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Special Issue "Diacylglycerol Kinases in Signal Transduction"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (28 February 2021).

Special Issue Editor

Dr. Gianluca Baldanzi
E-Mail Website
Guest Editor
Università degli Studi del Piemonte Orientale “Amedeo Avogadro”, Department of Translational Medicine, Center for Translational Research on Autoimmune & Allergic Diseases, Novara, Italy
Interests: diacylglycerol kinase; lipid signaling; receptor signal transduction; apoptosis; T cell receptor

Special Issue Information

Dear Colleagues,

The phosphorylation of diacylglycerol to phosphatidic acid tunes the level and localization of two key signaling lipids. Thus, diacylglycerol kinases constitute a critical node in signal transduction and a fascinating target for novel therapies. In particular, the increasing number of proteins that are known to be regulated either by diacylglycerol or by phosphatidic acid maintain the great interest in those enzymes. Despite its widespread patterns of expression, the biological function of diacylglycerol kinase has mainly only been explored in the immune and nervous system, while translational approaches have focused on cell transformation and cancer.

By including both research articles and reviews, this Special Issue aims to capture the state of art of the research on the role of diacylglycerol kinase in signaling and phospholipid metabolism. The main focus will be on progressive advancements in the understanding of diacylglycerol kinase regulation and the biological role in different cellular contexts as well as contribution to disease development. Of particular interest are the recent efforts aiming to capitalize the available knowledge in terms of therapeutic advancements using pharmacological inhibitors and genetic tools in spite of the incomplete knowledge of diacylglycerol kinase structure.

Dr. Gianluca Baldanzi
Guest Editor

Manuscript Submission Information

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Keywords

  • lipid metabolism
  • signal transduction
  • inhibitors
  • genetic models
  • immune function
  • cancer

Published Papers (5 papers)

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Research

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Article
Precise Regulation of the Basal PKCγ Activity by DGKγ Is Crucial for Motor Coordination
Int. J. Mol. Sci. 2020, 21(21), 7866; https://doi.org/10.3390/ijms21217866 - 23 Oct 2020
Cited by 3 | Viewed by 659
Abstract
Diacylglycerol kinase γ (DGKγ) is a lipid kinase to convert diacylglycerol (DG) to phosphatidic acid (PA) and indirectly regulates protein kinase C γ (PKCγ) activity. We previously reported that the basal PKCγ upregulation impairs cerebellar long-term depression (LTD) in the conventional DGKγ knockout [...] Read more.
Diacylglycerol kinase γ (DGKγ) is a lipid kinase to convert diacylglycerol (DG) to phosphatidic acid (PA) and indirectly regulates protein kinase C γ (PKCγ) activity. We previously reported that the basal PKCγ upregulation impairs cerebellar long-term depression (LTD) in the conventional DGKγ knockout (KO) mice. However, the precise mechanism in impaired cerebellar LTD by upregulated PKCγ has not been clearly understood. Therefore, we first produced Purkinje cell-specific DGKγ KO (tm1d) mice to investigate the specific function of DGKγ in Purkinje cells and confirmed that tm1d mice showed cerebellar motor dysfunction in the rotarod and beam tests, and the basal PKCγ upregulation but not PKCα in the cerebellum of tm1d mice. Then, the LTD-induced chemical stimulation, K-glu (50 mM KCl + 100 µM, did not induce phosphorylation of PKCα and dissociation of GluR2 and glutamate receptor interacting protein (GRIP) in the acute cerebellar slices of tm1d mice. Furthermore, treatment with the PKCγ inhibitor, scutellarin, rescued cerebellar LTD, with the phosphorylation of PKCα and the dissociation of GluR2 and GRIP. In addition, nonselective transient receptor potential cation channel type 3 (TRPC3) was negatively regulated by upregulated PKCγ. These results demonstrated that DGKγ contributes to cerebellar LTD by regulation of the basal PKCγ activity. Full article
(This article belongs to the Special Issue Diacylglycerol Kinases in Signal Transduction)
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Review

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Review
Diacylglycerol Kinase alpha in X Linked Lymphoproliferative Disease Type 1
Int. J. Mol. Sci. 2021, 22(11), 5816; https://doi.org/10.3390/ijms22115816 - 29 May 2021
Viewed by 894
Abstract
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 [...] Read more.
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 the adaptor protein SAP results in altered T cell receptor signalling, due in part to persistent DGKα activity. This activity constrains diacylglycerol levels, attenuating downstream pathways such as PKCθ and Ras/MAPK and decreasing T cell restimulation induced cell death. This is a form of apoptosis triggered by prolonged T cell activation that is indeed defective in CD8+ cells of X-linked lymphoproliferative disease type 1 patients. Accordingly, inhibition or downregulation of DGKα activity restores in vitro a correct diacylglycerol dependent signal transduction, cytokines production and restimulation induced apoptosis. In animal disease models, DGKα inhibitors limit CD8+ expansion and immune-mediated tissue damage, suggesting the possibility of using inhibitors of diacylglycerol kinase as a new therapeutic approach. Full article
(This article belongs to the Special Issue Diacylglycerol Kinases in Signal Transduction)
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Review
Beyond Lipid Signaling: Pleiotropic Effects of Diacylglycerol Kinases in Cellular Signaling
Int. J. Mol. Sci. 2020, 21(18), 6861; https://doi.org/10.3390/ijms21186861 - 18 Sep 2020
Cited by 2 | Viewed by 1045
Abstract
The diacylglycerol kinase family, which can attenuate diacylglycerol signaling and activate phosphatidic acid signaling, regulates various signaling transductions in the mammalian cells. Studies on the regulation of diacylglycerol and phosphatidic acid levels by various enzymes, the identification and characterization of various diacylglycerol and [...] Read more.
The diacylglycerol kinase family, which can attenuate diacylglycerol signaling and activate phosphatidic acid signaling, regulates various signaling transductions in the mammalian cells. Studies on the regulation of diacylglycerol and phosphatidic acid levels by various enzymes, the identification and characterization of various diacylglycerol and phosphatidic acid-regulated proteins, and the overlap of different diacylglycerol and phosphatidic acid metabolic and signaling processes have revealed the complex and non-redundant roles of diacylglycerol kinases in regulating multiple biochemical and biological networks. In this review article, we summarized recent progress in the complex and non-redundant roles of diacylglycerol kinases, which is expected to aid in restoring dysregulated biochemical and biological networks in various pathological conditions at the bed side. Full article
(This article belongs to the Special Issue Diacylglycerol Kinases in Signal Transduction)
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Review
New Era of Diacylglycerol Kinase, Phosphatidic Acid and Phosphatidic Acid-Binding Protein
Int. J. Mol. Sci. 2020, 21(18), 6794; https://doi.org/10.3390/ijms21186794 - 16 Sep 2020
Cited by 17 | Viewed by 2083
Abstract
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 [...] Read more.
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 has been generally thought that all DGK isozymes utilize the DG species derived from the turnover. However, it was recently revealed that DGK isozymes, except for DGKε, phosphorylate diverse DG species, which are not derived from phosphatidylinositol turnover. In addition, various PA-binding proteins (PABPs), which have different selectivities for PA species, were recently found. These results suggest that DGK–PA–PABP axes can potentially construct a large and complex signaling network and play physiologically and pathologically important roles in addition to DGK-dependent attenuation of DG–DG-binding protein axes. For example, 1-stearoyl-2-docosahexaenoyl-PA produced by DGKδ interacts with and activates Praja-1, the E3 ubiquitin ligase acting on the serotonin transporter, which is a target of drugs for obsessive-compulsive and major depressive disorders, in the brain. This article reviews recent research progress on PA species produced by DGK isozymes, the selective binding of PABPs to PA species and a phosphatidylinositol turnover-independent DG supply pathway. Full article
(This article belongs to the Special Issue Diacylglycerol Kinases in Signal Transduction)
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Review
Subcellular Localization Relevance and Cancer-Associated Mechanisms of Diacylglycerol Kinases
Int. J. Mol. Sci. 2020, 21(15), 5297; https://doi.org/10.3390/ijms21155297 - 26 Jul 2020
Cited by 2 | Viewed by 1506
Abstract
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 [...] Read more.
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 highlight that DGKs are an essential component of the PI cycle that localize within several subcellular compartments, including the nucleus and plasma membrane, together with their PI substrates and that they are involved in mediating major cancer cell mechanisms such as growth and metastasis. DGKs control cancer cell survival, proliferation, and angiogenesis by regulating Akt/mTOR and MAPK/ERK pathways. In addition, some DGKs control cancer cell migration by regulating the activities of the Rho GTPases Rac1 and RhoA. Full article
(This article belongs to the Special Issue Diacylglycerol Kinases in Signal Transduction)
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