The Lipid Second Messenger Phosphatidic Acid Frees mTORC1 from Inhibition by DEPTOR

The mammalian target of rapamycin complex 1 (mTORC1) integrates a variety of intra- and extra-cellular signals to control cell growth. To do so, mTORC1 is regulated, in part, by the endogenous inhibitor DEPTOR. A study led by Dr. Mee-Sup Yoon and Christina Rosenberger in the lab of Cell and Developmental Biology department head, Dr. Jie Chen, revealed that DEPTOR is rapidly and temporarily dissociated from mTORC1 upon mitogenic stimulation.

This mitogen stimulated DEPTOR dissociation is dependent on the mTORC1 regulator, phospholipase D (PLD), and recapitulated with the addition of the PLD product phosphatidic acid (PA). Interestingly, this study also revealed that only PA species with unsaturated fatty acid chains, such as those produced by PLD, are capable of displacing DEPTOR and activating mTORC1, with high affinity for the FRB domain of mTOR. These findings from the Chen lab and colleagues reveal a novel mechanism of mTOR regulation and provide a molecular explanation for the exquisite specificity of PA function.