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    DGKη1 (type II DGK) has a separated catalytic domain [10], [13], whereas the domains of DGKα, ε and ζ are not split [1], [2], [3], [4], [5]. Therefore, the structural difference may cause the distinct affinity for DG among these isozymes. Because other type II DGKs (η2, δ1, δ2 and κ) also have the separated catalytic domain [8], [10], [12], [15], it is anticipated that these isoforms may also be the DG-high affinity isozymes. However, because the activities of these isoforms expressed in COS-7 Apatinib australia are rather low, it has been difficult to determine their kinetic parameters. The DGK isozymes are divided into five subgroups by structural features: type I (α, β and γ), II (δ, η and κ), III (ε), IV (ζ and ι) and V (θ) [1], [2], [3], [4], [5]. Moreover, arachidonic acid-containing DG-selectivity can also be used to categorize the isozymes into two groups: arachidonoyl DG-selective isozyme (ε) versus non-selective isozymes (α, β, γ, δ, η, κ, ζ, ι and θ) [1], [2], [3], [4], [5]. In addition to these categorizations, the results of this study provide a new classification based on different affinities for DG: high DG affinity type (η1) versus low DG affinity type (α, ε and ζ) (affinities of other isozymes for DG are presently unknown). These DG affinity differences are probably essential for the isozymes in serving their individual functions. DGKη1 is localized in the cytoplasm and is quickly translocated to unidentified punctate vesicles in the cytoplasm, but not to the plasma membrane, in response to osmotic shock [10]. We also revealed osmotic shock-dependent redistribution of DGKη1 to non-ionic detergent-resistant membrane microdomains [30]. Detergent-resistant membranes including lipid rafts are microdomains formed by the tight packing of sphingolipids and cholesterol [31]. Therefore, it is possible that there is only a low amount of DG in the detergent-resistant membrane microdomains, allowing us to speculate that DGKη1 may act in these microdomains where DG is not enriched. It is likely that different DGK isozymes are utilized under distinct conditions comprising different DG concentrations. For example, DGKη1 may play an important role under unstimulated conditions or at the early stage of cell stimulation where only low concentrations of DG are available (Supplemental Fig. S5A). In addition, the detergent-resistant membrane microdomains described above may be classified into the low DG conditions even in stimulated cells. Unlike DGKη1, DGKs α, ε and ζ may more strongly phosphorylate DG at relatively later stages of cell stimulation, when high concentrations of DG are already present (Supplemental Fig. S5B). However, further studies are needed to test Induced mutation possibility. In this study, we revealed that DGKη1 is a unique isozyme having high affinity for DG. This result adds a new level of complexity to the DGK scenario in which 10 DGK isozymes participate in a wide variety of cellular functions [1], [2], [3], [4], [5]. DGKη1 has been reported to be involved in EGF-dependent cell proliferation [17] and in the pathogenesis of lung cancer [18] and bipolar disorder [19], [20]. It will be interesting to determine what role the high DG affinity DGK isozyme plays in modulating these physiologically and pathologically important events.
    Acknowledgments This work was supported in part by Grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (22370047, 23116505, 25116704, 25860042, and 26291017); the Japan Science and Technology Agency (AS221Z00794F, AS231Z00139G, and AS251Z01788Q); 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; and the Skylark Food Science Institute.