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  • The most significant source of DAG originates from the PLC


    The most significant source of DAG originates from the PLC family of enzymes, which produces DAG in an agonist-regulated reaction. PLCs constitute a wide family of enzymes acting on both phosphatidilinositols (PI) and phosphatidilcoline (PC) (Li et al., 2010) in the plasma membrane and other intracellular locations. The best characterized members are PI-specific PLC, a multigene family of enzymes that play a key role in signal transduction. PI-PLC are cytosolic enzymes which translocate to the plasma membrane and become active in response to signaling through G protein coupled receptors (mainly PLCβ), receptor and soluble tyrosine kinases (classically PLCγ), active small GTPases of the Ras family (PLCɛ), phosphatidylinositol bisphosphate (PIP2, such as PLCδ) and calcium (primarily PLCζ and PLCη) (Kadamur and Ross, 2013). A second source of DAG comes from phosphatidic pdk1 (PA) dephosphorylation, which is carried out by the lipin family of PA-specific phosphatases (PAP) and by the broad specificity lipid phosphate phosphatases (Brindley et al., 2009). Lipins are mainly associated with the nuclear and endoplasmic reticulum membranes to produce DAG for the biosynthesis of triglycerides (Zhang et al., 2012). The involvement of PA phosphatases in signal transduction by decreasing PA and increasing DAG at intracellular membranes has been suggested in several studies, but remains poorly characterized (Baron and Malhotra, 2002, Mor et al., 2007). Conversely, DAG generated by triglyceride lipase (TAGL) is further degraded to free fatty acid and glycerol, indicating TAGL does not contribute significantly to cellular DAG levels (Inoue et al., 2011). Sphingomyelin synthases (SMS) represent a third recognized intracellular source of DAG in signal transduction. These enzymes synthesize sphingomyelin by utilizing phosphatidylcholine as a donor of the phosphocholine group to ceramide, which produces DAG as an additional product of the reaction (Villani et al., 2008). SMS enzymes are activated by growth factors and oncogenes, which can result in sufficient DAG accumulation to induce signaling such as PKD (protein kinase D) recruitment and activation at the Golgi (Baron and Malhotra, 2002).
    Rapid DAG metabolism limits its concentration and localizes signals Basal DAG is generated continuously by dephosphorylation of PA at endomembranes and mitochondrial outer membranes (Sato et al., 2006). A low level of PLC activation at the plasma membrane by receptors for extracellular matrix and soluble factors may also contribute to basal DAG signaling (Markegard et al., 2011). Thus the limited quantity of DAG present in different membranes (1–2 mol%) implies a balance between synthesis, diffusion and rapid metabolism in cells. Indeed, studies with short chain DAG analogs (dioctanoyl-glycerol) indicates that DAG is rapidly metabolized to triglycerides, PC and, in lower amounts, PA (Florin-Christensen et al., 1993). Unsaturated DAG such as 1-stearoyl-2-arachidonoyl-sn-glycerol is instead metabolized mainly to PC but also to PA and PI (Florin-Christensen et al., 1992, Florin-Christensen et al., 1993). The main metabolic pathway for saturated DAG is the synthesis of triglycerides in the endoplasmic reticulum by DAG-acyltransferase (DGAT) (Yen et al., 2008), and for synthesis of PC and PE. Phospholipid synthesis takes place in the ER, where CEPT transfers phosphor-ethanolamine from CDP-ethanolamine to DAG, and at the Golgi, where CPT transfers phosphor-choline from CDP-choline to DAG (Henneberry et al., 2002). The DAG pools involved in triglyceride and phospholipid synthesis are generally thought to be inactive for signaling. Indeed, the impairment of the lipid biosynthetic pathways that normally consume DAG does not result in activation of DAG signaling, but in redirection of the excess DAG along alternative metabolic routes (Lagace and Ridgway, 2013).
    Diacylglycerol kinases and the regulation of “signaling” DAG