Affinage

RAPGEF3

Rap guanine nucleotide exchange factor 3 · UniProt O95398

Length
923 aa
Mass
103.8 kDa
Annotated
2026-04-28
100 papers in source corpus 40 papers cited in narrative 40 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RAPGEF3 (EPAC1) is a cAMP-activated guanine nucleotide exchange factor that transduces cAMP signals independently of PKA, primarily by catalyzing GDP/GTP exchange on Rap1 and, to a lesser extent, on R-Ras (PMID:12402047, PMID:16754664). cAMP binding releases an autoinhibitory interaction between the C-terminal helical lid of the cAMP-binding domain and the catalytic region, triggering a hinge-motion conformational change that exposes GEF activity (PMID:12888551, PMID:19553663). Activated Rap1 engages downstream effectors—including PLCε, integrins, tight junction proteins, ion channels (KATP, BKCa, Kv7), and the PI3K/Akt/NOS/CaMKII axis—to regulate vascular barrier integrity, cardiomyocyte hypertrophy and Ca²⁺ handling, insulin secretion, exocytosis, neurite outgrowth, axon specification, and cell migration (PMID:16269655, PMID:28476660, PMID:26269639, PMID:29158262, PMID:18032709). EPAC1 operates within scaffolded signaling complexes involving AKAPs, PP2A, and SUR1, enabling compartmentalized regulation of Akt, KATP channels, and calcineurin/NFAT signaling in cell-type-specific contexts (PMID:18550542, PMID:18565730, PMID:16613879).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2002 High

    Establishing that cAMP activates Rap1 through a PKA-independent GEF resolved whether all cAMP signaling funneled through PKA, revealing EPAC1 as a parallel cAMP effector.

    Evidence Selective cAMP analogue (8CPT-2Me-cAMP) activated Epac-dependent Rap1 but not PKA-dependent ERK in multiple cell lines

    PMID:12402047

    Open questions at the time
    • Structural basis of cAMP selectivity between Epac and PKA not yet resolved
    • Endogenous physiological contexts not yet defined
  2. 2003 High

    Defining the autoinhibitory lid mechanism explained how cAMP binding allosterically activates Epac's catalytic domain, establishing the molecular switch that governs GEF activation.

    Evidence Mutagenesis of the cAMP-binding domain lid coupled with in vitro GEF assays and cAMP analogue titration

    PMID:12888551 PMID:19553663

    Open questions at the time
    • Full-length crystal structure of active Epac1 not determined at that time
    • Role of the DEP and REM domains in autoinhibition not fully dissected
  3. 2004 High

    Discovery that EPAC1 acts as a direct GEF for R-Ras and signals through Rap2B/PLCε/Ca²⁺ to H-Ras/ERK expanded the substrate repertoire beyond Rap1 and connected EPAC to phospholipase and calcium signaling.

    Evidence In vitro GEF reconstitution with R-Ras, dominant-negative Rap2B/RapGAPII blocking ERK activation, PLD stimulation assays

    PMID:15319437 PMID:16754664

    Open questions at the time
    • Whether R-Ras is a physiologically relevant substrate in all tissues remains unresolved
    • Relative contribution of Rap1 vs. Rap2B vs. R-Ras pathways in different cell types unclear
  4. 2005 High

    Placing Epac upstream of calcineurin/NFAT in cardiomyocyte hypertrophy and upstream of PKCε in nociceptor sensitization demonstrated that EPAC1 drives cell-type-specific Ca²⁺-dependent signaling outputs with physiological and pathological relevance.

    Evidence Epac-selective agonist in neonatal cardiomyocytes with calcineurin/Rac inhibitors; Epac agonist plus PLC/PLD/PKCε inhibitors in DRG neurons with behavioral pain readout

    PMID:15987941 PMID:16269655

    Open questions at the time
    • Whether Epac1 vs Epac2 isoforms contribute differentially to cardiac hypertrophy not yet resolved
    • Endogenous GPCR identity activating Epac in cardiomyocytes not fully defined
  5. 2006 High

    Identification of Epac1/SUR1 complexes at KATP channels and Epac-triggered Ca²⁺ mobilization from ryanodine-sensitive stores established EPAC1 as a direct regulator of ion channel function and intracellular Ca²⁺ release.

    Evidence Co-IP of Epac with SUR1, patch-clamp showing Epac-dependent KATP inhibition blocked by dominant-negative Epac1; confocal Ca²⁺ imaging in IMCD with ryanodine receptor blockers

    PMID:16613879 PMID:16684923

    Open questions at the time
    • Stoichiometry and structural basis of Epac-SUR1 interaction not defined
    • Whether Epac directly modulates ryanodine receptors or acts via intermediaries unclear
  6. 2008 High

    Discovery that Epac scaffolds with Akt/PP2A and with AKAP150/PKA/Akt revealed that EPAC1 operates within multiprotein signaling complexes enabling compartmentalized and bidirectional regulation of Akt phosphorylation.

    Evidence Co-IP of Epac-Akt-PP2A with functional phosphatase assay; co-IP of AKAP150-Epac-PKA-Akt in neurons with AKAP-disrupting peptides and siRNA

    PMID:18550542 PMID:18565730

    Open questions at the time
    • Whether Epac1 vs Epac2 occupy the same or distinct AKAP complexes unclear
    • Post-translational modifications regulating scaffold assembly not characterized
  7. 2008 High

    Linking Epac to CaMKII-dependent arrhythmogenesis and β-AR-induced hypertrophic gene program via Ras/calcineurin/CaMKII cemented a pro-pathological cardiac signaling axis downstream of cAMP that is distinct from PKA.

    Evidence Epac-selective agonist in Langendorff-perfused hearts with CaMKII inhibitor; Epac1 siRNA in adult cardiomyocytes with Ras/calcineurin/CaMKII inhibitors

    PMID:18323524 PMID:18600344 PMID:20576488

    Open questions at the time
    • Whether chronic Epac inhibition is cardioprotective in heart failure models not tested at this stage
    • Relative contribution of CaMKII vs calcineurin arm not quantified
  8. 2009 High

    Demonstration that EPAC1 controls endothelial angiogenesis via PI3K/Akt/eNOS, vascular relaxation via BKCa and endothelial SKCa/IKCa/NOS, and integrin-dependent progenitor cell homing established EPAC1 as a central regulator of vascular function.

    Evidence Epac1 siRNA suppressing Akt/eNOS with in vivo neovascularization; tension recording and Ca²⁺ spark imaging in mesenteric arteries; integrin affinity assays and hind limb ischemia model for progenitor homing

    PMID:18032709 PMID:19385062 PMID:23959673

    Open questions at the time
    • Whether Epac1 is the dominant isoform in all vascular beds not established
    • Structural basis for Epac-PI3K coupling unknown
  9. 2009 High

    Defining the cAMP/Epac/Rap1/PLCε/IP3 cascade for acrosomal Ca²⁺ release during sperm exocytosis showed EPAC1 as the cAMP sensor for fertilization-relevant exocytosis, with Rab3A activated indirectly downstream.

    Evidence In vitro GEF assay showing no direct Epac activity on Rab3A; PLCε siRNA and Rap1-GTP pulldown in human sperm; TAT-cAMP sponge approach

    PMID:19546222 PMID:26704387

    Open questions at the time
    • Whether Epac1 or Epac2 is the dominant isoform in human sperm exocytosis not definitively resolved
    • Direct visualization of Epac-Rap1-PLCε signalosome in sperm not achieved
  10. 2012 High

    Development of selective Epac inhibitors (ESI-09, CE3F4) with defined mechanisms of action provided critical pharmacological tools and confirmed that cellular phenotypes attributed to Epac (migration, Rap1 activation, insulin secretion) are on-target.

    Evidence CE3F4 uncompetitive kinetics in cell-free GEF assay; ESI-09 blocking Rap1 activation and Akt phosphorylation with functional readouts in cancer and β-cells

    PMID:23066090 PMID:23139415 PMID:25183009

    Open questions at the time
    • Off-target effects of ESI-09 at higher concentrations debated
    • In vivo pharmacokinetics and selectivity of these inhibitors not fully characterized
  11. 2015 High

    EPAC1 knockout neurons displaying axon specification defects, rescued by pharmacological activation, established a non-redundant role for EPAC1-Rap1b in neuronal polarity, extending its function beyond growth cone guidance to fundamental cell fate decisions.

    Evidence EPAC1 KO mouse neurons, shRNA knockdown, Epac-selective agonist inducing supernumerary axons with mature markers (ankyrin G, synaptophysin, vGLUT1)

    PMID:26269639

    Open questions at the time
    • Whether EPAC2 compensates partially in EPAC1 KO neurons not tested
    • Downstream effectors linking Rap1b to polarity determinants (Par complex, etc.) not identified
  12. 2017 High

    Mapping the complete β-AR-cAMP-Epac-PI3K-Akt-NOS1-CaMKII series pathway for SR Ca²⁺ leak, alongside Epac-Rap1 control of tight junctions and retinal vascular permeability, unified cardiac and vascular pathophysiology under EPAC1 signaling.

    Evidence Ca²⁺ spark frequency and FRET-CaMKII reporter with sequential pharmacological inhibitors in cardiomyocytes; Rap1B siRNA and Epac agonist/antagonist with in vivo retinal permeability

    PMID:27855271 PMID:28476660 PMID:29158262

    Open questions at the time
    • Whether NOS1 vs NOS3 selectivity is cell-type dependent unclear
    • Structural basis for Epac-PI3K coupling in cardiomyocytes not defined
  13. 2017 High

    EPAC1 was placed downstream of PGE2/EP2 receptors in macrophage IL-33 production, revealing an innate immune signaling function and expanding EPAC's role to inflammatory cytokine regulation.

    Evidence EP2 and mPGES-1 KO macrophages, EPAC knockdown, EPAC-selective agonist, in vivo Alternaria lung inflammation model

    PMID:28341741

    Open questions at the time
    • Whether EPAC1 regulates other alarmin cytokines besides IL-33 not investigated
    • Downstream Rap1 effectors mediating IL-33 transcription not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the isoform-specific contributions of EPAC1 vs EPAC2 across tissues, the structural basis of EPAC1 scaffolding with AKAP/PP2A/PI3K complexes, and whether chronic pharmacological EPAC1 inhibition is therapeutically viable in cardiac or vascular disease.
  • No high-resolution structure of full-length active EPAC1 in complex with Rap1 and scaffold partners
  • Therapeutic window for EPAC1 inhibition in vivo not established
  • Isoform-specific knockout phenotype comparison across cardiovascular, neuronal, and immune systems incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0098772 molecular function regulator activity 5
Localization
GO:0005829 cytosol 3 GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-1500931 Cell-Cell communication 3 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-168256 Immune System 1
Partners
ABCC8AKAP5AKT1MAP1APPP2CARAP1ARAP1BRRAS
Complex memberships
AKAP150-Epac-PKA-Akt complexEpac-SUR1 complexEpac1-Akt-PP2A complex

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 EPAC1 (RAPGEF3) functions as a cAMP-activated guanine nucleotide exchange factor (GEF) for Rap1; a selective cAMP analogue (8CPT-2Me-cAMP) activates Epac but not PKA, demonstrating that cAMP-induced Rap1 activation and ERK regulation are independent processes. Selective cAMP analogue pharmacology (8CPT-2Me-cAMP), in vitro and cell-based GEF assays, ERK activity measurements Nature cell biology High 12402047
2003 Epac activation requires cAMP binding that releases inhibitory interaction between the C-terminal helical lid of the cAMP-binding domain and the catalytic region; mutational analysis of the lid region modulates activation potency of cAMP analogues. Mutational analysis of Epac cAMP-binding domain lid region, in vitro GEF activity assays with cAMP analogues The Journal of biological chemistry High 12888551
2004 EPAC1 directly interacts with R-Ras and catalyzes GDP/GTP exchange on R-Ras in vitro; Epac-mediated R-Ras activation downstream of Gs-coupled receptors specifically controls phospholipase D stimulation. In vitro GEF assay (recombinant Epac1 + R-Ras), dominant-negative Epac1 mutant, siRNA depletion of Epac1, Rap GTPase-activating protein II expression The Journal of biological chemistry High 16754664
2004 EPAC1 interacts with the light chain 2 (LC2) of microtubule-associated protein 1A (MAP1A) via its cAMP-binding domain; this interaction was confirmed by two-hybrid, co-immunoprecipitation, and GST pull-down assays. Yeast two-hybrid screen, co-immunoprecipitation, GST pull-down assay, immunolocalization in HEK293 and COS1 cells The Biochemical journal Medium 15202935
2004 Epac1 activates H-Ras and subsequently ERK1/2 via a pathway involving Rap2B and phospholipase C-epsilon (PLC-ε), leading to intracellular Ca2+ increase that activates a Ca2+-sensitive Ras-GEF (possibly RasGRP1); dominant-negative Rap2B and RapGAPII block this pathway. Dominant-negative mutants (H-Ras, Rap2B), Epac-selective cAMP analogue, constitutively active Rap2B, cAMP-binding-deficient Epac1 mutant, ERK1/2 activity assays The Journal of biological chemistry High 15319437
2005 In IB4+ DRG nociceptors, cAMP signals to PKCε via Epac (not PKA), with Epac acting upstream of phospholipase C and PLD, both required for PKCε translocation and activation; this pathway mediates cAMP-induced mechanical hyperalgesia. Selective Epac agonist, pharmacological inhibition of PLC/PLD/PKCε, behavioral pain model, cultured DRG neurons The Journal of neuroscience High 15987941
2005 Epac activation in cardiomyocytes induces hypertrophy through Ca2+-dependent activation of Rac, calcineurin/NFAT pathway; Rac and calcineurin inhibition blunts the Epac-induced hypertrophic response. Epac-selective cAMP analogue, dominant-negative Rac, calcineurin inhibitor, NFAT reporter assay in neonatal cardiomyocytes Circulation research High 16269655
2006 Epac1 and Epac2 co-immunoprecipitate with full-length sulphonylurea receptor 1 (SUR1) in HEK cells; Epac-selective cAMP analogues inhibit ATP-sensitive K+ (KATP) channel function in human beta cells and INS-1 cells, an effect abolished by dominant-negative Epac1. Co-immunoprecipitation (Epac + SUR1), patch-clamp electrophysiology, dominant-negative Epac1 transfection, Epac-selective vs. PKA-selective cAMP analogues The Journal of physiology High 16613879
2006 Epac activation triggers intracellular Ca2+ mobilization via ryanodine-sensitive stores and apical exocytotic insertion of aquaporin-2 (AQP2) in inner medullary collecting duct (IMCD), independent of PKA. Confocal fluorescence microscopy in perfused IMCD, Epac-selective cAMP agonist, ryanodine receptor blocker, PKA inhibitors, immunolocalization of AQP2 American journal of physiology. Renal physiology Medium 16684923
2007 Anthrax edema toxin-generated cAMP inhibits endothelial cell chemotaxis via Epac and Rap1; activated Epac or Rap1 induces cytoskeletal changes and blocks chemotaxis; ET also induces transcription of Epac2 and MR-GEF/RapGEF5. cAMP analogue pharmacology, constitutively active Epac/Rap1 overexpression, chemotaxis assays, cytoskeletal imaging The Journal of biological chemistry Medium 17491018
2007 Pharmacological activation of Epac1 increases Rap1 activity, stimulates beta1- and beta2-integrin-dependent adhesion and migration of endothelial progenitor cells, rapidly increases lateral mobility and affinity of beta1-integrins, and enhances homing to ischemic muscle in vivo. Epac-selective cAMP analogue, Rap1 activity assay (pulldown), integrin affinity/avidity assays, hind limb ischemia mouse model Blood High 18032709
2008 Epac1 mediates beta-adrenergic receptor-induced cardiomyocyte hypertrophy through Ras (not Rap1), calcineurin, and CaMKII in a PKA-independent manner; Epac1 knockdown reduces beta-AR-induced hypertrophic gene program. Epac-selective analogue, Epac1 siRNA knockdown, Ras/Rap1 activity assays, calcineurin and CaMKII inhibitors, adult ventricular myocytes Circulation research High 18323524
2008 Epac forms a complex with Akt and PP2A; cAMP activates Epac-associated PP2A in a PKA- and Rap1-dependent manner, leading to Akt dephosphorylation; both Epac- and PKA-specific analogues synergistically regulate this Epac-Rap1b-PP2A module controlling Akt. Co-immunoprecipitation (Epac-Akt-PP2A complex), Epac-selective vs. PKA-selective cAMP analogues, dominant-negative Epac, dominant-negative PP2A, phosphatase activity assay The Journal of biological chemistry High 18550542
2008 AKAP150 forms complexes with PKA, PKB/Akt, and Epac in neurons; Epac activation increases PKB/Akt phosphorylation in a Rap-dependent manner, and this effect is mediated through AKAP150-anchored signaling; Epac2 siRNA preferentially blocks this Epac-mediated Akt phosphorylation. Co-immunoprecipitation (AKAP150 with Epac/PKA/Akt), Epac-selective analogue, siRNA knockdown of Epac1/Epac2, PKA-anchoring-deficient AKAP150 mutant, AKAP-disrupting peptides Cellular signalling High 18565730
2008 Epac activation induces ventricular arrhythmias in intact murine hearts associated with altered intracellular Ca2+ homeostasis in ventricular myocytes; these effects are reduced by CaMKII inhibition, placing CaMKII downstream of Epac in cardiac Ca2+ dysregulation. Langendorff-perfused mouse heart, monophasic action potential recording, programmed electrical stimulation, fluorescence Ca2+ imaging, CaMKII inhibitor (KN-93), Epac-selective cAMP analogue Pflugers Archiv Medium 18600344
2008 Epac (RAPGEF3) promotes DRG neurite outgrowth and regeneration on spinal cord tissue in a cAMP-dependent, PKA-independent manner; siRNA knockdown of Epac reduces neurite outgrowth and prevents cAMP-elevation-induced growth; asymmetric Epac activation promotes attractive growth cone turning. Epac-selective cAMP analogue, siRNA knockdown, neurite outgrowth assays on spinal cord substrate, growth cone turning assay Molecular and cellular neurosciences High 18583150
2009 Epac stimulates GDP/GTP exchange on Rap1 upstream of PLC, leading to IP3-dependent Ca2+ mobilization from acrosomal stores during sperm exocytosis; Epac also indirectly activates Rab3A (not via direct GEF activity) via a pathway downstream of soluble adenylyl cyclase/cAMP/Epac but not Rap1. Recombinant Epac in vitro GEF assay on Rab3A and Rap1, Epac-selective cAMP analogue, PLC inhibitors, Ca2+ mobilization measurements in human sperm The Journal of biological chemistry High 19546222
2009 Epac activation reduces Ca2+ transient amplitude and increases myofilament Ca2+ sensitivity in cardiomyocytes; Epac increases phosphorylation of cardiac Troponin I and MyBP-C via PKC and CaMKII (not PKA), constituting a novel regulator of myofilament function. Epac-selective analogue, constitutively active Epac in vivo infection, permeabilized cardiomyocyte Ca2+ sensitivity assays, PKC/CaMKII inhibitors, sarcomeric protein phosphorylation analysis Proceedings of the National Academy of Sciences High 19666481
2009 Epac1 activates H-Ras in neonatal cardiac myocytes via a PLC/IP3R/Ca2+ cascade downstream of Rap; Epac1 activation induces HDAC4 nuclear export and, in the presence of HDAC4, HDAC5 also becomes responsive; CaMKII mediates MEF2 activation, linking Epac to pro-hypertrophic gene expression. RapGAP overexpression, PLC/IP3R inhibitors, constitutively active Epac1, HDAC4/5 translocation assays, CaMKII inhibitor, MEF2 reporter in cardiac myocytes Cellular signalling High 20576488
2009 EPAC1 promotes angiogenesis in endothelial cells via Akt/eNOS/NO signaling and ERK phosphorylation in a PI3K-dependent, PKA-independent manner; siRNA knockdown of Epac1 suppresses Akt/eNOS phosphorylation and angiogenesis without affecting CREB phosphorylation or VEGF expression. Epac-selective cAMP analogue (8CPT-2Me-cAMP), Epac1 siRNA knockdown, phosphorylation assays, in vitro angiogenesis assay, in vivo neovascularization Cellular signalling High 19385062
2009 Epac1 mediates cAMP-induced inhibition of migration and proliferation in prostate carcinoma cells through inhibition of MAP kinase and RhoA signaling, while activating Rap1. Epac-selective cAMP analogue, Rap1/RhoA pulldown assays, MAP kinase immunoblotting, scratch migration assay, [3H]thymidine incorporation, phalloidin cytoskeleton staining British journal of cancer Medium 19920825
2009 Epac increases melanoma cell migration via syndecan-2 translocation to lipid rafts regulated by tubulin polymerization through the Epac/PI3K pathway, and via increased NDST-1 expression leading to enhanced heparan sulfate production. Epac-specific agonist, Epac overexpression, Epac siRNA, syndecan-2 localization assay, in vivo lung colonization model American journal of physiology. Cell physiology Medium 19657062
2010 Epac1 genetic disruption in mice abolishes 3-nitropropionic acid-induced neuronal apoptosis in vivo; Epac promotes cortical neuron-specific apoptosis by transcriptionally upregulating Bim expression, and Bim silencing attenuates Epac-induced neuronal apoptosis. Epac1 knockout mice, 3-NP in vivo model, Bim siRNA, TUNEL staining, DNA fragmentation assay, Bim mRNA quantification The Journal of biological chemistry High 20516079
2011 Taurocholate-induced hepatocyte polarization proceeds through a cAMP-Epac-MEK-Rap1-LKB1-AMPK pathway; inhibition of Epac downstream targets Rap1 and MEK blocks taurocholate-induced bile canalicular network formation. Pharmacological inhibitors of adenylyl cyclase, PKA, Epac, Rap1, MEK; kinase activation assays (MEK, LKB1, AMPK); rat hepatocyte sandwich cultures; bile canaliculi imaging Proceedings of the National Academy of Sciences High 21220320
2011 RAPGEF3 is localized to the acrosome and subacrosomal ring in equine sperm; activation of RAPGEF3/RAPGEF4 induces acrosomal exocytosis in capacitated sperm and prevents hyperpolarization of the sperm plasma membrane, identifying a role for RAPGEF3 in membrane potential regulation during fertilization. Indirect immunofluorescence localization, RAPGEF3/4-selective cAMP analogue (8pCPT), acrosomal exocytosis assay, membrane potential measurements Biology of reproduction Medium 21471298
2012 The Epac-Rap1 signaling pathway controls cAMP-mediated Weibel-Palade body (WPB) exocytosis in endothelial cells; siRNA knockdown of Epac1 abolishes epinephrine-induced Rap1 activation and reduces WPB exocytosis; Rap1GAP overexpression or Rap1 siRNA also reduces epinephrine-induced exocytosis. siRNA knockdown of Epac1 and Rap1, Rap1GAP overexpression, WPB exocytosis assay, Rap1 activation pulldown, epinephrine stimulation The Journal of biological chemistry High 22511766
2012 EPAC1 plays an important role in pancreatic cancer cell migration and invasion; the EPAC-specific inhibitor ESI-09 blocks intracellular EPAC-mediated Rap1 activation and Akt phosphorylation, as well as EPAC-mediated insulin secretion. EPAC-specific inhibitor (ESI-09), Rap1 activation assay, Akt phosphorylation, migration and invasion assays, insulin secretion assay Molecular pharmacology Medium 23066090
2012 CE3F4, a tetrahydroquinoline Epac1 inhibitor, blocks Epac1 GEF activity toward Rap1 in cell-free systems and intact cells without inhibiting PKA or directly affecting Rap1 GDP exchange; kinetic analysis indicates uncompetitive inhibition with respect to Epac1 agonists. Cell-free GEF assay, intact cell Rap1 activation assay, PKA holoenzyme activity assay, kinetics of inhibition, structure-activity relationship analysis The Journal of biological chemistry High 23139415
2009 Epac activation induces vascular relaxation in rat mesenteric arteries through two mechanisms: (1) increasing ryanodine receptor-dependent Ca2+ sparks to activate BKCa channels in smooth muscle, and (2) endothelium-dependent SKCa/IKCa channel activation and NOS stimulation. Isometric tension recording, patch-clamp (STOCs), Ca2+ spark imaging (Fluo-4), iberiotoxin, apamin, TRAM-34, L-NAME, ryanodine, endothelium removal The Journal of physiology High 23959673
2009 Epac activation mediates hinge-motion-dependent conformational change in the enzyme: substitution of conserved phenylalanine 435 with glycine (F435G) in Epac2 yields constitutively active enzyme without cAMP, while F435W impedes hinge motion and dramatically reduces catalytic activity. Site-directed mutagenesis, in vitro GEF activity assay, small angle X-ray scattering (SAXS) for structural parameters The Journal of biological chemistry High 19553663
2015 Phospholipase Cε (PLCε) is required for the acrosome reaction downstream of Rap1 and upstream of intra-acrosomal Ca2+ mobilization; the cAMP/Epac/Rap1/PLCε/IP3 cascade constitutes the signaling module for acrosomal Ca2+ release during sperm exocytosis. TAT-cAMP sponge (sequester endogenous cAMP), siRNA for PLCε, Rap1-GTP pulldown, Ca2+ mobilization measurement, Rab3-GTP pulldown Biochimica et biophysica acta High 26704387
2015 Spinal 5-HT7 receptor-induced phrenic motor facilitation is mediated by EPAC and downstream mTORC1 in a PKA-independent manner; selective EPAC inhibitor (ESI-05) abolishes 5-HT7-induced facilitation while PKA inhibitor does not; direct EPAC activation (8-pCPT) is sufficient for facilitation. Intrathecal drug administration in anesthetized rats, selective EPAC inhibitor (ESI-05), PKA inhibitor (KT-5720), selective EPAC activator, mTORC1 inhibitor (rapamycin), phrenic nerve electrophysiology Journal of neurophysiology Medium 26269554
2015 EPAC1 (RAPGEF3) regulates neuronal polarity and axon specification through Rap1b activation; EPAC1 knockout neurons show axon elongation and polarization defects; EPAC pharmacological activation induces supernumerary axons with mature axon markers. Epac-selective analogue (8-pCPT), shRNA knockdown of EPAC1, EPAC1 knockout mice neurons, Rap1b activation assay, immunostaining of axon markers (ankyrin G, synaptophysin, vGLUT1) The Journal of neuroscience High 26269639
2016 EPAC-dependent vasorelaxation in mesenteric arteries occurs via Kv7 channel activation by Rap1a/Rap2 (downstream of EPAC), demonstrated by proximity ligation assay showing Kv7.4 co-localizes with Rap1a/Rap2 after EPAC stimulation; isoproterenol relaxation in mesenteric but not renal arteries is EPAC-dependent. Isometric tension recording, Kv7 inhibitor (linopirdine), EPAC inhibitor, PKA inhibitor, proximity ligation assay (Kv7.4 + Rap1a/Rap2 + AKAP), isolated mesenteric vs. renal arteries Arteriosclerosis, thrombosis, and vascular biology Medium 27789473
2017 KLF2 transcriptionally controls RAPGEF3 (EPAC1) expression, maintaining endothelial barrier via Rac1 activation; KLF2 knockdown reduces RAPGEF3-Rac1 signaling and increases endothelial permeability; KLF2 overexpression ameliorates LPS-induced lung injury in mice. ChIP assay, luciferase reporter assay, siRNA knockdown, small GTPase activity assay, permeability measurements, KLF2 overexpression in mice, lung injury model American journal of respiratory and critical care medicine High 27855271
2017 β-AR-induced SR Ca2+ leak in cardiomyocytes proceeds via a single series pathway: β-AR-cAMP-Epac-PI3K-Akt-NOS1-CaMKII; Epac activation (8-CPT) mimics β-AR-induced SR Ca2+ leak, blocked by NOS inhibition; PI3K and Akt are implicated between Epac and NOS1. Ca2+ spark frequency measurement, tetracaine-induced SR Ca2+ load assay, FRET-based CaMKII activity reporter, ryanodine receptor phosphorylation, pharmacological inhibitors for NOS/PI3K/Akt, Epac-selective agonist Journal of molecular and cellular cardiology High 28476660
2017 EPAC-Rap1 signaling prevents and reverses VEGF- and TNF-α-induced retinal vascular permeability; Rap1B knockdown or EPAC antagonist increases endothelial permeability; GTP-bound Rap1 promotes tight junction assembly; EPAC activation inhibits VEGFR signaling through Ras/MEK/ERK. Epac-selective agonist and antagonist, Rap1B siRNA knockdown, in vitro permeability assay, in vivo retinal permeability, tight junction immunofluorescence, VEGFR/ERK signaling assays The Journal of biological chemistry High 29158262
2017 LPS-induced IL-33 production in macrophages requires endogenous PGE2 and EP2 receptors acting through cAMP/EPAC (not PKA); EPAC-selective agonist mimics PGE2 amplification of IL-33, and EPAC knockdown attenuates it. EPAC-selective agonist and antagonist, EPAC knockdown, mPGES-1 and EP2 knockout macrophages, IL-33 ELISA, in vivo Alternaria lung inflammation model The Journal of biological chemistry High 28341741
2021 Exendin-4 stimulates autophagy in pancreatic β-cells via RAPGEF4/EPAC2-Ca2+-PPP3/calcineurin-TFEB axis; this pathway is independent of AMPK and mTOR; inhibition of this cascade prevents exendin-4-mediated cell survival; overexpression of TFEB mimics exendin-4 protective effects. Chemical inhibitors and siRNA knockdown of RAPGEF4/EPAC2, calcineurin inhibitors, TFEB overexpression, autophagic flux assays, caspase-3 activity, INS-1E cells and human islets Autophagy Medium 34338148
2014 Allosteric inhibitor compound 5376753 (thiobarbituric acid derivative) binds the hinge region of the cAMP-binding domain of Epac1 and selectively inhibits Epac activity and cell migration without affecting PKA. Computational molecular modeling, BRET-based CAMYEL assay, Rap1 activity assay, vasodilator-stimulated phosphoprotein phosphorylation (PKA readout), cell migration assay The Journal of biological chemistry Medium 25183009

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 A novel Epac-specific cAMP analogue demonstrates independent regulation of Rap1 and ERK. Nature cell biology 613 12402047
2006 Epac proteins: multi-purpose cAMP targets. Trends in biochemical sciences 436 17084085
2010 Epac: defining a new mechanism for cAMP action. Annual review of pharmacology and toxicology 391 20055708
2008 Epac and PKA: a tale of two intracellular cAMP receptors. Acta biochimica et biophysica Sinica 305 18604457
2006 Cell physiology of cAMP sensor Epac. The Journal of physiology 216 16973695
2012 A novel EPAC-specific inhibitor suppresses pancreatic cancer cell migration and invasion. Molecular pharmacology 188 23066090
2005 Epac mediates a cAMP-to-PKC signaling in inflammatory pain: an isolectin B4(+) neuron-specific mechanism. The Journal of neuroscience : the official journal of the Society for Neuroscience 187 15987941
2008 Epac mediates beta-adrenergic receptor-induced cardiomyocyte hypertrophy. Circulation research 178 18323524
2018 Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development. Physiological reviews 176 29537337
2013 Increased sugar uptake promotes oncogenesis via EPAC/RAP1 and O-GlcNAc pathways. The Journal of clinical investigation 164 24316969
2005 cAMP-binding protein Epac induces cardiomyocyte hypertrophy. Circulation research 161 16269655
2016 Cyclic AMP Sensor EPAC Proteins and Their Role in Cardiovascular Function and Disease. Circulation research 143 26941424
2007 Epac-selective cAMP analogs: new tools with which to evaluate the signal transduction properties of cAMP-regulated guanine nucleotide exchange factors. Cellular signalling 135 17716863
2003 Ligand-mediated activation of the cAMP-responsive guanine nucleotide exchange factor Epac. The Journal of biological chemistry 135 12888551
2008 The cyclic AMP effector Epac integrates pro- and anti-fibrotic signals. Proceedings of the National Academy of Sciences of the United States of America 134 18434542
2009 The role of Epac proteins, novel cAMP mediators, in the regulation of immune, lung and neuronal function. British journal of pharmacology 127 19912228
2006 cAMP sensor Epac as a determinant of ATP-sensitive potassium channel activity in human pancreatic beta cells and rat INS-1 cells. The Journal of physiology 118 16613879
2009 EPAC proteins transduce diverse cellular actions of cAMP. British journal of pharmacology 117 19210747
2011 Bile acid stimulates hepatocyte polarization through a cAMP-Epac-MEK-LKB1-AMPK pathway. Proceedings of the National Academy of Sciences of the United States of America 113 21220320
2022 cAMP Signaling in Cancer: A PKA-CREB and EPAC-Centric Approach. Cells 107 35805104
2008 Epac mediates cyclic AMP-dependent axon growth, guidance and regeneration. Molecular and cellular neurosciences 105 18583150
2009 Forskolin increases angiogenesis through the coordinated cross-talk of PKA-dependent VEGF expression and Epac-mediated PI3K/Akt/eNOS signaling. Cellular signalling 104 19385062
2024 cAMP-PKA/EPAC signaling and cancer: the interplay in tumor microenvironment. Journal of hematology & oncology 100 38233872
2011 Rap-linked cAMP signaling Epac proteins: compartmentation, functioning and disease implications. Cellular signalling 100 21402149
2004 Epac- and Ca2+ -controlled activation of Ras and extracellular signal-regulated kinases by Gs-coupled receptors. The Journal of biological chemistry 94 15319437
2015 Biochemical and pharmacological characterizations of ESI-09 based EPAC inhibitors: defining the ESI-09 "therapeutic window". Scientific reports 93 25791905
2012 Identification of a tetrahydroquinoline analog as a pharmacological inhibitor of the cAMP-binding protein Epac. The Journal of biological chemistry 89 23139415
2010 PKA and Epac synergistically inhibit smooth muscle cell proliferation. Journal of molecular and cellular cardiology 86 20971121
2009 Epac activates the small G proteins Rap1 and Rab3A to achieve exocytosis. The Journal of biological chemistry 83 19546222
2019 EPAC-lung: pooled analysis of circulating tumour cells in advanced non-small cell lung cancer. European journal of cancer (Oxford, England : 1990) 77 31254940
2015 The future of EPAC-targeted therapies: agonism versus antagonism. Trends in pharmacological sciences 76 25744542
2013 Epac-inhibitors: facts and artefacts. Scientific reports 76 24149987
2007 Activation of Epac stimulates integrin-dependent homing of progenitor cells. Blood 72 18032709
2014 Glucagon stimulates hepatic FGF21 secretion through a PKA- and EPAC-dependent posttranscriptional mechanism. PloS one 71 24733293
2009 The cAMP binding protein Epac regulates cardiac myofilament function. Proceedings of the National Academy of Sciences of the United States of America 71 19666481
2006 Epac-mediated Ca(2+) mobilization and exocytosis in inner medullary collecting duct. American journal of physiology. Renal physiology 71 16684923
2010 Differential roles of Epac in regulating cell death in neuronal and myocardial cells. The Journal of biological chemistry 68 20516079
2008 Neuronal AKAP150 coordinates PKA and Epac-mediated PKB/Akt phosphorylation. Cellular signalling 68 18565730
2008 Epac activation, altered calcium homeostasis and ventricular arrhythmogenesis in the murine heart. Pflugers Archiv : European journal of physiology 66 18600344
2006 Cyclic AMP-dependent and Epac-mediated activation of R-Ras by G protein-coupled receptors leads to phospholipase D stimulation. The Journal of biological chemistry 64 16754664
2012 Anti-inflammatory role of the cAMP effectors Epac and PKA: implications in chronic obstructive pulmonary disease. PloS one 61 22363678
2020 Stimulation of GLP-1 Receptor Inhibits Methylglyoxal-Induced Mitochondrial Dysfunctions in H9c2 Cardiomyoblasts: Potential Role of Epac/PI3K/Akt Pathway. Frontiers in pharmacology 60 32547400
2015 Epac is required for GLP-1R-mediated inhibition of oxidative stress and apoptosis in cardiomyocytes. Molecular endocrinology (Baltimore, Md.) 60 25719403
2013 Adiponectin attenuates angiotensin II-induced oxidative stress in renal tubular cells through AMPK and cAMP-Epac signal transduction pathways. American journal of physiology. Renal physiology 60 23535586
2014 Involvement of cAMP/EPAC/TRPM2 activation in glucose- and incretin-induced insulin secretion. Diabetes 59 24824430
2013 Cyclic AMP sensor EPAC proteins and energy homeostasis. Trends in endocrinology and metabolism: TEM 59 24231725
2017 The EPAC-Rap1 pathway prevents and reverses cytokine-induced retinal vascular permeability. The Journal of biological chemistry 58 29158262
2017 β-Adrenergic induced SR Ca2+ leak is mediated by an Epac-NOS pathway. Journal of molecular and cellular cardiology 57 28476660
2010 Epac activation induces histone deacetylase nuclear export via a Ras-dependent signalling pathway. Cellular signalling 55 20576488
2018 PDE/cAMP/Epac/C/EBP-β Signaling Cascade Regulates Mitochondria Biogenesis of Tubular Epithelial Cells in Renal Fibrosis. Antioxidants & redox signaling 53 29216750
2017 Experimental Lung Injury Reduces Krüppel-like Factor 2 to Increase Endothelial Permeability via Regulation of RAPGEF3-Rac1 Signaling. American journal of respiratory and critical care medicine 52 27855271
2007 Anthrax edema toxin inhibits endothelial cell chemotaxis via Epac and Rap1. The Journal of biological chemistry 52 17491018
2009 Epac inhibits migration and proliferation of human prostate carcinoma cells. British journal of cancer 51 19920825
2015 Exchange protein directly activated by cAMP encoded by the mammalian rapgef3 gene: Structure, function and therapeutics. Gene 50 26119090
2006 Differential and brain region-specific regulation of Rap-1 and Epac in depressed suicide victims. Archives of general psychiatry 50 16754837
2008 A novel Epac-Rap-PP2A signaling module controls cAMP-dependent Akt regulation. The Journal of biological chemistry 48 18550542
2019 Role of PI3K/Akt and MEK/ERK Signalling in cAMP/Epac-Mediated Endothelial Barrier Stabilisation. Frontiers in physiology 47 31787905
2009 Involvement of cAMP/Epac/PI3K-dependent pathway in the antiproteolytic effect of epinephrine on rat skeletal muscle. Molecular and cellular endocrinology 46 19804812
2016 The role of Epac in the heart. Cellular and molecular life sciences : CMLS 45 27549789
2015 Spinal 5-HT7 receptors induce phrenic motor facilitation via EPAC-mTORC1 signaling. Journal of neurophysiology 44 26269554
2016 Kv7 Channel Activation Underpins EPAC-Dependent Relaxations of Rat Arteries. Arteriosclerosis, thrombosis, and vascular biology 42 27789473
2019 Exchange protein activated by cyclic-adenosine monophosphate (Epac) regulates atrial fibroblast function and controls cardiac remodelling. Cardiovascular research 41 30016400
2013 Exchange protein activated by cAMP (Epac) induces vascular relaxation by activating Ca2+-sensitive K+ channels in rat mesenteric artery. The Journal of physiology 41 23959673
2012 Distinct PKA and Epac compartmentalization in airway function and plasticity. Pharmacology & therapeutics 41 23089371
2011 Epac-Rap signaling reduces cellular stress and ischemia-induced kidney failure. Journal of the American Society of Nephrology : JASN 41 21493776
2009 Epac increases melanoma cell migration by a heparan sulfate-related mechanism. American journal of physiology. Cell physiology 41 19657062
2015 Proarrhythmic effect of sustained EPAC activation on TRPC3/4 in rat ventricular cardiomyocytes. Journal of molecular and cellular cardiology 39 26219954
2018 Protective Effect of Quercetin in LPS-Induced Murine Acute Lung Injury Mediated by cAMP-Epac Pathway. Inflammation 38 29569077
2017 Endogenous prostaglandin E2 amplifies IL-33 production by macrophages through an E prostanoid (EP)2/EP4-cAMP-EPAC-dependent pathway. The Journal of biological chemistry 38 28341741
2014 PKA and Epac activation mediates cAMP-induced vasorelaxation by increasing endothelial NO production. Vascular pharmacology 38 24469067
2013 Regulatory T-cells and cAMP suppress effector T-cells independently of PKA-CREM/ICER: a potential role for Epac. The Biochemical journal 38 24007532
2018 Phoenixin-14 stimulates differentiation of 3T3-L1 preadipocytes via cAMP/Epac-dependent mechanism. Biochimica et biophysica acta. Molecular and cell biology of lipids 37 30251651
2015 The signaling module cAMP/Epac/Rap1/PLCε/IP3 mobilizes acrosomal calcium during sperm exocytosis. Biochimica et biophysica acta 37 26704387
2019 Adenosine Receptor Signaling Targets Both PKA and Epac Pathways to Polarize Dendritic Cells to a Suppressive Phenotype. Journal of immunology (Baltimore, Md. : 1950) 35 31722989
2016 Epac-protein kinase C alpha signaling in purinergic P2X3R-mediated hyperalgesia after inflammation. Pain 35 26963850
2013 Recent advances in the discovery of small molecules targeting exchange proteins directly activated by cAMP (EPAC). Journal of medicinal chemistry 35 24256330
2012 The Epac-Rap1 signaling pathway controls cAMP-mediated exocytosis of Weibel-Palade bodies in endothelial cells. The Journal of biological chemistry 35 22511766
2011 Urocortins improve dystrophic skeletal muscle structure and function through both PKA- and Epac-dependent pathways. The American journal of pathology 35 22192627
2010 Crosstalk between PKA and Epac regulates the phenotypic maturation and function of human dendritic cells. Journal of immunology (Baltimore, Md. : 1950) 35 20729327
2009 Mechanism of Epac activation: structural and functional analyses of Epac2 hinge mutants with constitutive and reduced activities. The Journal of biological chemistry 35 19553663
2010 Possible role of the exchange protein directly activated by cyclic AMP (Epac) in the cyclic AMP-dependent functional differentiation and syncytialization of human placental BeWo cells. Human reproduction (Oxford, England) 34 20663796
2010 New perspectives in cyclic AMP-mediated axon growth and guidance: The emerging epoch of Epac. Brain research bulletin 34 20851749
2019 Methylglyoxal and a spinal TRPA1-AC1-Epac cascade facilitate pain in the db/db mouse model of type 2 diabetes. Neurobiology of disease 33 30807826
2021 Exendin-4 stimulates autophagy in pancreatic β-cells via the RAPGEF/EPAC-Ca2+-PPP3/calcineurin-TFEB axis. Autophagy 32 34338148
2020 The Role of Epac in Cancer Progression. International journal of molecular sciences 32 32899451
2013 Glucagon stimulates ghrelin secretion through the activation of MAPK and EPAC and potentiates the effect of norepinephrine. Endocrinology 32 23307791
2021 Epac: new emerging cAMP-binding protein. BMB reports 31 33298248
2018 Insights into exchange factor directly activated by cAMP (EPAC) as potential target for cancer treatment. Molecular and cellular biochemistry 31 29417338
2011 Guanine-nucleotide exchange factors (RAPGEF3/RAPGEF4) induce sperm membrane depolarization and acrosomal exocytosis in capacitated stallion sperm. Biology of reproduction 31 21471298
2004 Exchange protein directly activated by cAMP (EPAC) interacts with the light chain (LC) 2 of MAP1A. The Biochemical journal 30 15202935
2019 Laminin-driven Epac/Rap1 regulation of epithelial barriers on decellularized matrix. Acta biomaterialia 29 31593773
2018 Epac Function and cAMP Scaffolds in the Heart and Lung. Journal of cardiovascular development and disease 28 29401660
2014 Epac and the high affinity rolipram binding conformer of PDE4 modulate neurite outgrowth and myelination using an in vitro spinal cord injury model. British journal of pharmacology 28 24467222
2014 Hydrogen peroxide stimulation of CFTR reveals an Epac-mediated, soluble AC-dependent cAMP amplification pathway common to GPCR signalling. British journal of pharmacology 28 25220136
2023 Activation of the Epac/Rap1 signaling pathway alleviates blood-brain barrier disruption and brain damage following cerebral ischemia/reperfusion injury. International immunopharmacology 27 36931001
2017 The role of small GTPases and EPAC-Rap signaling in the regulation of the blood-brain and blood-retinal barriers. Tissue barriers 27 28632993
2015 Exchange Protein Directly Activated by cAMP (EPAC) Regulates Neuronal Polarization through Rap1B. The Journal of neuroscience : the official journal of the Society for Neuroscience 27 26269639
2015 EPAC activation inhibits acetaldehyde-induced activation and proliferation of hepatic stellate cell via Rap1. Canadian journal of physiology and pharmacology 27 26854595
2014 Possible roles of the cAMP-mediators EPAC and RAP1 in decidualization of rat uterus. Reproduction (Cambridge, England) 26 24586073
2014 Allosteric inhibition of Epac: computational modeling and experimental validation to identify allosteric sites and inhibitors. The Journal of biological chemistry 26 25183009