EPAC and PKA allow cAMP dual control over DNA-PK nuclear translocation (original) (raw)

Huston, Elaine ORCID: https://orcid.org/0009-0001-6978-7134, Lynch, Martin J., Mohamed, Ahmed, Collins, Daniel M., Hill, Elaine V., McLeod, Ruth, Krause, Eberhard, Baillie, George S. ORCID: https://orcid.org/0000-0003-2469-6316 and Houslay, Miles 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.

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Funder and Project Information

1

Phosphodiesterase-4 isoforms - intracellular targeting, regulation and potential therapeutic targets

Miles Houslay

G0600765

Institute of Neuroscience and Psychology

1

Protein interactions and compartmentalisation in cell signalling

Walter Kolch

G0400053

MCSB - BIOCHEMISTRY & CELL BIOLOGY

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