The CREB coactivator TORC2 functions as a calcium- and cAMP-sensitive coincidence detector
The CREB coactivator TORC2 functions as a calcium- and cAMP-sensitive coincidence detector
复制标题
DOI：
10.1016/j.cell.2004.09.015
复制
发表时间：
2004-10-01
期刊：
影响因子：
64.5
通讯作者：
Montminy, M
中科院分区：
文献类型：
--
作者：
Screaton, RA;Conkright, MD;Montminy, M
在饲养过程中，循环葡萄糖和肠道激素的升高部分通过钙和camp依赖性转录因子CREB的激活来促进胰岛细胞的活力。在这里，我们描述了一个信号模块，通过刺激CREB共激活因子TORC2的去磷酸化和核进入，介导这些途径对细胞基因表达的协同作用。该模块由钙调节磷酸酶钙调磷酸酶和丝氨酸/苏氨酸激酶SIK2组成，两者都与TORC2相关。在静息条件下，TORC2通过磷酸化依赖的与14-3-3蛋白的相互作用被隔离在细胞质中。葡萄糖和肠道激素触发钙和cAMP第二信使通路，通过对TORC2去磷酸化的互补作用破坏TORC2:14-3-3复合物；钙内流增加钙调磷酸酶活性，而cAMP抑制SIK2激酶活性。我们的研究结果说明了磷酸酶/激酶模块如何连接两条信号通路，以响应营养和激素信号。
Elevations in circulating glucose and gut hormones during feeding promote pancreatic islet cell viability in part via the calcium- and cAMP-dependent activation of the transcription factor CREB. Here, we describe a signaling module that mediates the synergistic effects of these pathways on cellular gene expression by stimulating the dephosphorylation and nuclear entry of TORC2, a CREB coactivator. This module consists of the calcium-regulated phosphatase calcineurin and the Ser/Thr kinase SIK2, both of which associate with TORC2. Under resting conditions, TORC2 is sequestered in the cytoplasm via a phosphorylation-dependent interaction with 14-3-3 proteins. Triggering of the calcium and cAMP second messenger pathways by glucose and gut hormones disrupts TORC2:14-3-3 complexes via complementary effects on TORC2 dephosphorylation; calcium influx increases calcineurin activity, whereas cAMP inhibits SIK2 kinase activity. Our results illustrate how a phosphatase/kinase module connects two signaling pathways in response to nutrient and hormonal cues.