Phosphatidic acid-mediated mitogenic activation of mTOR signaling

The mammalian target of rapamycin (mTOR) governs cell growth and proliferat ion by mediating the mitogen- and nutrient-dependent signal transduction th at regulates messenger RNA translation. We identified phosphatidic acid (PA ) as a critical component of mTOR signaling. In our study, mitogenic stimul ation of mammalian cells led to a phospholipase D-dependent accumulation of cellular PA, which was required for activation of mTOR downstream effector s. PA directly interacted with the domain in mTOR that is targeted by rapam ycin, and this interaction was positively correlated with mTOR's ability to activate downstream effectors. The involvement of PA in mTOR signaling rev eals an important function of this lipid in signal transduction and protein synthesis, as well as a direct link between mTOR and mitogens. Furthermore , these studies suggest a potential mechanism for the in vivo actions of th e immunosuppressant rapamycin.