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J. Biol. Chem. 278 (35): 33465-33473

© 2003 by The American Society for Biochemistry and Molecular Biology, Inc.

Exchange Factors of the RasGRP Family Mediate Ras Activation in the Golgi*,

María J. Caloca {ddagger}, José L. Zugaza {ddagger}, and Xosé R. Bustelo §

Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, University of Salamanca, Consejo Superior de Investigaciones Científicas, Campus Unamuno, E-37007 Salamanca, Spain

Abstract: H-Ras and N-Ras become activated both at the plasma membrane and in endomembrane structures such as the Golgi apparatus. This compartmentalized activation is relevant from a signaling standpoint, because effector molecules can become activated differently depending on the region of the cell where Ras proteins are activated. An unsolved question in this new regulatory mechanism is the understanding of how Ras proteins become activated in endomembranes. To approach this problem, we have studied the subcellular distribution and activities of a number of Ras guanosine nucleotide exchange factors. Our results indicate that Ras activation at the plasma membrane and endoplasmic reticulum is an unspecific process that can be achieved by most Ras activators. In contrast, GTP loading of Ras at the Golgi is only induced by members of the Ras guanosine nucleotide releasing protein family. In agreement with these observations, Ras guanosine nucleotide releasing proteins are the only Ras activators showing localization in the Golgi. These results indicate that the compartmentalized activation of effector pathways by Ras proteins depends not only on the specific localization of the GTPases but also in the availability of GDP/GTP exchange factors capable of activating Ras proteins in specific subcellular compartments.

Received for publication March 19, 2003. Revision received May 6, 2003.

* This work was supported by the United States National Cancer Institute, National Institutes of Health Grant CA7373501, British Association for International Cancer Research Grant 00-061, and Programa General del Conocimiento PM99–0093 (Spanish Ministry of Science and Technology). The Centro de Investigación del Cáncer was supported by endowments from the Consejo Superior de Investigaciones Científicas, University of Salamanca, Castilla-León Autonomous Government, the National Cancer Network of the Spanish Fondo de Investigaciones Sanitarias (Spanish Ministry of Health), the Foundation for Cancer Research of Salamanca, and the Solórzano and Moraza Foundations. 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.

The on-line version of this article (available at contains Figs. S1 and S2.

{ddagger} Investigators from the Ramón y Cajal Program (Spanish Ministry of Science and Technology) associated with the University of Salamanca.

§ To whom correspondence should be addressed. Tel.: 34-923-294802; Fax: 34-923-294743; E-mail: xbustelo{at}

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