Alternative titles; symbols
HGNC Approved Gene Symbol: RAPGEF3
Cytogenetic location: 12q13.11 Genomic coordinates (GRCh38): 12:47,734,363-47,758,880 (from NCBI)
cAMP is a second messenger that induces a wide range of responses in different cell types, including activation of the RAS-related GTPase RAP1A (179520). By searching databases for proteins with cAMP-binding sites and homology to guanine nucleotide exchange factors (GEFs) for RAS (190020) and RAP1, followed by RT-PCR, de Rooij et al. (1998) isolated a cDNA encoding EPAC. Sequence analysis predicted that the 881-amino acid EPAC protein has a cAMP-binding site; a GEF homology domain; a RAS exchange motif, which may be important in GEF structure stabilization; and a DEP (dishevelled, egl10, pleckstrin) domain, which may be involved in membrane attachment. Northern blot analysis revealed ubiquitous expression of EPAC, with highest levels in kidney and heart. Binding analysis confirmed a direct interaction between EPAC and cAMP. Functional analysis showed that EPAC is a GEF for RAP1A that is directly regulated by cAMP.
Using differential display for brain-enriched genes related to signaling in striatum, and by screening for second messenger motifs, Kawasaki et al. (1998) obtained cDNAs encoding EPAC, which they called cAMP-GEFI, and cAMP-GEFII (RAPGEF4; 606058). Expression of cAMP-GEFI and cAMP-GEFII activated RAP1A after forskolin and 3-isobutyl-1-methylxanthine stimulation, independent of the protein kinase A (see 176911) pathway. cAMP-GEFI and cAMP-GEFII expression did not activate or only slightly activated other RAS superfamily members after stimulation. Mutational analysis determined that the cAMP-binding site of cAMP-GEFI is necessary for activation of RAP1A. Northern blot analysis detected wide expression of a predominant 4.0-kb cAMP-GEFI transcript in various tissues and brain regions. In situ hybridization analysis demonstrated broad, low-level expression of cAMP-GEFI in adult rat brain and selective expression in neonatal brain, including septum and thalamus.
Dodge-Kafka et al. (2005) identified a cAMP-responsive signaling complex maintained by the muscle-specific A-kinase anchoring protein (AKAP6; 604691) that includes PKA (188830), PDE4D3 (600129), and EPAC1. These intermolecular interactions facilitate the dissemination of distinct cAMP signals through each effector protein. Anchored PKA stimulates PDE4D3 to reduce local cAMP concentrations, whereas an mAKAP-associated ERK5 (602521) kinase module suppresses PDE4D3. PDE4D3 also functions as an adaptor protein that recruits EPAC1, an exchange factor for the small GTPase Rap1, to enable cAMP-dependent attenuation of ERK5. Pharmacologic and molecular manipulations of the mAKAP complex showed that anchored ERK5 can induce cardiomyocyte hypertrophy. Thus, Dodge-Kafka et al. (2005) concluded that 2 coupled cAMP-dependent feedback loops are coordinated within the context of the AKAP6 complex, suggesting that local control of cAMP signaling by AKAP proteins is more intricate than had been appreciated.
Hochbaum et al. (2008) found that thyroid-stimulating hormone (TSH; see 188540)-mediated activation of the G protein Rap1b (179530), a substrate for both Epac and PKA, was independent of PKA action. In thyroid cells, Epac and PKA acted synergistically in TSH or cAMP-mediated proliferation. Analysis with a dominant-negative Epac mutant further revealed that activation of Epac was required for TSH or cAMP-mediated mitogenesis in thyroid cells. Epac activity was strictly dependent on its proper compartmentalization, which was determined by its DEP domain. Disruption of the DEP-dependent subcellular targeting of Epac abolished cAMP-Epac-mediated Rap1 activation and THS-mediated cell proliferation. These results demonstrated that Epac, in addition to PKA, has a role in cAMP-stimulated cell proliferation.
Stumpf (2022) mapped the RAPGEF3 gene to chromosome 12q13.11 based on an alignment of the RAPGEF3 sequence (GenBank BC092404) with the genomic sequence (GRCh38).
Liu et al. (2020) found that cAMP/Epac1 pathway was activated and induced neurodegeneration in retinal ischemia-reperfusion (IR) injury in wildtype mice. Examination of downstream targets of Epac1 signaling after ischemic injury showed that Epac1 upregulation mediated retinal neuronal death after ischemic injury through apoptosis and necroptosis. Epac1 -/- mice were fertile and showed no obvious morphologic abnormalities, with normal retinal structure and normal retinal neuronal function. However, Epac1 deletion reduced both apoptotic and necroptotic cell death after IR injury in Epac1 -/- mice, and resulted in reduced retinal vascular inflammation and permeability following retinal ischemia. Epac1 functioned as a transducer of retinal neuronal death, and as a result, Epac1 deletion protected retinal ganglion cells (RGCs) from cell death in Epac1 -/- mice. Likewise, pharmacologic blocking of Epac1 in wildtype mice alleviated RGC injury after retinal ischemia and prevented retinal neurodegeneration. Epac1 in microglia/myeloid cells and astrocytes was dispensable for ischemic injury-induced retinal neurodegeneration and was not a major mediator of RGC death. In agreement, RGC-specific deletion of Epac1 in neurons alleviated RGC death after IR injury in mice, further indicating that Epac1 deficiency in RGCs was indeed responsible for their increased survival. Analysis of cultured primary RGCs revealed that Epac1 induced RGC death through CaMKII (614986). Analysis of a mouse microbead-induced glaucoma model further indicated that Epac1 plays a critical role in neurodegeneration during chronic glaucoma.
de Rooij, J., Zwartkruis, F. J. T., Verheijen, M. H. G., Cool, R. H., Nijman, S. M. B., Wittinghofer, A., Bos, J. L. Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP. Nature 396: 474-477, 1998. [PubMed: 9853756] [Full Text: https://doi.org/10.1038/24884]
Dodge-Kafka, K. L., Soughayer, J., Pare, G. C., Michel, J. J. C., Langeberg, L. K., Kapiloff, M. S., Scott, J. D. The protein kinase A anchoring protein mAKAP coordinates two integrated cAMP effector pathways. Nature 437: 574-578, 2005. [PubMed: 16177794] [Full Text: https://doi.org/10.1038/nature03966]
Hochbaum, D., Hong, K., Barila, G., Ribeiro-Neto, F., Altschuler, D. L. Epac, in synergy with cAMP-dependent protein kinase (PKA), is required for cAMP-mediated mitogenesis. J. Biol. Chem. 283: 4464-4468, 2008. [PubMed: 18063584] [Full Text: https://doi.org/10.1074/jbc.C700171200]
Kawasaki, H., Springett, G. M., Mochizuki, N., Toki, S., Nakaya, M., Matsuda, M., Housman, D. E., Graybiel, A. M. A family of cAMP-binding proteins that directly activate Rap1. Science 282: 2275-2279, 1998. [PubMed: 9856955] [Full Text: https://doi.org/10.1126/science.282.5397.2275]
Liu, W., Ha, Y., Xia, F., Zhu, S., Li, Y., Shi, S., Mei, F. C., Merkley, K., Vizzeri, G., Motamedi, M., Cheng, X., Liu, H., Zhang, W. Neuronal Epac1 mediates retinal neurodegeneration in mouse models of ocular hypertension. J. Exp. Med. 217: e20190930, 2020. [PubMed: 31918438] [Full Text: https://doi.org/10.1084/jem.20190930]
Stumpf, A. M. Personal Communication. Baltimore, Md. 04/01/2022.