Editors' ChoiceSpatial Regulation

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Science Signaling  12 May 2009:
Vol. 2, Issue 70, pp. ec161
DOI: 10.1126/scisignal.270ec161

Redundancy in signaling systems often seems to show that a process worth regulating once is also worth regulating a second time. A new example is provided by Ponsioen et al., who show that Epac1, a guanine nucleotide exchange factor (GEF) for the small guanosine triphosphatase Rap, responds to increased concentrations of cyclic AMP (cAMP, adenosine 3′,5′-monophosphate) with a conformational change that not only enhances its GEF activity but also provides spatial control by rapidly targeting the protein to the plasma membrane. The authors monitored the localization of a green fluorescent protein (GFP)–tagged version of Epac1 in human embryonic kidney (HEK293) cells. Time-lapse confocal microscopy showed movement of the fluorescent protein within minutes after stimulation of the cells to increase production of cAMP. With an analog of cAMP that specifically binds to Epac1, the authors showed that direct binding to Epac1 was required for translocation, rather than an indirect mechanism mediated by cAMP-dependent protein kinase or other targets of cAMP. Fluorescence resonance energy transfer experiments showed localization of GFP-EPAC within 7 nm of the membrane. Release of caged cAMP caused translocation that was halfway complete within 5 seconds. Total internal reflection fluorescence and confocal microscopy showed that the translocation of Epac1 correlated with specific activation of Rap at the plasma membrane. One of Rap’s numerous functions is to regulate cell motility, and in Jurkat T cells the Epac1-specific analog of cAMP enhanced cell adhesion. In their discussion, the authors ponder the advantages of regulating localization of GEFs or GAPs (GTPase-activating proteins) rather than that of the small GTPases themselves and why a spatial regulatory mechanism layered on top of direct conformational regulation of GEF activity by Epac1 might be advantageous to the cell.

B. Ponsioen, M. Gloerich, L. Ritsma, H. Rehmann, J. L. Bos, K. Jalink, Direct spatial control of Epac1 by cyclic AMP. Mol Cell. Biol. 29, 2521–2531 (2009). [Abstract] [Full Text]

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