Wild-Type NRas and KRas Perform Distinct Functions during Transformation

Abstract

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.

We thank J. Boehm, J. DeCaprio, W. Hahn, L. Garraway, W. Sellers, and M. Brown for providing reagents, T. Jacks and R. Kucherlapati for providing mice, and A. Toker, J. S. Brugge, D. Pellman, H. Shih, and C. Das for critically reading the manuscript.

This work was supported by funding from the National Cancer Institute (M.E.E.).