Brief Communication abstract
Nature Cell Biology 4, 901 - 906 (2002)
Published online: 28 October 2002 | doi:10.1038/ncb874
A novel Epac-specific cAMP analogue demonstrates independent regulation of Rap1 and ERK
Jorrit M. Enserink1,6, Anne E. Christensen2,6, Johan de Rooij1,3,6, Miranda van Triest1, Frank Schwede4, Hans Gottfried Genieser4, Stein O. Døskeland2, Jonathan L. Blank5 & Johannes L. Bos1
cAMP is involved in a wide variety of cellular processes that were thought to be mediated by protein kinase A (PKA)1. However, cAMP also directly regulates Epac1 and Epac2, guanine nucleotide-exchange factors (GEFs) for the small GTPases Rap1 and Rap2 (refs 2,3). Unfortunately, there is an absence of tools to discriminate between PKA- and Epac-mediated effects. Therefore, through rational drug design we have developed a novel cAMP analogue, 8-(4-chloro-phenylthio)-2'-O-methyladenosine-3',5'-cyclic monophosphate (8CPT-2Me-cAMP), which activates Epac, but not PKA, both in vitro and in vivo. Using this analogue, we tested the widespread model that Rap1 mediates cAMP-induced regulation of the extracellular signal-regulated kinase (ERK)4, 5. However, both in cell lines in which cAMP inhibits growth-factor-induced ERK activation and in which cAMP activates ERK, 8CPT-2Me-cAMP did not affect ERK activity. Moreover, in cell lines in which cAMP activates ERK, inhibition of PKA and Ras, but not Rap1, abolished cAMP-mediated ERK activation. We conclude that cAMP-induced regulation of ERK and activation of Rap1 are independent processes.
- Department of Physiological Chemistry and Centre for Biomedical Genetics, University Medical Center Utrecht, Universiteitsweg 100, 3584CG Utrecht, The Netherlands
- Department of Anatomy and Cell Biology, University of Bergen, Årstadveien 19, N-5009, Bergen, Norway
- Semaia Pharmaceuticals, Buntlaan 44, 3971 JD Driebergen, The Netherlands
- BIOLOG Life Science Institute, P.O.Box 107125, D-28071, Bremen, Germany
- Department of Cell Physiology and Pharmacology, University of Leicester School of Medicine, P.O. Box 138, Leicester LE1 9HN, UK
- These authors contributed equally to this work
Correspondence to: Johannes L. Bos1 e-mail: J.L.Bos @med.uu.nl
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