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J. Biol. Chem., Vol. 278, Issue 7, 4572-4581, February 14, 2003

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Differences on the Inhibitory Specificities of H-Ras, K-Ras, and N-Ras (N17) Dominant Negative Mutants Are Related to Their Membrane Microlocalization^*

David Matallanas, Imanol Arozarena^§¶, María T. Berciano, David S. Aaronson^§**, Angel Pellicer^§§, Miguel Lafarga, and Piero Crespo^§¶¶

From the ^§ Departamentos de Biología Molecular and  Anatomía y Biología Celular, Universidad de Cantabria, Santander 39011, Spain, the  Department of Pathology and Kaplan Comprehensive Cancer Center, New York University School of Medicine, New York, New York 10016, and the  Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Centíficas, Arturo Duperier 4, Madrid 28029, Spain

Ras GTPases include the isoforms H-Ras, K-Ras, and N-Ras. Despite their great biochemical and biological similarities, evidence is mounting suggesting that Ras proteins may not be functionally redundant. A widespread strategy for studying small GTPases is the utilization of dominant inhibitory mutants that specifically block the activation of their respective wild-type proteins. As such, H-Ras N17 has proved to be extremely valuable as a tool to probe Ras functions. However, a comparative study on the inhibitory specificities of H-, K-, and N-Ras N17 mutants has not been approached thus far. Herein, we demonstrate that H-, K-, and N-Ras N17 mutants exhibit markedly distinct inhibitory effects toward H-, K-, and N-Ras. H-Ras N17 can effectively inhibit the activation of all three isoforms. K-Ras N17 completely blocks the activation of K-Ras and is only slightly inhibitory on H-Ras. N-Ras N17 can mainly inhibit N-Ras activation. In light of the recent data on the compartmentalization of H-Ras and K-Ras in the plasma membrane, here we present for the first time a description of N-Ras cellular microlocalization. Overall, our results on Ras N17 mutants specificities exhibit a marked correlation with the localization of the Ras isoforms to distinct membrane microdomains.

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