Affinage

RAPGEF3

Rap guanine nucleotide exchange factor 3 · UniProt O95398

Length
923 aa
Mass
103.8 kDa
Annotated
2026-06-10
100 papers in source corpus 46 papers cited in narrative 46 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RAPGEF3 (EPAC1) is a cAMP-activated guanine nucleotide exchange factor that couples receptor-driven cAMP elevation to activation of the small GTPases Rap1 and Rap2 in a PKA-independent manner, thereby serving as a parallel cAMP effector arm controlling adhesion, barrier function, secretion, and cell-type-specific transcriptional and Ca2+ programs (PMID:12402047, PMID:15319437). Direct cAMP binding to its regulatory domain relieves an autoinhibitory interaction with the catalytic domain — a conformational switch directly visualized in living cells by intramolecular FRET and abolished by cAMP-binding-dead mutants (PMID:15550931). EPAC1 signaling is spatially compartmentalized: subcellular-targeted reporters show faster activation at the plasma membrane than in cytosol or mitochondria (PMID:15545605), DEP-domain-dependent membrane targeting is required for Rap1 activation and mitogenesis (PMID:18063584), and EPAC1 is positioned by direct interactions with tubulin/microtubules and with MAP1A light chain 2 (PMID:16880999, PMID:15202935). Downstream of Rap, EPAC1 engages effector cascades including Rap2B–PLCε–Ca2+ to activate Ras/ERK (PMID:15319437), and controls integrin-α3β1-dependent adhesion and spreading (PMID:15302884). Through these modules it stabilizes endothelial and epithelial junctions — preserving VE-cadherin and tight junctions to limit vascular permeability (PMID:18178724, PMID:29158262) — and drives regulated exocytosis, including Weibel-Palade body release in endothelium (PMID:22511766) and the cAMP–Epac–Rap1–PLCε–IP3–Ca2+ cascade that mobilizes acrosomal calcium during sperm exocytosis (PMID:26704387). In cardiomyocytes EPAC1 activation produces hypertrophy and altered Ca2+ handling via Ras, Rac/calcineurin/NFAT, and CaMKII/PKC, increasing myofilament Ca2+ sensitivity and promoting arrhythmia, all independent of PKA (PMID:18323524, PMID:19666481, PMID:16269655). EPAC1 also exerts cell-type-specific control of survival and plasticity, transcriptionally upregulating the pro-apoptotic factor Bim in cortical neurons (PMID:20516079) and, in forebrain neurons, driving miR-124-mediated suppression of Zif268 to support LTP, spatial learning, and social behavior (PMID:22365550). In secretory and metabolic tissues EPAC1/EPAC2 activate TRPM2 cation channels to facilitate insulin secretion (PMID:24824430). Selective cAMP analogues and the EPAC antagonists ESI-09 and CE3F4 provide pharmacological tools that confirm its GEF activity and PKA independence (PMID:12402047, PMID:23139415, PMID:23066090).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2002 High

    Established that EPAC1 is a cAMP-activated GEF for Rap1 acting independently of PKA, defining a second cAMP effector arm distinct from the kinase pathway.

    Evidence Rational design of the PKA-sparing cAMP analogue 8CPT-2Me-cAMP with in vitro and cell-based Rap1/ERK activation assays

    PMID:12402047

    Open questions at the time
    • Did not resolve the structural mechanism of cAMP-dependent activation
    • Physiological receptor contexts not yet mapped
  2. 2004 High

    Defined the activation mechanism as a cAMP-induced relief of autoinhibition between regulatory and catalytic domains, and showed this activation is spatially compartmentalized within the cell.

    Evidence Intramolecular CFP-Epac1-YFP FRET sensors in live cells with binding-dead mutants and subcellular-targeted reporters

    PMID:15545605 PMID:15550931

    Open questions at the time
    • Identity of the scaffolds enforcing compartment-specific kinetics not fully defined
    • No atomic structure of the conformational transition
  3. 2004 High

    Connected EPAC1 to specific downstream physiology, linking Rap1 to integrin-α3β1 adhesion and Rap2B to a PLCε–Ca2+–Ras/ERK branch.

    Evidence Selective analogues, integrin-blocking antibodies, dominant-negative Rap1/Rap2B, and cAMP-binding-dead EPAC1 mutants in multiple cell lines

    PMID:15302884 PMID:15319437

    Open questions at the time
    • Whether Rap1 vs Rap2 selectivity is intrinsic or context-driven not resolved
    • Direct PLCε binding not demonstrated
  4. 2004 Medium

    Identified protein partners that spatially position EPAC1, showing localization is achieved through cytoskeletal and scaffold interactions.

    Evidence Yeast two-hybrid, reciprocal Co-IP, and GST domain-mapping pull-downs identifying MAP1A-LC2 binding via the cAMP-binding domain; microtubule/tubulin co-purification

    PMID:15202935 PMID:16880999

    Open questions at the time
    • Single-lab interactions without reciprocal validation across groups for tubulin
    • Functional impact of MAP1A-LC2 binding on signaling not quantified
  5. 2007 Medium

    Demonstrated that DEP-domain-dependent membrane targeting is functionally required for Rap1 activation and proliferative responses, establishing localization as obligatory for signaling output.

    Evidence DEP-deletion and dominant-negative constructs with Rap1 pull-down and thyroid mitogenesis assays

    PMID:18063584

    Open questions at the time
    • Membrane lipid/protein anchor recognized by the DEP domain not identified
    • Single-lab, single cell-type result
  6. 2008 High

    Defined EPAC1 as a major driver of cardiomyocyte hypertrophy and altered Ca2+ handling through Ras, calcineurin and CaMKII, dissociating these effects from both Rap1 and PKA.

    Evidence siRNA knockdown, dominant-negative Ras, calcineurin/CaMKII inhibitors, and aortic constriction in vivo with hypertrophic markers and Ca2+ imaging

    PMID:16269655 PMID:18323524 PMID:18600344

    Open questions at the time
    • How EPAC1 activates Ras independently of Rap not mechanistically resolved
    • Direct EPAC1-CaMKII coupling unclear
  7. 2008 Medium

    Showed EPAC1 modulates additional intracellular targets — Akt/PP2A complexes, nuclear DNA-PK, and barrier-junction proteins — placing it within survival, repair and permeability circuits.

    Evidence Co-IP of EPAC-Akt-PP2A complex with in-complex phosphatase assays; nuclear fractionation and DSB repair assays; intact microvessel permeability with VE-cadherin imaging

    PMID:18178724 PMID:18550542 PMID:18728186

    Open questions at the time
    • These complexes documented by single-lab Co-IP without reciprocal/structural validation
    • Mechanism of EPAC1 nuclear targeting not defined
  8. 2009 High

    Revealed cell-type-specific outcomes, including a developmental switch in growth-cone cAMP effector usage and pro-apoptotic Bim induction in neurons versus contractile remodeling in heart.

    Evidence FRET biosensors and turning assays in embryonic vs postnatal neurons; Epac1 knockout mice and Bim siRNA; permeabilized cardiomyocyte Ca2+-sensitivity assays

    PMID:18583150 PMID:19666481 PMID:20007468 PMID:20516079

    Open questions at the time
    • Molecular basis for cell-type-specific transcriptional outputs (e.g., Bim) not resolved
    • Determinants of Epac vs PKA developmental switch unknown
  9. 2012 Medium

    Linked EPAC1 to regulated secretion, phagosomal autophagy and neuronal plasticity, broadening its role in vesicle trafficking and gene-regulatory programs.

    Evidence siRNA/Rap1GAP for Weibel-Palade body exocytosis; phagosomal localization with calpain inhibitors for autophagy; forebrain knockout mice with miR-124/Zif268 rescue

    PMID:22365550 PMID:22511766 PMID:22654658

    Open questions at the time
    • How EPAC1 controls miR-124 transcription mechanistically unclear
    • Phagosomal recruitment mechanism not defined
  10. 2013 High

    Characterized EPAC1 in vascular tone and channel regulation, showing it activates Kv7, BKCa and ryanodine-receptor-coupled Ca2+ signaling to drive vasorelaxation.

    Evidence Myography, Ca2+ spark imaging, patch clamp, and proximity ligation assays linking Rap1a/Rap2 to Kv7.4 in mesenteric vessels

    PMID:19491242 PMID:23959673 PMID:27789473

    Open questions at the time
    • Vessel-bed specificity (mesenteric vs renal) mechanistically unexplained
    • Direct EPAC1-channel complexes not structurally defined
  11. 2015 High

    Reconstituted the full cAMP–Epac–Rap1–PLCε–IP3–Ca2+ module required for sperm acrosomal exocytosis, establishing EPAC1 in regulated calcium-dependent membrane fusion.

    Evidence TAT-cAMP sponge, Epac-selective analogue, dominant-negative Rap1, PLCε inhibition, and Ca2+/acrosome reaction assays; immunolocalization to the acrosome

    PMID:21471298 PMID:26704387

    Open questions at the time
    • Spatial organization of the cascade on the acrosomal membrane not resolved
    • Relative contributions of EPAC1 vs EPAC2 not fully separated
  12. 2021 Medium

    Extended EPAC1 into metabolic and disease-relevant signaling, regulating TRPM2-dependent insulin secretion, β-cell autophagy via calcineurin/TFEB, and anti-inflammatory/anti-fibrotic pathways in kidney and heart.

    Evidence TRPM2-knockout mice and patch clamp; siRNA with calcineurin inhibitors and TFEB; in vivo db/db and MI models with C/EBP-β/SOCS3/STAT3 and Smad3 dissection

    PMID:24824430 PMID:30016400 PMID:34103688 PMID:34338148

    Open questions at the time
    • Many disease pathways rest on single-lab in vivo models
    • Direct vs indirect engagement of TFEB and STAT3 circuits unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single cAMP-activated GEF achieves its highly cell-type- and compartment-specific outputs — selecting between Rap1, Rap2, Ras and non-canonical effectors — remains the central unresolved question.
  • No unifying model linking scaffold/localization choice to effector selection
  • Endogenous receptor-to-EPAC1 coupling specificity poorly mapped
  • Structural basis of effector discrimination unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3
Localization
GO:0005886 plasma membrane 3 GO:0005856 cytoskeleton 2 GO:0005634 nucleus 1 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-397014 Muscle contraction 2 R-HSA-5653656 Vesicle-mediated transport 2
Partners
ABCC8AKT1KCNQ4MAP1APPP2CARAP1ARAP2BTUBB

Evidence

Reading pass · 46 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) was developed that activates EPAC but not PKA, demonstrating that cAMP-induced Rap1 activation and ERK regulation are independent processes. Rational drug design of selective cAMP analogue; in vitro and in vivo activation assays; cell-based ERK activity assays with PKA/Ras/Rap1 inhibitors Nature cell biology High 12402047
2004 EPAC1 undergoes a cAMP-induced conformational change (relief of autoinhibitory interaction between regulatory and catalytic domains) detectable as a FRET change in a CFP-Epac-YFP fusion; this in vivo conformational change serves as the molecular basis for cAMP-dependent activation. FRET imaging in mammalian cells using CFP-Epac1-YFP fusion; cAMP-binding mutant abolishes response; comparison with PKA-based sensor EMBO reports High 15550931
2004 EPAC1 activation by cAMP occurs faster at the plasma membrane than in the cytoplasm or mitochondria; cAMP dynamics and effector activation are spatiotemporally compartmentalized in living cells. Targeted CFP-Epac1-YFP FRET reporters directed to plasma membrane, cytoplasm, mitochondria and nucleus; live-cell imaging with beta-adrenergic receptor stimulation Proceedings of the National Academy of Sciences of the United States of America High 15545605
2004 EPAC1 activates the cAMP-Epac-Rap1 pathway to regulate cell adhesion and spreading on laminin-5 specifically through the alpha3beta1 integrin, but not the alpha6beta4 integrin, in a PKA-independent manner. PKA-independent cAMP analogue stimulation; dominant-negative Rap1; integrin-blocking antibodies; adhesion and spreading assays in multiple cell lines The Journal of biological chemistry High 15302884
2004 EPAC1 signals via Rap2B to activate phospholipase C-epsilon (PLCε), increase intracellular Ca2+, and thereby activate H-Ras and ERK1/2 downstream of Gs-coupled receptors; a cAMP-binding-deficient EPAC1 mutant and dominant-negative Rap2B suppress this pathway. Dominant-negative and constitutively active Rap2B mutants; cAMP-binding-deficient EPAC1 mutant; Rap GTPase-activating protein II; Ca2+ measurements; ERK activity assays The Journal of biological chemistry High 15319437
2005 EPAC1 directly interacts with tubulin, co-purifies with cellular microtubules, and co-localizes with the mitotic spindle; association with microtubules suppresses EPAC-mediated Rap1 activation, while EPAC binding promotes microtubule formation. Co-purification with cellular microtubules; co-immunoprecipitation; co-localization (immunofluorescence); Rap1 activation assays in presence/absence of microtubule association Molecular bioSystems Medium 16880999
2005 EPAC1 activation induces cardiomyocyte hypertrophy through a Ca2+-dependent activation of Rac, calcineurin/NFAT signaling pathway; blockade of calcineurin or Rac blunts the hypertrophic response. Epac-selective cAMP analogue in primary cardiomyocytes; calcineurin inhibitor; dominant-negative Rac; NFAT reporter; hypertrophic marker expression Circulation research Medium 16269655
2004 EPAC1 interacts with the light chain 2 (LC2) of microtubule-associated protein MAP1A; the interaction is mediated by the cAMP-binding domain of EPAC1 (not the DEP or catalytic domains), and EPAC1 co-localizes with LC2 in the perinuclear region and filamentous structures. Yeast two-hybrid screen of brain libraries; co-immunoprecipitation in co-transfected HEK293 cells; GST pull-down with domain deletion mutants; immunolocalization The Biochemical journal Medium 15202935
2007 EPAC1-dependent subcellular localization via its DEP domain is required for cAMP-mediated Rap1 activation and thyroid-stimulating hormone-induced mitogenesis; disruption of DEP-dependent targeting abolishes Epac-Rap1 activation and cell proliferation. Dominant-negative EPAC mutant; DEP domain deletion constructs; thyroid cell proliferation/DNA synthesis assays; Rap1 activation (pull-down) assays The Journal of biological chemistry Medium 18063584
2008 EPAC1 induces cardiomyocyte hypertrophy via the small GTPase Ras and activates calcineurin and CaMKII in a Rap1-independent, PKA-independent manner downstream of beta-adrenergic receptor stimulation; Epac1 knockdown reduces beta-AR-induced hypertrophy. siRNA knockdown of Epac1; Epac-selective cAMP analogue; dominant-negative Ras; calcineurin/CaMKII inhibitors; Ras activation assays; hypertrophic marker expression in primary cardiomyocytes Circulation research High 18323524
2008 EPAC is coupled to Rap2 in the nucleus and mediates cAMP-dependent nuclear export and activation of DNA-PK; PKA provides an opposing (inhibitory) input. Spatially discrete PDE-dependent cAMP degradation systems modulate the balance between EPAC and PKA arms, influencing DNA double-strand break repair and PKB/Akt Ser-473 phosphorylation. Epac-selective and PKA-selective cAMP analogues; nuclear/cytoplasmic fractionation; DNA-PK activity assays; etoposide-induced DSB repair assays; PKB/Akt phosphorylation (Western blot) Proceedings of the National Academy of Sciences of the United States of America Medium 18728186
2008 EPAC1 forms a complex with Akt and PP2A; cAMP via both EPAC and PKA synergistically activates EPAC-associated PP2A phosphatase activity in a Rap1b-dependent manner, leading to Akt dephosphorylation and inhibition. Co-immunoprecipitation of EPAC-Akt-PP2A complex; dominant-negative EPAC and PP2A constructs; phosphatase activity assay; PKA- and EPAC-selective cAMP analogues; Akt phosphorylation assays The Journal of biological chemistry Medium 18550542
2008 EPAC activation in cardiomyocytes produces arrhythmias associated with altered Ca2+ homeostasis; the arrhythmogenic effect depends on CaMKII activity. Langendorff-perfused hearts with Epac-selective analogue; monophasic action potential recordings; CaMKII inhibitor KN-93; fluorescence Ca2+ imaging of isolated ventricular myocytes Pflugers Archiv : European journal of physiology Medium 18600344
2008 EPAC1 activation promotes fibroblast migration via Rap1, but inhibits collagen synthesis in a Rap1-independent manner; TGF-β1 transcriptionally downregulates Epac1 expression, and overexpression of Epac1 inhibits TGF-β1-induced collagen synthesis. Epac-selective cAMP analogue; Rap1 knockdown; Epac1 overexpression and siRNA; collagen synthesis assay; migration assay; multiple fibroblast cell types Proceedings of the National Academy of Sciences of the United States of America Medium 18434542
2008 EPAC activation inhibits PAF-induced hyperpermeability in intact rat microvessels via stabilization of VE-cadherin at cell-cell junctions through the Epac/Rap1 pathway. Hydraulic conductivity measurement in rat venular microvessels; Epac-selective cAMP analogue; VE-cadherin immunofluorescence American journal of physiology. Heart and circulatory physiology Medium 18178724
2008 EPAC activation inhibits epithelial cell migration by slowing focal adhesion dynamics and inhibiting polarized membrane protrusion; these effects extend beyond integrin affinity modulation. HGF/TGFβ-induced migration assays; forced integrin activation controls; live-cell focal adhesion dynamics imaging; Rap activation assays Cellular signalling Medium 18346875
2009 EPAC1 exists in a complex with vascular KATP channel subunits and inhibits KATP channel activity via a Ca2+-dependent mechanism requiring calcineurin (PP-2B) activation; this is PKA-independent. Co-immunoprecipitation of EPAC with KATP subunits; whole-cell patch clamp; Ca2+ imaging (Fura-2); calcineurin inhibitors cyclosporin A and ascomycin; BAPTA chelation The Journal of physiology Medium 19491242
2009 EPAC1 promotes DRG neurite outgrowth and mediates growth cone attraction to cAMP, netrin-1, and MAG gradients in embryonic neurons; siRNA knockdown of EPAC reduces outgrowth and prevents cAMP-dependent neurite regeneration on spinal cord tissue. Epac-selective cAMP analogue; siRNA knockdown; DRG neurite outgrowth assays; growth cone turning assays; spinal cord tissue substrate assays Molecular and cellular neurosciences Medium 18583150
2009 Embryonic growth cone attraction to cAMP, netrin-1, and MAG gradients is mediated by Epac, whereas repulsion in adult growth cones is mediated by PKA; FRET demonstrates netrin-1 activates Epac in embryonic but PKA in postnatal neurons, revealing a developmental switch in cAMP effector usage. FRET-based Epac and PKA biosensors in live neurons; growth cone turning assays with selective analogues; siRNA knockdown The Journal of neuroscience : the official journal of the Society for Neuroscience High 20007468
2009 EPAC1 activation increases cardiac myofilament Ca2+ sensitivity and phosphorylation of cardiac Troponin I and Myosin Binding Protein-C via PKC and CaMKII (not PKA); EPAC reduces Ca2+ transient amplitude while increasing cell shortening. Epac-selective cAMP analogue; constitutively active Epac in vivo infection; permeabilized cardiomyocyte Ca2+ sensitivity assay; PKC and CaMKII inhibitors; phosphoprotein detection Proceedings of the National Academy of Sciences of the United States of America High 19666481
2009 EPAC1 activation triggers apoptosis specifically in cortical neurons (not cardiomyocytes) by transcriptionally upregulating Bim; EPAC1 knockout mice show reduced neuronal apoptosis in a 3-nitropropionic acid model. Epac-selective agonist; Epac1 genetic knockout mice; Bim siRNA knockdown; TUNEL and DNA fragmentation assays; qRT-PCR for Bim The Journal of biological chemistry High 20516079
2009 EPAC activation via the Epac/PI3K pathway promotes Akt and Foxo3a phosphorylation in skeletal muscle, mediating the antiproteolytic effect of epinephrine independently of PKA. Epac-selective cAMP analogue in isolated EDL muscles; PI3K inhibitor wortmannin; PKA agonist and inhibitor H89; Akt/Foxo3a phosphorylation (Western blot); proteolysis rate measurement Molecular and cellular endocrinology Medium 19804812
2010 EPAC and PKA synergize via a Rap1-independent mechanism to mediate cAMP-induced growth arrest in vascular smooth muscle cells; neither pathway alone is sufficient, and Rap1 inhibition does not negate the combined effect. Selective PKA and Epac cAMP analogues; constitutively active Epac; Rap1GAP overexpression; Rap1 siRNA; Rb phosphorylation; BrdU incorporation; ERK/JNK phosphorylation Journal of molecular and cellular cardiology Medium 20971121
2011 Taurocholate stimulates hepatocyte polarization and bile canalicular network formation through a cAMP-Epac-MEK-Rap1-LKB1-AMPK signaling cascade; inhibition of Epac, Rap1, or MEK blocks the effect. Rat hepatocyte sandwich cultures; adenylyl cyclase inhibitor; Epac-selective analogue; Rap1 and MEK inhibitors; kinase activation assays (LKB1, AMPK) Proceedings of the National Academy of Sciences of the United States of America Medium 21220320
2011 EPAC/Rap1 pharmacological activation preserves tubular epithelial cell adhesion and barrier function during hypoxia in vitro and reduces renal failure in an ischemia-reperfusion mouse model in vivo. Epac-selective cAMP analogue (8-pCPT-2'-O-Me-cAMP); mouse IRI model; barrier function measurement; β-catenin and clusterin-α immunostaining Journal of the American Society of Nephrology : JASN Medium 21493776
2012 EPAC1 null mutation impairs LTP, spatial learning, and social interactions by promoting miR-124 transcription which suppresses Zif268 translation; knockdown of miR-124 restores Zif268 and reverses all EPAC-/- phenotypes. EPAC1/2 conditional forebrain knockout mice; LTP electrophysiology; behavioral tests; miR-124 knockdown and overexpression; Zif268 Western blot Neuron High 22365550
2012 EPAC1-mediated Rap1 activation and Akt phosphorylation are required for pancreatic cancer cell migration and invasion; ESI-09, a noncyclic nucleotide EPAC antagonist, blocks Epac-mediated Rap1 activation and Akt phosphorylation as well as insulin secretion. EPAC-specific inhibitor ESI-09; Rap1 activation assay; Akt phosphorylation (Western blot); migration and invasion assays; insulin secretion assay in β-cells Molecular pharmacology Medium 23066090
2012 EPAC1 coupled to Rap1 controls cAMP-dependent exocytosis of Weibel-Palade bodies (WPBs) in endothelial cells; siRNA knockdown of EPAC1 abolishes epinephrine-induced Rap1 activation and reduces WPB exocytosis. siRNA knockdown of EPAC1; Rap1 activation assay; Rap1GAP overexpression; WPB exocytosis assay (VWF release); epinephrine stimulation The Journal of biological chemistry Medium 22511766
2012 EPAC1 and Rap2b are recruited to the S. aureus-containing phagosome, and EPAC-Rap2b signaling through calpain activation regulates autophagic response to alpha-hemolysin in a PKA-independent manner. Immunofluorescence localization of EPAC and Rap2b to phagosomes; EPAC-selective analogue; calpain inhibitors; autophagy assays; siRNA knockdown PLoS pathogens Medium 22654658
2012 EPAC regulates SGLT expression and translocation to lipid rafts in renal proximal tubule cells via ERK, p38 MAPK, and NF-κB signaling, requiring caveolin-1 and F-actin organization. Epac-selective cAMP analogue; SGLT expression (Western blot); lipid raft fractionation; cytochalasin D (F-actin disruption); cav-1 siRNA; α-MG uptake assay Biochimica et biophysica acta Medium 22230192
2013 Increased glucose uptake activates RAP1 via EPAC (exchange protein directly activated by cAMP) through pyruvate kinase M2 (PKM2) interaction with soluble adenylyl cyclase, contributing to oncogenic signaling and loss of epithelial polarity in a 3D culture model. 3D mammary epithelial culture; GLUT3 overexpression; EPAC/RAP1 pathway inhibitors; PKM2 pulldown/interaction studies; soluble adenylyl cyclase inhibition The Journal of clinical investigation Medium 24316969
2013 EPAC1 inhibition by CE3F4 (a tetrahydroquinoline analog) blocks EPAC1 GEF activity toward Rap1 via an uncompetitive inhibition mechanism; the formyl group at position 1 and bromine at position 5 are essential for activity; CE3F4 does not compete for cAMP binding. Cell-free GEF activity fluorescence assay; intact cell Rap1 activation assay; PKA holoenzyme activity assay (negative); structure-activity relationship analysis; kinetics of inhibition The Journal of biological chemistry Medium 23139415
2014 EPAC activation inhibits VEGF- and TNF-α-induced retinal vascular permeability and inhibits VEGFR signaling through the Ras/MEK/ERK pathway; Rap1B knockdown or EPAC antagonist increases endothelial permeability, and GTP-bound Rap1 promotes tight junction assembly. EPAC-selective analogue and antagonist; siRNA knockdown of Rap1B; Ras/MEK/ERK signaling (Western blot); permeability assays in vitro and in vivo; tight junction immunostaining The Journal of biological chemistry Medium 29158262
2015 The cAMP-Epac-Rap1-PLCε-IP3 signaling module mobilizes intra-acrosomal calcium during sperm exocytosis; each step (cAMP, Epac, Rap1, PLCε) is required upstream of IP3-dependent calcium release from the acrosome. TAT-cAMP sponge to sequester cAMP; Epac-selective analogue; dominant-negative Rap1; PLCε inhibition; Rap1/Rab3/Rab27 GTP-loading assays; Ca2+ mobilization assay; acrosome reaction assay Biochimica et biophysica acta High 26704387
2016 EPAC-dependent vasorelaxation in mesenteric arteries occurs via activation of Kv7 channels; proximity ligation assay shows Kv7.4 co-localizes with Rap1a and Rap2 (EPAC downstream targets) upon isoproterenol stimulation specifically in mesenteric (not renal) arteries. Isometric tension recording; Kv7 channel inhibitor linopirdine; EPAC inhibitor; PKA inhibitor; proximity ligation assay for Kv7.4-AKAP and Kv7.4-Rap1a/Rap2 complexes; isolated myocytes Arteriosclerosis, thrombosis, and vascular biology Medium 27789473
2013 EPAC induces vascular relaxation in rat mesenteric arteries by increasing Ca2+ sparks from ryanodine receptors to activate BKCa channels in smooth muscle, and via endothelial SKCa/IKCa channels and NOS activation. Myography; iberiotoxin and apamin/TRAM-34 (K+ channel blockers); ryanodine; Ca2+ spark imaging (Fluo-4); NOS inhibitor L-NAME; endothelium denudation; patch clamp (STOCs and current clamp) The Journal of physiology High 23959673
2009 EPAC1 mediates melanoma cell migration and metastasis via translocation of syndecan-2 to lipid rafts (through Epac/PI3K/tubulin polymerization) and via increased NDST-1-dependent heparan sulfate production; EPAC overexpression enhances lung colonization in mice. siRNA knockdown; Epac overexpression; lipid raft fractionation; syndecan-2 translocation imaging; PI3K inhibitor; migration assay; NDST-1 expression and translation rate; mouse lung colonization model American journal of physiology. Cell physiology Medium 19657062
2007 Anthrax edema toxin (an adenylyl cyclase) inhibits endothelial cell chemotaxis through downstream EPAC activation and Rap1; EPAC or activated Rap1 alone reproduces cytoskeletal changes and chemotaxis block; ET also induces transcription of EPAC2 (RapGEF4) and MR-GEF/RapGEF5. Anthrax ET treatment of HMVECs; Epac-selective analogue; constitutively active Rap1; cytoskeletal staining; chemotaxis assay; transcriptional profiling The Journal of biological chemistry Medium 17491018
2011 RAPGEF3 (EPAC1) localizes to the acrosome and subacrosomal ring in equine sperm; activation of RAPGEF3/RAPGEF4 induces acrosomal exocytosis in capacitated sperm and prevents membrane hyperpolarization during capacitation, supporting a role in Ca2+-dependent acrosome reaction via membrane depolarization. Indirect immunofluorescence localization; Epac-selective cAMP analogue stimulation; acrosomal exocytosis quantification; sperm membrane potential measurement Biology of reproduction Medium 21471298
2017 hCG activates Erk1/2 in human endometrial stromal cells through the cAMP/EPAC pathway (not PKA, PKC, or PI3K); EPAC inhibition and siRNA knockdown prevent hCG-induced Erk1/2 phosphorylation and subsequent progesterone receptor upregulation. EPAC inhibitor; siRNA knockdown of EPAC; pathway inhibitors (PKA, PKC, PI3K); pErk1/2 Western blot; PR expression by immunofluorescence and qRT-PCR; primary human ESC cultures Molecular human reproduction Medium 28333280
2016 EPAC-PKCα signaling mediates Epac-dependent sensitization of P2X3 receptors in DRG neurons after inflammation; PKCα is downstream of EPAC and mediates enhancement of P2X3R-dependent hyperalgesia via a distinct translocation pattern from PKCε. Epac agonist CPT; EPAC antagonists; classical PKC inhibitor Go6976; PKCα-siRNA; P2X3R current recordings; behavioral hyperalgesia assays; pPKCα immunostaining Pain Medium 26963850
2018 EPAC activation drives inflammation-induced sensitization of TRPV1 in DRG neurons via PKCα and PKCε; EPAC agonist increases membrane TRPV1 expression and pPKCα levels; PKCα and PKCε inhibitors block EPAC-mediated TRPV1 potentiation. Epac agonist CPT; EPAC antagonists; PKCα/PKCε inhibitors; patch clamp of TRPV1 currents; behavioral nociception assays; TRPV1 and pPKC immunostaining and colocalization Pain Medium 30015706
2021 Exendin-4 stimulates autophagic flux in pancreatic β-cells through the RAPGEF3/EPAC1-calcium-PPP3/calcineurin-TFEB axis, independent of AMPK and MTOR; RAPGEF4/EPAC2 is the primary mediator of this pathway identified by siRNA knockdown. siRNA knockdown of RAPGEF3/RAPGEF4; calcineurin inhibitors; TFEB overexpression; autophagy flux assays; Ca2+ signaling measurements; db/db mouse in vivo model Autophagy Medium 34338148
2021 EPAC1 activation ameliorates tubulointerstitial inflammation in diabetic nephropathy through the C/EBP-β/SOCS3/STAT3 pathway; EPAC activation restores C/EBP-β, promotes its nuclear translocation, upregulates SOCS3, and inhibits STAT3 phosphorylation and MCP-1 expression. Epac-selective analogue in db/db mice and HK-2 cells; siRNA knockdown of C/EBP-β and SOCS3; SOCS3 overexpression; STAT3 phosphorylation (Western blot); macrophage migration assay Acta pharmacologica Sinica Medium 34103688
2019 EPAC1 expression in left atrial fibroblasts is suppressed by HF/norepinephrine (via α-AR/Smad3) and upregulated by β2-AR activation; Epac1 activation reduces collagen expression and LA fibrosis post-MI, whereas Epac1 loss increases fibroblast collagen production. Epac-selective activator and antagonist ESI-09; β-AR subtype-selective agonists/antagonists; Smad3 inhibitor SIS3; collagen expression assays; in vivo MI mouse model with Sp-8-pCPT treatment; echocardiography Cardiovascular research Medium 30016400
2014 EPAC activation in pancreatic β-cells activates TRPM2 nonselective cation channels (NSCC) through a PKA-independent cAMP/EPAC pathway to facilitate membrane depolarization and insulin secretion; TRPM2-deficient mice lack this NSCC activation. GLP-1/exendin-4/glucose stimulation; PKA inhibitors; EPAC-selective analogue; TRPM2-knockout mice; patch clamp recordings of NSCC Diabetes Medium 24824430

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 618 12402047
2006 Epac proteins: multi-purpose cAMP targets. Trends in biochemical sciences 438 17084085
2004 Fluorescent indicators of cAMP and Epac activation reveal differential dynamics of cAMP signaling within discrete subcellular compartments. Proceedings of the National Academy of Sciences of the United States of America 401 15545605
2010 Epac: defining a new mechanism for cAMP action. Annual review of pharmacology and toxicology 395 20055708
2004 Detecting cAMP-induced Epac activation by fluorescence resonance energy transfer: Epac as a novel cAMP indicator. EMBO reports 354 15550931
2004 Epac: A new cAMP-binding protein in support of glucagon-like peptide-1 receptor-mediated signal transduction in the pancreatic beta-cell. Diabetes 329 14693691
2008 Epac and PKA: a tale of two intracellular cAMP receptors. Acta biochimica et biophysica Sinica 306 18604457
2013 Exchange protein directly activated by cAMP (epac): a multidomain cAMP mediator in the regulation of diverse biological functions. Pharmacological reviews 229 23447132
2006 Cell physiology of cAMP sensor Epac. The Journal of physiology 218 16973695
2012 A novel EPAC-specific inhibitor suppresses pancreatic cancer cell migration and invasion. Molecular pharmacology 189 23066090
2018 Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development. Physiological reviews 180 29537337
2008 Epac mediates beta-adrenergic receptor-induced cardiomyocyte hypertrophy. Circulation research 179 18323524
2013 Increased sugar uptake promotes oncogenesis via EPAC/RAP1 and O-GlcNAc pathways. The Journal of clinical investigation 165 24316969
2005 cAMP-binding protein Epac induces cardiomyocyte hypertrophy. Circulation research 162 16269655
2012 EPAC null mutation impairs learning and social interactions via aberrant regulation of miR-124 and Zif268 translation. Neuron 159 22365550
2011 Activation of GPR4 by acidosis increases endothelial cell adhesion through the cAMP/Epac pathway. PloS one 149 22110680
2016 Cyclic AMP Sensor EPAC Proteins and Their Role in Cardiovascular Function and Disease. Circulation research 147 26941424
2012 cAMP and Epac in the regulation of tissue fibrosis. British journal of pharmacology 145 22233238
2007 Epac-selective cAMP analogs: new tools with which to evaluate the signal transduction properties of cAMP-regulated guanine nucleotide exchange factors. Cellular signalling 138 17716863
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 136 18434542
2009 The role of Epac proteins, novel cAMP mediators, in the regulation of immune, lung and neuronal function. British journal of pharmacology 129 19912228
2009 EPAC proteins transduce diverse cellular actions of cAMP. British journal of pharmacology 118 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
2008 Epac: effectors and biological functions. Naunyn-Schmiedeberg's archives of pharmacology 113 18176800
2022 cAMP Signaling in Cancer: A PKA-CREB and EPAC-Centric Approach. Cells 112 35805104
2008 EPAC and PKA allow cAMP dual control over DNA-PK nuclear translocation. Proceedings of the National Academy of Sciences of the United States of America 108 18728186
2004 The cAMP-Epac-Rap1 pathway regulates cell spreading and cell adhesion to laminin-5 through the alpha3beta1 integrin but not the alpha6beta4 integrin. The Journal of biological chemistry 106 15302884
2024 cAMP-PKA/EPAC signaling and cancer: the interplay in tumor microenvironment. Journal of hematology & oncology 105 38233872
2008 Epac mediates cyclic AMP-dependent axon growth, guidance and regeneration. Molecular and cellular neurosciences 105 18583150
2011 Rap-linked cAMP signaling Epac proteins: compartmentation, functioning and disease implications. Cellular signalling 102 21402149
2009 The cAMP effectors Epac and protein kinase a (PKA) are involved in the hepatic cystogenesis of an animal model of autosomal recessive polycystic kidney disease (ARPKD). Hepatology (Baltimore, Md.) 100 19065671
2004 Epac- and Ca2+ -controlled activation of Ras and extracellular signal-regulated kinases by Gs-coupled receptors. The Journal of biological chemistry 94 15319437
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
2008 Epac/Rap1 pathway regulates microvascular hyperpermeability induced by PAF in rat mesentery. American journal of physiology. Heart and circulatory physiology 79 18178724
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
2009 cAMP-dependent axon guidance is distinctly regulated by Epac and protein kinase A. The Journal of neuroscience : the official journal of the Society for Neuroscience 73 20007468
2007 Epac, in synergy with cAMP-dependent protein kinase (PKA), is required for cAMP-mediated mitogenesis. The Journal of biological chemistry 73 18063584
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 67 18600344
2009 Role of the cAMP-binding protein Epac in cardiovascular physiology and pathophysiology. Pflugers Archiv : European journal of physiology 63 19855995
2014 Involvement of cAMP/EPAC/TRPM2 activation in glucose- and incretin-induced insulin secretion. Diabetes 62 24824430
2015 Epac is required for GLP-1R-mediated inhibition of oxidative stress and apoptosis in cardiomyocytes. Molecular endocrinology (Baltimore, Md.) 60 25719403
2013 Cyclic AMP sensor EPAC proteins and energy homeostasis. Trends in endocrinology and metabolism: TEM 60 24231725
2017 The EPAC-Rap1 pathway prevents and reverses cytokine-induced retinal vascular permeability. The Journal of biological chemistry 58 29158262
2014 cAMP signalling in the vasculature: the role of Epac (exchange protein directly activated by cAMP). Biochemical Society transactions 57 24450633
2017 The cAMP effectors PKA and Epac activate endothelial NO synthase through PI3K/Akt pathway in human endothelial cells. Biochemical pharmacology 56 28912066
2018 PDE/cAMP/Epac/C/EBP-β Signaling Cascade Regulates Mitochondria Biogenesis of Tubular Epithelial Cells in Renal Fibrosis. Antioxidants & redox signaling 53 29216750
2009 Exchange protein activated by cAMP (Epac) mediates cAMP-dependent but protein kinase A-insensitive modulation of vascular ATP-sensitive potassium channels. The Journal of physiology 53 19491242
2015 Exchange protein directly activated by cAMP encoded by the mammalian rapgef3 gene: Structure, function and therapeutics. Gene 52 26119090
2009 Epac inhibits migration and proliferation of human prostate carcinoma cells. British journal of cancer 52 19920825
2007 Anthrax edema toxin inhibits endothelial cell chemotaxis via Epac and Rap1. The Journal of biological chemistry 52 17491018
2019 Role of PI3K/Akt and MEK/ERK Signalling in cAMP/Epac-Mediated Endothelial Barrier Stabilisation. Frontiers in physiology 51 31787905
2008 cAMP-induced Epac-Rap activation inhibits epithelial cell migration by modulating focal adhesion and leading edge dynamics. Cellular signalling 51 18346875
2006 Differential and brain region-specific regulation of Rap-1 and Epac in depressed suicide victims. Archives of general psychiatry 50 16754837
2012 Epac in cardiac calcium signaling. Journal of molecular and cellular cardiology 49 23220153
2007 Protein kinase A, not Epac, suppresses hedgehog activity and regulates glucocorticoid sensitivity in acute lymphoblastic leukemia cells. The Journal of biological chemistry 49 17895245
2005 Interplay between exchange protein directly activated by cAMP (Epac) and microtubule cytoskeleton. Molecular bioSystems 49 16880999
2008 A novel Epac-Rap-PP2A signaling module controls cAMP-dependent Akt regulation. The Journal of biological chemistry 48 18550542
2016 The role of Epac in the heart. Cellular and molecular life sciences : CMLS 46 27549789
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 Kv7 Channel Activation Underpins EPAC-Dependent Relaxations of Rat Arteries. Arteriosclerosis, thrombosis, and vascular biology 44 27789473
2012 cAMP and EPAC are key players in the regulation of the signal transduction pathway involved in the α-hemolysin autophagic response. PLoS pathogens 44 22654658
2007 Epac and the cardiovascular system. Current opinion in pharmacology 43 17276729
2011 Epac-Rap signaling reduces cellular stress and ischemia-induced kidney failure. Journal of the American Society of Nephrology : JASN 42 21493776
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
2009 Epac increases melanoma cell migration by a heparan sulfate-related mechanism. American journal of physiology. Cell physiology 41 19657062
2008 Renal expression of exchange protein directly activated by cAMP (Epac) 1 and 2. American journal of physiology. Renal physiology 41 18495799
2018 Phoenixin-14 stimulates differentiation of 3T3-L1 preadipocytes via cAMP/Epac-dependent mechanism. Biochimica et biophysica acta. Molecular and cell biology of lipids 39 30251651
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 39 28341741
2014 PKA and Epac activation mediates cAMP-induced vasorelaxation by increasing endothelial NO production. Vascular pharmacology 39 24469067
2015 The signaling module cAMP/Epac/Rap1/PLCε/IP3 mobilizes acrosomal calcium during sperm exocytosis. Biochimica et biophysica acta 38 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) 36 31722989
2014 Epac-Rap signaling reduces oxidative stress in the tubular epithelium. Journal of the American Society of Nephrology : JASN 36 24511123
2010 Crosstalk between PKA and Epac regulates the phenotypic maturation and function of human dendritic cells. Journal of immunology (Baltimore, Md. : 1950) 36 20729327
2017 hCG activates Epac-Erk1/2 signaling regulating Progesterone Receptor expression and function in human endometrial stromal cells. Molecular human reproduction 35 28333280
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
2020 The Role of Epac in Cancer Progression. International journal of molecular sciences 34 32899451
2020 Protein kinase A inhibitor proteins (PKIs) divert GPCR-Gαs-cAMP signaling toward EPAC and ERK activation and are involved in tumor growth. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 33 32830375
2021 Epac activation ameliorates tubulointerstitial inflammation in diabetic nephropathy. Acta pharmacologica Sinica 32 34103688
2021 Exendin-4 stimulates autophagy in pancreatic β-cells via the RAPGEF/EPAC-Ca2+-PPP3/calcineurin-TFEB axis. Autophagy 32 34338148
2018 Insights into exchange factor directly activated by cAMP (EPAC) as potential target for cancer treatment. Molecular and cellular biochemistry 32 29417338
2021 Epac: new emerging cAMP-binding protein. BMB reports 31 33298248
2012 Regulation of SGLT expression and localization through Epac/PKA-dependent caveolin-1 and F-actin activation in renal proximal tubule cells. Biochimica et biophysica acta 31 22230192
2011 Guanine-nucleotide exchange factors (RAPGEF3/RAPGEF4) induce sperm membrane depolarization and acrosomal exocytosis in capacitated stallion sperm. Biology of reproduction 31 21471298
2018 Inflammation induces Epac-protein kinase C alpha and epsilon signaling in TRPV1-mediated hyperalgesia. Pain 30 30015706
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
2017 Lithium and an EPAC-specific inhibitor ESI-09 synergistically suppress pancreatic cancer cell proliferation and survival. Acta biochimica et biophysica Sinica 28 28475672
2017 The role of small GTPases and EPAC-Rap signaling in the regulation of the blood-brain and blood-retinal barriers. Tissue barriers 28 28632993

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