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

Khosravi-Far, R., White, M. A., Westwick, J. K., Solski, P. A., Chrzanowska-Wodnicka, M., Van Aelst, L., Wigler, M. H., Der, C. J. (July 1996) Oncogenic Ras activation of Raf/mitogen-activated protein kinase-independent pathways is sufficient to cause tumorigenic transformation. Mol Cell Biol, 16 (7). pp. 3923-33. ISSN 0270-7306 (Print)

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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 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.

Item Type:	Paper
Uncontrolled Keywords:	3T3 Cells Animals Ca(2+)-Calmodulin Dependent Protein Kinase metabolism Cell Transformation Neoplastic GTP-Binding Proteins metabolism Genes ras Humans JNK Mitogen- Activated Protein Kinases Kinetics Luciferases metabolism MAP Kinase Kinase 4 MAP Kinase Kinase Kinase 1 Mice Mitogen Activated Protein Kinase Kinases Protein Kinases metabolism Protein Serine Threonine Kinases metabolism Proto-Oncogene Proteins metabolism Proto Oncogene Proteins c-raf Recombinant Proteins metabolism Transfection
Subjects:	bioinformatics > genomics and proteomics > annotation > gene expression profiling annotation bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > RAS bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene expression bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > oncogene
CSHL Authors:	Van Aelst, Linda Wigler, Michael H.
Communities:	CSHL labs > Van Aelst lab CSHL labs > Wigler lab
Depositing User:	CSHL Librarian
Date:	July 1996
Date Deposited:	12 Apr 2012 15:17
Last Modified:	04 Nov 2016 20:42
PMCID:	PMC231389
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/26210

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