The interaction of Epac1 and Ran promotes Rap1 activation at the nuclear envelope.
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.
Liu
Chang
C
Vollum Institute, Department of Cell and Developmental Biology, Oregon Health & Science University, Portland, OR 97239, USA.
Takahashi
Maho
M
Li
Yanping
Y
Dillon
Tara J
TJ
Kaech
Stefanie
S
Stork
Philip J S
PJ
D001483:Base Sequence; D000242:Cyclic AMP / Q000378:metabolism; D004789:Enzyme Activation; D049452:Green Fluorescent Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008954:Models, Biological; D009685:Nuclear Envelope / Q000378:metabolism*; D022022:Nuclear Pore / Q000378:metabolism; D054730:Protein Interaction Domains and Motifs; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D020931:ran GTP-Binding Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020827:rap1 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
D020662:Guanine Nucleotide Exchange Factors; C120587:RAN protein, human; C116122:RAPGEF3 protein, human; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D000242:Cyclic AMP; D020931:ran GTP-Binding Protein; D020827:rap1 GTP-Binding Proteins