Yang, W.; Mei, F.; Lin, W.; Lee, J. E.; Nie, S.; Bley, C. J.; Hoelz, A. J.; Cheng, X.

Exchange protein directly activated by cAMP (EPAC1), a multifunctional intracellular cAMP receptor, dynamically localizes to various cellular loci, engaging with diverse molecular partners to maintain cellular homeostasis. The study investigates the role of the SUMO interacting motif (SIM) in the subcellular targeting and cellular functions of EPAC1. It reveals that the SIM is a critical structural element for EPAC1\'s association with RanBP2/Nup358, a nucleoporin of the cytoplasmic filament component of the nuclear pore complex (NPC). Mutational disruption of EPAC1 SIM interferes with EPAC1\'s ability to activate its canonical effectors, small GTPases, Rap1 and Rap2, and non-canonical functions, such as the formation of nuclear condensates and cellular SUMOylation. Because SIM is also directly involved in cAMP binding, RanBP2\'s association with EPAC1 with the SIM attenuates EPAC1\'s cAMP binding affinity to generate an EPAC1 signaling microdomain with reduced cAMP sensitivity around the NPC. The coupling between EPAC1\'s scaffold association and cAMP binding enables EPAC1 to tune its sensitivity to stress stimuli spatially depending on the cellular locations. These findings provide novel structural insights into EPAC1 signaling, highlighting the importance of SIM in EPAC1\'s cellular functions and potential novel strategies for therapeutically targeting EPAC1.