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Abstract
Rap1, a small GTPase regulating proliferation, differentiation, and adhesion, is activated by cAMP‑responsive guanine nucleotide exchange factors (GEFs) Epac1 and Epac2. This work tests the hypothesis that Rap1 signaling is spatially regulated through compartment‑specific targeting of these GEFs. Epac2 interacts with Ras‑GTP, which recruits it to the plasma membrane and enables efficient Rap1 activation when combined with cAMP signaling. In PC12 cells, this coordination enhances ERK activation and neurite outgrowth. Proteomic analysis revealed that Epac1 associates with nuclear pore complex components, including Ran, through a unique RA domain, enabling Rap1 activation at the nuclear envelope. Together, these findings show that Epac1 and Epac2 localize to distinct subcellular compartments via Ran and Ras interactions, allowing cAMP to activate discrete Rap1 pools and diversify downstream signaling.