title: The nucleoporin RanBP2 tethers the cAMP effector Epac1 and inhibits its catalytic activity.
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.
authors.affiliation: Molecular Cancer Research, Centre for Biomedical Genetics and Cancer Genomics Centre, University Medical Center Utrecht, 3584 CG Utrecht, Netherlands.
authors.forename: Martijn
authors.initials: M
authors.lastname: Gloerich
authors.forename: Marjolein J
authors.initials: MJ
authors.lastname: Vliem
authors.forename: Esther
authors.initials: E
authors.lastname: Prummel
authors.forename: Lars A T
authors.initials: LA
authors.lastname: Meijer
authors.forename: Marije G A
authors.initials: MG
authors.lastname: Rensen
authors.forename: Holger
authors.initials: H
authors.lastname: Rehmann
authors.forename: Johannes L
authors.initials: JL
authors.lastname: Bos
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D022022:Nuclear Pore / Q000378:metabolism; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D020798:Two-Hybrid System Techniques; D016335:Zinc Fingers; D020666:ras-GRF1 / Q000235:genetics / Q000378:metabolism
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D018832:Molecular Chaperones; D028861:Nuclear Pore Complex Proteins; C116122:RAPGEF3 protein, human; D011993:Recombinant Fusion Proteins; C094493:ran-binding protein 2; D020666:ras-GRF1; D000242:Cyclic AMP