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J. Biol. Chem. 276 (19): 15609-15615

© 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

Differential Activation of the Rac Pathway by Ha-Ras and K-Ras*

Amy B. WalshDagger § and Dafna Bar-SagiDagger

From the Dagger  Department of Molecular Genetics and Microbiology and the § Graduate Program in Physiology and Biophysics, State University of New York, Stony Brook, New York 11794

Ras proteins are key regulators of cell growth and differentiation. Mammalian cells express three closely related Ras proteins: Ha-Ras, K-Ras, and N-Ras. We have compared the abilities of the Ha-Ras and K-Ras isoforms to activate the Rac effector pathway, using three Rac-dependent readouts: induction of membrane ruffling and pinocytosis, stimulation of cell motility, and Pak binding. The total surface area of membrane ruffles induced by K-RasV12 was 2-fold greater than that induced by Ha-RasV12. Likewise, the number of K-RasV12-induced pinocytic vesicles per cell was ~2-fold greater than that induced by Ha-RasV12. In a wound healing assay, K-RasV12-injected cells migrated twice as fast as Ha-RasV12-injected cells. Moreover, the Pak binding activity of Rac, which is indicative of the amount of GTP-bound Rac, was higher in K-RasV12-expressing cells than Ha-RasV12-expressing cells. These results suggest that K-Ras activates Rac more efficiently than Ha-Ras. The preferential activation of Rac by K-Ras is dependent on the mode of membrane anchoring and impacts on the ability of K-Ras to regulate cell survival.

* This work was supported by National Institutes of Health Grant CA55360.The costs of publication of this article were defrayed in part by the payment of page charges. The 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: Dept. of Molecular Genetics and Microbiology, State University of New York at Stony Brook, Stony Brook, NY 11794-5222. Tel.: 631-632-9737; Fax: 631-632-8891; E-mail:

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

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