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词条 RAPGEF3
释义

  1. History and discovery

  2. Gene

  3. Protein family

  4. Protein structure and mechanism of activation

  5. Tissue distribution and cellular localization

  6. Clinical relevance

  7. Pharmacological agonists and antagonists

  8. Notes

  9. References

  10. Further reading

{{Infobox_gene}}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.[1][2][3]

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.[3] 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.[2] 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.[4][5][6]

Gene

Human RAPGEF3 gene is present on chromosome 12 (12q13.11: 47,734,367-47,771,041).[7] 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).[1]

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.[8] 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.[9][10] 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.[11][12] 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.[13][14] Entropically favorable changes in protein dynamics have also been implicated in cAMP mediated EPAC activation.[15][16]

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.[17] In mice, high levels of EPAC1 mRNA are detected in kidney, ovary, skeletal muscle, thyroid and certain areas of the brain.[3]

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.[18] Through interactions with an array of cellular partners, EPAC1 has been shown to form discrete signalsomes at plasma membrane,[14][19][20][21] nuclear-envelope,[22][23][24] and cytoskeleton,[25][26][27] 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 data, genetic and pharmacological analyses of EPAC1 in mice have revealed that EPAC1 plays important roles in cardiac stresses and heart failure,[28][29] leptin resistance and energy homeostasis,[30][31][32] chronic pain,[33][34] infection,[35][36] cancer metastasis[37] and metabolism.[38]

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.[39][40] Further modifications allowed the development of more membrane permeable and metabolically stable EPAC-specific agonists.[41][42][43][44]

A high throughput screening effort resulted in the discovery of several novel EPAC specific inhibitors (ESIs),[45][46][47] among which two ESIs act as EPAC2 selective antagonists with negligible activity towards EPAC1.[46] Another ESI, CE3F4, with modest selectivity for EPAC1 over EPAC2, has also been reported.[48] 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.[35][37][49]

Notes

{{Academic-written review
| wikidate = 2015
| journal = Gene
| title = {{#property:P1476|from=Q28608179}}
| authors = {{#property:P2093|from=Q28608179}}
| date = {{#property:P577|from=Q28608179}}
| volume = {{#property:P478|from=Q28608179}}
| issue = {{#property:P433|from=Q28608179}}
| pages = {{#property:P304|from=Q28608179}}
| doi = {{#property:P356|from=Q28608179}}
| pmid = {{#property:P698|from=Q28608179}}
| pmc = {{#property:P932|from=Q28608179}}
}}

References

1. ^1 {{cite web|title=Entrez|url=https://www.ncbi.nlm.nih.gov/gene/10411|website=Entrez gene|accessdate=19 June 2015}}
2. ^1 {{cite journal | vauthors = de Rooij J, Zwartkruis FJ, Verheijen MH, Cool RH, Nijman SM, Wittinghofer A, Bos JL | title = Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP | journal = Nature | volume = 396 | issue = 6710 | pages = 474–7 | date = Dec 1998 | pmid = 9853756 | doi = 10.1038/24884 }}
3. ^1 2 {{cite journal | vauthors = Kawasaki H, Springett GM, Mochizuki N, Toki S, Nakaya M, Matsuda M, Housman DE, Graybiel AM | title = A family of cAMP-binding proteins that directly activate Rap1 | journal = Science | volume = 282 | issue = 5397 | pages = 2275–9 | date = Dec 1998 | pmid = 9856955 | doi=10.1126/science.282.5397.2275}}
4. ^{{cite journal | vauthors = Mei FC, Qiao J, Tsygankova OM, Meinkoth JL, Quilliam LA, Cheng X | title = Differential signaling of cyclic AMP: opposing effects of exchange protein directly activated by cyclic AMP and cAMP-dependent protein kinase on protein kinase B activation | journal = The Journal of Biological Chemistry | volume = 277 | issue = 13 | pages = 11497–504 | date = Mar 2002 | pmid = 11801596 | doi = 10.1074/jbc.M110856200 }}
5. ^{{cite journal | vauthors = Cheng X, Ji Z, Tsalkova T, Mei F | title = Epac and PKA: a tale of two intracellular cAMP receptors | journal = Acta Biochimica et Biophysica Sinica | volume = 40 | issue = 7 | pages = 651–62 | date = Jul 2008 | pmid = 18604457 | doi=10.1111/j.1745-7270.2008.00438.x | pmc=2630796}}
6. ^{{cite journal | vauthors = Huston E, Lynch MJ, Mohamed A, Collins DM, Hill EV, MacLeod R, Krause E, Baillie GS, Houslay MD | title = EPAC and PKA allow cAMP dual control over DNA-PK nuclear translocation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 35 | pages = 12791–6 | date = Sep 2008 | pmid = 18728186 | doi = 10.1073/pnas.0805167105 | pmc=2529053}}
7. ^{{cite web|title=Ensembl|url=http://e79.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000079337;r=12:47734367-47771040|website=H. Human RAPGEF3 gene.|accessdate=19 June 2015}}
8. ^{{cite journal | vauthors = Rehmann H, Das J, Knipscheer P, Wittinghofer A, Bos JL | title = Structure of the cyclic-AMP-responsive exchange factor Epac2 in its auto-inhibited state | journal = Nature | volume = 439 | issue = 7076 | pages = 625–8 | date = Feb 2006 | pmid = 16452984 | doi = 10.1038/nature04468 }}
9. ^{{cite journal | vauthors = de Rooij J, Rehmann H, van Triest M, Cool RH, Wittinghofer A, Bos JL | title = Mechanism of regulation of the Epac family of cAMP-dependent RapGEFs | journal = The Journal of Biological Chemistry | volume = 275 | issue = 27 | pages = 20829–36 | date = Jul 2000 | pmid = 10777494 | doi = 10.1074/jbc.M001113200 }}
10. ^{{cite journal | vauthors = Rehmann H, Rueppel A, Bos JL, Wittinghofer A | title = Communication between the regulatory and the catalytic region of the cAMP-responsive guanine nucleotide exchange factor Epac | journal = The Journal of Biological Chemistry | volume = 278 | issue = 26 | pages = 23508–14 | date = Jun 2003 | pmid = 12707263 | doi = 10.1074/jbc.M301680200 }}
11. ^{{cite journal | vauthors = Rehmann H, Arias-Palomo E, Hadders MA, Schwede F, Llorca O, Bos JL | title = Structure of Epac2 in complex with a cyclic AMP analogue and RAP1B | journal = Nature | volume = 455 | issue = 7209 | pages = 124–7 | date = Sep 2008 | pmid = 18660803 | doi = 10.1038/nature07187 }}
12. ^{{cite journal | vauthors = Tsalkova T, Blumenthal DK, Mei FC, White MA, Cheng X | title = Mechanism of Epac activation: structural and functional analyses of Epac2 hinge mutants with constitutive and reduced activities | journal = The Journal of Biological Chemistry | volume = 284 | issue = 35 | pages = 23644–51 | date = Aug 2009 | pmid = 19553663 | doi = 10.1074/jbc.M109.024950 | pmc=2749139}}
13. ^{{cite journal | vauthors = Li S, Tsalkova T, White MA, Mei FC, Liu T, Wang D, Woods VL, Cheng X | title = Mechanism of intracellular cAMP sensor Epac2 activation: cAMP-induced conformational changes identified by amide hydrogen/deuterium exchange mass spectrometry (DXMS) | journal = The Journal of Biological Chemistry | volume = 286 | issue = 20 | pages = 17889–97 | date = May 2011 | pmid = 21454623 | doi = 10.1074/jbc.M111.224535 | pmc=3093864}}
14. ^1 {{cite journal | vauthors = Consonni SV, Gloerich M, Spanjaard E, Bos JL | title = cAMP regulates DEP domain-mediated binding of the guanine nucleotide exchange factor Epac1 to phosphatidic acid at the plasma membrane | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 10 | pages = 3814–9 | date = Mar 2012 | pmid = 22343288 | doi = 10.1073/pnas.1117599109 | pmc=3309772}}
15. ^{{cite journal | vauthors = Das R, Chowdhury S, Mazhab-Jafari MT, Sildas S, Selvaratnam R, Melacini G | title = Dynamically driven ligand selectivity in cyclic nucleotide binding domains | journal = The Journal of Biological Chemistry | volume = 284 | issue = 35 | pages = 23682–96 | date = Aug 2009 | pmid = 19403523 | doi = 10.1074/jbc.M109.011700 | pmc=2749143}}
16. ^{{cite journal | vauthors = VanSchouwen B, Selvaratnam R, Fogolari F, Melacini G | title = Role of dynamics in the autoinhibition and activation of the exchange protein directly activated by cyclic AMP (EPAC) | journal = The Journal of Biological Chemistry | volume = 286 | issue = 49 | pages = 42655–69 | date = Dec 2011 | pmid = 21873431 | doi = 10.1074/jbc.M111.277723 | pmc=3234915}}
17. ^{{cite web|title=Human Protein Altas|url=http://www.proteinatlas.org/ENSG00000079337-RAPGEF3/tissue|website=RAPGEF3|accessdate=19 June 2015}}
18. ^{{cite journal | vauthors = Qiao J, Mei FC, Popov VL, Vergara LA, Cheng X | title = Cell cycle-dependent subcellular localization of exchange factor directly activated by cAMP | journal = The Journal of Biological Chemistry | volume = 277 | issue = 29 | pages = 26581–6 | date = Jul 2002 | pmid = 12000763 | doi = 10.1074/jbc.M203571200 }}
19. ^{{cite journal | vauthors = Ponsioen B, Gloerich M, Ritsma L, Rehmann H, Bos JL, Jalink K | title = Direct spatial control of Epac1 by cyclic AMP | journal = Molecular and Cellular Biology | volume = 29 | issue = 10 | pages = 2521–31 | date = May 2009 | pmid = 19273589 | doi = 10.1128/MCB.01630-08 | pmc=2682048}}
20. ^{{cite journal | vauthors = Gloerich M, Ponsioen B, Vliem MJ, Zhang Z, Zhao J, Kooistra MR, Price LS, Ritsma L, Zwartkruis FJ, Rehmann H, Jalink K, Bos JL | title = Spatial regulation of cyclic AMP-Epac1 signaling in cell adhesion by ERM proteins | journal = Molecular and Cellular Biology | volume = 30 | issue = 22 | pages = 5421–31 | date = Nov 2010 | pmid = 20855527 | doi = 10.1128/MCB.00463-10 | pmc=2976368}}
21. ^{{cite journal | vauthors = Hochbaum D, Barila G, Ribeiro-Neto F, Altschuler DL | title = Radixin assembles cAMP effectors Epac and PKA into a functional cAMP compartment: role in cAMP-dependent cell proliferation | journal = The Journal of Biological Chemistry | volume = 286 | issue = 1 | pages = 859–66 | date = Jan 2011 | pmid = 21047789 | doi = 10.1074/jbc.M110.163816 | pmc=3013045}}
22. ^{{cite journal | vauthors = Dodge-Kafka KL, Soughayer J, Pare GC, Carlisle Michel JJ, Langeberg LK, Kapiloff MS, Scott JD | title = The protein kinase A anchoring protein mAKAP coordinates two integrated cAMP effector pathways | journal = Nature | volume = 437 | issue = 7058 | pages = 574–8 | date = Sep 2005 | pmid = 16177794 | doi = 10.1038/nature03966 | pmc=1636584}}
23. ^{{cite journal | vauthors = Gloerich M, Bos JL | title = Regulating Rap small G-proteins in time and space | journal = Trends in Cell Biology | volume = 21 | issue = 10 | pages = 615–23 | date = Oct 2011 | pmid = 21820312 | doi = 10.1016/j.tcb.2011.07.001 }}
24. ^{{cite journal | vauthors = Liu C, Takahashi M, Li Y, Dillon TJ, Kaech S, Stork PJ | title = The interaction of Epac1 and Ran promotes Rap1 activation at the nuclear envelope | journal = Molecular and Cellular Biology | volume = 30 | issue = 16 | pages = 3956–69 | date = Aug 2010 | pmid = 20547757 | doi = 10.1128/MCB.00242-10 | pmc=2916442}}
25. ^{{cite journal | vauthors = Mei FC, Cheng X | title = Interplay between exchange protein directly activated by cAMP (Epac) and microtubule cytoskeleton | journal = Molecular BioSystems | volume = 1 | issue = 4 | pages = 325–31 | date = Oct 2005 | pmid = 16880999 | doi = 10.1039/b511267b }}
26. ^{{cite journal | vauthors = Sehrawat S, Cullere X, Patel S, Italiano J, Mayadas TN | title = Role of Epac1, an exchange factor for Rap GTPases, in endothelial microtubule dynamics and barrier function | journal = Molecular Biology of the Cell | volume = 19 | issue = 3 | pages = 1261–70 | date = Mar 2008 | pmid = 18172027 | doi = 10.1091/mbc.E06-10-0972 | pmc=2262967}}
27. ^{{cite journal | vauthors = Sehrawat S, Ernandez T, Cullere X, Takahashi M, Ono Y, Komarova Y, Mayadas TN | title = AKAP9 regulation of microtubule dynamics promotes Epac1-induced endothelial barrier properties | journal = Blood | volume = 117 | issue = 2 | pages = 708–18 | date = Jan 2011 | pmid = 20952690 | doi = 10.1182/blood-2010-02-268870 | pmc=3031489}}
28. ^{{cite journal | vauthors = Métrich M, Lucas A, Gastineau M, Samuel JL, Heymes C, Morel E, Lezoualc'h F | title = Epac mediates beta-adrenergic receptor-induced cardiomyocyte hypertrophy | journal = Circulation Research | volume = 102 | issue = 8 | pages = 959–65 | date = Apr 2008 | pmid = 18323524 | doi = 10.1161/CIRCRESAHA.107.164947 }}
29. ^{{cite journal | vauthors = Okumura S, Fujita T, Cai W, Jin M, Namekata I, Mototani Y, Jin H, Ohnuki Y, Tsuneoka Y, Kurotani R, Suita K, Kawakami Y, Hamaguchi S, Abe T, Kiyonari H, Tsunematsu T, Bai Y, Suzuki S, Hidaka Y, Umemura M, Ichikawa Y, Yokoyama U, Sato M, Ishikawa F, Izumi-Nakaseko H, Adachi-Akahane S, Tanaka H, Ishikawa Y | title = Epac1-dependent phospholamban phosphorylation mediates the cardiac response to stresses | journal = The Journal of Clinical Investigation | volume = 124 | issue = 6 | pages = 2785–801 | date = Jun 2014 | pmid = 24892712 | doi = 10.1172/JCI64784 | pmc=4038559}}
30. ^{{cite journal | vauthors = Fukuda M, Williams KW, Gautron L, Elmquist JK | title = Induction of leptin resistance by activation of cAMP-Epac signaling | journal = Cell Metabolism | volume = 13 | issue = 3 | pages = 331–9 | date = Mar 2011 | pmid = 21356522 | doi = 10.1016/j.cmet.2011.01.016 | pmc=3747952}}
31. ^{{cite journal | vauthors = Yan J, Mei FC, Cheng H, Lao DH, Hu Y, Wei J, Patrikeev I, Hao D, Stutz SJ, Dineley KT, Motamedi M, Hommel JD, Cunningham KA, Chen J, Cheng X | title = Enhanced leptin sensitivity, reduced adiposity, and improved glucose homeostasis in mice lacking exchange protein directly activated by cyclic AMP isoform 1 | journal = Molecular and Cellular Biology | volume = 33 | issue = 5 | pages = 918–26 | date = Mar 2013 | pmid = 23263987 | doi = 10.1128/MCB.01227-12 | pmc=3623083}}
32. ^{{cite journal | vauthors = Almahariq M, Mei FC, Cheng X | title = Cyclic AMP sensor EPAC proteins and energy homeostasis | journal = Trends in Endocrinology and Metabolism | volume = 25 | issue = 2 | pages = 60–71 | date = Feb 2014 | pmid = 24231725 | doi = 10.1016/j.tem.2013.10.004 | pmc=3946731}}
33. ^{{cite journal | vauthors = Eijkelkamp N, Linley JE, Torres JM, Bee L, Dickenson AH, Gringhuis M, Minett MS, Hong GS, Lee E, Oh U, Ishikawa Y, Zwartkuis FJ, Cox JJ, Wood JN | title = A role for Piezo2 in EPAC1-dependent mechanical allodynia | journal = Nature Communications | volume = 4 | pages = 1682 | date = 2013 | pmid = 23575686 | doi = 10.1038/ncomms2673 | pmc=3644070}}
34. ^{{cite journal | vauthors = Wang H, Heijnen CJ, van Velthoven CT, Willemen HL, Ishikawa Y, Zhang X, Sood AK, Vroon A, Eijkelkamp N, Kavelaars A | title = Balancing GRK2 and EPAC1 levels prevents and relieves chronic pain | journal = The Journal of Clinical Investigation | volume = 123 | issue = 12 | pages = 5023–34 | date = Dec 2013 | pmid = 24231349 | doi = 10.1172/JCI66241 | pmc=3859388}}
35. ^1 {{cite journal | vauthors = Gong B, Shelite T, Mei FC, Ha T, Hu Y, Xu G, Chang Q, Wakamiya M, Ksiazek TG, Boor PJ, Bouyer DH, Popov VL, Chen J, Walker DH, Cheng X | title = Exchange protein directly activated by cAMP plays a critical role in bacterial invasion during fatal rickettsioses | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 48 | pages = 19615–20 | date = Nov 2013 | pmid = 24218580 | doi = 10.1073/pnas.1314400110 | pmc=3845138}}
36. ^{{cite journal | vauthors = Tao X, Mei F, Agrawal A, Peters CJ, Ksiazek TG, Cheng X, Tseng CT | title = Blocking of exchange proteins directly activated by cAMP leads to reduced replication of Middle East respiratory syndrome coronavirus | journal = Journal of Virology | volume = 88 | issue = 7 | pages = 3902–10 | date = Apr 2014 | pmid = 24453361 | doi = 10.1128/JVI.03001-13 | pmc=3993534}}
37. ^1 {{cite journal | vauthors = Almahariq M, Chao C, Mei FC, Hellmich MR, Patrikeev I, Motamedi M, Cheng X | title = Pharmacological inhibition and genetic knockdown of exchange protein directly activated by cAMP 1 reduce pancreatic cancer metastasis in vivo | journal = Molecular Pharmacology | volume = 87 | issue = 2 | pages = 142–9 | date = Feb 2015 | pmid = 25385424 | doi = 10.1124/mol.114.095158 | pmc=4293446}}
38. ^{{cite journal | vauthors = Onodera Y, Nam JM, Bissell MJ | title = Increased sugar uptake promotes oncogenesis via EPAC/RAP1 and O-GlcNAc pathways | journal = The Journal of Clinical Investigation | volume = 124 | issue = 1 | pages = 367–84 | date = Jan 2014 | pmid = 24316969 | doi = 10.1172/JCI63146 | pmc=3871217}}
39. ^{{cite journal | vauthors = Enserink JM, Christensen AE, de Rooij J, van Triest M, Schwede F, Genieser HG, Døskeland SO, Blank JL, Bos JL | title = A novel Epac-specific cAMP analogue demonstrates independent regulation of Rap1 and ERK | journal = Nature Cell Biology | volume = 4 | issue = 11 | pages = 901–6 | date = Nov 2002 | pmid = 12402047 | doi = 10.1038/ncb874 }}
40. ^{{cite journal | vauthors = Christensen AE, Selheim F, de Rooij J, Dremier S, Schwede F, Dao KK, Martinez A, Maenhaut C, Bos JL, Genieser HG, Døskeland SO | title = cAMP analog mapping of Epac1 and cAMP kinase. Discriminating analogs demonstrate that Epac and cAMP kinase act synergistically to promote PC-12 cell neurite extension | journal = The Journal of Biological Chemistry | volume = 278 | issue = 37 | pages = 35394–402 | date = Sep 2003 | pmid = 12819211 | doi = 10.1074/jbc.M302179200 }}
41. ^{{cite journal | vauthors = Poppe H, Rybalkin SD, Rehmann H, Hinds TR, Tang XB, Christensen AE, Schwede F, Genieser HG, Bos JL, Doskeland SO, Beavo JA, Butt E | title = Cyclic nucleotide analogs as probes of signaling pathways | journal = Nature Methods | volume = 5 | issue = 4 | pages = 277–8 | date = Apr 2008 | pmid = 18376388 | doi = 10.1038/nmeth0408-277 }}
42. ^{{cite journal | vauthors = Vliem MJ, Ponsioen B, Schwede F, Pannekoek WJ, Riedl J, Kooistra MR, Jalink K, Genieser HG, Bos JL, Rehmann H | title = 8-pCPT-2'-O-Me-cAMP-AM: an improved Epac-selective cAMP analogue | journal = ChemBioChem | volume = 9 | issue = 13 | pages = 2052–4 | date = Sep 2008 | pmid = 18633951 | doi = 10.1002/cbic.200800216 }}
43. ^{{cite journal | vauthors = Holz GG, Chepurny OG, Schwede F | title = Epac-selective cAMP analogs: new tools with which to evaluate the signal transduction properties of cAMP-regulated guanine nucleotide exchange factors | journal = Cellular Signalling | volume = 20 | issue = 1 | pages = 10–20 | date = Jan 2008 | pmid = 17716863 | doi = 10.1016/j.cellsig.2007.07.009 | pmc=2215344}}
44. ^{{cite journal | vauthors = Schwede F, Bertinetti D, Langerijs CN, Hadders MA, Wienk H, Ellenbroek JH, de Koning EJ, Bos JL, Herberg FW, Genieser HG, Janssen RA, Rehmann H | title = Structure-guided design of selective Epac1 and Epac2 agonists | journal = PLoS Biology | volume = 13 | issue = 1 | pages = e1002038 | date = Jan 2015 | pmid = 25603503 | doi = 10.1371/journal.pbio.1002038 | pmc=4300089}}
45. ^{{cite journal | vauthors = Tsalkova T, Mei FC, Cheng X | title = A fluorescence-based high-throughput assay for the discovery of exchange protein directly activated by cyclic AMP (EPAC) antagonists | journal = PLOS ONE | volume = 7 | issue = 1 | pages = e30441 | date = 2012 | pmid = 22276201 | doi = 10.1371/journal.pone.0030441 | pmc=3262007}}
46. ^1 {{cite journal | vauthors = Tsalkova T, Mei FC, Li S, Chepurny OG, Leech CA, Liu T, Holz GG, Woods VL, Cheng X | title = Isoform-specific antagonists of exchange proteins directly activated by cAMP | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 45 | pages = 18613–8 | date = Nov 2012 | pmid = 23091014 | doi = 10.1073/pnas.1210209109 | pmc=3494926}}
47. ^{{cite journal | vauthors = Almahariq M, Tsalkova T, Mei FC, Chen H, Zhou J, Sastry SK, Schwede F, Cheng X | title = A novel EPAC-specific inhibitor suppresses pancreatic cancer cell migration and invasion | journal = Molecular Pharmacology | volume = 83 | issue = 1 | pages = 122–8 | date = Jan 2013 | pmid = 23066090 | doi = 10.1124/mol.112.080689 | pmc=3533471}}
48. ^{{cite journal | vauthors = Courilleau D, Bisserier M, Jullian JC, Lucas A, Bouyssou P, Fischmeister R, Blondeau JP, Lezoualc'h F | title = Identification of a tetrahydroquinoline analog as a pharmacological inhibitor of the cAMP-binding protein Epac | journal = The Journal of Biological Chemistry | volume = 287 | issue = 53 | pages = 44192–202 | date = Dec 2012 | pmid = 23139415 | doi = 10.1074/jbc.M112.422956 | pmc=3531735}}
49. ^{{cite journal | vauthors = Zhu Y, Chen H, Boulton S, Mei F, Ye N, Melacini G, Zhou J, Cheng X | title = Biochemical and pharmacological characterizations of ESI-09 based EPAC inhibitors: defining the ESI-09 "therapeutic window" | journal = Scientific Reports | volume = 5 | pages = 9344 | date = 20 March 2015 | pmid = 25791905 | doi = 10.1038/srep09344 | pmc=4366844}}

Further reading

{{refbegin|33em}}
  • {{cite journal | vauthors = Chen H, Wild C, Zhou X, Ye N, Cheng X, Zhou J | title = Recent advances in the discovery of small molecules targeting exchange proteins directly activated by cAMP (EPAC) | journal = Journal of Medicinal Chemistry | volume = 57 | issue = 9 | pages = 3651–65 | date = May 2014 | pmid = 24256330 | doi = 10.1021/jm401425e | pmc=4016168}}
  • {{cite journal | vauthors = Gloerich M, Bos JL | title = Epac: defining a new mechanism for cAMP action | journal = Annual Review of Pharmacology and Toxicology | volume = 50 | pages = 355–75 | pmid = 20055708 | doi = 10.1146/annurev.pharmtox.010909.105714 | year=2010}}
  • {{cite journal | vauthors = Gloerich M, Bos JL | title = Regulating Rap small G-proteins in time and space | journal = Trends in Cell Biology | volume = 21 | issue = 10 | pages = 615–23 | date = Oct 2011 | pmid = 21820312 | doi = 10.1016/j.tcb.2011.07.001 }}
  • {{cite journal | vauthors = Parnell E, Palmer TM, Yarwood SJ | title = The future of EPAC-targeted therapies: agonism versus antagonism | journal = Trends in Pharmacological Sciences | volume = 36 | issue = 4 | pages = 203–14 | date = Apr 2015 | pmid = 25744542 | doi = 10.1016/j.tips.2015.02.003 | pmc=4392396}}
  • {{cite journal | vauthors = Schmidt M, Dekker FJ, Maarsingh H | title = Exchange protein directly activated by cAMP (epac): a multidomain cAMP mediator in the regulation of diverse biological functions | journal = Pharmacological Reviews | volume = 65 | issue = 2 | pages = 670–709 | date = Apr 2013 | pmid = 23447132 | doi = 10.1124/pr.110.003707 }}
{{refend}}
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