EPAC and PKA allow cAMP dual control over DNA-PK nuclear translocation (PNAS, 2008, 105:12791-12796)

報告日期: 2009/05/26
報告時間: 15:10/16:00
報告學生: 陳玉霖(英文報告)
講評老師: 黃溫雅


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


Elaine Huston, Martin J. Lynch, Ahmed Mohamed, Daniel M. Collins, Elaine V. Hill, Ruth MacLeod, Eberhard Krause, George S. Baillie, and Miles D. Houslay


PNAS 2008; 105(35): 12791–12796.


Speaker:Uy-Lin Chen (陳玉霖)

Commentator: Wenya Huang, Ph. D. (黃溫雅 老師)

Date: 5/26 15:10 – 16:00


DNA-dependent protein kinase (DNA-PK) plays a central role in the DNA repair systems that are essential for the maintenance of chromosomal integrity. It can be regulated by PKA through three PKA phosphorylation sites while it can activate antiapoptotic PKB/Akt.  The translocation of DNA-PK between nuclear and cytoplasm is vital for its function. However, the regulation of DNA-PK trafficking mechanism remains unknown. Cyclic AMP (cAMP) is synthesized from adenylyl cyclase (AC) activation by Gas-containing G-protein- coupled receptors (GPCRs). cAMP is an important intracellular second messenger in cell communication, especially in response to hormone action. On the other hand, phosphodiesterases hydrolyze both cAMP and cGMP, thus regulating the intracellular cAMP and cGMP gradient. Moreover, PED4 plays a major role of inactivating cAMP and confers isoform-specific targeting to distinct intracellular site in HEK-B2 cells. The author observed that adenylyl cyclase activator forskolin causes a dramatic translocation of DNA-PK to the cytoplasm. Further study revealed that cAMP has dual control role between PKA and EPAC in the regulation of DNA-PK trafficking. They found that EPAC is coupled to Rap2-dependent nuclear exit of DNA-PK leading to PKA/Akt phosphorylation at Ser-473. However, PKA antagonizes EPAC action by promoting DNA-PK nuclear entry through the phosphorylation of DNA-PK at Ser-1790. This study provides evidence for a compartmentalized regulatory system of cAMP modulation and how this system regulates DNA-PK trafficking between cytoplasm and nucleus.



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