Journal
MOLECULAR AND CELLULAR BIOLOGY
Volume 30, Issue 22, Pages 5406-5420Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00217-10
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Funding
- 21C Frontier Functional Proteomics Project [FRP08B1-160]
- Korean Ministry of Education, Science, and Technology [KPF-2008-005-C00036]
- Medical Research Council (United Kingdom) [G0600765]
- Fondation Leducg [06CVD02]
- MRC [G0600765] Funding Source: UKRI
- Medical Research Council [G0600765] Funding Source: researchfish
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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.
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