Affinage

DGKZ

Diacylglycerol kinase zeta · UniProt Q13574

Length
928 aa
Mass
104.0 kDa
Annotated
2026-04-28
73 papers in source corpus 28 papers cited in narrative 28 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DGKζ is a lipid kinase that terminates diacylglycerol (DAG) signaling by phosphorylating DAG to phosphatidic acid, and uniquely among the ten DGK isoforms also phosphorylates ceramide to produce ceramide-1-phosphate via a ceramide kinase-independent pathway (PMID:8626588, PMID:36906254). DGKζ shuttles between cytosol, plasma membrane, and nucleus under PKCα-dependent phosphorylation of its MARCKS domain and CRM1-dependent nuclear export; nuclear DGKζ induces G1 cell cycle arrest by downregulating cyclin D1, upregulating TIS21/BTG2, and reducing retinoblastoma protein phosphorylation (PMID:9716136, PMID:20023381, PMID:17488950, PMID:19263516). In T cells, DGKζ metabolizes DAG at the immunological synapse to limit RasGRP/Ras/ERK and PKCα activation, and genetic deletion of DGKζ prevents T cell anergy induction and enhances NK cell antitumor cytotoxicity (PMID:11257115, PMID:17028587, PMID:23525016, PMID:27342844). DGKζ also scaffolds signaling complexes through its C1 domains (binding Rac1), PDZ-binding motif (binding syntrophins and SNX27), and ankyrin repeats, thereby coordinating neurite outgrowth, mast cell degranulation, cardiac hypertrophy suppression, and TGFβR2 membrane stability independently of or in addition to its catalytic activity (PMID:16055737, PMID:16717114, PMID:18219172, PMID:35115500).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 1996 High

    Establishing the enzymatic identity of DGKζ resolved what catalytic activity a new DGK family member possessed, showing it is a DAG kinase with stereoselective 1,2-DAG specificity and a unique domain architecture including ankyrin repeats and a MARCKS phosphorylation site domain.

    Evidence cDNA cloning and in vitro lipid kinase assay in COS-7 cells

    PMID:8626588

    Open questions at the time
    • No endogenous substrate specificity for acyl chain species demonstrated
    • Physiological role unknown at this point
  2. 1998 High

    Demonstrating that DGKζ localizes to the nucleus and that PKC isoforms regulate this localization via the MARCKS domain established a feedback cycle in which DAG activates PKC, which then controls DAG metabolism by redirecting DGKζ subcellularly, with nuclear DGKζ attenuating cell growth.

    Evidence Conditional expression, nuclear fractionation, live-cell imaging, PKC isoform-specific modulation

    PMID:9716136

    Open questions at the time
    • Nuclear substrates of DGKζ not identified
    • Mechanism of growth attenuation not defined
  3. 2001 High

    Identifying DGKζ as a specific negative regulator of RasGRP-dependent Ras activation answered how DAG-driven Ras signaling is terminated downstream of the TCR, establishing that DGKζ catalytic activity in a complex with RasGRP metabolizes DAG needed for RasGRP C1-domain activation.

    Evidence Co-immunoprecipitation, co-localization, Ras activation assays, kinase-dead mutant overexpression in Jurkat T cells

    PMID:11257115

    Open questions at the time
    • Stoichiometry and structural basis of DGKζ–RasGRP complex unknown
    • Whether this mechanism operates in primary T cells not shown
  4. 2001 High

    Discovery of the syntrophin–DGKζ interaction through the C-terminal PDZ-binding motif revealed a scaffolding function and showed that syntrophins regulate DGKζ nuclear trafficking, forming a ternary complex with dystrophin in brain.

    Evidence Yeast two-hybrid, reciprocal co-immunoprecipitation, pulldown, deletion mutant analysis in HeLa cells and neurons

    PMID:11352924

    Open questions at the time
    • Functional consequence of syntrophin binding on DGKζ catalytic output not measured
    • Role of ternary complex in vivo not established
  5. 2002 High

    Structure–function dissection of DGKζ translocation showed that zinc fingers and the catalytic domain are required for enzymatic activity, while PKC-driven MARCKS domain phosphorylation and intact zinc fingers are essential for plasma membrane recruitment, establishing a domain-level regulatory architecture.

    Evidence Real-time confocal videomicroscopy with GFP-tagged domain mutants in Jurkat cells

    PMID:12015310

    Open questions at the time
    • Receptor specificity mechanism not fully defined
    • Lipid-binding properties of individual C1 domains not characterized
  6. 2003 High

    Identifying PKCα as the kinase that directly phosphorylates DGKζ's MARCKS domain and inhibits its catalytic activity established a reciprocal feedback: DGKζ removes DAG that activates PKCα, and PKCα phosphorylation inhibits DGKζ, allowing sustained DAG signaling when PKC is strongly activated.

    Evidence In vitro kinase assay, co-immunoprecipitation, phosphomimetic/phospho-null mutagenesis, DAG measurement, cell growth assay

    PMID:12890670

    Open questions at the time
    • Whether other PKC isoforms contribute quantitatively in vivo not resolved
    • Phosphatase reversing this modification not identified
  7. 2003 High

    In skeletal muscle, DGKζ–syntrophin complexes translocate to the plasma membrane via PKC-dependent MARCKS phosphorylation, and DGKζ colocalizes with Rac1 and F-actin at lamellipodia; loss from the sarcolemma in dystrophin-deficient mdx muscle linked DGKζ to muscular dystrophy pathology.

    Evidence Co-immunoprecipitation, subcellular fractionation, immunofluorescence, phosphomimetic mutants, mdx mouse model

    PMID:14551255

    Open questions at the time
    • Causal contribution of DGKζ loss to mdx phenotype not tested by rescue
    • ERK-dependent phosphorylation site not mapped
  8. 2004 High

    Proteomic identification of c-Src as a GnRH-stimulated DGKζ interactor, together with increased DGKζ activity and shortened ERK signaling, revealed a receptor-regulated DGKζ activation mechanism in endocrine cells.

    Evidence MALDI-TOF MS, reciprocal co-immunoprecipitation, lipid kinase assay, ERK kinetics in gonadotrope cells

    PMID:14707140

    Open questions at the time
    • Whether c-Src directly phosphorylates DGKζ not determined
    • Downstream LHβ transcriptional consequence not confirmed by loss-of-function
  9. 2005 High

    Demonstrating that DGKζ promotes neurite outgrowth through a kinase-independent, Rac1/syntrophin-dependent scaffolding mechanism separated DGKζ's catalytic and non-catalytic functions and identified the C1 domains as the Rac1 binding site.

    Evidence Overexpression, dominant-negative mutants, co-immunoprecipitation, pulldown assays in N1E-115 cells and primary cortical neurons

    PMID:16055737

    Open questions at the time
    • Whether Rac1 activation state is regulated by DGKζ binding not determined
    • In vivo neuronal phenotype of DGKζ knockout not reported here
  10. 2005 High

    DGKζ overexpression in cardiomyocytes blocked endothelin-1-induced hypertrophy by preventing PKCε translocation and ERK/AP-1 activation, establishing DGKζ as a negative regulator of the DAG–PKC–MAPK hypertrophic pathway.

    Evidence Adenoviral overexpression, PKC translocation assay, ERK activity, luciferase reporter, leucine uptake, cell surface area in neonatal rat cardiomyocytes

    PMID:15781737

    Open questions at the time
    • Loss-of-function (knockout) cardiac phenotype not yet shown
    • Specific PA-mediated downstream effects not distinguished from DAG removal
  11. 2006 High

    Genetic knockout of DGKζ revealed its dual role in immune cells: it is required for T cell anergy induction (DGKζ-null T cells resist anergy and produce IL-2) and for mast cell degranulation (DGKζ-null mast cells show impaired degranulation but enhanced Ras-ERK and cytokine production), demonstrating context-dependent regulation of DAG signaling.

    Evidence DGKζ knockout mice, in vivo anergy model, T cell proliferation, mast cell degranulation, calcium flux, PLC-γ activity

    PMID:16717114 PMID:17028587

    Open questions at the time
    • Mechanism for mast cell PLC-γ dependence on DGKζ unclear
    • Relative contributions of DGKα and DGKζ in T cell anergy not fully delineated
  12. 2007 High

    Nuclear DGKζ was shown to block cells in G1 through a mechanism requiring both nuclear localization and kinase activity, reducing retinoblastoma protein phosphorylation; siRNA knockdown increased S/G2/M entry and impaired myogenic differentiation, connecting nuclear DAG metabolism to cell cycle control.

    Evidence Conditional overexpression with kinase-dead and nuclear-excluded mutants, siRNA knockdown, flow cytometry, BrdU incorporation, pRb Western blot in C2C12 cells

    PMID:17488950

    Open questions at the time
    • Direct nuclear DAG/PA substrate pools not measured
    • Kinase target linking PA production to Rb hypophosphorylation not identified
  13. 2008 High

    In vivo cardiac rescue of Gαq-transgenic heart failure by DGKζ transgenic overexpression validated DGKζ as a physiologically relevant negative regulator of PKC-JNK/p38 hypertrophic signaling, extending cell-based findings to an animal disease model.

    Evidence Double-transgenic mouse model with echocardiography, hemodynamic catheterization, PKC/JNK/p38 phosphorylation, survival analysis

    PMID:18219172

    Open questions at the time
    • Whether endogenous DGKζ levels change in heart failure not shown
    • Cardiac-specific DGKζ knockout phenotype not reported
  14. 2009 Medium

    Identification of cyclin D1 downregulation and TIS21/BTG2 upregulation as downstream effectors of nuclear DGKζ provided a molecular pathway from nuclear PA production to G1 arrest and retinoblastoma protein hypophosphorylation.

    Evidence DNA microarrays, RT-PCR, Western blot, overexpression/siRNA in C2C12 cells

    PMID:19263516

    Open questions at the time
    • Direct mechanism by which PA or DAG depletion controls TIS21 transcription unknown
    • Single cell type studied
  15. 2010 High

    Mapping a functional CRM1-dependent nuclear export sequence (NES) in DGKζ established that its nucleocytoplasmic shuttling is actively regulated by both import (NLS in MARCKS domain) and export signals, with NES mutation enhancing G1 arrest.

    Evidence Site-directed mutagenesis of NES, leptomycin B treatment, subcellular fractionation, flow cytometry in C2C12 cells

    PMID:20023381

    Open questions at the time
    • Whether post-translational modifications regulate NES accessibility not tested
    • Interaction with CRM1/exportin not directly demonstrated biochemically
  16. 2013 High

    Showing that DGKζ limits PKCα residence time at the immunological synapse in T cells, with DGKζ-null T cells exhibiting prolonged PKCα localization and enhanced Ras/ERK signaling, established DGKζ as a spatiotemporal regulator of the DAG signaling gradient at the IS.

    Evidence DGKζ knockout mice, live-cell PKCα imaging, L-selectin shedding, Ras/ERK activation assays

    PMID:23525016

    Open questions at the time
    • Whether PA production at the IS has independent signaling roles not addressed
    • Contribution of DGKα at the IS not delineated
  17. 2016 High

    Genetic deletion of DGKζ in NK cells enhanced cytotoxicity and tumor rejection in an ERK-dependent manner, positioning DGKζ as a druggable checkpoint for NK cell-based immunotherapy.

    Evidence DGKζ knockout mice, NK cell activation assays, ERK inhibitor rescue, in vivo TAP-deficient tumor model

    PMID:27342844

    Open questions at the time
    • Whether combined DGKα/ζ deletion further enhances NK activity not tested here
    • Mechanism by which DGKζ selectively affects activating but not inhibitory receptor pathways unclear
  18. 2022 High

    DGKζ was found to promote breast cancer metastasis by producing PA that alters TGFβR2 partitioning between lipid raft and non-raft membrane domains, stabilizing TGFβR2 and sustaining TGFβ/Smad3 signaling—revealing a novel PA-mediated membrane biophysics mechanism.

    Evidence CRISPR knockout, overexpression, RNA-seq, TGFβR2 endocytosis assay, lipid raft fractionation, in vitro and in vivo metastasis assays

    PMID:35115500

    Open questions at the time
    • Whether this PA-lipid raft mechanism operates in normal tissues not tested
    • Structural basis for PA-induced membrane fluidity change not defined
  19. 2022 Medium

    Identifying SNX27 as a trafficking partner that delivers DGKζ to the immunological synapse via PDZ domain interaction explained how the DAG gradient at the IS is established, as SNX27 silencing abolished both DGKζ polarization and MTOC translocation.

    Evidence Proteomic PDZ-interactome analysis, SNX27 siRNA, live-cell DAG gradient imaging, MTOC polarization assay

    PMID:35095913

    Open questions at the time
    • Whether SNX27 recycles DGKζ from endosomes not tested
    • Interaction not validated by reciprocal co-immunoprecipitation
  20. 2023 High

    Discovery that DGKζ uniquely among all ten DGK isoforms phosphorylates ceramide to produce ceramide-1-phosphate expanded its substrate scope beyond DAG, identifying a CerK-independent C1P biosynthetic pathway.

    Evidence Parallel overexpression of all 10 DGK isoforms, in vitro assay with purified DGKζ, DGKζ knockout, LC-MS lipidomics

    PMID:36906254

    Open questions at the time
    • Physiological roles of DGKζ-derived C1P not established
    • Whether ceramide kinase activity is regulated independently of DAG kinase activity unknown
    • Structural basis for dual substrate recognition not defined
  21. 2023 Medium

    Base-editing mutagenesis screens in primary human T cells mapped specific residues in DGKζ that tune T cell activation, identifying both gain-of-function and loss-of-function alleles and validating DGKζ as a graded immunomodulatory target.

    Evidence Large-scale base-editing mutagenesis screen targeting 385 genes in primary human T cells with functional readout

    PMID:38093011

    Open questions at the time
    • Biochemical mechanism of individual gain/loss-of-function mutations not dissected
    • Whether identified residues affect catalytic activity vs. localization vs. interactions unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for DGKζ's dual DAG/ceramide kinase activity, the identity of nuclear PA targets that mediate cell cycle arrest, whether cardiac-specific DGKζ loss-of-function causes spontaneous cardiomyopathy, and how DGKζ's catalytic and scaffolding functions are independently regulated in different cell types.
  • No crystal or cryo-EM structure of DGKζ available
  • Nuclear PA effectors remain unidentified
  • Cardiac-specific knockout phenotype not reported
  • Relative contribution of catalytic vs. scaffolding functions not quantified in vivo

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 3 GO:0098772 molecular function regulator activity 3 GO:0008289 lipid binding 2 GO:0060090 molecular adaptor activity 2
Localization
GO:0005634 nucleus 5 GO:0005829 cytosol 2 GO:0005856 cytoskeleton 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-168256 Immune System 4 R-HSA-1640170 Cell Cycle 3 R-HSA-1430728 Metabolism 2
Partners
MAPK3PLCB1PRKCARAC1RASGRP1SNTG1SNX27SRC
Complex memberships
DGKζ–Rac1–syntrophin complexDGKζ–RasGRP complexDGKζ–syntrophin–dystrophin complex

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 Human DGKζ was cloned and characterized as a diacylglycerol kinase that converts diacylglycerol to phosphatidic acid. It contains two zinc fingers, an ATP binding site, four ankyrin repeats, and a unique MARCKS phosphorylation site domain. It shows stereoselectivity for 1,2-diacylglycerol over 1,3-diacylglycerol but no specificity for molecular species of long-chain diacylglycerols. cDNA cloning, transfection in COS-7 cells, in vitro diacylglycerol kinase activity assay The Journal of biological chemistry High 8626588
1998 A fraction of DGKζ localizes to the nucleus where it reduces nuclear diacylglycerol levels. The nuclear localization signal resides in the MARCKS-homologous domain. Two specific isoforms of protein kinase C regulate DGKζ's nuclear localization, defining a regulatory cycle in which DAG activates PKC, which then controls DAG metabolism by altering DGKζ subcellular location. Conditional nuclear expression of DGKζ attenuates cell growth. Conditional expression system, nuclear fractionation, live-cell imaging, PKC isoform-specific activation/inhibition Nature High 9716136
2001 DGKζ, but not other DGK isoforms, specifically eliminates Ras activation induced by RasGRP by metabolizing the DAG required for RasGRP's C1 domain-mediated activation. DGKζ co-immunoprecipitates and co-localizes with RasGRP, forming a signaling complex. This interaction is enhanced by phorbol esters (DAG analogues). Kinase-dead DGKζ overexpression in Jurkat cells prolongs Ras activation after TCR ligation, confirming that enzymatic activity is required. Co-immunoprecipitation, co-localization, Ras activation assays, kinase-dead mutant overexpression in Jurkat cells The Journal of cell biology High 11257115
2001 γ1-Syntrophin interacts with DGKζ via its PDZ domain binding to the C-terminal PDZ-binding motif of DGKζ. This interaction is necessary and sufficient for complex formation. DGKζ recruits γ1-syntrophin into the nucleus via the PDZ-binding motif. Disrupting this interaction causes DGKζ to accumulate in the nucleus while γ1-syntrophin remains cytoplasmic. DGKζ, γ1-syntrophin, and dystrophin form a ternary complex in brain. Yeast two-hybrid screen, co-immunoprecipitation, pulldown assays, deletion mutant analysis, co-localization in HeLa cells and neurons The Journal of biological chemistry High 11352924
2002 DGKζ rapidly translocates from cytosol to plasma membrane in living Jurkat T-cells following muscarinic receptor stimulation. Intact zinc fingers and the catalytic domain are required for full enzymatic activity. PKC-driven MARCKS domain phosphorylation and intact zinc fingers are essential for plasma membrane translocation. The C-terminal domain provides receptor-response specificity; DGKζ does not translocate in response to endogenous TCR stimulation under these conditions. Real-time confocal videomicroscopy with GFP-tagged DGKζ, domain truncations, deletions, and point mutations, kinase activity assays The Journal of biological chemistry High 12015310
2003 PKCα phosphorylates DGKζ on serines within the MARCKS phosphorylation site domain (PSD) both in vitro and in cells. DGKζ co-immunoprecipitates with PKCα. Phosphorylation of the MARCKS PSD (mimicked by S→D mutations) reduces DGKζ kinase activity. Activation of PKCα by PMA inhibits wild-type but not S→D mutant DGKζ activity. Cells expressing the phosphomimetic mutant have higher DAG levels and grow more rapidly. In vitro kinase assay, in vivo phosphorylation, co-immunoprecipitation, phosphomimetic/phospho-null site-directed mutagenesis, DAG measurement, cell growth assay The Journal of biological chemistry High 12890670
2003 In skeletal muscle, DGKζ and syntrophins form a complex that translocates from cytosol to plasma membrane in a PKC-dependent manner via phosphorylation of the DGKζ MARCKS domain. DGKζ mutants unable to bind syntrophins are mislocalized and an activated syntrophin-binding-deficient mutant induces atypical actin cytoskeletal changes. DGKζ co-localizes with F-actin and Rac1 in lamellipodia. ERK-dependent phosphorylation also regulates DGKζ–cytoskeleton association. DGKζ is reduced at the sarcolemma of dystrophin-deficient mdx myofibers but retained at NMJs. Co-immunoprecipitation, subcellular fractionation, immunofluorescence, dominant-negative and phosphomimetic mutants, mdx mouse model Molecular biology of the cell High 14551255
2003 DGKζ is primarily a nuclear protein in neurons, and its nuclear transport depends on a cooperative interaction between the NLS and the C-terminal region including ankyrin repeats, indicating the NLS is a cryptic site whose exposure is regulated by the C-terminal ankyrin repeat-containing region. Immunohistochemistry in brain tissue, cDNA transfection with deletion mutants in primary cultured neurons The European journal of neuroscience Medium 14511325
2004 GnRH receptor activation induces association between catalytically active c-Src and DGKζ, identified by proteomic mass spectrometry and confirmed by reciprocal co-immunoprecipitation. GnRH stimulation significantly increases DGKζ catalytic activity in HEK293 and gonadotrope LβT2 cells. Overexpression of DGKζ shortens ERK activation timescale in gonadotropes, suggesting DGKζ controls ERK-dependent LHβ transcription induction. MALDI-TOF mass spectrometry, reciprocal co-immunoprecipitation, lipid kinase assay, ERK activation kinetics assay The Journal of biological chemistry High 14707140
2005 DGKζ overexpression inhibits endothelin-1-induced cardiomyocyte hypertrophy by blocking PKCε translocation, ERK activation, and AP-1 DNA-binding activity downstream of DAG signaling. This results in inhibition of ANF gene induction and reduction of leucine uptake and cardiomyocyte surface area. Adenoviral overexpression of DGKζ, PKC translocation assay, ERK activity assay, luciferase reporter assay, [3H]-leucine uptake, cell surface area measurement Circulation High 15781737
2005 DGKζ promotes neurite outgrowth in N1E-115 neuroblastoma cells through a mechanism that is independent of its kinase activity but dependent on its C-terminal PDZ-binding motif interacting with syntrophins. DGKζ directly interacts with Rac1 through a binding site within its C1 domains. DGKζ, syntrophin, and Rac1 form a ternary complex. PKC-mediated phosphorylation of the MARCKS domain negatively regulates DGKζ binding to active Rac1. Dominant-negative DGKζ mutants inhibit neurite outgrowth from cortical neurons. Overexpression, dominant-negative mutants, co-immunoprecipitation, pulldown assays, dominant-negative Rac1, PKC activation with PMA Molecular and cellular biology High 16055737
2006 DGKζ-deficient mast cells show impaired degranulation after FcεRI cross-linking, associated with diminished PLCγ activity, reduced calcium flux, and decreased PKCβII membrane recruitment. In contrast, Ras-ERK signals and IL-6 production are enhanced. This demonstrates dissociation between cytokine production and degranulation pathways regulated by DGKζ. DGKζ knockout mice, degranulation assays, calcium flux measurement, PLCγ activity assay, PKCβII translocation assay, cytokine ELISA The Journal of experimental medicine High 16717114
2006 DGKζ-deficient T cells, when stimulated under anergy-inducing conditions, proliferate and produce IL-2, demonstrating that DGKζ-mediated DAG metabolism is required for T cell anergy induction. Pharmacological inhibition of DGKα activity in DGKζ-deficient T cells prevented anergy induction similarly to CD28 co-stimulation. DGKζ knockout mice, in vivo anergy induction model, T cell proliferation assay, IL-2 production assay, pharmacological DGK inhibition Nature immunology High 17028587
2007 Nuclear DGKζ blocks C2C12 myoblasts in the G1 phase of the cell cycle in a manner requiring both nuclear localization and kinase activity (kinase-dead or nuclear-excluded mutants do not cause arrest). Nuclear DGKζ overexpression decreases phosphorylation of retinoblastoma protein at Ser-807/811. siRNA knockdown of endogenous DGKζ increases cells in S and G2/M phases and prevents cell cycle block during myogenic differentiation. Conditional overexpression, kinase-dead mutant, nuclear-excluded mutant, siRNA knockdown, flow cytometry, BrdU incorporation, Western blot for pRb FASEB journal High 17488950
2006 DGKζ localizes to nuclear speckle domains and associates with the nuclear matrix. It co-localizes and interacts with phosphoinositide-specific PLCβ1 in the nucleus of C2C12 myoblasts. Nuclear DGKζ expression increases during myogenic differentiation, and siRNA knockdown of DGKζ impairs myogenic differentiation. Immunocytochemistry, confocal microscopy, immuno-electron microscopy, co-immunoprecipitation, nuclear matrix fractionation, siRNA knockdown Journal of cellular physiology Medium 16897754
2008 DGKζ transgenic overexpression in the heart rescues Gαq transgenic mice from cardiac dysfunction and lethal heart failure by blocking PKC isoform translocation and attenuating JNK and p38 MAPK phosphorylation. DGKζ improves survival of Gαq-TG mice, demonstrating its function as a negative regulator of Gαq-PKC cardiac hypertrophy signaling in vivo. Double-transgenic mouse model, cardiac function assessment (echocardiography, catheterization), PKC translocation assay, JNK/p38 phosphorylation, survival analysis Circulation journal High 18219172
2008 DGKζ acts as an upstream regulator of protein kinase D during oxidative stress-induced intestinal cell injury. Inhibition of DGKζ (by R59022, siRNA, or kinase-dead mutant overexpression) decreases H2O2-induced apoptosis and increases PKD phosphorylation. Endogenous nuclear DGKζ rapidly translocates to the cytoplasm following H2O2 treatment. DGK inhibitor R59022, siRNA transfection, kinase-dead mutant overexpression, DNA fragmentation assay, PKD phosphorylation Western blot, live-cell imaging Biochemical and biophysical research communications Medium 18694729
2009 Nuclear DGKζ downregulates cyclin D1 expression and upregulates TIS21/BTG2/PC3, a transcriptional repressor of cyclin D1. TIS21/BTG2/PC3 overexpression blocks cells in G1 and decreases pRb Ser807/811 phosphorylation, phenocopying DGKζ overexpression. siRNA knockdown of TIS21/BTG2/PC3 impairs myogenic differentiation. DNA microarrays, Real-Time RT-PCR, Western blot, overexpression, siRNA knockdown, flow cytometry Cellular signalling Medium 19263516
2010 DGKζ contains a functional nuclear export sequence (NES) between amino acid residues 362–370. Site-directed mutagenesis of the NES causes DGKζ to accumulate in the nucleus. Treatment with leptomycin B (CRM1 inhibitor) similarly causes nuclear accumulation of both endogenous and ectopic DGKζ, demonstrating CRM1-dependent nuclear export. Enhanced nuclear localization by NES mutation increases G0/G1 cell cycle block in C2C12 cells. Site-directed mutagenesis, leptomycin B treatment, subcellular fractionation, flow cytometry Cell cycle High 20023381
2013 DGKζ negatively regulates PKCα translocation kinetics to the immunological synapse. DGKζ-deficient T cells show increased and prolonged PKCα localization at the IS, resulting in enhanced Ras/ERK activation amplitude and duration, and augmented L-selectin shedding. PKCα activity limits its own persistence at the IS. DGKζ knockout mice, live-cell imaging, L-selectin shedding assay, Ras/ERK activation assay, PKCα translocation imaging Journal of cell science High 23525016
2016 Genetic deletion of DGKζ in NK cells enhances NK cell cytokine production, degranulation, and cytotoxicity upon stimulation through multiple activating receptors in an ERK-dependent manner, without affecting inhibitory receptor expression or function. DGKζ-deficient mice show improved rejection of a TAP-deficient tumor in vivo. DGKζ knockout mice, NK cell stimulation assays, ERK inhibitor experiments, tumor rejection assay in vivo Journal of immunology High 27342844
2019 DGKζ deficiency in macrophages results in reduced production of TNF-α, IL-6, and IL-1β, limited M1 macrophage polarization, and decreased STAT1 and STAT3 phosphorylation in TLR2- and TLR9-dependent inflammatory models. DGKζ levels are increased in macrophages from mice with cytokine storm syndrome. DGKζ knockout mice, TLR stimulation assays, cytokine ELISA, flow cytometry for macrophage polarization, Western blot for STAT phosphorylation Journal of immunology Medium 31801815
2019 DGKζ in osteosarcoma cells associates with ERK1/2, as identified by immunoprecipitation coupled to mass spectrometry. DGKζ knockdown decreases MYC pathway activity (including CCND1, CDKN2B, CDK6, PCNA, EGR1), inhibits proliferation, and promotes apoptosis in vitro and suppresses xenograft growth in vivo. IP-MS, shRNA knockdown, Affymetrix GeneChip, xenograft tumor model Frontiers in oncology Medium 30662872
2022 DGKζ promotes metastasis in triple-negative breast cancer by activating the TGFβ/TGFβR2/Smad3 signaling pathway through inhibition of caveolin/lipid raft-dependent endocytosis and degradation of TGFβR2. The metabolite phosphatidic acid (produced by DGKζ) alters TGFβR2 partitioning between lipid rafts and non-lipid rafts by affecting plasma membrane fluidity. CRISPR-Cas9 knockout, overexpression, RNA-seq, TGFβR2 endocytosis assay, Smad3 phosphorylation Western blot, lipid raft fractionation, in vitro and in vivo metastasis assays Cell death & disease High 35115500
2022 SNX27, via its PDZ domain interaction, controls polarization of DGKζ to the immunological synapse. SNX27 silencing abolishes DAG gradient formation at the IS and prevents MTOC translocation, demonstrating that SNX27-mediated trafficking of DGKζ is required for proper IS organization. Proteomic analysis of PDZ-SNX27 interactors, SNX27 siRNA silencing, live-cell imaging of DAG gradients, MTOC polarization assay Frontiers in immunology Medium 35095913
2023 DGKζ is a novel ceramide-1-phosphate (C1P)-producing enzyme. Among all ten DGK isoforms, only DGKζ increases C1P production upon overexpression. Purified DGKζ directly phosphorylates ceramide to produce C1P in vitro. Genetic deletion of DGKζ decreases NBD-C1P formation and endogenous C18:1/24:1- and C18:1/26:0-C1P levels, with C18:1/26:0-C1P not decreased by CerK knockout, confirming a distinct CerK-independent pathway. Transient overexpression of all 10 DGK isoforms, in vitro enzyme activity assay with purified DGKζ, DGKζ genetic knockout, LC-MS lipid quantification Biochimica et biophysica acta. Molecular and cell biology of lipids High 36906254
2023 The selective DGKζ inhibitor ASP1570 enhances DAG-mediated signaling in NK cells, augmenting IFNγ production and degranulation upon activating receptor stimulation in vitro and enhancing NK cell-mediated tumor clearance in vivo. Pharmacological inhibition with ASP1570, NK cell activation assays, IFNγ ELISA, degranulation assay, in vivo tumor clearance model International immunopharmacology Medium 37935092
2023 Base-editing mutagenesis screens in primary human T cells identified specific amino acid residues in DGKZ that are critical for regulating T cell activation and cytokine production, revealing both gain-of-function and loss-of-function alleles that tune T cell function. Large-scale base-editing mutagenesis in primary human T cells, sgRNA library targeting 385 genes, functional screening for T cell activation Nature Medium 38093011

Source papers

Stage 0 corpus · 73 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Protein kinase C regulates the nuclear localization of diacylglycerol kinase-zeta. Nature 261 9716136
2006 Disruption of diacylglycerol metabolism impairs the induction of T cell anergy. Nature immunology 258 17028587
1996 Molecular cloning and characterization of a novel human diacylglycerol kinase zeta. The Journal of biological chemistry 167 8626588
2001 Interaction of gamma 1-syntrophin with diacylglycerol kinase-zeta. Regulation of nuclear localization by PDZ interactions. The Journal of biological chemistry 103 11352924
2011 Association between genetic variation in a region on chromosome 11 and schizophrenia in large samples from Europe. Molecular psychiatry 99 21747397
2001 Diacylglycerol kinase zeta regulates Ras activation by a novel mechanism. The Journal of cell biology 98 11257115
2003 Nuclear localization of diacylglycerol kinase zeta in neurons. The European journal of neuroscience 81 14511325
2003 Diacylglycerol kinase-zeta localization in skeletal muscle is regulated by phosphorylation and interaction with syntrophins. Molecular biology of the cell 76 14551255
1997 Molecules in focus: diacylglycerol kinase. The international journal of biochemistry & cell biology 76 9438377
2003 Protein kinase C alpha phosphorylates and negatively regulates diacylglycerol kinase zeta. The Journal of biological chemistry 74 12890670
2023 Base-editing mutagenesis maps alleles to tune human T cell functions. Nature 68 38093011
2014 Diacylglycerol kinase α establishes T cell polarity by shaping diacylglycerol accumulation at the immunological synapse. Science signaling 62 25161317
2002 Dynamics of diacylglycerol kinase zeta translocation in living T-cells. Study of the structural domain requirements for translocation and activity. The Journal of biological chemistry 62 12015310
2005 Regulation of neurite outgrowth in N1E-115 cells through PDZ-mediated recruitment of diacylglycerol kinase zeta. Molecular and cellular biology 60 16055737
2021 Epigenome-wide DNA methylation signature of benzo[a]pyrene exposure and their mediation roles in benzo[a]pyrene-associated lung cancer development. Journal of hazardous materials 58 33887567
2005 Adenovirus-mediated overexpression of diacylglycerol kinase-zeta inhibits endothelin-1-induced cardiomyocyte hypertrophy. Circulation 56 15781737
2012 Reduction in IL-33 expression exaggerates ischaemia/reperfusion-induced myocardial injury in mice with diabetes mellitus. Cardiovascular research 52 22258632
2006 Impaired degranulation but enhanced cytokine production after Fc epsilonRI stimulation of diacylglycerol kinase zeta-deficient mast cells. The Journal of experimental medicine 49 16717114
2011 Integrated genomic profiling identifies loss of chromosome 11p impacting transcriptomic activity in aggressive pituitary PRL tumors. Brain pathology (Zurich, Switzerland) 48 21251114
2008 p53 induces distinct epigenetic states at its direct target promoters. BMC genomics 48 18922183
2016 Diacylglycerol Kinase ζ Is a Target To Enhance NK Cell Function. Journal of immunology (Baltimore, Md. : 1950) 44 27342844
2007 Nuclear diacylglycerol kinase-zeta is a negative regulator of cell cycle progression in C2C12 mouse myoblasts. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 42 17488950
2018 Genes Whose Gain or Loss-Of-Function Increases Skeletal Muscle Mass in Mice: A Systematic Literature Review. Frontiers in physiology 40 29910734
2004 Gonadotropin-releasing hormone-induced activation of diacylglycerol kinase-zeta and its association with active c-src. The Journal of biological chemistry 39 14707140
2007 Morphological changes and spatial regulation of diacylglycerol kinase-zeta, syntrophins, and Rac1 during myoblast fusion. Cell motility and the cytoskeleton 37 17410543
2006 Subnuclear localization and differentiation-dependent increased expression of DGK-zeta in C2C12 mouse myoblasts. Journal of cellular physiology 36 16897754
2018 Establishing a human adrenocortical carcinoma (ACC)-specific gene mutation signature. Cancer genetics 28 30477734
1998 The cloning and developmental regulation of murine diacylglycerol kinase zeta. FEBS letters 27 9657393
2015 TCR signaling intensity controls CD8+ T cell responsiveness to TGF-β. Journal of leukocyte biology 26 26153417
2010 Identification of a functional nuclear export sequence in diacylglycerol kinase-zeta. Cell cycle (Georgetown, Tex.) 26 20023381
2009 TIS21/BTG2/PC3 and cyclin D1 are key determinants of nuclear diacylglycerol kinase-zeta-dependent cell cycle arrest. Cellular signalling 26 19263516
2015 The Effector Domain of MARCKS Is a Nuclear Localization Signal that Regulates Cellular PIP2 Levels and Nuclear PIP2 Localization. PloS one 25 26470026
2003 An N-terminal fragment of ProSAAS (a granin-like neuroendocrine peptide precursor) is associated with tau inclusions in Pick's disease. Biochemical and biophysical research communications 24 12914799
2008 Diacylglycerol kinase zeta rescues G alpha q-induced heart failure in transgenic mice. Circulation journal : official journal of the Japanese Circulation Society 23 18219172
2017 Dysregulated miR34a/diacylglycerol kinase ζ interaction enhances T-cell activation in acquired aplastic anemia. Oncotarget 20 28008152
2013 Transient PKCα shuttling to the immunological synapse is governed by DGKζ and regulates L-selectin shedding. Journal of cell science 20 23525016
2021 Downregulation of Diacylglycerol kinase zeta (DGKZ) suppresses tumorigenesis and progression of cervical cancer by facilitating cell apoptosis and cell cycle arrest. Bioengineered 19 33926342
2022 DGKZ promotes TGFβ signaling pathway and metastasis in triple-negative breast cancer by suppressing lipid raft-dependent endocytosis of TGFβR2. Cell death & disease 17 35115500
2015 RNA sequencing identifies upregulated kyphoscoliosis peptidase and phosphatidic acid signaling pathways in muscle hypertrophy generated by transgenic expression of myostatin propeptide. International journal of molecular sciences 17 25860951
2019 DGKZ Acts as a Potential Oncogene in Osteosarcoma Proliferation Through Its Possible Interaction With ERK1/2 and MYC Pathway. Frontiers in oncology 16 30662872
2019 Diacylglycerol Kinase ζ Regulates Macrophage Responses in Juvenile Arthritis and Cytokine Storm Syndrome Mouse Models. Journal of immunology (Baltimore, Md. : 1950) 15 31801815
2019 Identification of target genes in neuroinflammation and neurodegeneration after traumatic brain injury in rats. PeerJ 15 31875163
2012 Diacylglycerol kinase θ: regulation and stability. Advances in biological regulation 15 23266086
2024 Integration of network pharmacology, lipidomics, and transcriptomics analysis to reveal the mechanisms underlying the amelioration of AKT-induced nonalcoholic fatty liver disease by total flavonoids in vine tea. Food & function 13 38630029
2020 Effects of Acanthopanax senticosus (Rupr. & Maxim.) Harms on cerebral ischemia-reperfusion injury revealed by metabolomics and transcriptomics. Journal of ethnopharmacology 13 32768643
2019 Knockdown of diacylglycerol kinase zeta (DGKZ) induces apoptosis and G2/M phase arrest in human acute myeloid leukemia HL-60 cells through MAPK/survivin/caspase pathway. Die Pharmazie 13 31288898
2016 African-specific variability in the acetylcholine muscarinic receptor M4: association with cocaine and heroin addiction. Pharmacogenomics 9 27269905
2015 Selective localization of diacylglycerol kinase (DGK)ζ in the terminal tubule cells in the submandibular glands of early postnatal mice. Histochemistry and cell biology 9 25952157
2023 The diacylglycerol kinase ζ inhibitor ASP1570 augments natural killer cell function. International immunopharmacology 8 37935092
2022 Sorting Nexin 27 Enables MTOC and Secretory Machinery Translocation to the Immune Synapse. Frontiers in immunology 8 35095913
2022 Identification of Candidate Genes for Pigmentation in Camels Using Genotyping-by-Sequencing. Animals : an open access journal from MDPI 8 35565522
2022 Systematic validation and assessment of immunohistochemical markers for central nervous system pathology in cetaceans, with emphasis on auditory pathways. PloS one 8 35648776
2019 Analytical Method for Diacylglycerol Kinase ζ Activity in Cells Using Protein Myristoylation and Liquid Chromatography-Tandem Mass Spectrometry. Lipids 8 31736090
2023 Momordicine I alleviates isoproterenol-induced cardiomyocyte hypertrophy through suppression of PLA2G6 and DGK-ζ. The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology 7 36575935
2023 Identification and characterization of diacylglycerol kinase ζ as a novel enzyme producing ceramide-1-phosphate. Biochimica et biophysica acta. Molecular and cell biology of lipids 7 36906254
2023 The Regulation Network of Glycerolipid Metabolism as Coregulators of Immunotherapy-Related Myocarditis. Cardiovascular therapeutics 7 37388276
2008 Diacylglycerol kinase regulation of protein kinase D during oxidative stress-induced intestinal cell injury. Biochemical and biophysical research communications 7 18694729
2024 Distinctive genomic features of human T-lymphotropic virus type 1-related adult T-cell leukemia-lymphoma in Western populations. Haematologica 6 39113648
2024 Whole-genome sequencing identifies novel genes for autism in Chinese trios. Science China. Life sciences 6 39126614
2021 Putative Internal Control Genes in Bovine Milk Small Extracellular Vesicles Suitable for Normalization in Quantitative Real Time-Polymerase Chain Reaction. Membranes 6 34940434
2019 Expression analysis and genotyping of DGKZ: a GWAS-derived risk gene for schizophrenia. Molecular biology reports 6 31087244
2023 Exome Sequencing Implicates DGKZ , ESRRA , and GXYLT1 for Modulating Granuloma Formation in Crohn Disease. Journal of pediatric gastroenterology and nutrition 5 37347142
2022 Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. International journal of molecular sciences 5 36232920
2024 Whole Exome Sequencing Identifies Epithelial and Immune Dysfunction-Related Biomarkers in Food Protein-Induced Enterocolitis Syndrome. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 4 39348862
2024 Cannabinerol (CBNR) Influences Synaptic Genes Associated with Cytoskeleton and Ion Channels in NSC-34 Cell Line: A Transcriptomic Study. Biomedicines 3 38255294
2019 Epitope Mapping of Anti-Diacylglycerol Kinase Zeta Monoclonal Antibody DzMab-1 for Immunohistochemical Analyses. Monoclonal antibodies in immunodiagnosis and immunotherapy 3 31355694
2023 Comparative Analysis of Transcriptome Profiles in Patients with Thromboangiitis Obliterans. Genes 2 38275601
2025 Ophthalmological manifestations and plasma markers of inflammation in Ebola survivors in post-treatment era. Scientific reports 1 40301432
2021 Immunohistochemical Markers of Apoptotic and Hypoxic Damage Facilitate Evidence-Based Assessment in Pups with Neurological Disorders. Veterinary sciences 1 34679033
2026 A Large-Scale Multi-omics Polygenic Risk Score Analysis Identified Candidate Biomarkers Associated with Heel Bone Mineral Density. Calcified tissue international 0 41874668
2025 MicroRNA analysis of porcine muscle tissue involved in phosphoinositol metabolism. Frontiers in veterinary science 0 40777826
2025 Diacylglycerol kinase gene Dgkh deficiency disrupts testicular lipid balance in male mice without affecting fertility. Reproduction (Cambridge, England) 0 40921406
2025 Integrating genetic regulation and schizophrenia-specific splicing quantitative expression with GWAS prioritizes novel risk genes for schizophrenia. Translational psychiatry 0 41053005