Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang, Kyungbook 790-784, South Korea.
Mol Cell Biol. 2010 Nov;30(22):5406-20. doi: 10.1128/MCB.00217-10. Epub 2010 Sep 13.
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.
哺乳动物雷帕霉素靶蛋白复合物 1（mTORC1）是一个分子枢纽，可响应多种细胞外刺激调节蛋白质合成。环腺苷酸（cAMP）被认为是控制 mTOR 的重要第二信使；然而，该途径的信号成分尚未阐明。在这里，我们鉴定出 cAMP 磷酸二酯酶 4D（PDE4D）是 Rheb 的结合伴侣，它作为 mTORC1 的 cAMP 特异性负调节剂起作用。在基础条件下，PDE4D 以非催化方式与 Rheb 结合，这种结合方式不依赖其 cAMP 水解活性，从而抑制 Rheb 激活 mTORC1 的能力。然而，升高的 cAMP 水平会破坏 PDE4D 与 Rheb 的相互作用，并增加 Rheb 与 mTOR 的相互作用。这种增强的 Rheb-mTOR 相互作用诱导 mTORC1 的激活和帽依赖性翻译，这是 mTORC1 的一种细胞功能。总之，我们的结果表明了 mTORC1 的一种新的调节机制，其中 Rheb 和 PDE4D 之间由 cAMP 决定的动态相互作用提供了一个关键的、独特的调节事件。我们还提出了 PDE4 作为 cAMP 信号转导分子的新作用。
