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  • The following is the supplementary data

    2021-07-27

    The following is the supplementary data related to this article.
    Introduction Diacylglycerol kinase (DGK) phosphorylates diacylglycerol (DG) to produce phosphatidic wst-1 assay (PA) (Baldanzi, 2014, Goto et al., 2006, Merida et al., 2008, Sakane et al., 2007, Topham and Epand, 2009). To date, ten mammalian DGK isozymes, α, β, γ, δ, ε, ζ, η, θ, ι and κ, have been identified (Fig. 1). Moreover, several alternative splicing products—such as δ1 and δ2 wst-1 assay (Sakane et al., 2002); η1–η4 (Murakami et al., 2003, Murakami et al., 2016, Shionoya et al., 2015); ζ1 and ζ2 (Ding et al., 1997); and ι1–ι3 (Ito et al., 2004)—have also been found. These isozymes are subdivided into five groups, type I (α, β and γ), II (δ, η and κ), III (ε), IV (ζ and ι) and V (θ), according to structural features (Fig. 1) (Baldanzi, 2014, Goto et al., 2006, Merida et al., 2008, Sakane et al., 2007, Topham and Epand, 2009). Each group is characterized by subtype-specific functional domains, such as EF-hand motifs (type I), pleckstrin homology and sterile α motif domains (type II), ankyrin repeats (type IV) and a ras-associating domain (type V) (Fig. 1). DGK isozymes regulate a wide variety of physiological and pathological events (Sakane et al., 2007, Sakane et al., 2016, Sakane et al., 2008). For example, type I DGKα, which is activated in a calcium-dependent manner (Sakane et al., 1990, Sakane et al., 1991), is involved in a wide variety of pathophysiological events, such as T-cell anergy induction (Olenchock et al., 2006, Zha et al., 2006), cell motility and invasion (Cutrupi et al., 2000, Rainero et al., 2014), and cancer cell growth/apoptosis (Takeishi et al., 2012, Torres-Ayuso et al., 2014, Yanagisawa et al., 2007). Therefore, a selective and potent inhibitor for DGKα (Liu et al., 2016) can be an ideal anti-cancer drug candidate that attenuates cancer cell proliferation and simultaneously enhances immune responses, including anti-cancer immunity. Knockout (KO) mice of DGKβ exhibited bipolar disorder (mania)-like phenotypes (Kakefuda et al., 2010, Shirai et al., 2010). DGKγ regulated lamellipodium formation (Tsushima et al., 2004), antigen-induced mast cell degranulation (Sakuma et al., 2014) and insulin secretion (Kurohane Kaneko et al., 2013). DGKδ positively regulated epidermal growth factor receptor signaling (Crotty et al., 2006), and DGKδ deficiency also caused hyperglycemia-induced peripheral insulin resistance and thereby exacerbated the severity of type II diabetes (Chibalin et al., 2008). In addition, brain-specific conditional DGKδ-KO mice showed obsessive compulsive disorder-like behaviors (Usuki et al., 2016). DGKη acts as a critical regulator of B-Raf/C-Raf-dependent cell proliferation (Yasuda et al., 2009), and DGKη-deficient mice demonstrated bipolar disorder (mania)-like phenotypes (Isozaki et al., 2016). DGKκ is implicated in fragile X syndrome (Tabet et al., 2016). DGKε regulates seizure susceptibility and long-term potentiation (Rodriguez De Turco et al., 2001). DGKζ negatively regulates T-cell response (Zhong et al., 2003). In addition, DGKζ is involved in the maintenance of spine density (Kim et al., 2009) and reciprocally regulates p53 and nuclear factor-κB (Tanaka et al., 2013, Tanaka et al., 2016, Tsuchiya et al., 2015). DGKι inhibits Ras guanylnucleotide-releasing protein (GRP) 3-dependent-Rap1 signaling (Regier et al., 2005). DGKθ is suggested to be associated with susceptibility to Parkinson's disease by genome-wide association studies (Pankratz et al., 2009, Simon-Sanchez et al., 2011). DG and PA consist of various molecular species with different acyl chains at the sn-1 and sn-2 positions, and consequently, mammalian cells contain more than 50 structurally distinct DG/PA species. DGK is a component of PI turnover and initiates PI regeneration (Hodgkin et al., 1998) (Fig. 2). This fact generated a dogma that all DGK isozymes utilize 18:0/20:4-DG (X:Y = the total number of carbon atoms: the total number of double bonds), which is derived from PI turnover. In this context, DGKε indeed utilizes 18:0/20:4-DG in vitro and in vivo (Rodriguez De Turco et al., 2001, Shulga et al., 2011, Tang et al., 1996) (Fig. 2). However, nine other DGK isozymes failed to exhibit substrate selectivity for 18:0/20:4-DG in vitro. Thus, we questioned whether these nine isozymes indeed utilize 18:0/20:4-DG species in cells. Although several reports addressed this question (Pettitt and Wakelam, 1999, Van der Bend et al., 1994), the answer is still unclear because those studies used exogenously generated/added DG species and overexpressed DGK isozymes, which are probably distributed at random apart from their original locations. It is likely that the enzymes metabolized DG species under such non-physiological conditions. Therefore, to address this question more convincingly, we quantitatively detected cell stimulation- and endogenous DGK isozyme-dependent changes in PA molecular species, which are minor components of phospholipids in cells. However, it has been difficult to quantitatively determine small changes in PA species levels in physiological and pathological events.