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- Title
A novel Epac-specific cAMP analogue demonstrates independent regulation of Rap1 and ERK.
- Authors
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.
- 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-2MecAMP), 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 growthfactor-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 cAMPmediated ERK activation. We conclude that cAMP-induced regulation of ERK and activation of Rap1 are independent processes.
- Subjects
CYTOLOGY; BIOLOGY; CELLS
- Publication
Nature Cell Biology, 2002, Vol 4, Issue 11, p901
- ISSN
1465-7392
- Publication type
Article
- DOI
10.1038/ncb874