59 7 br Funding JAN hold a predoctoral fellowship

Funding JAN hold a predoctoral fellowship from Spanish Ministry of Economy and Competitiveness (MINECO), MTL is a Formación de Personal Investigador fellows and EA is a Formación de Profesorado Universitario fellow of the Spanish Ministry of Education. This work was supported in part by grants from the Spanish Ministry of Economy and Competitiveness (BFU 2013-47640P), the Spanish Ministry of Health (Instituto de Salud Carlos III; Cancer Program Grant RD12/0036/0059), and the Madrid regional government (IMMUNOTHERCAM S2010/BMD-2326) to IM.
Competing interests
Acknowledgements
Introduction Diacylglycerol kinase (DGK) phosphorylates diacylglycerol (DG) in biomembranes to produce phosphatidic 59 7 (PA) [1], [2], [3], [4], [5], [6]. To date, ten mammalian DGK isozymes (α, β, γ, δ, ε, ζ, η, θ, ι and κ) have been identified. These DGK isozymes are divided into five groups (type I: α, β and γ; type II: δ, η and κ; type III: ε; type IV: ζ and ι; type V: θ) according to their structural features [1], [2], [3], [4], [5], [6]. DGK isozymes are known to be involved in a wide variety of patho-physiological functions. For example, DGKα (type I) induces clonal anergy [7], [8]. On the other hand, this isozyme also prevents melanoma apoptosis [9] and promotes hepatocellular carcinoma proliferation [10], 3D cancer cell growth [11] and angiogenesis [12]. DGKβ (type I) is an important regulator in neurite spine formation [13]. DGKγ (type I) serves as an upstream suppressor of Rac1 and lamellipodium formation [14]. This isozyme regulates allergic reactions [15] and insulin secretion [16]. In addition to epidermal growth factor signaling [17], DGKδ (type II) is an important factor in hyperglycemia-induced peripheral insulin resistance, thereby exacerbating the severity of type-2 diabetes [18], [19]. DGKη (type II) enhances C-Raf activity and B-Raf/C-Raf heterodimerization in cancer cells [20]. It was also reported that the gene encoding DGKη is implicated in the etiology of bipolar disorder [21]. DGKκ (type II) is associated with risk of hypospadias [22]. DGKε (type III) controls seizure susceptibility and long-term potentiation through modulating arachidonoyl-inositol lipid signaling [23]. DGKζ (type IV) is an important regulator of dendritic spine maintenance [24]. This isozyme is also known to regulate endothelin-1-induced cardiomyocyte hypertrophy [25]. DGKι (type IV) regulates Ras guanyl-releasing protein 3 and inhibits Rap1 signaling [26] and presynaptic release during metabotropic glutamate receptor-dependent long-term depression [27]. DGKθ (type V) has been implicated in familial Parkinson disease [28] and bile acid signaling [29]. Although DGKs have been established as important biomembrane-related modulators as described above, their enzymological properties have not been fully elucidated. 30years ago, Kanoh et al. purified DGKα from porcine liver and demonstrated that the enzyme had 10–20% 2-monoacylglycerol (MG) kinase (MGK) activity compared with its DGK activity [30]. However, its 1-MGK activity was <4% relative to its DGK activity. Gantayet et al. reported that DGKε also exhibited 6.4% 2-MGK activity compared with its DGK activity [31]. However, because a comprehensive analysis has not been done, the MGK activities of the other isozymes are presently unknown.