The DOI matches its Crossref record; 25 of the 25 references it cites were found in a registry or an index.
Mechanism of Regulation of the Epac Family of cAMP-dependent RapGEFs
Open accessAbstract
Epac1 (cAMP-GEFI) and Epac2 (cAMP-GEFII) are closely related guanine nucleotide exchange factors (GEFs) for the small GTPase Rap1, which are directly regulated by cAMP. Here we show that both GEFs efficiently activate Rap2 as well. A third member of the family, Repac (GFR), which lacks the cAMP dependent regulatory sequences, is a constitutive activator of both Rap1 and Rap2. In contrast to Epac1, Epac2 contains a second cAMP binding domain at the N terminus, as does the Epac homologue from Caenorhabditis elegans. Affinity measurements show that this distal cAMP binding domain (the A-site) binds cAMP with much lower affinity than the cAMP binding domain proximal to the catalytic domain (the B-site), which is present in both Epac1 and Epac2. Deletion mutant analysis shows that the high affinity cAMP binding domains are sufficient to regulate the GEFs in vitro. Interestingly, isolated fragments containing the B-sites of either Epac1 or Epac2, but not the A-site from Epac2, inhibit the catalytic domains in trans. This inhibition is relieved by the addition of cAMP. In addition to the cAMP binding domains, both Epac1 and Epac2 have a DEP domain. Deletion of this domain does not affect regulation of Epac1 activity but affects membrane localization. From these results, we conclude that all three members of the Epac family regulate both Rap1 and Rap2. Furthermore, we conclude that the catalytic activity of Epac1 is constrained by a direct interaction between GEF and high affinity cAMP binding domains in the absence of cAMP. Epac1 becomes activated by a release of this inhibition when cAMP is bound.
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Cites
Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP
de Rooij, J., Zwartkruis, F. J. T., Verheijen, M. H. G., Cool, R. H., Nijman, S. M. B., Wittinghofer, A., & Bos, J. L. (1998) · Nature · doi:10.1038/24884 · Cited by 1,969
Self-citationA Family of cAMP-Binding Proteins That Directly Activate Rap1
Kawasaki, H., Springett, G. M., Mochizuki, N., Toki, S., Nakaya, M., Matsuda, M., Housman, D. E., & Graybiel, A. M. (1998) · Science · doi:10.1126/science.282.5397.2275 · Cited by 1,362
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The Small Gtpase, Rap1, Mediates Cd31-Induced Integrin Adhesion
Reedquist, K. A., Ross, E., Koop, E. A., Wolthuis, R. M. F., Zwartkruis, F. J. T., van Kooyk, Y., Salmon, M., Buckley, C. D., & Bos, J. L. (2000) · The Journal of Cell Biology · doi:10.1083/jcb.148.6.1151 · Cited by 415
Self-citationRapid Ca2+-mediated activation of Rap1 in human platelets
Franke, B. (1997) · The EMBO Journal · doi:10.1093/emboj/16.2.252 · Cited by 396
Regulatory Subunit Of Protein Kinase A: Structure of Deletion Mutant with cAMP Binding Domains
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A Rap guanine nucleotide exchange factor enriched highly in the basal ganglia
Kawasaki, H., Springett, G. M., Toki, S., Canales, J. J., Harlan, P., Blumenstiel, J. P., Chen, E. J., Bany, I. A., Mochizuki, N., Ashbacher, A., et al. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.22.13278 · Cited by 357
Gotoh, T., Hattori, S., Nakamura, S., Kitayama, H., Noda, M., Takai, Y., Kaibuchi, K., Matsui, H., Hatase, O., Takahashi, H., et al. (1995) · Molecular and Cellular Biology · doi:10.1128/mcb.15.12.6746 · Cited by 356
All in the family? New insights and questions regarding interconnectivity of Ras, Rap1 and Ral
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Self-citationInhibition of GTPase Activating Protein Stimulation of Ras-p21 GTPase by the K rev -1 Gene Product
Frech, M., John, J., Pizon, V., Chardin, P., Tavitian, A., Clark, R., McCormick, F., & Wittinghofer, A. (1990) · Science · doi:10.1126/science.2164710 · Cited by 251
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Novel Single Chain cAMP Sensors for Receptor-induced Signal Propagation
Nikolaev, V. O., Bünemann, M., Hein, L., Hannawacker, A., & Lohse, M. J. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.c400302200 · Cited by 688
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Bos, J. L. (2006) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2006.10.002 · Cited by 532
Self-citationOrganization and Ca2+Regulation of Adenylyl Cyclases in cAMP Microdomains
Willoughby, D., & Cooper, D. M. F. (2007) · Physiological Reviews · doi:10.1152/physrev.00049.2006 · Cited by 451
Essential role of Epac2/Rap1 signaling in regulation of insulin granule dynamics by cAMP
Shibasaki, T., Takahashi, H., Miki, T., Sunaga, Y., Matsumura, K., Yamanaka, M., Zhang, C., Tamamoto, A., Satoh, T., Miyazaki, J.-I., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0707054104 · Cited by 425
Metadata
- Authors
- de Rooij, J., Rehmann, H., van Triest, M., Cool, R. H., Wittinghofer, A., & Bos, J. L.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2000-07
- Volume
- 275
- Issue
- 27
- Pages
- 20829-20836
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2039629780
- Cited by
- 398
- References
- 25
- FWCI
- 6.08
- Type
- journal article
- Language
- en
- Open access
- hybrid
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