Huston, E., Lynch, M. J., Mohamed, A., Collins, D. M., Hill, E. V., McLeod, R., Krause, E., Baillie, G. S. and Houslay, M. D. (2008) EPAC and PKA allow cAMP dual control over DNA-PK nuclear translocation. Proceedings of the National Academy of Sciences of the United States of America, 105(35), pp. 12791-12796. (doi: 10.1073/pnas.0805167105)
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Publisher's URL: http://dx.doi.org/10.1073/pnas.0805167105
Abstract
We identify a compartmentalized signaling system that identifies a functional role for the GTP exchange factor, exchange protein activated by cAMP (EPAC) coupled to Rap2 in the nucleus. In this system, cAMP regulates the nuclear/cytoplasmic trafficking of DNA-dependent protein kinase (DNA-PK), a critical kinase that acts to repair double-stranded breaks (DSBs) in damaged DNA and to phosphorylate the cell survival kinase, PKB/Akt. Intersecting regulatory inputs for cAMP employ EPAC to transduce positive effects, namely the Rap2-dependent nuclear exit and activation of DNA-PK, whereas protein kinase A (PKA) provides the negative input by antagonizing these actions. We identify this as a compartmentalized regulatory system where modulation of cAMP input into the stimulatory, EPAC and inhibitory, PKA intersecting arms is provided by spatially discrete, cAMP degradation systems. The distribution of DNA-PK between nuclear and cytoplasmic compartments can thus potentially be influenced by relative inputs of cAMP signaling through the EPAC and PKA pathways. Through this signaling system EPAC activation can thereby impact on the Ser-473 phosphorylation status of PKB/Akt and the repair of etoposide-induced DSBs.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Houslay, Professor Miles and Baillie, Professor George and Huston, Dr Elaine and Collins, Dr Daniel and Lynch, Dr Martin |
| Authors: | Huston, E., Lynch, M. J., Mohamed, A., Collins, D. M., Hill, E. V., McLeod, R., Krause, E., Baillie, G. S., and Houslay, M. D. |
| Subjects: | Q Science > QH Natural history > QH345 Biochemistry |
| College/School: | College of Medical Veterinary and Life Sciences > School of Molecular Biosciences College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience |
| Journal Name: | Proceedings of the National Academy of Sciences of the United States of America |
| Publisher: | National Academy of Sciences |
| ISSN: | 0027-8424 |
| ISSN (Online): | 1091-6490 |
| Published Online: | 26 August 2008 |
| Related URLs: |
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