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J. Biol. Chem., Vol. 279, Issue 36, 37398-37406, September 3, 2004

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Transformation Potential of Ras Isoforms Correlates with Activation of Phosphatidylinositol 3-Kinase but Not ERK^*

Weiquan Li, Tianqing Zhu, and Kun-Liang Guan¶||

From the Life Sciences Institute, the Department of Biological Chemistry and the ^¶Institute of Gerontology, University of Michigan, Ann Arbor, Michigan 48109

The Ras oncoproteins activate the Raf-MEK-ERK kinase pathway, which plays an important role in cellular transformation. We observed that H-RasV12 exhibited a higher transforming potential than either K-RasV12 or N-RasV12 in both NIH3T3 fibroblasts and RIE-1 rat epithelial cell cultures. Surprisingly N-Ras and K-Ras were more potent than H-Ras in activation of mitogen-activated protein (MAP) kinase activity and ternary complex factor-dependent transcription. In contrast, H-Ras was more effective in activation of phosphatidylinositol 3-kinase (PI3K) and AKT. Co-expression of constitutively active AKT, a downstream target of PI3K, cooperated with H-RasV12, K-RasV12, or N-RasV12 in transformation. Furthermore co-expression of the constitutively active MEK and AKT resulted in focus formation, while neither active MEK1 nor active AKT alone transformed NIH3T3 cells. Our data demonstrated that the transforming potential of Ras was not directly correlated with the ability of Ras to activate the MAP kinase cascade. In contrast, the ability to activate PI3K and AKT correlated with the ability of Ras to induce cellular transformation, suggesting an important role of PI3K-AKT in cellular transformation. Our data also demonstrated that, under these assay conditions, activation of the MAP kinase cascade was not sufficient to induce NIH3T3 cell transformation.

Received for publication, May 24, 2004

^* This work was supported by grants from the National Institutes of Health (to K.-L. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed. E-mail: kunliang{at}umich.edu.

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