DGKA

DGKA (diacylglycerol kinase alpha) is a lipid kinase that phosphorylates diacylglycerol (DAG) to phosphatidic acid (PA), functioning as a critical signaling switch that terminates DAG-dependent pathways while simultaneously generating PA as a bioactive second messenger. In T cells, DGKA acts downstream of PLC-γ to suppress RAS/MAPK (ERK/JNK), PI3K/AKT, and mTORC1 signaling, restraining effector function and promoting T-cell exhaustion; its inhibition restores cytolytic capacity of tumor-infiltrating lymphocytes and enhances anti-PD-1 immunotherapy responses (PMID:22573804, PMID:33608256, PMID:41459935). In cancer cells, DGKA-generated PA drives distinct oncogenic programs: it facilitates JNK-mediated c-JUN activation and WEE1 upregulation to confer platinum chemoresistance, activates MAPK signaling for proliferation, and sustains macropinocytosis-dependent phospholipid homeostasis in mTORC1-hyperactive cells (PMID:32341033, PMID:33593821, PMID:38143235). DGKA also directly binds and phosphorylates SRC (Tyr416) and FAK (Tyr397) through domain-specific interactions, scaffolding a DGKA/SRC/FAK complex that promotes epithelial–mesenchymal transition and angiogenesis via WNT/β-catenin and VEGF signaling (PMID:35131384).

1. 2012 High

   Establishing DGKA as a checkpoint in TCR signaling that suppresses effector function in human TILs resolved how DAG metabolism restrains anti-tumor immunity downstream of PLC-γ.

   Evidence Pharmacologic DGK-α inhibition in primary human CD8+ TILs with phospho-ERK/JNK/AKT western blots and degranulation assays

   PMID:22573804

   Open questions at the time

   • Relative contributions of DGKA versus DGKζ in TIL hypofunction were not separated
   • No genetic knockout confirmation in human T cells
   • Whether DGKA inhibition affects T-cell persistence in vivo was untested
2. 2013 Medium

   Identifying DGKA as a direct miR-297 target and survival factor in glioblastoma showed that post-transcriptional regulation of DGKA levels determines tumor cell viability under hypoxic stress.

   Evidence 3′UTR luciferase reporter assay and DGKA overexpression rescue of miR-297-induced cytotoxicity in glioblastoma cells

   PMID:24158111

   Open questions at the time

   • No endogenous miR-297 loss-of-function to confirm physiological regulation
   • Downstream effectors of DGKA-dependent survival were not mapped
3. 2020 High

   Demonstrating that DGKA-produced PA recruits JNK to c-JUN, driving WEE1 transcription and platinum resistance, defined a complete PA → JNK → c-JUN → WEE1 signaling axis in ovarian cancer chemoresistance.

   Evidence RNAi synthetic lethal screen, kinase-dead DGKA mutants, phosphoproteomics, pharmacologic inhibition, and patient-derived tumor validation

   PMID:32341033

   Open questions at the time

   • Direct PA-JNK binding site or mechanism of recruitment not structurally resolved
   • Whether this axis operates in other platinum-treated tumor types was untested
4. 2020 Medium

   Genetic ablation studies separating DGKα and DGKζ contributions showed that DGKα specifically promotes TH1 differentiation while double deficiency unleashes TH17 via mTORC1/S6K1, revealing isoform-specific control of T-helper fate.

   Evidence DGKα and DGKζ single and double knockout mouse T cells with in vitro TH differentiation assays and mTORC1/S6K1 western blotting

   PMID:32010133

   Open questions at the time

   • Mechanism by which DGKα selectively supports TH1 over TH17 not identified
   • Human T-helper differentiation effects not confirmed
5. 2021 High

   Showing that DGKA sustains macropinocytosis and phospholipid homeostasis in TSC2-deficient cells via a PA-dependent axis linked lipid kinase activity to nutrient acquisition in mTORC1-hyperactive tumors.

   Evidence PA lipidomics in Tsc2−/− MEFs, macropinocytosis assays, lysosome quantification, genetic DGKA knockdown in a mouse LAM model

   PMID:33593821

   Open questions at the time

   • Whether DGKA-PA drives macropinocytosis in other mTORC1-hyperactive contexts (e.g., PTEN-loss) was not tested
   • PA effector(s) that directly regulate macropinosome formation remain unidentified
6. 2021 Medium

   Demonstrating that DGKA inhibition delays exhaustion of reinvigorated T cells during anti-PD-1 therapy established DGKA as a combinatorial immunotherapy target beyond simple T-cell activation.

   Evidence In vivo tumor models with pharmacologic DGKA inhibition combined with anti-PD-1; T-cell exhaustion markers and AKT pathway analysis

   PMID:33608256

   Open questions at the time

   • Molecular mechanism by which DGKA promotes exhaustion versus hypofunction was not delineated
   • Cancer cell-intrinsic AKT effects were not fully separated from T-cell effects
7. 2022 Medium

   Domain-mapping of DGKA interactions with SRC (via SH3–C-terminal domain) and FAK (via catalytic domain–FERM domain) revealed an unexpected scaffolding and tyrosine kinase-like activity, expanding DGKA function beyond lipid phosphorylation to direct protein phosphorylation and EMT/angiogenesis signaling.

   Evidence Reciprocal Co-IP with truncation constructs, phospho-SRC(Y416)/phospho-FAK(Y397) western blots, in vitro invasion assays and in vivo pharmacologic inhibition in NSCLC

   PMID:35131384

   Open questions at the time

   • Direct in vitro kinase assay demonstrating DGKA phosphorylates SRC/FAK as a protein kinase was not shown
   • Structural basis for a lipid kinase phosphorylating tyrosine residues is unresolved
   • Single-lab finding; independent replication needed
8. 2023 Medium

   Confirmation that DGKA promotes proliferation through PA-MAPK signaling in cholangiocarcinoma generalized the PA → MAPK proliferative axis beyond ovarian cancer.

   Evidence DGKA knockdown/overexpression with EdU, colony formation, RNA-seq, and MAPK western blotting in cholangiocarcinoma cells

   PMID:38143235

   Open questions at the time

   • Specific MAPK components activated by PA were not mapped
   • In vivo validation in cholangiocarcinoma models was limited
9. 2025 Medium

   A dual DGKα/ζ inhibitor validated in human TIL systems confirmed clinical translational potential of DGKA inhibition to reverse T-cell hypofunction, though isoform-specific contributions could not be separated.

   Evidence NSCLC mouse adoptive transfer, ex vivo human TIL stimulation, precision-cut tumor slice assay with BiTE

   PMID:41459935

   Open questions at the time

   • Isoform-specific contribution of DGKα versus DGKζ not deconvolved
   • Long-term in vivo efficacy and autoimmune toxicity not assessed

• The structural basis for DGKA's reported protein kinase activity toward SRC and FAK, the identity of direct PA effectors mediating macropinocytosis, and full isoform-specific separation of DGKα versus DGKζ in human anti-tumor immunity remain unresolved.
• No crystal or cryo-EM structure of DGKA to explain dual lipid/protein kinase activity
• Direct PA-binding effectors in macropinocytosis not identified
• Isoform-selective DGKα inhibitors for clean human in vivo studies are lacking