Phosphatidic Acid-Mediated Mitogenic Activation of mTOR Signaling

Abstract

The mammalian target of rapamycin (mTOR) governs cell growth and proliferation by mediating the mitogen- and nutrient-dependent signal transduction that regulates messenger RNA translation. We identified phosphatidic acid (PA) as a critical component of mTOR signaling. In our study, mitogenic stimulation of mammalian cells led to a phospholipase D-dependent accumulation of cellular PA, which was required for activation of mTOR downstream effectors. PA directly interacted with the domain in mTOR that is targeted by rapamycin, and this interaction was positively correlated with mTOR's ability to activate downstream effectors. The involvement of PA in mTOR signaling reveals 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 the immunosuppressant rapamycin.

Phorbol 12-myristate 13-acetate and serum synergize to promote rapamycin-insensitive cell proliferation via protein kinase C-eta

“…A similar mechanism, albeit indirect, may also participate in the rapamycin resistance described in our studies. It is believed that phosphatidic acid (PA) and rapamycin compete for binding sites on mTOR, and this mechanism accounts for PA-mediated rapamycin resistance in breast cancer cells (Fang et al, 2001). As PA is known to activate PKC isozymes, it is possible that PKC activation could lead to PLD production of PA and phosphatidylcholine that, in turn, would activate PKC isozymes (Lang et al, 1995).…”

New strategies in sport nutrition to increase exercise performance

“…As such, PA plays a fundamental role in the regulation of cellular metabolism [181]. As discussed in previous sections, in addition to its metabolic role, PA has also emerged as a key signaling intermediate in skeletal muscle following the observation that PA can activate mTORC1 and by extension increase protein synthesis in vitro [182] (Figure 2). Whilst the interaction between PA and mTORC1 has been Following the training period, the authors reported a 12.7% increase in squat strength and a 2.6% increase in LBM in the PA group, compared to a 9.3% improvement in squat strength and a 0.1% change in LBM in the placebo group.…”

Rapamycin and mTOR kinase inhibitors

“…Unfortunately, they did not show if the compound inhibits mTOR kinase activity in vitro. Interestingly, these investigators also found that phosphatidic acid, which activates mTOR [40], interacts with the FRB domain in the same binding pocket as rapamycin. It remains unclear why binding of phosphatidic acid activates mTOR whereas rapamycin binding has the opposite effect.…”