DGKA

DGKA (DGK-α) is an ATP-dependent diacylglycerol kinase that phosphorylates diacylglycerol to generate phosphatidic acid (PA), a reaction whose kinetics depend on lipid surface concentration and are enhanced by phosphatidylserine and PA itself (PMID:16042397). Through this DAG-consuming, PA-generating activity DGKA acts as a node controlling two opposing biological programs. In T cells it suppresses distal TCR signaling, lowering steady-state ERK phosphorylation and blocking stimulus-induced ERK, JNK, and AKT activation downstream of PLC-γ (PMID:22573804), driving T-cell exhaustion during anti-PD-1 therapy (PMID:33608256) and shaping T helper fate decisions, where its loss selectively impairs TH1 differentiation in a gene-dosage-dependent manner with DGKζ (PMID:32010133). In tumor cells DGKA is pro-oncogenic: its PA product facilitates JNK recruitment to c-JUN to activate c-JUN transcriptional output and confer cisplatin resistance (PMID:32341033), drives proliferation via PA metabolism and MAPK signaling (PMID:38143235), and promotes growth through AKT (PMID:33608256). DGKA also physically scaffolds and phosphorylates SRC (at Tyr416) and FAK (at Tyr397) via distinct domain contacts, assembling a DGKA/SRC/FAK complex that activates WNT/β-catenin and VEGF signaling to drive EMT and angiogenesis (PMID:35131384), and it sustains macropinocytosis-driven phospholipid homeostasis and lysosomal activity in TSC2-deficient cells (PMID:33593821). Pharmacologic inhibition of DGKA reverses both arms of this biology — restoring effector T-cell function and augmenting anti-tumor immunity (PMID:22573804, PMID:33608256, PMID:41459935) while depleting PA in tumor cells (PMID:33593821).

1. 2005 High

   Established the core biochemical reaction by showing DGKA directly phosphorylates diacylglycerol in an ATP-dependent manner, defining its substrate specificity and lipid regulation.

   Evidence In vitro mixed-micelle enzymatic assay with kinetic analysis and lipid activator titration (Dictyostelium ortholog)

   PMID:16042397

   Open questions at the time

   • Characterized in the Dictyostelium ortholog rather than human DGKA
   • Does not establish in vivo substrate pools or subcellular site of catalysis
2. 2012 Medium

   Placed DGKA functionally in the TCR signaling cascade by showing it brakes distal signaling downstream of PLC-γ but upstream of MAPK/AKT, and that inhibiting it restores cytotoxic T-cell function.

   Evidence Pharmacologic DGKA inhibition in primary human CD8+ TILs with phospho-flow cytometry and functional degranulation/IFN-γ assays

   PMID:22573804

   Open questions at the time

   • Pharmacologic inhibition does not exclude off-target effects
   • Does not directly measure DAG/PA changes at the immune synapse
3. 2013 Medium

   Identified an upstream regulatory input by showing DGKA is a direct miR-297 target whose activity is required for glioblastoma survival.

   Evidence 3'UTR luciferase reporter assay, immunoblot, overexpression rescue, glioblastoma xenograft

   PMID:24158111

   Open questions at the time

   • Does not define the downstream effector linking DGKA to survival in glioblastoma
   • Single-lab validation
4. 2020 Medium

   Defined a gene-dosage role for DGKA in T helper fate, distinguishing its non-redundant control of TH1 differentiation from a shared role with DGKζ in restraining TH17 via mTORC1.

   Evidence DGKα knockout mice, in vitro TH differentiation assays, in vivo airway inflammation model, mTORC1/S6K1 readouts

   PMID:32010133

   Open questions at the time

   • Mechanism distinguishing TH1 sensitivity from TH2/TH17 not resolved
   • Does not link the differentiation defect directly to DAG/PA flux
5. 2020 High

   Demonstrated that DGKA's lipid kinase product PA acts as a signaling intermediate driving c-JUN activation and chemoresistance, converting a lipid enzyme into a transcriptional driver.

   Evidence RNAi synthetic-lethal screen, catalytic-dead rescue, phospho-proteomics, pharmacologic inhibition with cisplatin, patient-derived tumor validation

   PMID:32341033

   Open questions at the time

   • Precise molecular mechanism by which PA recruits JNK to c-JUN not structurally defined
   • Generality across tumor types beyond ovarian cancer not established
6. 2021 Medium

   Connected DGKA to PD-1 resistance and tumor-intrinsic growth, showing its inhibition postpones T-cell exhaustion while DGKA in cancer cells drives growth via AKT.

   Evidence Pharmacologic/genetic DGKA loss-of-function, in vivo tumor models, anti-PD-1 combination, Western blotting for AKT

   PMID:33608256

   Open questions at the time

   • Does not separate T-cell-intrinsic from tumor-intrinsic contributions in vivo
   • Mechanism upstream of AKT activation not defined
7. 2021 High

   Revealed a metabolic-homeostasis role beyond signaling: DGKA-derived PA supports macropinocytosis and lysosomal function to maintain phospholipid balance in TSC2-deficient cells.

   Evidence High-throughput drug screen, ritanserin inhibition, lipidomic PA quantification, macropinocytosis/lysosome assays, Tsc2-/- mouse models, genetic knockdown

   PMID:33593821

   Open questions at the time

   • Mechanistic link between PA and macropinocytic machinery not fully defined
   • Relevance to non-TSC2 contexts unclear
8. 2022 Medium

   Uncovered a non-catalytic scaffolding/kinase function in which DGKA binds and phosphorylates SRC and FAK through distinct domain contacts to drive metastatic signaling.

   Evidence Reciprocal Co-IP, domain-mapping pulldowns, phosphorylation assays, knockdown/overexpression invasion and metastasis models

   PMID:35131384

   Open questions at the time

   • Whether SRC/FAK phosphorylation requires DGKA lipid kinase activity is unresolved
   • Single-lab finding without independent reciprocal confirmation
9. 2023 Medium

   Extended the pro-proliferative PA-MAPK axis to intrahepatic cholangiocarcinoma, reinforcing PA metabolism as a generalizable oncogenic mechanism.

   Evidence DGKA knockdown/overexpression, EdU/colony-formation proliferation assays, RNA-seq, Western blotting for MAPK

   PMID:38143235

   Open questions at the time

   • Specific MAPK effector and PA species not identified
   • Single tumor-type model
10. 2025 Medium

    Provided translational validation that DGKα/ζ inhibition enhances adoptive T-cell therapy by increasing intratumoral infiltration and reducing TIL hypofunction.

    Evidence In vivo adoptive transfer NSCLC model, ex vivo human tumor TIL assays, precision-cut tumor slices, BiTE stimulation

    PMID:41459935

    Open questions at the time

    • Dual DGKα/ζ inhibitor does not isolate DGKα-specific contribution
    • Durability of the response not assessed

• It remains unresolved how DGKA's lipid kinase activity, its PA-dependent transcriptional and metabolic outputs, and its direct SRC/FAK kinase/scaffold function are integrated and differentially deployed across T cells versus tumor cells.
• No structural model of substrate or partner engagement for human DGKA
• Mechanism of context-specific localization and substrate selection unknown
• Whether SRC/FAK phosphorylation is catalytic-activity-dependent is undefined