Affinage

RAPGEF4

Rap guanine nucleotide exchange factor 4 · UniProt Q8WZA2

Length
1011 aa
Mass
115.5 kDa
Annotated
2026-06-10
50 papers in source corpus 27 papers cited in narrative 26 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RAPGEF4 (Epac2/cAMP-GEFII) is a direct cAMP sensor and guanine nucleotide exchange factor for Rap1 that drives a PKA-independent branch of cAMP signaling controlling regulated exocytosis and cellular morphology (PMID:11056535, PMID:26390815). In pancreatic beta-cells it nucleates a multiprotein exocytotic complex with Rim2, the Ca2+ sensor Piccolo, the KATP-channel subunit SUR1, and the L-type voltage-dependent Ca2+ channel (alpha1 1.2 subunit), integrating ATP, cAMP, and Ca2+ signals to potentiate incretin- and sulfonylurea-stimulated insulin secretion through a PKA-independent mechanism (PMID:11056535, PMID:11598134, PMID:12401793, PMID:14660679, PMID:22118705); cAMP binding inhibits its association with SUR1, regulating assembly of this complex (PMID:12601083, PMID:15561922). Its membrane localization depends on the N-terminal cAMP-binding domain A, and SNAP-25 engagement couples it to the rapidly releasable granule pool (PMID:19170062, PMID:19509185), while at the fusion site it recruits amisyn and dynamin-1 to restrict and slow fusion pore expansion (PMID:31099751). In neurons, RAPGEF4 is activated by neuroligin and drives Rap-dependent dendritic spine shrinkage, AMPA receptor removal, and synaptic depression, with autism-associated missense mutations altering its GEF activity and spine morphology (PMID:19734897); it is also required for electrophysiological maturation of primate prefrontal cortical neurons downstream of CHD8 (PMID:40398411, PMID:37398253). Beyond these roles it mediates a GLP-1R→Epac2→atrial natriuretic peptide axis in cardiomyocytes (PMID:23542788) and GLP-1R agonist-induced beta-cell autophagy via a Ca2+–calcineurin–TFEB pathway (PMID:34338148). RAPGEF4 acts as a negative regulator of endothelial migration and tubulogenesis (PMID:17491018, PMID:34593918).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 2000 High

    Established RAPGEF4 as a direct cAMP target that drives Ca2+-dependent exocytosis independently of PKA, defining a previously unrecognized branch of cAMP signaling.

    Evidence Co-IP/binding to Rim and Rim2 plus reconstituted exocytosis with PKA inhibitor controls

    PMID:11056535

    Open questions at the time
    • Direct Rap1 GEF activity not yet linked to the exocytotic readout here
    • Full effector complex not yet defined
  2. 2001 High

    Showed the cAMP-GEFII–Rim2 pathway operates in native beta-cells in parallel with PKA to mediate incretin-potentiated insulin secretion, quantifying the relative contribution of each arm.

    Evidence Antisense knockdown in pancreatic islets with H-89 combinatorial pharmacology

    PMID:11598134

    Open questions at the time
    • Antisense knockdown can have off-target effects
    • Molecular link between Rim2 binding and secretion not resolved
  3. 2001 High

    Demonstrated alternative promoter usage generates a liver-specific isoform lacking the first cAMP-binding and DEP domains yet retaining Rap1 GEF activity, separating catalytic activity from cAMP-sensing modules.

    Evidence cDNA cloning, expression mapping, and GEF activity assay

    PMID:11707077

    Open questions at the time
    • Physiological function of the liver isoform not established
    • Regulation of the truncated isoform unclear
  4. 2002 High

    Identified Piccolo as the Ca2+-sensing component of the cAMP-GEFII·Rim2 complex, explaining how Ca2+ dependence is conferred on cAMP-induced exocytosis.

    Evidence Co-IP, Ca2+-dependent dimerization assays, antisense knockdown with secretion readout

    PMID:12401793

    Open questions at the time
    • Stoichiometry of the complex not defined
    • Direct demonstration of Ca2+ sensing in vivo limited
  5. 2003 High

    Resolved the full beta-cell signaling complex (cAMP-GEFII, Rim2, Piccolo, SUR1, L-type VDCC) and the SUR1–NBF1 interaction, showing how ATP, cAMP, and Ca2+ signals are physically integrated at the exocytotic site.

    Evidence Co-IP, immunolocalization, SUR1-knockout electrophysiology, dominant-negative Rim2

    PMID:12601083 PMID:14660679

    Open questions at the time
    • Spatial organization of the complex at single-granule resolution unresolved
    • Mechanism of cAMP-dependent Cl- influx incompletely defined
  6. 2004 Medium

    Demonstrated cAMP regulates the assembly state of the KATP/cAMP-GEFII/Piccolo/VDCC complex, providing a switch mechanism whereby cAMP binding releases RAPGEF4 from SUR1.

    Evidence Co-IP and pull-down with 8-bromo-cAMP and ATP perturbations

    PMID:15561922

    Open questions at the time
    • Biochemical assays only; in-cell dynamics of assembly not shown
    • Single lab
  7. 2003 Medium

    Linked RAPGEF4 to GLP-1-stimulated ryanodine receptor Ca2+ release and mitochondrial ATP synthesis, broadening its role beyond direct exocytic machinery to intracellular Ca2+ mobilization.

    Evidence Dominant-negative mutant and pharmacological inhibitors with mitochondrial ATP/Ca2+ imaging in MIN6 cells

    PMID:12410638

    Open questions at the time
    • Dominant-negative specificity not orthogonally confirmed
    • Single cell line and lab
  8. 2005 Medium

    Generalized the PKA-independent Epac2 exocytic arm to neuroendocrine melanotrophs and assigned it to a distinct kinetic component of secretion.

    Evidence Patch-clamp capacitance in pituitary slices with Epac- and PKA-selective agonists

    PMID:15994184

    Open questions at the time
    • Molecular effectors in melanotrophs not identified
    • Single lab
  9. 2009 High

    Mapped RAPGEF4 membrane targeting to cAMP-binding domain A and showed this localization is required for secretory function, explaining isoform-specific activity.

    Evidence Domain deletion/splice variant analysis, membrane-targeting rescue, secretion assays, KO mice

    PMID:19170062

    Open questions at the time
    • Membrane lipid/protein anchor for domain A not identified
  10. 2009 Medium

    Connected RAPGEF4 to the SNARE machinery via SNAP-25, defining its requirement for cAMP potentiation of the immediately releasable granule pool.

    Evidence Protein-binding assays plus capacitance measurements with truncated SNAP-25/BoNT/A in INS-1 cells

    PMID:19509185

    Open questions at the time
    • Direct vs Rim2-bridged SNAP-25 binding not resolved
    • Single lab
  11. 2009 High

    Defined a neuronal role: neuroligin-activated RAPGEF4 drives Rap-dependent spine shrinkage and synaptic depression, with autism mutations perturbing its GEF activity and synaptic output.

    Evidence Activation/inhibition in cortical neurons, spine imaging, electrophysiology, neuroligin Co-IP, mutant GEF assays

    PMID:19734897

    Open questions at the time
    • Rap effectors mediating spine remodeling not fully mapped
    • In vivo behavioral consequence of mutants not tested here
  12. 2012 Medium

    Established that sulfonylureas (except gliclazide) act partly through Epac2/Rap1, defining RAPGEF4 as a pharmacological target of these drugs.

    Evidence Pharmacological comparison of sulfonylureas with Epac2/Rap1 activation assays

    PMID:22118705

    Open questions at the time
    • Review-level synthesis; direct binding mode of each drug to Epac2 not detailed
    • Single group
  13. 2013 High

    Extended RAPGEF4 to cardiac physiology, defining a GLP-1R→Epac2→ANP axis that lowers blood pressure.

    Evidence Membrane translocation imaging and multiple knockout mouse lines with ANP and vasorelaxation readouts

    PMID:23542788

    Open questions at the time
    • Rap effector coupling to ANP granule release in cardiomyocytes not detailed
  14. 2013 Medium

    Demonstrated a developmental/endocytic role for Rapgef4 downstream of Gnas/cAMP in renal proximal tubule growth and transport.

    Evidence Morpholino knockdown in Xenopus and agonist treatment with albumin uptake assays in human tubular cells

    PMID:23352791

    Open questions at the time
    • Downstream Rap effectors in tubular cells unidentified
    • Morpholino off-target effects
  15. 2014 Medium

    Identified an EPAC2→CALR→LIF/PTGS2 axis in endometrial gland epithelium, expanding RAPGEF4 to reproductive tissue gene regulation.

    Evidence siRNA knockdown of EPAC2 and CALR with selective cAMP analogs and senescence assays

    PMID:25378661

    Open questions at the time
    • Mechanism linking EPAC2 to CALR expression unknown
    • Single lab
  16. 2015 Medium

    Provided structural basis for cAMP-induced activation, showing dynamic conformational changes accompany cAMP sensing and Rap GEF activity.

    Evidence Crystallographic analysis (review synthesizing prior structures)

    PMID:26390815

    Open questions at the time
    • Structures of full effector complex not resolved
    • Review format
  17. 2015 Medium

    Showed adenylyl-cyclase isoform selectivity (AC6 not AC7) routes PACAP-driven cAMP to Epac2/p38 signaling, illustrating compartmentalized cAMP signaling through RAPGEF4.

    Evidence shRNA knockdown of AC6/AC7 with phospho-p38 readout and cholesterol depletion in PC12 cells

    PMID:25769305

    Open questions at the time
    • Direct Epac2-p38 coupling mechanism not defined
    • Single lab
  18. 2016 Medium

    Implicated RAPGEF4 in mood regulation and hippocampal neurogenesis via knockout behavioral phenotypes rescuable by SSRI.

    Evidence Epac2-knockout mouse behavioral tests, neurogenesis assay, fluoxetine treatment

    PMID:27598965

    Open questions at the time
    • Molecular pathway linking Epac2 to neurogenesis unresolved
    • Single lab
  19. 2019 High

    Defined a fusion-pore-restricting function: RAPGEF4 acutely recruits amisyn and dynamin-1 to slow pore expansion, revealing control of the kinetics of granule cargo release.

    Evidence TIRF imaging of fusion pore dynamics in Rapgef4-/- mice with effector recruitment imaging and pharmacology

    PMID:31099751

    Open questions at the time
    • Whether Rap1 GEF activity is required for recruitment not resolved
    • Direct binding of Epac2 to amisyn/dynamin-1 not biochemically mapped
  20. 2021 Medium

    Established a RAPGEF4→Ca2+→calcineurin→TFEB axis driving exendin-4-induced autophagy and beta-cell survival, linking RAPGEF4 to cytoprotective transcriptional programs.

    Evidence siRNA knockdown in INS-1E cells and human islets, TFEB overexpression, db/db mouse exendin-4 treatment

    PMID:34338148

    Open questions at the time
    • Step linking Rap1 activation to calcineurin not defined
    • Single lab
  21. 2021 Medium

    Identified EPAC2 as a negative regulator of endothelial tube formation and migration, consistent with its earlier anti-chemotactic role.

    Evidence Reciprocal overexpression and siRNA in HMVECs with Matrigel and migration assays

    PMID:34593918

    Open questions at the time
    • Cytoskeletal effector pathway not fully mapped
    • Single lab
  22. 2025 High

    Placed RAPGEF4 downstream of CHD8 as required for primate prefrontal cortical neuron electrophysiological maturation, demonstrated by knockdown and rescue.

    Evidence Patch-seq, single-nucleus multiomics, CHD8 knockdown and RAPGEF4 restoration in macaque and human organotypic slices

    PMID:37398253 PMID:40398411

    Open questions at the time
    • Molecular targets driving membrane potential/Na+ current changes not identified
    • Whether GEF activity mediates maturation untested
  23. 2025 Medium

    Showed hepatic EPAC2 is dispensable for the GCGR→GNAS→PKA liver-alpha-cell loop, sharpening the boundary between PKA-dependent and Epac2-dependent cAMP responses.

    Evidence siRNA/ASO knockdown of GCGR/GNAS/PKA/EPAC2 in mouse liver with metabolic readouts (negative result for EPAC2)

    PMID:40095004

    Open questions at the time
    • Negative result; possible compensation or incomplete knockdown not excluded
    • Single lab
  24. 2026 Medium

    Identified EPAC2 upregulation in fragile X model cortex and showed pharmacological antagonism rescues circuit and behavioral phenotypes, nominating it as a therapeutic target.

    Evidence Cell-type-specific translatomics, EPAC2 antagonist treatment in Fmr1-KO mice, circuit electrophysiology and behavior

    PMID:42155452

    Open questions at the time
    • Mechanism linking EPAC2 upregulation to circuit dysfunction not defined
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RAPGEF4 GEF/Rap1 activity is mechanistically partitioned among its many tissue-specific outputs (exocytosis, fusion-pore control, spine remodeling, autophagy, neuronal maturation) remains unresolved.
  • No unified model linking Rap1 effector choice to distinct cellular outputs
  • Structures of full physiological effector complexes not solved
  • Whether catalytic GEF activity is required for all phenotypes not systematically tested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0060089 molecular transducer activity 2 GO:0140299 molecular sensor activity 2
Localization
GO:0005886 plasma membrane 3 GO:0005829 cytosol 1
Pathway
R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-162582 Signal Transduction 2 R-HSA-9612973 Autophagy 1
Partners
ABCC8CACNA1CDNM1NLGN1PCLORIMS2SNAP25
Complex memberships
cAMP-GEFII·Rim2·Piccolo·SUR1·L-type VDCC exocytotic complex

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 cAMP-GEFII (RAPGEF4) directly binds to Rim (Rab3-interacting molecule) and a new isoform Rim2, and mediates cAMP-induced, Ca2+-dependent exocytosis that is not blocked by PKA inhibitors, establishing it as a direct cAMP target in regulated exocytosis via a PKA-independent mechanism. Co-immunoprecipitation/binding assays, reconstituted exocytosis system, PKA inhibitor pharmacology Nature cell biology High 11056535
2001 The cAMP-GEFII–Rim2 pathway mediates PKA-independent incretin-potentiated insulin secretion in native pancreatic beta-cells; antisense knockdown of cAMP-GEFII alone inhibited incretin-potentiated secretion ~50%, and combined with PKA inhibitor H-89 inhibited ~80–90%, demonstrating both pathways act in parallel. Antisense oligodeoxynucleotide knockdown in pancreatic islets, insulin secretion assays, PKA inhibitor (H-89) pharmacology The Journal of biological chemistry High 11598134
2001 The EPAC2/cAMP-GEFII gene encodes a liver-specific isoform (79 kDa) initiated from exon 10, lacking the first cAMP-binding domain and DEP domain, that retains GEF activity toward Rap1, demonstrating alternative promoter usage creates functionally distinct isoforms. cDNA cloning, primer extension, RT-PCR, in situ hybridization, immunoblot, GEF activity assay Genomics High 11707077
2002 cAMP-GEFII forms a complex with Rim2 and Piccolo; Piccolo acts as a Ca2+-sensor by forming Ca2+-dependent homodimers and heterodimers with Rim2, and antisense knockdown of Piccolo inhibits cAMP analog-induced insulin secretion, implicating the cAMP-GEFII·Rim2·Piccolo complex in cAMP-induced exocytosis. Co-immunoprecipitation, dimerization assays (Ca2+-dependent), antisense oligodeoxynucleotide knockdown in pancreatic islets, insulin secretion assay The Journal of biological chemistry High 12401793
2003 SUR1 (sulfonylurea receptor 1, a subunit of the KATP channel) physically interacts with cAMP-GEFII through its nucleotide-binding fold 1 (NBF1); this interaction is decreased by high concentrations of cAMP. SUR1-deficient beta-cells completely lack the PKA-independent component of cAMP-stimulated exocytosis, and this defect is associated with impaired cAMP-dependent Cl- influx into granules required for granule priming. Co-immunoprecipitation, antisense knockdown, capacitance measurements in SUR1-knockout mouse beta-cells, insulin release assays The Journal of general physiology High 12601083
2003 cAMP-GEFII mediates GLP-1-stimulated ryanodine receptor-dependent Ca2+ release from intracellular stores and subsequent mitochondrial ATP synthesis in MIN6 beta-cells; a dominant-negative form of cAMP-GEFII (G114E,G422D) blocked this xestospongin C-insensitive (RyR-mediated) component of [ATP]m increase. Dominant-negative mutant expression, pharmacological inhibitors (xestospongin C, ryanodine, H-89), mitochondrial ATP/Ca2+ imaging in MIN6 cells The Biochemical journal Medium 12410638
2003 cAMP-GEFII, Rim2, Piccolo, SUR1, and L-type VDCC (alpha1 1.2 subunit) form an integrated signaling complex in pancreatic beta-cells: SUR1 interacts with cAMP-GEFII via NBF1; Rim2 interacts with cAMP-GEFII and requires its Rab3-binding region for plasma membrane localization; Piccolo and Rim2 both bind directly to the VDCC alpha1 1.2 subunit. This complex integrates ATP, cAMP, and Ca2+ signals for insulin granule exocytosis. Co-immunoprecipitation, immunolocalization in MIN6 cells, dominant-negative Rim2 overexpression with exocytosis measurements The Journal of biological chemistry High 14660679
2004 SUR1, cAMP-GEFII, and Piccolo can form a trimeric complex; interaction of cAMP-GEFII with SUR1 is inhibited by 8-bromo-cAMP (but not by ATP), and this inhibition persists in the presence of ATP, indicating cAMP regulates the assembly state of the KATP/cAMP-GEFII/Piccolo/VDCC complex. Co-immunoprecipitation with cAMP analog treatments, pull-down assays Diabetes Medium 15561922
2005 In mouse melanotrophs, cAMP stimulates exocytosis through both PKA-dependent and Epac2/cAMP-GEFII-dependent pathways; the 8-pCPT-2Me-cAMP (Epac-selective agonist) specifically potentiated the linear (rapidly releasable) component of exocytosis, while PKA inhibition abolished the threshold component, demonstrating separable roles. Whole-cell patch-clamp capacitance measurements in pituitary tissue slices, pharmacological dissection with Epac-selective agonist, PKA inhibitors (H-89, Rp-cAMPS), and PKA-selective agonist (6-Phe-cAMP) The Journal of physiology Medium 15994184
2007 Anthrax edema toxin-generated cAMP inhibits endothelial cell chemotaxis via Epac2 (RAPGEF4) and its substrate Rap1; activated Epac or Rap1 induces cytoskeletal changes and blocks chemotaxis in human microvascular endothelial cells, and ET induces transcription of Epac2/RAPGEF4. Activated Epac/Rap1 overexpression, endothelial cell chemotaxis assays, cytoskeletal imaging The Journal of biological chemistry Medium 17491018
2009 The N-terminal cAMP-binding domain A of Epac2A is critical for its plasma membrane localization in MIN6 cells; Epac2B (a splice variant lacking this domain) localizes to the cytoplasm and fails to potentiate hormone secretion, whereas adding a membrane-targeting signal to Epac2B restores its secretory function. Immunocytochemistry, domain deletion/splice variant analysis, membrane-targeting signal fusion, insulin secretion assay in MIN6 cells, characterization of Epac2-knockout mice Journal of cellular physiology High 19170062
2009 Epac2 (RAPGEF4) activation in cortical neurons induces spine shrinkage, increases spine motility, removes GluR2/3-containing AMPA receptors from synapses, and depresses excitatory transmission; inhibition of Epac2 promotes spine enlargement and stabilization. Epac2 interaction with neuroligin promotes membrane recruitment and enhances its GEF activity. Autism-associated rare missense mutations in EPAC2 alter basal and neuroligin-stimulated GEF activity, dendritic Rap signaling, synaptic protein distribution, and spine morphology. Epac2 activation/inhibition in cultured rat cortical neurons, live imaging of spine dynamics, electrophysiology, GluR2 immunostaining, neuroligin co-immunoprecipitation, GEF activity assays for autism-associated mutants Nature neuroscience High 19734897
2009 SNAP-25 physically interacts with both cAMP-GEFII and RIM2; truncation of SNAP-25 C-terminus abolishes cAMP potentiation of rapid exocytosis from the immediately releasable pool (the cAMP-GEFII/PKA-independent pathway) in insulin-secreting cells, while reserve pool mobilization by cAMP is preserved. Capacitance measurements, protein-binding assays, Western blot, INS-1 cells overexpressing truncated SNAP-25 or BoNT/A American journal of physiology. Endocrinology and metabolism Medium 19509185
2012 Sulfonylureas (except gliclazide) activate Epac2/Rap1 signaling to promote insulin granule exocytosis; Epac2 is required for the full insulinotropic effect of sulfonylureas as well as for incretin-potentiated insulin secretion; gliclazide uniquely does not activate Epac2 and is specific to KATP channel inhibition. Pharmacological comparison of sulfonylureas, Epac2-dependent signaling assays, Rap1 activation assays Diabetes, obesity & metabolism Medium 22118705
2013 GLP-1 receptor activation promotes translocation of Epac2 (RAPGEF4) to the cardiomyocyte membrane; Epac2 deficiency eliminates GLP-1R-dependent stimulation of atrial natriuretic peptide (ANP) secretion from cardiac atria, establishing a GLP-1R→Epac2→ANP axis that reduces blood pressure. Epac2 membrane translocation imaging, Epac2-knockout mice (ANP secretion assays), conditioned medium aortic ring relaxation assay, GLP-1R-knockout and Nppa-knockout mice Nature medicine High 23542788
2013 In Xenopus pronephros, Rapgef4-dependent signaling downstream of Gnas/cAMP controls exo- and endocytosis and regulates proximal tubular growth; a Rapgef4-specific agonist in a human proximal tubular cell line increased albumin uptake and decreased secretion, phenocopying cholera toxin effects. Antisense morpholino knockdown in Xenopus embryos, pharmacological agonist/antagonist treatments, FITC-albumin uptake/secretion assays in human proximal tubular cells Developmental biology Medium 23352791
2014 EPAC2 (RAPGEF4) in endometrial glandular epithelial cells regulates calreticulin (CALR) protein and mRNA expression; EPAC2 or CALR knockdown suppresses PKA-agonist-induced LIF and COX2 (PTGS2) expression and PGE2 secretion, and increases cellular senescence markers, establishing an EPAC2→CALR→LIF/PTGS2 axis in endometrial gland function. siRNA knockdown of EPAC2 and CALR in EM1 cells, EPAC-selective and PKA-selective cAMP analogs, gene/protein expression analysis, senescence-associated beta-galactosidase assay Journal of molecular endocrinology Medium 25378661
2015 Crystallographic analysis of Epac2 revealed that cAMP-induced activation is accompanied by dynamic structural changes, and the protein functions as a direct cAMP sensor with GEF activity toward Rap. Crystallographic analysis (structural review synthesizing prior crystal structures) Gene Medium 26390815
2015 PACAP-38 activation of Epac2/Rapgef4 downstream signaling (p38 phosphorylation) requires AC6 but not AC7; this selectivity depends on the vicinal constraint of PAC1 receptor and AC6, while coupling of Epac2 to p38 determines how cAMP is parcellated to physiological responses in neuroendocrine PC12 cells. lentiviral shRNA knockdown of AC6 and AC7, PACAP-38 stimulation, phospho-p38 and phospho-CREB immunoblotting, methyl-beta-cyclodextrin cholesterol depletion Molecular pharmacology Medium 25769305
2016 Epac2-knockout mice exhibit anxiety, depression, learning and memory deficits, and impaired hippocampal cell proliferation; Prozac (fluoxetine, SSRI) treatment ameliorates these phenotypes in Epac2-/- mice, establishing Epac2 as a required component of cAMP/serotonin-dependent mood regulation and hippocampal neurogenesis. Epac2-knockout mouse behavioral tests (open field, fear conditioning), hippocampal cell proliferation assay, SSRI treatment 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 via GLP-1 receptor agonists or sulfonylureas restricts and slows fusion pore expansion and peptide release via this Epac2-dependent mechanism; this effect is absent in Epac2-/- (Rapgef4-/-) mice or upon Epac2 pharmacological inactivation. Total internal reflection fluorescence (TIRF) imaging of fusion pore dynamics, Epac2-/- (Rapgef4-/-) knockout mice, pharmacological Epac2 inactivation, Epac2 overexpression, amisyn/dynamin-1 recruitment imaging eLife High 31099751
2021 RAPGEF4/EPAC2 is essential for exendin-4-induced autophagic flux in pancreatic beta-cells via a RAPGEF4/EPAC2→Ca2+→PPP3/calcineurin→TFEB axis; knockdown of RAPGEF4 prevents exendin-4-mediated cell survival and autophagic flux, while TFEB overexpression mimics the cytoprotective effect. siRNA knockdown of RAPGEF4 in INS-1E cells and human islets, chemical inhibitors, TFEB overexpression, db/db mouse in vivo treatment with exendin-4, lysosomal marker analysis Autophagy Medium 34338148
2021 EPAC2 overexpression in human microvascular endothelial cells suppresses Matrigel-driven tubulogenesis, inhibits cell migration, and changes cell morphology to a round shape; EPAC2 knockdown enhances tube formation, migration, and produces elongated cells with filopodia-like protrusions, identifying EPAC2 as a negative regulator of endothelial tube formation. RAPGEF4 overexpression and siRNA knockdown in HMVECs, Matrigel tube formation assay, migration assay, morphological imaging Scientific reports Medium 34593918
2025 RAPGEF4 is required for proper electrophysiological maturation (resting membrane potential and inward sodium current) of neurons in the primate prefrontal cortex; CHD8 knockdown in human and macaque organotypic slices impairs neuronal maturation by downregulating RAPGEF4, and restoring RAPGEF4 expression rescues electrophysiological maturation in CHD8-deficient neurons. Patch-seq, single-nucleus multiomic analyses, shRNA knockdown of CHD8, RAPGEF4 restoration experiments in organotypic slices from macaque and human Neuron High 37398253 40398411
2025 Hepatic EPAC2 (RAPGEF4) knockdown does not affect hepatic amino acid catabolism gene suppression, hyperaminoacidemia, or alpha-cell hyperplasia caused by glucagon receptor (GCGR) blockade, indicating EPAC2 (unlike PKA) is not required for the liver-alpha-cell loop; the GCGR→GNAS→PKA pathway (not EPAC2) mediates hepatic amino acid catabolism. siRNA/ASO-mediated knockdown of GCGR, GNAS, PKA, and EPAC2 in mouse liver; measurement of plasma amino acids, hepatic amino acid catabolism genes, and alpha-cell mass Diabetes Medium 40095004
2026 Rapgef4/Epac2 is upregulated in cortical excitatory and inhibitory neurons of Fmr1-knockout (fragile X syndrome model) mice; treatment with a specific EPAC2 antagonist restored cortical circuit function and ameliorated multiple behavioral phenotypes in Fmr1 KO mice, identifying EPAC2 as a potential therapeutic target for fragile X syndrome. Cell-type-specific translatomic sequencing (Patch-seq), EPAC2 antagonist treatment in Fmr1-KO mice, cortical circuit electrophysiology, behavioral assays Neuron Medium 42155452

Source papers

Stage 0 corpus · 50 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 417 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 290 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 167 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 88 26295306
2009 Critical role of the N-terminal cyclic AMP-binding domain of Epac2 in its subcellular localization and function. Journal of cellular physiology 82 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
2018 Folic acid supplementation alters the DNA methylation profile and improves insulin resistance in high-fat-diet-fed mice. The Journal of nutritional biochemistry 53 29986310
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
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
2013 Signaling in sperm: toward a molecular understanding of the acquisition of sperm motility in the mouse epididymis. Biology of reproduction 39 24006282
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
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 36 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 22 37800580
2016 Role of EPAC in cAMP-Mediated Actions in Adrenocortical Cells. Frontiers in endocrinology 17 27379015
2025 Multimodal analyses reveal genes driving electrophysiological maturation of neurons in the primate prefrontal cortex. Neuron 12 40398411
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
2022 EPAC Regulates Melanoma Growth by Stimulating mTORC1 Signaling and Loss of EPAC Signaling Dependence Correlates with Melanoma Progression. Molecular cancer research : MCR 8 35834616
2020 EPAC2: A new and promising protein for glioma pathogenesis and therapy. Oncology reviews 8 32395202
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
2025 Hepatic PKA Mediates Liver and Pancreatic α-Cell Cross Talk. Diabetes 4 40095004
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
2025 Downregulation of FASN in granulosa cells and its impact on ovulatory dysfunction in PCOS. Journal of ovarian research 3 40170064
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 Breast Cancer-Secreted DPP3 Promotes Lung Metastasis by Remodelling the Vascular Niche in Lung via the Rap1 Signalling Pathway. Journal of extracellular vesicles 2 41311249
2026 Translatome profiling reveals opposing alterations in inhibitory and excitatory neurons of fragile X mice and identifies EPAC2 as a therapeutic target. Neuron 0 42155452
2026 Targeting dysregulated glycolysis in type 2 diabetic osteoporosis: Identification of a diagnostic gene signature and therapeutic validation of calcifediol. Life sciences 0 42184924
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

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