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. 2013 Jun;24(6):272-8.
doi: 10.1016/j.tem.2013.02.003. Epub 2013 Mar 16.

Phosphatidic acid and lipid-sensing by mTOR

David A Foster  1
Affiliations

Phosphatidic acid and lipid-sensing by mTOR

David A Foster. Trends Endocrinol Metab. 2013 Jun.

Abstract

Mammalian _target of rapamycin (mTOR) has been implicated as a sensor of nutrient sufficiency for dividing cells and is activated by essential amino acids and glucose. However, cells also require lipids for membrane biosynthesis. A central metabolite in the synthesis of membrane phospholipids is phosphatidic acid (PA), which is required for the stability and activity of mTOR complexes. Although PA is commonly generated by the phospholipase D-catalyzed hydrolysis of phosphatidylcholine, PA is also generated by diacylglycerol kinases and lysophosphatidic acid acyltransferases, which are at the center of phospholipid biosynthesis. It is proposed that the responsiveness of mTOR/TOR to PA evolved as a means for sensing lipid precursors for membrane biosynthesis prior to doubling the mass of a cell and dividing.

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Figures

Figure 1
Figure 1. Nutrient signals to mTOR
Regulation of mTOR has many inputs. The PI3K input involves the generation of PIP3 from PIP2, which recruits and activates phosphoinositide-dependent kinase 1 (PDK1), which then phosphorylates Akt at Thr308. Subsequently, Akt phosphorylates and suppresses the GAP activity of the tuberous sclerosis complex (TSC) consisting of TSC1 and TSC2 (TSC1/2). Suppression of TSC1/2 results in elevated activation of the GTPase Rheb, which leads to a complex activation of mTORC1 via the activation of PLD1 and suppression of FKBP38 whereby elevated PLD activity generates the PA necessary for the formation of mTORC1 complex, and FKBP38 dissociates from mTORC1(49). This pathway is also impacted by AMPK, which in combination with the tumor suppressor LKB1 activates TSC1/2, which suppresses Rheb and thus mTOR – under conditions where ATP levels are low and AMP levels are high. Akt is also phosphorylated by mTORC2 at Ser473 in response to insulin and insulin-like growth factor 1 (IGF1), in a PLD-dependent manner. Phosphorylation at this site has been correlated with altered substrate specificity and kinase activity for Akt. Insulin also increases the level of glucose transporters and increased uptake of glucose (18). A common theme in this complex signaling network leading to mTORC1 activation is that it is highly sensitive to the presence of glucose and amino acids – nutrients needed for cell growth.
Figure 2
Figure 2. Phosphatidic acid metabolism
(a) PA can be generated by three major mechanisms – first by the de novo synthesis pathway that involves the acylation of G3P by GPAT and LPAAT (Blue). G3P is generated by the reduction of the glycolytic intermediate DHAP. The FAs that acylate G3P can be synthesized by FAS and then elongated and mono-desaturated in mammalian cells. However, dietary essential FAs are required in mammalian cells for the synthesis of poly-unsaturated FAs needed for the acylation of membrane phospholipids. The second pathway involves the phosphorylation of DG by DG kinases (Green). The DG required for this pathway must come from either deacylated triglyceride or PLC-generated DG derived primarily from phosphatidylinositol-4,5-trisphosphate. Thus, DG kinase can generate PA in response to growth factor induced PLC, or from stored lipids via triglyceride lipases. The third pathway involves the hydrolysis of phosphatidylcholine by PLD (Black). This pathway is not likely involved in the generation of PA for membrane biosynthesis since the PA is derived from a membrane phospholipid. The same is true for the PLC pathway that hydrolyzes phosphatidylinositol to generate DG. These pathways likely represent growth factor-dependent stimulation of PA production that occurs in the absence of membrane biosynthesis and is restricted to multicellular organisms. As indicated, PA is a substrate for the synthesis of phosphatidylinositol (PI), phsophatidylglycerol (PG) and cardiolipin (CL). DG generated by PA phosphatase (PA P’tase) is the substrate for the synthesis phosphatidylserine (PS), phosphatidylethanolamine (PE), and phosphatidylcholine (PC) (Red). (b) PA is generated from the glycolytic intermediate DHAP. Glycolysis represents the conversion of the 6-carbon glucose to two molecules of the 3-carbon pyruvate. The last step is catalyzed by pyruvate kinase (PK), which in dividing cells involves an embryonic isoform known as PKM2, which has a slower catalytic rate (41) that can be made even slower by tyrosine phosphorylation (42). The outcome of the reduced pyruvate kinase activity coupled with increased glucose uptake is the accumulation of glycolytic intermediates (43). The elevated level of glycolytic intermediates is the conversion to molecules for anabolic synthesis of biological molecules that are needed to double the mass of a dividing cell. The most understood utilization of a glycolytic intermediate is the pentose phosphate shunt, which generates ribose that can be utilized in the synthesis of nucleic acids (Blue). The pentose phosphate shunt also leads to the generation of NADPH that can be utilized in anabolic reactions – especially FA synthesis. Amino acids, most notably serine, are generated from 3-phosphoglycerate (PHG) via the conversion to phosphopyruvate by PHG dehydrogenase and then to serine by phosphoserine amino transferase (Green). Glycerol-3-phosphate, the substrate for the acyltransferases that generate PA, is generated from DHAP by reduction to G3P by G3P dehydrogenase (Red). Of interest, the enzyme that converts DHAP to glyceraldhyde-3-phosphate, triose phosphate isomerase, is suppressed by phosphoenolpyruvate (45).
Figure 3
Figure 3. Regulation of TOR by phosphatidic acid
(a) There are two major destinations for newly synthesized PA – membrane phospholipids when cells are in a proliferative mode, and triglycerides when cells are in a storage mode. In storage mode it is postulated that there is more newly synthesized saturated palmitic acid used for triglyceride synthesis; whereas in proliferation mode, there are more elongated and desaturated FAs utilized to maintain membrane fluidity and provide poly-unsaturated FAs (PUFAs) for eicosanoid synthesis. PA with two saturated FAs was reported to suppress mTORC2 (48). Thus, there appears to a mechanism whereby mTOR can distinguish between PA directed towards membrane biosynthesis and PA directed to triglyceride storage. (b) The PA-binding domain of TOR is within the region of TOR that also binds rapamycin (5, 52). This sequence contains a critical Arg residue at position 2109 (human sequence), critical for PA binding (5). There is also a conserved positively charged amino acid at the adjacent position at 2110, and highly conserved regions flanking these two positive charges all the way from yeast to humans. Sequence number is relative to Arg 2109 of the human sequence. Many of these sequences were assembled previously (53).
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References

    1. Polak P, Hall MN. mTOR and the control of whole body metabolism. Curr. Opin. Cell Biol. 2009;21:209–218. - PubMed
    1. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006;124:471–484. - PubMed
    1. Sengupta S, Peterson TR, Sabatini DM. Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. Mol Cell. 2010;40:310–322. - PMC - PubMed
    1. Avruch J, Long X, Ortiz-Vega S, Rapley J, Papageorgiou A, Dai N. Amino acid regulation of TOR complex 1. Am. J. Phys. Endocrin. Metab. 2009;296:E592–E602. - PMC - PubMed
    1. Fang Y, Vilella-Bach M, Bachmann R, Flanigan A, Chen J. Phosphatidic acid-mediated mitogenic activation of mTOR signaling. Science. 2001;294:1942–1945. - PubMed

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