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首页> 外文期刊>Molecular and Cellular Biology >Cyclic AMP Controls mTOR through Regulation of the Dynamic Interaction between Rheb and Phosphodiesterase 4D
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Cyclic AMP Controls mTOR through Regulation of the Dynamic Interaction between Rheb and Phosphodiesterase 4D

机译：循环AMP通过调节Rheb和磷酸二酯酶4D之间的动态相互作用来控制mTOR

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摘要

The mammalian target of rapamycin complex 1 (mTORC1) is a molecular hub that regulates protein synthesis in response to a number of extracellular stimuli. Cyclic AMP (cAMP) is considered to be an important second messenger that controls mTOR; however, the signaling components of this pathway have not yet been elucidated. Here, we identify cAMP phosphodiesterase 4D (PDE4D) as a binding partner of Rheb that acts as a cAMP-specific negative regulator of mTORC1. Under basal conditions, PDE4D binds Rheb in a noncatalytic manner that does not require its cAMP-hydrolyzing activity and thereby inhibits the ability of Rheb to activate mTORC1. However, elevated cAMP levels disrupt the interaction of PDE4D with Rheb and increase the interaction between Rheb and mTOR. This enhanced Rheb-mTOR interaction induces the activation of mTORC1 and cap-dependent translation, a cellular function of mTORC1. Taken together, our results suggest a novel regulatory mechanism for mTORC1 in which the cAMP-determined dynamic interaction between Rheb and PDE4D provides a key, unique regulatory event. We also propose a new role for PDE4 as a molecular transducer for cAMP signaling.
机译：雷帕霉素复合物1（mTORC1）的哺乳动物靶标是一个分子枢纽，可响应多种细胞外刺激来调节蛋白质的合成。循环AMP（cAMP）被认为是控制mTOR的重要第二信使。然而，该途径的信号传导成分尚未阐明。在这里，我们确定cAMP磷酸二酯酶4D（PDE4D）作为Rheb的结合伴侣，它充当mTORC1的cAMP特异性负调节剂。在基本条件下，PDE4D以不需要催化cAMP水解活性的非催化方式结合Rheb，从而抑制Rheb激活mTORC1的能力。但是，升高的cAMP水平会破坏PDE4D与Rheb的相互作用，并增加Rheb与mTOR之间的相互作用。 Rheb-mTOR相互作用的增强诱导了mTORC1的激活和帽依赖性翻译，即mTORC1的细胞功能。两者合计，我们的结果表明mTORC1的新型调节机制，其中Rheb和PDE4D之间的cAMP决定的动态相互作用提供了关键的独特调节事件。我们还提出了PDE4作为cAMP信号传导分子转导子的新作用。

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