Phospholipase D and the Maintenance of Phosphatidic Acid Levels for Regulation of Mammalian Target of Rapamycin (mTOR)

Abstract

Phosphatidic acid (PA) is a critical metabolite at the heart of membrane phospholipid biosynthesis. However, PA also serves as a critical lipid second messenger that regulates several proteins implicated in the control of cell cycle progression and cell growth. Three major metabolic pathways generate PA: phospholipase D (PLD), diacylglycerol kinase (DGK), and lysophosphatidic acid acyltransferase (LPAAT). The LPAAT pathway is integral to de novo membrane phospholipid biosynthesis, whereas the PLD and DGK pathways are activated in response to growth factors and stress. The PLD pathway is also responsive to nutrients. A key target for the lipid second messenger function of PA is mTOR, the mammalian/mechanistic target of rapamycin, which integrates both nutrient and growth factor signals to control cell growth and proliferation. Although PLD has been widely implicated in the generation of PA needed for mTOR activation, it is becoming clear that PA generated via the LPAAT and DGK pathways is also involved in the regulation of mTOR. In this minireview, we highlight the coordinated maintenance of intracellular PA levels that regulate mTOR signals stimulated by growth factors and nutrients, including amino acids, lipids, glucose, and Gln. Emerging evidence indicates compensatory increases in one source of PA when another source is compromised, highlighting the importance of being able to adapt to stressful conditions that interfere with PA production. The regulation of PA levels has important implications for cancer cells that depend on PA and mTOR activity for survival.

Reciprocal Regulation of AMP-activated Protein Kinase and Phospholipase D

“…It could also indicate sufficient glucose and glutamine, which are key nutrients that are incorporated into PA (50). We have proposed that the PA requirement of mTOR evolved as a means to sense the presence of sufficient materials for membrane synthesis to complement the ability to sense amino acids (50,51). Consistent with this hypothesis, the enzymes involved in the de novo synthesis of PA stimulate mTOR (52,53), indicating that the PA requirement of mTOR is related to the ability to synthesis membrane phospholipids.…”

“…PA occupies a central spot in membrane phospholipid biosynthesis and is therefore an ideal indicator of lipid sufficiency. It could also indicate sufficient glucose and glutamine, which are key nutrients that are incorporated into PA (50). We have proposed that the PA requirement of mTOR evolved as a means to sense the presence of sufficient materials for membrane synthesis to complement the ability to sense amino acids (50,51).…”

Inhibited Insulin Signaling in Mouse Hepatocytes Is Associated with Increased Phosphatidic Acid but Not Diacylglycerol

“…We have reported that GPAT1-derived PA disrupts the assembly of mTOR and rictor, thereby diminishing phosphorylation of phospho-Akt (Ser-473) and inhibiting insulin signaling (12). Others, however, have shown that PLD-derived PA promotes the assembly of both mTOR-raptor and mTOR-rictor (16,33). How can chemically identical molecules have opposite functions?…”

“…Akt in Mouse Hepatocytes-The PLD-mediated hydrolysis of phosphatidylcholine to produce PA has taken center stage in mTOR signaling (32,33). PA derived via PLD stimulates mTORC1/S6K1 signaling and increases the phosphorylation of IRS-1 on serines 307, 632, and 636/639, residues that inhibit insulin signaling to Akt (34,35).…”

Thematic Minireview Series on Phospholipase D and Cancer

“…In the fourth and last minireview, "Phospholipase D and the Maintenance of Phosphatidic Acid Levels for Regulation of mTOR", Foster et al (38) highlight the coordinated maintenance of intracellular PA levels that regulate mTOR signaling, as stimulated by growth factors and nutrients. This minireview discusses how cells compensate for the loss of one PA-generating system with the activation of an alternate system to generate PA.…”