Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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Non-Redundancy within the RAS Oncogene Family: Insights into Mutational Disparities in Cancer

  • Lau, Ken S. (Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital and Department of Pathology, Harvard Medical School) ;
  • Haigis, Kevin M. (Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital and Department of Pathology, Harvard Medical School)
  • Received : 2009.09.08
  • Accepted : 2009.09.11
  • Published : 2009.10.31
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Abstract

The RAS family of oncoproteins has been studied extensively for almost three decades. While we know that activation of RAS represents a key feature of malignant transformation for many cancers, we are only now beginning to understand the complex underpinnings of RAS biology. Here, we will discuss emerging cancer genome sequencing data in the context of what is currently known about RAS function. Taken together, retrospective studies of primary human tissues and prospective studies of experimental models support the notion that the variable mutation frequencies exhibited by the RAS oncogenes reflect unique functions of the RAS oncoproteins.

Keywords

Acknowledgement

Supported by : National Cancer Institute, National Institute for General Medical Science, Merlino Family Endowment Fund

References

  1. Abraham, S.J., Nolet, R.P., Calvert, R.J., Anderson, L.M., and Gaponenko, V. (2009). The Hypervariable region of K-Ras4B is responsible for its specific interactions with calmodulin. Biochemistry 48, 7575-7583 https://doi.org/10.1021/bi900769j
  2. Bivona, T.G., Quatela, S.E., Bodemann, B.O., Ahearn, I.M., Soskis, M.J., Mor, A., Miura, J., Wiener, H.H., Wright, L., Saba, S.G., et al. (2006). PKC regulates a farnesyl-electrostatic switch on KRas that promotes its association with Bcl-XL on mitochondria and induces apoptosis. Mol. Cell 21, 481-493 https://doi.org/10.1016/j.molcel.2006.01.012
  3. Borner, C., Schlagbauer Wadl, H., Fellay, I., Selzer, E., Polterauer, P., and Jansen, B. (1999). Mutated N-ras upregulates Bcl-2 in human melanoma in vitro and in SCID mice. Melanoma Res. 9, 347-350 https://doi.org/10.1097/00008390-199908000-00002
  4. Braun, B.S., Tuveson, D.A., Kong, N., Le, D.T., Kogan, S.C., Rozmus, J., Le Beau, M.M., Jacks, T.E., and Shannon, K.M. (2004). Somatic activation of oncogenic Kras in hematopoietic cells initiates a rapidly fatal myeloproliferative disorder. Proc. Natl. Acad. Sci. USA 101, 597-602 https://doi.org/10.1073/pnas.0307203101
  5. Chang, E.H., Gonda, M.A., Ellis, R.W., Scolnick, E.M., and Lowy, D.R. (1982). Human genome contains four genes homologous to transforming genes of Harvey and Kirsten murine sarcoma viruses. Proc. Natl. Acad. Sci. USA 79, 4848-4852 https://doi.org/10.1073/pnas.79.16.4848
  6. Chiu, V.K., Bivona, T., Hach, A., Sajous, J.B., Silletti, J., Wiener, H., Johnson, R.L., 2nd, Cox, A.D., and Philips, M.R. (2002). Ras signalling on the endoplasmic reticulum and the Golgi. Nat. Cell Biol. 4, 343-350 https://doi.org/10.1038/ncb783
  7. Cox, A.D., and Der, C.J. (2003). The dark side of Ras: regulation of apoptosis. Oncogene 22, 8999-9006 https://doi.org/10.1038/sj.onc.1207111
  8. Der, C.J., Krontiris, T.G., and Cooper, G.M. (1982). 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 https://doi.org/10.1073/pnas.79.11.3637
  9. Dumaz, N., Hayward, R., Martin, J., Ogilvie, L., Hedley, D., Curtin, J.A., Bastian, B.C., Springer, C., and Marais, R. (2006). In melanoma, RAS mutations are accompanied by switching signaling from BRAF to CRAF and disrupted cyclic AMP signaling. Cancer Res. 66, 9483-9491 https://doi.org/10.1158/0008-5472.CAN-05-4227
  10. Edkins, S., O’Meara, S., Parker, A., Stevens, C., Reis, M., Jones, S., Greenman, C., Davies, H., Dalgliesh, G., Forbes, S., et al. (2006). Recurrent KRAS codon 146 mutations in human colorectal cancer. Cancer Biol. Ther. 5, 928-932
  11. Elad-Sfadia, G., Haklai, R., Ballan, E., Gabius, H.J., and Kloog, Y. (2002). Galectin-1 augments Ras activation and diverts Ras signals to Raf-1 at the expense of phosphoinositide 3-kinase. J. Biol. Chem. 277, 37169-37175 https://doi.org/10.1074/jbc.M205698200
  12. Elad-Sfadia, G., Haklai, R., Balan, E., and Kloog, Y. (2004). Galectin-3 augments K-Ras activation and triggers a Ras signal that attenuates ERK but not phosphoinositide 3-kinase activity. J. Biol. Chem. 279, 34922-34930 https://doi.org/10.1074/jbc.M312697200
  13. Engelman, J.A., Luo, J., and Cantley, L.C. (2006). The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat. Rev. Genet. 7, 606-619 https://doi.org/10.1038/nrg1879
  14. Guerra, C., Mijimolle, N., Dhawahir, A., Dubus, P., Barradas, M., Serrano, M., Campuzano, V., and Barbacid, M. (2003). Tumor induction by an endogenous K-ras oncogene is highly dependent on cellular context. Cancer Cell 4, 111-120 https://doi.org/10.1016/S1535-6108(03)00191-0
  15. Haigis, K.M., Kendall, K.R., Wang, Y., Cheung, A., Haigis, M.C., Glickman, J.N., Niwa-Kawakita, M., Sweet-Cordero, A., Sebolt- Leopold, J., Shannon, K.M., et al. (2008). Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon. Nat. Genet. 40, 600-608 https://doi.org/10.1038/ng.115
  16. Hamilton, M., and Wolfman, A. (1998). Ha-ras and N-ras regulate MAPK activity by distinct mechanisms in vivo. Oncogene 16, 1417-1428 https://doi.org/10.1038/sj.onc.1201653
  17. Hancock, J.F. (2003). Ras proteins: different signals from different locations. Nat. Rev. 4, 373-384 https://doi.org/10.1038/nrm1105
  18. Harvey, J.J. (1964). An unidentified virus which causes the rapid production of tumours in mice. Nature 204, 1104-1105
  19. Henis, Y.I., Hancock, J.F., and Prior, I.A. (2009). Ras acylation, compartmentalization and signaling nanoclusters (Review). Mol. Membr. Biol. 26, 80-92 https://doi.org/10.1080/09687680802649582
  20. Jansen, B., Schlagbauer-Wadl, H., Eichler, H.G., Wolff, K., van Elsas, A., Schrier, P.I., and Pehamberger, H. (1997). Activated N-ras contributes to the chemoresistance of human melanoma in severe combined immunodeficiency (SCID). mice by blocking apoptosis. Cancer Res. 57, 362-365
  21. Keller, J.W., Franklin, J.L., Graves-Deal, R., Friedman, D.B., Whitwell, C.W., and Coffey, R.J. (2007a). Oncogenic KRAS provides a uniquely powerful and variable oncogenic contribution among RAS family members in the colonic epithelium. J. Cell. Physiol. 210, 740-749 https://doi.org/10.1002/jcp.20898
  22. Keller, J.W., Haigis, K.M., Franklin, J.L., Whitehead, R.H., Jacks, T., and Coffey, R.J. (2007b). Oncogenic K-RAS subverts the antiapoptotic role of N-RAS and alters modulation of the NRAS: gelsolin complex. Oncogene 26, 3051-3059 https://doi.org/10.1038/sj.onc.1210103
  23. Khokhlatchev, A., Rabizadeh, S., Xavier, R., Nedwidek, M., Chen, T., Zhang, X.F., Seed, B., and Avruch, J. (2002). Identification of a novel Ras-regulated proapoptotic pathway. Curr. Biol. 12, 253-265 https://doi.org/10.1016/S0960-9822(02)00683-8
  24. Kirsten, W.H., Schauf, V., and McCoy, J. (1970). Properties of a murine sarcoma virus. Bibl. Haematol. 36, 246-249
  25. Klampfer, L., Huang, J., Sasazuki, T., Shirasawa, S., and Augenlicht, L. (2004). Oncogenic Ras promotes butyrate-induced apoptosis through inhibition of gelsolin expression. J. Biol. Chem. 279, 36680-36688 https://doi.org/10.1074/jbc.M405197200
  26. Leon, J., Guerrero, I., and Pellicer, A. (1987). Differential expression of the ras gene family in mice. Mol. Cell. Biol. 7, 1535-1540 https://doi.org/10.1128/MCB.7.4.1535
  27. Liao, J., Planchon, S.M., Wolfman, J.C., and Wolfman, A. (2006). Growth factor-dependent AKT activation and cell migration requires the function of c-K(B).-Ras versus other cellular ras isoforms. J. Biol. Chem. 281, 29730-29738 https://doi.org/10.1074/jbc.M600668200
  28. Maher, J., Baker, D.A., Manning, M., Dibb, N.J., and Roberts, I.A. (1995). Evidence for cell-specific differences in transformation by N-, H- and K-ras. Oncogene 11, 1639-1647
  29. Moodie, S.A., Willumsen, B.M., Weber, M.J., and Wolfman, A. (1993). Complexes of Ras.GTP with Raf-1 and mitogenactivated protein kinase kinase. Science 260, 1658-1661 https://doi.org/10.1126/science.8503013
  30. Mor, A., and Philips, M.R. (2006). Compartmentalized Ras/MAPK signaling. Annu. Rev. Immunol. 24, 771-800 https://doi.org/10.1146/annurev.immunol.24.021605.090723
  31. Parada, L.F., Tabin, C.J., Shih, C., and Weinberg, R.A. (1982). Human EJ bladder carcinoma oncogene is homologue of Harvey sarcoma virus ras gene. Nature 297, 474-478 https://doi.org/10.1038/297474a0
  32. Parikh, C., Subrahmanyam, R., and Ren, R. (2007). Oncogenic NRAS, KRAS, and HRAS exhibit different leukemogenic potentials in mice. Cancer Res. 67, 7139-7146 https://doi.org/10.1158/0008-5472.CAN-07-0778
  33. Philips, M.R. (2005). Compartmentalized signalling of Ras. Biochem. Soc. Trans. 33, 657-661 https://doi.org/10.1042/BST0330657
  34. Plowman, S.J., and Hancock, J.F. (2005). Ras signaling from plasma membrane and endomembrane microdomains. Biochim. Biophys. Acta 1746, 274-283 https://doi.org/10.1016/j.bbamcr.2005.06.004
  35. Prior, I.A., and Hancock, J.F. (2001). Compartmentalization of Ras proteins. J. Cell Sci. 114, 1603-1608
  36. Quinlan, M.P., Quatela, S.E., Philips, M.R., and Settleman, J. (2008). Activated Kras, but not Hras or Nras, may initiate tumors of endodermal origin via stem cell expansion. Mol. Cell. Biol. 28, 2659-2674 https://doi.org/10.1128/MCB.01661-07
  37. Quinlan, M.P., and Settleman, J. (2009). Isoform-specific ras functions in development and cancer. Future Oncol. 5, 105-116 https://doi.org/10.2217/14796694.5.1.105
  38. Radu, M., and Chernoff, J. (2009). The DeMSTification of mammalian Ste20 kinases. Curr. Biol. 19, R421-425 https://doi.org/10.1016/j.cub.2009.04.022
  39. Rodriguez-Viciana, P., Warne, P.H., Dhand, R., Vanhaesebroeck, B., Gout, I., Fry, M.J., Waterfield, M.D., and Downward, J. (1994). Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 370, 527-532 https://doi.org/10.1038/370527a0
  40. Santos, E., Tronick, S.R., Aaronson, S.A., Pulciani, S., and Barbacid, M. (1982). 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 https://doi.org/10.1038/298343a0
  41. Seger, R., and Krebs, E.G. (1995). The MAPK signaling cascade. FASEB J. 9, 726-735 https://doi.org/10.1096/fasebj.9.9.7601337
  42. Sensi, M., Nicolini, G., Petti, C., Bersani, I., Lozupone, F., Molla, A., Vegetti, C., Nonaka, D., Mortarini, R., Parmiani, G., et al. (2006). Mutually exclusive NRASQ61R and BRAFV600E mutations at the single-cell level in the same human melanoma. Oncogene 25, 3357-3364 https://doi.org/10.1038/sj.onc.1209379
  43. Shalom-Feuerstein, R., Cooks, T., Raz, A., and Kloog, Y. (2005). Galectin-3 regulates a molecular switch from N-Ras to K-Ras usage in human breast carcinoma cells. Cancer Res. 65, 7292-7300 https://doi.org/10.1158/0008-5472.CAN-05-0775
  44. Shimizu, K., Goldfarb, M., Suard, Y., Perucho, M., Li, Y., Kamata, T., Feramisco, J., Stavnezer, E., Fogh, J., and Wigler, M.H. (1983). Three human transforming genes are related to the viral ras oncogenes. Proc. Natl. Acad. Sci. USA 80, 2112-2116 https://doi.org/10.1073/pnas.80.8.2112
  45. Sidhu, R.S., Clough, R.R., and Bhullar, R.P. (2003). $Ca^2^+$/calmodulin binds and dissociates K-RasB from membrane. Biochem. Biophys. Res. Commun. 304, 655-660 https://doi.org/10.1016/S0006-291X(03)00635-1
  46. Simi, L., Pratesi, N., Vignoli, M., Sestini, R., Cianchi, F., Valanzano, R., Nobili, S., Mini, E., Pazzagli, M., and Orlando, C. (2008). High-resolution melting analysis for rapid detection of KRAS, BRAF, and PIK3CA gene mutations in colorectal cancer. Am. J. Clin. Pathol. 130, 247-253 https://doi.org/10.1309/LWDY1AXHXUULNVHQ
  47. To, M.D., Wong, C.E., Karnezis, A.N., Del Rosario, R., Di Lauro, R., and Balmain, A. (2008). Kras regulatory elements and exon 4A determine mutation specificity in lung cancer. Nat. Genet. 40, 1240-1244 https://doi.org/10.1038/ng.211
  48. Tuveson, D.A., Shaw, A.T., Willis, N.A., Silver, D.P., Jackson, E.L., Chang, S., Mercer, K.L., Grochow, R., Hock, H., Crowley, D., et al. (2004). Endogenous oncogenic K-ras(G12D). stimulates proliferation and widespread neoplastic and developmental defects. Cancer Cell 5, 375-387 https://doi.org/10.1016/S1535-6108(04)00085-6
  49. Villalonga, P., Lopez-Alcala, C., Bosch, M., Chiloeches, A., Rocamora, N., Gil, J., Marais, R., Marshall, C.J., Bachs, O., and Agell, N. (2001). Calmodulin binds to K-Ras, but not to H- or N-Ras, and modulates its downstream signaling. Mol. Cell. Biol. 21, 7345-7354 https://doi.org/10.1128/MCB.21.21.7345-7354.2001
  50. Vojtek, A.B., Hollenberg, S.M., and Cooper, J.A. (1993). Mammalian Ras interacts directly with the serine/threonine kinase Raf. Cell 74, 205-214 https://doi.org/10.1016/0092-8674(93)90307-C
  51. Walsh, A.B., and Bar-Sagi, D. (2001). Differential activation of the Rac pathway by Ha-Ras and K-Ras. J. Biol. Chem. 276, 15609-15615 https://doi.org/10.1074/jbc.M010573200
  52. Warne, P.H., Viciana, P.R., and Downward, J. (1993). Direct interaction of Ras and the amino-terminal region of Raf-1 in vitro. Nature 364, 352-355 https://doi.org/10.1038/364352a0
  53. Wellbrock, C., Karasarides, M., and Marais, R. (2004). The RAF proteins take centre stage. Nat. Rev. 5, 875-885 https://doi.org/10.1038/nrm1498
  54. Whitwam, T., Vanbrocklin, M.W., Russo, M.E., Haak, P.T., Bilgili, D., Resau, J.H., Koo, H.M., and Holmen, S.L. (2007). Differential oncogenic potential of activated RAS isoforms in melanocytes. Oncogene 26, 4563-4570 https://doi.org/10.1038/sj.onc.1210239
  55. Wolfman, J.C., and Wolfman, A. (2000). Endogenous c-N-Ras provides a steady-state anti-apoptotic signal. J. Biol. Chem. 275, 19315-19323 https://doi.org/10.1074/jbc.M000250200
  56. Yan, Z., Chen, M., Perucho, M., and Friedman, E. (1997). Oncogenic Ki-ras but not oncogenic Ha-ras blocks integrin beta1- chain maturation in colon epithelial cells. J. Biol. Chem. 272, 30928-30936 https://doi.org/10.1074/jbc.272.49.30928
  57. Yan, J., Roy, S., Apolloni, A., Lane, A., and Hancock, J.F. (1998). Ras isoforms vary in their ability to activate Raf-1 and phosphoinositide 3-kinase. J. Biol. Chem. 273, 24052-24056 https://doi.org/10.1074/jbc.273.37.24052
  58. Zhang, X.F., Settleman, J., Kyriakis, J.M., Takeuchi-Suzuki, E., Elledge, S.J., Marshall, M.S., Bruder, J.T., Rapp, U.R., and Avruch, J. (1993). Normal and oncogenic p21ras proteins bind to the amino-terminal regulatory domain of c-Raf-1. Nature 364, 308-313 https://doi.org/10.1038/364308a0
  59. Zuber, J., Tchernitsa, O.I., Hinzmann, B., Schmitz, A.C., Grips, M., Hellriegel, M., Sers, C., Rosenthal, A., and Schafer, R. (2000). A genome-wide survey of RAS transformation targets. Nat. Genet. 24, 144-152 https://doi.org/10.1038/72799

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