{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRAPGEF4, which encodes the cAMP‐responsive signaling protein Epac2, plays a pivotal role as a direct sensor of intracellular cyclic AMP. Structural studies have revealed that Epac2 contains dual cyclic nucleotide‐binding domains and a DEP module that, together with a critical “hinge” region, undergo conformational rearrangements upon cAMP binding. This allosteric switch relieves autoinhibition of the catalytic guanine nucleotide exchange factor domain so that Rap1 can be activated, thereby initiating a cascade of downstream signals essential for diverse cellular processes. These mechanistic and structural insights are supported by crystallographic and biophysical analyses that delineate how cAMP engagement regulates Epac2’s activity and its interaction with Rap1."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its structural activation, Epac2 serves as a versatile regulator of cellular signaling in many tissues. In neurons, Epac2 modulates ion channel activity and enhances memory retrieval, thereby influencing neuronal excitability and cognitive function. In endocrine cells—such as pancreatic β‑cells, adrenal cortical cells, and glucagon‐secreting α‑cells—Epac2 regulates hormone production and secretion through modulation of fusion pore dynamics and gene expression. Epac2 also contributes to the fine tuning of inflammatory responses in airway smooth muscle, participates in osteoclast differentiation critical for bone remodeling, and orchestrates cytoskeletal reorganization in kidney tubular and trophoblastic cells, as well as in endometrial decidualization. Collectively, these studies highlight Epac2’s central role in coordinating diverse physiological responses including cardiac contractility and cell migration."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "18"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nClinically, genetic and functional studies have implicated RAPGEF4 in the pathogenesis of several disorders. Rare nonsynonymous variants in RAPGEF4 have been linked to autism spectrum disorders and mood disturbances, and association studies suggest that genetic variation at the RAPGEF4 locus may influence fasting plasma glucose levels and risk for metabolic dysregulation. In addition, alterations in Epac2 signaling have been associated with neuropsychiatric conditions—including major depressive disorder—and identified as potential therapeutic targets in cancer, melanoma progression, and viral infections such as respiratory syncytial virus. Moreover, diminished Epac2 activity has been observed in models of neurodevelopmental disorders, such as Lesch–Nyhan syndrome, underscoring its importance in proper cytoskeletal organization and neuronal migration. These diverse findings collectively position RAPGEF4/Epac2 as an essential mediator whose proper function is critical for both normal physiology and disease pathogenesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "19", "end_ref": "30"}]}, {"type": "t", "text": ""}]}]}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Holger Rehmann, Balaji Prakash, Eva Wolf, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Mechanism of Epac activation: structural and functional analyses of Epac2 hinge mutants with constitutive and reduced activities."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M109.024950"}], "href": "https://doi.org/10.1074/jbc.M109.024950"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19553663"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19553663"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Sheng Li, Tamara Tsalkova, Mark A White, et al. 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