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Mol. Cell. Biol. 29 (10): 2521-2531

Copyright © 2009 by the American Society for Microbiology. All rights reserved.

Direct Spatial Control of Epac1 by Cyclic AMP{triangledown} ,{dagger}

Bas Ponsioen,1,2,{ddagger} Martijn Gloerich,3,{ddagger} Laila Ritsma,1,3 Holger Rehmann,3 Johannes L. Bos,3*, and Kees Jalink1*

Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands,1 Division of Cellular Biochemistry and Centre of Biomedical Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands,2 Department of Physiological Chemistry, Centre of Biomedical Genetics and Cancer Genomics Centre, University Medical Center Utrecht, Utrecht, The Netherlands3

Received for publication 20 October 2008. Revision received 1 December 2008. Accepted for publication 27 February 2009.

Abstract: Epac1 is a guanine nucleotide exchange factor (GEF) for the small G protein Rap and is directly activated by cyclic AMP (cAMP). Upon cAMP binding, Epac1 undergoes a conformational change that allows the interaction of its GEF domain with Rap, resulting in Rap activation and subsequent downstream effects, including integrin-mediated cell adhesion and cell-cell junction formation. Here, we report that cAMP also induces the translocation of Epac1 toward the plasma membrane. Combining high-resolution confocal fluorescence microscopy with total internal reflection fluorescence and fluorescent resonance energy transfer assays, we observed that Epac1 translocation is a rapid and reversible process. This dynamic redistribution of Epac1 requires both the cAMP-induced conformational change as well as the DEP domain. In line with its translocation, Epac1 activation induces Rap activation predominantly at the plasma membrane. We further show that the translocation of Epac1 enhances its ability to induce Rap-mediated cell adhesion. Thus, the regulation of Epac1-Rap signaling by cAMP includes both the release of Epac1 from autoinhibition and its recruitment to the plasma membrane.

* Corresponding author. Mailing address for Kees Jalink: Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands. Phone: 31 20 512 1933. Fax: 31 20 512 1944. E-mail: K.Jalink{at}nki.nl. Mailing address for Johannes L. Bos: Department of Physiological Chemistry, Centre of Biomedical Genetics and Cancer Genomics Centre, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands. Phone: 31 88 756 8989. Fax: 31 88 756 8101. E-mail: J.L.Bos{at}umcutrecht.nl

{triangledown} Published ahead of print on 9 March 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} These authors contributed equally.

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