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J. Cell Biol. 193 (6): 1009-1020

Copyright © 2011 by the Rockefeller University Press.


The nucleoporin RanBP2 tethers the cAMP effector Epac1 and inhibits its catalytic activity

Martijn Gloerich, Marjolein J. Vliem, Esther Prummel, Lars A.T. Meijer, Marije G.A. Rensen, Holger Rehmann, , and Johannes L. Bos

Molecular Cancer Research, Centre for Biomedical Genetics and Cancer Genomics Centre, University Medical Center Utrecht, 3584 CG Utrecht, Netherlands

Correspondence to J.L. Bos J.L.Bos{at}

Abstract: Cyclic adenosine monophosphate (cAMP) is a second messenger that relays a wide range of hormone responses. In this paper, we demonstrate that the nuclear pore component RanBP2 acts as a negative regulator of cAMP signaling through Epac1, a cAMP-regulated guanine nucleotide exchange factor for Rap. We show that Epac1 directly interacts with the zinc fingers (ZNFs) of RanBP2, tethering Epac1 to the nuclear pore complex (NPC). RanBP2 inhibits the catalytic activity of Epac1 in vitro by binding to its catalytic CDC25 homology domain. Accordingly, cellular depletion of RanBP2 releases Epac1 from the NPC and enhances cAMP-induced Rap activation and cell adhesion. Epac1 also is released upon phosphorylation of the ZNFs of RanBP2, demonstrating that the interaction can be regulated by posttranslational modification. These results reveal a novel mechanism of Epac1 regulation and elucidate an unexpected link between the NPC and cAMP signaling.

Abbreviations: Epac, exchange protein directly activated by cAMP • GAP, GTPase-activating protein • GEF, guanine nucleotide exchange factor • NPC, nuclear pore complex • OA, okadaic acid • RA, Ras association • REM, Ras exchange motif • ZNF, zinc finger

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