Faculty Collaboration Database

Oncogenic Ras activation of Raf/mitogen-activated protein kinase-independent pathways is sufficient to cause tumorigenic transformation. Mol Cell Biol 1996 Jul;16(7):3923-33

Date

07/01/1996

Pubmed ID

8668210

Pubmed Central ID

PMC231389

DOI

10.1128/MCB.16.7.3923

Scopus ID

2-s2.0-0029890896 (requires institutional sign-in at Scopus site)   335 Citations

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.

Author List

Khosravi-Far R, White MA, Westwick JK, Solski PA, Chrzanowska-Wodnicka M, Van Aelst L, Wigler MH, Der CJ

Author

Magdalena Chrzanowska PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

3T3 Cells
Animals
Calcium-Calmodulin-Dependent Protein Kinases
Cell Transformation, Neoplastic
GTP-Binding Proteins
Genes, ras
Humans
JNK Mitogen-Activated Protein Kinases
Kinetics
Luciferases
MAP Kinase Kinase 4
MAP Kinase Kinase Kinase 1
Mice
Mitogen-Activated Protein Kinase Kinases
Protein Kinases
Proto-Oncogene Proteins
Proto-Oncogene Proteins c-raf
Recombinant Proteins
Transfection