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  1. Article ; Online: Immune Checkpoint Receptors Signaling in T Cells.

    Baldanzi, Gianluca

    International journal of molecular sciences

    2022  Volume 23, Issue 7

    Abstract: The characterization of the receptors negatively modulating lymphocyte function is rapidly advancing, driven by success in tumor immunotherapy. As a result, the number of immune checkpoint receptors characterized from a functional perspective and ... ...

    Abstract The characterization of the receptors negatively modulating lymphocyte function is rapidly advancing, driven by success in tumor immunotherapy. As a result, the number of immune checkpoint receptors characterized from a functional perspective and targeted by innovative drugs continues to expand. This review focuses on the less explored area of the signaling mechanisms of these receptors, of those expressed in T cells. Studies conducted mainly on PD-1, CTLA-4, and BTLA have evidenced that the extracellular parts of some of the receptors act as decoy receptors for activating ligands, but in all instances, the tyrosine phosphorylation of their cytoplasmatic tail drives a crucial inhibitory signal. This negative signal is mediated by a few key signal transducers, such as tyrosine phosphatase, inositol phosphatase, and diacylglycerol kinase, which allows them to counteract TCR-mediated activation. The characterization of these signaling pathways is of great interest in the development of therapies for counteracting tumor-infiltrating lymphocyte exhaustion/anergy independently from the receptors involved.
    MeSH term(s) Diacylglycerol Kinase ; Phosphoric Monoester Hydrolases ; Phosphorylation ; Protein Tyrosine Phosphatases/metabolism ; Receptors, Immunologic/metabolism ; T-Lymphocytes/metabolism ; Tyrosine/metabolism
    Chemical Substances Receptors, Immunologic ; Tyrosine (42HK56048U) ; Diacylglycerol Kinase (EC 2.7.1.107) ; Phosphoric Monoester Hydrolases (EC 3.1.3.2) ; myo-inositol-1 (or 4)-monophosphatase (EC 3.1.3.25) ; Protein Tyrosine Phosphatases (EC 3.1.3.48)
    Language English
    Publishing date 2022-03-24
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms23073529
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  2. Article ; Online: Immune Checkpoint Receptors Signaling in T Cells

    Gianluca Baldanzi

    International Journal of Molecular Sciences, Vol 23, Iss 3529, p

    2022  Volume 3529

    Abstract: The characterization of the receptors negatively modulating lymphocyte function is rapidly advancing, driven by success in tumor immunotherapy. As a result, the number of immune checkpoint receptors characterized from a functional perspective and ... ...

    Abstract The characterization of the receptors negatively modulating lymphocyte function is rapidly advancing, driven by success in tumor immunotherapy. As a result, the number of immune checkpoint receptors characterized from a functional perspective and targeted by innovative drugs continues to expand. This review focuses on the less explored area of the signaling mechanisms of these receptors, of those expressed in T cells. Studies conducted mainly on PD-1, CTLA-4, and BTLA have evidenced that the extracellular parts of some of the receptors act as decoy receptors for activating ligands, but in all instances, the tyrosine phosphorylation of their cytoplasmatic tail drives a crucial inhibitory signal. This negative signal is mediated by a few key signal transducers, such as tyrosine phosphatase, inositol phosphatase, and diacylglycerol kinase, which allows them to counteract TCR-mediated activation. The characterization of these signaling pathways is of great interest in the development of therapies for counteracting tumor-infiltrating lymphocyte exhaustion/anergy independently from the receptors involved.
    Keywords PDL-1 ; SLAM ; ITIM ; ITSM ; DGK ; Src ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 571
    Language English
    Publishing date 2022-03-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Diacylglycerol Kinases in Signal Transduction.

    Centonze, Sara / Baldanzi, Gianluca

    International journal of molecular sciences

    2022  Volume 23, Issue 15

    Abstract: In recent years, the significant research efforts put into the clarification of the PI3K/AKT/mTOR pathway resulted in the approval of the first targeted therapies based on lipid kinase inhibitors [ ... ]. ...

    Abstract In recent years, the significant research efforts put into the clarification of the PI3K/AKT/mTOR pathway resulted in the approval of the first targeted therapies based on lipid kinase inhibitors [...].
    MeSH term(s) Diacylglycerol Kinase/genetics ; Diacylglycerol Kinase/metabolism ; Diglycerides ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphoinositide-3 Kinase Inhibitors ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction
    Chemical Substances Diglycerides ; Phosphoinositide-3 Kinase Inhibitors ; Diacylglycerol Kinase (EC 2.7.1.107) ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1)
    Language English
    Publishing date 2022-07-29
    Publishing country Switzerland
    Document type Editorial
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms23158423
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  4. Article: Editorial: miRNAs and their role in endocrine cancer progression: from prognosis to treatment.

    Kushwaha, Prem Prakash / Doglietto, Francesco / Baldanzi, Gianluca

    Frontiers in endocrinology

    2023  Volume 14, Page(s) 1257692

    MeSH term(s) Humans ; MicroRNAs/genetics ; Neoplasms ; Neoplastic Processes ; Endocrine Gland Neoplasms ; Prognosis
    Chemical Substances MicroRNAs
    Language English
    Publishing date 2023-08-18
    Publishing country Switzerland
    Document type Editorial ; Research Support, Non-U.S. Gov't
    ZDB-ID 2592084-4
    ISSN 1664-2392
    ISSN 1664-2392
    DOI 10.3389/fendo.2023.1257692
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  5. Article ; Online: Diacylglycerol Kinases in Signal Transduction

    Sara Centonze / Gianluca Baldanzi

    International Journal of Molecular Sciences, Vol 23, Iss 8423, p

    2022  Volume 8423

    Abstract: In recent years, the significant research efforts put into the clarification of the PI3K/AKT/mTOR pathway resulted in the approval of the first targeted therapies based on lipid kinase inhibitors [.] ...

    Abstract In recent years, the significant research efforts put into the clarification of the PI3K/AKT/mTOR pathway resulted in the approval of the first targeted therapies based on lipid kinase inhibitors [.]
    Keywords n/a ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Language English
    Publishing date 2022-07-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Inhibition of diacylglycerol kinases as a physiological way to promote diacylglycerol signaling.

    Baldanzi, Gianluca

    Advances in biological regulation

    2014  Volume 55, Page(s) 39–49

    Abstract: Diacylglycerol is a key regulator of cell physiology, controlling the membrane recruitment and activation of signaling molecules. Accordingly, diacylglycerol generation and metabolism are strictly controlled, allowing for localized regulation of its ... ...

    Abstract Diacylglycerol is a key regulator of cell physiology, controlling the membrane recruitment and activation of signaling molecules. Accordingly, diacylglycerol generation and metabolism are strictly controlled, allowing for localized regulation of its concentration. While the increased production of diacylglycerol upon receptor triggering is well recognized, the modulation of diacylglycerol metabolism by diacylglycerol kinases (DGKs) is less characterized. Some agonists induce DGK activation and recruitment to the plasma membrane, promoting diacylglycerol metabolism to phosphatidic acid. Conversely, several reports indicate that signaling pathways that selectively inhibits DGK isoforms can enhance cellular diacylglycerol levels and signal transduction. For example, the impairment of DGKθ activity by RhoA binding to the catalytic domain represents a conserved mechanism controlling diacylglycerol signaling from Caenorhabditis elegans motoneurons to mammalian hepatocytes. Similarly, DGKα activity is inhibited in lymphocytes by TCR signaling, thus contributing to a rise in diacylglycerol concentration for downstream signaling. Finally, DGKμ activity is inhibited by ischemia-reperfusion-generated reactive oxygen species in airway endothelial cells, promoting diacylglycerol-mediated ion channel opening and edema. In those systems, DGKs provide a gatekeeper function by blunting diacylglycerol levels or possibly establishing permissive domains for diacylglycerol signaling. In this review, I discuss the possible general relevance of DGK inhibition to enhanced diacylglycerol signaling.
    MeSH term(s) Animals ; Blood Platelets/drug effects ; Blood Platelets/enzymology ; Diacylglycerol Kinase/antagonists & inhibitors ; Diacylglycerol Kinase/metabolism ; Diglycerides/pharmacology ; Humans ; Reactive Oxygen Species/pharmacology ; Signal Transduction
    Chemical Substances 1,2-diacylglycerol ; Diglycerides ; Reactive Oxygen Species ; Diacylglycerol Kinase (EC 2.7.1.107)
    Language English
    Publishing date 2014-05
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2667413-0
    ISSN 2212-4934 ; 2212-4926
    ISSN (online) 2212-4934
    ISSN 2212-4926
    DOI 10.1016/j.jbior.2014.02.001
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Uc I Zs.364: Show issues Location:
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  7. Article ; Online: Diacylglycerol Kinase alpha in X Linked Lymphoproliferative Disease Type 1.

    Velnati, Suresh / Centonze, Sara / Girivetto, Federico / Baldanzi, Gianluca

    International journal of molecular sciences

    2021  Volume 22, Issue 11

    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 ... ...

    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 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
    MeSH term(s) Animals ; Biomarkers ; Diacylglycerol Kinase/chemistry ; Diacylglycerol Kinase/genetics ; Diacylglycerol Kinase/metabolism ; Disease Susceptibility ; Enzyme Activation ; Genes, X-Linked ; Genetic Association Studies/methods ; Genetic Loci ; Humans ; Lymphocyte Activation/genetics ; Lymphocyte Activation/immunology ; Lymphoproliferative Disorders/diagnosis ; Lymphoproliferative Disorders/etiology ; Lymphoproliferative Disorders/metabolism ; Protein Binding ; Signal Transduction ; Signaling Lymphocytic Activation Molecule Associated Protein/metabolism ; Structure-Activity Relationship ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism
    Chemical Substances Biomarkers ; Signaling Lymphocytic Activation Molecule Associated Protein ; Diacylglycerol Kinase (EC 2.7.1.107)
    Language English
    Publishing date 2021-05-29
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms22115816
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  8. Article ; Online: DGKα in Neutrophil Biology and Its Implications for Respiratory Diseases.

    Baldanzi, Gianluca / Malerba, Mario

    International journal of molecular sciences

    2019  Volume 20, Issue 22

    Abstract: 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 ... ...

    Abstract 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 transcript. Together with in vitro experiments, this suggests that DGKs may represent potential therapeutic targets for disorders where inflammation, and neutrophils in particular, plays a major role. In this paper we focus on obstructive respiratory diseases, including asthma and chronic obstructive pulmonary disease (COPD), but also rare genetic diseases such as alpha-1-antitrypsin deficiency. Indeed, the biological role of DGKα is understudied outside the T lymphocyte field. The recent wave of research aiming to develop novel and specific inhibitors as well as KO mice will allow a better understanding of DGK's role in neutrophilic inflammation. Better knowledge and pharmacologic tools may also allow DGK to move from the laboratory bench to clinical trials.
    MeSH term(s) Animals ; Diacylglycerol Kinase/immunology ; Diacylglycerol Kinase/metabolism ; Humans ; Immunity ; Inflammation/immunology ; Inflammation/metabolism ; Inflammation/pathology ; Neutrophils/immunology ; Neutrophils/metabolism ; Neutrophils/pathology ; Respiratory Tract Diseases/immunology ; Respiratory Tract Diseases/metabolism ; Respiratory Tract Diseases/pathology ; Signal Transduction ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; T-Lymphocytes/pathology
    Chemical Substances Diacylglycerol Kinase (EC 2.7.1.107)
    Language English
    Publishing date 2019-11-13
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2019364-6
    ISSN 1422-0067 ; 1422-0067 ; 1661-6596
    ISSN (online) 1422-0067
    ISSN 1422-0067 ; 1661-6596
    DOI 10.3390/ijms20225673
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  9. Article ; Online: Diacylglycerol Kinase alpha in X Linked Lymphoproliferative Disease Type 1

    Suresh Velnati / Sara Centonze / Federico Girivetto / Gianluca Baldanzi

    International Journal of Molecular Sciences, Vol 22, Iss 5816, p

    2021  Volume 5816

    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 ... ...

    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 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.
    Keywords signal transduction ; activation-induced cell death ; PKC ; ERK ; SHP-2 ; SLAM ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Language English
    Publishing date 2021-05-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: Potential role of diacylglycerol kinases in immune-mediated diseases.

    Baldanzi, Gianluca / Ragnoli, Beatrice / Malerba, Mario

    Clinical science (London, England : 1979)

    2020  Volume 134, Issue 13, Page(s) 1637–1658

    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, ... ...

    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 deep investigations. DGK α and ζ resulted in negatively regulating synergistic way basal and receptor induced DAG signals in T cells as well as leukocytes. In this way, they contributed to keep under control the immune response but also downmodulate immune response against tumors. Alteration in DGKα activity is also implicated in the pathogenesis of genetic perturbations of the immune function such as the X-linked lymphoproliferative disease 1 and localized juvenile periodontitis. These findings suggested a participation of DGK to the pathogenetic mechanisms underlying several immune-mediated diseases and prompted several researches aiming to target DGK with pharmacologic and molecular strategies. Those findings are discussed inhere together with experimental applications in tumors as well as in other immune-mediated diseases such as asthma.
    MeSH term(s) Animals ; Diacylglycerol Kinase/genetics ; Diacylglycerol Kinase/immunology ; Diglycerides/immunology ; Humans ; Immune System Diseases/enzymology ; Immune System Diseases/genetics ; Immune System Diseases/immunology ; T-Lymphocytes/immunology
    Chemical Substances Diglycerides ; Diacylglycerol Kinase (EC 2.7.1.107)
    Language English
    Publishing date 2020-07-29
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 206835-7
    ISSN 1470-8736 ; 0301-0538 ; 0009-0360 ; 0143-5221
    ISSN (online) 1470-8736
    ISSN 0301-0538 ; 0009-0360 ; 0143-5221
    DOI 10.1042/CS20200389
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    In stock of ZB MED Cologne/Königswinter

    Ua VI Zs.220: Show issues Location:
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