Review
Diacylglycerol kinases as sources of phosphatidic acid

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Abstract

There are ten mammalian diacylglycerol kinases (DGKs) whose primary role is to terminate diacylglycerol (DAG) signaling. However, it is becoming increasingly apparent that DGKs also influence signaling events through their product, phosphatidic acid (PA). They do so in some cases by associating with proteins and then modifying their activity by generating PA. In other cases, DGKs broadly regulate signaling events by virtue of their ability to provide PA for the synthesis of phosphatidylinositols (PtdIns).

Introduction

DAG is generated by the hydrolysis of phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) by PtdIns-specific phospholipase C (PLC) enzymes [1]. Remaining in the membrane, it binds proteins with cysteine-rich, C1 domains, and activates several of these proteins including protein kinase C (PKC) isoforms [2] and Ras guanyl nucleotide-releasing proteins (RasGRPs) [3]. In other cases, DAG recruits but does not activate proteins such as protein kinase D, the Munc13 proteins, and the chimaerins [3]. Additionally, DAG appears to activate some transient receptor potential channels that do not harbor C1 domains [4]. Its effects on numerous and diverse targets underscores the importance of DAG signaling and indicates that DAG modulates a broad array of biological events. It is critical then that intracellular DAG levels be tightly regulated and it is now widely agreed that under most circumstances, conversion of DAG to PA by the DGKs is the major route to terminate DAG signaling. But PA, itself, has a broad array of signaling properties that are very distinct from those of DAG. Their ability to generate PA suggests that DGKs might also influence biological events by generating this lipid. In fact, there are now several examples indicating that DGKs modulate signaling events not only by metabolizing DAG to terminate its effects, but also by producing PA.

DGKs have been identified in unicellular organisms such as bacteria, but these DGKs are structurally different from those identified in higher eukaryotes such as Drosophila melanogaster [5], [6], [7], Arabidopsis thaliana [8], [9], Caenorhabditis elegans [10], [11], and mammals [12]. For example, bacterial DGK, unlike higher eukaryote DGKs, is a small, integral membrane protein that phosphorylates other lipids in addition to DAG [13]. And a recently identified yeast DGK is similar to cytidyltransferases and uses CTP as a phosphate donor rather than the ATP used by DGKs in higher eukaryotes [14], [15]. Finally, a multisubstrate lipid kinase (MuLK) that also phosphorylates DAG was recently identified [16], [17]. Unlike mammalian DGKs, MuLK phosphorylates non-DAG lipids and its structure is not very homologous to that of DGKs. This review will focus on DGKs in higher eukaryotes, with a specific focus on their role in generating PA that influences biological events.

Section snippets

Common structural features of the mammalian DGK enzymes

DGK activity was first identified about forty years ago [18], and an 80 kDa DGK enzyme was purified to homogeneity from pig brain cytosol in 1983 [19]. Based on the partial sequence from the 80 kDa enzyme, Sakane et al. isolated a full-length, porcine DGK cDNA in 1990 [20]. But based on antibody studies, additional DGK enzymes appeared to exist [21], prompting an exhaustive search for other DGK isoforms. Nine additional isoforms have since been identified (Fig. 1), making this a rather large

DGKs influence specific biological events depending on their binding partners

Each DGK isotype is expressed in numerous tissues, and usually multiple DGK isotypes are expressed in the same tissue and even within the same cell [50]. For example we detected all known DGK isoforms in mouse brain extracts [51] and have found expression of at least six DGK isoforms in mouse embryo fibroblasts (J.C. and M.K.T. unpublished observations). When multiple DGK isoforms are expressed in a cell type, they are usually from different subfamilies, suggesting that the subfamilies have

PA signaling events mediated by DGKs

Most of the mechanisms described below involve DGKs ζ and α, suggesting that these might be the only DGK isoforms that modulate signaling events by producing PA. However, other DGK isoforms have not been similarly tested, so one cannot rule out the possibility that they might also function in this manner.

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

Summary and conclusions

While DGKs are better known as enzymes that metabolize diacylglycerol, there are also several reports indicating that they can additionally function by providing PA. In some cases, this PA binds and activates proteins such as PtdIns4P 5-kinases to influence cell function, while in other cases the PA is a critical component for the re-synthesis of PtdIns. In either case, disrupting DGK function causes aberrant signaling. This concept in which DGKs provide PA to influence signaling events is

Acknowledgements

This work was supported by the Huntsman Cancer Foundation (to M.K.T.), the R. Harold Burton Foundation (to M.K.T.), the National Institutes of Health Grants R01-CA95463 (to M.K.T.) and The Cancer Research Society, Inc. (to S.H.G.).

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