Ty of New York, New York, New YorkPhosphatidic acid (PA) is actually a crucial metabolite in the heart of membrane phospholipid biosynthesis. However, PA also serves as a essential lipid second messenger that regulates numerous proteins implicated inside the control of cell cycle progression and cell growth. Three main metabolic pathways create 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 development components and tension. The PLD pathway can also be responsive to nutrients. A essential target for the lipid second messenger function of PA is mTOR, the mammalian/mechanistic target of rapamycin, which integrates both nutrient and development factor signals to manage cell growth and proliferation. Although PLD has been broadly implicated in the generation of PA necessary for mTOR activation, it is actually becoming clear that PA generated by way of 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 elements and nutrients, like amino acids, lipids, glucose, and Gln. Emerging proof indicates compensatory increases in one source of PA when one more source is compromised, highlighting the value of having the ability to adapt to stressful situations that interfere with PA production. The regulation of PA levels has critical implications for cancer cells that rely on PA and mTOR activity for survival.phospholipid biosynthesis (Fig. 1), and as a consequence, the degree of PA is meticulously controlled to preserve lipid homeostasis (1, two). Also, PA has emerged as a important factor for quite a few crucial signaling molecules that regulate cell cycle progression and survival, which includes the protein kinases mTOR (mammalian/ mechanistic target of rapamycin) (three) and Raf (four). Of significance, each mTOR and Raf have already been implicated in human cancer. Consistent with this emerging role for PA in regulating cell proliferation, elevated expression and/or activity of enzymes that generate PA is commonly observed in human cancer, most notably phospholipase D (PLD) (5, six), that is elevated particularly in KRasdriven cancers (7).196862-45-0 manufacturer Other enzymes that generate PA (lysophosphatidic acid (LPA) acyltransferase (LPAAT), and diacylglycerol (DG) kinase (DGK) (Fig.191348-16-0 manufacturer 1)) have also been implicated in human cancers (10 4).PMID:23771862 Importantly, LPAAT and DGK have already been shown to stimulate mTOR (14 7), reinforcing the importance of the PAmTOR axis in the manage of cell development and proliferation. In addition, there appears to be compensatory production of PA below stressful conditions exactly where a single source of PA is compromised (7, 18). The LPAAT pathway, which can be an integral component on the de novo pathway for biosynthesis of membrane phospholipids, is most likely by far the most significant supply of PA for lipid biosynthesis. Having said that, growth factors (6) and nutrients (19, 20) also stimulate PA production by means of the action of phospholipases that breakdown membrane phospholipids, potentially top to high PA concentrations at distinct places and occasions. This can be accomplished by PLD, or a mixture of phospholipase C (PLC), which generates DG, and also the subsequent conversion to PA by DGK. The generation of PA from membrane phospholipids by phospholipases produces PA predominantly for second messenger effects.