ArticleJournal of immunology (Baltimore, Md. : 1950)2011
SAP-mediated inhibition of diacylglycerol kinase α regulates TCR-induced diacylglycerol signaling.
Article in Journal of immunology (Baltimore, Md. : 1950), 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 51 citations in OpenAlex.
- Article
- Modulators of Diacylglycerol Kinase Activity: A Review of Advances and Challenges.Medicinal research reviews · 2026Review
- CRISPR-Cas9 knockout of DGKα/ζ improves the anti-tumor activities of TAG-72 CAR-T cells in ovarian cancer.Molecular therapy. Oncology · 2025Article
- Harnessing the tumor microenvironment to boost adoptive T cell therapy with engineered lymphocytes for solid tumors.Seminars in immunopathology · 2024Review
- Tumor-Infiltrating Normal B Cells Revealed by Immunoglobulin Repertoire Clonotype Analysis Are Highly Prognostic and Crucial for Antitumor Immune Responses in DLBCL.Clinical cancer research : an official journal of the American Association for Cancer Research · 2023Article
- Molecular and temporal control of restimulation-induced cell death (RICD) in T lymphocytes.Frontiers in cell death · 2023Article
- Wiskott-Aldrich syndrome protein interacts and inhibits diacylglycerol kinase alpha promoting IL-2 induction.Frontiers in immunology · 2023Article
- Immune Checkpoint Receptors Signaling in T Cells.International journal of molecular sciences · 2022Review
- T cell receptor (TCR) signaling in health and disease.Signal transduction and targeted therapy · 2021Review
- Diacylglycerol kinase α inhibition cooperates with PD-1-targeted therapies to restore the T cell activation program.Cancer immunology, immunotherapy : CII · 2021Article
- Diacylglycerol Kinase alpha in X Linked Lymphoproliferative Disease Type 1.International journal of molecular sciences · 2021Review
- Structure activity relationship studies on Amb639752: toward the identification of a common pharmacophoric structure for DGKα inhibitors.Journal of enzyme inhibition and medicinal chemistry · 2020Article
- Negative control of diacylglycerol kinase ζ-mediated inhibition of T cell receptor signaling by nuclear sequestration in mice.European journal of immunology · 2020Article
- Graded diacylglycerol kinases α and ζ activities ensure mucosal-associated invariant T-cell development in mice.European journal of immunology · 2020Article
- Higher Incidence of B Cell Malignancies in Primary Immunodeficiencies: A Combination of Intrinsic Genomic Instability and Exocytosis Defects at the Immunological Synapse.Frontiers in immunology · 2020Review
- Diacylglycerol Kinase Alpha in Radiation-Induced Fibrosis: Potential as a Predictive Marker or Therapeutic Target.Frontiers in oncology · 2020Review
- DGK α and ζ Activities Control TFrontiers in immunology · 2019Article
- Diacylglycerol kinase α inactivation is an integral component of the costimulatory pathway that amplifies TCR signals.Cancer immunology, immunotherapy : CII · 2018Article
- FOXP3 renders activated human regulatory T cells resistant to restimulation-induced cell death by suppressing SAP expression.Cellular immunology · 2018Article
- X-Linked Lymphoproliferative Disease Type 1: A Clinical and Molecular Perspective.Frontiers in immunology · 2018Review
Corrections and comments
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Authors and funding
20 authors at 8 institutions in 6 countries.
Funding
Abstract
Diacylglycerol kinases (DGKs) metabolize diacylglycerol to phosphatidic acid. In T lymphocytes, DGKα acts as a negative regulator of TCR signaling by decreasing diacylglycerol levels and inducing anergy. In this study, we show that upon costimulation of the TCR with CD28 or signaling lymphocyte activation molecule (SLAM), DGKα, but not DGKζ, exits from the nucleus and undergoes rapid negative regulation of its enzymatic activity. Inhibition of DGKα is dependent on the expression of SAP, an adaptor protein mutated in X-linked lymphoproliferative disease, which is essential for SLAM-mediated signaling and contributes to TCR/CD28-induced signaling and T cell activation. Accordingly, overexpression of SAP is sufficient to inhibit DGKα, whereas SAP mutants unable to bind either phospho-tyrosine residues or SH3 domain are ineffective. Moreover, phospholipase C activity and calcium, but not Src-family tyrosine kinases, are also required for negative regulation of DGKα. Finally, inhibition of DGKα in SAP-deficient cells partially rescues defective TCR/CD28 signaling, including Ras and ERK1/2 activation, protein kinase C membrane recruitment, induction of NF-AT transcriptional activity, and IL-2 production. Thus SAP-mediated inhibition of DGKα sustains diacylglycerol signaling, thereby regulating T cell activation, and it may represent a novel pharmacological strategy for X-linked lymphoproliferative disease treatment.
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