Affinage

DGKD

Diacylglycerol kinase delta · UniProt Q16760

Length
1214 aa
Mass
134.5 kDa
Annotated
2026-06-09
79 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 10/10 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DGKD encodes diacylglycerol kinase δ (DGKδ), a lipid kinase that phosphorylates diacylglycerol (DAG) to phosphatidic acid (PA) and thereby attenuates DAG-driven protein kinase C (PKC) signaling across metabolic, proliferative, neuronal, and trafficking contexts (PMID:8626538, PMID:17021016). The protein is built from a PH domain, two C1 zinc fingers, and a C-terminal SAM domain, and is expressed as two splice isoforms (DGKδ1 and DGKδ2) that differ in their N-terminus and in their capacity to translocate to the plasma membrane (PMID:12200442). SAM-domain–mediated, zinc-stabilized homo-oligomerization holds DGKδ in cytoplasmic vesicles; PKC-dependent phosphorylation downstream of phorbol ester or high glucose dissociates the oligomers and drives PH/C1-dependent translocation to the plasma membrane, where DGKδ consumes DAG (PMID:12084710, PMID:20857926, PMID:22974639). A central physiological output of this circuit is metabolic control: glucose-stimulated DGKδ relocalization lowers DAG and PKCα activity to enable insulin receptor signaling and GLUT4-mediated glucose uptake, and DGKδ deficiency in muscle causes DAG accumulation, insulin resistance, impaired AMPK and lipid oxidation, and obesity — a state mirrored in human diabetic skeletal muscle (PMID:17675299, PMID:18267070, PMID:26530149). DGKδ obtains its DAG substrate from a phosphatidylinositol-independent route, partnering with the DAG-supplying enzymes SMSr, PC-PLC, and PHOSPHO1 to generate saturated/monounsaturated PA species (PMID:25112873, PMID:31980461, PMID:39992810). Through its PKC-modulating activity DGKδ also stabilizes EGFR by preserving USP8 and limiting EGFR ubiquitination, and supports Akt signaling by restraining PKCα-driven, β-arrestin-1/PHLPP2-mediated Akt dephosphorylation, controlling proliferation, migration, and survival (PMID:17021016, PMID:20064931, PMID:23184957). Independently of its kinase activity, the SAM and PH domains target DGKδ to ER exit sites, where it regulates COPII-dependent ER-to-Golgi transport and releases IFT88-containing vesicles for primary cilium delivery to support Sonic hedgehog signaling; the kinase activity together with AP2α binding drives clathrin-dependent endocytosis (PMID:11809841, PMID:17880279, PMID:28706295). In the brain, DGKδ generates 18:0/22:6-PA that binds and activates the Praja-1 E3 ligase (via the MAGE-D1 adaptor) to ubiquitinate and degrade the serotonin transporter, and its loss produces OCD-like behavior corrected by SSRI (PMID:27423518, PMID:31891772, PMID:32134507). DGKδ further suppresses β-cell proliferation, is required for skeletal muscle development and regeneration, and is stabilized by USP11-mediated deubiquitination (PMID:33774855, PMID:39603461, PMID:39781426). Loss of DGKD function impairs calcium-sensing receptor (CaSR) signaling, linking DGKD variants to urinary calcium handling and kidney stone disease, with rescue by the calcimimetic cinacalcet (PMID:31729369, PMID:40372791).

Mechanistic history

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

    Established DGKδ as a distinct DAG kinase, defining the catalytic activity and domain architecture that underlie all later mechanistic work.

    Evidence cDNA cloning and in vitro DGK activity assay of transfected enzyme in COS-7 cells

    PMID:8626538

    Open questions at the time
    • No physiological substrate or DAG species defined
    • No cellular pathway context
  2. 2002 High

    Resolved how DGKδ is held inactive and switched on, showing SAM-domain oligomerization and PKC-dependent phosphorylation gate PH-domain translocation to the plasma membrane, and that splice isoforms differ in this control.

    Evidence Alternative splicing analysis, phorbol ester stimulation, yeast two-hybrid, gel filtration, co-IP and localization in cells

    PMID:12084710 PMID:12200442

    Open questions at the time
    • PKC phosphorylation site not mapped
    • Physiological trigger beyond phorbol ester unknown at this stage
  3. 2002 High

    Revealed a kinase-independent trafficking role, showing the SAM and PH domains target DGKδ to the ER and suppress COPII-dependent ER-to-Golgi transport.

    Evidence Wild-type and kinase-dead expression in NIH3T3 cells with VSV-G transport, BFA washout, and domain deletion assays

    PMID:11809841

    Open questions at the time
    • Cargo selectivity not defined
    • Mechanism of COPII inhibition unresolved
  4. 2006 High

    Defined the core physiological logic — DGKδ degrades DAG to limit PKC, and its loss deranges PKC-EGFR signaling — with a lethal eyelid-open phenotype phenocopying EGFR knockout.

    Evidence Mouse gene knockout with DAG, EGFR phosphorylation, and PKC autophosphorylation measurements

    PMID:17021016

    Open questions at the time
    • Tissue-specific contributions not separated
    • Downstream effectors of altered PKC not enumerated
  5. 2007 High

    Connected DGKδ to glucose homeostasis, showing glucose-triggered DGKδ membrane translocation lowers DAG/PKCα to enable insulin receptor signaling and GLUT4 translocation.

    Evidence Antisense knockdown, subcellular fractionation, and signaling/glucose-uptake assays in L6 myotubes

    PMID:17675299

    Open questions at the time
    • Signal coupling glucose to translocation not defined here
    • Isoform responsible not yet pinned down
  6. 2008 High

    Linked DGKδ to human type 2 diabetes, demonstrating reduced muscle DGKδ in patients and that haploinsufficiency causes DAG accumulation, insulin resistance, and obesity.

    Evidence Human muscle biopsies and DGKδ haploinsufficient mice with kinase activity, glucose transport, and metabolic flexibility readouts

    PMID:18267070

    Open questions at the time
    • Causality vs consequence of reduced expression in patients not fully resolved
    • Therapeutic targeting not tested
  7. 2008 High

    Identified a clathrin-endocytosis role requiring both AP2α binding via DXF motifs and kinase activity, mediated by the DGKδ2 isoform.

    Evidence Co-IP, domain/motif mapping, kinase-dead mutagenesis, and transferrin/EGF uptake rescue after siRNA knockdown

    PMID:17880279

    Open questions at the time
    • Local PA pool driving endocytosis not directly measured
    • Cargo range beyond transferrin/EGF unknown
  8. 2009 Medium

    Added RACK1 as a phorbol-ester-regulated DGKδ partner recruited to clathrin-coated vesicles, integrating DGKδ with PKC scaffolding.

    Evidence Yeast two-hybrid, co-IP with domain mapping, and colocalization in COS-7 cells

    PMID:19416640

    Open questions at the time
    • Functional consequence of RACK1 recruitment not established
    • No reciprocal validation in physiological cells
  9. 2010 High

    Detailed how DGKδ controls EGFR abundance and Akt activity through PKCα, showing PKCα-driven loss of USP8 and PHLPP2/β-arrestin-1-mediated Akt dephosphorylation in DGKδ-deficient cells.

    Evidence DGKδ knockout cells with ubiquitination, USP8 expression, PKCα/PHLPP depletion, and Akt pathway analyses

    PMID:20064931 PMID:23184957

    Open questions at the time
    • Direct PA targets within these pathways not identified
    • Tissue relevance of the PHLPP2 axis untested in vivo
  10. 2010 High

    Showed zinc binding drives DGKδ-SAM into helical polymers required for cytoplasmic puncta, membrane translocation control, and COPII inhibition, mechanistically grounding the oligomerization switch.

    Evidence In vitro SAM polymer/zinc-binding studies with mutagenesis linked to cellular localization and COPII assays

    PMID:20857926

    Open questions at the time
    • Regulation of zinc-dependent assembly in vivo unknown
    • Structural model of the full polymer not resolved
  11. 2012 High

    Defined isoform-specific, PI3-kinase-dependent translocation, showing DGKδ1 responds to high glucose via PH/C1 domains while the SAM domain restrains translocation.

    Evidence Localization imaging with PI3K inhibitors and domain deletion mutants in HEK293/C2C12 cells

    PMID:22974639

    Open questions at the time
    • Upstream sensor of glucose not identified
    • Link between PI3K and SAM-domain release unresolved
  12. 2014 High

    Established DGKδ substrate specificity and its DAG source, showing DGKδ2 phosphorylates 16:0-containing DAG supplied by PC-PLC, not PI turnover.

    Evidence LC/MS PA species analysis with siRNA/overexpression, PC-PLC inhibitor D609, and PC-PLC co-IP in C2C12 cells

    PMID:25112873

    Open questions at the time
    • Identity of the PC-PLC enzyme not defined here
    • Functional consequence of specific PA species not yet assigned
  13. 2017 Medium

    Extended the trafficking role to ciliogenesis, showing DGKδ releases IFT88 vesicles from ER exit sites to support Sonic hedgehog signaling.

    Evidence RNAi/knockout, IFT88-DGKδ co-IP, COPII association, and Shh signaling assays in vitro and in vivo

    PMID:28706295

    Open questions at the time
    • Whether kinase activity is required not established
    • Mechanism of IFT88 vesicle release unresolved
  14. 2018 Medium

    Uncovered a serotonergic function, showing brain DGKδ loss raises SERT and disrupts serotonin metabolism, producing OCD-like behavior rescued by SSRI, with DGKδ also restraining neurite outgrowth.

    Evidence Brain-specific conditional knockout with behavior, fluoxetine rescue, HPLC 5-HT, SERT co-IP, and neurite assays

    PMID:27423518 PMID:29486157

    Open questions at the time
    • Mechanism of SERT regulation not yet defined at this stage
    • Cell types responsible for behavior unresolved
  15. 2019 High

    Resolved the SERT mechanism, showing kinase-activity-dependent DGKδ recruits MAGE-D1 and Praja-1 to ubiquitinate and degrade SERT.

    Evidence Co-IP of DGKδ with SERT/MAGE-D1/Praja-1, domain mapping, catalytic mutants, ubiquitination assay, and MG-132 rescue

    PMID:31891772

    Open questions at the time
    • The PA species linking kinase activity to Praja-1 not yet identified here
    • Stoichiometry of the complex unknown
  16. 2019 Medium

    Placed DGKD in the CaSR signaling pathway, linking its loss-of-function to impaired CaSR signaling and urinary calcium handling in kidney stone patients.

    Evidence siRNA knockdown in CaSR-expressing cells with signaling assay, cinacalcet rescue, and genetic locus correlation

    PMID:31729369

    Open questions at the time
    • Molecular mechanism coupling DGKδ to CaSR signaling not defined
    • In vivo calcium phenotype not directly tested
  17. 2020 High

    Closed the lipid-signaling loop for SERT, showing DGKδ selectively generates 18:0/22:6-PA that binds and activates Praja-1, and identifying SMSr as a SAM-domain partner supplying DAG.

    Evidence Knockout-brain lipidomics, PA-Praja-1 binding/activity assays, and SMSr-DGKδ SAM co-IP with LC-MS/MS and in vitro kinase assays

    PMID:31980461 PMID:32134507

    Open questions at the time
    • How a single PA species achieves Praja-1 selectivity unresolved
    • Generality of SMSr supply across tissues untested
  18. 2021 High

    Defined DGKδ as a nuclear-localized suppressor of β-cell proliferation whose loss protects against streptozotocin-induced β-cell loss.

    Evidence β-cell-specific conditional knockout with Ki-67/cyclin B1/BrdU readouts and streptozotocin model

    PMID:33774855

    Open questions at the time
    • Nuclear substrate/target of DGKδ in β-cells unknown
    • Relationship to PKC signaling in this context unresolved
  19. 2024 High

    Identified post-translational stabilization of DGKδ, showing USP11 deubiquitinates DGKδ and is required to maintain its levels and downstream glucose uptake.

    Evidence Interactome analysis, co-IP with domain mapping, USP11 inhibition (mitoxantrone/siRNA), ubiquitination and glucose-uptake assays

    PMID:39603461

    Open questions at the time
    • E3 ligase ubiquitinating DGKδ not identified
    • Regulation of USP11-DGKδ engagement unknown
  20. 2024 High

    Established DGKδ as required for skeletal muscle development and injury-induced regeneration, with upregulation in satellite cells after injury.

    Evidence Myf5-Cre conditional knockout, cardiotoxin injury model, and muscle-marker immunohistochemistry/Western blot

    PMID:39781426

    Open questions at the time
    • Molecular mechanism in satellite cell differentiation not defined
    • Lipid signaling basis of the regeneration defect unknown
  21. 2025 Medium

    Added PHOSPHO1 as a candidate PI-turnover-independent DAG supplier and strengthened the DGKD-CaSR-kidney stone link with variant-specific loss-of-function and Mendelian randomization.

    Evidence In vitro PHOSPHO1 phospholipase assays with D609 and DG quantification; CaSR signaling with DGKD variants, cinacalcet rescue, and Mendelian randomization

    PMID:39992810 PMID:40372791

    Open questions at the time
    • Direct demonstration that PHOSPHO1 feeds DGKδ in vivo lacking
    • Causal mechanism of variants on CaSR signaling not fully defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How DGKδ's distinct PA species are spatially channeled to specific effectors (Praja-1, AP2α-coupled endocytosis, CaSR, nuclear β-cell targets) across tissues, and what unifies its kinase-dependent versus kinase-independent functions, remains unresolved.
  • No structure of full-length DGKδ in its membrane-engaged state
  • Effector selectivity for individual PA species mechanistically unexplained
  • E3 ligase opposing USP11 stabilization unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 4 GO:0060090 molecular adaptor activity 2 GO:0140096 catalytic activity, acting on a protein 2 GO:0008289 lipid binding 1
Localization
GO:0005886 plasma membrane 4 GO:0005829 cytosol 3 GO:0031410 cytoplasmic vesicle 3 GO:0005783 endoplasmic reticulum 2 GO:0005634 nucleus 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1430728 Metabolism 3 R-HSA-392499 Metabolism of proteins 3 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-1266738 Developmental Biology 2
Partners
AP2A1IFT88PHOSPHO1PJA1/PRAJA-1RACK1SLC6A4/SERTSMSR/SAMD8USP11
Complex memberships
AP-2 clathrin adaptor complex

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 DGKδ was cloned and identified as a diacylglycerol kinase with lipid kinase activity (phosphorylates DAG to produce phosphatidic acid). It contains a pleckstrin homology (PH) domain, two cysteine-rich zinc finger-like C1 structures, a C-terminal SAM-like domain, and a long Glu/Ser-rich insertion. DGK activity was detected in the particulate fraction of COS-7 cells expressing transfected DGKδ cDNA. The enzyme activity was independent of phosphatidylserine (unlike previously cloned DGKs alpha, beta, gamma). cDNA cloning, heterologous expression in COS-7 cells, in vitro DGK activity assay The Journal of biological chemistry High 8626538
2002 Alternative splicing of the DGKD gene generates two isoforms: DGKδ1 (130 kDa) and DGKδ2 (135 kDa, with 52 N-terminal residues extended). DGKδ1 translocates from cytoplasm to plasma membrane via its PH domain in response to phorbol ester stimulation, whereas DGKδ2 remains cytoplasmic because the delta2-specific N-terminal sequence blocks phorbol ester-dependent translocation. The two isoforms form homo- and hetero-oligomers as shown by co-immunoprecipitation of differently tagged proteins. Alternative splicing analysis, phorbol ester stimulation assays, subcellular localization by imaging, co-immunoprecipitation The Journal of biological chemistry High 12200442
2002 DGKδ suppresses anterograde ER-to-Golgi transport via its SAM domain (acting as ER-targeting motif) and PH domain. Low-level expression redistributed Golgi membrane markers to the ER, delayed VSV-G protein transport, and abolished COPII-coated structure formation (labeled with Sec13p) without affecting COPI structures. Kinase-dead DGKδ mutants were equally effective, indicating the catalytic activity is not required for this function. Both SAM and PH domains were required. Expression of wild-type and kinase-dead DGKδ in NIH3T3 cells, VSV-G transport assay, BFA washout assay, immunofluorescence, domain deletion analysis Molecular biology of the cell High 11809841
2002 DGKδ forms homo-oligomeric structures via its C-terminal SAM domain, forming dimers and tetramers. Phorbol ester stimulation induces PKC-dependent phosphorylation of DGKδ, dissociation of oligomers, and translocation from cytoplasmic vesicles to the plasma membrane. DGKδ mutants lacking self-association localized constitutively at the plasma membrane even without phorbol ester. Staurosporine (PKC inhibitor) blocked all phorbol ester effects. Yeast two-hybrid, bacterial expression of SAM domain-MBP fusion, gel filtration, co-immunoprecipitation, phorbol ester stimulation, PKC inhibitor (staurosporine) treatment, subcellular localization The Journal of biological chemistry High 12084710
2006 DGKδ deficiency in mice causes DAG accumulation, increased PKC-dependent threonine phosphorylation of EGFR, and reduced EGFR protein expression and activity. DGKδ-deficient pups showed open eyelids at birth and died shortly after birth, phenocopying EGFR knockout mice. Increased PKC autophosphorylation and enhanced phosphorylation of other PKC substrates was observed in DGKδ knockout cells, indicating DGKδ regulates EGFR by modulating PKC signaling. Gene knockout in mice, biochemical measurement of DAG, EGFR phosphorylation, PKC autophosphorylation assays Proceedings of the National Academy of Sciences of the United States of America High 17021016
2007 DGKδ subcellular localization is regulated by glucose: in L6 myotubes overexpressing human insulin receptors, 25 mM glucose for 5 min transiently redistributed DGKδ (but not DGKα) from cytosol to plasma membrane fraction, reducing intracellular DAG and PKCα activity, and transactivating insulin receptor signaling and GLUT4 translocation. Antisense silencing of DGKδ (but not DGKα) prevented the effect of high glucose on PKCα activity, insulin receptor signaling, and glucose uptake. Antisense knockdown, subcellular fractionation, DGK activity assay, PKCα activity assay, insulin receptor signaling assay, GLUT4 translocation The Journal of biological chemistry High 17675299
2008 DGKδ (specifically DGKδ2) regulates clathrin-dependent endocytosis by binding to the AP2α subunit of the AP-2 complex via DXF-type motifs (F369DTFRIL and D746PF in the catalytic domain). DGKδ2 colocalized with clathrin-coated pits. Mutants lacking AP2α binding ability or kinase-negative mutants failed to rescue transferrin uptake inhibited by DGKδ siRNA knockdown, demonstrating that both the AP2α interaction and kinase activity are required for the endocytic function. Co-immunoprecipitation, siRNA knockdown, domain mapping, kinase-dead mutagenesis, transferrin and EGF uptake assay The Biochemical journal High 17880279
2008 Reduced DGKδ expression and DGK activity were found in skeletal muscle from type 2 diabetic patients and diabetic animals. DGKδ haploinsufficiency in mice increased diacylglycerol content, reduced peripheral insulin sensitivity, insulin signaling, and glucose transport, and led to age-dependent obesity. Metabolic flexibility (transition between lipid and carbohydrate utilization) was impaired in DGKδ haploinsufficient mice. Correction of glycemia in diabetic animals restored DGKδ protein and DGK kinase activity. Human skeletal muscle biopsies, DGKδ haploinsufficient mouse model, DGK kinase activity assay, glucose transport assay, metabolic flexibility measurements Cell High 18267070
2009 DGKδ associates with RACK1 (receptor for activated C kinase 1) via WD40 repeats 5-7 of RACK1 interacting with aa 896-1097 of DGKδ. The interaction was selective for DGKδ over type I DGKs and was dynamically regulated by phorbol ester. DGKδ appeared to recruit RACK1 to clathrin-coated vesicles and co-localized with RACK1. Yeast two-hybrid screening, co-immunoprecipitation in COS-7 cells, subcellular localization, phorbol ester stimulation Biochimica et biophysica acta Medium 19416640
2010 DGKδ and PKCα regulate EGFR abundance through the deubiquitinase USP8. In DGKδ-deficient cells, ubiquitination of EGFR was enhanced, reducing steady-state EGFR levels and promoting ligand-induced EGFR degradation. This was not due to changes in the ubiquitinating apparatus but to reduced expression of USP8. PKCα, excessively active in DGKδ-deficient cells, inhibited Akt, which normally stabilizes USP8. Depletion of PKCα rescued USP8 levels and normalized EGFR degradation. DGKδ knockout cells, ubiquitination assay, USP8 expression analysis, PKCα depletion, Akt pathway analysis The Journal of biological chemistry High 20064931
2010 The SAM domain of DGKδ forms helical polymers that are stabilized by zinc binding. Zinc drives organization of DGKδ-SAM into large sheets of polymers. A SAM domain mutant refractory to zinc binding diminishes cytoplasmic puncta formation, shows partially impaired regulation of transport to the plasma membrane, and lacks the ability to inhibit CopII-coated vesicle formation. Biochemical analysis of SAM domain, zinc binding studies, mutagenesis, cell-based localization assay, CopII vesicle formation assay Biochemistry High 20857926
2012 DGKδ deficiency reduces Akt phosphorylation downstream of three receptor tyrosine kinases. Mechanistically, PKCα (excessively active in DGKδ-deficient cells) promotes dephosphorylation of Akt through PHLPP2 (not PHLPP1). β-arrestin 1 acts as a scaffold for PHLPP2 and Akt1, providing mechanism specificity. Depletion of either PKCα or PHLPP2 rescued Akt phosphorylation in DGKδ-deficient cells. DGKδ deficiency reduced cell proliferation and migration and enhanced apoptosis. DGKδ-deficient cells, Akt phosphorylation assays, PKCα and PHLPP1/2 depletion, siRNA knockdown, cell proliferation and migration assays The Journal of biological chemistry High 23184957
2012 DGKδ1 (but not DGKδ2 or type II DGKη1/2) specifically translocates from cytoplasm to plasma membrane within 5 min in response to high glucose in HEK293 and C2C12 cells. This translocation is regulated via the PI3-kinase pathway (blocked by LY294002 and GDC-0941). The PH and C1 domains are required for plasma membrane translocation, while the SAM domain negatively regulates it. Subcellular localization imaging, PI3-kinase inhibitors, domain deletion mutants, high glucose stimulation Biochimica et biophysica acta High 22974639
2014 DGKδ2 preferentially phosphorylates palmitic acid (16:0)-containing diacylglycerol species (generating 30:0-, 32:0-, 34:0-PA and moderately 30:1-, 32:1-, 34:1-PA) in response to high glucose in C2C12 myoblasts. These DG species are supplied from the phosphatidylcholine-specific phospholipase C (PC-PLC) pathway (blocked by D609 inhibitor), not from the phosphatidylinositol turnover pathway. PC-PLC was co-immunoprecipitated with DGKδ2, indicating a physical interaction. LC/MS for PA species analysis, DGKδ-specific siRNA knockdown, DGKδ2 overexpression, PC-PLC inhibitor D609, co-immunoprecipitation, MS/MS analysis The Journal of biological chemistry High 25112873
2015 DGKδ deficiency impairs AMPK activation and signaling in isolated skeletal muscle, with concomitant impaired lipid oxidation and elevated incorporation of free fatty acids into triglycerides. DGKδ haploinsufficient mice showed reduced voluntary running activity and impaired work performance (altered force production and relaxation dynamics) during repeated contractions. DGKδ haploinsufficient mice, AMPK signaling assays, lipid oxidation measurements, voluntary running wheel, ex vivo muscle contraction force measurements American journal of physiology. Endocrinology and metabolism Medium 26530149
2016 Brain-specific DGKδ-knockout mice display OCD-like behaviors (compulsive checking, increased marble burying) alleviated by fluoxetine (SSRI). DGKδ deficiency increased the number of long axons/neurites in primary cortical neurons and knockdown neuroblastoma cells, whereas DGKδ overexpression decreased long axon/neurite number, indicating DGKδ regulates axon/neurite outgrowth. Brain-specific conditional DGKδ knockout mice, novel object recognition test, marble burying test, fluoxetine treatment, neurite outgrowth measurements in primary neurons and Neuro-2a cells Brain research High 27423518
2017 DGKδ is required for ER exit site function: it triggers the release of IFT88-containing vesicles from ER exit sites (ERES) for transport to the primary cilium. IFT88 interacts with DGKδ, and IFT88 associates with COPII-coated vesicles at ERES. DGKδ is required for supporting Sonic hedgehog (Shh) signaling both in vitro and in vivo. RNAi silencing and gene knockout, IFT88-DGKδ co-immunoprecipitation, COPII vesicle association assay, Shh signaling assays Scientific reports Medium 28706295
2018 DGKδ deficiency in the brain increases serotonin transporter (SERT) protein levels in the cerebral cortex, decreases tryptophan hydroxylase-2 expression, increases monoamine oxidase-A expression, and reduces serotonin (5-HT) levels. DGKδ interacted and co-localized with SERT in cortical neurons. Brain-specific DGKδ knockout mice, Western blot for SERT/TPH2/MAO-A, HPLC for 5-HT quantification, co-immunoprecipitation, colocalization imaging Biochemical and biophysical research communications Medium 29486157
2018 DGKδ controls down-regulation of cyclin D1 during C2C12 myogenic differentiation. DGKδ siRNA knockdown increased cyclin D1 and phospho-conventional/novel PKC (cnPKC) levels, and decreased myogenin expression and myosin heavy chain-positive cell number. These results indicate DGKδ regulates early myoblast differentiation by attenuating PKC signaling to control cyclin D1 down-regulation. siRNA knockdown, Western blot for cyclin D1/myogenin/myosin heavy chain/phospho-PKC, BrdU incorporation assay Biochimie Medium 29859210
2019 DGKδ induces ubiquitination and proteasomal degradation of serotonin transporter (SERT) in a catalytic activity-dependent manner. Mechanistically, DGKδ interacts with MAGE-D1 adaptor protein and Praja-1 E3 ubiquitin-protein ligase, and enhances SERT ubiquitination through Praja-1. The catalytic subdomain-a and coiled-coil structure-containing region of DGKδ interacts with the C-terminal cytoplasmic region of SERT. Proteasome inhibitor MG-132 blocked DGKδ-dependent SERT degradation. Co-immunoprecipitation (DGKδ-SERT, DGKδ-MAGE-D1, DGKδ-Praja-1), domain mapping, catalytic mutants, ubiquitination assay, proteasome inhibitor treatment Biochimica et biophysica acta. Molecular and cell biology of lipids High 31891772
2019 DGKD knockdown impairs calcium-sensing receptor (CaSR) signal transduction in vitro, and this impairment is rectified by the calcimimetic cinacalcet. DGKD-associated genetic loci in kidney stone patients correlate with urinary calcium excretion, placing DGKD in the CaSR signaling pathway. siRNA knockdown of DGKD in CaSR-expressing cells, CaSR signaling assay, cinacalcet rescue Nature communications Medium 31729369
2020 1-stearoyl-2-docosahexaenoyl (18:0/22:6)-phosphatidic acid (PA), selectively generated by DGKδ from 18:0/22:6-DG, specifically binds to and enhances the activity of Praja-1 E3 ubiquitin ligase. In DGKδ-knockout mouse brain, 18:0/22:6-PA was decreased while 18:0/22:6-DG accumulated, confirming DGKδ selectively phosphorylates this DG species. Thus DGKδ generates a specific PA species that activates its downstream effector Praja-1 to degrade SERT. DGKδ-knockout mouse brain lipidomics (LC/MS), PA-Praja-1 binding assay, Praja-1 activity assay FEBS letters High 32134507
2020 DGKδ interacts with sphingomyelin synthase-related protein (SMSr) through their respective SAM domains (SMSr-SAMD co-immunoprecipitates with DGKδ-SAMD; full-length interactions confirmed). SMSr overexpression significantly enhanced production of 16:0- or 16:1-containing PA species in DGKδ-overexpressing COS-7 cells. SMSr also enhanced DGKδ activity via their SAMDs in vitro, establishing SMSr as an upstream DG-providing enzyme for DGKδ. Co-immunoprecipitation (SAMD fragments and full-length), LC-MS/MS for PA species, in vitro DGK activity assay The Journal of biological chemistry High 31980461
2021 β-cell-specific DGKδ knockout mice showed lower blood glucose, higher plasma insulin, better glucose tolerance, increased small islets and Ki-67-positive islet cells, and elevated cyclin B1 expression. DGKδ knockdown in MIN6 β-cells increased BrdU incorporation and cyclin B1 expression. Streptozotocin-induced hyperglycemia and β-cell loss were alleviated in βDGKδ KO mice. DGKδ expression was detected in the nucleus of β-cells, establishing DGKδ as a suppressor of β-cell proliferation. β-cell-specific conditional DGKδ KO mice, Ki-67/cyclin B1 immunostaining, BrdU incorporation assay, streptozotocin model FASEB journal High 33774855
2024 USP11 (ubiquitin-specific peptidase 11) specifically interacts with DGKδ protein complex and deubiquitinates DGKδ to stabilize it. The catalytic domain 1 region of USP11 and the C1 domains plus catalytic subdomain-a of DGKδ mediate their association. Inhibition of USP11 (by mitoxantrone or siRNA) markedly decreased DGKδ protein levels and increased DGKδ ubiquitination, impairing cellular glucose uptake. DGKδ-interactome analysis, co-immunoprecipitation, domain mapping, USP11 inhibitor (mitoxantrone), siRNA knockdown, ubiquitination assay, glucose uptake assay Biochimica et biophysica acta. Molecular cell research High 39603461
2024 DGKδ is required for skeletal muscle development and regeneration. Myf5-promoter-driven conditional DGKδ knockout mice showed reduced body weight and skeletal muscle mass with reduced myofiber thickness. After cardiotoxin-induced muscle injury, DGKδ expression was highly upregulated, and DGKδ-deficient muscles showed reduced myofiber thickness, decreased embryonic myosin heavy chain and myogenin expression, and fewer newly formed centronucleated myofibers. DGKδ was expressed in myogenin-positive satellite cells around injured myofibers. Conditional DGKδ knockout (Myf5-Cre), cardiotoxin injury model, immunohistochemistry for muscle markers, Western blot FASEB bioAdvances High 39781426
2025 PHOSPHO1 (a cytosolic phosphatase) exhibits D609-sensitive PC-PLC and PE-PLC activities, generating saturated and/or monounsaturated fatty acid-containing DG species. DGKδ cosedimented and colocalized with PHOSPHO1, identifying PHOSPHO1 as a candidate upstream DG-supplying enzyme for DGKδ in a PI-turnover-independent pathway. In vitro phospholipase activity assay with purified PHOSPHO1, D609 inhibitor, PHOSPHO1 overexpression with DG quantification, co-sedimentation and colocalization assays FEBS letters Medium 39992810
2025 Reduced DGKδ expression and DGKD missense variants (identified via GWAS/Mendelian randomization) impaired CaSR signal transduction in vitro. This impairment was ameliorated by cinacalcet, a positive CaSR allosteric modulator. Drug target Mendelian randomization indicated reducing serum calcium via DGKD may reduce kidney stone disease relative risk by up to 90%. In vitro CaSR signaling assay with DGKD knockdown and missense variants, cinacalcet rescue, Mendelian randomization The Journal of clinical investigation Medium 40372791

Source papers

Stage 0 corpus · 79 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Downregulation of diacylglycerol kinase delta contributes to hyperglycemia-induced insulin resistance. Cell 195 18267070
2013 Meta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations. PLoS genetics 158 24068962
1996 Molecular cloning of a novel diacylglycerol kinase isozyme with a pleckstrin homology domain and a C-terminal tail similar to those of the EPH family of protein-tyrosine kinases. The Journal of biological chemistry 158 8626538
2019 Genetic variants of calcium and vitamin D metabolism in kidney stone disease. Nature communications 108 31729369
2005 Identification and characterization of a novel human type II diacylglycerol kinase, DGK kappa. The Journal of biological chemistry 107 16210324
1996 Cloning and characterization of a glucocorticoid-induced diacylglycerol kinase. The Journal of biological chemistry 91 8702685
2002 Alternative splicing of the human diacylglycerol kinase delta gene generates two isoforms differing in their expression patterns and in regulatory functions. The Journal of biological chemistry 90 12200442
2006 Diacylglycerol kinase delta regulates protein kinase C and epidermal growth factor receptor signaling. Proceedings of the National Academy of Sciences of the United States of America 80 17021016
2019 Germline genetic patterns underlying familial rheumatoid arthritis, systemic lupus erythematosus and primary Sjögren's syndrome highlight T cell-initiated autoimmunity. Annals of the rheumatic diseases 68 31848144
2007 Glucose regulates diacylglycerol intracellular levels and protein kinase C activity by modulating diacylglycerol kinase subcellular localization. The Journal of biological chemistry 67 17675299
2020 New Era of Diacylglycerol Kinase, Phosphatidic Acid and Phosphatidic Acid-Binding Protein. International journal of molecular sciences 66 32947951
2017 Where do substrates of diacylglycerol kinases come from? Diacylglycerol kinases utilize diacylglycerol species supplied from phosphatidylinositol turnover-independent pathways. Advances in biological regulation 66 28918129
2002 Diacylglycerol kinase delta suppresses ER-to-Golgi traffic via its SAM and PH domains. Molecular biology of the cell 66 11809841
2002 Phorbol ester-regulated oligomerization of diacylglycerol kinase delta linked to its phosphorylation and translocation. The Journal of biological chemistry 61 12084710
2012 Wiki-pi: a web-server of annotated human protein-protein interactions to aid in discovery of protein function. PloS one 57 23209562
2017 Chronic administration of myristic acid improves hyperglycaemia in the Nagoya-Shibata-Yasuda mouse model of congenital type 2 diabetes. Diabetologia 53 28707095
2014 Diacylglycerol kinase δ phosphorylates phosphatidylcholine-specific phospholipase C-dependent, palmitic acid-containing diacylglycerol species in response to high glucose levels. The Journal of biological chemistry 52 25112873
2001 Nuclear diacylglycerol kinase-theta is activated in response to alpha-thrombin. The Journal of biological chemistry 51 11309392
2012 Identification of kinases regulating prostate cancer cell growth using an RNAi phenotypic screen. PloS one 44 22761715
2007 Disruption of diacylglycerol kinase delta (DGKD) associated with seizures in humans and mice. American journal of human genetics 41 17357084
2015 Diacylglycerol kinase-δ regulates AMPK signaling, lipid metabolism, and skeletal muscle energetics. American journal of physiology. Endocrinology and metabolism 31 26530149
2008 Regulation of clathrin-dependent endocytosis by diacylglycerol kinase delta: importance of kinase activity and binding to AP2alpha. The Biochemical journal 30 17880279
2014 Expression and localization of type II diacylglycerol kinase isozymes δ and η in the developing mouse brain. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 29 25362140
2020 1-Stearoyl-2-docosahexaenoyl-phosphatidic acid interacts with and activates Praja-1, the E3 ubiquitin ligase acting on the serotonin transporter in the brain. FEBS letters 26 32134507
2016 Myristic Acid Enhances Diacylglycerol Kinase δ-Dependent Glucose Uptake in Myotubes. Lipids 26 27206979
2010 Zinc binding drives sheet formation by the SAM domain of diacylglycerol kinase δ. Biochemistry 25 20857926
2022 DNA methylation differences between male and female gonads of the oyster reveal the role of epigenetics in sex determination. Gene 24 35121028
2021 Sphingomyelin synthase-related protein generates diacylglycerol via the hydrolysis of glycerophospholipids in the absence of ceramide. The Journal of biological chemistry 24 33621517
2020 Diacylglycerol kinase δ and sphingomyelin synthase-related protein functionally interact via their sterile α motif domains. The Journal of biological chemistry 24 31980461
2016 Behavioral and pharmacological phenotypes of brain-specific diacylglycerol kinase δ-knockout mice. Brain research 23 27423518
2016 Diacylglycerol kinase ζ generates dipalmitoyl-phosphatidic acid species during neuroblastoma cell differentiation. Biochemistry and biophysics reports 23 28955976
2021 Increasing skeletal muscle carnitine content in older individuals increases whole-body fat oxidation during moderate-intensity exercise. Aging cell 22 33464721
2011 Diacylglycerol kinases are essential for hepatocyte growth factor-dependent proliferation and motility of Kaposi's sarcoma cells. Cancer science 22 21477072
2019 Creatine kinase muscle type specifically interacts with saturated fatty acid- and/or monounsaturated fatty acid-containing phosphatidic acids. Biochemical and biophysical research communications 21 31010675
2012 Diacylglycerol kinase δ modulates Akt phosphorylation through pleckstrin homology domain leucine-rich repeat protein phosphatase 2 (PHLPP2). The Journal of biological chemistry 21 23184957
2010 Diacylglycerol kinase delta and protein kinase C(alpha) modulate epidermal growth factor receptor abundance and degradation through ubiquitin-specific protease 8. The Journal of biological chemistry 21 20064931
2019 Diacylglycerol kinase δ destabilizes serotonin transporter protein through the ubiquitin-proteasome system. Biochimica et biophysica acta. Molecular and cell biology of lipids 20 31891772
2015 mRNA expression of diacylglycerol kinase isoforms in insulin-sensitive tissues: effects of obesity and insulin resistance. Physiological reports 19 25847921
2013 Diacylglycerol kinase delta promotes lipogenesis. Biochemistry 19 24090246
2023 Optical Genome Mapping Identifies Novel Recurrent Structural Alterations in Childhood ETV6::RUNX1+ and High Hyperdiploid Acute Lymphoblastic Leukemia. HemaSphere 18 37469802
2017 ER residency of the ceramide phosphoethanolamine synthase SMSr relies on homotypic oligomerization mediated by its SAM domain. Scientific reports 18 28120887
2014 Regulation of diacylglycerol kinase δ2 expression in C2C12 skeletal muscle cells by free fatty acids. Lipids 18 24852321
2012 Diacylglycerol kinase δ1 transiently translocates to the plasma membrane in response to high glucose. Biochimica et biophysica acta 18 22974639
2017 DGKδ triggers endoplasmic reticulum release of IFT88-containing vesicles destined for the assembly of primary cilia. Scientific reports 16 28706295
2009 Diacylglycerol kinase delta associates with receptor for activated C kinase 1, RACK1. Biochimica et biophysica acta 15 19416640
2023 Inflammation and altered metabolism impede efficacy of functional electrical stimulation in critically ill patients. Critical care (London, England) 13 37932834
2013 Knockdown of diacylglycerol kinase delta inhibits adipocyte differentiation and alters lipid synthesis. Obesity (Silver Spring, Md.) 13 23703849
2025 Genetic variants predisposing to an increased risk of kidney stone disease. The Journal of clinical investigation 12 40372791
2019 Myristic acid specifically stabilizes diacylglycerol kinase δ protein in C2C12 skeletal muscle cells. Biochimica et biophysica acta. Molecular and cell biology of lipids 12 30980919
2015 Genome-wide association study of serum minerals levels in children of different ethnic background. PloS one 12 25886283
2013 Clonal expansion analysis of transposon insertions by high-throughput sequencing identifies candidate cancer genes in a PiggyBac mutagenesis screen. PloS one 12 23940809
2024 Diacylglycerol kinase delta overexpression improves glucose clearance and protects against the development of obesity. Metabolism: clinical and experimental 11 38843995
2018 Abnormalities of the serotonergic system in diacylglycerol kinase δ-deficient mouse brain. Biochemical and biophysical research communications 10 29486157
2018 Diacylglycerol kinase δ controls down-regulation of cyclin D1 for C2C12 myogenic differentiation. Biochimie 10 29859210
2017 DaMab-2: Anti-Human DGKα Monoclonal Antibody for Immunocytochemistry. Monoclonal antibodies in immunodiagnosis and immunotherapy 10 28742439
2022 Targeting circDGKD Intercepts TKI's Effects on Up-Regulation of Estrogen Receptor β and Vasculogenic Mimicry in Renal Cell Carcinoma. Cancers 9 35406411
2022 Myristic acid selectively augments β-tubulin levels in C2C12 myotubes via diacylglycerol kinase δ. FEBS open bio 9 35856166
2015 Association of common variants in the calcium-sensing receptor gene with serum calcium levels in East Asians. Journal of human genetics 9 25972035
2021 Diacylglycerol kinase δ functions as a proliferation suppressor in pancreatic β-cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 8 33774855
2024 Adiponectin mRNA Conjugated with Lipid Nanoparticles Specifically Targets the Pathogenesis of Type 2 Diabetes. Aging and disease 7 38916734
2024 Upstream and downstream pathways of diacylglycerol kinase : Novel phosphatidylinositol turnover-independent signal transduction pathways. Advances in biological regulation 7 39368888
2023 Comparative analysis of PDZ-binding motifs in the diacylglycerol kinase family. The FEBS journal 7 37942667
2022 Hepatic glycerolipid metabolism is critical to the egg laying rate of Guangxi Ma chickens. Gene 7 35472624
1999 Construction and sequence analysis of subtraction complementary DNA libraries from human preimplantation embryos. Journal of assisted reproduction and genetics 7 10224565
2025 Human PHOSPHO1 exhibits phosphatidylcholine- and phosphatidylethanolamine-phospholipase C activities and interacts with diacylglycerol kinase δ. FEBS letters 5 39992810
2023 Role of Diacylglycerol Kinases in Acute Myeloid Leukemia. Biomedicines 5 37509516
2019 Screening of subtype-specific activators and inhibitors for diacylglycerol kinase. Journal of biochemistry 5 30715374
2019 d-Glycerate kinase deficiency in a neuropediatric patient. Brain & development 5 31837836
2021 Diacylglycerol kinase η colocalizes and interacts with apoptosis signal-regulating kinase 3 in response to osmotic shock. Biochemistry and biophysics reports 4 33997319
2024 Ubiquitin-specific peptidase 11 selectively interacts with and deubiquitination-dependently stabilizes diacylglycerol kinase δ to maintain cellular glucose uptake. Biochimica et biophysica acta. Molecular cell research 2 39603461
2024 IDENTIFICATION AND VERIFICATION OF FEATURE BIOMARKERS ASSOCIATED WITH CHOLINE METABOLISM IN SEPSIS-INDUCED CARDIOMYOPATHY. Shock (Augusta, Ga.) 2 39637364
2024 Diacylglycerol kinase δ is required for skeletal muscle development and regeneration. FASEB bioAdvances 2 39781426
2017 A Case of 22q11 Deletion Syndrome (22q11DS) with a Panayiotopoulos Epileptic Pattern: Are Additional Copy-Number Variations a Possible Second Hit in Modulating the 22q11DS Phenotype? Frontiers in pediatrics 2 28377914
2025 Saturated fatty acid- and/or monounsaturated fatty acid-containing-phosphatidic acids selectively interact with and activate phosphoglycerate mutase 1. Biochemistry and biophysics reports 1 41080753
2025 Sex-specific circRNA-miRNA-mRNA networks in peripheral blood mononuclear cells of patients with idiopathic pulmonary arterial hypertension: a pilot study. Frontiers in genetics 1 41431653
2023 Development of Therapeutic Agents with a Novel Mechanism of Action Targeting Pancreatic β-Cells for Diabetes. Biological & pharmaceutical bulletin 1 37121690
2012 Analysis of the genotype of diacylglycerol kinase delta single-nucleotide polymorphisms in Parkinson disease in the Han Chinese population. Neurology India 1 22406787
2025 Diacylglycerol kinase gene Dgkh deficiency disrupts testicular lipid balance in male mice without affecting fertility. Reproduction (Cambridge, England) 0 40921406
2020 Epitope mapping of an anti-diacylglycerol kinase delta monoclonal antibody DdMab-1. Biochemistry and biophysics reports 0 32944659

Missed literature

Know a paper Affinage missed for DGKD? Flag it for the maintainers and the community.

No submissions yet.