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  • LPA is known to regulate


    LPA is known to regulate the peroxisome proliferator-activated receptor γ and the reorganization of actin cytoskeleton [58]. However, the physiological functions of LPA in cells are still poorly understood. The simultaneous production of PA with/without 1-LPA or 2-LPA may be important to maximize a variety of physiological functions of DGKs [1], [2], [3], [4], [5], [6]. This study provides a new aspect of DGK and will enhance the elucidation of the physiological functions of LPA in cells.
    Conflicts of interest
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    Acknowledgments This work was supported by MEXT/JSPS KAKENHI Grant Numbers 22370047 (Grant-in-Aid for Scientific Research (B)), 23116505 (Grant-in-Aid for Scientific Research on Innovative Areas), 25116704 (Grant-in-Aid for Scientific Research on Innovative Areas), 26291017 (Grant-in-Aid for Scientific Research (B)) and 15K14470 (Grant-in-Aid for Challenging Exploratory Research), the Japan Science and Technology Agency (AS221Z00794F, AS231Z00139G, AS251Z01788Q and AS2621643Q), the Naito Foundation, the Hamaguchi Foundation for the Advancement of Biochemistry, the Daiichi-Sankyo Foundation of Life Science, the Terumo Life Science Foundation, the Futaba Electronic Memorial Foundation, the Daiwa Securities Health Foundation, the Ono Medical Research Foundation, the Japan Foundation for Applied Enzymology, the Food Science Institute Foundation, the Skylark Food Science Institute, the Asahi Group Foundation and the Venture Business Laboratory of Chiba University (FS).
    Introduction Diacylglycerol kinase (DGK) is a lipid-metabolizing enzyme that phosphorylates diacylglycerol to produce phosphatidic acid. Diacylglycerol and phosphatidic monocarboxylate transporters act as lipid second messengers in a wide variety of biological processes in mammalian cells (English, 1996, Exton, 1994, Hodgkin et al., 1998). Thus, DGK plays a pivotal role in various intracellular signaling pathways by regulating diacylglycerol and phosphatidic acid concentrations. DGK represents a large enzyme family (Goto et al., 2006, Merida et al., 2008, Sakane et al., 2007, Topham and Epand, 2009). Ten DGK isozymes (α, β, γ, δ, η, κ, ε, ζ, ι, and θ) have been identified and classified into five subtypes based on their structural features. The type II DGK (Sakai and Sakane, 2012) comprises δ (Sakane et al., 1996), η (Klauck et al., 1996), and κ (Imai et al., 2005). Moreover, alternative splicing products of DGKδ (δ1 and δ2) (Sakane et al., 2002) and DGKη (η1 and η2) (Murakami et al., 2003) have been identified. All of the type II DGK isoforms possess a pleckstrin homology domain at their N-termini and a separate catalytic region, and DGKs δ1, δ2, and η2, but not DGKη1, contain a sterile α-motif domain at their C-termini. DGKδ2 specifically contains the Pro-rich 52 residues extending from the N-terminus (Sakane et al., 2002). A tumor-promoting phorbol ester, 12-O-tetradecanoylphorbol 13-acetate, induces the phosphorylation, oligomer-monomer conversion and translocation to the plasma membrane of DGKδ1 (Imai et al., 2002, Imai et al., 2004, Sakane et al., 2002). DGKδ1 translocates from the cytoplasm to the plasma membrane via the pH and C1 domains in response to high glucose levels (Takeuchi et al., 2012). DGKδ forms oligomeric (at least tetrameric) structures in vitro and in vivo and that the SAM domain plays a critical role in oligomer formation (Harada et al., 2008, Imai et al., 2002, Knight et al., 2010, Sakane et al., 2002). Based on the analysis of DGKδ-knockout (KO) mice, it has recently been reported that DGKδ regulates the epidermal growth factor receptor pathway in epithelial cells of the lungs and skin (Crotty et al., 2006) and insulin receptor signaling in skeletal muscle (Chibalin et al., 2008, Miele et al., 2007) by modulating PKC activity. In addition to being expressed in skeletal muscle cells (Chibalin et al., 2008, Miele et al., 2007, Sakai et al., 2014, Sakane et al., 1996), DGKδ was abundantly expressed in mouse brains (Usuki et al., 2015). DGKδ2, but not DGKδ1, was highly expressed in layers II–VI of the cerebral cortex, hippocampus, dentate gyrus, the mitral cell, monocarboxylate transporters granule cell and glomerular layers of the olfactory bulb and the granule cell layer of the cerebellum in one- to 32-week-old mice (Usuki et al., 2015). DGKδ2 was expressed just after birth, and its expression levels dramatically increased from one to four weeks. Moreover, DGKδ has been reported to be related to neurological disorders (Leach et al., 2007). A female patient with a de novo balanced translocation, 46,X,t(X;2)(p11.2;q37)dn, exhibited seizures, capillary abnormality, developmental delay, infantile hypotonia and obesity (Leach et al., 2007). However, the functions of DGKδ in neurological disorders are still unclear.