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A novel Epac-specific cAMP analogue demonstrates independent regulation of Rap1 and ERK

Enserink, Jorrit M., Christensen, Anne E., de Rooij, Johan, van Triest, Miranda, Schwede, Frank, Genieser, Hans Gottfried, Døskeland, Stein O., Blank, Jonathan L., Bos, Johannes L.·2002·Nature Cell Biology
DOI 10.1038/ncb874
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Abstract

cAMP is involved in a wide variety of cellular processes that were thought to be mediated by protein kinase A (PKA). 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). 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.

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Metadata

Authors
Enserink, J. M., Christensen, A. E., de Rooij, J., van Triest, M., Schwede, F., Genieser, H. G., Døskeland, S. O., Blank, J. L., & Bos, J. L.
Venue
Nature Cell Biology
Publisher
Springer Science and Business Media LLC
Published
2002-10-28
Volume
4
Issue
11
Pages
901-906
ISSN
  • 1465-7392
  • 1476-4679
DOI
10.1038/ncb874
Cited by
625
References
0
Language
en
Licence
www.springer.com/tdm (tdm)

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