The Interaction of Epac1 and Ran Promotes Rap1 Activation at the Nuclear Envelope

Abstract

Epac1 (exchange protein directly activated by cyclic AMP [cAMP]) couples intracellular cAMP to the activation of Rap1, a Ras family GTPase that regulates cell adhesion, proliferation, and differentiation. Using mass spectrometry, we identified the small G protein Ran and Ran binding protein 2 (RanBP2) as potential binding partners of Epac1. Ran is a small G protein best known for its role in nuclear transport and can be found at the nuclear pore through its interaction with RanBP2. Here we demonstrate that Ran-GTP and Epac1 interact with each other in vivo and in vitro. This binding requires a previously uncharacterized Ras association (RA) domain in Epac1. Surprisingly, the interaction of Epac1 with Ran is necessary for the efficient activation of Rap1 by Epac1. We propose that Ran and RanBP2 anchor Epac1 to the nuclear pore, permitting cAMP signals to activate Rap1 at the nuclear envelope.

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Articles of Significant Interest Selected from This Issue by the Editors

We thank Zhiping Wang, Mike Forte, Mihail Iordanov, and Larry David for discussions; John Klimek, Debra McMillen, and Srilatha Tavisala for technical assistance; and Ian Macara and Johannes Bos for sharing of reagents.

This work was funded by NIH NCI grant CA72971 to P.J.S.S., a Vertex Scholarship to C.L., and training grant NIH-5-T32-CA106195-06A1 to Y.L.