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. 1996 Jul;16(7):3923–3933. doi: 10.1128/mcb.16.7.3923

Oncogenic Ras activation of Raf/mitogen-activated protein kinase-independent pathways is sufficient to cause tumorigenic transformation.

R Khosravi-Far 1, M A White 1, J K Westwick 1, P A Solski 1, M Chrzanowska-Wodnicka 1, L Van Aelst 1, M H Wigler 1, C J Der 1
PMCID: PMC231389  PMID: 8668210

Abstract

Substantial evidence supports a critical role for the activation of the Raf-1/MEK/mitogen-activated protein kinase pathway in oncogenic Ras-mediated transformation. For example, dominant negative mutants of Raf-1, MEK, and mitogen-activated protein kinase all inhibit Ras transformation. Furthermore, the observation that plasma membrane-localized Raf-1 exhibits the same transforming potency as oncogenic Ras suggests that Raf-1 activation alone is sufficient to mediate full Ras transforming activity. However, the recent identification of other candidate Ras effectors (e.g., RalGDS and phosphatidylinositol-3 kinase) suggests that activation of other downstream effector-mediated signaling pathways may also mediate Ras transforming activity. In support of this, two H-Ras effector domain mutants, H-Ras(12V, 37G) and H-Ras(12V, 40C), which are defective for Raf binding and activation, induced potent tumorigenic transformation of some strains of NIH 3T3 fibroblasts. These Raf-binding defective mutants of H-Ras induced a transformed morphology that was indistinguishable from that induced by activated members of Rho family proteins. Furthermore, the transforming activities of both of these mutants were synergistically enhanced by activated Raf-1 and inhibited by the dominant negative RhoA(19N) mutant, indicating that Ras may cause transformation that occurs via coordinate activation of Raf-dependent and -independent pathways that involves Rho family proteins. Finally, cotransfection of H-Ras(12V, 37G) and H-Ras(12V, 40C) resulted in synergistic cooperation of their focus-forming activities, indicating that Ras activates at least two Raf-independent, Ras effector-mediated signaling events.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Akasaka K., Tamada M., Wang F., Kariya K., Shima F., Kikuchi A., Yamamoto M., Shirouzu M., Yokoyama S., Kataoka T. Differential structural requirements for interaction of Ras protein with its distinct downstream effectors. J Biol Chem. 1996 Mar 8;271(10):5353–5360. doi: 10.1074/jbc.271.10.5353. [DOI] [PubMed] [Google Scholar]
  2. Alessi D. R., Cohen P., Ashworth A., Cowley S., Leevers S. J., Marshall C. J. Assay and expression of mitogen-activated protein kinase, MAP kinase kinase, and Raf. Methods Enzymol. 1995;255:279–290. doi: 10.1016/s0076-6879(95)55031-3. [DOI] [PubMed] [Google Scholar]
  3. Alessi D. R., Saito Y., Campbell D. G., Cohen P., Sithanandam G., Rapp U., Ashworth A., Marshall C. J., Cowley S. Identification of the sites in MAP kinase kinase-1 phosphorylated by p74raf-1. EMBO J. 1994 Apr 1;13(7):1610–1619. doi: 10.1002/j.1460-2075.1994.tb06424.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Avraham H., Weinberg R. A. Characterization and expression of the human rhoH12 gene product. Mol Cell Biol. 1989 May;9(5):2058–2066. doi: 10.1128/mcb.9.5.2058. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bar-Sagi D., Feramisco J. R. Induction of membrane ruffling and fluid-phase pinocytosis in quiescent fibroblasts by ras proteins. Science. 1986 Sep 5;233(4768):1061–1068. doi: 10.1126/science.3090687. [DOI] [PubMed] [Google Scholar]
  6. Boguski M. S., McCormick F. Proteins regulating Ras and its relatives. Nature. 1993 Dec 16;366(6456):643–654. doi: 10.1038/366643a0. [DOI] [PubMed] [Google Scholar]
  7. Bonner T. I., Kerby S. B., Sutrave P., Gunnell M. A., Mark G., Rapp U. R. Structure and biological activity of human homologs of the raf/mil oncogene. Mol Cell Biol. 1985 Jun;5(6):1400–1407. doi: 10.1128/mcb.5.6.1400. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Bottorff D., Stang S., Agellon S., Stone J. C. RAS signalling is abnormal in a c-raf1 MEK1 double mutant. Mol Cell Biol. 1995 Sep;15(9):5113–5122. doi: 10.1128/mcb.15.9.5113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Bourne H. R., Sanders D. A., McCormick F. The GTPase superfamily: a conserved switch for diverse cell functions. Nature. 1990 Nov 8;348(6297):125–132. doi: 10.1038/348125a0. [DOI] [PubMed] [Google Scholar]
  10. Chang E. C., Barr M., Wang Y., Jung V., Xu H. P., Wigler M. H. Cooperative interaction of S. pombe proteins required for mating and morphogenesis. Cell. 1994 Oct 7;79(1):131–141. doi: 10.1016/0092-8674(94)90406-5. [DOI] [PubMed] [Google Scholar]
  11. Chant J., Stowers L. GTPase cascades choreographing cellular behavior: movement, morphogenesis, and more. Cell. 1995 Apr 7;81(1):1–4. doi: 10.1016/0092-8674(95)90363-1. [DOI] [PubMed] [Google Scholar]
  12. Clark G. J., Cox A. D., Graham S. M., Der C. J. Biological assays for Ras transformation. Methods Enzymol. 1995;255:395–412. doi: 10.1016/s0076-6879(95)55042-9. [DOI] [PubMed] [Google Scholar]
  13. Coso O. A., Chiariello M., Yu J. C., Teramoto H., Crespo P., Xu N., Miki T., Gutkind J. S. The small GTP-binding proteins Rac1 and Cdc42 regulate the activity of the JNK/SAPK signaling pathway. Cell. 1995 Jun 30;81(7):1137–1146. doi: 10.1016/s0092-8674(05)80018-2. [DOI] [PubMed] [Google Scholar]
  14. Cowley S., Paterson H., Kemp P., Marshall C. J. Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells. Cell. 1994 Jun 17;77(6):841–852. doi: 10.1016/0092-8674(94)90133-3. [DOI] [PubMed] [Google Scholar]
  15. Cox A. D., Solski P. A., Jordan J. D., Der C. J. Analysis of Ras protein expression in mammalian cells. Methods Enzymol. 1995;255:195–220. doi: 10.1016/s0076-6879(95)55023-2. [DOI] [PubMed] [Google Scholar]
  16. Dent P., Haser W., Haystead T. A., Vincent L. A., Roberts T. M., Sturgill T. W. Activation of mitogen-activated protein kinase kinase by v-Raf in NIH 3T3 cells and in vitro. Science. 1992 Sep 4;257(5075):1404–1407. doi: 10.1126/science.1326789. [DOI] [PubMed] [Google Scholar]
  17. Der C. J., Finkel T., Cooper G. M. Biological and biochemical properties of human rasH genes mutated at codon 61. Cell. 1986 Jan 17;44(1):167–176. doi: 10.1016/0092-8674(86)90495-2. [DOI] [PubMed] [Google Scholar]
  18. Dickson B., Sprenger F., Morrison D., Hafen E. Raf functions downstream of Ras1 in the Sevenless signal transduction pathway. Nature. 1992 Dec 10;360(6404):600–603. doi: 10.1038/360600a0. [DOI] [PubMed] [Google Scholar]
  19. Downward J. Signal transduction. Rac and Rho in tune. Nature. 1992 Sep 24;359(6393):273–274. doi: 10.1038/359273a0. [DOI] [PubMed] [Google Scholar]
  20. Drugan J. K., Khosravi-Far R., White M. A., Der C. J., Sung Y. J., Hwang Y. W., Campbell S. L. Ras interaction with two distinct binding domains in Raf-1 may be required for Ras transformation. J Biol Chem. 1996 Jan 5;271(1):233–237. doi: 10.1074/jbc.271.1.233. [DOI] [PubMed] [Google Scholar]
  21. Egan S. E., Weinberg R. A. The pathway to signal achievement. Nature. 1993 Oct 28;365(6449):781–783. doi: 10.1038/365781a0. [DOI] [PubMed] [Google Scholar]
  22. Fabian J. R., Daar I. O., Morrison D. K. Critical tyrosine residues regulate the enzymatic and biological activity of Raf-1 kinase. Mol Cell Biol. 1993 Nov;13(11):7170–7179. doi: 10.1128/mcb.13.11.7170. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Feig L. A., Cooper G. M. Inhibition of NIH 3T3 cell proliferation by a mutant ras protein with preferential affinity for GDP. Mol Cell Biol. 1988 Aug;8(8):3235–3243. doi: 10.1128/mcb.8.8.3235. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Feig L. A. The many roads that lead to Ras. Science. 1993 May 7;260(5109):767–768. doi: 10.1126/science.8484117. [DOI] [PubMed] [Google Scholar]
  25. Hall A. Ras-related proteins. Curr Opin Cell Biol. 1993 Apr;5(2):265–268. doi: 10.1016/0955-0674(93)90114-6. [DOI] [PubMed] [Google Scholar]
  26. Hall A. ras and GAP--who's controlling whom? Cell. 1990 Jun 15;61(6):921–923. doi: 10.1016/0092-8674(90)90054-i. [DOI] [PubMed] [Google Scholar]
  27. Han L., Colicelli J. A human protein selected for interference with Ras function interacts directly with Ras and competes with Raf1. Mol Cell Biol. 1995 Mar;15(3):1318–1323. doi: 10.1128/mcb.15.3.1318. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Han M., Golden A., Han Y., Sternberg P. W. C. elegans lin-45 raf gene participates in let-60 ras-stimulated vulval differentiation. Nature. 1993 May 13;363(6425):133–140. doi: 10.1038/363133a0. [DOI] [PubMed] [Google Scholar]
  29. Hauser C. A., Westwick J. K., Quilliam L. A. Ras-mediated transcription activation: analysis by transient cotransfection assays. Methods Enzymol. 1995;255:412–426. doi: 10.1016/s0076-6879(95)55043-7. [DOI] [PubMed] [Google Scholar]
  30. Hill C. S., Marais R., John S., Wynne J., Dalton S., Treisman R. Functional analysis of a growth factor-responsive transcription factor complex. Cell. 1993 Apr 23;73(2):395–406. doi: 10.1016/0092-8674(93)90238-l. [DOI] [PubMed] [Google Scholar]
  31. Hill C. S., Treisman R. Transcriptional regulation by extracellular signals: mechanisms and specificity. Cell. 1995 Jan 27;80(2):199–211. doi: 10.1016/0092-8674(95)90403-4. [DOI] [PubMed] [Google Scholar]
  32. Hill C. S., Wynne J., Treisman R. The Rho family GTPases RhoA, Rac1, and CDC42Hs regulate transcriptional activation by SRF. Cell. 1995 Jun 30;81(7):1159–1170. doi: 10.1016/s0092-8674(05)80020-0. [DOI] [PubMed] [Google Scholar]
  33. Hofer F., Fields S., Schneider C., Martin G. S. Activated Ras interacts with the Ral guanine nucleotide dissociation stimulator. Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):11089–11093. doi: 10.1073/pnas.91.23.11089. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Howe L. R., Leevers S. J., Gómez N., Nakielny S., Cohen P., Marshall C. J. Activation of the MAP kinase pathway by the protein kinase raf. Cell. 1992 Oct 16;71(2):335–342. doi: 10.1016/0092-8674(92)90361-f. [DOI] [PubMed] [Google Scholar]
  35. Khosravi-Far R., Chrzanowska-Wodnicka M., Solski P. A., Eva A., Burridge K., Der C. J. Dbl and Vav mediate transformation via mitogen-activated protein kinase pathways that are distinct from those activated by oncogenic Ras. Mol Cell Biol. 1994 Oct;14(10):6848–6857. doi: 10.1128/mcb.14.10.6848. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Khosravi-Far R., Der C. J. The Ras signal transduction pathway. Cancer Metastasis Rev. 1994 Mar;13(1):67–89. doi: 10.1007/BF00690419. [DOI] [PubMed] [Google Scholar]
  37. 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. 1995 Nov;15(11):6443–6453. doi: 10.1128/mcb.15.11.6443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. 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. 1994 Nov;14(11):7483–7491. doi: 10.1128/mcb.14.11.7483. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Kolch W., Heidecker G., Lloyd P., Rapp U. R. Raf-1 protein kinase is required for growth of induced NIH/3T3 cells. Nature. 1991 Jan 31;349(6308):426–428. doi: 10.1038/349426a0. [DOI] [PubMed] [Google Scholar]
  40. Kuriyama M., Harada N., Kuroda S., Yamamoto T., Nakafuku M., Iwamatsu A., Yamamoto D., Prasad R., Croce C., Canaani E. Identification of AF-6 and canoe as putative targets for Ras. J Biol Chem. 1996 Jan 12;271(2):607–610. doi: 10.1074/jbc.271.2.607. [DOI] [PubMed] [Google Scholar]
  41. Kyriakis J. M., App H., Zhang X. F., Banerjee P., Brautigan D. L., Rapp U. R., Avruch J. Raf-1 activates MAP kinase-kinase. Nature. 1992 Jul 30;358(6385):417–421. doi: 10.1038/358417a0. [DOI] [PubMed] [Google Scholar]
  42. Lange-Carter C. A., Pleiman C. M., Gardner A. M., Blumer K. J., Johnson G. L. A divergence in the MAP kinase regulatory network defined by MEK kinase and Raf. Science. 1993 Apr 16;260(5106):315–319. doi: 10.1126/science.8385802. [DOI] [PubMed] [Google Scholar]
  43. 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. 1994 Jun 2;369(6479):411–414. doi: 10.1038/369411a0. [DOI] [PubMed] [Google Scholar]
  44. Lu X., Melnick M. B., Hsu J. C., Perrimon N. Genetic and molecular analyses of mutations involved in Drosophila raf signal transduction. EMBO J. 1994 Jun 1;13(11):2592–2599. doi: 10.1002/j.1460-2075.1994.tb06549.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Mansour S. J., Matten W. T., Hermann A. S., Candia J. M., Rong S., Fukasawa K., Vande Woude G. F., Ahn N. G. Transformation of mammalian cells by constitutively active MAP kinase kinase. Science. 1994 Aug 12;265(5174):966–970. doi: 10.1126/science.8052857. [DOI] [PubMed] [Google Scholar]
  46. Marais R., Wynne J., Treisman R. The SRF accessory protein Elk-1 contains a growth factor-regulated transcriptional activation domain. Cell. 1993 Apr 23;73(2):381–393. doi: 10.1016/0092-8674(93)90237-k. [DOI] [PubMed] [Google Scholar]
  47. Marshall C. J. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell. 1995 Jan 27;80(2):179–185. doi: 10.1016/0092-8674(95)90401-8. [DOI] [PubMed] [Google Scholar]
  48. Marshall M. S. The effector interactions of p21ras. Trends Biochem Sci. 1993 Jul;18(7):250–254. doi: 10.1016/0968-0004(93)90175-m. [DOI] [PubMed] [Google Scholar]
  49. Minden A., Lin A., Claret F. X., Abo A., Karin M. Selective activation of the JNK signaling cascade and c-Jun transcriptional activity by the small GTPases Rac and Cdc42Hs. Cell. 1995 Jun 30;81(7):1147–1157. doi: 10.1016/s0092-8674(05)80019-4. [DOI] [PubMed] [Google Scholar]
  50. 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. 1993 Jun 11;260(5114):1658–1661. doi: 10.1126/science.8503013. [DOI] [PubMed] [Google Scholar]
  51. Olson M. F., Ashworth A., Hall A. An essential role for Rho, Rac, and Cdc42 GTPases in cell cycle progression through G1. Science. 1995 Sep 1;269(5228):1270–1272. doi: 10.1126/science.7652575. [DOI] [PubMed] [Google Scholar]
  52. Perona R., Esteve P., Jiménez B., Ballestero R. P., Ramón y Cajal S., Lacal J. C. Tumorigenic activity of rho genes from Aplysia californica. Oncogene. 1993 May;8(5):1285–1292. [PubMed] [Google Scholar]
  53. Prasad R., Gu Y., Alder H., Nakamura T., Canaani O., Saito H., Huebner K., Gale R. P., Nowell P. C., Kuriyama K. Cloning of the ALL-1 fusion partner, the AF-6 gene, involved in acute myeloid leukemias with the t(6;11) chromosome translocation. Cancer Res. 1993 Dec 1;53(23):5624–5628. [PubMed] [Google Scholar]
  54. Prendergast G. C., Khosravi-Far R., Solski P. A., Kurzawa H., Lebowitz P. F., Der C. J. Critical role of Rho in cell transformation by oncogenic Ras. Oncogene. 1995 Jun 15;10(12):2289–2296. [PubMed] [Google Scholar]
  55. Qiu R. G., Chen J., Kirn D., McCormick F., Symons M. An essential role for Rac in Ras transformation. Nature. 1995 Mar 30;374(6521):457–459. doi: 10.1038/374457a0. [DOI] [PubMed] [Google Scholar]
  56. Qiu R. G., Chen J., McCormick F., Symons M. A role for Rho in Ras transformation. Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11781–11785. doi: 10.1073/pnas.92.25.11781. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Quilliam L. A., Khosravi-Far R., Huff S. Y., Der C. J. Guanine nucleotide exchange factors: activators of the Ras superfamily of proteins. Bioessays. 1995 May;17(5):395–404. doi: 10.1002/bies.950170507. [DOI] [PubMed] [Google Scholar]
  58. Rao V. N., Reddy E. S. elk-1 proteins interact with MAP kinases. Oncogene. 1994 Jul;9(7):1855–1860. [PubMed] [Google Scholar]
  59. Reuter C. W., Catling A. D., Jelinek T., Weber M. J. Biochemical analysis of MEK activation in NIH3T3 fibroblasts. Identification of B-Raf and other activators. J Biol Chem. 1995 Mar 31;270(13):7644–7655. doi: 10.1074/jbc.270.13.7644. [DOI] [PubMed] [Google Scholar]
  60. Ridley A. J., Hall A. The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell. 1992 Aug 7;70(3):389–399. doi: 10.1016/0092-8674(92)90163-7. [DOI] [PubMed] [Google Scholar]
  61. Ridley A. J., Paterson H. F., Johnston C. L., Diekmann D., Hall A. The small GTP-binding protein rac regulates growth factor-induced membrane ruffling. Cell. 1992 Aug 7;70(3):401–410. doi: 10.1016/0092-8674(92)90164-8. [DOI] [PubMed] [Google Scholar]
  62. Roberts T. M. Cell biology. A signal chain of events. Nature. 1992 Dec 10;360(6404):534–535. doi: 10.1038/360534a0. [DOI] [PubMed] [Google Scholar]
  63. Rodriguez-Viciana P., Warne P. H., Dhand R., Vanhaesebroeck B., Gout I., Fry M. J., Waterfield M. D., Downward J. Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature. 1994 Aug 18;370(6490):527–532. doi: 10.1038/370527a0. [DOI] [PubMed] [Google Scholar]
  64. Russell M., Lange-Carter C. A., Johnson G. L. Direct interaction between Ras and the kinase domain of mitogen-activated protein kinase kinase kinase (MEKK1). J Biol Chem. 1995 May 19;270(20):11757–11760. doi: 10.1074/jbc.270.20.11757. [DOI] [PubMed] [Google Scholar]
  65. Schaap D., van der Wal J., Howe L. R., Marshall C. J., van Blitterswijk W. J. A dominant-negative mutant of raf blocks mitogen-activated protein kinase activation by growth factors and oncogenic p21ras. J Biol Chem. 1993 Sep 25;268(27):20232–20236. [PubMed] [Google Scholar]
  66. Schlessinger J. How receptor tyrosine kinases activate Ras. Trends Biochem Sci. 1993 Aug;18(8):273–275. doi: 10.1016/0968-0004(93)90031-h. [DOI] [PubMed] [Google Scholar]
  67. Self A. J., Paterson H. F., Hall A. Different structural organization of Ras and Rho effector domains. Oncogene. 1993 Mar;8(3):655–661. [PubMed] [Google Scholar]
  68. Shirouzu M., Koide H., Fujita-Yoshigaki J., Oshio H., Toyama Y., Yamasaki K., Fuhrman S. A., Villafranca E., Kaziro Y., Yokoyama S. Mutations that abolish the ability of Ha-Ras to associate with Raf-1. Oncogene. 1994 Aug;9(8):2153–2157. [PubMed] [Google Scholar]
  69. Smith M. R., DeGudicibus S. J., Stacey D. W. Requirement for c-ras proteins during viral oncogene transformation. Nature. 1986 Apr 10;320(6062):540–543. doi: 10.1038/320540a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. 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 U S A. 1994 Dec 20;91(26):12609–12613. doi: 10.1073/pnas.91.26.12609. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Stanton V. P., Jr, Nichols D. W., Laudano A. P., Cooper G. M. Definition of the human raf amino-terminal regulatory region by deletion mutagenesis. Mol Cell Biol. 1989 Feb;9(2):639–647. doi: 10.1128/mcb.9.2.639. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. 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. 1994 Jun 3;264(5164):1463–1467. doi: 10.1126/science.7811320. [DOI] [PubMed] [Google Scholar]
  73. Tsuda L., Inoue Y. H., 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. 1993 Feb 12;72(3):407–414. doi: 10.1016/0092-8674(93)90117-9. [DOI] [PubMed] [Google Scholar]
  74. Van Aelst L., Barr M., Marcus S., Polverino A., Wigler M. Complex formation between RAS and RAF and other protein kinases. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):6213–6217. doi: 10.1073/pnas.90.13.6213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Van Aelst L., White M. A., Wigler M. H. Ras partners. Cold Spring Harb Symp Quant Biol. 1994;59:181–186. doi: 10.1101/sqb.1994.059.01.022. [DOI] [PubMed] [Google Scholar]
  76. Vojtek A. B., Hollenberg S. M., Cooper J. A. Mammalian Ras interacts directly with the serine/threonine kinase Raf. Cell. 1993 Jul 16;74(1):205–214. doi: 10.1016/0092-8674(93)90307-c. [DOI] [PubMed] [Google Scholar]
  77. Warne P. H., Viciana P. R., Downward J. Direct interaction of Ras and the amino-terminal region of Raf-1 in vitro. Nature. 1993 Jul 22;364(6435):352–355. doi: 10.1038/364352a0. [DOI] [PubMed] [Google Scholar]
  78. Wasylyk C., Wasylyk B., Heidecker G., Huleihel M., Rapp U. R. Expression of raf oncogenes activates the PEA1 transcription factor motif. Mol Cell Biol. 1989 May;9(5):2247–2250. doi: 10.1128/mcb.9.5.2247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  79. Westwick J. K., Cox A. D., Der C. J., Cobb M. H., Hibi M., Karin M., Brenner D. A. Oncogenic Ras activates c-Jun via a separate pathway from the activation of extracellular signal-regulated kinases. Proc Natl Acad Sci U S A. 1994 Jun 21;91(13):6030–6034. doi: 10.1073/pnas.91.13.6030. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. Westwick J. K., Weitzel C., Minden A., Karin M., Brenner D. A. Tumor necrosis factor alpha stimulates AP-1 activity through prolonged activation of the c-Jun kinase. J Biol Chem. 1994 Oct 21;269(42):26396–26401. [PubMed] [Google Scholar]
  81. White M. A., Nicolette C., Minden A., Polverino A., Van Aelst L., Karin M., Wigler M. H. Multiple Ras functions can contribute to mammalian cell transformation. Cell. 1995 Feb 24;80(4):533–541. doi: 10.1016/0092-8674(95)90507-3. [DOI] [PubMed] [Google Scholar]
  82. Wigler M., Field J., Powers S., Broek D., Toda T., Cameron S., Nikawa J., Michaeli T., Colicelli J., Ferguson K. Studies of RAS function in the yeast Saccharomyces cerevisiae. Cold Spring Harb Symp Quant Biol. 1988;53(Pt 2):649–655. doi: 10.1101/sqb.1988.053.01.074. [DOI] [PubMed] [Google Scholar]
  83. Wigler M., Pellicer A., Silverstein S., Axel R., Urlaub G., Chasin L. DNA-mediated transfer of the adenine phosphoribosyltransferase locus into mammalian cells. Proc Natl Acad Sci U S A. 1979 Mar;76(3):1373–1376. doi: 10.1073/pnas.76.3.1373. [DOI] [PMC free article] [PubMed] [Google Scholar]
  84. Williams L. T. Missing links between receptors and Ras. Curr Biol. 1992 Nov;2(11):601–603. doi: 10.1016/0960-9822(92)90169-b. [DOI] [PubMed] [Google Scholar]
  85. Zhang X. F., Settleman J., Kyriakis J. M., Takeuchi-Suzuki E., Elledge S. J., Marshall M. S., Bruder J. T., Rapp U. R., Avruch J. Normal and oncogenic p21ras proteins bind to the amino-terminal regulatory domain of c-Raf-1. Nature. 1993 Jul 22;364(6435):308–313. doi: 10.1038/364308a0. [DOI] [PubMed] [Google Scholar]
  86. Zheng C. F., Guan K. L. Activation of MEK family kinases requires phosphorylation of two conserved Ser/Thr residues. EMBO J. 1994 Mar 1;13(5):1123–1131. doi: 10.1002/j.1460-2075.1994.tb06361.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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