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J. Biol. Chem., Vol. 281, Issue 5, 2506-2514, February 3, 2006

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The RAP1 Guanine Nucleotide Exchange Factor Epac2 Couples Cyclic AMP and Ras Signals at the Plasma Membrane^*

From the Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, and Walther Cancer Institute, Indianapolis, Indiana 46202

Epac-1 and -2 (exchange proteins directly activated by cyclic AMP) are guanine-nucleotide exchange factors for the GTPases Rap1 and -2. Epac2 but not Epac1 was found to possess a RA (Ras association) domain similar to that found in the Ras effector Ral-GDS. This domain specifically bound Ras-GTP, enabling oncogenic Ras to translocate Epac2 from the cytosol to the plasma membrane. Consequently, a small pool of plasma membrane-bound Rap1 was activated at the expense of bulk Rap1 located on intracellular organelles. Whereas translocation of Epac2 was not mimicked by challenge with epidermal growth factor alone, costimulation with forskolin, prostaglandin E₂, or an Epac-selective cyclic AMP analog-induced rapid relocation of GFP-Epac2 but not -Epac1 to the plasma membrane in a Ras-dependent manner. Deletion of the cyclic AMP-binding domain overcame the need for nucleotide, suggesting that this domain normally masked the RA domain in the resting GEF. Thus, Epac2 can respond to costimulation by agonists that jointly elevate Ras-GTP and cyclic AMP levels, activating a specific pool of Rap1 at the plasma membrane. Therefore, despite its previous description as a Ras antagonist or independently functioning GTPase, Rap1/Krev-1 may additionally act downstream of Ras in cells that express the cyclic AMP-regulated GEF, Epac2.

Received for publication, July 26, 2005 , and in revised form, November 18, 2005.

^* This work was supported by American Cancer Society Grant RPG-00-125-01TBE, National Institutes of Health Grant CA108647 and a Biomedical Research Grant from Indiana University School of Medicine (to L. A. Q.), American Heart Association Predoctoral Fellowship 0110245Z (to Y. L.), and National Institutes of Health Training Grant T32-H07774 (to J. F. R.). 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.

¹ Current address: Access Business Group, Ada, MI.

² Current address: Dept. of Surgery, University of California, San Francisco, CA.

³ Current address: Methodist Research Institute, Indianapolis, IN.

⁴ To whom correspondence should be addressed: 635 Barnhill Drive, MS-4053, Indianapolis, IN 46202-5122. Tel.: 317-274-8550; Fax: 317-274-4686; E-mail: lquillia{at}iupui.edu.

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