  166. Matallanas, D. et al. Distinct utilization of effectors and biological outcomes resulting from site-specific Ras activation: Ras functions in lipid rafts and Golgi complex are dispensable for proliferation and transformation. Mol. Cell. Biol. 26, 100–116 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Augsten, M. et al. Live-cell imaging of endogenous Ras-GTP illustrates predominant Ras activation at the plasma membrane. EMBO Rep. 7, 46–51 (2006).

    CAS  PubMed  Google Scholar 

  168. Prior, I. A. et al. GTP-dependent segregation of H-ras from lipid rafts is required for biological activity. Nature Cell Biol. 3, 368–375 (2001).

    CAS  PubMed  Google Scholar 

  169. Cawthon, R. M. et al. A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations. Cell 62, 193–201 (1990).

    CAS  PubMed  Google Scholar 

  170. Marchuk, D. A. et al. cDNA cloning of the type 1 neurofibromatosis gene: complete sequence of the NF1 gene product. Genomics 11, 931–940 (1991).

    CAS  PubMed  Google Scholar 

  171. Viskochil, D. et al. Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. Cell 62, 187–192 (1990).

    CAS  PubMed  Google Scholar 

  172. Rodriguez-Viciana, P. et al. Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome. Science 311, 1287–1290 (2006).

    CAS  PubMed  Google Scholar 

  173. Cichowski, K. & Jacks, T. NF1 tumor suppressor gene function: narrowing the GAP. Cell 104, 593–604 (2001).

    CAS  PubMed  Google Scholar 

  174. Brannan, C. I. et al. Targeted disruption of the neurofibromatosis type-1 gene leads to developmental abnormalities in heart and various neural crest-derived tissues. Genes Dev. 8, 1019–1029 (1994).

    CAS  PubMed  Google Scholar 

  175. Gitler, A. D. et al. Tie2-Cre-induced inactivation of a conditional mutant Nf1 allele in mouse results in a myeloproliferative disorder that models juvenile myelomonocytic leukemia. Pediatr. Res. 55, 581–584 (2004).

    CAS  PubMed  Google Scholar 

  176. Ismat, F. A., Xu, J., Lu, M. M. & Epstein, J. A. The neurofibromin GAP-related domain rescues endothelial but not neural crest development in Nf1 mice. J. Clin. Invest. 116, 2378–2384 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Mohi, M. G. & Neel, B. G. The role of Shp2 (PTPN11) in cancer. Curr. Opin. Genet. Dev. 17, 23–30 (2007).

    CAS  PubMed  Google Scholar 

  178. Tartaglia, M. et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nature Genet. 29, 465–468 (2001).

    CAS  PubMed  Google Scholar 

  179. Keilhack, H., David, F. S., McGregor, M., Cantley, L. C. & Neel, B. G. Diverse biochemical properties of Shp2 mutants. Implications for disease phenotypes. J. Biol. Chem. 280, 30984–30993 (2005).

    CAS  PubMed  Google Scholar 

  180. Tartaglia, M. & Gelb, B. D. Noonan syndrome and related disorders: genetics and pathogenesis. Annu. Rev. Genomics Hum. Genet. 6, 45–68 (2005).

    CAS  PubMed  Google Scholar 

  181. Chan, R. J. et al. Human somatic PTPN11 mutations induce hematopoietic-cell hypersensitivity to granulocyte-macrophage colony-stimulating factor. Blood 105, 3737–3742 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Araki, T. et al. Mouse model of Noonan syndrome reveals cell type- and gene dosage-dependent effects of Ptpn11 mutation. Nature Med. 10, 849–857 (2004).

    CAS  PubMed  Google Scholar 

  183. Flotho, C. et al. RAS mutations and clonality analysis in children with juvenile myelomonocytic leukemia (JMML). Leukemia 13, 32–37 (1999).

    CAS  PubMed  Google Scholar 

  184. Gorlin, R. J., Anderson, R. C. & Moller, J. H. The leopard (multiple lentigines) syndrome revisited. Laryngoscope 81, 1674–1681 (1971).

    CAS  PubMed  Google Scholar 

  185. Roberts, A. et al. The cardiofaciocutaneous syndrome. J. Med. Genet. 43, 833–842 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Seeburg, P. H., Colby, W. W., Capon, D. J., Goeddel, D. V. & Levinson, A. D. Biological properties of human c-Ha-ras1 genes mutated at codon 12. Nature 312, 71–75 (1984).

    CAS  PubMed  Google Scholar 

  187. Schubbert, S. et al. Germline KRAS mutations cause Noonan syndrome. Nature Genet. 38, 331–336 (2006).

    CAS  PubMed  Google Scholar 

  188. Roberts, A. E. et al. Germline gain-of-function mutations in SOS1 cause Noonan syndrome. Nature Genet. 39, 70–74 (2007).

    CAS  PubMed  Google Scholar 

  189. Kohl, N. E. et al. Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice. Nature Med. 1, 792–797 (1995). One of the initial reports suggesting the feasibility of the FTI approach in vivo.

    CAS  PubMed  Google Scholar 

  190. James, G. L., Goldstein, J. L. & Brown, M. S. Polylysine and CVIM sequences of K-RasB dictate specificity of prenylation and confer resistance to benzodiazepine peptidomimetic in vitro. J. Biol. Chem. 270, 6221–6226 (1995).

    CAS  PubMed  Google Scholar 

  191. Sepp-Lorenzino, L. et al. A peptidomimetic inhibitor of farnesyl:protein transferase blocks the anchorage-dependent and -independent growth of human tumor cell lines. Cancer Res. 55, 5302–5309 (1995).

    CAS  PubMed  Google Scholar 

  192. Sun, J., Qian, Y., Hamilton, A. D. & Sebti, S. M. Ras CAAX peptidomimetic FTI 276 selectively blocks tumor growth in nude mice of a human lung carcinoma with K-Ras mutation and p53 deletion. Cancer Res. 55, 4243–4247 (1995).

    CAS  PubMed  Google Scholar 

  193. Mangues, R. et al. Antitumor effect of a farnesyl protein transferase inhibitor in mammary and lymphoid tumors overexpressing N-ras in transgenic mice. Cancer Res. 58, 1253–1259 (1998).

    CAS  PubMed  Google Scholar 

  194. Lebowitz, P. F., Casey, P. J., Prendergast, G. C. & Thissen, J. A. Farnesyltransferase inhibitors alter the prenylation and growth-stimulating function of RhoB. J. Biol. Chem. 272, 15591–15594 (1997).

    CAS  PubMed  Google Scholar 

  195. Basso, A. D. et al. The farnesyl transferase inhibitor (FTI) SCH66336 (lonafarnib) inhibits Rheb farnesylation and mTOR signaling. Role in FTI enhancement of taxane and tamoxifen anti-tumor activity. J. Biol. Chem. 280, 31101–31108 (2005).

    CAS  PubMed  Google Scholar 

  196. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Ashar, H. R. et al. Farnesyl transferase inhibitors block the farnesylation of CENP-E and CENP-F and alter the association of CENP-E with the microtubules. J. Biol. Chem. 275, 30451–30457 (2000).

    CAS  PubMed  Google Scholar 

  198. Hrycyna, C. A., Sapperstein, S. K., Clarke, S. & Michaelis, S. The Saccharomyces cerevisiae STE14 gene encodes a methyltransferase that mediates C-terminal methylation of a-factor and RAS proteins. EMBO J. 10, 1699–1709 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Kato, K. et al. Isoprenoid addition to Ras protein is the critical modification for its membrane association and transforming activity. Proc. Natl Acad. Sci. USA 89, 6403–6407 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. Bergo, M. O. et al. Absence of the CAAX endoprotease Rce1: effects on cell growth and transformation. Mol. Cell. Biol. 22, 171–181 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. Bergo, M. O. et al. Inactivation of Icmt inhibits transformation by oncogenic K-Ras and B-Raf. J. Clin. Invest. 113, 539–550 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  202. Winter-Vann, A. M. et al. Targeting Ras signaling through inhibition of carboxyl methylation: an unexpected property of methotrexate. Proc. Natl Acad. Sci. USA 100, 6529–6534 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Winter-Vann, A. M. et al. A small-molecule inhibitor of isoprenylcysteine carboxyl methyltransferase with antitumor activity in cancer cells. Proc. Natl Acad. Sci. USA 102, 4336–4341 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. Mukhopadhyay, T., Tainsky, M., Cavender, A. C. & Roth, J. A. Specific inhibition of K-ras expression and tumorigenicity of lung cancer cells by antisense RNA. Cancer Res. 51, 1744–1748 (1991).

    CAS  PubMed  Google Scholar 

  205. Funato, T., Ishii, T., Kambe, M., Scanlon, K. J. & Sasaki, T. Anti-K-ras ribozyme induces growth inhibition and increased chemosensitivity in human colon cancer cells. Cancer Gene Ther. 7, 495–500 (2000).

    CAS  PubMed  Google Scholar 

  206. Zhang, Y. A., Nemunaitis, J., Scanlon, K. J. & Tong, A. W. Anti-tumorigenic effect of a K-ras ribozyme against human lung cancer cell line heterotransplants in nude mice. Gene Ther. 7, 2041–2050 (2000).

    CAS  PubMed  Google Scholar 

  207. Kijima, H. et al. Ribozyme against mutant K-ras mRNA suppresses tumor growth of pancreatic cancer. Int. J. Oncol. 24, 559–564 (2004).

    CAS  PubMed  Google Scholar 

  208. Coffey, M. C., Strong, J. E., Forsyth, P. A. & Lee, P. W. Reovirus therapy of tumors with activated Ras pathway. Science 282, 1332–1334 (1998).

    CAS  PubMed  Google Scholar 

  209. Strong, J. E., Coffey, M. C., Tang, D., Sabinin, P. & Lee, P. W. The molecular basis of viral oncolysis: usurpation of the Ras signaling pathway by reovirus. EMBO J. 17, 3351–3362 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. Bollag, G., Freeman, S., Lyons, J. F. & Post, L. E. Raf pathway inhibitors in oncology. Curr. Opin. Investig. Drugs 4, 1436–1441 (2003).

    CAS  PubMed  Google Scholar 

  211. Sebolt-Leopold, J. S. et al. Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nature Med. 5, 810–816 (1999).

    CAS  PubMed  Google Scholar 

  212. Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. & Lowe, S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602 (1997). Indicated that forced overexpression of Ras in primary cells promoted growth arrest through the p53 and p16 pathways.

    CAS  PubMed  Google Scholar 

  213. Wei, W., Jobling, W. A., Chen, W., Hahn, W. C. & Sedivy, J. M. Abolition of cyclin-dependent kinase inhibitor p16Ink4a and p21Cip1/Waf1 functions permits Ras-induced anchorage-independent growth in telomerase-immortalized human fibroblasts. Mol. Cell. Biol. 23, 2859–2870 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  214. Voorhoeve, P. M. & Agami, R. The tumor-suppressive functions of the human INK4A locus. Cancer Cell 4, 311–319 (2003).

    CAS  PubMed  Google Scholar 

  215. Hahn, W. C. et al. Creation of human tumour cells with defined genetic elements. Nature 400, 464–468 (1999).

    CAS  PubMed  Google Scholar 

  216. Benanti, J. A. & Galloway, D. A. Normal human fibroblasts are resistant to RAS-induced senescence. Mol. Cell. Biol. 24, 2842–2852 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. Tuveson, D. A. et al. Endogenous oncogenic K-ras(G12D) stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell 5, 375–387 (2004).

    CAS  PubMed  Google Scholar 

  218. Johnson, L. et al. Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature 410, 1111–1116 (2001).

    CAS  PubMed  Google Scholar 

  219. Iwasa, H., Han, J. & Ishikawa, F. Mitogen-activated protein kinase p38 defines the common senescence-signalling pathway. Genes Cells 8, 131–144 (2003).

    CAS  PubMed  Google Scholar 

  220. Lee, A. C. et al. Ras proteins induce senescence by altering the intracellular levels of reactive oxygen species. J. Biol. Chem. 274, 7936–7940 (1999).

    CAS  PubMed  Google Scholar 

  221. McCubrey, J. A., Lahair, M. M. & Franklin, R. A. Reactive oxygen species-induced activation of the MAP kinase signaling pathways. Antioxid. Redox Signal 8, 1775–1789 (2006).

    CAS  PubMed  Google Scholar 

  222. Sun, P. et al. PRAK is essential for ras-induced senescence and tumor suppression. Cell 128, 295–308 (2007).

    CAS  PubMed  Google Scholar 

  223. Campbell, S. L., Khosravi-Far, R., Rossman, K. L., Clark, G. J. & Der, C. J. Increasing complexity of Ras signaling. Oncogene 17, 1395–1413 (1998).

    CAS  PubMed  Google Scholar 

  224. Wright, L. P. & Philips, M. R. Thematic review series: lipid posttranslational modifications. CAAX modification and membrane targeting of Ras. J. Lipid Res. 47, 883–891 (2006).

    CAS  PubMed  Google Scholar 

  225. Whyte, D. B. et al. K- and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors. J. Biol. Chem. 272, 14459–14464 (1997).

    CAS  PubMed  Google Scholar 

  226. Choy, E. et al. Endomembrane trafficking of ras: the CAAX motif targets proteins to the ER and Golgi. Cell 98, 69–80 (1999).

    CAS  PubMed  Google Scholar 

  227. Apolloni, A., Prior, I. A., Lindsay, M., Parton, R. G. & Hancock, J. F. H-ras but not K-ras traffics to the plasma membrane through the exocytic pathway. Mol. Cell. Biol. 20, 2475–2487 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  228. Simons, K. & Ikonen, E. Functional rafts in cell membranes. Nature 387, 569–572 (1997).

    CAS  PubMed  Google Scholar 

  229. Rocks, O. et al. An acylation cycle regulates localization and activity of palmitoylated Ras isoforms. Science 307, 1746–1752 (2005).

    CAS  PubMed  Google Scholar 

  230. Jura, N., Scotto-Lavino, E., Sobczyk, A. & Bar-Sagi, D. Differential modification of Ras proteins by ubiquitination. Mol. Cell 21, 679–687 (2006).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank C. Der for comments on the manuscript and G. Bell for help in structural configurations. The authors' research is supported, in part, by the Breast Cancer Research Foundation (R.A.W), National Institues of Health (NIH) P01 CA08111 (R.A.W.), NIH U54 CA12515 (R.A.W.), NIH SPORE P50 CA089393 (R.A.W.), Susan Komen Breast Cancer Foundation (A.E.K.), Harvard Specialized Program for Research Excellence (A.E.K.), Whitehead Institute-Genzyme fellowship (A.E.K.) and the Ludwig Center for Molecular Oncology at Massachusetts Institue of Technology, USA.

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DATABASES

ProteinDataBank 

1bkd

1wq1

4q21

5p21

FirstGlance in Jmol (3D structures) 

1bkd

1wq1

4q21

5p21

Interpro

Cdc25

DH

PH

SH2

SH3

OMIM

Costello syndrome

JMML

LEOPARD syndrome

neurofibromatosis type-1 syndrome

Noonan syndrome

FURTHER INFORMATION

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Glossary

Rous sarcoma virus

(RSV). A retrovirus that was discovered in 1916 by Peyton Rous by injecting a cell-free extract of chicken tumour into healthy chickens. The extract was found to induce oncogenesis in Plymouth Rock chickens.

G proteins

A family of proteins involved in second messenger cascades. They function as molecular switches, alternating between an inactive GDP-bound and active GTP-bound state.

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).

Guanine nucleotide-exchange factor

(GEF). A protein that facilitates the exchange of GDP for GTP in the nucleotide-binding pocket of a GTP-binding protein.

Anoikis

The induction of programmed cell death by the detachment of cells from the extracellular matrix.

Lipid raft

A membrane microdomain that is enriched in cholesterol, sphingolipids and lipid-modified proteins, such as glycosyl phosphatidylinositol (GPI)-linked proteins and palmitoylated proteins. These microdomains often function as platforms for signalling events.

Cardio-facio-cutaneous diseases

Congenital developmental disorders caused by disregulated Ras signalling. These diseases are characterized by the accumulation of sporadic tumours as well as skeletal, cardiac and visual abnormalities.

Neural crest

A group of embryonic cells that separate from the embryonic neural plate and migrate, giving rise to the spinal and autonomic ganglia, peripheral glia, chromaffin cells, melanocytes and some haematopoietic cells.

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Karnoub, A., Weinberg, R. Ras oncogenes: split personalities. Nat Rev Mol Cell Biol 9, 517–531 (2008). https://doi.org/10.1038/nrm2438

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