Ask about this productRelated genes to: RAPGEF3 Blocking Peptide
- Gene:
- RAPGEF3 NIH gene
- Name:
- Rap guanine nucleotide exchange factor 3
- Previous symbol:
- -
- Synonyms:
- cAMP-GEFI, EPAC, bcm910
- Chromosome:
- 12q13.11
- Locus Type:
- gene with protein product
- Date approved:
- 2004-03-01
- Date modifiied:
- 2016-10-05
Related products to: RAPGEF3 Blocking Peptide
Related articles to: RAPGEF3 Blocking Peptide
- Exchange protein directly activated by cAMP 1 (EPAC1) modulates Rap signaling and fibrosis. We report benzofuran oxoacetic acids as non-nucleotide EPAC1 agonists. Convergent synthesis delivered C2-diversified analogues (overall yields ≈ 3-7%). Fluorescent competition at isolated CNBDs mapped isoform engagement: several analogues favored EPAC1 (e.g., , , and ), favored EPAC2, and small C2 changes tuned bias. In cells, EPAC1-transfected U2OS assays showed significant Rap1-GTP increases for , and , with no activation in EPAC2 cells and no detectable protein kinase A activity. In disease-relevant contexts, the series attenuated IL-6/STAT3 signaling in human umbilical vascular endothelial cells and inhibited TGF-β1-induced fibroblast-to-myofibroblast transition (αSMA, Collagen I) with midmicromolar potencies; known drugs, and , remained more potent, yet nintedanib was markedly more cytotoxic. Across assays, some binding-phenotype disconnects emerged, plausibly reflecting exposure, signaling bias, and cell-context effects. Overall, benzofuran oxoacetic acids provide EPAC-pathway probes with a favorable tolerability window and scope for potency optimization as antifibrotics. - Source: PubMed
Publication date: 2026/03/14
Morgan DavidWiejak JolantaPowell Frederick GFitzpatrick ChiaraYarwood Stephen JBarker Graeme - BackgroundAcetyl tributyl citrate (ATBC), an eco-friendly plasticizer, exhibits poorly characterized neurotoxic effects.ObjectiveWe integrated network toxicology, machine learning, and molecular docking to elucidate molecular mechanisms underlying the link between ATBC exposure and Alzheimer's disease (AD) pathogenesis.MethodsPotential action targets of ATBC were screened from ChEMBL, TargetNet, and SwissTarget Prediction databases; disease-associated targets were derived from differential expression analysis of GEO datasets. Overlapping candidates underwent protein-protein interaction network construction (STRING) and subsequent Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Machine learning employing SHAP prioritized pivotal targets, while molecular docking and dynamics simulations validated binding affinities.ResultsWe identified 68 shared targets, of which five were designated as critical (CCKBR, RAF1, GABRG2, STS, RAPGEF3). GO enrichment revealed that ATBC compromises neuronal function and synaptic plasticity by perturbing glial cell differentiation, synaptic transmission, benzodiazepine receptor activity, and serine/threonine kinase activity. KEGG analysis implicated neuroactive ligand-receptor interactions, calcium, FoxO, and PI3K-Akt signaling pathways. Molecular simulations confirmed stable compound-target binding.ConclusionsThis integrative computational approach elucidates mechanisms underlying plasticizer-associated neurotoxicity in AD, establishing a framework for investigating neurological impacts of environmental contaminants. - Source: PubMed
Publication date: 2026/03/13
Peng TaoXu PeiliGuo XiaofangLin JianZhang MengfanLiu XinghuaYe JianglinLin Xingdong - This study investigated the effects of fluoxetine on noise-induced injuries to the cochlea and auditory nerve, with a focus on its impact on perineuronal nets (PNNs) and gene expression changes in the ventral cochlear nuclei (VCN). - Source: PubMed
Publication date: 2026/02/03
An Hyun-JuChoi SujinLee SoonchulYeo HyunjeongKim So Young - RAP guanine exchange factors (RAPGEF3/4) also known as EPAC1/2 (Exchange Protein Activated by cyclic AMP) are important signaling proteins. In cutaneous melanoma, we reported that loss of dependency on RAPGEF3/4 is associated with metastatic progression. Here, we investigated the molecular mechanisms underlying EPAC1/2 signaling in melanoma. Using transformed human melanocytes, chemical inhibition and genetic deletion of EPAC in mice, we show that EPAC activation is an early event in melanomagenesis and is required for the growth of transformed melanocytes and melanomagenesis . Query of the Cancer Genome Atlas (TCGA) and immunohistochemical analysis of melanoma tumors showed that low EPAC mRNA and RAP1-GTP protein correlate with better diseases free survival of patients with primary melanoma. RNAseq analysis of patient-matched primary and metastatic melanoma cells treated with EPAC inhibitor ESI-09 revealed that TXNIP, an important regulator of redox homeostasis, is a downstream effector of EPAC-RAP1 signaling. Our data also show that EPACs promote melanoma growth by regulation of redox homeostasis and mitochondrial reactive oxygen species through activation of mechanistic target of rapamycin complex 1 (mTORC1) that stabilizes hypoxia-inducible factor 1-alpha (HIF-1α), a transcriptional activator of TXNIP and glycolytic enzymes. Our data suggest that targeting mechanisms that metastatic melanoma cells employ to bypass EPAC dependency as a potential therapeutic approach for melanoma. - Source: PubMed
Publication date: 2025/12/29
Teertam Sireesh KumarSingh Mithalesh KAltameemi SarahGude SoniaRoy SushmitaRossman RyanNewton Michael ABennett Daniel DAhmad NihalCheng XiaodongSetaluri Vijayasaradhi - Ewing sarcoma (ES) is an aggressive bone malignancy with poor outcomes for chemotherapy-resistant patients, yet the mechanisms underlying vincristine resistance remain unclear. Here, we identify protein kinase inhibitor alpha (PKIA) as a critical driver of chemoresistance through cAMP-EPAC signaling reprogramming. Transcriptomic analysis of vincristine-resistant ES cells revealed PKIA upregulation, which correlated with poor survival in clinical cohorts (HR = 2.14, p < 0.001). Mechanistically, PKIA overexpression elevated intracellular cAMP levels but suppressed PKA activity, instead activating the noncanonical EPAC-Rap1-ERK pathway to promote drug efflux and survival. Pharmacological inhibition of EPAC with ESI-09 reversed resistance (IC~50~ reduction: 52%, p < 0.01), while PKIA knockdown restored vincristine sensitivity in xenografts. Strikingly, PKIA exhibited a dual role, with low expression in primary ES (potentially tumor-suppressive) and high expression in resistant/metastatic tumors (prosurvival), mirroring observations in prostate and hepatocellular cancers. Our work establishes PKIA as a therapeutic vulnerability and supports targeting the cAMP-EPAC axis to overcome chemoresistance in high-risk ES. - Source: PubMed
Publication date: 2025/11/28
Zhou XinYu YatingQiu HaoDeng Zhongliang