Huston Elaine, Lynch Martin J, Mohamed Ahmed, Collins Daniel M, Hill Elaine V, MacLeod Ruth, Krause Eberhard, Baillie George S, Houslay Miles D
Neuroscience and Molecular Pharmacology, Faculty of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland, UK.
Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):12791-6. doi: 10.1073/pnas.0805167105. Epub 2008 Aug 26.
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.
我们鉴定出一种区室化信号系统，该系统确定了鸟苷三磷酸（GTP）交换因子——环磷酸腺苷（cAMP）激活的交换蛋白（EPAC）在细胞核中与Rap2偶联时的功能作用。在该系统中，cAMP调节DNA依赖性蛋白激酶（DNA-PK）的核/质转运，DNA-PK是一种关键激酶，作用是修复受损DNA中的双链断裂（DSB）并磷酸化细胞存活激酶PKB/Akt。cAMP的交叉调节输入利用EPAC转导积极作用，即Rap2依赖性的DNA-PK核输出和激活，而蛋白激酶A（PKA）通过拮抗这些作用提供消极输入。我们将此鉴定为一种区室化调节系统，其中通过空间上离散的cAMP降解系统对进入刺激性的EPAC和抑制性的PKA交叉臂的cAMP输入进行调节。因此，DNA-PK在核和细胞质区室之间的分布可能会受到通过EPAC和PKA途径的cAMP信号相对输入的影响。通过这种信号系统，EPAC激活从而可能会影响PKB/Akt的Ser-473磷酸化状态以及依托泊苷诱导的DSB的修复。
