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

Elaine Huston, Martin Lynch, Ahmed Mohamed, Daniel Collins, Elaine Hill, Ruth MacLeod, Eberhard Krause, George Baillie, Miles Houslay

Research output: Contribution to journalArticle

86 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)12791-12796
Number of pages6
JournalProceedings of the National Academy of Sciences
Volume105
Issue number35
Early online date26 Aug 2008
DOIs
Publication statusPublished - 2 Sep 2008

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DNA-Activated Protein Kinase
Cyclic AMP-Dependent Protein Kinases
Proteins
Phosphotransferases
Etoposide
Guanosine Triphosphate
Cell Survival
Phosphorylation
DNA

Keywords

  • phosphodiesterase
  • PDE4
  • rolipram
  • EPAC
  • Akt
  • PKB
  • double stranded breaks
  • DNA repair
  • DSB

Cite this

Huston, Elaine ; Lynch, Martin ; Mohamed, Ahmed ; Collins, Daniel ; Hill, Elaine ; MacLeod, Ruth ; Krause, Eberhard ; Baillie, George ; Houslay, Miles. / EPAC and PKA allow cAMP dual control over DNA-PK nuclear translocation. In: Proceedings of the National Academy of Sciences . 2008 ; Vol. 105, No. 35. pp. 12791-12796 .
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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.",
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author = "Elaine Huston and Martin Lynch and Ahmed Mohamed and Daniel Collins and Elaine Hill and Ruth MacLeod and Eberhard Krause and George Baillie and Miles Houslay",
note = "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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Huston, E, Lynch, M, Mohamed, A, Collins, D, Hill, E, MacLeod, R, Krause, E, Baillie, G & Houslay, M 2008, 'EPAC and PKA allow cAMP dual control over DNA-PK nuclear translocation', Proceedings of the National Academy of Sciences , vol. 105, no. 35, pp. 12791-12796 . https://doi.org/10.1073/pnas.0805167105

EPAC and PKA allow cAMP dual control over DNA-PK nuclear translocation. / Huston, Elaine; Lynch, Martin; Mohamed, Ahmed; Collins, Daniel; Hill, Elaine; MacLeod, Ruth; Krause, Eberhard; Baillie, George; Houslay, Miles.

In: Proceedings of the National Academy of Sciences , Vol. 105, No. 35, 02.09.2008, p. 12791-12796 .

Research output: Contribution to journalArticle

TY - JOUR

T1 - EPAC and PKA allow cAMP dual control over DNA-PK nuclear translocation

AU - Huston, Elaine

AU - Lynch, Martin

AU - Mohamed, Ahmed

AU - Collins, Daniel

AU - Hill, Elaine

AU - MacLeod, Ruth

AU - Krause, Eberhard

AU - Baillie, George

AU - Houslay, Miles

N1 - 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.

PY - 2008/9/2

Y1 - 2008/9/2

N2 - 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.

AB - 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.

KW - phosphodiesterase

KW - PDE4

KW - rolipram

KW - EPAC

KW - Akt

KW - PKB

KW - double stranded breaks

KW - DNA repair

KW - DSB

U2 - 10.1073/pnas.0805167105

DO - 10.1073/pnas.0805167105

M3 - Article

VL - 105

SP - 12791

EP - 12796

JO - Proceedings of the National Academy of Sciences

JF - Proceedings of the National Academy of Sciences

SN - 1091-6490

IS - 35

ER -