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

Roya Khosravi-Far, Michael A. White, John K. Westwick, Patricia A. Solski, Magdalena Chrzanowska-Wodnicka, Linda Van Aelst, Michael H. Wigler, Channing J. Der

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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 flbroblasts. 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.

Original languageEnglish (US)
Pages (from-to)3923-3933
Number of pages11
JournalMolecular and Cellular Biology
Volume16
Issue number7
StatePublished - 1996

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Neoplastic Cell Transformation
Mitogen-Activated Protein Kinase Kinases
Mitogen-Activated Protein Kinases
Phosphatidylinositol 3-Kinase
Proteins
Cell Membrane

ASJC Scopus subject areas

  • Cell Biology
  • Genetics
  • Molecular Biology

Cite this

Khosravi-Far, R., White, M. A., Westwick, J. K., Solski, P. A., Chrzanowska-Wodnicka, M., Van Aelst, L., ... Der, C. J. (1996). Oncogenic ras activation of Raf/mitogen-activated protein kinase-independent pathways is sufficient to cause tumorigenic transformation. Molecular and Cellular Biology, 16(7), 3923-3933.

Oncogenic ras activation of Raf/mitogen-activated protein kinase-independent pathways is sufficient to cause tumorigenic transformation. / Khosravi-Far, Roya; White, Michael A.; Westwick, John K.; Solski, Patricia A.; Chrzanowska-Wodnicka, Magdalena; Van Aelst, Linda; Wigler, Michael H.; Der, Channing J.

In: Molecular and Cellular Biology, Vol. 16, No. 7, 1996, p. 3923-3933.

Research output: Contribution to journalArticle

Khosravi-Far, R, White, MA, Westwick, JK, Solski, PA, Chrzanowska-Wodnicka, M, Van Aelst, L, Wigler, MH & Der, CJ 1996, 'Oncogenic ras activation of Raf/mitogen-activated protein kinase-independent pathways is sufficient to cause tumorigenic transformation', Molecular and Cellular Biology, vol. 16, no. 7, pp. 3923-3933.
Khosravi-Far, Roya ; White, Michael A. ; Westwick, John K. ; Solski, Patricia A. ; Chrzanowska-Wodnicka, Magdalena ; Van Aelst, Linda ; Wigler, Michael H. ; Der, Channing J. / Oncogenic ras activation of Raf/mitogen-activated protein kinase-independent pathways is sufficient to cause tumorigenic transformation. In: Molecular and Cellular Biology. 1996 ; Vol. 16, No. 7. pp. 3923-3933.
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