RAPGEF3

Rap guanine nucleotide exchange factor 3 also known as exchange factor directly activated by cAMP 1 (EPAC1) or cAMP-regulated guanine nucleotide exchange factor I (cAMP-GEFI) is a protein that in humans is encoded by the RAPGEF3 gene.[5][6][7]

RAPGEF3
Identifiers
Aliases	RAPGEF3, CAMP-GEFI, EPAC, EPAC1, HSU79275, bcm910, Rap guanine nucleotide exchange factor 3
External IDs	OMIM: 606057 MGI: 2441741 HomoloGene: 21231 GeneCards: RAPGEF3
Gene location (Human) Chr. Chromosome 12 (human)[1] Band 12q13.11 Start 47,734,363 bp[1] End 47,771,040 bp[1]
Gene location (Mouse) Chr. Chromosome 15 (mouse)[2] Band 15|15 F1 Start 97,744,770 bp[2] End 97,767,972 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • nucleotide binding • protein domain specific binding • cAMP binding • GO:0001948 protein binding • Rap guanyl-nucleotide exchange factor activity • guanyl-nucleotide exchange factor activity Cellular component • filopodium • microvilli • cortical actin cytoskeleton • extracellular exosome • endomembrane system • lamellipodium • intracellular • membrane • cell membrane Biological process • establishment of endothelial barrier • regulation of actin cytoskeleton reorganization • GO:0007243 intracellular signal transduction • regulation of insulin secretion • small GTPase mediated signal transduction • Rap protein signal transduction • positive regulation of syncytium formation by plasma membrane fusion • regulation of histone H3-K9 acetylation • positive regulation of peptidyl-serine phosphorylation • positive regulation of angiogenesis • positive regulation of protein acetylation • positive regulation of protein export from nucleus • GO:0032320, GO:0032321, GO:0032855, GO:0043089, GO:0032854 positive regulation of GTPase activity • angiogenesis • cellular proliferation • cAMP-mediated signaling • positive regulation of stress fiber assembly • signal transduction • cellular response to cAMP • negative regulation of syncytium formation by plasma membrane fusion Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	10411	223864
Ensembl	ENSG00000079337	ENSMUSG00000022469
UniProt	O95398	Q8VCC8
RefSeq (mRNA)	NM_001098531 NM_001098532 NM_006105	NM_001177810 NM_001177811 NM_144850 NM_001357630
RefSeq (protein)	NP_001092001 NP_001092002 NP_006096	NP_001171281 NP_001171282 NP_659099 NP_001344559
Location (UCSC)	Chr 12: 47.73 – 47.77 Mb	Chr 15: 97.74 – 97.77 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

As the name suggests, EPAC proteins (EPAC1 and EPAC2) are a family of intracellular sensors for cAMP, and function as nucleotide exchange factors for the Rap subfamily of RAS-like small GTPases.

History and discovery

Since the landmark discovery of the prototypic second messenger cAMP in 1957, three families of eukaryotic cAMP receptors have been identified to mediate the intracellular functions of cAMP. While protein kinase A (PKA) or cAMP-dependent protein kinase and cyclic nucleotide regulated ion channel (CNG and HCN) were initially unveiled in 1968 and 1985 respectively; EPAC genes were discovered in 1998 independently by two research groups. Kawasaki et al. identified cAMP-GEFI and cAMP-GEFII as novel genes enriched in brain using a differential display protocol and by screening clones with cAMP-binding motif.[7] De Rooij and colleagues performed a database search for proteins with sequence homology to both GEFs for Ras and Rap1 and to cAMP-binding sites, which led to the identification and subsequent cloning of RAPGEF3 gene.[6] The discovery of EPAC family cAMP sensors suggests that the complexity and possible readouts of cAMP signaling are much more elaborate than previously envisioned. This is due to the fact that the net physiological effects of cAMP entail the integration of EPAC- and PKA-dependent pathways, which may act independently, converge synergistically, or oppose each other in regulating a specific cellular function.[8][9][10]

Gene

Human RAPGEF3 gene is present on chromosome 12 (12q13.11: 47,734,367-47,771,041).[11] Out of the many predicted transcript variants, three that are validated in the NCBI database include transcript variant 1 (6,239 bp), 2 (5,773 bp) and 3 (6,003 bp). While variant 1 encodes for EPAC1a (923 amino acids), both variant 2 and 3 encode EPAC1b (881 amino acids).[5]

Protein family

In mammals, the EPAC protein family contains two members: EPAC1 (this protein) and EPAC2 (RAPGEF4). They further belong to a more extended family of Rap/Ras-specific GEF proteins that also include C3G (RAPGEF1), PDZ-GEF1 (RAPGEF2), PDZ-GEF2 (RAPGEF6), Repac (RAPGEF5), CalDAG-GEF1 (ARHGEF1), CalDAG-GEF3 (ARHGEF3), PLCε1 (PLCE1) and RasGEF1A, B, C.

Protein structure and mechanism of activation

EPAC proteins consist of two structural lobes/halves connected by the so-called central “switchboard” region.[12] The N terminal regulatory lobe is responsible for cAMP binding while the C-terminal lobe contains the nucleotide exchange factor activity. At the basal cAMP-free state, EPAC is kept in an auto-inhibitory conformation, in which the N-terminal lobe folds on top of the C-terminal lobe, blocking the active site.[13][14] Binding of cAMP to EPAC induces a hinge motion between the regulatory and catalytic halves. As a consequence, the regulatory lobe moves away from catalytic lobe, freeing the active site.[15][16] In addition, cAMP also prompts conformational changes within the regulatory lobe that lead to the exposure of a lipid binding motif, allowing the proper targeting of EPAC1 to the plasma membrane.[17][18] Entropically favorable changes in protein dynamics have also been implicated in cAMP mediated EPAC activation.[19][20]

Tissue distribution and cellular localization

Human and mice EPAC1 mRNA expression is rather ubiquitous. As per Human Protein Atlas documentation, EPAC1 mRNA is detectable in all normal human tissues. Further, medium to high levels of corresponding protein are also measureable in more than 50% of the 80 tissue samples analyzed.[21] In mice, high levels of EPAC1 mRNA are detected in kidney, ovary, skeletal muscle, thyroid and certain areas of the brain.[7]

EPAC1 is a multifunctional protein whose cellular functions are tightly regulated in spatial and temporal manners. EPAC1 is localized to various subcellular locations during different stages of the cell cycle.[22] Through interactions with an array of cellular partners, EPAC1 has been shown to form discrete signalsomes at plasma membrane,[18][23][24][25] nuclear-envelope,[26][27][28] and cytoskeleton,[29][30][31] where EPAC1 regulates numerous cellular functions.

Clinical relevance

Studies based on genetically engineered mouse models of EPAC1 have provided valuable insights into understanding the in vivo functions of EPAC1 under both physiological and pathophysiological conditions. Overall, mice deficient of EPAC1 or both EPAC1 and EPAC2 appear relatively normal without major phenotypic defects. These observations are consistent with the fact that cAMP is a major stress response signal not essential for survival. This makes EPAC1 an attractive target for therapeutic intervention as the on-target toxicity of EPAC-based therapeutics will likely be low. Up to date, genetic and pharmacological analyses of EPAC1 in mice have revealed that EPAC1 plays important roles in cardiac stresses and heart failure,[32][33] leptin resistance and energy homeostasis,[34][35][36] chronic pain,[37][38] infection,[39][40] cancer metastasis,[41] metabolism[42] and secondary hemostasis.[43] Interestingly, EPAC1 deficient mice have prolonged clotting time and fewer, younger, larger and more agonist-responsive blood platelets. EPAC1 is not present in mature platelets, but is required for normal megakaryopoiesis and the subsequent expression of several important proteins involved in key platelets functions.[43]

Pharmacological agonists and antagonists

There have been significant interests in discovering and developing small modulators specific for EPAC proteins for better understanding the functions of EPAC mediated cAMP signaling, as well as for exploring the therapeutic potential of targeting EPAC proteins. Structure-based design targeting the key difference between the cAMP binding sites of EPAC and PKA led to the identification of a cAMP analogue, 8-pCPT-2’-O-Me-cAMP that is capable of selectively activate EPAC1.[44][45] Further modifications allowed the development of more membrane permeable and metabolically stable EPAC-specific agonists.[46][47][48][49]

A high throughput screening effort resulted in the discovery of several novel EPAC specific inhibitors (ESIs),[50][51][52] among which two ESIs act as EPAC2 selective antagonists with negligible activity towards EPAC1.[51] Another ESI, CE3F4, with modest selectivity for EPAC1 over EPAC2, has also been reported.[53] The discovery of EPAC specific antagonists represents a research milestone that allows the pharmacological manipulation of EPAC activity. In particular, one EPAC antagonist, ESI-09, with excellent activity and minimal toxicity in vivo, has been shown to be a useful pharmacological tool for probing physiological functions of EPAC proteins and for testing therapeutic potential of targeting EPAC in animal disease models.[39][41][54]

Notes

References

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2. GRCm38: Ensembl release 89: ENSMUSG00000022469 - Ensembl, May 2017
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22. Qiao J, Mei FC, Popov VL, Vergara LA, Cheng X (July 2002). "Cell cycle-dependent subcellular localization of exchange factor directly activated by cAMP". The Journal of Biological Chemistry. 277 (29): 26581–6. doi:10.1074/jbc.M203571200. PMID 12000763.
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28. Liu C, Takahashi M, Li Y, Dillon TJ, Kaech S, Stork PJ (August 2010). "The interaction of Epac1 and Ran promotes Rap1 activation at the nuclear envelope". Molecular and Cellular Biology. 30 (16): 3956–69. doi:10.1128/MCB.00242-10. PMC 2916442. PMID 20547757.
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39. Gong B, Shelite T, Mei FC, Ha T, Hu Y, Xu G, et al. (November 2013). "Exchange protein directly activated by cAMP plays a critical role in bacterial invasion during fatal rickettsioses". Proceedings of the National Academy of Sciences of the United States of America. 110 (48): 19615–20. doi:10.1073/pnas.1314400110. PMC 3845138. PMID 24218580.
40. Tao X, Mei F, Agrawal A, Peters CJ, Ksiazek TG, Cheng X, Tseng CT (April 2014). "Blocking of exchange proteins directly activated by cAMP leads to reduced replication of Middle East respiratory syndrome coronavirus". Journal of Virology. 88 (7): 3902–10. doi:10.1128/JVI.03001-13. PMC 3993534. PMID 24453361.
41. Almahariq M, Chao C, Mei FC, Hellmich MR, Patrikeev I, Motamedi M, Cheng X (February 2015). "Pharmacological inhibition and genetic knockdown of exchange protein directly activated by cAMP 1 reduce pancreatic cancer metastasis in vivo". Molecular Pharmacology. 87 (2): 142–9. doi:10.1124/mol.114.095158. PMC 4293446. PMID 25385424.
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50. Tsalkova T, Mei FC, Cheng X (2012). "A fluorescence-based high-throughput assay for the discovery of exchange protein directly activated by cyclic AMP (EPAC) antagonists". PLOS ONE. 7 (1): e30441. doi:10.1371/journal.pone.0030441. PMC 3262007. PMID 22276201.
51. Tsalkova T, Mei FC, Li S, Chepurny OG, Leech CA, Liu T, et al. (November 2012). "Isoform-specific antagonists of exchange proteins directly activated by cAMP". Proceedings of the National Academy of Sciences of the United States of America. 109 (45): 18613–8. doi:10.1073/pnas.1210209109. PMC 3494926. PMID 23091014.
52. Almahariq M, Tsalkova T, Mei FC, Chen H, Zhou J, Sastry SK, et al. (January 2013). "A novel EPAC-specific inhibitor suppresses pancreatic cancer cell migration and invasion". Molecular Pharmacology. 83 (1): 122–8. doi:10.1124/mol.112.080689. PMC 3533471. PMID 23066090.
53. Courilleau D, Bisserier M, Jullian JC, Lucas A, Bouyssou P, Fischmeister R, et al. (December 2012). "Identification of a tetrahydroquinoline analog as a pharmacological inhibitor of the cAMP-binding protein Epac". The Journal of Biological Chemistry. 287 (53): 44192–202. doi:10.1074/jbc.M112.422956. PMC 3531735. PMID 23139415.
54. Zhu Y, Chen H, Boulton S, Mei F, Ye N, Melacini G, et al. (March 2015). "Biochemical and pharmacological characterizations of ESI-09 based EPAC inhibitors: defining the ESI-09 "therapeutic window"". Scientific Reports. 5: 9344. doi:10.1038/srep09344. PMC 4366844. PMID 25791905.

Further reading

• Chen H, Wild C, Zhou X, Ye N, Cheng X, Zhou J (May 2014). "Recent advances in the discovery of small molecules targeting exchange proteins directly activated by cAMP (EPAC)". Journal of Medicinal Chemistry. 57 (9): 3651–65. doi:10.1021/jm401425e. PMC 4016168. PMID 24256330.
• Gloerich M, Bos JL (2010). "Epac: defining a new mechanism for cAMP action". Annual Review of Pharmacology and Toxicology. 50: 355–75. doi:10.1146/annurev.pharmtox.010909.105714. PMID 20055708.
• Gloerich M, Bos JL (October 2011). "Regulating Rap small G-proteins in time and space". Trends in Cell Biology. 21 (10): 615–23. doi:10.1016/j.tcb.2011.07.001. PMID 21820312.
• Parnell E, Palmer TM, Yarwood SJ (April 2015). "The future of EPAC-targeted therapies: agonism versus antagonism". Trends in Pharmacological Sciences. 36 (4): 203–14. doi:10.1016/j.tips.2015.02.003. PMC 4392396. PMID 25744542.
• Schmidt M, Dekker FJ, Maarsingh H (April 2013). "Exchange protein directly activated by cAMP (epac): a multidomain cAMP mediator in the regulation of diverse biological functions". Pharmacological Reviews. 65 (2): 670–709. doi:10.1124/pr.110.003707. PMID 23447132.
• Nygaard G, Herfindal L, Asrud KS, Bjørnstad R, Kopperud RK, Oveland E, et al. (August 2017). "Epac1-deficient mice have bleeding phenotype and thrombocytes with decreased GPIbβ expression". Scientific Reports. 7 (1): 8725. doi:10.1038/s41598-017-08975-y. PMC 5562764. PMID 28821815.