cAMP controls mTOR through regulation of the dynamic interaction between Rheb and Phosphodiesterase 4D

Kim, H. W., Ha, S. H., Lee, M. N., Huston, E., Kim, D.-H., Jang, S. K., Suh, P.-G., Houslay, M. D. and Ryu, S. H. (2010) cAMP controls mTOR through regulation of the dynamic interaction between Rheb and Phosphodiesterase 4D. Molecular and Cellular Biology, 30(22), pp. 5406-5420. (doi:10.1128/MCB.00217-10)

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Publisher's URL: http://dx.doi.org/10.1128/MCB.00217-10

Abstract

The mammalian target of rapamycin complex 1 (mTORC1) is a molecular hub that regulates protein synthesis in response to a number of extracellular stimuli. 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 non-catalytic 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

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Houslay, Professor Miles and Huston, Dr Elaine
Authors: Kim, H. W., Ha, S. H., Lee, M. N., Huston, E., Kim, D.-H., Jang, S. K., Suh, P.-G., Houslay, M. D., and Ryu, S. H.
College/School:College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
Journal Name:Molecular and Cellular Biology
Publisher:American Society for Microbiology
ISSN:0270-7306
ISSN (Online):1098-5549
Published Online:13 September 2010
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
438301Phosphodiesterase-4 isoforms - intracellular targeting, regulation and potential therapeutic targetsMiles HouslayMedical Research Council (MRC)G0600765Institute of Neuroscience and Psychology
432501Transatlantic networks of excellence in cardiovascular diseaseMiles HouslayFoundation Leducq (LEDUCQ-VIL)06 CVD 02Institute of Neuroscience and Psychology