title: The cAMP sensors, EPAC1 and EPAC2, display distinct subcellular distributions despite sharing a common nuclear pore localisation signal.
abstract: We have identified a conserved nuclear pore localisation signal (NPLS; amino acids 764-838 of EPAC1) in the catalytic domains of the cAMP-sensors, EPAC1 and EPAC2A. Consequently, EPAC1 is mainly localised to the nuclear pore complex in HEK293T cells where it becomes activated following stimulation with cAMP. In contrast, structural models indicate that the cAMP-binding domain of EPAC2A (CNBD1) blocks access to the conserved NPLS in EPAC2A, reducing its ability to interact with nuclear binding sites. Consequently, a naturally occurring EPAC2 isoform, EPAC2B, which lacks CNBD1 is enriched in nuclear fractions, similar to EPAC1. Structural differences in EPAC isoforms may therefore determine their intracellular location and their response to elevations in intracellular cAMP.
authors: Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, G12 8QQ, UK.
authors: Euan
authors: E
authors: Parnell
authors: Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, G12 8QQ, UK.
authors: Brian O
authors: BO
authors: Smith
authors: Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, G12 8QQ, UK. Electronic address: stephen.yarwood@glasgow.ac.uk.
authors: Stephen J
authors: SJ
authors: Yarwood
mesh_terms: D020134:Catalytic Domain; D000242:Cyclic AMP / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000032:analysis / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008958:Models, Molecular; D019913:Nuclear Localization Signals; D022022:Nuclear Pore / Q000378:metabolism*
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D019913:Nuclear Localization Signals; C116122:RAPGEF3 protein, human; C442864:RAPGEF4 protein, human; D000242:Cyclic AMP
keywords: EPAC; Nucleus; Targeting; cAMP