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1

Gravina, Teresa, Chiara Maria Teresa Boggio, Elisa Gorla, et al. "Role of Diacylglycerol Kinases in Acute Myeloid Leukemia." Biomedicines 11, no. 7 (2023): 1877. http://dx.doi.org/10.3390/biomedicines11071877.

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Diacylglycerol kinases (DGKs) play dual roles in cell transformation and immunosurveillance. According to cancer expression databases, acute myeloid leukemia (AML) exhibits significant overexpression of multiple DGK isoforms, including DGKA, DGKD and DGKG, without a precise correlation with specific AML subtypes. In the TGCA database, high DGKA expression negatively correlates with survival, while high DGKG expression is associated with a more favorable prognosis. DGKA and DGKG also feature different patterns of co-expressed genes. Conversely, the BeatAML and TARGET databases show that high DG
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2

Tabet, Ricardos, Enora Moutin, Jérôme A. J. Becker, et al. "Fragile X Mental Retardation Protein (FMRP) controls diacylglycerol kinase activity in neurons." Proceedings of the National Academy of Sciences 113, no. 26 (2016): E3619—E3628. http://dx.doi.org/10.1073/pnas.1522631113.

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Fragile X syndrome (FXS) is caused by the absence of the Fragile X Mental Retardation Protein (FMRP) in neurons. In the mouse, the lack of FMRP is associated with an excessive translation of hundreds of neuronal proteins, notably including postsynaptic proteins. This local protein synthesis deregulation is proposed to underlie the observed defects of glutamatergic synapse maturation and function and to affect preferentially the hundreds of mRNA species that were reported to bind to FMRP. How FMRP impacts synaptic protein translation and which mRNAs are most important for the pathology remain u
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3

YAMADA, Keiko, Fumio SAKANE, Norio MATSUSHIMA та Hideo KANOH. "EF-hand motifs of α, β and γ isoforms of diacylglycerol kinase bind calcium with different affinities and conformational changes". Biochemical Journal 321, № 1 (1997): 59–64. http://dx.doi.org/10.1042/bj3210059.

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The three diacylglycerol kinase isoenzymes (DGKα, DGKβ and DGKγ) cloned so far contain in common a tandem repeat of EF-hand motifs. However, the Ca2+ dependences of the DGK activities are known to be variable between isoenzymes, and the Ca2+-binding activities of these motifs have not been tested except for those present in DGKα. We therefore attempted to define the intrinsic properties of EF-hands occurring in the DGK isoenzymes. For this purpose we bacterially expressed and purified the EF-hand motifs (termed DKE forms) of the three DGKs. Equilibrium dialysis with the purified DKE forms show
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4

Ren, Xiaodi, Yvonne Lo, Michelle Pusey та ін. "Abstract 3789: INCB177054: A novel, potent, orally bioavailable DGKα/ζ dual inhibitor enhances T-cell function and demonstrates potent antitumor activity". Cancer Research 85, № 8_Supplement_1 (2025): 3789. https://doi.org/10.1158/1538-7445.am2025-3789.

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Abstract Host immune responses play an important role in fighting cancers; therefore, improving these responses against tumor cells is of high interest in cancer therapy. Diacylglycerol (DAG) is a key second messenger that transduces T-cell receptor (TCR) activation signal to downstream effectors through DAG-binding proteins. DAG kinase (DGK) isoforms α and ζ are the major enzymes that modulate DAG levels in T cells and serve as intracellular checkpoints to attenuate TCR activation. Here, we describe INCB177054, a novel, potent, selective, and orally bioavailable small molecule DGKα/ζ dual inh
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5

Baldanzi, Gianluca, та Mario Malerba. "DGKα in Neutrophil Biology and Its Implications for Respiratory Diseases". International Journal of Molecular Sciences 20, № 22 (2019): 5673. http://dx.doi.org/10.3390/ijms20225673.

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Diacylglycerol kinases (DGKs) play a key role in phosphoinositide signaling by removing diacylglycerol and generating phosphatidic acid. Besides the well-documented role of DGKα and DGKζ as negative regulators of lymphocyte responses, a robust body of literature points to those enzymes, and specifically DGKα, as crucial regulators of leukocyte function. Upon neutrophil stimulation, DGKα activation is necessary for migration and a productive response. The role of DGKα in neutrophils is evidenced by its aberrant behavior in juvenile periodontitis patients, which express an inactive DGKα transcri
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6

Gharbi, Severine I., Esther Rincón, Antonia Avila-Flores та ін. "Diacylglycerol kinase ζ controls diacylglycerol metabolism at the immunological synapse". Molecular Biology of the Cell 22, № 22 (2011): 4406–14. http://dx.doi.org/10.1091/mbc.e11-03-0247.

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Diacylglycerol (DAG) generation at the T cell immunological synapse (IS) determines the correct activation of antigen-specific immune responses. DAG kinases (DGKs) α and ζ act as negative regulators of DAG-mediated signals by catalyzing DAG conversion to phosphatidic acid (PA). Nonetheless, the specific input of each enzyme and their spatial regulation during IS formation remain uncharacterized. Here we report recruitment of endogenous DGKα and DGKζ to the T cell receptor (TCR) complex following TCR/CD28 engagement. Specific DGK gene silencing shows that PA production at the activated complex
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7

Katagiri, Yuji, Tsukasa Ito, Sachiko Saino-Saito, et al. "Expression and localization of diacylglycerol kinase isozymes and enzymatic features in rat lung." American Journal of Physiology-Lung Cellular and Molecular Physiology 288, no. 6 (2005): L1171—L1178. http://dx.doi.org/10.1152/ajplung.00237.2004.

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Diacylglycerol kinase (DGK) catalyzes phosphorylation of diacylglycerol to generate phosphatidic acid, and both molecules are known to serve as second messengers as well as important intermediates for the synthesis of various lipids. In this study, we investigated the spatiotemporal expression patterns of DGK isozymes together with the developmental changes of the mRNA expression and enzymatic property in rat lung. Northern blot and RT-PCR analyses showed that mRNAs for DGKα, -ε, and -ζ were detected in the lung. By immunohistochemical examination, DGKα and -ζ were shown to be coexpressed in a
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8

Topham, Matthew K., та Stephen M. Prescott. "Diacylglycerol Kinase ζ Regulates Ras Activation by a Novel Mechanism". Journal of Cell Biology 152, № 6 (2001): 1135–44. http://dx.doi.org/10.1083/jcb.152.6.1135.

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Guanine nucleotide exchange factors (GEFs) activate Ras by facilitating its GTP binding. Ras guanyl nucleotide-releasing protein (GRP) was recently identified as a Ras GEF that has a diacylglycerol (DAG)-binding C1 domain. Its exchange factor activity is regulated by local availability of signaling DAG. DAG kinases (DGKs) metabolize DAG by converting it to phosphatidic acid. Because they can attenuate local accumulation of signaling DAG, DGKs may regulate RasGRP activity and, consequently, activation of Ras. DGKζ, but not other DGKs, completely eliminated Ras activation induced by RasGRP, and
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9

ROCHE, Marc A. de la, Janet L. SMITH, Maribel RICO та ін. "Dictyostelium discoideum has a single diacylglycerol kinase gene with similarity to mammalian θ isoforms". Biochemical Journal 368, № 3 (2002): 809–15. http://dx.doi.org/10.1042/bj20021027.

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Diacylglycerol kinases (DGKs) phosphorylate the neutral lipid diacylglycerol (DG) to produce phosphatidic acid (PA). In mammalian systems DGKs are a complex family of at least nine isoforms that are thought to participate in down-regulation of DG-based signalling pathways and perhaps activation of PA-stimulated signalling events. We report here that the simple protozoan amoeba Dictyostelium discoideum appears to contain a single gene encoding a DGK enzyme. This gene, dgkA, encodes a deduced protein that contains three C1-type cysteine-rich repeats, a DGK catalytic domain most closely related t
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10

DU, Xiangnan, Ying JIANG, Weijun QIAN, Xiaolan LU та James P. WALSH. "Fatty acids inhibit growth-factor-induced diacylglycerol kinase α activation in vascular smooth-muscle cells". Biochemical Journal 357, № 1 (2001): 275–82. http://dx.doi.org/10.1042/bj3570275.

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We have previously shown that unsaturated fatty acids amplify platelet-derived-growth-factor (PDGF)-induced protein kinase C (PKC) activation in vascular smooth-muscle cells (VSMCs). Diacylglycerol-induced PKC activation is normally terminated by diacylglycerol kinases (DGKs). We thus hypothesized that fatty acids act by inhibiting a DGK. Fractionation of VSMC extracts demonstrated that the DGK α isoform was the major DGK activity present. PDGF markedly increased the DGK activity of cultured cells. An inhibitor selective for the DGK α isoform,R59949[3-{2-[4-(bis-(4-fluorophenyl)methylene]piper
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11

Dougan, Stephanie K. "Abstract SY12-04: Lowering the TCR signaling threshold with a DGKa/z dual inhibitor potentiates anti-tumor immunity." Cancer Research 83, no. 7_Supplement (2023): SY12–04—SY12–04. http://dx.doi.org/10.1158/1538-7445.am2023-sy12-04.

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Abstract Checkpoint blockade immunotherapies expand neoantigen- or virus-specific T cells, and poor responsiveness to immunotherapy is associated with lower mutational burden in tumors of non-viral origin. Although mouse models demonstrate that lower affinity T cells recognizing self-antigens can contribute to tumor control if sufficiently activated, therapeutic options for enhancing T cell priming are limited. Diacylglycerol kinases (DGKs) suppress DAG signaling by converting DAG to phosphatidic acid, thereby attenuating pathways downstream of TCR signaling. Using a novel dual DGKa/z inhibito
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12

Takahashi, Daisuke, та Fumio Sakane. "Expression and purification of human diacylglycerol kinase α from baculovirus-infected insect cells for structural studies". PeerJ 6 (10 серпня 2018): e5449. http://dx.doi.org/10.7717/peerj.5449.

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Diacylglycerol kinases (DGKs) are lipid kinases that modulate the levels of lipid second messengers, diacylglycerol and phosphatidic acid. Recently, increasing attention has been paid to its α isozyme (DGKα) as a potential target for cancer immunotherapy. DGKα consists of the N-terminal regulatory domains including EF-hand motifs and C1 domains, and the C-terminal catalytic domain (DGKα-CD). To date, however, no structures of mammalian DGKs including their CDs have yet been reported, impeding our understanding on the catalytic mechanism of DGKs and the rational structure-based drug design. Her
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13

Hernandez-Lara, Miguel Angel, Santosh K. Yadav, Sushrut D. Shah, et al. "Regulation of Airway Smooth Muscle Cell Proliferation by Diacylglycerol Kinase: Relevance to Airway Remodeling in Asthma." International Journal of Molecular Sciences 23, no. 19 (2022): 11868. http://dx.doi.org/10.3390/ijms231911868.

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Airway remodeling in asthma involves the hyperproliferation of airway smooth muscle (ASM) cells. However, the molecular signals that regulate ASM growth are not completely understood. Gq-coupled G protein-coupled receptor and receptor tyrosine kinase signaling regulate ASM cell proliferation via activation of phospholipase C, generation of inositol triphosphate (IP3) and diacylglycerol (DAG). Diacylglycerol kinase (DGK) converts DAG into phosphatidic acid (PA) and terminates DAG signaling while promoting PA-mediated signaling and function. Herein, we hypothesized that PA is a pro-mitogenic sec
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14

AbdulSalam, Safnas F., Mia M. Eason, Holly A. Fowle, Anna L. Stuart, and Kurumi Y. Horiuchi. "Abstract 170: Development of diacylglycerol kinase assays to facilitate isoform specific inhibitor discovery." Cancer Research 82, no. 12_Supplement (2022): 170. http://dx.doi.org/10.1158/1538-7445.am2022-170.

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Abstract Diacylglycerol (DAG) and phosphatidic acid (PA) are two key second messengers in signaling and metabolic pathways. Diacylglycerol kinase (DGK) phosphorylate DAG to produce PA, acting as a central switch between the various signal transduction pathways activated by these second messengers. Ten DGK isoforms (α, β, γ, δ, ε, ζ, η, θ, ι, and κ) have been identified and categorized into five classes based on their structural features. DGKα is highly expressed in several cancers including hepatoma, lymphoma and melanoma, and has been shown to promote cancer survival by positively regulating
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15

Imai, Shin-ichi, Masahiro Kai, Satoshi Yasuda, Hideo Kanoh та Fumio Sakane. "Identification and Characterization of a Novel Human Type II Diacylglycerol Kinase, DGKκ". Journal of Biological Chemistry 280, № 48 (2005): 39870–81. http://dx.doi.org/10.1074/jbc.m500669200.

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16

Hernández-Montiel, Wilber, Nubia Noemi Cob-Calan, Lilia E. Cahuich-Tzuc, et al. "Runs of Homozygosity and Gene Identification in Pelibuey Sheep Using Genomic Data." Diversity 14, no. 7 (2022): 522. http://dx.doi.org/10.3390/d14070522.

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The runs of homozygosity (ROHs), the inbreeding coefficient, and the effective population size (Ne) in Pelibuey sheep were analyzed in 24 Pelibuey ewes from two lambs at parturition and 24 ewes that gave birth to a single lamb using the Ilumina OvineSNP50 BeadChip. The Ne decreased from 535 to 192 in the first ten generations. A total of 2194 ROHs were identified on the basis of single nucleotide polymorphisms (SNPs), were identified in the prolific group and 2185 SNPs in ROH in the non-prolific group. The distribution of the lengths of the ROH, considering both groups, were found to be: 4065
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17

Liu, Cheng-hu, Fabiana S. Machado, Rishu Guo, et al. "Diacylglycerol kinase zeta regulates microbial recognition and host resistance to Toxoplasma gondii (51.16)." Journal of Immunology 178, no. 1_Supplement (2007): S99. http://dx.doi.org/10.4049/jimmunol.178.supp.51.16.

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Abstract Mammalian Toll-like receptors (TLRs) recognize microbial pathogen-associated molecular patterns and are critical for innate immunity against microbial infection. Diacylglycerol kinases (DGKs) regulate the intracellular levels of two important second messengers involved in signaling from many surface receptors by converting diacylglycerol (DAG) to phosphatidic acid (PA). Here, we demonstrate that the ζ isoform of the DGK family (DGKζ) is expressed in macrophages (Mϕ) and dendritic cells (DC). DGKζ deficiency results in impaired IL-12 and TNFα production following TLR stimulation in vit
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18

Kakehi, Tomoko, Keiko Yagi, Naoaki Saito, and Yasuhito Shirai. "Effects of vitamin E and its derivatives on diabetic nephropathy in Rats and identification of diacylglycerol kinase subtype involved in the improvement of diabetic nephropathy." Functional Foods in Health and Disease 7, no. 10 (2017): 816. http://dx.doi.org/10.31989/ffhd.v7i10.386.

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Background: Diabetes is a significant social issue. Controlling diabetic complications such as nephropathy is very important for QOL of diabetic patients. One of the mechanisms which causes diabetic complications is the abnormal activation of protein kinase C (PKC) by increased diacylglycerol (DG) from hyperglycemia. Diacylglycerol kinase (DGK) can attenuate PKC activity by converting DG to phosphatidic acid. Thus far, d-a-tocopherol (VtE) treatment has been shown to prevent early changes of diabetic renal dysfunctions by activating DGK. However, it is still unknown whether VtE derivatives imp
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19

Fazio, Antonietta, Eric Owusu Obeng, Isabella Rusciano, et al. "Subcellular Localization Relevance and Cancer-Associated Mechanisms of Diacylglycerol Kinases." International Journal of Molecular Sciences 21, no. 15 (2020): 5297. http://dx.doi.org/10.3390/ijms21155297.

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An increasing number of reports suggests a significant involvement of the phosphoinositide (PI) cycle in cancer development and progression. Diacylglycerol kinases (DGKs) are very active in the PI cycle. They are a family of ten members that convert diacylglycerol (DAG) into phosphatidic acid (PA), two-second messengers with versatile cellular functions. Notably, some DGK isoforms, such as DGKα, have been reported to possess promising therapeutic potential in cancer therapy. However, further studies are needed in order to better comprehend their involvement in cancer. In this review, we highli
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20

Moroi, Alyssa J., Nicole M. Zwifelhofer, Matthew J. Riese, Debra K. Newman та Peter J. Newman. "Diacylglycerol kinase ζ is a negative regulator of GPVI-mediated platelet activation". Blood Advances 3, № 7 (2019): 1154–66. http://dx.doi.org/10.1182/bloodadvances.2018026328.

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Abstract Diacylglycerol kinases (DGKs) are a family of enzymes that convert diacylglycerol (DAG) into phosphatidic acid (PA). The ζ isoform of DGK (DGKζ) has been reported to inhibit T-cell responsiveness by downregulating intracellular levels of DAG. However, its role in platelet function remains undefined. In this study, we show that DGKζ was expressed at significant levels in both platelets and megakaryocytes and that DGKζ-knockout (DGKζ-KO) mouse platelets were hyperreactive to glycoprotein VI (GPVI) agonists, as assessed by aggregation, spreading, granule secretion, and activation of rele
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21

Liu, Cheng-Hu, Fabiana S. Machado, Rishu Guo та ін. "Diacylglycerol kinase ζ regulates microbial recognition and host resistance to Toxoplasma gondii". Journal of Experimental Medicine 204, № 4 (2007): 781–92. http://dx.doi.org/10.1084/jem.20061856.

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Mammalian Toll-like receptors (TLRs) recognize microbial pathogen-associated molecular patterns and are critical for innate immunity against microbial infection. Diacylglycerol (DAG) kinases (DGKs) regulate the intracellular levels of two important second messengers involved in signaling from many surface receptors by converting DAG to phosphatidic acid (PA). We demonstrate that the ζ isoform of the DGK family (DGKζ) is expressed in macrophages (Mφ) and dendritic cells. DGKζ deficiency results in impaired interleukin (IL) 12 and tumor necrosis factor α production following TLR stimulation in v
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22

Gu, Wangxian, Guoqing Wan, Yanjun Zheng та ін. "BIOM-55. DGKζ-TARGETED REGULATION OF MIR-34A IN THE PROLIFERATION AND TUMORIGENICITY OF HUMAN GLIOBLASTOMA". Neuro-Oncology 22, Supplement_2 (2020): ii13. http://dx.doi.org/10.1093/neuonc/noaa215.052.

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Abstract Diacylglycerol kinase (DGK) is a lipid kinase that catalyzes the phosphorylation of diacylglycerol (DAG) to produce phosphatidic acid (PA), which uses ATP as a phosphate donor. Diacylglycerol kinases ζ(DGKζ) is characterized as specific type IV due to its myristoylated alanine-rich C-kinase substrate (MARCKS), ankyrin, and PDZ binding domain. Similar to other DGKs, DGKζ is also reported to be abnormally expressed in human colorectal cancer cells, and it is indispensable for the proliferation of cancer cells. However, its implications in human glioblastoma (GBM) is largely unknown. Bot
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SAKANE, Fumio, Masahiro KAI, Ikuo WADA, Shin-ichi IMAI та Hideo KANOH. "The C-terminal part of diacylglycerol kinase α lacking zinc fingers serves as a catalytic domain". Biochemical Journal 318, № 2 (1996): 583–90. http://dx.doi.org/10.1042/bj3180583.

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All mammalian diacylglycerol kinase (DGK) isoenzymes so far cloned consist of four conserved regions, namely C1, C2 (tandem EF-hand structures), C3 (tandem cysteine-rich zinc finger sequences) and the C-terminal C4 domains. To determine the catalytic domain we expressed in COS-7 cells various truncation mutants of pig DGKα and assessed their enzyme activities. We found that the C4 domain lacking the whole N-terminal region including the zinc fingers possessed DGK activity that was dependent on the concentrations of diacylglycerol and ATP very similarly, as did the wild-type DGKα. Furthermore t
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24

Sun, Deheng, Hongfu Lu, Huaxing Yu, et al. "Abstract 1855: Targeting DGKA for immuno-oncology therapy: ISM4312A, a novel DGKA inhibitor with robust anti-tumor activity." Cancer Research 83, no. 7_Supplement (2023): 1855. http://dx.doi.org/10.1158/1538-7445.am2023-1855.

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Abstract Diacylglycerol kinases (DGKs), a family of isozymes that phosphorylate the membrane lipid, diacylglycerol (DAG), to phosphatidic acid (PA), are important players in signal transduction cascades. DAG and PA act as vital second messengers that regulate multiple cellular signal transduction pathways including PKC and MAPK. DGKα (DGKA), one of the ten human DGK isoforms, has been reported to play a role in mediating numerous aspects of cancer progression including survival, migration, and invasion of cancer cells. Emerging data indicate that DGKA mediates T-cell dysfunction during anti-PD
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Baldanzi, Gianluca, Beatrice Ragnoli, and Mario Malerba. "Potential role of diacylglycerol kinases in immune-mediated diseases." Clinical Science 134, no. 13 (2020): 1637–58. http://dx.doi.org/10.1042/cs20200389.

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Abstract The mechanism promoting exacerbated immune responses in allergy and autoimmunity as well as those blunting the immune control of cancer cells are of primary interest in medicine. Diacylglycerol kinases (DGKs) are key modulators of signal transduction, which blunt diacylglycerol (DAG) signals and produce phosphatidic acid (PA). By modulating lipid second messengers, DGK modulate the activity of downstream signaling proteins, vesicle trafficking and membrane shape. The biological role of the DGK α and ζ isoforms in immune cells differentiation and effector function was subjected to in d
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26

Sakane, Fumio, Fumi Hoshino, and Chiaki Murakami. "New Era of Diacylglycerol Kinase, Phosphatidic Acid and Phosphatidic Acid-Binding Protein." International Journal of Molecular Sciences 21, no. 18 (2020): 6794. http://dx.doi.org/10.3390/ijms21186794.

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Diacylglycerol kinase (DGK) phosphorylates diacylglycerol (DG) to generate phosphatidic acid (PA). Mammalian DGK consists of ten isozymes (α–κ) and governs a wide range of physiological and pathological events, including immune responses, neuronal networking, bipolar disorder, obsessive-compulsive disorder, fragile X syndrome, cancer, and type 2 diabetes. DG and PA comprise diverse molecular species that have different acyl chains at the sn-1 and sn-2 positions. Because the DGK activity is essential for phosphatidylinositol turnover, which exclusively produces 1-stearoyl-2-arachidonoyl-DG, it
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You, Jae-Sung, Hannah C. Lincoln, Chan-Ran Kim та ін. "The Role of Diacylglycerol Kinase ζ and Phosphatidic Acid in the Mechanical Activation of Mammalian Target of Rapamycin (mTOR) Signaling and Skeletal Muscle Hypertrophy". Journal of Biological Chemistry 289, № 3 (2013): 1551–63. http://dx.doi.org/10.1074/jbc.m113.531392.

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The activation of mTOR signaling is essential for mechanically induced changes in skeletal muscle mass, and previous studies have suggested that mechanical stimuli activate mTOR (mammalian target of rapamycin) signaling through a phospholipase D (PLD)-dependent increase in the concentration of phosphatidic acid (PA). Consistent with this conclusion, we obtained evidence which further suggests that mechanical stimuli utilize PA as a direct upstream activator of mTOR signaling. Unexpectedly though, we found that the activation of PLD is not necessary for the mechanically induced increases in PA
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28

Masai, I., A. Okazaki, T. Hosoya, and Y. Hotta. "Drosophila retinal degeneration A gene encodes an eye-specific diacylglycerol kinase with cysteine-rich zinc-finger motifs and ankyrin repeats." Proceedings of the National Academy of Sciences 90, no. 23 (1993): 11157–61. http://dx.doi.org/10.1073/pnas.90.23.11157.

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The Drosophila visual mutant, carrying the retinal degeneration A gene (rdgA), has photoreceptor cells that degenerate within a week after eclosion. Morphological studies suggested that this mutant harbors abnormalities in membrane turnover of the photoreceptor cells. Biochemically, the rdgA mutant lacks an eye-specific and membrane-associated diacylglycerol kinase (DGK; EC 2.7.1.107) activity in a gene-dosage-dependent manner, suggesting that rdgA gene encodes a DGK. We report the molecular cloning and characterization of a DGK gene, which maps to the rdgA locus. This gene, designated as DGK2
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WALKER, Anthony J., Annette DRAEGER, Brahim HOUSSA, Wim J. VAN BLITTERSWIJK, Vasken OHANIAN та Jacqueline OHANIAN. "Diacylglycerol kinase θ is translocated and phosphoinositide 3-kinase-dependently activated by noradrenaline but not angiotensin II in intact small arteries". Biochemical Journal 353, № 1 (2000): 129–37. http://dx.doi.org/10.1042/bj3530129.

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Diacylglycerol (DG) kinase (DGK) phosphorylates the lipid second messenger DG to phosphatidic acid. We reported previously that noradrenaline (NA), but not angiotensin II (AII), increases membrane-associated DGK activity in rat small arteries [Ohanian and Heagerty (1994) Biochem. J. 300, 51–56]. Here, we have identified this DGK activity as DGKθ, present in both smooth muscle and endothelial cells of these small vessels. Subcellular fractionation of artery homogenates revealed that DGKθ was present in nuclear, plasma membrane (and/or Golgi) and cytosolic fractions. Upon NA stimulation, DGKθ tr
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30

Luo, Bai, Stephen M. Prescott та Matthew K. Topham. "Association of diacylglycerol kinase ζ with protein kinase C α". Journal of Cell Biology 160, № 6 (2003): 929–37. http://dx.doi.org/10.1083/jcb.200208120.

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Activation of PKC depends on the availability of DAG, a signaling lipid that is tightly and dynamically regulated. DAG kinase (DGK) terminates DAG signaling by converting it to phosphatidic acid. Here, we demonstrate that DGKζ inhibits PKCα activity and that DGK activity is required for this inhibition. We also show that DGKζ directly interacts with PKCα in a signaling complex and that the binding site in DGKζ is located within the catalytic domain. Because PKCα can phosphorylate the myristoylated alanine-rich C-kinase substrate (MARCKS) motif of DGKζ, we tested whether this modification could
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Hsu, Ku-Lung, Adam L. Borne, Jeffrey W. Brulet, et al. "Towards identification of a lipid metabolic checkpoint for immuno-oncology." Journal of Immunology 202, no. 1_Supplement (2019): 71.7. http://dx.doi.org/10.4049/jimmunol.202.supp.71.7.

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Abstract Lipid phosphorylation is an understudied regulatory mechanism for T cell metabolism and signaling. Specifically, diacylglycerol kinases (DGKs) modulate intracellular levels of the secondary messengers diacylglycerol and phosphatidic acid, which are implicated in regulation of T cell activation and anergy. Development of isoform-selective DGK inhibitors is challenging but needed to understand specificity of DGK biology in vivo. Towards this goal, we use ATP acyl phosphate activity-based probes and quantitative mass spectrometry to define, for the first time, the DGK ATP-binding site (D
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Tomoka Namba, Tomoka, Daiki Hayashi, Itsuko Fukuda, Shuji Ueda, and Yasuhito Shirai. "Tocotrienols activate diacylglycerol kinase a via 67 KDa laminin receptor." Functional Food Science - Online ISSN: 2767-3146 5, no. 5 (2025): 160–69. https://doi.org/10.31989/ffs.v5i5.1638.

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Background: Diabetes is a significant social issue. Controlling diabetic complications such as nephropathy is crucial for the quality of life (QOL) of diabetic patients. The abnormal activation of protein kinase C (PKC) through increased diacylglycerol levels (DG) due to hyperglycemia is a common mechanism that causes diabetic complications. Diacylglycerol kinase (DGK) can attenuate PKC activity by converting DG to phosphatidic acid. Thus far, d-α-tocopherol (αToc) treatment has been shown to prevent early changes of diabetic renal dysfunctions by activating DGKα via the 67KDa laminin receptor
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33

Mérida, Isabel, Javier Arranz-Nicolás, Cristina Rodríguez-Rodríguez, and Antonia Ávila-Flores. "Diacylglycerol kinase control of protein kinase C." Biochemical Journal 476, no. 8 (2019): 1205–19. http://dx.doi.org/10.1042/bcj20180620.

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Abstract The diacylglycerol kinases (DGK) are lipid kinases that transform diacylglycerol (DAG) into phosphatidic acid (PA) in a reaction that terminates DAG-based signals. DGK provide negative regulation to conventional and novel protein kinase C (PKC) enzymes, limiting local DAG availability in a tissue- and subcellular-restricted manner. Defects in the expression/activity of certain DGK isoforms contribute substantially to cognitive impairment and mental disorders. Abnormal DGK overexpression in tumors facilitates invasion and resistance to chemotherapy preventing tumor immune destruction b
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34

Niizeki, Takeshi, Yasuchika Takeishi, Takanori Arimoto та ін. "Cardiac-specific overexpression of diacylglycerol kinase ζ attenuates left ventricular remodeling and improves survival after myocardial infarction". American Journal of Physiology-Heart and Circulatory Physiology 292, № 2 (2007): H1105—H1112. http://dx.doi.org/10.1152/ajpheart.00927.2006.

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Left ventricular (LV) remodeling, including cardiomyocyte necrosis, scar formation, LV geometric changes, and cardiomyocyte hypertrophy, contributes to cardiac dysfunction and mortality after myocardial infarction (MI). Although precise cellular signaling mechanisms for LV remodeling are not fully elucidated, Gq protein-coupled receptor signaling pathway, including diacylglycerol (DAG) and PKC, are involved in this process. DAG kinase (DGK) phosphorylates DAG and controls cellular DAG levels, thus acting as a negative regulator of PKC and subsequent cellular signaling. We previously reported t
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35

Bruneau, Sarah, Mélanie Néel, Lubka T. Roumenina та ін. "Loss of DGKε induces endothelial cell activation and death independently of complement activation". Blood 125, № 6 (2015): 1038–46. http://dx.doi.org/10.1182/blood-2014-06-579953.

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Key Points Loss of DGKε in endothelial cells induces cell death, impairs angiogenic responses, and leads to an activated and prothrombotic phenotype. DGKE silencing in resting endothelial cells does not affect complement activation at their surface.
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Arranz-Nicolas, Javier, Cristina Rodríguez-Rodríguez, Rosa Liébana та ін. "519 Diacylglycerol kinase ζ limits IL-2-dependent control of PD-1 expression in tumor-infiltrating T lymphocytes". Journal for ImmunoTherapy of Cancer 8, Suppl 3 (2020): A555. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0519.

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BackgroundTumors evade T cell responses targeting them through the upregulation of tolerance-inducing mechanisms. One of the best characterized is that of PD-1/PD-1L engagement, that in healthy CD8+ T cells limits cytotoxic responses against self-antigens and that tumors employ to neutralize T cell attack. Antibody-based therapies aimed to block the PD-1/PD-1L axis have rendered notable results, but most patients eventually develop resistance. This failure is attributed to CD8+ T cells achieving an exhausted phenotype where recovery is hardly feasible. The dysfunctional phenotype of tumor-infi
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37

Zhong, Xiaoping, Chi-Keung Wan та Rishu Guo. "Synergistic role of diacylglycerol kinases α and ζ in T cell development and self-tolerance (137.37)". Journal of Immunology 182, № 1_Supplement (2009): 137.37. http://dx.doi.org/10.4049/jimmunol.182.supp.137.37.

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Abstract Signal for the T cell receptor (TCR) plays critical roles in T cell development and function. TCR signaling can induce positive or negative selection of thymocytes, induces activation or anergy of mature T cells, and induce conventional T cell activation or regulatory T cells to suppress immune function. The mechanisms that modulate TCR signaling to direct these distinct outcomes have been poorly understood. Diacylglycerol (DAG) kinases (DGKs) are a family of enzymes that convert DAG to phosphatidic acid (PA) through phosphorylation. In mammals, ten DGK isoforms have been identified.
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Okada, Naoki, Ko Sugiyama, Hidemitsu Kitamura, and Akinobu Taketomi. "Inhibition of diacylglycerol kinase alpha to augment antitumor effector T cells in tumor-bearing host." Journal of Clinical Oncology 37, no. 4_suppl (2019): 293. http://dx.doi.org/10.1200/jco.2019.37.4_suppl.293.

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293 Background: Diacylglycerol kinases (DGKs), lipid kinases transforming diacylglycerol to phosphatidic acid, play important roles in intracellular signal transduction. Diacylglycerol kinase alpha (DGKa), an isozyme of DGKs, is well-known to promote proliferation of cancer cells by suppression of the apoptosis. Additionally, a previous report demonstrated that activation of DGKa induced anergy state of T lymphocytes in vivo. In this study, we investigated whether inhibition of DGKa not only suppress the tumorigenesis of cancer cells but also activate anti-tumor immunity. Methods: We first inv
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Liu, Yishi, Zehui Yang, Xiaoman Zhou, Zijie Li, and Nakanishi Hideki. "Diacylglycerol Kinases and Its Role in Lipid Metabolism and Related Diseases." International Journal of Molecular Sciences 25, no. 23 (2024): 13207. https://doi.org/10.3390/ijms252313207.

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Lipids are essential components of eukaryotic membranes, playing crucial roles in membrane structure, energy storage, and signaling. They are predominantly synthesized in the endoplasmic reticulum (ER) and subsequently transported to other organelles. Diacylglycerol kinases (DGKs) are a conserved enzyme family that phosphorylate diacylglycerol (DAG) to produce phosphatidic acid (PA), both of which are key intermediates in lipid metabolism and second messengers involved in numerous cellular processes. Dysregulation of DGK activity is associated with several diseases, including cancer and metabo
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40

Cai, Kai, та Marion B. Sewer. "Diacylglycerol kinase θ couples farnesoid X receptor-dependent bile acid signalling to Akt activation and glucose homoeostasis in hepatocytes". Biochemical Journal 454, № 2 (2013): 267–74. http://dx.doi.org/10.1042/bj20130609.

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DGKs (diacylglycerol kinases) catalyse the conversion of diacylglycerol into PA (phosphatidic acid), a positive modulator of mTOR (mammalian target of rapamycin). We have found that chenodeoxycholic acid and the synthetic FXR (farnesoid X receptor) ligand GW4064 induce the mRNA and protein expression of DGKθ in the HepG2 cell line and in primary human hepatocytes. Reporter gene studies using 1.5 kB of the DGKθ promoter fused to the luciferase gene revealed that bile acids increase DGKθ transcriptional activity. Mutation of putative FXR-binding sites attenuated the ability of GW4046 to increase
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Singh, Brenal K., Wen Lu, Amanda M. Schmidt Paustian та ін. "Diacylglycerol kinase ζ promotes allergic airway inflammation and airway hyperresponsiveness through distinct mechanisms". Science Signaling 12, № 597 (2019): eaax3332. http://dx.doi.org/10.1126/scisignal.aax3332.

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Asthma is a chronic allergic inflammatory airway disease caused by aberrant immune responses to inhaled allergens, which leads to airway hyperresponsiveness (AHR) to contractile stimuli and airway obstruction. Blocking T helper 2 (TH2) differentiation represents a viable therapeutic strategy for allergic asthma, and strong TCR-mediated ERK activation blocks TH2 differentiation. Here, we report that targeting diacylglycerol (DAG) kinase zeta (DGKζ), a negative regulator of DAG-mediated cell signaling, protected against allergic asthma by simultaneously reducing airway inflammation and AHR thoug
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Abramovici, Hanan, Parmiss Mojtabaie, Robin J. Parks та ін. "Diacylglycerol Kinase ζ Regulates Actin Cytoskeleton Reorganization through Dissociation of Rac1 from RhoGDI". Molecular Biology of the Cell 20, № 7 (2009): 2049–59. http://dx.doi.org/10.1091/mbc.e07-12-1248.

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Activation of Rac1 GTPase signaling is stimulated by phosphorylation and release of RhoGDI by the effector p21-activated kinase 1 (PAK1), but it is unclear what initiates this potential feed-forward mechanism for regulation of Rac activity. Phosphatidic acid (PA), which is produced from the lipid second messenger diacylglycerol (DAG) by the action of DAG kinases (DGKs), is known to activate PAK1. Here, we investigated whether PA produced by DGKζ initiates RhoGDI release and Rac1 activation. In DGKζ-deficient fibroblasts PAK1 phosphorylation and Rac1–RhoGDI dissociation were attenuated, leading
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Merino-Cortés, Sara V., Sofia R. Gardeta, Sara Roman-Garcia та ін. "Diacylglycerol kinase ζ promotes actin cytoskeleton remodeling and mechanical forces at the B cell immune synapse". Science Signaling 13, № 627 (2020): eaaw8214. http://dx.doi.org/10.1126/scisignal.aaw8214.

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Diacylglycerol kinases (DGKs) limit antigen receptor signaling in immune cells by consuming the second messenger diacylglycerol (DAG) to generate phosphatidic acid (PA). Here, we showed that DGKζ promotes lymphocyte function–associated antigen 1 (LFA-1)–mediated adhesion and F-actin generation at the immune synapse of B cells with antigen-presenting cells (APCs), mostly in a PA-dependent manner. Measurement of single-cell mechanical force generation indicated that DGKζ-deficient B cells exerted lower forces at the immune synapse than did wild-type B cells. Nonmuscle myosin activation and trans
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Velnati, Suresh, Sara Centonze, Federico Girivetto, and Gianluca Baldanzi. "Diacylglycerol Kinase alpha in X Linked Lymphoproliferative Disease Type 1." International Journal of Molecular Sciences 22, no. 11 (2021): 5816. http://dx.doi.org/10.3390/ijms22115816.

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Diacylglycerol kinases are intracellular enzymes that control the balance between the secondary messengers diacylglycerol and phosphatidic acid. DGKα and DGKζ are the prominent isoforms that restrain the intensity of T cell receptor signalling by metabolizing PLCγ generated diacylglycerol. Thus, their activity must be tightly controlled to grant cellular homeostasis and refine immune responses. DGKα is specifically inhibited by strong T cell activating signals to allow for full diacylglycerol signalling which mediates T cell response. In X-linked lymphoproliferative disease 1, deficiency of th
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45

Mérida, Isabel, Antonia Ávila-Flores, and Ernesto Merino. "Diacylglycerol kinases: at the hub of cell signalling." Biochemical Journal 409, no. 1 (2007): 1–18. http://dx.doi.org/10.1042/bj20071040.

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DGKs (diacylglycerol kinases) are members of a unique and conserved family of intracellular lipid kinases that phosphorylate DAG (diacylglycerol), catalysing its conversion into PA (phosphatidic acid). This reaction leads to attenuation of DAG levels in the cell membrane, regulating a host of intracellular signalling proteins that have evolved the ability to bind this lipid. The product of the DGK reaction, PA, is also linked to the regulation of diverse functions, including cell growth, membrane trafficking, differentiation and migration. In multicellular eukaryotes, DGKs provide a link betwe
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Nagaya, Hisao, Ikuo Wada, Yan-Jun Jia та Hideo Kanoh. "Diacylglycerol Kinase δ Suppresses ER-to-Golgi Traffic via Its SAM and PH Domains". Molecular Biology of the Cell 13, № 1 (2002): 302–16. http://dx.doi.org/10.1091/mbc.01-05-0255.

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We report here that the anterograde transport from the endoplasmic reticulum (ER) to the Golgi was markedly suppressed by diacylglycerol kinase δ (DGKδ) that uniquely possesses a pleckstrin homology (PH) and a sterile α motif (SAM) domain. A low-level expression of DGKδ in NIH3T3 cells caused redistribution into the ER of the marker proteins of the Golgi membranes and the vesicular-tubular clusters (VTCs). In this case DGKδ delayed the ER-to-Golgi traffic of vesicular stomatitis virus glycoprotein (VSV G) and also the reassembly of the Golgi apparatus after brefeldin A (BFA) treatment and wash
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Olenchock, Benjamin A., Rishu Guo, Michael A. Silverman та ін. "Impaired degranulation but enhanced cytokine production after FcεRI stimulation of diacylglycerol kinase ζ–deficient mast cells". Journal of Experimental Medicine 203, № 6 (2006): 1471–80. http://dx.doi.org/10.1084/jem.20052424.

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Calcium and diacylglycerol are critical second messengers that together effect mast cell degranulation after allergen cross-linking of immunoglobulin (Ig)E-bound FcεRI. Diacylglycerol kinase (DGK)ζ is a negative regulator of diacylglycerol-dependent signaling that acts by converting diacylglycerol to phosphatidic acid. We reported previously that DGKζ−/− mice have enhanced in vivo T cell function. Here, we demonstrate that these mice have diminished in vivo mast cell function, as revealed by impaired local anaphylactic responses. Concordantly, DGKζ−/− bone marrow–derived mast cells (BMMCs) dem
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Chianale, Federica, Santina Cutrupi, Elena Rainero та ін. "Diacylglycerol Kinase-α Mediates Hepatocyte Growth Factor-induced Epithelial Cell Scatter by Regulating Rac Activation and Membrane Ruffling". Molecular Biology of the Cell 18, № 12 (2007): 4859–71. http://dx.doi.org/10.1091/mbc.e07-02-0177.

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Diacylglycerol kinases (Dgk) phosphorylate diacylglycerol (DG) to phosphatidic acid (PA), thus turning off and on, respectively, DG-mediated and PA-mediated signaling pathways. We previously showed that hepatocyte growth factor (HGF), vascular endothelial growth factor, and anaplastic lymphoma kinase activate Dgkα in endothelial and leukemia cells through a Src-mediated mechanism and that activation of Dgkα is required for chemotactic, proliferative, and angiogenic signaling in vitro. Here, we investigate the downstream events and signaling pathways regulated by Dgkα, leading to cell scatter a
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Niizeki, Takeshi, Yasuchika Takeishi, Tatsuro Kitahara та ін. "Diacylglycerol kinase-ε restores cardiac dysfunction under chronic pressure overload: a new specific regulator of Gαq signaling cascade". American Journal of Physiology-Heart and Circulatory Physiology 295, № 1 (2008): H245—H255. http://dx.doi.org/10.1152/ajpheart.00066.2008.

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Gαq protein-coupled receptor (GPCR) signaling pathway, which includes diacylglycerol (DAG) and protein kinase C (PKC), plays a critical role in cardiac hypertrophy. DAG kinase (DGK) catalyzes DAG phosphorylation and controls cellular DAG levels, thus acting as a regulator of GPCR signaling. It has been reported that DGKε acts specifically on DAG produced by inositol cycling. In this study, we examined whether DGKε prevents cardiac hypertrophy and progression to heart failure under chronic pressure overload. We generated transgenic mice with cardiac-specific overexpression of DGKε (DGKε-TG) usi
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Sakane, Fumio, Fumi Hoshino, Masayuki Ebina, Hiromichi Sakai та Daisuke Takahashi. "The Roles of Diacylglycerol Kinase α in Cancer Cell Proliferation and Apoptosis". Cancers 13, № 20 (2021): 5190. http://dx.doi.org/10.3390/cancers13205190.

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Diacylglycerol (DG) kinase (DGK) phosphorylates DG to generate phosphatidic acid (PA). The α isozyme is activated by Ca2+ through its EF-hand motifs and tyrosine phosphorylation. DGKα is highly expressed in several refractory cancer cells including melanoma, hepatocellular carcinoma, and glioblastoma cells. In melanoma cells, DGKα is an antiapoptotic factor that activates nuclear factor-κB (NF-κB) through the atypical protein kinase C (PKC) ζ-mediated phosphorylation of NF-κB. DGKα acts as an enhancer of proliferative activity through the Raf–MEK–ERK pathway and consequently exacerbates hepato
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