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The catalytic activity-independent functions of Phosphodiesterase 4D5 in mTORC1 and Phospholipase D2 regulation

The catalytic activity-independent functions of Phosphodiesterase 4D5 in mTORC1 and Phospholipase D2 regulation
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Cyclic 3’, 5’-monophosphate (cAMP) is a second messenger involved in various cellular functions as a response to environmental cues. The canonical function of various cyclic nucleotide phosphodiesterases (PDEs) is delicate control of the intracellular cAMP level. Most PDE related cellular functions are controlled either by the cAMP hydrolyzing activity of PDEs at particular subcellular locations or by the regulation of PDEs’ enzymatic activity through diverse binding partners. Although many studies were focused on the spatiotemporal regulation of PDE for the degradation of cAMP, the non-canonical functions of PDEs, which are independent of its cAMP hydrolysis activity, are not well understood. 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, I 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. In this study, my 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. I also propose a new role for PDE4 as a molecular transducer for cAMP signaling. Phospholipase D (PLD) is an enzyme that hydrolyzes phosphatidylcholine (PC) into phosphatidic acid (PA) in response to various signals. Although many reports have suggested various activation mechanisms of PLD through a number of stimuli or upstream molecules, the deactivation mechanism of PLD has not yet been fully understood. In this study, I identify Phosphodiesterase 4D5 (PDE4D5) as a binding partner of PLD2 that functions as a negative regulator of PLD signaling. In addition, PDE4D5 can recognize intracellular levels of PA which are increased by PLD activity, and enhance interactions with PLD2 resulting in inhibited PLD2 activity. Indeed, the negative effects of PDE4D5 on PLD2 activity are independent of its hydrolyzing activity for cAMP. I also suggest a novel function of PDE4D5 as a molecular sensor for turn-off of PLD signaling. In this study, I propose novel non-canonical functions of PDE4D5 that are independent of cAMP hydrolyzing activity. I also suggest that PDE4D5 functions as a molecular sensor for two second messengers, cAMP and PA. They may provide a starting concept for the study of PDE as a dynamic hub and a molecular sensor in the signaling network of cells.
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