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J. Biol. Chem., Vol. 283, Issue 52, 36425-36434, December 26, 2008

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ADP-ribosylation Factor 1 Controls the Activation of the Phosphatidylinositol 3-Kinase Pathway to Regulate Epidermal Growth Factor-dependent Growth and Migration of Breast Cancer Cells^*

Pierre-Luc Boulay, Mathieu Cotton, Paul Melançon, and Audrey Claing, Recipient of a New Investigator Award from the CIHR¹

From the Department of Pharmacology, Faculty of Medicine, University of Montréal, Montréal, Quebec H3C 3J7 and the Department of Cell Biology, University of Alberta, Alberta, Edmonton T6G 2H7, Canada

Activation of intracellular signaling pathways by growth factors is one of the major causes of cancer development and progression. Recent studies have demonstrated that monomeric G proteins of the Ras family are key regulators of cell proliferation, migration, and invasion. Using an invasive breast cancer cell lines, we demonstrate that the ADP-ribosylation factor 1 (ARF1), a small GTPase classically associated with the Golgi, is an important regulator of the biological effects induced by epidermal growth factor. Here, we show that this ARF isoform is activated following epidermal growth factor stimulation and that, in MDA-MB-231 cells, ARF1 is found in dynamic plasma membrane ruffles. Inhibition of endogenous ARF1 expression results in the inhibition of breast cancer cell migration and proliferation. The underlying mechanism involves the activation of the phosphatidylinositol 3-kinase pathway. Our data demonstrate that depletion of ARF1 markedly impairs the recruitment of the phosphatidylinositol 3-kinase catalytic subunit (p110) to the plasma membrane, and the association of the regulatory subunit (p85) to the activated receptor. These results uncover a novel molecular mechanism by which ARF1 regulates breast cancer cell growth and invasion during cancer progression.

Received for publication, May 12, 2008 , and in revised form, November 5, 2008.

^* This work was supported in part by the Canadian Institutes of Health Research (CIHR, Grant MOP-79470 to A. C.). 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 http://www.jbc.org) contains supplemental Figs. S1–S4.

¹ To whom correspondence should be addressed: P. O. Box 6128, Downtown Station, Montreal, Quebec H3C 3J7, Canada. Tel.: 514-343-6352; Fax: 514-343-2291; E-mail: audrey.claing{at}umontreal.ca.

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