Skip to main content
Log in

The Ras signal transduction pathway

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

Considerable progress has been made over the past year in elucidating the mechanisms by which extracellular signals are transduced via cell surface receptors to trigger changes in gene expression which determine the growth and differentiated state of a cell. In particular, Ras proteins have been implicated as key intermediates that mediate the signal from upstream tyrosine kinases to a downstream cascade of serine/threonine kinases, which then activate nuclear factors that control gene expression and protein synthesis. How Ras proteins function is regulated in this role as a molecular switch, and how the signal is transmitted between the various components of the pathway, are now being determined. Finally, the Rho family of Ras-related proteins, which regulate the actin cytoskeleton, have also been implicated as mediators of oncogenic Ras transformation. The brisk pace at which the key components of Ras-mediated signal transduction pathways are being identified hold great promise that new targets for therapeutic intervention in cancer may now be identified.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Barbacid M:ras genes. Ann Rev Biochem 56: 779–827, 1987

    Google Scholar 

  2. Bos JL:ras oncogenes in human cancer: a review. Cancer Res 49: 4682–4689, 1989

    Google Scholar 

  3. Clark GJ, Der CJ: Ras proto-oncogene activation in human malignancy. In: Dickey B, Birnbaumer L (eds) Springer-Verlag, Heidelberg, 1992, pp in press

    Google Scholar 

  4. Satoh T, Nakafuku M, Kaziro Y: Function of Ras as a molecular switch in signal transduction. J Biol Chem 267: 24149–24152, 1992

    Google Scholar 

  5. Lowy DR, Zhang K, DeClue JE, Willumsen BM: Regulation of p21ras activity. TIG 7: 346–351, 1991

    Google Scholar 

  6. Bollag G, McCormick F: Regulators and effectors ofras proteins. Ann Rev Cell Biol 7: 601–633, 1991

    Google Scholar 

  7. Downward J: Regulatory mechanisms forras proteins. BioEssays 14: 177–184, 1992

    Google Scholar 

  8. Haubruck H, McCormick F: Ras p21: effects and regulation. Biochim Biophys Acta 1072: 215–229, 1991

    Google Scholar 

  9. Bollag G, McCormick F: GTPase activating proteins. Cancer Biol 3: 199–208, 1992

    Google Scholar 

  10. Hall A: Signal transduction through small GTPases - a tale of two GAPS. Cell 69: 389–391, 1992

    Google Scholar 

  11. Downward J: Exchange rate mechanisms. Nature 358: 282–283, 1992

    Google Scholar 

  12. Bollag G, McCormick F: Identification of a novel ras regulator: a guanine nucleotide dissociation inhibitor. FASEB J 7: 1993

  13. Roberts TM: A signal chain of events. Nature 360: 534–535, 1992

    Google Scholar 

  14. Rubin GM: Signal transduction and the fate of the R7 photoreceptor inDrosophila. TIG 7: 372–377, 1991

    Google Scholar 

  15. Sternberg PW, Horvitz HR: Signal transduction duringC. elegans vulval development. TIG 7: 366–370, 1991

    Google Scholar 

  16. Broach JR: RAS genes in Saccharomyces cerevisiae: signal transduction in search of a pathway. TIG 7: 28–33, 1991

    Google Scholar 

  17. Pazin MJ, Williams LT: Triggering signaling cascades by receptor tyrosine kinases. TIBS 17: 374–378, 1992

    Google Scholar 

  18. Ridley AJ, Hall A: Function for ras in sight. Nature 355: 497–498, 1992

    Google Scholar 

  19. McCormick F: How receptors turn Ras on. Nature 363: 15–16, 1993

    Google Scholar 

  20. Satoh T, Kaziro Y: Ras in signal transduction. Cancer Biol 3: 169–177, 1992

    Google Scholar 

  21. Pawson T, Gish GD: SH2 and SH3 domains: from structure to function. Cell 71: 359–362, 1992

    Google Scholar 

  22. Feig LA: The many roads that lead to ras. Science 260: 767–768, 1993

    Google Scholar 

  23. Hall A: Ras-related GTPases and the cytoskeleton. Mol Biol Cell 3: 475–479, 1992

    Google Scholar 

  24. Downward J: Rac and rho in tune. Nature 359: 273–274, 1992

    Google Scholar 

  25. Feramisco JR, Gross M, Kamata T, Rosenberg M, Sweet RW: 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

    Google Scholar 

  26. Adams JM, Cory S: Transgenic models of tumor development. Science 254: 1161–1167, 1991

    Google Scholar 

  27. Sukumar S:ras oncogenes in chemical carcinogenis. In: Vogt PK (ed) Oncogenes and Retroviruses, Selected Reviews. Springer-Verlag, Berlin, 1989, pp 93–114

    Google Scholar 

  28. Mangues R, Pellicer A:ras activation in experimental carcinogenesis. Cancer Biol 3: 229–239, 1992

    Google Scholar 

  29. Bourne HR, Sanders DA, McCormick F: The GTPase superfamily: a conserved switch for diverse cell functions. Nature 348: 125–132, 1990

    Google Scholar 

  30. Bourne HR, Sanders DA, McCormick F: The GTPase superfamily: conserved structure and molecular mechanism. Nature 349: 117–126, 1990

    Google Scholar 

  31. Bollag G, McCormick F: NF is enough of GAP. Nature 3563: 663–664, 1992

    Google Scholar 

  32. McCormick F, Martin GA, Clark R, Bollag G, Polakis P: Regulation ofras p21 by GTPase activating proteins. Cold Spring Harb Sym Quant Biol 56: 237–241, 1991

    Google Scholar 

  33. Trahey M, Wong G, Halenbeck R, Rubinfeld B, Martin GA, Ladner M, Long CM, Crosier WJ, Watt K, Koths K, McCormick F: Molecular cloning of two types of GAP complementary DNA from human placenta. Science 242: 1697–1700, 1988

    Google Scholar 

  34. Adari H, Lowy DR, Willumsen BM, Der CJ, McCormick F: GTPase activating protein (GAP) interacts with the p21 ras effector binding domain. Science 240: 518–521, 1988

    Google Scholar 

  35. Calés C, Hancock JF, Marshall CJ, Hall A: The cytoplasmic protein GAP is implicated as the target for regulation by the ras gene product. Nature 332: 548–551, 1988

    Google Scholar 

  36. Martin GA, Yatani A, Clark R, Conroy L, Polakis P, Brown AM, McCormick F: GAP domains responsible for ras p21-dependent inhibition of muscarinic atrial K+ channel currents. Science 255: 192–194, 1992

    Google Scholar 

  37. Clark JD, Lin L-L, Kriz RW, Ramesha CS, Sultzman LA, Lin AY, Milona N, Knopf JL: A novel arachidonic acidselective cytosolic PLA2 contains a Ca2+-dependent translocation domain with homology to PKC and GAP. Cell 65: 1043–1051, 1991

    Google Scholar 

  38. Mayer BJ, Ren R, Clark KL, Baltimore D: A putative modular domain present in diverse signaling proteins. Cell 73: 629–630, 1993

    Google Scholar 

  39. Pawson T: SH2 and SH3 domains. Curr Op Cell Biol 2: 432–437, 1992

    Google Scholar 

  40. Mayer BJ, Baltimore D: Signalling through SH2 and SH3 domains. Trends Cell Biol 3: 8–13, 1993

    Google Scholar 

  41. Wood ER, McDonald OB, Sahyoun N: Quantitative analysis of SH2 domain binding. J Biol Chem 267: 14138–14144, 1992

    Google Scholar 

  42. Ren R, Mayer BJ, Cicchetti P, Baltimore D: Identification of a ten-amino acid proline-rich SH3 binding site. Science 259: 1157–1161, 1993

    Google Scholar 

  43. Koch CA, Anderson D, Moran MF, Ellis C, Pawson T: SH2 and SH3 domains: elements that control interactions of cytoplasmic signaling proteins. Science 252: 668–674, 1991

    Google Scholar 

  44. Wallace MR, Marchuk DA, Andersen LB, Letcher R, Odeh HM, Saulino AM: Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science 249: 181–186, 1990

    Google Scholar 

  45. Viskochil D, Buchberg AM, Xu G, Cawthon RM, Stevens J, Wolff RK, Culver M, Carey JC, Copeland NG, Jenkins NA, White R, O'Connell P: Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. Cell 62: 187–192, 1990

    Google Scholar 

  46. Cawthon RM, Weiss R, Xu G, Viskochil D, Culver M, Stevens J, Robertson M, Dunn D, Gesteland R, O'Connell P, White R: A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations. Cell 62: 193–201, 1990

    Google Scholar 

  47. Xu G, Lin B, Tanaka K, Dunn D, Wood D, Gesteland R, White R, Weiss R, Tamanoi F: The catalytic domain of the neurofibromatosis type 1 gene product stimulatesras GTPase and complementsira mutants of S. cerevisiae. Cell 63: 835–841, 1990

    Google Scholar 

  48. Martin GA, Viskochil D, Bollag G, McCabe PC, Crosier WJ, Haubruck H, Conroy L, Clark R, O'Connell P, Cawthon RM, Innis MA, McCormick F: The GAP-related domain of the neurofibromatosis type 1 gene product interacts withras p21. Cell 63: 843–849, 1990

    Google Scholar 

  49. Ballester R, Marchuk D, Boguski M, Saulino A, Letcher R, Wigler M, Collins F: TheNF1 locus encodes a protein functionally related to mammalian GAP and yeastIRA proteins. Cell 63: 851–859, 1990

    Google Scholar 

  50. Andersen LB, Fountain JW, Gutmann DH, Tarlé SA, Glover TW, Dracopoli NC, Housman DE, Collins FS: Mutations in the neurofibromatosis 1 gene in sporadic malignant melanoma cell lines. Nature Genet 3: 118–126, 1993

    Google Scholar 

  51. Seizinger BR: NF1: a prevalent cause of tumorigenesis in human cancers? Nature Genet 3: 97–99, 1993

    Google Scholar 

  52. Bourne HR, Stryer L: The target sets the tempo. Nature 358: 541–543, 1992

    Google Scholar 

  53. McCormick F: GAP as ras effector or negative regulator? Mol Carcinogen 3: 185–187, 1990

    Google Scholar 

  54. McCormick F:ras GTPase activating protein: signal transmitter and signal terminator. Cell 56: 5–8, 1989

    Google Scholar 

  55. Zhang K, DeClue JE, Vass WC, Papageorge AG, McCormick F, Lowy DR: Suppression of c-ras transformationon by GTPase-activating protein. Nature 346: 754–756, 1990

    Google Scholar 

  56. Gibbs JB, Marshall MS, Scolnick EM, Dixon RAF, Vogel US: Modulation of guanine nucleotides bound to ras in NIH3T3 cells by oncogenes, growth factors, and the GTPase activating protein (GAP). J Biol Chem 265: 20437–20442, 1990

    Google Scholar 

  57. Basu TN, Gutmann DH, Fletcher JA, Glover TW, Collins FS, Downward J: Aberrant regulation ofras proteins in malignant tumour cells from type 1 neurofibromatosis patients. Nature 356: 713–715, 1992

    Google Scholar 

  58. DeClue JE, Papageorge AG, Fletcher JA, Diehl SR, Ratner N, Vass WC, Lowy DR: Abnormal regulation of mammalian p21ras contributes to malignant tumor growth in von Recklinghausen (type 1) neurofibromatosis. Cell 69: 265–273, 1992

    Google Scholar 

  59. Vogel US, Dixon RAF, Schaber MD, Diehl RE, Marshall MS, Scolnick EM, Sigal IS, Gibbs JB: Cloning of bovine GAP and its interaction with oncogenic ras p21. Nature 335: 90–93, 1988

    Google Scholar 

  60. Adari H, Trahey M, McCormick F, Stone JC, Willumsen BM, Papageorge AG, Zhang K: Interaction between guanosine triphosphatase activating protein (GAP) and the effector domain of ras encoded proteins. Science 240: 518–521, 1988

    Google Scholar 

  61. DeClue JE, Stone JC, Blanchard RA, Papageorge AG, Martin P, Zhang K, Lowy DR: Aras effector domain mutant which is temperature sensitive for cellular transformation: interactions with GTPase-activating protein and NF-1. Mol Cell Biol 11: 3132–3138, 1991

    Google Scholar 

  62. Farnsworth CL, Marshall MS, Gibbs JB, Stacey DW, Feig LA: Preferential inhibition of the oncogenic form of RasH by mutations in the GAP binding/‘effector’ domain. Cell 64: 625–633, 1991

    Google Scholar 

  63. Kitayama H, Sugimoto Y, Matsuzaki T, Ikawa Y, Noda M: Aras-related gene with transformation suppressor activity. Cell 56: 77–84, 1989

    Google Scholar 

  64. Frech M, John J, Pizon V, Chardin P, Tavitian A, Clark R, McCormick F, Wittinghofer A: The protein product of the Krev-1 gene (rap1A) inhibits GAP activation of p21. Science: 1990

  65. Yatani A, Okabe K, Halenbeck R, Polakis P, McCormick F, Brown AM: Ras p21 and GAP inhibit coupling of muscarinic receptors to atrialT channels. Cell 60: 769–776, 1990

    Google Scholar 

  66. Clark GJ, Quilliam LA, Hisaka MM, Der CJ: Differential antagonism of Ras biological activity by catalytic and Src homology domains of Ras GTPase activation protein. Proc Natl Acad Sci USA 90: 4887–4891, 1993

    Google Scholar 

  67. Anderson D, Koch CA, Grey L, Ellis C, Moran MF, Pawson T: Binding of SH2 domains of phospholipase Cdeltal, GAP and Src to activated growth factor receptors. Science 250: 979–982, 1990

    Google Scholar 

  68. Moran MF, Koch CA, Anderson D, Ellis C, England L, Martin GS, Pawson T: Src homology region 2 domains direct protein-protein interactions in signal transduction. Proc Natl Acad Sci USA 87: 8622–8626, 1990

    Google Scholar 

  69. Fantl WJ, Escobedo JA, Martin GA, Turck CW, del Rosario M, McCormick F, Williams LT: Distinct phosphotyrosines on a growth factor receptor bind to specific molecules that mediate different signaling pathways. Cell 69: 413–423, 1992

    Google Scholar 

  70. Ellis C, Moran M, McCormick F, Pawson T: Phosphorylation of GAP and GAP-associated proteis by transforming and mitogenic tyrosine kinases. Nature 343: 377–380, 1990

    Google Scholar 

  71. Medema RH, deLaat WL, Martin GA, McCormick F, Bos JL: GTPase-activating protein SH2-SH3 domains induce gene expression in a Ras-dependent fashion. Mol Cell Biol 12: 3425–3430, 1992

    Google Scholar 

  72. Schweighoffer F, Barlat I, Chevallier-Multon M-C, Tocque B: Implication of GAP in ras-dependent transactivation of a polyoma enhancer sequence. Science 256: 825–827, 1992

    Google Scholar 

  73. Duchesne M, Schweighoffer F, Parker F, Clerc F, Frobert Y, Thang MN, Tocqué B: Identification of the SH3 domain of GAP as an essential sequence for Ras-GAP-mediated signaling. Science 259: 525–528, 1993

    Google Scholar 

  74. Bollag G, McCormick F: Differential regulation of ras-GAP and neurofibromatosis gene product activities. Nature 351: 576–578, 1991

    Google Scholar 

  75. The I, Murthy AE, Hannigan GE, Jacoby LB, Menon AG, Gusella JF, Bernards A: Neurofibromatosis type 1 gene mutations in neuroblastoma. Nature Genet 3: 62–66, 1993

    Google Scholar 

  76. Wolfman A, Macara IG: A cytosolic protein catalyzes the release of GDP from p21ras. Science 248: 67–69, 1990

    Google Scholar 

  77. West M, Kung H-F, Kamata T: A novel membrane factor stimulates guanine nucleotide exchange reaction ofras proteins. FEBS Lett 259: 245–248, 1990

    Google Scholar 

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

    Google Scholar 

  79. Broek D, Toda T, Michaeli T, Levin L, Birchmeier C, Zoller M, Powers S, Wigler M: The S. cerevisiaeCDC25 gene product regulates theRAS/Adenylate cyclase pathway. Cell 48: 789–799, 1987

    Google Scholar 

  80. Jones S, Vignais M-L, Broach JR: TheCDC25 protein ofSaccharomyces cerevisiae promotes exchange of guanine nucleotides bound to ras. Mol Cell Biol 11: 2641–2646, 1991

    Google Scholar 

  81. Hughes DA, Fukui Y, Yamamoto M: Homologous activators ofras in fission and budding yeast. Nature 344: 355–357, 1990

    Google Scholar 

  82. Bonfini L, Karlovich CA, Dasgupta C, Banerjee U: TheSon of sevenless gene product: a putative activator of ras. Science 255: 603–606, 1992

    Google Scholar 

  83. Shou C, Farnsworth CL, Neel BG, Feig LA: Molecular cloning of cDNAs encoding a guanine-nucleotide-releasing factor for Ras p21. Nature 358: 351–354, 1992

    Google Scholar 

  84. Wei W, Mosteller RD, Sanyal P, Gonzales E, McKinney D, Dasgupta C, Li P, Liu B-X, Broek D: Identification of a mammalian gene structurally and functionally related to theCDC25 gene ofSaccharomyces cerevisiae. Proc Natl Acad Sci USA 89: 7100–7104, 1992

    Google Scholar 

  85. Martegani E, Vanoni M, Zippel R, Coccetti P, Brambilla R, Farrari C, Sturani E, Alberghina L: Cloning by functional complementation of a mouse cDNA encoding a homolog ofCDC25, aSaccharomyces cerevisiae Ras activator. EMBO J 11: 2151–2157, 1992

    Google Scholar 

  86. Cen H, Papageorge AG, Zippel R, Lowy DR, Zhang K: Isolation of multiple mouse cDNAs with coding homology toSaccharomyces cerevisiae CDC25: identification of a region related to Bcr, Vav, Dbl and CDC24. EMBO J 11: 4007–4015, 1992

    Google Scholar 

  87. Bowtell D, Fu P, Simon M, Senior P: Identification of murine homologues of theDrosophila Son of sevenless gene: potential aivators ofras. Proc Natl Acad Sci USA 89: 6511–6515, 1992

    Google Scholar 

  88. Chardin P, Camonis JH, Gale NW, Van Aelst L, Schlessinger J, Wigler MH, Bar-Sagi D: Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2. Science 260: 1338–1343, 1993

    Google Scholar 

  89. Gulbins E, Coggeshall KM, Baier G, Katzav S, Burn P, Altman A: Tyrosine kinase-stimulated guanine nucleotide exchange activity of Vav in T cell activation. Science 260: 822–825, 1993

    Google Scholar 

  90. Katzav S, Martin-Zanca D, Barbacid M:vav, a novel human oncogene derived from a locus ubiquitously expressed in hematopoietic cells. EMBO J 8: 2283–2290, 1989

    Google Scholar 

  91. Adams JM, Houston H, Allen J, Lints T, Harvey R: The hematopoietically expressedvav proto-oncogene shares homology with thedbl GDP-GTP exchange factor, thebcr gene and a yeast gene (CDC24) involved in cytoskeletal organization. Oncogene 7: 611–618, 1992

    Google Scholar 

  92. Eva A, Aaronson SA: Isolation of a new human oncogene from a diffuse B-cell lymphoma. Nature 316: 273–275, 1985

    Google Scholar 

  93. Hart MJ, Eva A, Evans T, Aaronson SA, Cerione RA: Catalysis of guanine nucleotide exchange on the CDC42Hs protein by thedbl oncogene product. Nature 354: 311–314, 1991

    Google Scholar 

  94. Kaibuchi K, Mizuno T, Fujioka H, Yamamoto T, Kishi K, Fukumoto Y, Hori Y, Takai Y: Molecular cloning of the cDNA for stimulatory GDP/GTP exchange protein for smg p21s (ras p21-like small GTP-binding proteins) and characterization of stimulatory GDP/GTP exchange protein. Mol Cell Biol 11: 2873–2880, 1991

    Google Scholar 

  95. Mizuno T, Kaibuchi K, Yamamoto T, Kawamura M, Sakoda T, Fujioka H, Matsuura Y, Takai Y: A stimulatory GDP/GTP exchange protein forsmg p21 is active on the posttranslationally processed form of c-Ki-ras p21 andrhoA p21. Proc Natl Acad Sci USA 88: 6442–6446, 1991

    Google Scholar 

  96. Ando S, Kaibuchi K, Sasaki T, Hiraoka K, Nishiyama T, Mizuno T, Asada M, Nunoi H, Matsuda I, Matsuura Y, Polakis P, McCormick F, Takai Y: Post-translational processing ofrac p21s is important both for their interaction with the GDP/GTP exchange proteins and for their activation of NADPH oxidase. J Biol Chem 267: 25709–25713, 1992

    Google Scholar 

  97. Araki S, Kikuchi A, Hata Y, Isomura M, Takai Y: Regulation of reversible binding of smg p25A, a ras p21-like GTP-binding protein, to synaptic plasma membranes and vesicles by its specific regulatory protein, GDP dissociation inhibitor. J Biol Chem 265: 13007–13015, 1990

    Google Scholar 

  98. Fukumoto Y, Kaibuchi K, Hori Y, Fujioka H, Araki S, Ueda T, Kikuchi A, Takai Y: Molecular cloning and characterization of a novel type of regulatory protein (GDI) for the rho proteins, ras p21-like small GTP-binding proteins. Oncogene 5: 1321–1328, 1990

    Google Scholar 

  99. Adamson P, Marshall CJ, Hall A, Tilbrook PA: Post-trans-lational modifications of p21rho proteins. J Biol Chem 267: 20033–20038, 1992

    Google Scholar 

  100. Maltese WA: Posttranslational modification of proteins by isoprenoids in mammalian cells. FASEB J 4: 3319–3328, 1990

    Google Scholar 

  101. Glomset J, Gelb M, Farnsworth C: The prenylation of proteins. Current Opinion in Lipidology 2: 118–124, 1991

    Google Scholar 

  102. Khosravi-Far R, Cox AD, Kato K, Der CJ: Protein prenylation: key to ras function and cancer intervention? Cell Growth and Diff 3: 461–469, 1992

    Google Scholar 

  103. Cox AD, Der CJ: Protein prenylation: more than just glue? Curr Op Cell Biol 4: 1008–1016, 1992

    Google Scholar 

  104. Hori Y, Kikuchi A, Isomura M, Katayama M, Miura Y, Fujioka H, Kaibuchi K, Takai Y: Post-translational modifications of the C-terminal region of therho protein are important for its interaction with membranes and the stimulatory and inhibitory GDP/GTP exchange proteins. Oncogene 6: 515–522, 1991

    Google Scholar 

  105. Araki S, Kaibuchi K, Sasaki T, Hata Y, Takai Y: Role of the C-terminal region ofsmg p25A in its interaction with membranes and the GDP/GTP exchange protein. Mol Cell Biol 11: 1438–1447, 1991

    Google Scholar 

  106. Li Y, Bolollag G, Clark R, Stevens J, Conroy L, Fults D, Ward K, Friedman E, Samowitz W, Robertson M, Bradley P, McCormick F, White R, Cawthon R: Somatic mutations in the neurofibromatosis 1 gene in human tumors. Cell 69: 275–281, 1992

    Google Scholar 

  107. Barlat I, Schweighoffer F, Chevallier-Multon MC, Duchesne M, Fath I, Landais D, Jacquet M, Tocque B: TheSaccharomyces cerevisiae gene product SDC25 C-domain functions as an oncoprotein in NIH3T3 cells. Oncogene 8: 215–218, 1993

    Google Scholar 

  108. Chevallier-Multon M-C, Schweighoffer F, Barlat I, Baudouy N, Fath I, Duchesne M, Tocqué B:Saccharomyces cerevisiae CDC25 (1028-1589) is a guanine nucleotide releasing factor for mammalian Ras proteins and is oncogenic in NIH3T3 cells. J Biol Chem 268: 11113–11118, 1993

    Google Scholar 

  109. Egan SE, Giddings BW, Brooks MW, Buday L, Sizeland AM, Weinberg RA: Association of sos ras exchange protein with Grb2 is implicated in tyrosine kinase signal transduction and transformation. Nature 363: 45–51, 1993

    Google Scholar 

  110. Fujioka H, Kaibuchi K, Kishi K, Yamamoto T, Kawamura M, Sakoda T, Mizuno T, Takai Y: Transforming andc-fos promoter/enhancer-stimulating activities of a stimulatory GDP/GTP exchange protein for small GTP-binding proteins. J Biol Chem 267: 926–930, 1992

    Google Scholar 

  111. Gibbs JB: Ras C-terminal processing enzymes - new drug targets? Cell 65: 1–4, 1991

    Google Scholar 

  112. Takai Y, Kaibuchi K, Kikuchi A, Kawata M: Small GTP-binding proteins. Int Rev Cytol 133: 187–230, 1992

    Google Scholar 

  113. Huang DCS, Marshall CJ, Haock JF: Plasma membrane-targetedras GTPase-activating protein is a potent suppressor of p21ras function. Mol Cell Biol 13: 2420–2431, 1993

    Google Scholar 

  114. Feig LA, Cooper GM: Inhibition of NIH 3T3 cell proliferation by a mutantras protein with preferential affinity for GDP. Mol Cell Biol 8: 3235–3243, 1988

    Google Scholar 

  115. Sistonen L, Hölttä E, Mäkelä TP, Keski-Oja J, Alitalo K: The cellular response to induction of the p21c-Ha-ras oncoprotein includes stimulation ofjun gene expression. EMBO J 8: 815–822, 1989

    Google Scholar 

  116. Pulverer BJ, Kyriakis JM, Avruch J, Nikolakaki E, Woodgett JR: Phosphorylation ofc-jun mediated by MAP kinases. Nature 353: 670–674, 1991

    Google Scholar 

  117. Mulcahy LS, Smith MR, Stacey DW: Requirement forras proto-oncogene function during serum-stimulated growth of NIH 3T3 cells. Nature 313: 241–243, 1985

    Google Scholar 

  118. Kung H-F, Smith MR, Bekesi E, Manne V, Stacey DW: Reversal of transformed phenotype by monoclonal antibodies against Ha-ras p21 proteins. Exp Cell Res 162: 363–371, 1986

    Google Scholar 

  119. Smith MR, DeGudicibus SJ, Stacey DW: Requirement for c-ras proteins during viral oncogene transformation. Nature 320: 540–543, 1986

    Google Scholar 

  120. Szeberényi J, Cai H, Cooper GM: Effect of a dominant inhibitory Ha-ras mutation on neuronal differentiation of PC12 cells. Mol Cell Biol 10: 5324–5332, 1990

    Google Scholar 

  121. Medema RH, Wubbolts R, Bos JL: Two dominant inhibitory mutants of p21ras interfere with insulin-induced gene expression. Mol Cell Biol 11: 5963–5967, 1991

    Google Scholar 

  122. Schweighoffer F, Cai H, Chevallier-Multon MC, Fath I, Cooper G, Tocque B: The Saccharomyces cerevisiae SDC25 C-domain gene product overcomes the dominant inhibitory activity of Ha-ras asn-17. Mol Cell Biol 13: 39–43, 1993

    Google Scholar 

  123. Stacey DW, DeGudicibus SR, Smith MR: Cellularras activity and tumor cell proliferation. Exp Cell Res 171: 232–242, 1987

    Google Scholar 

  124. Burgering BM, Medema RH, Maassen JA, van de Wetering ML, van der Eb AJ, McCormick F, Bos JL: Insulin stimulation of gene expression mediated by p21ras activation. EMBO J 10: 1103–1109, 1991

    Google Scholar 

  125. Satoh T, Endo M, Nakafuku M, Akiyama T, Yamamoto T, Kaziro Y: Accumulation of p21ras GTP in response to stimulation with epidermal growth factor and oncogene products with tyrosine kinase activity. Proc Natl Acad Sci USA 87: 7926–7929, 1990

    Google Scholar 

  126. Satoh T, Endo M, Nakafuku M, Nakamura S, Kaziro Y: Platelet-derived growth factor stimulates formation of active p21ras GTP complex in Swiss mouse 3T3 cells. Proc Natl Acad Sci USA 87: 5993–5997, 1990

    Google Scholar 

  127. Muroya K, Hattori S, Nakamura S: Nerve growth factor induces accumulation of the GTP-bound form of p21ras in rat pheochromocytoma PC12 cells. Oncogene 7: 277–281, 1992

    Google Scholar 

  128. Qiu M-S, Green SH: NGF and EGF rapidly activate p21ras in PC12 cells by distinct, convergent pathways involving tyrosine phosphorylation. Neuron 7: 937–946, 1991

    Google Scholar 

  129. Duronio V, Welham MJ, Abraham S, Dryden P, Schrader JW: p21ras activation via hemopoietin receptors and c-kit requires tyrosine kinase activity but not tyrosine phospho-rylation of p21ras GTPase-activating protein. Proc Natl Acad Sci USA 89: 1587–1591, 1992

    Google Scholar 

  130. Satoh T, Nakafuku M, Miyajima A, Kaziro Y: Involvement ofras p21 protein in signal-transduction pathways from interleukin 2, interleukin 3, and granulocyte/macrophage colony-stimulating factor, but not from interleukin 4. Proc Natl Acad Sci USA 88: 3314–3318, 1991

    Google Scholar 

  131. Torti M, Marti KB, Altschuler D, Yamamoto EG, Lapetina E: Erythropoietin induces p21ras activation and p120GAP tyrosine phsophorylation in human erythroleukemia cells. J Biol Chem 267: 8293–8298, 1992

    Google Scholar 

  132. Downward J, Graves JD, Warne PH, Rayter S, Cantrell DA: Stimulation of p21ras upon T-cell activation. Nature 346: 719–723, 1990

    Google Scholar 

  133. Graves JD, Downward J, Rayter S, Warne P, Tutt AL, Glennie M, Cantrell DA: CD2 antigen mediated activation of the guanine nucleotide binding proteins p21ras in human T lymphocytes. J Immunol 146: 3709–3712, 1991

    Google Scholar 

  134. Graves JD, Downward J, Izquierdo M, Rayter S, Warne PH, Cantrell DA: The growth factor IL-2 activates p21ras proteins in normal human T lymphocytes. J Immunol 148: 2417–2422, 1992

    Google Scholar 

  135. Hatakeyama M, Kono T, Kobayashi N, Kawahara A, Levin SD, Perlmutter RM, Taniguchi T: Interaction of the IL-2 receptor with thesrc-family kinase p56lck. Identification of novel intermolecular association. Science 252: 1523–1528, 1991

    Google Scholar 

  136. Li B-Q, Kaplan D, Kung H-F, Damata T: Nerve growth factor stimulation of the Ras-guanine nucleotide exchange factor and GAP activities. Science 256: 1456–1459, 1992

    Google Scholar 

  137. Medema RH, de Vries-Smits AMM, van der Zon GCM, Maassen JA, Bos JL: Ras activation by insulin and epidermal growth factor through enhanced exchange of guanine nucleotides on p21ras. Mol Cell Biol 13: 155–162, 1993

    Google Scholar 

  138. Williams LT: Missing links between receptors and Ras. Curr Op Cell Biol 2: 601–603, 1992

    Google Scholar 

  139. Kazlauskas A, Ellis C, Pawson T, Cooper JA: Binding of GAP to activated PDGF receptors. Science 247: 1578–1581, 1990

    Google Scholar 

  140. Kaplan DR, Morrison DK, Wong G, McCormick F, Williams LT: PDGF β-receptor stimulates tyrosine phosphorylation of GAP and association of GAP with a signaling complex. Cell 61: 125–133, 1990

    Google Scholar 

  141. Porras A, Nebreda AR, Benito M, Santos E: Activation of ras by insulin in 3T3 L1 cells does not involve GTPase-activating protein phosphorylation. J Biol Chem 267: 21124–21131, 1992

    Google Scholar 

  142. Reedijk M, Liu X, van der Geer P, Letwin K, Waterfield MD, Hunter T, Pawson T: Tyr721 regulates specific binding of the CSF-1 receptor kinase insert to PI 3'-kinase SH2 domains: a model for SH2-mediated receptor-target interactions. EMBO J 11: 1365–1372, 1992

    Google Scholar 

  143. Chang J-H, Wilson LK, Moyers JS, Zhang K, Parsons SJ: Increased levels of p21ras-GTP and enhanced DNA synthesis accompany elevated tyrosyl phosphorylation of GAP-association proteins, p190 and p62, in c-src overexpressors. Oncogene 8: 959–967, 1993

    Google Scholar 

  144. Moran MF, Polakis P, McCormick F, Pawson T, Ellis C: Protein-tyrosine kinases regulate the phosphorylation, protein interactions, subcellular distribution, and activity of p21ras GTPase-activating protein. Mol Cell Biol 11: 1804–1812, 1991

    Google Scholar 

  145. Settleman J, Narasimhan V, Foster LC, Weinberg RA: Molecular cloning of cDNAs encoding the GAP-associated protein p190: implications for a signaling pathway from Ras to the nucleus. Cell 69: 539–549, 1992

    Google Scholar 

  146. Tsai M-H, Yu C-L, Stacey DW: A cytoplasmic protein inhibits the GTPase activity of H-ras in a phospholipid-dependent manner. Science 250: 982–985, 1990

    Google Scholar 

  147. Yu C-L, Tsai M-H, Stacey DW: Cellular ras activity in phospholipid metabolism. Cell 52: 63–71, 1988

    Google Scholar 

  148. Han J-W, McCormick F, Macara IG: Regulation of Ras-GAP and the neurofibromatosis-1 gene product by Eicosanoids. Science 252: 576–579, 1991

    Google Scholar 

  149. Gross E, Goldberg D, Levitzki A: Phosphorylation of theS. cerevisiae Cdc-25 in response to glucose results in its dissociation from Ras. Nature 360: 762–765, 1992

    Google Scholar 

  150. Margolis B, Hu P, Katzav S, Li W, Oliver JM, Ullrich A, Weiss A, Schlessinger J: Tyrosine phosphorylation ofvav proto-oncogene product containing SH2 domain and transcription factor motifs. Nature 356: 71–74, 1992

    Google Scholar 

  151. Clark SG, Stern MJ, Horvitz HR:C. elegans cell-signalling genesem-5 encodes a protein with SH2 and SH3 domains. Nature 356: 340–344, 1992

    Google Scholar 

  152. Lowenstein EJ, Daly RJ, Batzer AG, Margolis B, Lammers R, Ullrich A, Skolnik EY, Bar-Sagi D, Schlessinger J: The SH2 and SH3 domain-containing protein GRB2 links receptor tyrosine kinases to ras signaling. Cell 70: 431–442, 1992

    Google Scholar 

  153. Simon MA, Dodson GS, Rubin GM: An SH3-SH2-SH3 protein is required for p21Ras1 activation and binds to sevenless and sos proteinsin vitro. Cell 73: 169–177, 1993

    Google Scholar 

  154. Rozakis-Adcock M, McGlade J, Mbamalu G, Pelicci G, Daly R, Li W, Batzer A, Thomas S, Brugge J, Pelicci PG, Schlessinger J, Pawson T: Association of the Shc and Grb-2/Sem-5 SH2-containing proteins is implicated in activation of the Ras pathway by tyrosine kinases. Nature 360: 689–692, 1992

    Google Scholar 

  155. Buday L, Downward J: Epidermal growth factor regulates p21ras through the formation of a complex of receptor, Grb2 adaptor protein, and Sos nucleotide exchange factor. Cell 73: 611–620, 1993

    Google Scholar 

  156. Gale NW, Kaplan S, Lowenstein EJ, Schlessinger J, Bar-Sagi D: Grb2 mediates the EGF-dependent activation of guanine nucleotide exchange on Ras. Nature 363: 88–92, 1993

    Google Scholar 

  157. Li N, Batzer A, Daly R, Yajnik V, Skolnik E, Chardin P, Bar-Sagi D, Margolis B, Schlessinger J: Guanine-nucleotide-releasing factor hSosl binds to Grb2 and links receptor tyrosine kinases to Ras signalling. Nature 363: 85–88, 1993

    Google Scholar 

  158. Olivier JP, Raabe T, Henkemeyer M, Dickson B, Mbamalu G, Margolis B, Schlessinger J, Hafen E, Pawson T: A Drosophila SH2-SH3 adaptor protein implicated in coupling the sevenless tyrosine kinase to an activator of ras guanine nucleotide exchange, Sos. Cell 73: 179–191, 1993

    Google Scholar 

  159. 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

    Google Scholar 

  160. Pelicci G, Lanfrancone L, Grignani F, McGlade J, Cavallo F, Forni G, Nicoletti I, Pawson T, Pelicci PG: A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction. Cell 70: 93–104, 1992

    Google Scholar 

  161. McGlade J, Cheng A, Pelicci G, Pelicci PG, Pawson T: Shc proteins are phosphorylated and regulated by the v-Src and v-Fps protein-tyrosine kinases. Proc Natl Acad Sci USA 89: 8869–8873, 1992

    Google Scholar 

  162. Leevers SJ, Marshall CJ: MAP kinase regulation - the oncogene connection. Trends Cell Biol 2: 283–286, 1992

    Google Scholar 

  163. Morrison DK, Kaplan DR, Rapp U, Roberts TM: Signal transduction from membrane to cytoplasm: growth factors and membrane-bound oncogene products increase Raf-1 phosphorylation and associated protein kinase activity. Proc Natl Acad Sci USA 85: 8855–8859, 1988

    Google Scholar 

  164. Heidecker G, Kolch W, Morrison DK, Rapp UR: The role of Raf-1 phosphorylation in signal transduction. Adv Cancer Res 58: 53–73, 1992

    Google Scholar 

  165. Bruder JT, Heidecker G, Rapp UR: Serum-, TPA, and Ras-induced expression from Ap-1/Ets-driven promoters requires Raf-1 kinase. Genes Dev 6: 545–556, 1992

    Google Scholar 

  166. Wood KW, Sarnecki C, Roberts TM, Blenis J:ras mediates nerve growth factor receptor modulation of three signaltransducing protein kinases: MAP kinase, Raf-1, and RSK. Cell 68: 1041–1050, 1992

    Google Scholar 

  167. Dickson B, Sprenger F, Morrison D, Hafen E: Raf functions downstream of Rasl in the sevenless signal transduction pathway. Nature 360: 600–603, 1992

    Google Scholar 

  168. Sprenger F, Trosclair MM, Morrison DK: Biochemical analysis of Torso and D-Raf duringDrosophila embryogenesis: implications for terminal signal transduction. Mol Cell Biol 13: 1163–1172, 1993

    Google Scholar 

  169. Han M, Golden A, Han Y, Sternberg PW:C. elegans lin-45 raf gene participates inlet-60 ras-stimulated vulval differentiation. Nature 363: 133–140, 1993

    Google Scholar 

  170. Moodie SA, Willumsen BM, Weber MJ, Wolfman A: Complexes of Ras-GTP with Raf-1 and mitogen-activated protein kinase kinase. Science 260: 1658–1661, 1993

    Google Scholar 

  171. Kyriakis JM, App H, Zhang X-f, Banerjee P, Brautigan DL, Rapp UR, Avruch J: Raf-1 activates MAP kinase-kinase. Nature 358: 417–421, 1992

    Google Scholar 

  172. Liaw G-J, Steingrimsson E, Pignoni F, Courey AJ, Lengyel JA: Characterization of downstream elements in a Raf-1 pathway. Proc Natl Acad Sci USA 90: 858–862, 1993

    Google Scholar 

  173. Crews CM, Alessandrini A, Erikson RL: Erks: their fifteen minutes has arrived. Cell Growth and Diff 3: 135–142, 1992

    Google Scholar 

  174. Ahn NG, Seger R, Krebs EG: The mitogen-activated protein kinase activator. Curr Op Cell Biol 4: 992–999, 1992

    Google Scholar 

  175. Adams PD, Parker PJ: Activation of mitogen-activated protein (MAP) kinase by a MAP kinase-kinase. J Biol Chem 267: 13135–13137, 1992

    Google Scholar 

  176. Dent P, Haser W, Haystead TAJ, Vincent LA, Roberts TM, Sturgill TW: Activation of mitogen-activated protein kinase kinase by v-Raf in NIH 3T3 cells andin vitro. Science 257: 1404–1407, 1992

    Google Scholar 

  177. Wu J, Harrison JK, Vincent LA, Haystead C, Haystead TAJ, Michel H, Hunt DF, Lynch KR, Sturgill TW: Molecular structure of a protein-tyrosine/threonine kinase activating p42 mitogen-activated protein (MAP) kinase: MAP kinase kinase. Proc Natl Acad Sci USA 90: 173–177, 1993

    Google Scholar 

  178. Crews CM, Alessandrini A, Erikson RL: The primary structure of MEK, a protein kinase that phosphorylates theERK gene product. Science 258: 478–480, 1992

    Google Scholar 

  179. Crews CM, Erikson RL: Purification of a murine proteintyrosine/threonine kinase that phosphorylates and activates theErk-1 gene product: relationship to the fission yeastbyr1 gene product. Proc Natl Acad Sci USA 89: 8205–8209, 1992

    Google Scholar 

  180. Seger R, Ahn NG, Boulton TG, Yancopoulos GD, Panatotatos N, Radziejewska E, Ericsson L, Bratlien RL, Cobb MH, Krebs EG: Microtubule-associated protein 2 kinases, ERK1 and ERK2, undergo autophosphorylation on both tyrosine and threonine residues: implications for their mechanism of activation. Proc Natl Acad Sci USA 88: 6142–6146, 1991

    Google Scholar 

  181. Sprague GF, Jr.: Kinase cascade conserved. Curr Op Cell Biol 2: 587–589, 1992

    Google Scholar 

  182. Errede B, Levin DE: A conserved kinase cascade for MAP kinase activation in yeast. Curr Biol 5: 254–260, 1993

    Google Scholar 

  183. Errede B, Gartner A, Zhou Z, Nasmyth K, Ammerer G: MAP kinase-related FUS3 fromS. cerevisiae is activated by STE7in vitro. Nature 362: 261–264, 1993

    Google Scholar 

  184. Elion EA, Satterberg B, Kranz JE: FUS3 phosphorylates multiple components of the mating signal transduction cascade: evidence for STE12 and FAR1. Mol Biol Cell 4: 495–510, 1993

    Google Scholar 

  185. Tsuda L, Inoue YH, Yoo M-A, Mizuno M, Hata M, Lim Y-M, Adachi-Yamada T, Ryo H, Masamune Y, Nishida Y: A protein kinase similar to MAP kinase activator acts downstream of the Raf kinase in Drosophila. Cell 72: 407–414, 1993

    Google Scholar 

  186. Gupta SK, Gallego C, Johnson GL, Heasley LE: MAP kinase is constitutively activated in gip2 and src transformed Rat 1a fibroblasts. J Biol Chem 267: 7987–7990, 1992

    Google Scholar 

  187. Gallego C, Gupta SK, Heasley LE, Qian N-X, Johnson GL: Mitogen-activated protein kinase activation resulting from selective oncogene expression in NIH 3T3 and Rat 1a cells. Proc Natl Acad Sci USA 89: 7355–7359, 1992

    Google Scholar 

  188. Lange-Carter CA, Pleiman CM, Gardner AM, Blumer KJ, Johnson GL: A divergence in the MAP kinase regulatory network defined by MEK kinase and raf. Science 260: 315–319, 1993

    Google Scholar 

  189. Robbins DJ, Zhen E, Owaki H, Vanderbilt CA, Ebert D, Geppert TD, Cobb MH: Regulation and properties of extracellular signal-regulated protein kinases 1 and 2in vitro J Biol Chem 268: 5097–5106, 1993

    Google Scholar 

  190. Seth A, Gonzalez FA, Gupta S, Raden DL, Davis RJ: Signal transduction within the nucleus by mitogen-activated protein kinase. J Biol Chem 267: 24796–24804, 1992

    Google Scholar 

  191. Baker SJ, Kerppola TK, Luk D, Vandenberg MT, Marshak DR, Curran T, Abate C: Jun is phosphorylated by several protein kinases at the same sites that are modified in serum-stimulated fibroblasts. Mol Cell Biol 12: 4694–4705, 1992

    Google Scholar 

  192. Cheng J-T, Cobb MH, Baer R: Phosphorylation of the TAL1 oncoprotein by the extracellular-signal-regulated protein kinase ERK1. Mol Cell Biol 13: 801–808, 1993

    Google Scholar 

  193. Gille H, Sharrocks AD, Shaw PE: Phosphorylation of transcription factor p62TCF by MAP kinase stimulates ternary complex formation at c-fos promoter. Nature 358: 414–417, 1992

    Google Scholar 

  194. Heidecker G, Kölch W, Morrison DK, Rapp UR: The role of Raf-1 phosphorylation in signal transduction. Adv Cancer Res 58: 53–73, 1992

    Google Scholar 

  195. Stokoe D, Campbell DG, Nakielny S, Hidaka H, Leevers SJ, Marshall C, Cohen P: MAPKAP kinase-2: a novel protein kinase activated by mitogen-activated protein kinase. EMBO J 11: 3985–3994, 1992

    Google Scholar 

  196. Chen RH, Sarnecki C, Blenis J: Nuclear localization and regulation of erk- and rsk-encoded protein kinases. Mol Cell Biol 12: 915–927, 1992

    Google Scholar 

  197. Valencia A, Chardin P, Wittinghofer A, Sander C: Theras protein family: evolutionary tree and role of conserved amino acids. Biochemistry 30: 4637–4648, 1991

    Google Scholar 

  198. Kahn RA, Der CJ, Bokoch GM: The ras superfamily of GTP-binding proteins: guidelines on nomenclature. FASEB J 6: 2512–2513, 1992

    Google Scholar 

  199. Vincent S, Jeanteur P, Fort P: Growth-regulated expression ofrhoG, a new member of theras homolog gene family. Mol Cell Biol 12: 3138–3148, 1992

    Google Scholar 

  200. Mohr C, Koch G, Just I, Aktories K: ADP-ribosylation byClostridium botulinum C3 exoenzyme increases steadystate GTPase activities of recombinant rhoA and rhoB proteins. FEBS 297: 95–99, 1992

    Google Scholar 

  201. Paterson HF, Self AJ, Garrett MD, Just I, Aktories K, Hall A: Microinjection of recombinant p21rho induces rapid changes in cell morphology. J Cell Biol 111: 1001–1007, 1990

    Google Scholar 

  202. Ridley AJ, Hall A: The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell 70: 389–399, 1992

    Google Scholar 

  203. Ridley AJ, Paterson HF, Johnston CL, Diekmann D, Hall A: The small GTP-binding protein rac regulates growth factor-induced membrane ruffling. Cell 70: 401–410, 1992

    Google Scholar 

  204. Bokoch GM, Der CJ: Emerging concepts in the Ras superfamily of GTP-binding proteins. FASEB J in press, 1993

  205. Settleman J, Narasimhan V, Foster LC, Weinberg RA: Molecular cloning of cDNAs encoding the GAP-associated protein p190: implications for a signaling pathway from ras to the nucleus. Cell 69: 539–549, 1992

    Google Scholar 

  206. Avraham H, Weinberg RA: Characterization and expression of the humanrhoH12 gene product. Mol Cell Biol 9.5: 2058–2066, 1989

    Google Scholar 

  207. Perona R, Esteve P, Jiménez B, Ballestero RP, Ramón Y, Cajal S, Lacal JC: Tumorigenic activity ofrho genes fromAplysia californica. Oncogene 8: 1285–1292, 1993

    Google Scholar 

  208. Jahner D, Hunter T: The ras-related gene rhoB is an immediate-early gene inducible by v-Fps, epidermal growth factor, and platelet-derived growth factor in rat fibroblasts. Mol Cell Biol 11: 3682–3690, 1991

    Google Scholar 

  209. Diekmann D, Brill S, Garrett MD, Totty N, Hsuan J, Monfries C, Hall C, Lim L, Hall A: Bcr encodes a GTPase-activating protein for p21rac. Nature 351: 400–402, 1991

    Google Scholar 

  210. Arlinghaus RB: Multiple BCR-related gene products and their proposed involvement in ligand-induced signal transduction pathways. Mol Carcinogen 5: 171–173, 1992

    Google Scholar 

  211. Miki T, Smith CL, Long JE, Eva A, Fleming TP: Oncogeneect2 is related to regulators of small GTP-binding proteins. Nature 362: 462–465, 1993

    Google Scholar 

  212. Thomas G: MAP kinase by any other name smells just as sweet. Cell 68: 3–6, 1992

    Google Scholar 

  213. Brugge JS: New intracellular targets for therapeutic drug design. Science 260: 918–919, 1993

    Google Scholar 

  214. Kohl NE, Mosser SD, deSolms SJ, Giuliani EA, Graham SL, Smith RL, Scolnick EM, Oliff A, Gibbs JB: Selective inhibition ofras-dependent cell transformation by a farnesyl-protein transferase inhibitor. Science in press, 1993

  215. Axelrod JH, Bar-Sinai A, Levitzki A: p21rasGAP antisense oligonucleotides blockras signalling. Science in press, 1993

  216. Garcia AM, Rowell C, Ackermann K, Kowalczyk JJ, Lewis MD: Peptidomimetic inhibitors ofras farnesylation and function in whole cells. J Biol Chem in press, 1993

  217. Burgering B, Medema R, Maassen JA, van de Wetering ML, van der Eb AJ, McCormick F, Bos JL: Insulin stimulation of gene expression mediated by p21ras activation. EMBO J 10: 1103–1109, 1991

    Google Scholar 

  218. Nakafuku M, Satoh T, Kaziro Y: Differentiation factors, including nerve growth factor, fibroblast growth factor, and interleukin-6, induce an accumulation of an active ras GTP complex in rat pheochromocytoma PC12 cells. J Biol Chem 267: 19448–19454, 1992

    Google Scholar 

  219. Mulder KM, Morris SL: Activation of p21ras by transforming growth factor β in epithelial cells. J Biol Chem 267: 5027–5031, 1992

    Google Scholar 

  220. Bortner DM, Langer SJ, Ostrowski MC: Non-nuclear oncogenes and the regulation of gene expression in transformed cells. Crit Rev Oncogenesis 4: 137–160, 1993

    Google Scholar 

  221. Melo JV, Gordon DE, Cross NCP, Goldman JM: The ABL-BCR fusion gene is expressed in chronic myeloid leukemia. Blood 81: 158–165, 1993

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Khosravi-Far, R., Der, C.J. The Ras signal transduction pathway. Cancer Metast Rev 13, 67–89 (1994). https://doi.org/10.1007/BF00690419

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00690419

Key words

Navigation