Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 35, Pages 12791-12796Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0805167105
Keywords
phosphodiesterase; PDE4; rolipram; PKB; Akt
Categories
Funding
- Medical Research Council [G8604010, G0600765, G0400053]
- European Union [037189]
- Foriclation Leducq [06VD02]
- MRC [G8604010, G0600765, G0400053] Funding Source: UKRI
- Medical Research Council [G8604010, G0400053, G0600765] Funding Source: researchfish
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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 PKIB/Akt and the repair of etoposide-induced DSBs.
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