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  • The outcome of DGK function will thus depend

    2020-05-22

    The outcome of DGK function will thus depend on the binding partners of each DGK isoform, and the effects that they exert can be quite different. A clear example of this concept has been demonstrated for the type IV DGKs, ζ and ι, which are structurally very similar but have opposing effects on Ras signaling. DGKζ was found to attenuate Ras signaling, both in vitro[53], [54] and in vivo[55]. Its effects on Ras are due to the ability of DGKζ to bind and inhibit RasGRP1 [53], a Ras activator that requires DAG for its function. By metabolizing DAG, DGKζ inhibits the activity of RasGRP1. Its ability to regulate RasGRP1 was unique among the five other DGK isotypes that were tested; even an alternatively spliced form of DGKζ did not inhibit RasGRP1. Given the structural similarity between DGKζ and DGKι, one would predict that they would have similar signaling outcomes. It was surprising then when we subsequently discovered that DGKι had the opposite effects on Ras signaling: while DGKζ deficiency enhanced Ras activity, DGKι deficiency reduced it [56]. The effects of DGKι on Ras signaling were caused by its inhibition of RasGRP3. In conditions of DGKι deficiency, RasGRP3 activity was augmented, which led to activation Rap1 that then interfered with Ras signaling [56]. Collectively these observations indicate that DGKs achieve functional specificity based upon the company that they keep. Additional examples of DGKs specifically binding to DAG target proteins to regulate their activity have been published [57], [58], indicating that this is a common way to regulate DAG levels and the proteins that this lipid influences. Based on the structural diversity of the DGK family, it is likely that each DGK regulates a distinct set of DAG signaling proteins, a concept that is supported by mouse knockout studies showing that mice with targeted dibromide of individual DGK isoforms have distinct phenotypes [51], [55], [56], [59], [60]. But, in addition to inhibiting the activity of proteins influenced by DAG, DGKs also appear to modulate proteins that are influenced by PA (Fig. 2, right panel). Several examples of DGKs modulating signaling events by producing PA are discussed in detail below.
    PA signaling events mediated by DGKs
    Role of DGKs in regenerating PtdIns PtdIns(4,5)P2 is enriched in unsaturated fatty acids [44], so there must be a mechanism that promotes this enrichment. PtdIns(4,5)P2 is re-synthesized from DAG in a series of reactions known as the PtdIns cycle (Fig. 4) and the DGK reaction is the first step in this sequence. Evidence indicates that DGKɛ, by virtue of its specificity for DAG that has unsaturated fatty acids, helps enrich PtdIns(4,5)P2 with unsaturated fatty acids, but there is also evidence that other DGK isoforms might also contribute.
    Summary and conclusions
    Acknowledgements
    Introduction Diacylglycerol (DG) kinase (DGK) is an enzyme that phosphorylates DG to convert it into phosphatidic acid (PA) [[1], [2], [3], [4]]. Both DG and PA act as second messengers that regulate many key enzymes [[1], [2], [3], [4]]. Therefore, DGK plays an important role in the regulation of a number of intracellular signaling pathways. Mammalian DGKs comprise a large protein family that consists of ten isozymes, which are classified into five subgroups based on the presence of a variety of regulatory domains [[1], [2], [3], [4]]. Type I DGKs, which consist of α, β and γ-isozymes, contain two sets of Ca2+-binding EF-hand motifs (EFh) at their N-termini [5,6]. In addition to EF-hands, type I DGK isozymes possess an N-terminal recoverin homology domain (RVHD), two cysteine-rich C1 domains (C1D) and a C-terminal catalytic domain (CD). Interestingly, the distinct tissue- and cell-dependent expression patterns of these isozymes suggest that, even though they belong to the same subfamily, each member exhibits specialized functions in particular types of cells. Moreover, we have previously reported that the EF-hand motifs in type I DGKs have different affinities for Ca2+ and therefore possess distinct propensities for Ca2+-induced conformational changes [7,8].