{"gene":"DGKA","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2012,"finding":"DGK-α (DGKA) suppresses distal TCR signaling in CD8+ tumor-infiltrating T cells by reducing steady-state ERK phosphorylation and blocking stimulus-induced ERK, JNK, and AKT phosphorylation; pharmacologic inhibition of DGK-α improved ERK phosphorylation and lytic granule exocytosis, placing DGKA downstream of PLC-γ but upstream of MAPK/AKT pathways.","method":"Pharmacologic inhibition of DGK-α in primary human CD8+ TILs with phospho-flow cytometry for ERK/JNK/AKT and functional assays (degranulation, IFN-γ production)","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean pharmacologic inhibition with defined signaling readouts, single lab, two orthogonal functional methods","pmids":["22573804"],"is_preprint":false},{"year":2020,"finding":"DGKA confers cisplatin resistance in ovarian cancer through its lipid kinase activity: the DGKA product phosphatidic acid (PA) facilitates JNK recruitment to c-JUN and promotes c-JUN nuclear localization, activating c-JUN transcriptional output and upregulating the cell-cycle regulator WEE1.","method":"RNAi synthetic lethal screening, DGKA catalytic-dead variant rescue, phospho-proteomics, genomic screens, pharmacologic DGKA inhibition with cisplatin co-treatment, patient-derived tumor validation","journal":"Clinical cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (RNAi, dominant-negative variant, phospho-proteomics, pharmacologic inhibition), validated in patient-derived tumors","pmids":["32341033"],"is_preprint":false},{"year":2013,"finding":"DGK-α is a direct functional target of miR-297 in glioblastoma; 3'UTR luciferase assays confirmed miR-297 targets the DGK-α 3'UTR, and DGK-α overexpression rescued the cytotoxic effects of miR-297, demonstrating that DGK-α activity is required for glioblastoma cell survival downstream of miR-297.","method":"3'UTR luciferase reporter assay, immunoblot, DGK-α overexpression rescue, glioblastoma xenograft mouse model","journal":"Neuro-oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — 3'UTR reporter plus rescue experiment, single lab, two orthogonal methods","pmids":["24158111"],"is_preprint":false},{"year":2022,"finding":"DGKA physically interacts with SRC and FAK: the C-terminal domain of DGKA binds the SRC SH3 domain, while the DGKA catalytic domain interacts with the FAK FERM domain. DGKA phosphorylates SRC at Tyr416 and FAK at Tyr397, activating the DGKA/SRC/FAK complex and initiating downstream WNT/β-catenin and VEGF signaling to drive EMT and angiogenesis in NSCLC.","method":"Co-immunoprecipitation, domain-mapping pulldowns, phosphorylation assays, DGKA knockdown and overexpression in vitro invasion and in vivo metastasis models","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with domain mapping and phosphorylation readouts, single lab, multiple orthogonal approaches","pmids":["35131384"],"is_preprint":false},{"year":2021,"finding":"DGKA mediates T-cell exhaustion during anti-PD-1 therapy; pharmacologic ablation of Dgka postponed T-cell exhaustion and delayed resistance to PD-1 blockade. Additionally, DGKA expression in cancer cells promoted tumor cell growth via the AKT signaling pathway.","method":"Pharmacologic DGKA inhibition, in vivo tumor models, anti-PD-1 combination treatment, Western blotting for AKT signaling","journal":"Cancer immunology research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacologic and genetic loss-of-function with defined signaling readouts, single lab","pmids":["33608256"],"is_preprint":false},{"year":2020,"finding":"DGKα deficiency selectively impairs TH1 differentiation without affecting TH2 or TH17 differentiation; simultaneous loss of DGKα and DGKζ additionally promotes TH17 differentiation via increased mTORC1/S6K1 signaling, demonstrating a dosage-dependent role for DGKα in T helper cell fate decisions downstream of TCR-DAG signaling.","method":"DGKα knockout mice, in vitro TH differentiation assays, in vivo airway inflammation model, mTORC1/S6K1 signaling readouts","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with defined differentiation phenotypes and signaling pathway placement, single lab","pmids":["32010133"],"is_preprint":false},{"year":2021,"finding":"DGKA supports macropinocytosis in TSC2-deficient cells to maintain phospholipid homeostasis; phosphatidic acid levels are elevated 5-fold in Tsc2-/- cells, and DGKA inhibition with ritanserin depletes PA, rewires phospholipid metabolism, reduces macropinocytic albumin uptake, limits lysosome number and activity, and prevents alveolar destruction in a mouse model of lymphangioleiomyomatosis.","method":"High-throughput drug screen, ritanserin pharmacologic inhibition, lipidomic PA quantification, macropinocytosis assays, lysosome assays, Tsc2-/- mouse models, genetic DGKA knockdown in vivo","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (pharmacologic + genetic KD, lipidomics, functional assays, two in vivo models), single lab with rigorous controls","pmids":["33593821"],"is_preprint":false},{"year":2023,"finding":"DGKA promotes cell proliferation in intrahepatic cholangiocarcinoma by enhancing phosphatidic acid (PA) metabolism and activating MAPK signaling, as demonstrated by cell proliferation assays, EdU assay, colony formation, and RNA-sequencing following DGKA manipulation.","method":"DGKA knockdown/overexpression, cell proliferation assay, EdU assay, colony formation, RNA-sequencing, Western blotting for MAPK signaling","journal":"Cancer communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional readouts with defined signaling pathway output, single lab","pmids":["38143235"],"is_preprint":false},{"year":2018,"finding":"In Dictyostelium discoideum, ablation of dgkA reduces sensitivity to valproic acid, branched medium-chain fatty acids with seizure control activity, and lithium; VPA, lithium, and novel epilepsy treatments function through DAG regulation, and DGKA is necessary for compound-specific increases in DAG levels following treatment, placing DGKA in the phosphoinositide recycling pathway linked to PKC activity.","method":"dgkA null mutant generation, behavioral/developmental assays, DAG level measurements, pharmacologic compound testing","journal":"Disease models & mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic null with defined molecular (DAG levels) and phenotypic readouts, Dictyostelium ortholog model, single lab","pmids":["30135067"],"is_preprint":false},{"year":2005,"finding":"Dictyostelium DGKA catalyzes ATP-dependent phosphorylation of diacylglycerols (DiC8, DiC6) in Michaelis-Menten kinetics; with physiologically relevant long-chain DAGs the kinetics are substrate-surface-concentration-dependent and detergent-dependent (Michaelis-Menten in octyl glucoside at low surface concentrations, sigmoidal at high concentrations; sigmoidal at all concentrations in Triton X-100); catalytic activity is significantly enhanced by phosphatidylserine and phosphatidic acid.","method":"In vitro enzymatic assay with mixed micelles, kinetic analysis (Michaelis-Menten and sigmoidal fitting), lipid activator titration","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro reconstituted enzymatic assay with systematic kinetic characterization under multiple defined conditions, single lab","pmids":["16042397"],"is_preprint":false},{"year":2025,"finding":"Pharmacologic dual inhibition of DGKα and DGKζ (INCB165451) in human T cells enhances anti-tumor efficacy of adoptively transferred TILs in NSCLC mouse models by increasing intratumoral T cell infiltration and reducing TIL hypofunction, demonstrated by enhanced cytokine production; the inhibitor also augmented T cell activation in human tumor slices stimulated by anti-EGFR/anti-CD3 BiTE.","method":"In vivo adoptive T cell transfer NSCLC mouse model, ex vivo human tumor digest TIL assays, precision-cut tumor slice assay, anti-CD3 stimulation, gene and protein expression of cytokines/chemokines","journal":"Oncoimmunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and ex vivo human models, multiple functional readouts, single lab, note that DGKα/ζ dual inhibitor does not isolate DGKα-specific effects","pmids":["41459935"],"is_preprint":false}],"current_model":"DGKA (DGK-α) is a diacylglycerol kinase that phosphorylates diacylglycerol to generate phosphatidic acid (PA); in T cells it acts as an intrinsic brake on TCR signaling by attenuating DAG-dependent ERK/JNK/AKT activation and promoting T-cell exhaustion, while in tumor cells PA produced by DGKA activates c-JUN (via JNK recruitment), MAPK, AKT, and mTORC1 signaling, supports macropinocytosis-driven phospholipid homeostasis, and enables physical interaction with and phosphorylation of SRC/FAK to drive metastatic signaling."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2005,"claim":"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)","pmids":["16042397"],"confidence":"High","gaps":["Characterized in the Dictyostelium ortholog rather than human DGKA","Does not establish in vivo substrate pools or subcellular site of catalysis"]},{"year":2012,"claim":"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","pmids":["22573804"],"confidence":"Medium","gaps":["Pharmacologic inhibition does not exclude off-target effects","Does not directly measure DAG/PA changes at the immune synapse"]},{"year":2013,"claim":"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","pmids":["24158111"],"confidence":"Medium","gaps":["Does not define the downstream effector linking DGKA to survival in glioblastoma","Single-lab validation"]},{"year":2020,"claim":"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","pmids":["32010133"],"confidence":"Medium","gaps":["Mechanism distinguishing TH1 sensitivity from TH2/TH17 not resolved","Does not link the differentiation defect directly to DAG/PA flux"]},{"year":2020,"claim":"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","pmids":["32341033"],"confidence":"High","gaps":["Precise molecular mechanism by which PA recruits JNK to c-JUN not structurally defined","Generality across tumor types beyond ovarian cancer not established"]},{"year":2021,"claim":"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","pmids":["33608256"],"confidence":"Medium","gaps":["Does not separate T-cell-intrinsic from tumor-intrinsic contributions in vivo","Mechanism upstream of AKT activation not defined"]},{"year":2021,"claim":"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","pmids":["33593821"],"confidence":"High","gaps":["Mechanistic link between PA and macropinocytic machinery not fully defined","Relevance to non-TSC2 contexts unclear"]},{"year":2022,"claim":"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","pmids":["35131384"],"confidence":"Medium","gaps":["Whether SRC/FAK phosphorylation requires DGKA lipid kinase activity is unresolved","Single-lab finding without independent reciprocal confirmation"]},{"year":2023,"claim":"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","pmids":["38143235"],"confidence":"Medium","gaps":["Specific MAPK effector and PA species not identified","Single tumor-type model"]},{"year":2025,"claim":"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","pmids":["41459935"],"confidence":"Medium","gaps":["Dual DGKα/ζ inhibitor does not isolate DGKα-specific contribution","Durability of the response not assessed"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[9,1,6]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[9]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[9,6]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3]}],"localization":[],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,3]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,4,5,10]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[6,9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,3,7]}],"complexes":["DGKA/SRC/FAK complex"],"partners":["SRC","FAK","JNK","JUN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P23743","full_name":"Diacylglycerol kinase alpha","aliases":["80 kDa diacylglycerol kinase","Diglyceride kinase alpha","DGK-alpha"],"length_aa":735,"mass_kda":82.6,"function":"Diacylglycerol kinase that converts diacylglycerol/DAG into phosphatidic acid/phosphatidate/PA and regulates the respective levels of these two bioactive lipids (PubMed:15544348, PubMed:2175712). Thereby, acts as a central switch between the signaling pathways activated by these second messengers with different cellular targets and opposite effects in numerous biological processes (PubMed:15544348, PubMed:2175712). Also plays an important role in the biosynthesis of complex lipids (Probable). Can also phosphorylate 1-alkyl-2-acylglycerol in vitro as efficiently as diacylglycerol provided it contains an arachidonoyl group (PubMed:15544348). Also involved in the production of alkyl-lysophosphatidic acid, another bioactive lipid, through the phosphorylation of 1-alkyl-2-acetyl glycerol (PubMed:22627129)","subcellular_location":"Cytoplasm, cytosol","url":"https://www.uniprot.org/uniprotkb/P23743/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DGKA","classification":"Not Classified","n_dependent_lines":8,"n_total_lines":1208,"dependency_fraction":0.006622516556291391},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DGKA","total_profiled":1310},"omim":[{"mim_id":"616711","title":"TAO KINASE 3; TAOK3","url":"https://www.omim.org/entry/616711"},{"mim_id":"610681","title":"PHOSPHOFRUCTOKINASE, MUSCLE TYPE; PFKM","url":"https://www.omim.org/entry/610681"},{"mim_id":"610307","title":"CERAMIDE KINASE; CERK","url":"https://www.omim.org/entry/610307"},{"mim_id":"607092","title":"SPHINGOSINE KINASE 2; SPHK2","url":"https://www.omim.org/entry/607092"},{"mim_id":"125855","title":"DIACYLGLYCEROL KINASE, ALPHA, 80-KD; DGKA","url":"https://www.omim.org/entry/125855"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Mitochondria","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":184.5}],"url":"https://www.proteinatlas.org/search/DGKA"},"hgnc":{"alias_symbol":["DGK-alpha"],"prev_symbol":["DAGK","DAGK1"]},"alphafold":{"accession":"P23743","domains":[{"cath_id":"1.10.238.110","chopping":"9-193","consensus_level":"medium","plddt":74.163,"start":9,"end":193},{"cath_id":"3.40.50.10330","chopping":"365-491","consensus_level":"high","plddt":92.863,"start":365,"end":491},{"cath_id":"2.60.200.40","chopping":"499-717","consensus_level":"high","plddt":89.8995,"start":499,"end":717}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P23743","model_url":"https://alphafold.ebi.ac.uk/files/AF-P23743-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P23743-F1-predicted_aligned_error_v6.png","plddt_mean":82.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DGKA","jax_strain_url":"https://www.jax.org/strain/search?query=DGKA"},"sequence":{"accession":"P23743","fasta_url":"https://rest.uniprot.org/uniprotkb/P23743.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P23743/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P23743"}},"corpus_meta":[{"pmid":"22573804","id":"PMC_22573804","title":"High DGK-α and disabled MAPK pathways cause dysfunction of human tumor-infiltrating CD8+ T cells that is reversible by pharmacologic intervention.","date":"2012","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/22573804","citation_count":78,"is_preprint":false},{"pmid":"32341033","id":"PMC_32341033","title":"DGKA Provides Platinum Resistance in Ovarian Cancer Through Activation of c-JUN-WEE1 Signaling.","date":"2020","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/32341033","citation_count":53,"is_preprint":false},{"pmid":"24158111","id":"PMC_24158111","title":"A miR-297/hypoxia/DGK-α axis regulating glioblastoma survival.","date":"2013","source":"Neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/24158111","citation_count":40,"is_preprint":false},{"pmid":"21463370","id":"PMC_21463370","title":"Antagonistic regulation of dgkA and plsB genes of phospholipid synthesis by multiple stress responses in Escherichia coli.","date":"2011","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/21463370","citation_count":37,"is_preprint":false},{"pmid":"28316970","id":"PMC_28316970","title":"DGK-α: A Checkpoint in Cancer-Mediated Immuno-Inhibition and Target for Immunotherapy.","date":"2017","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/28316970","citation_count":35,"is_preprint":false},{"pmid":"35131384","id":"PMC_35131384","title":"DGKA interacts with SRC/FAK to promote the metastasis of non-small cell lung cancer.","date":"2022","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/35131384","citation_count":29,"is_preprint":false},{"pmid":"33608256","id":"PMC_33608256","title":"DGKA Mediates Resistance to PD-1 Blockade.","date":"2021","source":"Cancer immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/33608256","citation_count":26,"is_preprint":false},{"pmid":"30135067","id":"PMC_30135067","title":"Diacylglycerol kinase (DGKA) regulates the effect of the epilepsy and bipolar disorder treatment valproic acid in Dictyostelium discoideum.","date":"2018","source":"Disease models & mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/30135067","citation_count":21,"is_preprint":false},{"pmid":"38143235","id":"PMC_38143235","title":"Multiomics analysis reveals metabolic subtypes and identifies diacylglycerol kinase α (DGKA) as a potential therapeutic target for intrahepatic cholangiocarcinoma.","date":"2023","source":"Cancer communications (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/38143235","citation_count":17,"is_preprint":false},{"pmid":"16042397","id":"PMC_16042397","title":"Analysis of a novel diacylglycerol kinase from Dictyostelium discoideum: DGKA.","date":"2005","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16042397","citation_count":16,"is_preprint":false},{"pmid":"32842668","id":"PMC_32842668","title":"Involvement of hpap2 and dgkA Genes in Colistin Resistance Mediated by mcr Determinants.","date":"2020","source":"Antibiotics (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/32842668","citation_count":14,"is_preprint":false},{"pmid":"32010133","id":"PMC_32010133","title":"DGK α and ζ Activities Control TH1 and TH17 Cell Differentiation.","date":"2020","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/32010133","citation_count":13,"is_preprint":false},{"pmid":"33593821","id":"PMC_33593821","title":"Therapeutic Targeting of DGKA-Mediated Macropinocytosis Leads to Phospholipid Reprogramming in Tuberous Sclerosis Complex.","date":"2021","source":"Cancer 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models.","date":"2025","source":"Oncoimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/41459935","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9964,"output_tokens":2984,"usd":0.037326,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10514,"output_tokens":3685,"usd":0.072347,"stage2_stop_reason":"end_turn"},"total_usd":0.109673,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"DGK-α (DGKA) suppresses distal TCR signaling in CD8+ tumor-infiltrating T cells by reducing steady-state ERK phosphorylation and blocking stimulus-induced ERK, JNK, and AKT phosphorylation; pharmacologic inhibition of DGK-α improved ERK phosphorylation and lytic granule exocytosis, placing DGKA downstream of PLC-γ but upstream of MAPK/AKT pathways.\",\n      \"method\": \"Pharmacologic inhibition of DGK-α in primary human CD8+ TILs with phospho-flow cytometry for ERK/JNK/AKT and functional assays (degranulation, IFN-γ production)\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean pharmacologic inhibition with defined signaling readouts, single lab, two orthogonal functional methods\",\n      \"pmids\": [\"22573804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DGKA confers cisplatin resistance in ovarian cancer through its lipid kinase activity: the DGKA product phosphatidic acid (PA) facilitates JNK recruitment to c-JUN and promotes c-JUN nuclear localization, activating c-JUN transcriptional output and upregulating the cell-cycle regulator WEE1.\",\n      \"method\": \"RNAi synthetic lethal screening, DGKA catalytic-dead variant rescue, phospho-proteomics, genomic screens, pharmacologic DGKA inhibition with cisplatin co-treatment, patient-derived tumor validation\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (RNAi, dominant-negative variant, phospho-proteomics, pharmacologic inhibition), validated in patient-derived tumors\",\n      \"pmids\": [\"32341033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DGK-α is a direct functional target of miR-297 in glioblastoma; 3'UTR luciferase assays confirmed miR-297 targets the DGK-α 3'UTR, and DGK-α overexpression rescued the cytotoxic effects of miR-297, demonstrating that DGK-α activity is required for glioblastoma cell survival downstream of miR-297.\",\n      \"method\": \"3'UTR luciferase reporter assay, immunoblot, DGK-α overexpression rescue, glioblastoma xenograft mouse model\",\n      \"journal\": \"Neuro-oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — 3'UTR reporter plus rescue experiment, single lab, two orthogonal methods\",\n      \"pmids\": [\"24158111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DGKA physically interacts with SRC and FAK: the C-terminal domain of DGKA binds the SRC SH3 domain, while the DGKA catalytic domain interacts with the FAK FERM domain. DGKA phosphorylates SRC at Tyr416 and FAK at Tyr397, activating the DGKA/SRC/FAK complex and initiating downstream WNT/β-catenin and VEGF signaling to drive EMT and angiogenesis in NSCLC.\",\n      \"method\": \"Co-immunoprecipitation, domain-mapping pulldowns, phosphorylation assays, DGKA knockdown and overexpression in vitro invasion and in vivo metastasis models\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with domain mapping and phosphorylation readouts, single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"35131384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DGKA mediates T-cell exhaustion during anti-PD-1 therapy; pharmacologic ablation of Dgka postponed T-cell exhaustion and delayed resistance to PD-1 blockade. Additionally, DGKA expression in cancer cells promoted tumor cell growth via the AKT signaling pathway.\",\n      \"method\": \"Pharmacologic DGKA inhibition, in vivo tumor models, anti-PD-1 combination treatment, Western blotting for AKT signaling\",\n      \"journal\": \"Cancer immunology research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacologic and genetic loss-of-function with defined signaling readouts, single lab\",\n      \"pmids\": [\"33608256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DGKα deficiency selectively impairs TH1 differentiation without affecting TH2 or TH17 differentiation; simultaneous loss of DGKα and DGKζ additionally promotes TH17 differentiation via increased mTORC1/S6K1 signaling, demonstrating a dosage-dependent role for DGKα in T helper cell fate decisions downstream of TCR-DAG signaling.\",\n      \"method\": \"DGKα knockout mice, in vitro TH differentiation assays, in vivo airway inflammation model, mTORC1/S6K1 signaling readouts\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with defined differentiation phenotypes and signaling pathway placement, single lab\",\n      \"pmids\": [\"32010133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DGKA supports macropinocytosis in TSC2-deficient cells to maintain phospholipid homeostasis; phosphatidic acid levels are elevated 5-fold in Tsc2-/- cells, and DGKA inhibition with ritanserin depletes PA, rewires phospholipid metabolism, reduces macropinocytic albumin uptake, limits lysosome number and activity, and prevents alveolar destruction in a mouse model of lymphangioleiomyomatosis.\",\n      \"method\": \"High-throughput drug screen, ritanserin pharmacologic inhibition, lipidomic PA quantification, macropinocytosis assays, lysosome assays, Tsc2-/- mouse models, genetic DGKA knockdown in vivo\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (pharmacologic + genetic KD, lipidomics, functional assays, two in vivo models), single lab with rigorous controls\",\n      \"pmids\": [\"33593821\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DGKA promotes cell proliferation in intrahepatic cholangiocarcinoma by enhancing phosphatidic acid (PA) metabolism and activating MAPK signaling, as demonstrated by cell proliferation assays, EdU assay, colony formation, and RNA-sequencing following DGKA manipulation.\",\n      \"method\": \"DGKA knockdown/overexpression, cell proliferation assay, EdU assay, colony formation, RNA-sequencing, Western blotting for MAPK signaling\",\n      \"journal\": \"Cancer communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional readouts with defined signaling pathway output, single lab\",\n      \"pmids\": [\"38143235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In Dictyostelium discoideum, ablation of dgkA reduces sensitivity to valproic acid, branched medium-chain fatty acids with seizure control activity, and lithium; VPA, lithium, and novel epilepsy treatments function through DAG regulation, and DGKA is necessary for compound-specific increases in DAG levels following treatment, placing DGKA in the phosphoinositide recycling pathway linked to PKC activity.\",\n      \"method\": \"dgkA null mutant generation, behavioral/developmental assays, DAG level measurements, pharmacologic compound testing\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic null with defined molecular (DAG levels) and phenotypic readouts, Dictyostelium ortholog model, single lab\",\n      \"pmids\": [\"30135067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Dictyostelium DGKA catalyzes ATP-dependent phosphorylation of diacylglycerols (DiC8, DiC6) in Michaelis-Menten kinetics; with physiologically relevant long-chain DAGs the kinetics are substrate-surface-concentration-dependent and detergent-dependent (Michaelis-Menten in octyl glucoside at low surface concentrations, sigmoidal at high concentrations; sigmoidal at all concentrations in Triton X-100); catalytic activity is significantly enhanced by phosphatidylserine and phosphatidic acid.\",\n      \"method\": \"In vitro enzymatic assay with mixed micelles, kinetic analysis (Michaelis-Menten and sigmoidal fitting), lipid activator titration\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro reconstituted enzymatic assay with systematic kinetic characterization under multiple defined conditions, single lab\",\n      \"pmids\": [\"16042397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Pharmacologic dual inhibition of DGKα and DGKζ (INCB165451) in human T cells enhances anti-tumor efficacy of adoptively transferred TILs in NSCLC mouse models by increasing intratumoral T cell infiltration and reducing TIL hypofunction, demonstrated by enhanced cytokine production; the inhibitor also augmented T cell activation in human tumor slices stimulated by anti-EGFR/anti-CD3 BiTE.\",\n      \"method\": \"In vivo adoptive T cell transfer NSCLC mouse model, ex vivo human tumor digest TIL assays, precision-cut tumor slice assay, anti-CD3 stimulation, gene and protein expression of cytokines/chemokines\",\n      \"journal\": \"Oncoimmunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and ex vivo human models, multiple functional readouts, single lab, note that DGKα/ζ dual inhibitor does not isolate DGKα-specific effects\",\n      \"pmids\": [\"41459935\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DGKA (DGK-α) is a diacylglycerol kinase that phosphorylates diacylglycerol to generate phosphatidic acid (PA); in T cells it acts as an intrinsic brake on TCR signaling by attenuating DAG-dependent ERK/JNK/AKT activation and promoting T-cell exhaustion, while in tumor cells PA produced by DGKA activates c-JUN (via JNK recruitment), MAPK, AKT, and mTORC1 signaling, supports macropinocytosis-driven phospholipid homeostasis, and enables physical interaction with and phosphorylation of SRC/FAK to drive metastatic signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DGKA (DGK-\\u03b1) 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 [#9]. 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-\\u03b3 [#0], driving T-cell exhaustion during anti-PD-1 therapy [#4] and shaping T helper fate decisions, where its loss selectively impairs TH1 differentiation in a gene-dosage-dependent manner with DGK\\u03b6 [#5]. 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 [#1], drives proliferation via PA metabolism and MAPK signaling [#7], and promotes growth through AKT [#4]. 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/\\u03b2-catenin and VEGF signaling to drive EMT and angiogenesis [#3], and it sustains macropinocytosis-driven phospholipid homeostasis and lysosomal activity in TSC2-deficient cells [#6]. Pharmacologic inhibition of DGKA reverses both arms of this biology \\u2014 restoring effector T-cell function and augmenting anti-tumor immunity [#0, #4, #10] while depleting PA in tumor cells [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Established the core biochemical reaction by showing DGKA directly phosphorylates diacylglycerol in an ATP-dependent manner, defining its substrate specificity and lipid regulation.\",\n      \"evidence\": \"In vitro mixed-micelle enzymatic assay with kinetic analysis and lipid activator titration (Dictyostelium ortholog)\",\n      \"pmids\": [\"16042397\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Characterized in the Dictyostelium ortholog rather than human DGKA\", \"Does not establish in vivo substrate pools or subcellular site of catalysis\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Placed DGKA functionally in the TCR signaling cascade by showing it brakes distal signaling downstream of PLC-\\u03b3 but upstream of MAPK/AKT, and that inhibiting it restores cytotoxic T-cell function.\",\n      \"evidence\": \"Pharmacologic DGKA inhibition in primary human CD8+ TILs with phospho-flow cytometry and functional degranulation/IFN-\\u03b3 assays\",\n      \"pmids\": [\"22573804\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Pharmacologic inhibition does not exclude off-target effects\", \"Does not directly measure DAG/PA changes at the immune synapse\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified an upstream regulatory input by showing DGKA is a direct miR-297 target whose activity is required for glioblastoma survival.\",\n      \"evidence\": \"3'UTR luciferase reporter assay, immunoblot, overexpression rescue, glioblastoma xenograft\",\n      \"pmids\": [\"24158111\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not define the downstream effector linking DGKA to survival in glioblastoma\", \"Single-lab validation\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a gene-dosage role for DGKA in T helper fate, distinguishing its non-redundant control of TH1 differentiation from a shared role with DGK\\u03b6 in restraining TH17 via mTORC1.\",\n      \"evidence\": \"DGK\\u03b1 knockout mice, in vitro TH differentiation assays, in vivo airway inflammation model, mTORC1/S6K1 readouts\",\n      \"pmids\": [\"32010133\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism distinguishing TH1 sensitivity from TH2/TH17 not resolved\", \"Does not link the differentiation defect directly to DAG/PA flux\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"RNAi synthetic-lethal screen, catalytic-dead rescue, phospho-proteomics, pharmacologic inhibition with cisplatin, patient-derived tumor validation\",\n      \"pmids\": [\"32341033\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise molecular mechanism by which PA recruits JNK to c-JUN not structurally defined\", \"Generality across tumor types beyond ovarian cancer not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"evidence\": \"Pharmacologic/genetic DGKA loss-of-function, in vivo tumor models, anti-PD-1 combination, Western blotting for AKT\",\n      \"pmids\": [\"33608256\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not separate T-cell-intrinsic from tumor-intrinsic contributions in vivo\", \"Mechanism upstream of AKT activation not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed a metabolic-homeostasis role beyond signaling: DGKA-derived PA supports macropinocytosis and lysosomal function to maintain phospholipid balance in TSC2-deficient cells.\",\n      \"evidence\": \"High-throughput drug screen, ritanserin inhibition, lipidomic PA quantification, macropinocytosis/lysosome assays, Tsc2-/- mouse models, genetic knockdown\",\n      \"pmids\": [\"33593821\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link between PA and macropinocytic machinery not fully defined\", \"Relevance to non-TSC2 contexts unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Uncovered a non-catalytic scaffolding/kinase function in which DGKA binds and phosphorylates SRC and FAK through distinct domain contacts to drive metastatic signaling.\",\n      \"evidence\": \"Reciprocal Co-IP, domain-mapping pulldowns, phosphorylation assays, knockdown/overexpression invasion and metastasis models\",\n      \"pmids\": [\"35131384\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SRC/FAK phosphorylation requires DGKA lipid kinase activity is unresolved\", \"Single-lab finding without independent reciprocal confirmation\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended the pro-proliferative PA-MAPK axis to intrahepatic cholangiocarcinoma, reinforcing PA metabolism as a generalizable oncogenic mechanism.\",\n      \"evidence\": \"DGKA knockdown/overexpression, EdU/colony-formation proliferation assays, RNA-seq, Western blotting for MAPK\",\n      \"pmids\": [\"38143235\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific MAPK effector and PA species not identified\", \"Single tumor-type model\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided translational validation that DGK\\u03b1/\\u03b6 inhibition enhances adoptive T-cell therapy by increasing intratumoral infiltration and reducing TIL hypofunction.\",\n      \"evidence\": \"In vivo adoptive transfer NSCLC model, ex vivo human tumor TIL assays, precision-cut tumor slices, BiTE stimulation\",\n      \"pmids\": [\"41459935\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Dual DGK\\u03b1/\\u03b6 inhibitor does not isolate DGK\\u03b1-specific contribution\", \"Durability of the response not assessed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [9, 1, 6]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [9, 6]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 4, 5, 10]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [6, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 3, 7]}\n    ],\n    \"complexes\": [\"DGKA/SRC/FAK complex\"],\n    \"partners\": [\"SRC\", \"FAK\", \"JNK\", \"JUN\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}