Abstract
Diacylglycerol kinase (DGK) phosphorylates diacylglycerol (DG) to generate phosphatidic acid (PA). Mammalian DGK consists of ten isozymes (α–κ) and governs a wide range of physiological and pathological events, including immune responses, neuronal networking, bipolar disorder, obsessive-compulsive disorder, fragile X syndrome, cancer, and type 2 diabetes. DG and PA comprise diverse molecular species that have different acyl chains at the sn-1 and sn-2 positions. Because the DGK activity is essential for phosphatidylinositol turnover, which exclusively produces 1-stearoyl-2-arachidonoyl-DG, it has been generally thought that all DGK isozymes utilize the DG species derived from the turnover. However, it was recently revealed that DGK isozymes, except for DGKε, phosphorylate diverse DG species, which are not derived from phosphatidylinositol turnover. In addition, various PA-binding proteins (PABPs), which have different selectivities for PA species, were recently found. These results suggest that DGK–PA–PABP axes can potentially construct a large and complex signaling network and play physiologically and pathologically important roles in addition to DGK-dependent attenuation of DG–DG-binding protein axes. For example, 1-stearoyl-2-docosahexaenoyl-PA produced by DGKδ interacts with and activates Praja-1, the E3 ubiquitin ligase acting on the serotonin transporter, which is a target of drugs for obsessive-compulsive and major depressive disorders, in the brain. This article reviews recent research progress on PA species produced by DGK isozymes, the selective binding of PABPs to PA species and a phosphatidylinositol turnover-independent DG supply pathway.
Highlights
Diacylglycerol kinase (DGK) phosphorylates diacylglycerol (DG) to produce phosphatidic acid (PA) (Figure 1) [1,2,3,4,5]
These results suggest that DGK–PA–PA-binding proteins (PABPs) axes can potentially construct a large and complex signaling network and play physiologically and pathologically important roles in addition to DGK-dependent attenuation of DG–DG-binding protein axes
In addition to DG, PA has been reported to control a number of signaling proteins in mammals [11,12,13,14,15,16,17] such as protein kinases, including Raf-1 (C-Raf) kinase [18,19,20], PKCε [21,22], PKCζ [23] and mammalian target of rapamycin [24]; lipid kinases including phosphatidylinositol (PI)-4-phosphate 5-kinase (PIP5K) [25,26] and sphingosine kinase (SphK) 1 [27]; protein phosphatases including protein phosphatase-1 catalytic subunit (PP1c) [28]; lipid phosphatases including Lipin 1β [29]; phospholipases including phospholipase C (PLC) β1 and γ1 [30]; G-protein regulators including RasGAP [31] and chimaerin [32,33]; G-proteins including ADP-ribosylation factor (Arf) 1 [34] and Rac1 [35,36]; phosphodiesterases including cAMP phosphodiesterase (PDE)-4A1 [37,38]
Summary
Diacylglycerol kinase (DGK) phosphorylates diacylglycerol (DG) to produce phosphatidic acid (PA) (Figure 1) [1,2,3,4,5]. In addition to DG, PA has been reported to control a number of signaling proteins in mammals [11,12,13,14,15,16,17] such as protein kinases, including Raf-1 (C-Raf) kinase [18,19,20], PKCε (nPKC) [21,22], PKCζ (aPKC) [23] and mammalian target of rapamycin (mTOR) [24]; lipid kinases including phosphatidylinositol (PI)-4-phosphate 5-kinase (PIP5K) [25,26] and sphingosine kinase (SphK) 1 [27]; protein phosphatases including protein phosphatase-1 catalytic subunit (PP1c) [28]; lipid phosphatases including Lipin 1β [29]; phospholipases including phospholipase C (PLC) β1 and γ1 [30]; G-protein regulators including RasGAP [31] and chimaerin [32,33]; G-proteins including ADP-ribosylation factor (Arf) 1 [34] and Rac1 [35,36]; phosphodiesterases including cAMP phosphodiesterase (PDE)-4A1 [37,38].
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