Diacylglycerol kinase as a possible therapeutic target for neuronal diseases
© Shirai and Saito; licensee BioMed Central Ltd. 2014
Received: 17 January 2014
Accepted: 5 March 2014
Published: 7 April 2014
Diacylglycerol kinase (DGK) is a lipid kinase converting diacylglycerol to phosphatidic acid, and regulates many enzymes including protein kinase C, phosphatidylinositol 4-phosphate 5-kinase, and mTOR. To date, ten mammalian DGK subtypes have been cloned and divided into five groups, and they show subtype-specific tissue distribution. Therefore, each DGK subtype is thought to be involved in respective cellular responses by regulating balance of the two lipid messengers, diacylglycerol and phosphatidic acid. Indeed, the recent researches using DGK knockout mice have clearly demonstrated the importance of DGK in the immune system and its pathophysiological roles in heart and insulin resistance in diabetes. Especially, most subtypes show high expression in brain with subtype specific regional distribution, suggesting that each subtype has important and unique functions in brain. Recently, neuronal functions of some DGK subtypes have accumulated. Here, we introduce DGKs with their structural motifs, summarize the enzymatic properties and neuronal functions, and discuss the possibility of DGKs as a therapeutic target of the neuronal diseases.
Diacylglycerol kinase (DGK) is the enzyme which phosphorylates diacylglycerol (DG) resulting in the production of phosphatidic acid (PA) [1–5]. Both DG and PA are very important signaling molecules. DG regulates the activity and localization of several proteins, including protein kinase C (PKC), chimerins, Unc-13, and Ras guanyl nucleotide-releasing protein (RasGRP). PA also activates several enzymes, including phosphatidylinositol 4-phosphate 5-kinase, mammalian target of rapamycin (mTOR), and atypical isoforms of PKC [6–10]. Therefore, DGK is thought to be a key enzyme that regulates numerous cellular responses by regulating balance of the two lipid messengers.
Characteristics of mammalian DGK subtypes
Function/Phenotype of KO
thymus, spleen> > kidny, brain (oligodendrocytes)
Ca2+, PS dependent R59022 sensitive activated by PIP3, PI(3,4)P2
T cell anergy tumor invasion insulin release
brain(CP > hip, cortex, olf) > adrenal gland > small intestine
Ca2+, PS dependent activated by PI(4,5)P2
impairment of memory impairment of memory (mania-like) severe seizure
retina, brain(Cb, hip)> > other tissues
Ca2+, PS dependent R59022 sensitive
skeletal muscle > testis, colon
Ca2+, PS independent
type II diabetes EGF signaling, seizure
testis > brain, lung, spleen > heart
bipolar disorder (?), Ras-Raf-MEK signaling
testis > spleen, pracenta,
retina,brain,testis > ovary> > skeletal muscle heart
Ca2 + independent selectively for arachidonoyl DG
thymus > brain(Cb, hip, olf)> > skeltal muscle, heart, pancreas
Ca2 + insensitive Mg2+, PS dependent
T cell anergy, cell cycle control spine maintenamce
retina > brain (hip, CP, cortex, Cb, Dg)
Ras GRP, Rap 1 signaling
brain(Cb, hip)> > small intestine, liver etc.
Regulation of the enzymatic activity
Although the enzymatic characteristics of all DGK subtypes have not been investigated, the activities of some DGKs are regulated by ionic detergents and phospholipids [33, 34]. For example, the activities of DGKα and ζ depend on deoxycholate or cholic acid, so that a detergent, octyl glucoside, is used for the DGK assay. But the dependency of phospholipids seems to be subtype specific (Table 1). The activity of purified DGKα is remarkably enhanced by phosphatidylcholine (PC) but not by phosphatidylinositol (PI), while DGKζ is activated by PI and phosphatidylserine (PS), but not so remarkably by PC . DGKα is activated by PI3,4,5-trisphosphate (PIP3) and PI3,4-bisphosphate [PI(3,4)P2], while DGKβ is activated by PI4,5-bisphosphate [PI(4,5)P2] . Moreover, divalent cations including calcium and magnesium are also required for activation of DGKα and ζ [35, 51]. Specifically, Type I DGKs are believed to depend on calcium because they have the EF hand motif and RVH domains. The calcium dependency of DGKα has been clearly shown in vitro. In addition to its role as a calcium sensor, the N-terminus region has an inhibitory effect on the kinase activity [52, 53]. Indeed, the N-terminus region binds to its C-terminal region containing the kinase domain and C1 domain in the absence of calcium . However, the in vitro calcium-dependent activity of DGKβ and γ has not been reported, although their EF-hands seem to bind to calcium and to regulate their kinase activity as well. Information of the enzymatic properties of each DGK subtype is not enough, and the precise enzymatic characterization should be carried out using the purified proteins under the respective optimized conditions.
All DGKs except for DGKβ are localized in cytoplasm in several cells, but some DGKs show the translocation to the plasma membrane and/or intracellular organelles in response to several stimulations [35, 55–61]. For example, DGKγ is translocated from the cytoplasm to the plasma membrane by calcium, phorbol ester, and purinergic receptor stimulations . DGKα is also translocated to the plasma membrane by calcium , purinergic receptor stimulation , and T-cell receptor stimulation . Moreover, DGKδ translocates to the plasma membrane in response to phorbol ester . These are coincident with the fact that DG is produced on the plasma membrane and DGKs work there. In addition to the plasma membrane, DGKα is accumulated at the Golgi complex in the case of arachidonic acid and vitamin E stimulations [55, 58]. Furthermore, it is reported that DGKζ is translocated from the nucleus to the cytoplasm , and DGKθ and γ are localized in the nucleus [60, 61], consistent with the fluctuation of DG and PA contents in the nucleus [62–64]. These findings indicate that translocation is the key regulation mechanism to define where and how long each DGK works, and suggest that DGKs are important for the DG/PA metabolism in the plasma membrane and many organelles including nucleus and Golgi complex. In the case of DGKβ, the plasma membrane localization seems to be a critical for its physiological function .
The translocation and activation of some DGKs are regulated by the phosphorylation reaction. We have revealed that DGKγ is subtype-specifically phosphorylated by PKCγ at Ser-776 and Ser-779 upon the purinergic stimulation, resulting in up-regulation of its lipid kinase activity . The membrane translocation of DGKδ is regulated by the phosphorylation at Ser-22 and Ser-26 by conventional/classical PKC (cPKC) , and the nuclear export of DGKζ is dependent on the phosphorylation at the MARCKS homology domain by PKCα . Not only the serine phosphorylation but also the tyrosine phosphorylation is important: the membrane translocation of DGKα is dependent on phosphorylation at Tyr-334 (Tyr-335 in mouse) by Src family tyrosine kinases [58, 68, 69]. We also found that Tyr-218 of DGKα is phosphorylated by c-Abl tyrosine kinase and the phosphorylation regulates serum-induced nuclear export of the enzyme . These results indicate that the phosphorylation is one of the important regulation mechanisms for the spatial regulation of diacylglycerol signaling.
DGK and brain function related to neuronal disease
DGKβ and η in mood disorder and memory loss
Most subtypes of DGKs are abundant in brain (Table 1 and Ref. 22). Above all, high levels mRNA of DGK β, γ, ζ, ι, and θ are detected in the neurons. In situ hybridization reveals that DGKβ is expressed in the caudate putamen, accumbens nucleus, and hippocampus . Indeed, the protein expression of DGKβ in these regions is reported [29, 38]. DGKβ is not present at the birth but its expression is rapidly increased from day 14 to day 28, and is localized on the plasma membrane of spines , suggesting its importance in the neuronal network. Indeed, Goto et al. have reported that DGKβ is expressed at post synaptic sites in medium spiny neurons constituting the striatonigral and striatopallidal pathways [39, 71].
To investigate the neuronal functions of DGKβ, we produced its KO mice and found that the primary cultured hippocampal neurons from DGKβ KO mice had less branches and spines compared to the wild type. In addition, long-term potentiation in the hippocampal CA1 region of the DGKβ KO mice was reduced, causing impairment of cognitive functions including spatial and long-term memories in Y-maze and Morris water-maze tests . Furthermore, the KO mice showed impairment of emotion : DGKβ KO mice spent longer time in the center area in the open field test, and in the open arms in elevated plus maze test than the wild type. On the other hand, DGKβ KO mice showed normal input–output relationship and behavior in prepulse inhibition test and social interaction test [29, 31]. These results suggest that DGKβ KO mice have a mania-like behavior with memory loss, although their social skill and basal synaptic function are normal. The importance of DGKβ in the memory and emotion fits to the localization of DGKβ in hippocampus and caudate putamen, and its developmental changes .
Interestingly, the impairment of emotion and memory of DGKβ KO mice is rescued with the lithium treatment for ten days (, and unpublished data). The effect of lithium seems to involve in GSK3β inhibition . These results suggest that DGKβ can be a possible target of memory loss and mood disorder. Indeed, DGKβ is reported as one of the learning-regulated genes in a research of age-dependent memory impairment . This report indicates that histone acetylation is associated with age-dependent memory impairment and histone deacetylase inhibitor is expected as a drug for memory loss . Moreover, one of the splice variant forms of human DGKβ, which lacks 35 amino acids at the C-terminus but has an additional 4-amino-acid extension (DGKβ SV3; GenBank accession number AX032745), is associated with a human DGKβ EST that is annotated as differentially expressed in patients with mood disorders . The splice variant form does not induce branches and spines , supporting the important role of DGKβ in spine formation.
Similarly, a mutation in DGKη is reported to correlate with bipolar disorder [42–44], of which mRNA seems to be concentrated in hipocaumpus and dendate gyrus, although the expression level of the subtype in the brain is lower than in testis and tumor-derived cells . Baum et al. have reported strong association between bipolar disorder and SNPs located in a gene encoding DGKη by the genome-wide association study using the samples from European origin , and an increase in its mRNA level has been reported in some patients with bipolar disorder and schizophrenia [43, 44], On the other hand, other studies have not confirmed the association [75–77]. The controversial results may be due to the races and methods employed. The precise experimental procedures would be necessary to prove the involvement of DGKη in bipolar disorder.
DGKζ and ι in spine modulation and neurotransmitter release
DGKζ, which is abundant in cerebellum, hippocampus, and olfactory bulb, is involved in spine maintenance [47, 78]. For this function, its enzymatic activity and localization at the excitatory postsynaptic site by binding to some PSD95 family proteins through the PDZ-binding domain are critical. Interestingly, DGKζ is detected in the nucleus in the hippocampal neurons but it is translocated to the cytoplasm by ischemia or kainate stimulation [79, 80], suggesting its role in the protection against ischemia. The subtype is also expected to be involved in the leptin receptor signaling because it associates with leptin . However, detailed mechanisms are still unclear. DGKι also has the PDZ binding motif. The subtype is abundantly detected in hippocampus, dendate gyrus, and retina with moderate levels in the cortex, caudate-putamen, and thalamus [19, 22, 82]. However, the spine density and morphology of neurons in DGKι KO are normal . Instead, DGKι regulates the presynaptic release during metabotropic glutamate receptor-dependent long-term potentiation [32, 49]. Abnormal behaviors including impairment of memory and emotion of DGKζ and ι KO mice have not been reported yet.
DGKβ, ϵ, and δ in seizure
Seizure is a relatively common neuronal disease and at least three DGK subtypes are related to the disease. DGKϵ is uniformly expressed in brain, and its KO mice show an increased resistance to electroconvulsive and faster recovery than the wild type . DGKδ is also associated to seizure, although its neuronal expression is very low: DGKδ gene is disrupted in a female patient with a de novo balanced translocation, who exhibits seizure with several dysfunctions, and electroencephalographic assessment of DGKδ mutant mice revealed abnormal epileptic discharges and electrographc seizures . In addition, we also showed that seizure is severer in DGKβ KO mice than the wild type .
DGKα is detected in oligodentrocytes, although the subtype is not enriched in brain [11, 83]. DGKγ, which is predominantly localized in Purkinje cells and hippocampus, is present at birth and then gradually increased [13, 38]. The mRNA expression of DGKθ is the highest in cerebellum and hippocampus  and it is suggested that DGKθ is involved in neurotransmitter release . However, further examination would be necessary to understand physiological functions of DGKα, γ, and θ in brain.
As described above, some DGKs are important for neuronal functions. This is supported by their abundant and subtype-specific expression in brain. Generally, DGKs are likely involved in the spine formation and maintenance, contributing to higher brain function including memory and emotion. However, the detailed mechanisms of the DGK-mediated morphological change of spines and neurons are not clear. The membrane lipids including PA and DG seem to be the key molecules. Indeed, we found that mTOR and cPKC, which are activated by PA and DG respectively, are involved in the DGKβ-induced neurite induction and branching [unpublished data], and the kinase activity is necessary for the DGKζ-mediated spine maintenance [22, 47]. Alternatively, PIP2 and/or PIP3 may be additional key lipids because some DGKs can be activated by these inositol phospholipids, which are related to actin cytoskeletal rearrangement and membrane traffic . On the other hand, unknown mechanism like a kinase-independent pathway may additionally exist. For example, we have recently found that there is a kinase-independent pathway in the DGKβ-induced neurite induction and branching . Further investigations are necessary to reveal the whole story regulating the shape of the neuronal membrane by DGKs.
The facts described in this review suggest that some DGKs can be a target for the therapy of neuronal diseases including memory loss, mood disorder, and seizure. To develop the drugs targeting DGKs for these neuronal diseases, more precise experiments should be performed using human patients. For example, there is still no evidence that splice variant forms of DGKβ is expressed at protein level in human patients of bipolar disorder, although it is suggested to association with mood disorders . More importantly, it is necessary to find subtype-specific inhibitor and/or activator of each DGK subtype because DGKs have subtype-specific and numerous physiological functions as summarized in Table 1. Recently, Sakane et al. have developed a new DGK assay method suitable for the high throughput screening . Sakane’s and our groups are collaborating to find specific inhibitor and/or activator of each DGK subtype. In near future, it will be possible to provide information about DGK-subtype specific inhibitor and/or activator which would be useful for the development of drugs targeting DGK for neuronal diseases.
DGKs are involved in not only neuronal diseases but also other diseases including diabetes, immuno-dysfunctions, and cardiovascular diseases. In addition, the correlation between cancer and DGK has been recently reported. For example, DGKα is involved in the progression of human hepatocellular carcinoma , and is necessary for the invasion of lung cancer . These facts suggest that DGK can be a target of multiple diseases including diabetes, cancer, and neuronal diseases. Again, in addition to the comprehensive research to reveal subtype-specific functions DGKs, subtype-specific compounds would be necessary to develop drugs targeting DGKs without side effect.
- Topham MK, Prescott SM: Mammaliandiacylglycerol kinases, a family of lipid kinases with signaling functions. J Biol Chem. 1999, 274: 11447-11450. 10.1074/jbc.274.17.11447.View ArticlePubMedGoogle Scholar
- van Bitterswijk WJ, Houssa B: Properties and functions of diacylglycerol kinases. Cell Signal. 2000, 12: 595-605. 10.1016/S0898-6568(00)00113-3.View ArticleGoogle Scholar
- Sakane F, Imai S, Kai M, Yasuda S, Kanoh H: Diacylglycerol kinases: why so many of them?. Biochim Biophys Acta. 2007, 1771: 793-806. 10.1016/j.bbalip.2007.04.006.View ArticlePubMedGoogle Scholar
- Mérida I, Avila-Flores A, Merino E: Diacylglycerol kinases: at the hub of cell signaling. Biochem J. 2008, 409: 1-18. 10.1042/BJ20071040.View ArticlePubMedGoogle Scholar
- Shulga YV, Topham MK, Epand RM: Regulation and functions of diacylglycerol kinases. Chemical Rev. 2011, 111: 6186-6208. 10.1021/cr1004106.View ArticleGoogle Scholar
- Jones DR, Sanjuan MA, Merida I: Type Ialpha phosphatidylinositol 4-phosphate 5-kinase is a putative target for increased intracellular phosphatidic acid. FEBS Lett. 2000, 476: 160-165. 10.1016/S0014-5793(00)01702-6.View ArticlePubMedGoogle Scholar
- Luo B, Prescott SM, Topham MK: Diacylglycerol kinase zeta regulates phosphatidylinositol 4-phosphate 5-kinase Ialpha by a novel mechanism. Cell Signal. 2004, 16: 891-897. 10.1016/j.cellsig.2004.01.010.View ArticlePubMedGoogle Scholar
- Limatola C, Schaap D, Moolenaar WH, van Blitterswijk WJ: Phosphatidic acid activation of protein kinase C-zeta overexpressed in COS cells: comparison with other protein kinase C isotypes and other acidic lipids. Biochem J. 1994, 304: 1001-1008.PubMed CentralView ArticlePubMedGoogle Scholar
- Fang Y, Vilella-Bach M, Bachmann R, Flanigan A, Chen J: Phosphatidic acid-mediated mitogenic activation of mTOR signaling. Science. 2001, 294: 1942-1945. 10.1126/science.1066015.View ArticlePubMedGoogle Scholar
- Almena M, Merida I: Shaping up the membrane: diacylgycerol coordinates spatial orientation of signaling. Trends Biochem Sci. 2011, 36: 583-603.View ArticleGoogle Scholar
- Sakane F, Yamada K, Kanoh H, Yokoyama C, Tanabe T: Porcine diacylglycerol kinase sequence has zinc finger and E-F hand motifs. Nature. 2000, 334: 345-348.Google Scholar
- Goto K, Kondo H: Molecular cloning and expression of a 90-kDa diacylglycerol kinase that predominantly localizes in neurons. Proc Natl Acad Sci USA. 1993, 90: 7598-7602. 10.1073/pnas.90.16.7598.PubMed CentralView ArticlePubMedGoogle Scholar
- Goto K, Funayama M, Kondo H: Cloning and expression of a cytosckeleton-associated diacylglycerol kinase that is dominantly expressed in cerebellum. Proc Natl Acad Sci USA. 1994, 91: 13042-13046. 10.1073/pnas.91.26.13042.PubMed CentralView ArticlePubMedGoogle Scholar
- Tang W, Bunting M, Zimmerman GA, McIntyre TM, Prescott SM: Molecular cloning of a novel human diacylglycerol kianse highly selective for arachidonate-containing substrates. J Biol Chem. 1996, 271: 10237-10241. 10.1074/jbc.271.17.10237.View ArticlePubMedGoogle Scholar
- Sakane F, Imai S, Kai M, Wada I, Kanoh H: Molecular cloning of a novel diacylglycerol kinase isozyme with a pleckstrin homology domain and a C-terminal tail similar to those of the EPH family of protein-tyrosine kinases. J Biol Chem. 1996, 271: 8394-8401. 10.1074/jbc.271.14.8394.View ArticlePubMedGoogle Scholar
- Klauck TM, Xu X, Mousseau B, Jaken S: Cloning and characterization of a glucocorticoid-induced diacylglycerol kinase. J Biol Chem. 1996, 271: 19781-19788. 10.1074/jbc.271.33.19781.View ArticlePubMedGoogle Scholar
- Bunting M, Tang W, Zimmerman G, McIntyre TM, Prescott SM: Molecular cloning and characterization of a novel human diacylglycerol kinase ζ. J Biol Chem. 1996, 271: 10230-10236. 10.1074/jbc.271.17.10230.View ArticlePubMedGoogle Scholar
- Houssa B, Schaap D, van der Wal J, Goto K, Kondo H, Yamakawa A, Shibata M, Takenawa T, van Blitterswijk WJ: Cloning of a novel human diacylglycerol kinase (DGKη) containing three cysteine-rich domains, a prorine-rich region, and a pleckstrin homology domain with an overlapping Ras-associating domain. J Biol Chem. 1997, 272: 10422-10428. 10.1074/jbc.272.16.10422.View ArticlePubMedGoogle Scholar
- Ding L, Traer E, McIntyre TM, Zimmerman GA, Prescott SM: The cloning and characterization of a novel human diacylglycerol kinase, DGKι. J Biol Chem. 1998, 273: 32746-32752. 10.1074/jbc.273.49.32746.View ArticlePubMedGoogle Scholar
- Imai S, Kai M, Yasuda S, Kanoh H, Sakane F: Identification and characterization of a novel human type II diacylglycerol kinase, DGKκ. J Biol Chem. 2005, 280: 39870-39881. 10.1074/jbc.M500669200.View ArticlePubMedGoogle Scholar
- Shindo M, Irie K, Masuda A, Ohigashi H, Shirai Y, Miyasaka K, Saito N: Synthesis and Phrobol ester biniding of the cysteine-rich domains of diacylglycerol kinase (DGK) isozymes. J Biol Chem. 2003, 278: 18448-18454. 10.1074/jbc.M300400200.View ArticlePubMedGoogle Scholar
- Tu-Sekine B, Raben DM: Regulation and roles of neuronal diacylglycerolkinases: A lipid perspetive. Crit Rev Biochem Mol Biol. 2011, 46: 353-364. 10.3109/10409238.2011.577761.View ArticlePubMedGoogle Scholar
- Goto K, Kondo H: A 104 kDa diacylglycerol kinase containing ankyrin-like repeats localize in the cell nucleus. Proc Natl Acad Sci USA. 1996, 93: 11196-11201. 10.1073/pnas.93.20.11196.PubMed CentralView ArticlePubMedGoogle Scholar
- Sakai H, Sakane F: Recent progress on type II diacylglycerol kinases: the physiological functions of diacylglycerol kinase δ, η and κ and their involvement in disease. J Biochem. 2012, 152: 397-406. 10.1093/jb/mvs104.View ArticlePubMedGoogle Scholar
- Zha Y, Marks R, Ho AW, Peterson AC, Janardhan S, Brown I, Praveen K, Stang S, Stone JC, Gajewski TF: T cell anergy is reversed by active Ras and is regulated by diacylglycerol kinase-α. Nature Immunol. 2006, 11: 1166-1173.View ArticleGoogle Scholar
- Olenchock BA, Guo R, Carpenter JH, Jordan M, Topham MK, Koretzky GA, Zhong XP: Distruption of diacylglycerol metabolism impairs the induction of T cell anergy. Nat Immunol. 2006, 11: 1174-1181.View ArticleGoogle Scholar
- Goto K, Nakano T, Hozumi Y: Diacylglycerol kinase and animal models: the pathophysiological roles in the brain and heart. Advan Enzyme Regul. 2006, 46: 192-202. 10.1016/j.advenzreg.2006.01.005.View ArticleGoogle Scholar
- Chibalian AV, Leng Y, Vieira E, Krook A, Bjomholm M, Krook A, Bjo Rnholm M, Long YC, Kotova O, Zhong Z, Sakane F, Steiler T, Nylen C, Wang J, Laakso M, Topham MK, Gilbert M, Wallberg-Henriksson H, Zierath JR: Down regulation of diacylglycerol kinase delta contributes to hyperglycemia-induced insulin resistance. Cell. 2008, 132: 375-386. 10.1016/j.cell.2007.12.035.View ArticleGoogle Scholar
- Shirai Y, Kouzuki K, Kakefuda K, Moriguchi S, Ohyagi A, Horie K, Morita S, Shimazawa M, Fukunaga K, Takeda J, Saito N, Hara H: Essential role of neuron-enriched diacylglycerol kinase (DGK), DGKβ in neurite spine formation, contributing to cognitive function. PLoS ONE. 2010, 5: e11602-10.1371/journal.pone.0011602.PubMed CentralView ArticlePubMedGoogle Scholar
- Kakefuda K, Oyagi A, Ishisaka M, Tsumura K, Shimazawa M, Yokota K, Shirai Y, Horie K, Saito N, Takeda J, Hara H: Diacylglycerol kinase β knockout mice exhibit lithium-sensitive behavioral abnormalities. PLoS ONE. 2010, 5: e13447-10.1371/journal.pone.0013447.PubMed CentralView ArticlePubMedGoogle Scholar
- Ishisaka M, Tsuruma K, Shimazawa M, Shirai Y, Saito N, Hara H: Increased seizure susceptibility in a mouse with diacylglycerol kinase β deficiency. Neurosci Med. 2013, 4: 117-122. 10.4236/nm.2013.42019.View ArticleGoogle Scholar
- Kim K, Yang J, Kim E: Diacylglycerol kinases in the regulation of dendritic spines. J Neurochem. 2012, 112: 577-587.View ArticleGoogle Scholar
- Kanoh H, Kondoh H, Ono T: Diacylglycerol kinase from pig brain. J Biol Chem. 1983, 258: 1767-1774.PubMedGoogle Scholar
- Cipres A, Carrasco S, Merino E, Díaz E, Krishna UM, Falck JR, Martínez-A C, Mérida I: Regulation of diacylglycerol kinase a by phosphoinositide 3-kinase lipid products. J Biol Chem. 2003, 278: 35629-35635. 10.1074/jbc.M305635200.View ArticlePubMedGoogle Scholar
- Sakane F, Yamada K, Imai S, Kanoh H: Porcine 80-kDa diacylglycerol kinse is a calcium-binding and calcium/phospholipid-dependent enzyme and undergoes calcium-dependent translocation. J Biol Chem. 1991, 266: 7096-7100.PubMedGoogle Scholar
- Goto K, Watanabe M, Kondo H, Yuasa H, Sakane F, Kanoh H: Gene cloning, sequence, expression and in situ localization of 80 kDa diacylglycerol kinase specific to oligodendrocyte of rat brain. Mol Brain Res. 1992, 16: 75-87. 10.1016/0169-328X(92)90196-I.View ArticlePubMedGoogle Scholar
- Kurohane-Kaneko Y, Kobayashi Y, Motoki K, Nakata K, Miyagawa S, Yamamoto M, Hayashi D, Shirai Y, Sakane F, Ishikawa T: Depression of type I diacylglycerol kinases in pancreatic -cells from male mice results in impaired insulin secretion. Endocrinology. 2013, 154: 4089-4098. 10.1210/en.2013-1356.View ArticlePubMedGoogle Scholar
- Adachi N, Oyasu M, Taniguchi T, Yamaguchi Y, Takenaka R, Shirai Y, Saito N: Immunocytochemical localization of a neuron-specific diacylglycerol kinase β and γ in the developing rat brain. Mol Brain Res. 2005, 139: 288-299. 10.1016/j.molbrainres.2005.06.007.View ArticlePubMedGoogle Scholar
- Hozumi Y, Goto K: Diacylglycerol kinase β in neurons: Functional implications at the synapse and in disease. Adv Biol Reg. 2012, 52: 315-325. 10.1016/j.jbior.2012.03.003.View ArticleGoogle Scholar
- Leach NT, Sun Y, Michaud S, Zheng Y, Ligon KL, Ligon AH, Sander T, Korf BR, Lu W, Harris DJ, Gusella JF, Maas RL, Quade BJ, Cole AJ, Kelz MB, Morton CC: Disruption of diacylglycerol kinase delta (DGKD) associated with seizures in humans and mice. Am J Hum Genet. 2007, 80: 792-799. 10.1086/513019.PubMed CentralView ArticlePubMedGoogle Scholar
- Crotty T, Cal J, Sakne F, Taketomi A, Prescott SM, Topham MK: Diacylglycerol kinase δ regulates protein kinase C and epidermal growth factor receptor signaling. Proc Natl Acad Sci USA. 2006, 103: 15485-15490. 10.1073/pnas.0604104103.PubMed CentralView ArticlePubMedGoogle Scholar
- Baum AE, Akula N, Cabanero M, Cardona I, Corona W, Klemens B, Schulze TG, Cichon S, Rietschel M, Nöthen MM, Georgi A, Schumacher J, Schwarz M, Abou Jamra R, Höfels S, Propping P, Satagopan J, Detera-Wadleigh SD, Hardy J, McMahon FJ: A genome-wide association study implicates diacylglycerol kinase eta (DGKH) and several other genes in the etiology of bipolar disorder. Mol Psychiatry. 2008, 13: 197-207. 10.1038/sj.mp.4002012.PubMed CentralView ArticlePubMedGoogle Scholar
- Moya PR, Murphy DL, McMahon FJ, Wendland JR: Increased gene expression of diacylglycerol kinase eta in bipolar disorder. Int J Neuropsychophamacol. 2010, 13: 1127-1128. 10.1017/S1461145710000593.View ArticleGoogle Scholar
- Ollila HM, Soronen P, Silander K: Findings from bipolar disorder genome-wide association studies replicate in a Finish bipolar family-cohort. Mol Psychiaty. 2009, 14: 351-353. 10.1038/mp.2008.122.View ArticleGoogle Scholar
- Murakami T, Sakane F, Imai S, Houkin K, Kanoh H: Identification and characterization of two splice variants of human diacylglycerol kinase η. J Biol Chem. 2003, 278: 34364-34372. 10.1074/jbc.M301542200.View ArticlePubMedGoogle Scholar
- de Turco EB R, Tang W, Topham MK, Topham MK, Sakane F, Marcheselli VL, Chen C, Taketomi A, Prescott SM, Bazan NG: Diacylglycerol kinase ϵ regulates seizure susceptibility and long-term potentiation through arachidonoyl–inositol lipid signaling. Proc Natl Acd Sci USA. 2001, 98: 4740-4745. 10.1073/pnas.081536298.View ArticleGoogle Scholar
- Kim K, Yang J, Zhong XP, Kim MH, Kim YS, Lee HW, Han S, Choi J, Han K, Seo J, Prescott SM, Topham MK, Bae YC, Koretzky G, Choi SY, Kim E: Synaptic removal of diacylglycerol by DGKζ and PSD-95 regulates dendritic spine maintenance. EMBO J. 2009, 28: 1170-1179. 10.1038/emboj.2009.44.PubMed CentralView ArticlePubMedGoogle Scholar
- Kohyama-Koganeya A, Watanabe M, Hotta Y: Molecular cloning of a diacylglycerol kinase isozyme predominantly expressed in rat retina. FEBS Lett. 1997, 409: 258-264. 10.1016/S0014-5793(97)00526-7.View ArticlePubMedGoogle Scholar
- Yang J, Seo J, Nair R, Han S, Jang S, Kim K, Han K, Paik SK, Choi J, Lee S, Bae YC, Topham MK, Prescott SM, Rhee JS, Choi SY, Kim E: DGKι reguilates presynaptic release during mGluR-dependent LTD. EMBO J. 2011, 30: 165-180. 10.1038/emboj.2010.286.PubMed CentralView ArticlePubMedGoogle Scholar
- Reier DS, Higbee J, Lund KM, Sakane F, Prescott SM, Topham MK: Diacylglycerol kinase ι regulates Ras guanyl-releasing protein 3 and inhibits Rap1 signaling. Proc Natl Acad Sci USA. 2005, 102: 7595-7600. 10.1073/pnas.0500663102.View ArticleGoogle Scholar
- Kato M, Takenawa T: Purification and characterization of membrane-bound and cytosolic forms of diacylglycerol kinase from rat brain. J Biol Chem. 1990, 265: 794-800.PubMedGoogle Scholar
- Jiang Y, Qian W, Hawes JW, Walsh JP: A domain with homology to neuronal calcium sensors is required for calcium-dependent activation of diacylglycerol kinase α. J Biol Chem. 2000, 275: 34092-34099.View ArticlePubMedGoogle Scholar
- Sanjuan M, Jones DR, Izuierdo M, Mérida I: Role of diacylglycerol kinase α in the attenuation of receptor signaling. J Cell Biol. 2001, 153: 207-219. 10.1083/jcb.153.1.207.PubMed CentralView ArticlePubMedGoogle Scholar
- Takahashi M, Yamamoto T, Sakai H, Sakane F: Calcium negatively regulates an intramolecular interaction between the N-terminal recoverin homology and EF-hand motif domains and the C-terminal C1 and catalytic domains of diacylglycerol kinase α. Biochem Biophys Res Comun. 2012, 423: 571-576. 10.1016/j.bbrc.2012.06.006.View ArticleGoogle Scholar
- Shirai Y, Segawa S, Kuriyama M: Subtype-specific translocation of diacylglycerol kinase α and γ and its correlation with protein kinase C. J Biol Chem. 2000, 275: 24760-24766. 10.1074/jbc.M003151200.View ArticlePubMedGoogle Scholar
- Sanjua’n MA, Pradet-Balade B, Jones DR, Martínez-A C, Stone JC, Garcia-Sanz JA, Mérida I: T Cell Activation in vivo targets diacylglycerol kinase to the membrane: A novel mechanism for Ras Attenuation. J Immunol. 2003, 170: 2877-2883. 10.4049/jimmunol.170.6.2877.View ArticleGoogle Scholar
- Imai S, Sakane F, Kanoh H: Phorbol ester-regulated oligomerrization of diacylglycerol kinase δ linked to its phosphorylation and translocation. J Biol Chem. 2002, 277: 35323-35332. 10.1074/jbc.M202035200.View ArticlePubMedGoogle Scholar
- Fukunaga-Takenaka R, Shirai Y, Yagi K, Adachi N, Sakai N, Merino E, Merida I, Saito N: Importance of chroman ring and tyrosine phosphorylation in the subtype-specific translocation and activation of diacylglycerol kinase alpha by d-α-tocophenol. Genes Cells. 2005, 10: 311-319. 10.1111/j.1365-2443.2005.00842.x.View ArticlePubMedGoogle Scholar
- Topham M, Bunting M, Zimmerman GA, Adachi N, Sakai N, Merino E, Merida I, Saito N: Protein kinase C regulates the nuclear localization of diacylglycerol kinase-ζ. Nature. 1998, 394: 697-700. 10.1038/29337.View ArticlePubMedGoogle Scholar
- Tabellini G, Bortul R, Santi S, Riccio M, Baldini G, Cappellini A, Billi AM, Berezney R, Ruggeri A, Cocco L, Martelli AM: Diacylglycerol kinase-θ is localized in the speckle domains of the nucleus. Exp Cell Res. 2003, 287: 143-154. 10.1016/S0014-4827(03)00115-0.View ArticlePubMedGoogle Scholar
- Matsubara T, Shirai Y, Miyasaka K, Murakami T, Yamaguchi Y, Ueyama T, Kai M, Sakane F, Kanoh H, Hashimoto T, Kamada S, Kikkawa U, Saito N: Nuclear transportation of diacylglycerol kinase γ and its possible function in the nucleus. J Biol Chem. 2006, 281: 6152-6164. 10.1074/jbc.M509873200.View ArticlePubMedGoogle Scholar
- Martelli AM, Tabellini G, Bortul R, Manzoli L, Bareggi R, Baldini G, Grill V, Zweyer M, Narducci P, Cocco L: Enhanced nuclear diacylglycerol kinase activity in response to a mitogenic stimulation of quiescent Swiss 3T3 cells with insulin-like growth factor I. Cancer Res. 2000, 60: 815-821.PubMedGoogle Scholar
- Irvine R: Nuclear lipid signaling. Sci STKE. 2000, re1:Google Scholar
- Martelli AM, Fala F, Faenza I, Billi AM, Cappellini A, Manzoli L, Cocco L: Metabolism and signaling activities of nuclear lipids. Cell Mol Life Sci. 2004, 61: 1143-1156. 10.1007/s00018-004-3414-7.View ArticlePubMedGoogle Scholar
- Yamaguchi Y, Shirai Y, Matsubara T, Sanse K, Kuriyama M, Oshiro N, Yoshino K, Yonezawa K, Ono Y, Saito N: Phosphorylation and up-regulation of diacylglycerol kinase γ via its interaction with protein kinase C γ. J Biol Chem. 2006, 281: 31627-31637. 10.1074/jbc.M606992200.View ArticlePubMedGoogle Scholar
- Imai S, Kai M, Yamada K, Kanoh H, Sakane F: The plasma membrane translocation of diacylglycerol kinase δ1 is negatively regulated by conventional protein kinase C-dependent phosphorylation at Ser-22 and Ser-26 within the pleckstrin homology domain. Biochem J. 2004, 382: 957-966. 10.1042/BJ20040681.PubMed CentralView ArticlePubMedGoogle Scholar
- Luo B, Prescott SM, Topham MK: Association of diacylglycerol kinase ζ with protein kinase C a: spatial regulation of diacylglycerol signaling. J Cell Biol. 2003, 160: 929-937. 10.1083/jcb.200208120.PubMed CentralView ArticlePubMedGoogle Scholar
- Baldanzi G, Cutrupi S, Chianale F, Gnocchi V, Rainero E, Porporato P, Filigheddu N, van Blitterswijk WJ, Parolini O, Bussolino F, Sinigaglia F, Graziani A: Diacylglycerol kinase-a phosphorylation by Src on Y335 is required for activation, membrane recruitment and Hgf-induced cell motility. Oncogene. 2007, 27: 942-956.View ArticlePubMedGoogle Scholar
- Merino E, Avila-Flores A, Shirai Y, Moraga I, Saito N, Mérida I: Lck-dependent tyrosine phosphorylation of diacylglycerol kinase α regulates its membrane association in T cells. J Immunol. 2008, 180: 5805-5815. 10.4049/jimmunol.180.9.5805.View ArticlePubMedGoogle Scholar
- Matsubara M, Ikeda M, Kiso Y, Sakuma M, Yoshino K, Sakane F, Merida I, Saito N, Shirai Y: c-Abl tyrosine kinase regulates serum-induced nuclear export of diacylglycerol kinase α by phosphorylation at Tyr218. J Biol Chem. 2012, 287: 5507-5517. 10.1074/jbc.M111.296897.PubMed CentralView ArticlePubMedGoogle Scholar
- Hozumi Y, Fukuya M, Adachi N, Saito N, Otani K, Kondo H, Watanabe M, Goto K: Diacylglycerol kinase β accumulates on the perisynaptic site of medium spiny neurons in the striatum. Eur J Neurosci. 2008, 28: 2409-2422.View ArticlePubMedGoogle Scholar
- Peleg S, Sananbenesi F, Zovoitis A, Burkhardt S, Bahari-Javan S, Agis-Balboa RC, Cota P, Wittnam JL, Gogol-Doering A, Opitz L, Salinas-Riester G, Dettenhofer M, Kang H, Farinelli L, Chen W, Fischer A: Alteren histone acetylation is associated with age-dependent memory impairment in mice. Science. 2010, 328: 753-756. 10.1126/science.1186088.View ArticlePubMedGoogle Scholar
- Xu K, Dai XL, Haung HC, Jiang ZF: Targeting HDACs: A Promising Therapy for Alzheimer’s Disease. Oxid Med Cell Longev. 2011, ID 143269-Google Scholar
- Caricasole A, Bettini E, Sala C, Roncarati R, Kobayashi N, Caldara F, Goto K, Terstappen GC: Molecular cloning and characterization of the human diacylglycerol kinase β (DGKβ) gene. J Biol Chem. 2002, 277: 4790-4796. 10.1074/jbc.M110249200.View ArticlePubMedGoogle Scholar
- Tesli M, Kahler AK, Andreassen BK: No association between DGKH and bipolar disorder in a Scandinavian case–control sample. Psychiatr Genet. 2009, 19: 269-272. 10.1097/YPG.0b013e32832d302f.View ArticlePubMedGoogle Scholar
- Sklar P, Smoller JW, Fan J, Ferreira MA, Perlis RH, Chambert K, Nimgaonkar VL, McQueen MB, Faraone SV, Kirby A, de Bakker PI, Ogdie MN, Thase ME, Sachs GS, Todd-Brown K, Gabriel SB, Sougnez C, Gates C, Blumenstiel B, Defelice M, Ardlie KG, Franklin J, Muir WJ, McGhee KA, MacIntyre DJ, McLean A, VanBeck M, McQuillin A, Bass NJ, Robinson M, Lawrence J, Anjorin A, Curtis D: Whole-genome asscociation study of bipolar disorder. Mol Psychiary. 2008, 13: 558-569. 10.1038/sj.mp.4002151.View ArticleGoogle Scholar
- Yosifova A, Mushiroda T, Stoianov D, Vazharova R, Dimova I, Karachanak S, Zaharieva I, Milanova V, Madjirova N, Gerdjikov I, Tolev T, Velkova S, Kirov G, Owen MJ, O'Donovan MC, Toncheva D, Nakamura Y: Case–control association study of 65 candidates genes revealed a possible association of a SNP of HTR5A to be a factor susceptible to bipolar disease in Bulgarian population. J Affect Disord. 2009, 117: 87-97. 10.1016/j.jad.2008.12.021.View ArticlePubMedGoogle Scholar
- Yakubchyk Y, Abramovici H, Maillet JC, Daher E, Obagi C, Parks RJ, Topham MK, Gee SH: Regulation of nerurite outgrowth in N1E–115 cells through PDZ-mediated recruitment of diacylglycerol kinase ζ. Mol Cell Biol. 2005, 25: 7289-7302. 10.1128/MCB.25.16.7289-7302.2005.PubMed CentralView ArticlePubMedGoogle Scholar
- Ali H, Nakano T, Saino-Saito S, Hozumi Y, Katagiri Y, Kamii H, Sato S, Kayama T, Kondo H, Goto K: Selective translocation of diacylglycerol kinase ζ in hippocampal neurons under transient forebrain ischemia. Neurosci Lett. 2004, 372: 190-195. 10.1016/j.neulet.2004.09.052.View ArticlePubMedGoogle Scholar
- Saino-Saito S, Hozumi Y, Goto K: Excitotoxity by kainate-induced seizure diacylglycerol kinase ζ to shuttle from the nucleus to the cytoplasm in hippocampal neurons. Neurosci Lett. 2011, 494: 185-189. 10.1016/j.neulet.2011.02.062.View ArticlePubMedGoogle Scholar
- Liu Z, Chang GQ, Leibowitz SF: Diacylglycerol kinase zeta in hypothalamus interacts with long form leptin receptor. Relation to dietary fat and body weight regulation. J Biol Chem. 2001, 276: 5900-5907. 10.1074/jbc.M007311200.View ArticlePubMedGoogle Scholar
- Sommer W, Arlinde C, Caberlotto L, Thorsell A, Hyytia P, Heilig M: Differential expression of diacylglycerol kinase iota and L18A mRNAs in the brains of alcohol-preferring AA and alcohol-avoiding ANA rats. Mol Psychiatry. 2001, 6: 103-108. 10.1038/sj.mp.4000823.View ArticlePubMedGoogle Scholar
- Goto K, Kondo H: Heterogeneity of diacylglycerol kinase in terms of molecular structure, biochemical characteristics and gene expression localization in the brain. J Lipid Mediat Cell Signal. 1996, 14: 251-257. 10.1016/0929-7855(96)00533-0.View ArticlePubMedGoogle Scholar
- Tu-Sekine B, Raben DM: Regulation of DGKθ. J Cell Physiol. 2009, 220: 548-552. 10.1002/jcp.21813.View ArticlePubMedGoogle Scholar
- Takenawa T, Suetsugu S: The WASP–WAVE protein network: connecting the membrane to the cytoskeleton. Nature Rev Mol Cell Biol. 2007, 8: 37-48. 10.1038/nrm2069.View ArticleGoogle Scholar
- Kano T, Kouzuki T, Mizuno S, Ueda S, Yamanoue M, Sakane F, Saito N, Shirai Y: Both the C1 domain and a basic amino acid cluster at the C-terminus are important for the neurite and branch induction ability of DGKβ. Biochem Biophys Res Comun. 2014, in pressGoogle Scholar
- Sato M, Liu K, Sasaki S, Kunii N, Sakai H, Mizuno H, Saga H, Sakane F: Evaluations of the selectivities of the diacylglycerol kinase inhibitors R59022 and R59949 among diacylglycerol kinase isozymes using a new non-radioactive assay method. Pharmacology. 2013, 92: 99-107. 10.1159/000351849.View ArticlePubMedGoogle Scholar
- Takeishi K, Taketomi A, Shirabe K, Toshima T, Motomura T, Ikegami T, Yoshizumi T, Sakane F, Maehara Y: Diacylglycerol kinase alpha enhances hepatocellular carcinoma progression by activation of Ras–Raf–MEK–ERK pathway. J Hepatology. 2012, 57: 77-83. 10.1016/j.jhep.2012.02.026.View ArticleGoogle Scholar
- Rainero E, Caswell PT, Muller PAJ, Grindlay J, McCaffrey MW, Zhang Q, Wakelam MJ, Vousden KH, Graziani A, Norman JC: Diacylglycerol kinase α controls RCP-dependent integrin trafficking to promote invasive migration. J Cell Biol. 2012, 196: 277-295. 10.1083/jcb.201109112.PubMed CentralView ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.