Affinage

DGKD

Diacylglycerol kinase delta · UniProt Q16760

Length
1214 aa
Mass
134.5 kDa
Annotated
2026-04-28
79 papers in source corpus 30 papers cited in narrative 30 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DGKδ is a diacylglycerol kinase that phosphorylates saturated and monounsaturated fatty acid-containing diacylglycerol species—supplied by PC-PLC/SMSr/PHOSPHO1 pathways rather than PI-turnover—to generate phosphatidic acid, thereby terminating DAG-PKC signaling and producing bioactive PA species with distinct downstream effectors (PMID:25112873, PMID:31980461, PMID:32134507). Its subcellular distribution is governed by SAM domain-mediated zinc-dependent oligomerization, which retains DGKδ in cytoplasmic puncta; PKC-dependent phosphorylation or PI3K-dependent signals dissociate oligomers and drive PH/C1 domain-dependent translocation to the plasma membrane, where it attenuates DAG-PKC signaling to sustain insulin receptor/Akt activity, regulate EGFR stability, support clathrin-dependent endocytosis via AP2α binding, and promote SERT ubiquitin-proteasomal degradation through Praja-1 activation by 18:0/22:6-PA (PMID:12084710, PMID:20857926, PMID:17021016, PMID:17880279, PMID:31891772). As a residential ER lipid kinase, DGKδ also triggers COPII-dependent ER export of IFT88-containing vesicles required for ciliogenesis and Sonic hedgehog signaling (PMID:28706295). Loss of DGKδ in mice causes tissue-specific phenotypes including peripheral insulin resistance with age-dependent obesity in skeletal muscle haploinsufficiency, impaired myogenic differentiation and satellite cell-mediated regeneration, β-cell hyperproliferation, serotonergic hypofunction with OCD-like behavior in brain-specific knockouts, and neonatal lethality phenocopying EGFR-null mice in full knockouts (PMID:18267070, PMID:39781426, PMID:33774855, PMID:27423518, PMID:17021016).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1996 High

    Establishing DGKδ as a new DAG kinase family member with a unique domain architecture (PH, C1, SAM) answered the question of whether additional DGK isoforms with distinct regulatory properties existed.

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

    PMID:8626538

    Open questions at the time
    • Substrate specificity unknown
    • Physiological function not established
    • SAM domain function not determined
  2. 2002 High

    Discovery that alternative splicing generates two isoforms with distinct translocation behaviors, and that the SAM domain drives zinc-dependent homo-oligomerization controlling cytoplasm-to-membrane redistribution, established the core regulatory logic of DGKδ activation.

    Evidence Co-IP of isoform oligomers, phorbol ester-induced translocation imaging, yeast two-hybrid and gel filtration of SAM domain, domain deletion mutants in NIH3T3/COS-7 cells

    PMID:11809841 PMID:12084710 PMID:12200442

    Open questions at the time
    • Zinc-binding stoichiometry and structural basis of SAM polymers not resolved
    • Whether kinase activity is required for all trafficking functions unclear
  3. 2006 High

    Genetic ablation in mice revealed that DGKδ is essential for restraining DAG-PKC signaling in vivo, as knockout caused DAG accumulation, hyperactive PKC-mediated EGFR threonine phosphorylation, and neonatal lethality phenocopying EGFR-null mice.

    Evidence DGKδ knockout mice with DAG measurement, phospho-EGFR Western blot, phenotypic analysis

    PMID:17021016

    Open questions at the time
    • Tissue-specific contributions to lethality not dissected
    • Whether PA production or solely DAG clearance drives the phenotype not resolved
  4. 2008 High

    Two studies established DGKδ as a metabolic regulator: reduced expression in human type 2 diabetic muscle linked it to insulin resistance, haploinsufficient mice confirmed DAG-dependent impairment of insulin signaling and glucose transport, and AP2α binding coupled DGKδ kinase activity to clathrin-dependent endocytosis.

    Evidence Human skeletal muscle biopsies, DGKδ haploinsufficient mice with metabolic phenotyping, AP2α co-IP with domain mapping and transferrin uptake rescue

    PMID:17880279 PMID:18267070

    Open questions at the time
    • Mechanism connecting DGKδ-PA to AP2α-dependent vesicle formation not defined
    • Whether insulin resistance is solely PKC-mediated or involves PA effectors unknown
  5. 2010 High

    Biochemical reconstitution showed the SAM domain forms zinc-driven helical polymer sheets, and epistasis experiments in KO cells defined the DGKδ→DAG→PKCα→PHLPP2→Akt→USP8→EGFR degradation pathway, answering how DGKδ loss destabilizes EGFR.

    Evidence Electron microscopy of SAM polymers, zinc-binding mutant functional assays, DGKδ-KO MEFs with siRNA epistasis for PKCα/PHLPP2/USP8

    PMID:20064931 PMID:20857926

    Open questions at the time
    • Whether zinc-SAM polymers form in vivo not confirmed
    • PHLPP2-Akt-USP8 axis not validated in intact organisms
  6. 2012 High

    The PKCα-PHLPP2-Akt axis downstream of DGKδ was generalized beyond EGFR to three receptor tyrosine kinases, with β-arrestin 1 identified as the scaffold, and glucose-induced DGKδ1 translocation was shown to require PI3K and PH/C1 domains.

    Evidence DGKδ-KO cells with siRNA knockdown of PKCα/PHLPP1/PHLPP2/β-arrestin 1, PI3K inhibitor treatment and domain deletion mutants in HEK293/C2C12

    PMID:22974639 PMID:23184957

    Open questions at the time
    • PI3K-dependent translocation mechanism (lipid product sensed by PH domain?) not molecularly defined
    • In vivo relevance of β-arrestin 1 scaffolding not tested
  7. 2014 High

    LC-MS lipidomics resolved DGKδ substrate specificity: it preferentially phosphorylates 16:0-containing DAG species derived from the PC-PLC pathway, not PI-turnover-derived arachidonoyl-DAG, fundamentally redefining DGKδ as a DAG kinase operating in a non-canonical lipid metabolic branch.

    Evidence LC-MS PA species analysis after DGKδ siRNA/overexpression in C2C12 myoblasts, PC-PLC inhibitor D609, co-IP of PC-PLC with DGKδ2

    PMID:25112873

    Open questions at the time
    • Identity of the PC-PLC enzyme upstream of DGKδ not genetically confirmed
    • Whether substrate selectivity reflects DGKδ intrinsic preference or substrate availability unclear
  8. 2016 High

    Brain-specific knockout revealed that DGKδ regulates serotonergic tone and neuronal morphology, with loss causing OCD-like behavior rescued by fluoxetine and enhanced neurite outgrowth, expanding DGKδ function from metabolism to neuropsychiatric circuits.

    Evidence Brain-specific conditional KO mice with behavioral tests and pharmacological rescue, primary cortical neuron morphology analysis

    PMID:27423518

    Open questions at the time
    • Which DAG/PA species mediate serotonergic effects not identified at this point
    • Circuit-level localization of DGKδ-dependent serotonin changes not mapped
  9. 2017 High

    DGKδ was identified as a residential ER kinase that physically interacts with IFT88 and triggers COPII-dependent ER export of ciliary cargo, linking lipid kinase activity to ciliogenesis and Sonic hedgehog signaling.

    Evidence Co-IP of IFT88 with DGKδ, RNAi/KO with COPII vesicle and Shh reporter assays

    PMID:28706295

    Open questions at the time
    • How PA production at ERES promotes COPII vesicle budding mechanistically unresolved
    • Whether all ciliary cargo depends on DGKδ or only IFT88 not tested
  10. 2019 High

    The mechanism of DGKδ-dependent SERT regulation was fully delineated: DGKδ recruits the Praja-1 E3 ligase via MAGE-D1 to promote SERT ubiquitination and proteasomal degradation in a catalytic activity-dependent manner, explaining the serotonergic hypofunction in brain-specific knockouts.

    Evidence Co-IP and domain mapping of DGKδ-SERT-Praja-1 complex, ubiquitination assay with kinase-dead mutant and proteasome inhibitor MG-132

    PMID:29486157 PMID:31891772

    Open questions at the time
    • In vivo validation that Praja-1 mediates SERT turnover in DGKδ-KO brain not performed
    • Quantitative contribution of SERT accumulation vs. reduced serotonin synthesis to behavioral phenotype not established
  11. 2020 High

    Two discoveries connected DGKδ to specific lipid-protein signaling codes: in brain, DGKδ selectively produces 18:0/22:6-PA which activates Praja-1; in the ER, SMSr provides 16:0-containing DAG substrates via SAM-domain-mediated interaction, establishing tissue-specific upstream supply chains.

    Evidence KO brain lipidomics by LC-MS with PA-Praja-1 binding/activity assay; SMSr-DGKδ co-IP with SAM domain mutants and in vitro DGK activity reconstitution

    PMID:31980461 PMID:32134507

    Open questions at the time
    • Whether SMSr-DGKδ axis operates in skeletal muscle not tested
    • Structural basis of 18:0/22:6-PA recognition by Praja-1 unknown
  12. 2021 High

    β-cell-specific knockout showed DGKδ suppresses pancreatic β-cell proliferation via cyclin B1 regulation, revealing a tissue where DGKδ loss is beneficial (improved glucose tolerance), contrasting with its pro-insulin-signaling role in muscle.

    Evidence β-cell-specific DGKδ KO mice with glucose tolerance tests, Ki-67/BrdU proliferation assays, cyclin B1 Western blot

    PMID:33774855

    Open questions at the time
    • Whether proliferation effect is DAG- or PA-mediated not determined
    • Long-term β-cell function and exhaustion risk not assessed
  13. 2024 High

    DGKδ protein stability was shown to be maintained by USP11 deubiquitinase, and conditional skeletal muscle knockout demonstrated DGKδ is required for satellite cell-mediated muscle regeneration and myofiber maintenance.

    Evidence USP11-DGKδ co-IP with domain mapping, ubiquitination assay ± USP11 inhibitor/siRNA, glucose uptake assay; Myf5-Cre DGKδ KO with cardiotoxin injury and myogenic marker analysis

    PMID:39603461 PMID:39781426

    Open questions at the time
    • Whether USP11 regulates DGKδ in tissues beyond the tested cell lines unknown
    • Whether impaired regeneration is DAG/PKC-dependent or PA-dependent not tested
  14. 2025 Medium

    DGKD missense variants associated with kidney stone disease impair CaSR signaling, rescued by cinacalcet, and PHOSPHO1 was identified as a candidate cytosolic PC-PLC providing saturated DAG substrates for DGKδ.

    Evidence Variant overexpression with CaSR signaling assay and cinacalcet rescue; PHOSPHO1 enzymatic assay and co-sedimentation with DGKδ

    PMID:39992810 PMID:40372791

    Open questions at the time
    • PHOSPHO1-DGKδ physical interaction not validated by reciprocal co-IP
    • Whether DGKD variants cause kidney stone disease through CaSR-independent mechanisms not excluded
    • PHOSPHO1 contribution to DGKδ substrate pool not tested genetically

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of DGKδ substrate selectivity for saturated/monounsaturated DAGs, how PA production at ER exit sites mechanistically promotes COPII vesicle budding, and the relative contributions of DAG clearance versus PA generation to each tissue-specific phenotype.
  • No crystal or cryo-EM structure of DGKδ catalytic domain
  • No reconstituted system linking specific PA species to COPII coat assembly
  • Tissue-specific interactome not systematically mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 5 GO:0008289 lipid binding 3
Localization
GO:0005886 plasma membrane 4 GO:0005783 endoplasmic reticulum 2 GO:0005829 cytosol 2 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-1430728 Metabolism 4 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-1266738 Developmental Biology 3 R-HSA-112316 Neuronal System 2 R-HSA-392499 Metabolism of proteins 2
Partners
AP2A1GNB2L1IFT88MAGED1PJA1SAMD8SLC6A4USP11

Evidence

Reading pass · 30 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 a pleckstrin homology (PH) domain, two cysteine-rich zinc finger-like (C1) structures, a C-terminal SAM-like tail similar to EPH receptor tyrosine kinases, and a long Glu/Ser-rich insertion. Increased DGK activity was detected in the particulate fraction of COS-7 cells expressing transfected DGKδ cDNA, independent of phosphatidylserine activation. cDNA cloning, transfection in COS-7 cells, DGK activity assay, Northern blot The Journal of biological chemistry High 8626538
2002 Alternative splicing of human DGKD generates two isoforms (DGKδ1, 130 kDa; DGKδ2, 135 kDa) with distinct expression patterns and regulatory functions. DGKδ1 translocates from cytoplasm to plasma membrane via its PH domain in response to phorbol ester, whereas DGKδ2 remains cytoplasmic due to its N-terminal extension blocking translocation. The two isoforms form homo- and hetero-oligomers detected by co-immunoprecipitation. RT-PCR, phorbol ester stimulation, co-immunoprecipitation, subcellular fractionation, live cell imaging 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, without requiring kinase activity. DGKδ expression caused redistribution of Golgi and VTC marker proteins to the ER, delayed VSV-G transport, and abrogated COPII-coated structure formation (Sec13p-labeled) without affecting COPI retrograde structures. NIH3T3 cell expression, live imaging of VSV-G trafficking, BFA washout assay, kinase-dead mutant analysis, COPII/COPI marker immunostaining Molecular biology of the cell High 11809841
2002 DGKδ forms homo-oligomeric structures via its SAM domain in intact cells; phorbol ester stimulation induces PKC-dependent phosphorylation of DGKδ, dissociation of oligomers, and translocation from cytoplasmic vesicles to the plasma membrane. SAM-domain mutants unable to self-associate constitutively localize to the plasma membrane. Yeast two-hybrid, bacterially expressed SAM domain gel filtration, co-immunoprecipitation, phorbol ester stimulation, PKC inhibitor (staurosporine) treatment, subcellular fractionation The Journal of biological chemistry High 12084710
2006 DGKδ deficiency in mice causes DAG accumulation, increased PKC-mediated threonine phosphorylation of EGFR, reduced EGFR protein expression and activity, and enhanced phosphorylation of other PKC substrates. DGKδ knockout pups phenocopy EGFR knockout mice (open eyelids, neonatal lethality), establishing DGKδ as a regulator of PKC-EGFR signaling. Gene knockout in mice, Western blot for phospho-EGFR and PKC substrates, DAG measurement, phenotypic analysis Proceedings of the National Academy of Sciences of the United States of America High 17021016
2007 Short-term high glucose exposure transiently redistributes DGKδ from cytoplasm to plasma membrane in L6 myotubes, activating DGK activity and reducing intracellular DAG and PKCα activity, thereby transactivating insulin receptor signaling and GLUT4 translocation. Antisense silencing of DGKδ (but not DGKα) prevented these effects, establishing DGKδ as the mediator of glucose-induced acute DGK activation in skeletal muscle. L6 myotube antisense silencing, DGK inhibitor (R59949), subcellular fractionation, PKCα activity assay, insulin receptor phosphorylation, GLUT4 translocation imaging The Journal of biological chemistry High 17675299
2008 Reduced DGKδ expression and DGK activity were found in skeletal muscle of type 2 diabetic patients. DGKδ haploinsufficiency in mice increased DAG content, reduced peripheral insulin sensitivity, impaired insulin signaling and glucose transport, and caused age-dependent obesity and metabolic inflexibility, establishing DGKδ as a contributor to hyperglycemia-induced peripheral insulin resistance. Human skeletal muscle biopsies (T2D patients vs controls), DGKδ haploinsufficient mouse model, DAG measurement, insulin tolerance test, glucose transport assay, metabolic cage studies Cell High 18267070
2008 DGKδ2 binds to AP2α (adaptor protein 2 alpha) via DXF-type motifs (F369DTFRIL and D746PF) in the catalytic domain, interacting with the AP2α ear platform subdomain. This interaction, together with DGK kinase activity, is required for clathrin-dependent endocytosis (transferrin internalization). Mutants lacking AP2α binding or kinase activity failed to rescue endocytosis impaired by DGKδ siRNA knockdown. Co-immunoprecipitation, domain mapping, transferrin/EGF uptake assay, siRNA knockdown, overexpression of wild-type and mutant DGKδ2 The Biochemical journal High 17880279
2009 DGKδ interacts with RACK1 (receptor for activated C kinase 1) via WD40 repeats 5–7 of RACK1. Co-immunoprecipitation confirmed selective interaction of RACK1 with DGKδ but not type I DGKs in mammalian cells. The interaction is regulated by phorbol ester and DGKδ recruits RACK1 to clathrin-coated vesicles. Yeast two-hybrid screen, co-immunoprecipitation in COS-7 cells, phorbol ester treatment, colocalization imaging Biochimica et biophysica acta Medium 19416640
2010 DGKδ deficiency leads to enhanced ubiquitination of EGFR and reduced expression of deubiquitinase USP8, promoting EGFR degradation. This is mediated through excessive PKCα activity (due to DAG accumulation) inhibiting Akt, which normally stabilizes USP8. Depletion of PKCα or PHLPP2 rescued USP8 levels and normalized EGFR degradation in DGKδ-deficient cells. DGKδ knockout MEFs, siRNA knockdown of PKCα/PHLPP2, ubiquitination assay, Western blot for USP8/EGFR/Akt The Journal of biological chemistry High 20064931
2010 The SAM domain of DGKδ1 binds zinc at multiple sites, driving formation of large sheets of helical polymers. Zinc-binding is required for cytoplasmic puncta formation and regulation of plasma membrane transport; a SAM domain mutant refractory to zinc binding showed diminished puncta, partially impaired plasma membrane transport regulation, and lost ability to inhibit COPII vesicle formation. Biochemical zinc-binding assay, gel filtration, electron microscopy of SAM polymer sheets, DGKδ SAM zinc-binding mutant, live cell imaging of puncta, COPII vesicle formation assay Biochemistry High 20857926
2012 DGKδ deficiency reduces Akt phosphorylation downstream of three receptor tyrosine kinases via a pathway involving excessive PKCα activity promoting Akt dephosphorylation through PHLPP2, with β-arrestin 1 acting as scaffold for PHLPP2 and Akt1. Depletion of PKCα or PHLPP2 (but not PHLPP1) rescued Akt phosphorylation in DGKδ-deficient cells. DGKδ deficiency also reduced cell proliferation and migration and enhanced apoptosis. DGKδ knockout cells, siRNA knockdown of PKCα/PHLPP1/PHLPP2/β-arrestin 1, phospho-Akt Western blot, cell proliferation and migration assays The Journal of biological chemistry High 23184957
2012 DGKδ1, but not DGKδ2 or DGKη1/2, translocates from cytoplasm to plasma membrane within 5 min in response to high glucose. This translocation is dependent on PI3K signaling and requires both PH and C1 domains; the SAM domain negatively regulates this translocation. HEK293 and C2C12 cell imaging, PI3K inhibitor (LY294002, GDC-0941) treatment, domain deletion mutants, high glucose stimulation Biochimica et biophysica acta High 22974639
2014 DGKδ preferentially phosphorylates palmitic acid (16:0)-containing diacylglycerol species (30:0-, 32:0-, 34:0-PA and related monounsaturated species) in high glucose-stimulated C2C12 myoblasts. These DG substrates are supplied via the phosphatidylcholine-specific phospholipase C (PC-PLC) pathway, not from phosphatidylinositol turnover-derived 20:4-DG. PC-PLC was co-immunoprecipitated with DGKδ2. LC-MS analysis of PA species, DGKδ-specific siRNA knockdown, DGKδ2 overexpression, PC-PLC inhibitor D609, co-immunoprecipitation of PC-PLC with DGKδ2 The Journal of biological chemistry High 25112873
2015 DGKδ deficiency impairs AMPK activation and signaling in skeletal muscle, concomitant with impaired lipid oxidation and elevated incorporation of free fatty acids into triglycerides. DGKδ(+/-) mice also showed reduced voluntary running and impaired force production and relaxation dynamics during repeated contractions. DGKδ haploinsufficient mice, AMPK phosphorylation assay, lipid oxidation measurement, fatty acid incorporation assay, voluntary wheel running, ex vivo muscle contraction American journal of physiology. Endocrinology and metabolism High 26530149
2016 Brain-specific DGKδ knockout mice exhibit OCD-like behaviors (compulsive checking in novel object recognition, increased marble burying) alleviated by the serotonin reuptake inhibitor fluoxetine. DGKδ deficiency increases axon/neurite outgrowth in primary cortical neurons and DGKδ-knockdown neuroblastoma cells, while DGKδ overexpression decreases neurite number. Brain-specific conditional DGKδ KO mice, behavioral tests (novel object recognition, marble burying), fluoxetine pharmacological rescue, primary neuron and Neuro-2a cell morphology analysis Brain research High 27423518
2017 DGKδ is a residential lipid kinase in the ER that triggers release of IFT88-containing COPII-coated vesicles from ER exit sites (ERES) for delivery to primary cilia. IFT88 physically interacts with DGKδ. DGKδ is required for Sonic hedgehog (Shh) signal transduction both in vitro and in vivo. Co-immunoprecipitation of IFT88 with DGKδ, RNAi silencing and gene KO, COPII vesicle formation assay, Shh signaling reporter assay, primary cilia formation imaging Scientific reports High 28706295
2018 DGKδ deficiency in the brain increases SERT protein levels in the cerebral cortex, and DGKδ physically interacts and co-localizes with SERT. DGKδ-KO also decreases tryptophan hydroxylase-2 expression, increases monoamine oxidase-A expression, and reduces serotonin levels in the cerebral cortex, indicating comprehensive serotonergic hypofunction. Brain-specific DGKδ KO mice, Western blot for SERT/TPH2/MAO-A, serotonin ELISA, co-immunoprecipitation/colocalization of DGKδ and SERT Biochemical and biophysical research communications High 29486157
2018 DGKδ controls cyclin D1 downregulation during C2C12 myogenic differentiation by attenuating PKC signaling. DGKδ knockdown increased cyclin D1 expression and phospho-PKC (conventional and novel isoforms) while decreasing myogenin expression and myosin heavy chain-positive cell number. C2C12 myogenic differentiation model, DGKδ-specific siRNA, Western blot for cyclin D1/myogenin/MHC/phospho-PKC, MHC immunofluorescence Biochimie Medium 29859210
2019 DGKδ interacts with MAGE-D1 adaptor protein and Praja-1 E3 ubiquitin-protein ligase. DGKδ catalytic subdomain-a and coiled-coil region interact with the C-terminal cytoplasmic region of SERT. DGKδ promotes SERT ubiquitination through Praja-1 and induces SERT degradation via the ubiquitin-proteasome system in a DGKδ catalytic activity-dependent manner. Co-immunoprecipitation, domain mapping, overexpression/knockdown in cells, proteasome inhibitor MG-132, ubiquitination assay Biochimica et biophysica acta. Molecular and cell biology of lipids High 31891772
2019 DGKD knockdown in vitro impairs calcium-sensing receptor (CaSR) signal transduction, an effect rectified by the calcimimetic cinacalcet, placing DGKδ as a component of CaSR signaling and linking it to urinary calcium excretion. siRNA knockdown of DGKD in cells, CaSR signaling assay, cinacalcet rescue, GWAS and validation cohort correlation with urinary calcium Nature communications Medium 31729369
2020 DGKδ selectively phosphorylates 18:0/22:6-DG to generate 18:0/22:6-phosphatidic acid (PA) in the brain. 18:0/22:6-PA selectively binds to and enhances the E3 ubiquitin ligase activity of Praja-1, mechanistically linking DGKδ-generated PA species to SERT degradation. DGKδ-KO mouse brain lipidomic profiling (LC-MS), lipid-protein binding assay, Praja-1 activity assay with specific PA species FEBS letters High 32134507
2020 DGKδ interacts with sphingomyelin synthase-related protein (SMSr) through their respective SAM domains. SMSr overexpression enhances production of 16:0- or 16:1-containing PA species in DGKδ-overexpressing cells, and SMSr enhances DGKδ activity via their SAMDs in vitro, establishing SMSr as an upstream DG-providing enzyme for DGKδ. Co-immunoprecipitation of full-length and SAM domain deletion mutants, LC-MS/MS of PA species, in vitro DGKδ activity assay with SMSr The Journal of biological chemistry High 31980461
2021 β-cell-specific DGKδ knockout mice showed lower blood glucose, higher insulin, better glucose tolerance, increased Ki-67-positive islet cells, and elevated cyclin B1 expression, demonstrating DGKδ functions as a proliferation suppressor in pancreatic β-cells. DGKδ knockdown in MIN6 cells also increased BrdU incorporation and cyclin B1 expression. β-cell-specific DGKδ KO mice, glucose tolerance tests, Ki-67/BrdU proliferation assays, cyclin B1 Western blot, streptozotocin model FASEB journal High 33774855
2024 USP11 (ubiquitin-specific peptidase 11) physically interacts with DGKδ via USP11 catalytic domain 1 region and DGKδ C1 domains/catalytic subdomain-a. USP11 deubiquitinates and stabilizes DGKδ protein; USP11 inhibition or knockdown increases DGKδ ubiquitination and decreases DGKδ protein levels, 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 Myf5-promoter-driven conditional DGKδ knockout mice showed reduced body weight, decreased skeletal muscle mass, and reduced myofiber thickness. Cardiotoxin-induced muscle injury revealed that DGKδ is strongly upregulated in myogenin-positive satellite cells, and DGKδ deficiency impaired myofiber formation, myogenic marker expression (embryonic myosin heavy chain, myogenin), and satellite cell-mediated muscle regeneration. Conditional Myf5-Cre DGKδ KO mice, cardiotoxin injury model, immunofluorescence for satellite cell markers, Western blot for myogenic differentiation markers, histological analysis FASEB bioAdvances High 39781426
2025 Reduced DGKδ expression and KSD-associated DGKD missense variants impair CaSR signal transduction in vitro, demonstrable with cellular assays, and this impairment is ameliorated by cinacalcet (positive CaSR allosteric modulator), further confirming DGKδ as a functional partner of CaSR signaling. siRNA knockdown and missense variant overexpression in cells, CaSR signaling assay, cinacalcet pharmacological rescue The Journal of clinical investigation Medium 40372791
2025 PHOSPHO1, a cytosolic protein, exhibits D609-sensitive PC-PLC and PE-PLC activities and its overexpression increases saturated/monounsaturated fatty acid-containing DG levels in HEK293 cells. PHOSPHO1 co-sediments and co-localizes with DGKδ, identifying it as a candidate cytosolic DG-generating enzyme upstream of DGKδ. In vitro enzyme activity assay of purified PHOSPHO1 with PC/PE substrates, D609 inhibitor, DG species quantification by LC-MS in overexpressing cells, co-sedimentation and colocalization with DGKδ FEBS letters Medium 39992810
2013 DGKδ promotes lipogenesis: DGKδ expression is markedly increased during 3T3-L1 adipocyte differentiation, DGKδ transfection increases triglyceride synthesis, and DGKδ knockout MEFs show reduced synthesis of neutral and polar lipids, particularly those with shorter acyl chains, and lower expression of acetyl-CoA carboxylase, fatty acid synthase, and activation of ATP citrate lyase. 3T3-L1 differentiation assay, DGKδ transfection, DGKδ KO MEFs, glycerol incorporation assay, lipidomics, Western blot for lipogenic enzymes Biochemistry High 24090246
2019 Creatine kinase muscle type (CKM) specifically binds 16:0/16:0-PA and other saturated/monounsaturated fatty acid-containing PA species (but not PUFA-containing PAs, and not other phospholipids) with high affinity (Kd ~2.0 μM), identifying CKM as a selective downstream target of DGKδ-produced PA species in skeletal muscle. Protein pulldown from mouse skeletal muscle, lipid-protein binding assay with defined PA species, dissociation constant measurement Biochemical and biophysical research communications Medium 31010675

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
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
2013 Meta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations. PLoS genetics 156 24068962
2005 Identification and characterization of a novel human type II diacylglycerol kinase, DGK kappa. The Journal of biological chemistry 107 16210324
2019 Genetic variants of calcium and vitamin D metabolism in kidney stone disease. Nature communications 104 31729369
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
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
2020 New Era of Diacylglycerol Kinase, Phosphatidic Acid and Phosphatidic Acid-Binding Protein. International journal of molecular sciences 63 32947951
2002 Phorbol ester-regulated oligomerization of diacylglycerol kinase delta linked to its phosphorylation and translocation. The Journal of biological chemistry 60 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 52 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 30 26530149
2008 Regulation of clathrin-dependent endocytosis by diacylglycerol kinase delta: importance of kinase activity and binding to AP2alpha. The Biochemical journal 29 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 28 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
2020 Diacylglycerol kinase δ and sphingomyelin synthase-related protein functionally interact via their sterile α motif domains. The Journal of biological chemistry 24 31980461
2022 DNA methylation differences between male and female gonads of the oyster reveal the role of epigenetics in sex determination. Gene 23 35121028
2021 Sphingomyelin synthase-related protein generates diacylglycerol via the hydrolysis of glycerophospholipids in the absence of ceramide. The Journal of biological chemistry 23 33621517
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
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
2023 Optical Genome Mapping Identifies Novel Recurrent Structural Alterations in Childhood ETV6::RUNX1+ and High Hyperdiploid Acute Lymphoblastic Leukemia. HemaSphere 17 37469802
2017 DGKδ triggers endoplasmic reticulum release of IFT88-containing vesicles destined for the assembly of primary cilia. Scientific reports 15 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
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
2019 Myristic acid specifically stabilizes diacylglycerol kinase δ protein in C2C12 skeletal muscle cells. Biochimica et biophysica acta. Molecular and cell biology of lipids 11 30980919
2025 Genetic variants predisposing to an increased risk of kidney stone disease. The Journal of clinical investigation 10 40372791
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
2024 Diacylglycerol kinase delta overexpression improves glucose clearance and protects against the development of obesity. Metabolism: clinical and experimental 9 38843995
2022 Targeting circDGKD Intercepts TKI's Effects on Up-Regulation of Estrogen Receptor β and Vasculogenic Mimicry in Renal Cell Carcinoma. Cancers 9 35406411
2015 Association of common variants in the calcium-sensing receptor gene with serum calcium levels in East Asians. Journal of human genetics 9 25972035
2022 Myristic acid selectively augments β-tubulin levels in C2C12 myotubes via diacylglycerol kinase δ. FEBS open bio 8 35856166
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
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
2022 Hepatic glycerolipid metabolism is critical to the egg laying rate of Guangxi Ma chickens. Gene 5 35472624
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 3 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 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
2024 IDENTIFICATION AND VERIFICATION OF FEATURE BIOMARKERS ASSOCIATED WITH CHOLINE METABOLISM IN SEPSIS-INDUCED CARDIOMYOPATHY. Shock (Augusta, Ga.) 1 39637364
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