Affinage

RAPGEF4

Rap guanine nucleotide exchange factor 4 · UniProt Q8WZA2

Length
1011 aa
Mass
115.5 kDa
Annotated
2026-04-28
48 papers in source corpus 27 papers cited in narrative 27 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RAPGEF4 (Epac2/cAMP-GEFII) is a cAMP-activated guanine nucleotide exchange factor for Rap1/Rap2 GTPases that functions as a PKA-independent cAMP sensor mediating regulated exocytosis, synaptic remodeling, autophagy, and neuronal maturation. Upon cAMP binding to its N-terminal regulatory domain, Epac2 undergoes conformational activation and translocates to the plasma membrane, where it assembles multi-protein complexes with Rim2, Piccolo, SUR1, SNAP-25, and L-type Ca²⁺ channels to drive Ca²⁺-dependent insulin granule exocytosis and control fusion pore dynamics through recruitment of amisyn and dynamin-1 (PMID:11056535, PMID:12401793, PMID:14660679, PMID:31099751). In neurons, Epac2 interacts with neuroligin to regulate dendritic spine morphology, AMPA receptor trafficking, and excitatory transmission, and is required for electrophysiological maturation of prefrontal cortex neurons downstream of CHD8 (PMID:19734897, PMID:40398411). Epac2 also mediates GLP-1 receptor-stimulated atrial natriuretic peptide secretion in cardiomyocytes and drives protective autophagy in pancreatic beta-cells through a Ca²⁺–calcineurin–TFEB axis (PMID:23542788, PMID:34338148).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2000 High

    Identification of RAPGEF4 as a direct cAMP effector in exocytosis resolved how cAMP potentiates secretion independently of PKA, establishing the Epac2–Rim2 interaction as the molecular link between cAMP sensing and the exocytotic machinery.

    Evidence Co-immunoprecipitation, pulldown, and reconstituted exocytosis assay with PKA inhibitor

    PMID:11056535

    Open questions at the time
    • Structural basis of Epac2–Rim2 interaction not resolved
    • Relative contribution of Epac2 versus PKA in vivo not quantified
  2. 2001 High

    Demonstration that the Epac2–Rim2 pathway is essential for incretin-potentiated insulin secretion in native beta-cells moved the mechanism from reconstituted systems to physiological insulin release, answering whether this pathway operates in primary endocrine tissue.

    Evidence Antisense knockdown in isolated islets with PKA inhibitor H-89, insulin secretion measurement

    PMID:11598134

    Open questions at the time
    • No genetic knockout confirmation at this stage
    • Downstream effectors beyond Rim2 unknown
  3. 2002 High

    Discovery that Piccolo serves as a Ca²⁺ sensor within the cAMP-GEFII·Rim2·Piccolo complex explained how calcium dependence is integrated into the PKA-independent exocytotic pathway.

    Evidence Co-immunoprecipitation, pulldown, antisense knockdown, insulin secretion assay in beta-cells

    PMID:12401793

    Open questions at the time
    • Stoichiometry and assembly order of the ternary complex unknown
    • Whether other Ca²⁺ sensors substitute in non-beta-cell contexts untested
  4. 2003 High

    Mapping the interaction of Epac2 with SUR1 (via NBF1) and the connection of Rim2/Piccolo to L-type Ca²⁺ channels revealed a multi-protein signaling hub integrating KATP channel status, cAMP, and Ca²⁺ influx at the beta-cell plasma membrane.

    Evidence Co-immunoprecipitation, immunocytochemistry, dominant-negative overexpression in MIN6 cells; SUR1-/- mouse electrophysiology

    PMID:12601083 PMID:14660679

    Open questions at the time
    • Direct structural interface between SUR1 and Epac2 unresolved
    • Whether SUR1 interaction is permissive or instructive for GEF activity unclear
  5. 2003 High

    Showing that Epac2 mediates GLP-1-stimulated Ca²⁺ release through ryanodine receptors linked Epac2 to intracellular Ca²⁺ store mobilization and mitochondrial ATP production, broadening its role beyond plasma membrane exocytosis.

    Evidence Dominant-negative Epac2 mutant, pharmacological dissection with ryanodine/xestospongin C, mitochondrial Ca²⁺/ATP imaging in MIN6 cells

    PMID:12410638

    Open questions at the time
    • Whether Epac2 directly activates RyR or acts through Rap-dependent intermediaries unknown
  6. 2009 High

    Discovery that Epac2 interacts with neuroligin and regulates spine morphology, AMPA receptor trafficking, and excitatory synaptic transmission established a neuronal function for Epac2 beyond endocrine exocytosis, and linked autism-associated RAPGEF4 missense variants to altered GEF activity and dendritic signaling.

    Evidence Pharmacological activation, shRNA knockdown, co-immunoprecipitation, GEF assay, electrophysiology, and live imaging in cultured rat cortical neurons

    PMID:19734897

    Open questions at the time
    • In vivo validation of autism-associated variants lacking
    • Downstream Rap effectors mediating spine remodeling not identified
  7. 2009 High

    Defining that the N-terminal cAMP-binding domain A governs Epac2 plasma membrane localization and is required for secretory potentiation clarified why the Epac2B splice variant (lacking domain A) is functionally impaired, resolving isoform-specific differences in secretory function.

    Evidence Epac2 KO mouse, domain deletion/membrane-targeting rescue constructs, immunocytochemistry and secretion assays in MIN6 cells

    PMID:19170062

    Open questions at the time
    • Binding partner for domain A at the membrane not identified
    • Tissue-specific expression patterns of Epac2A vs Epac2B incompletely mapped
  8. 2013 High

    Genetic knockout of Epac2 in mice eliminated GLP-1R-dependent ANP secretion from cardiomyocytes, establishing Epac2 as an essential mediator in a gut–heart endocrine axis controlling blood pressure.

    Evidence Rapgef4-/- mice, live-cell imaging of Epac2 translocation, ANP secretion assays, blood pressure measurement, aortic ring relaxation

    PMID:23542788

    Open questions at the time
    • Whether Epac2 acts through Rap1 or an alternative effector in cardiomyocytes unknown
    • Human cardiovascular relevance not directly tested
  9. 2015 High

    Crystallographic resolution of Epac2 structural dynamics upon cAMP binding provided a molecular framework for how autoinhibition is relieved and the GEF domain becomes catalytically competent, answering how cAMP binding is mechanically transduced to Rap activation.

    Evidence Crystallographic structural analysis integrated with biochemical domain studies

    PMID:26390815

    Open questions at the time
    • Full-length Epac2 structure in complex with Rap and membrane lipids not determined
    • Allosteric coupling between the two cAMP-binding domains structurally unresolved
  10. 2019 High

    Demonstration that Epac2 controls fusion pore expansion by recruiting amisyn and dynamin-1 resolved the long-standing question of how cAMP modulates the kinetics (not just competence) of exocytosis, shifting understanding from granule priming to pore regulation.

    Evidence TIRF imaging, Epac2-/- mice, pharmacological inhibition/activation, amperometry/capacitance in beta-cells

    PMID:31099751

    Open questions at the time
    • Direct GEF-dependent versus GEF-independent mechanism for amisyn/dynamin-1 recruitment not distinguished
    • Whether this pore regulation mechanism operates in neurons unknown
  11. 2021 High

    Identification of Epac2 as a mediator of GLP-1R agonist-stimulated autophagy via Ca²⁺–calcineurin–TFEB revealed an entirely new cellular process controlled by Epac2 in beta-cells, distinct from its exocytotic role, answering how incretin signaling promotes beta-cell survival.

    Evidence siRNA knockdown, chemical inhibitors, TFEB overexpression rescue, autophagic flux assays, db/db mouse in vivo treatment

    PMID:34338148

    Open questions at the time
    • Whether Epac2-driven autophagy operates in non-beta-cell tissues untested
    • Specific Rap effector downstream of Epac2 in autophagy induction unidentified
  12. 2025 High

    Rescue of electrophysiological maturation deficits in CHD8-deficient prefrontal cortex neurons by RAPGEF4 re-expression established Epac2 as a critical downstream target of CHD8 for neuronal functional maturation, connecting an autism risk chromatin remodeler to cAMP–Rap signaling.

    Evidence Patch-seq, single-nucleus multiomic analysis, shRNA knockdown of CHD8, RAPGEF4 rescue overexpression in organotypic macaque and human cortical slices

    PMID:40398411

    Open questions at the time
    • Whether CHD8 directly regulates RAPGEF4 transcription or acts indirectly unresolved
    • Downstream Rap effectors mediating neuronal maturation not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of the Rap effectors mediating Epac2-dependent spine remodeling and neuronal maturation, whether fusion pore regulation by amisyn/dynamin-1 recruitment is GEF-dependent, the full-length membrane-associated Epac2 structure, and whether Epac2-driven autophagy generalizes beyond beta-cells.
  • Rap effectors downstream of Epac2 in neuronal contexts unidentified
  • Structural basis of Epac2 interaction with neuroligin and amisyn unknown
  • In vivo validation of autism-associated RAPGEF4 variants in animal models lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0098772 molecular function regulator activity 4
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-112316 Neuronal System 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-9612973 Autophagy 1
Partners
ABCC8AMISYNCHD8DNM1NLGN1PCLORIMS2SNAP25
Complex memberships
Epac2–Rim2–PiccoloEpac2–SUR1–Rim2

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 cAMP-GEFII (RAPGEF4/Epac2) directly binds to Rim (Rab3-interacting molecule) and Rim2, and through this interaction mediates cAMP-induced, Ca2+-dependent exocytosis in a PKA-independent manner, establishing it as a direct cAMP target in the exocytotic machinery. Co-immunoprecipitation, pulldown, reconstituted exocytosis assay with PKA inhibitor Nature cell biology High 11056535
2001 The cAMP-GEFII–Rim2 pathway is critical for incretin-potentiated insulin secretion in native pancreatic beta-cells, acting via a PKA-independent mechanism that depends on intracellular calcium and cAMP, and mediates both first and second phases of insulin secretion. Antisense oligodeoxynucleotide knockdown of cAMP-GEFII in isolated pancreatic islets, combined with PKA inhibitor H-89, measuring insulin secretion The Journal of biological chemistry High 11598134
2001 The EPAC2 gene encodes at least three isoforms including a liver-specific form (Epac2C/79 kDa) that lacks the first cAMP-binding domain and the DEP domain but retains GEF activity toward Rap1; gene maps to human chromosome 2q31 with 31+ exons. cDNA cloning from human liver, primer extension, RT-PCR, in situ hybridization, immunoblot, GEF activity assay Genomics High 11707077
2002 Piccolo, a CAZ protein, binds to cAMP-GEFII and forms Ca2+-dependent homodimers and heterodimers with Rim2, serving as a Ca2+ sensor in the cAMP-GEFII·Rim2·Piccolo complex required for cAMP-induced insulin secretion in pancreatic beta-cells. Co-immunoprecipitation, pulldown assays, antisense oligodeoxynucleotide knockdown, insulin secretion assay The Journal of biological chemistry High 12401793
2003 Sulfonylurea receptor 1 (SUR1), a subunit of KATP channels, interacts specifically with cAMP-GEFII through its nucleotide-binding fold 1 (NBF1), and this interaction is decreased by high cAMP concentrations; cAMP-GEFII co-localizes with Rim2 at the plasma membrane in insulin-secreting MIN6 cells, and Rim2 and Piccolo directly bind to the alpha1.2 subunit of L-type voltage-dependent Ca2+ channels. Co-immunoprecipitation, subcellular localization by immunocytochemistry, dominant-negative overexpression The Journal of biological chemistry High 14660679
2003 cAMP-GEFII mediates GLP-1-stimulated Ca2+ release through ryanodine receptors (RyR) in pancreatic MIN6 beta-cells, leading to mitochondrial ATP synthesis; a dominant-negative form of cAMP-GEFII (G114E, G422D) blocks RyR-mediated mitochondrial [ATP] increases. Dominant-negative cAMP-GEFII mutant overexpression, ryanodine/xestospongin C pharmacological dissection, mitochondrial Ca2+ and ATP imaging The Biochemical journal High 12410638
2003 cAMP-GEFII (Epac2) is required for the PKA-independent component of cAMP-stimulated exocytosis in pancreatic beta-cells, and SUR1 deficiency eliminates this PKA-independent exocytosis by preventing cAMP-stimulated Cl- influx into granules needed for priming. Antisense oligodeoxynucleotide knockdown, membrane capacitance measurements, SUR1-/- mouse islets, Epac-selective agonist 8CPT-2Me-cAMP The Journal of general physiology High 12601083
2004 SUR1, cAMP-GEFII, and Piccolo can form a multi-protein complex; cAMP (via 8-bromo-cAMP) inhibits cAMP-GEFII–SUR1 interaction but not the cAMP-GEFII–SUR1 interaction in the presence of ATP; Piccolo interacts with the alpha1.2 subunit of VDCC in a Ca2+-independent manner, integrating ATP, cAMP, and Ca2+ signals at a specialized beta-cell domain. Co-immunoprecipitation with pharmacological treatments (cAMP analogue, ATP) Diabetes Medium 15561922
2005 Epac2/cAMP-GEFII selectively stimulates the linear (ATP-independent, release-ready vesicle) component of Ca2+-dependent exocytosis in mouse pituitary melanotrophs, whereas PKA controls the threshold (ATP-dependent) component; these two pathways are pharmacologically dissociable. Whole-cell patch-clamp membrane capacitance measurements in pituitary tissue slices, Epac-selective agonist 8-pCPT-2Me-cAMP vs. PKA agonist/inhibitors The Journal of physiology Medium 15994184
2007 Epac2 (RapGEF4) activation by elevated cAMP (via anthrax edema toxin) induces cytoskeletal changes and inhibits chemotaxis in primary human microvascular endothelial cells through downstream Rap1 activation. Adenoviral overexpression of activated Epac/Rap1, pharmacological cAMP elevation, chemotaxis assay, cytoskeletal imaging The Journal of biological chemistry Medium 17491018
2009 Activation of Epac2 in rat cortical neurons induces spine shrinkage, increased spine motility, removal of synaptic GluR2/3-containing AMPA receptors, and depression of excitatory transmission; Epac2 interaction with neuroligin promotes membrane recruitment of Epac2 and enhances its GEF activity; autism-associated missense mutations in EPAC2/RAPGEF4 alter basal and neuroligin-stimulated GEF activity, dendritic Rap signaling, synaptic protein distribution and spine morphology. Pharmacological Epac2 activation, shRNA knockdown, co-immunoprecipitation, GEF activity assay, live imaging, electrophysiology in cultured rat cortical neurons Nature neuroscience High 19734897
2009 The N-terminal cAMP-binding domain A of Epac2A determines its plasma membrane localization in insulin-secreting MIN6 cells; Epac2B (lacking domain A) localizes primarily to cytoplasm and does not potentiate hormone secretion, whereas addition of a membrane-targeting signal to Epac2B restores secretory function. Identification of novel splice variant Epac2B in Epac2 KO mouse study, immunocytochemistry, hormone secretion assays in MIN6 cells with WT and mutant Epac2 constructs Journal of cellular physiology High 19170062
2009 SNAP-25 interacts with both cAMP-GEFII and Rim2, and is required for cAMP-dependent enhancement of the immediately releasable pool of insulin granules via the PKA-independent cAMP-GEFII pathway; truncation of SNAP-25 C-terminus abolishes cAMP potentiation of rapid exocytosis. Capacitance measurements, protein binding assays (pulldown), Western blot, overexpression of truncated SNAP-25 and BoNT/A in INS-1 cells American journal of physiology. Endocrinology and metabolism Medium 19509185
2011 RAPGEF4 (Epac2) localizes to the midpiece of equine sperm; activation of RAPGEF3/RAPGEF4 with selective agonist 8pCPT induces acrosomal exocytosis in capacitated stallion sperm and prevents capacitation-dependent membrane hyperpolarization, indicating RAPGEF4 regulates membrane potential and acrosomal exocytosis. Indirect immunofluorescence, acrosome reaction assay, membrane potential measurements, pharmacological agonist Biology of reproduction Medium 21471298
2012 Sulfonylureas activate Epac2 (cAMP-GEFII) to stimulate Rap1 signaling, promoting insulin granule exocytosis in a mechanism distinct from KATP channel closure; gliclazide is unique among sulfonylureas in that it does not activate Epac2, explaining its different secretory profile. Pharmacological studies comparing sulfonylurea effects on Epac2/Rap1 signaling and insulin secretion; mechanistic review integrating prior biochemical findings Diabetes, obesity & metabolism Medium 22118705
2013 GLP-1R activation promotes Epac2 (RAPGEF4) translocation to the membrane in cardiomyocytes, and Epac2 deficiency eliminates GLP-1R-dependent stimulation of atrial natriuretic peptide (ANP) secretion, placing Epac2 as a required mediator in the gut-heart GLP-1R–ANP axis regulating blood pressure. Genetic KO of Epac2 (Rapgef4-/-) mice, live cell imaging of Epac2 translocation, ANP secretion assays, blood pressure measurement, aortic ring relaxation assay Nature medicine High 23542788
2013 Rapgef4-dependent signaling downstream of Gnas/cAMP elevation regulates proximal tubular exo- and endocytosis in Xenopus pronephros and in human proximal tubular cells; a Rapgef4-specific agonist mimics cholera toxin effects on albumin uptake and secretion. Antisense morpholino knockdown in Xenopus, pharmacological agonist treatment, FITC-albumin uptake/secretion assay in human proximal tubular cell line Developmental biology Medium 23352791
2014 EPAC2 regulates calreticulin (CALR) expression in human endometrial glandular cells, and the EPAC2–CALR signaling axis is required for cAMP-stimulated expression of LIF and COX2/PTGS2 and prostaglandin E2 secretion; EPAC2 or CALR knockdown increases cellular senescence markers. siRNA knockdown of EPAC2 and CALR in EM1 cells, EPAC-selective vs. PKA-selective cAMP analogues, gene expression and PGE2 secretion assays, senescence assay Journal of molecular endocrinology Medium 25378661
2015 Crystallographic analyses reveal that activation of Epac2 by cAMP is accompanied by dynamic structural changes; Epac2 functions as a direct cAMP sensor that activates Rap GTPases via its GEF domain, with distinct structural domains (N-terminal cAMP-binding domain A, DEP domain, and catalytic GEF domain) each contributing to regulation and localization. Crystallographic structural analysis, domain function review integrating published structural and biochemical data Gene High 26390815
2015 Epac2/Rapgef4 (via PACAP-PAC1 receptor-AC6 pathway) acts as a cAMP sensor downstream of a specific adenylate cyclase isoform (AC6 but not AC7) in neuroendocrine PC12 cells, phosphorylating p38 as a downstream target; this signaling is disrupted by membrane cholesterol depletion. Lentiviral shRNA knockdown of AC6 or AC7, PACAP stimulation, phospho-p38 readout, methyl-β-cyclodextrin cholesterol depletion Molecular pharmacology Medium 25769305
2016 Epac2 knockout (Epac2-/-) mice exhibit anxiety, depression, and hippocampal neurogenesis defects; fluoxetine (SSRI/Prozac) treatment rescues open-field behavior and hippocampal cell proliferation in Epac2-/- mice, implicating Epac2 in serotonin/cAMP-mediated mood regulation and neurogenesis. Genetic KO mouse model, behavioral tests, hippocampal cell proliferation assays, SSRI pharmacological rescue Translational psychiatry Medium 27598965
2019 Epac2 (Rap-GEF4) controls fusion pore expansion during insulin exocytosis by acutely recruiting two pore-restricting proteins, amisyn and dynamin-1, to the exocytosis site; cAMP elevation restricts and slows fusion pore expansion and peptide release in a manner dependent on Epac2 (lost in Epac2-/- mice and with pharmacological Epac2 inactivation); GLP-1R agonists and sulfonylureas activate this pathway. Live-cell TIRF imaging, Epac2-/- mice, pharmacological Epac2 inhibition/activation, Epac2 overexpression, amperometry/capacitance measurements eLife High 31099751
2021 RAPGEF4/EPAC2 mediates exendin-4 (GLP-1R agonist)-stimulated autophagic flux in pancreatic beta-cells through a Ca2+-PPP3/calcineurin-TFEB axis, independent of AMPK and mTOR; EPAC2 knockdown abolishes exendin-4-induced autophagy and cell survival, and TFEB overexpression mimics EPAC2-dependent cell protection. siRNA knockdown of RAPGEF4, chemical inhibitors, TFEB overexpression, autophagic flux assays, db/db mouse in vivo treatment Autophagy High 34338148
2021 EPAC2 overexpression inhibits tubulogenesis and endothelial cell migration in Matrigel assays, while EPAC2 knockdown enhances tube formation and cell migration with elongated morphology and filopodia-like protrusions; RAPGEF4 expression increases during Matrigel-driven tubulogenesis, acting as a negative regulator of angiogenic network formation. Microarray, EPAC2 overexpression and siRNA knockdown in HMVECs, Matrigel tube formation assay, migration assay, morphology imaging Scientific reports Medium 34593918
2025 RAPGEF4 is required for electrophysiological maturation of prefrontal cortex neurons (resting membrane potential and inward sodium current) in rhesus macaque and human; CHD8 knockdown impairs neuronal maturation by downregulating RAPGEF4, and restoring RAPGEF4 expression rescues electrophysiological maturation in CHD8-deficient neurons. Patch-seq, single-nucleus multiomic analysis, shRNA knockdown of CHD8, RAPGEF4 rescue overexpression in organotypic slices from macaque and human, electrophysiological recordings Neuron High 40398411
2025 Hepatic EPAC2 (RAPGEF4) knockdown does not affect hepatic amino acid catabolism gene expression, plasma amino acid levels, or pancreatic alpha-cell hyperplasia, distinguishing EPAC2 from the hepatic GCGR-GNAS-PKA pathway that mediates these effects in the liver-alpha-cell loop. In vivo hepatic knockdown of GCGR, GNAS, PKA, and EPAC2 in mice; measurement of amino acid catabolism genes, plasma amino acids, alpha-cell mass Diabetes Medium 40095004
2025 Rapgef4 (Epac2) is among 184 genes concordantly dysregulated in both excitatory and inhibitory cortical neurons of Fmr1 KO (Fragile X) mice, is an FMRP target and ASD risk gene; pharmacological antagonism of EPAC2 restores cortical circuit function and ameliorates sensory behavioral phenotypes in Fmr1 KO mice. Cell-type specific mRNA sequencing (TRAP-seq), EPAC2 antagonist systemic administration, electrophysiological circuit recordings, behavioral assays in Fmr1 KO mice bioRxivpreprint Medium bio_10.1101_2025.04.21.649817

Source papers

Stage 0 corpus · 48 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure. Nature medicine 410 23542788
2000 cAMP-GEFII is a direct target of cAMP in regulated exocytosis. Nature cell biology 387 11056535
2001 Critical role of cAMP-GEFII--Rim2 complex in incretin-potentiated insulin secretion. The Journal of biological chemistry 289 11598134
2003 SUR1 regulates PKA-independent cAMP-induced granule priming in mouse pancreatic B-cells. The Journal of general physiology 212 12601083
2003 Glucagon-like peptide-1 mobilizes intracellular Ca2+ and stimulates mitochondrial ATP synthesis in pancreatic MIN6 beta-cells. The Biochemical journal 177 12410638
2002 Piccolo, a Ca2+ sensor in pancreatic beta-cells. Involvement of cAMP-GEFII.Rim2. Piccolo complex in cAMP-dependent exocytosis. The Journal of biological chemistry 166 12401793
2003 Interaction of ATP sensor, cAMP sensor, Ca2+ sensor, and voltage-dependent Ca2+ channel in insulin granule exocytosis. The Journal of biological chemistry 142 14660679
2009 Epac2 induces synapse remodeling and depression and its disease-associated forms alter spines. Nature neuroscience 133 19734897
2003 Screening of nine candidate genes for autism on chromosome 2q reveals rare nonsynonymous variants in the cAMP-GEFII gene. Molecular psychiatry 96 14593429
2015 Combined expressional analysis, bioinformatics and targeted proteomics identify new potential therapeutic targets in glioblastoma stem cells. Oncotarget 87 26295306
2009 Critical role of the N-terminal cyclic AMP-binding domain of Epac2 in its subcellular localization and function. Journal of cellular physiology 81 19170062
2015 A genome-wide approach to link genotype to clinical outcome by utilizing next generation sequencing and gene chip data of 6,697 breast cancer patients. Genome medicine 70 26474971
2007 Anthrax edema toxin inhibits endothelial cell chemotaxis via Epac and Rap1. The Journal of biological chemistry 52 17491018
2001 Characterization of the gene EPAC2: structure, chromosomal localization, tissue expression, and identification of the liver-specific isoform. Genomics 52 11707077
2018 Folic acid supplementation alters the DNA methylation profile and improves insulin resistance in high-fat-diet-fed mice. The Journal of nutritional biochemistry 51 29986310
2005 cAMP increases Ca2+-dependent exocytosis through both PKA and Epac2 in mouse melanotrophs from pituitary tissue slices. The Journal of physiology 50 15994184
2004 Integration of ATP, cAMP, and Ca2+ signals in insulin granule exocytosis. Diabetes 50 15561922
2012 Treating diabetes today: a matter of selectivity of sulphonylureas. Diabetes, obesity & metabolism 48 22118705
2015 Structure and functional roles of Epac2 (Rapgef4). Gene 47 26390815
2019 Fusion pore regulation by cAMP/Epac2 controls cargo release during insulin exocytosis. eLife 38 31099751
2016 Anxiety and depression with neurogenesis defects in exchange protein directly activated by cAMP 2-deficient mice are ameliorated by a selective serotonin reuptake inhibitor, Prozac. Translational psychiatry 38 27598965
2013 Signaling in sperm: toward a molecular understanding of the acquisition of sperm motility in the mouse epididymis. Biology of reproduction 38 24006282
2020 Two-stage Study of Familial Prostate Cancer by Whole-exome Sequencing and Custom Capture Identifies 10 Novel Genes Associated with the Risk of Prostate Cancer. European urology 37 32800727
2009 Truncation of SNAP-25 reduces the stimulatory action of cAMP on rapid exocytosis in insulin-secreting cells. American journal of physiology. Endocrinology and metabolism 37 19509185
2015 Orexin A regulates plasma insulin and leptin levels in a time-dependent manner following a glucose load in mice. Diabetologia 35 25813215
2021 Exendin-4 stimulates autophagy in pancreatic β-cells via the RAPGEF/EPAC-Ca2+-PPP3/calcineurin-TFEB axis. Autophagy 32 34338148
2011 Guanine-nucleotide exchange factors (RAPGEF3/RAPGEF4) induce sperm membrane depolarization and acrosomal exocytosis in capacitated stallion sperm. Biology of reproduction 31 21471298
2014 EPAC2-mediated calreticulin regulates LIF and COX2 expression in human endometrial glandular cells. Journal of molecular endocrinology 23 25378661
2023 Function of m5C RNA methyltransferase NOP2 in high-grade serous ovarian cancer. Cancer biology & therapy 21 37800580
2016 Role of EPAC in cAMP-Mediated Actions in Adrenocortical Cells. Frontiers in endocrinology 17 27379015
2015 Cyclic Adenosine 3',5'-Monophosphate Elevation and Biological Signaling through a Secretin Family Gs-Coupled G Protein-Coupled Receptor Are Restricted to a Single Adenylate Cyclase Isoform. Molecular pharmacology 11 25769305
2025 Multimodal analyses reveal genes driving electrophysiological maturation of neurons in the primate prefrontal cortex. Neuron 9 40398411
2020 EPAC2: A new and promising protein for glioma pathogenesis and therapy. Oncology reviews 8 32395202
2022 EPAC Regulates Melanoma Growth by Stimulating mTORC1 Signaling and Loss of EPAC Signaling Dependence Correlates with Melanoma Progression. Molecular cancer research : MCR 7 35834616
2013 Regulation of G-protein signaling via Gnas is required to regulate proximal tubular growth in the Xenopus pronephros. Developmental biology 6 23352791
2010 Over-expression of the DCLK gene transcript CARP decreases CA3/CA1 network excitability. Brain research 6 20659433
2021 Investigation of Diagnostic Biomarkers for Osteoporosis Based on Differentially Expressed Gene Profile with QCT and mDixon-Quant Techniques. Orthopaedic surgery 5 34516037
2021 Gene polymorphisms of insulin secretion signaling pathway associated with clopidogrel resistance in Han Chinese population. Journal of clinical laboratory analysis 5 34609028
2006 Depolarization and Ca(2+) down regulate CB1 receptors and CB1-mediated signaling in cerebellar granule neurons. Neuropharmacology 5 16412482
2022 Deciphering complex rearrangements at the breakpoint of an apparently balanced reciprocal translocation t(4:18)(q31;q11.2)dn and at a cryptic deletion: Further evidence of TLL1 as a causative gene for atrial septal defect. American journal of medical genetics. Part A 4 35567499
2024 Multimodal analyses reveal genes driving electrophysiological maturation of neurons in the primate prefrontal cortex. bioRxiv : the preprint server for biology 3 37398253
2021 EPAC2 acts as a negative regulator in Matrigel-driven tubulogenesis of human microvascular endothelial cells. Scientific reports 3 34593918
2025 Sex-specific molecular drivers of cardiac fibrosis in aging hearts. GeroScience 2 40025369
2025 Hepatic PKA Mediates Liver and Pancreatic α-Cell Cross Talk. Diabetes 2 40095004
2025 Downregulation of FASN in granulosa cells and its impact on ovulatory dysfunction in PCOS. Journal of ovarian research 1 40170064
2025 Breast Cancer-Secreted DPP3 Promotes Lung Metastasis by Remodelling the Vascular Niche in Lung via the Rap1 Signalling Pathway. Journal of extracellular vesicles 1 41311249
2025 Analysis of copy number variations and selection signatures using whole-genome sequencing data from 16 Chinese duck breeds. British poultry science 0 41123461
2020 The Epac2 coding gene (RAPGEF4) rs3769219 polymorphism is associated with protection against major depressive disorder in the Chinese Han population. Neuroscience letters 0 32905835