title: Oncogenic Ras activation of Raf/mitogen-activated protein kinase-independent pathways is sufficient to cause tumorigenic transformation.
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.
authors.affiliation: Department of Pharmacology, University of North Carolina at Chapel Hill, 27599-7365,USA.
authors.forename: R
authors.initials: R
authors.lastname: Khosravi-Far
authors.forename: M A
authors.initials: MA
authors.lastname: White
authors.forename: J K
authors.initials: JK
authors.lastname: Westwick
authors.forename: P A
authors.initials: PA
authors.lastname: Solski
authors.forename: M
authors.initials: M
authors.lastname: Chrzanowska-Wodnicka
authors.forename: L
authors.initials: L
authors.lastname: Van Aelst
authors.forename: M H
authors.initials: MH
authors.lastname: Wigler
authors.forename: C J
authors.initials: CJ
authors.lastname: Der
mesh_terms: D016475:3T3 Cells; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic; D019204:GTP-Binding Proteins / Q000378:metabolism; D011905:Genes, ras; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D007700:Kinetics; D008156:Luciferases / Q000378:metabolism; D048670:MAP Kinase Kinase 4; D048728:MAP Kinase Kinase Kinase 1; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection
chemical_list: D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D008156:Luciferases; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human; C482578:Map3k1 protein, mouse; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D019204:GTP-Binding Proteins