EPAC and PKA allow cAMP dual control over DNA-PK nuclear translocation

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Huston, Elaine and Lynch, Martin and Mohamed, Ahmed and Collins, Daniel and Hill, Elaine and MacLeod, Ruth and Krause, Eberhard and Baillie, George and Houslay, Miles (2008) EPAC and PKA allow cAMP dual control over DNA-PK nuclear translocation. Proceedings of the National Academy of Sciences, 105 (35). pp. 12791-12796. ISSN 0027-8424 (https://doi.org/10.1073/pnas.0805167105)

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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.

ORCID iDs

Huston, Elaine, Lynch, Martin, Mohamed, Ahmed, Collins, Daniel, Hill, Elaine, MacLeod, Ruth, Krause, Eberhard, Baillie, George and Houslay, Miles ORCID logoORCID: https://orcid.org/0000-0002-3826-8091;
  • Item type:Article
    ID code:41269
    Dates:
    Date
    Event
    2 September 2008
    Published
    26 August 2008
    Published Online
    Notes: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.
    Subjects:Medicine > Pharmacy and materia medica
    Department:Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
    Depositing user: Pure Administrator
    Date deposited:28 Sep 2012 13:24
    Last modified:11 Nov 2024 10:13
    URI:https://strathprints.strath.ac.uk/id/eprint/41269
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