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Molecular and Cellular Biology, October 2007, p. 6742-6755, Vol. 27, No. 19
0270-7306/07/$08.00+0     doi:10.1128/MCB.00234-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Wild-Type NRas and KRas Perform Distinct Functions during Transformation{triangledown}

Poppy P. Fotiadou, Chiaki Takahashi,{dagger} Hasan N. Rajabi, and Mark E. Ewen*

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115

Received 8 February 2007/ Returned for modification 16 March 2007/ Accepted 9 July 2007

The ras proto-oncogenes, of which there are four isoforms, are molecular switches that function in signal transduction pathways to control cell differentiation, proliferation, and survival. How the Ras isoforms orchestrate cellular processes that affect behavior is poorly understood. Further, why cells express two or more Ras isoforms is unknown. Here, using a genetically defined system, we show that the presence of both wild-type KRas and NRas isoforms is required for transformation because they perform distinct nonoverlapping functions: wild-type NRas regulates adhesion, and KRas coordinates motility. Remarkably, we find that Ras isoforms achieve functional specificity by engaging different signaling pathways to affect the same cellular processes, thereby coordinating cellular outcome. Although we find that signaling from both isoforms intersects in actin and microtubule cytoskeletons, our results suggest that KRas signals through Akt and Cdc42 while NRas signals through Raf and RhoA. Our analyses suggest a previously unappreciated convergence of different Ras isoforms on the dynamics of the processes involved in transformation.

* Corresponding author. Mailing address: Dana-Farber Cancer Institute and Harvard Medical School, 44 Binney Street, Boston, MA 02115. Phone: (617) 632-2206. Fax: (617) 632-5417. E-mail: mark_ewen{at}dfci.harvard.edu

{triangledown} Published ahead of print on 16 July 2007.

{dagger} Present address: The 21st Century Center of Excellence Program, Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.

Molecular and Cellular Biology, October 2007, p. 6742-6755, Vol. 27, No. 19
0270-7306/07/$08.00+0     doi:10.1128/MCB.00234-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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