{"gene":"AGK","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2004,"finding":"AGK (named MuLK) is a multi-substrate lipid kinase that phosphorylates diacylglycerol, ceramide, and 1-acylglycerol but not sphingosine; it co-fractionates with membranes and localizes to an internal membrane compartment; its activity is inhibited by sphingosine, enhanced by cardiolipin, stimulated by calcium at low magnesium, and inhibited by calcium at high magnesium concentrations.","method":"In vitro enzymatic assay with recombinant protein, subcellular fractionation, membrane localization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with recombinant enzyme, substrate specificity profiling, and localization by fractionation","pmids":["15252046"],"is_preprint":false},{"year":2020,"finding":"AGK binds to JAK2 in megakaryocytes/platelets independent of its kinase activity (G126E kinase-dead mutation does not affect platelet counts or megakaryocyte differentiation), and JAK2 V617F mutation enhances AGK-JAK2 binding and greatly facilitates JAK2/Stat3 signaling in response to thrombopoietin; AGK-deficient mice develop thrombocytopenia due to defective bone marrow thrombocytopoiesis.","method":"Co-immunoprecipitation, megakaryocyte/platelet-specific AGK knockout mice, kinase-dead AGK G126E knock-in mice, platelet functional assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, multiple genetic models (KO + knock-in), defined cellular phenotype with pathway placement","pmids":["32202634"],"is_preprint":false},{"year":2022,"finding":"AGK interacts with mitochondrial respiratory chain complex I subunits NDUFS2 and NDUFA10 via its DGK domain (kinase-independent) to maintain complex I function and hepatic mitochondrial integrity; AGK deficiency (but not kinase-dead G126E mutation) causes mitochondrial dysfunction, fatty acid metabolism dysregulation, and NASH progression.","method":"Hepatocyte-specific AGK knockout mice, AGK G126E knock-in mice, co-immunoprecipitation, dietary NASH models (CDAHFD, MCD)","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, multiple genetic models (KO + kinase-dead knock-in), defined pathway with domain mapping","pmids":["35547757"],"is_preprint":false},{"year":2023,"finding":"ZDHHC2-mediated S-palmitoylation of AGK promotes its translocation from mitochondria to the plasma membrane, where it activates the PI3K-AKT-mTOR signaling pathway and reduces sunitinib sensitivity in clear cell renal cell carcinoma.","method":"Palmitoylation assay, subcellular fractionation, signaling pathway analysis, cell and mouse models of sunitinib resistance","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — direct palmitoylation assay, localization by fractionation linked to functional signaling outcome, in vivo validation","pmids":["37078777"],"is_preprint":false},{"year":2023,"finding":"AGK promotes Talin-1 Ser425 phosphorylation in a kinase-activity-dependent manner, affecting αIIbβ3-mediated bidirectional signaling in platelets; this is independent of AGK's lipid synthesis (phosphatidic acid/lysophosphatidic acid) activity in platelets, and AGK deficiency or kinase-dead mutation reduces platelet aggregation, granule secretion, and delays arterial thrombus formation.","method":"Co-immunoprecipitation, mass spectrometry, immunofluorescence, Western blot, platelet-specific knockout and kinase-dead knock-in mice, in vivo thrombosis models","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 — Co-IP/MS identification of Talin-1, multiple genetic models, phosphorylation site mapping, in vivo thrombosis assays","pmids":["37051931"],"is_preprint":false},{"year":2025,"finding":"AGK forms a complex with HSP90 and JAK2 in CLL cells, promoting aberrant constitutive JAK2 activation independent of cytokine signaling; AGK is detected in nuclear localization associated with JAK2 in some CLL cells; JAK2 phosphorylates histone H3(Y41) (non-canonical substrate) but not STAT3, activating gene transcription; JAK2 also activates BCR signaling via LYN/BTK axis.","method":"Co-immunoprecipitation, biochemical and molecular biology assays in primary CLL cells, nuclear fractionation","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP in primary patient cells, nuclear localization by fractionation, mechanistic pathway dissection; single study","pmids":["39636206"],"is_preprint":false},{"year":2023,"finding":"AGK (acylglycerol kinase) is present in a proximity complex with the ROMK2 channel in mitochondria, confirmed by co-immunoprecipitation; the AGK products lysophosphatidic acid and phosphatidic acid stimulate ROMK2 channel activity in artificial lipid bilayers, suggesting localized lipid synthesis by channel-bound AGK regulates ROMK2 activity.","method":"TurboID proximity labeling, co-immunoprecipitation, artificial lipid bilayer electrophysiology, molecular docking","journal":"Biochimica et biophysica acta. Molecular and cell biology of lipids","confidence":"Medium","confidence_rationale":"Tier 2 — proximity labeling + Co-IP + functional bilayer assay; single study with multiple orthogonal methods","pmids":["38056763"],"is_preprint":false},{"year":2019,"finding":"AGK promotes glycolytic metabolism and effector function of CD8+ T cells by inactivating PTEN and boosting mTOR activity, thereby enhancing antitumor CD8+ T cell activity.","method":"Genetic loss-of-function and overexpression in CD8+ T cells, signaling pathway analysis (PTEN/mTOR)","journal":"Cell metabolism","confidence":"Medium","confidence_rationale":"Tier 2 — defined signaling mechanism (PTEN inactivation, mTOR activation) with functional T cell phenotype; cited as summary of primary work by Hu et al. 2019","pmids":["31390548"],"is_preprint":false},{"year":2014,"finding":"AGK overexpression in hepatocellular carcinoma enhances angiogenesis and inhibits apoptosis via activation of NF-κB signaling; silencing AGK reverses these effects in vitro and reduces tumorigenicity in vivo.","method":"AGK overexpression and knockdown in HCC cell lines, in vitro angiogenesis/apoptosis assays, xenograft mouse model, NF-κB pathway analysis","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 3 — defined signaling pathway (NF-κB) with loss- and gain-of-function, but NF-κB mechanism not biochemically dissected","pmids":["25474138"],"is_preprint":false},{"year":2021,"finding":"AGK is a component of the TIM22 complex in the inner mitochondrial membrane, mediating import of a subset of membrane proteins; AGK mutations alter both phospholipid metabolism and mitochondrial protein biogenesis; patient fibroblasts with a novel AGK splicing variant show decreased oxygen consumption rate and reduced OXPHOS complex I and V activity.","method":"Patient fibroblast functional assays (OCR, ECAR measurements by Seahorse), spectrophotometric OXPHOS complex activity, cDNA splicing analysis","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — functional mitochondrial assays with patient cells, splicing validated in vitro; single study","pmids":["34948281"],"is_preprint":false},{"year":2020,"finding":"In gastric cancer, YAP1 transcriptionally induces AGK expression through TEAD binding to the AGK promoter; AGK in turn inhibits Hippo pathway proteins and induces YAP1 nuclear localization, forming a positive feedback loop (YAP1-AGK loop).","method":"ChIP/promoter binding assay, knockdown/overexpression in gastric cancer cells, Hippo pathway signaling analysis, nuclear localization assay","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 3 — TEAD-promoter binding shown, feedback loop established by KD/OE with pathway readouts; single study","pmids":["32827244"],"is_preprint":false},{"year":2015,"finding":"AGK directly promotes PI3K/AKT/FoxO3a signaling in oral squamous cell carcinoma cells; miR-194 suppresses AGK and thereby reduces cyclin D1 and increases p21 expression via this pathway.","method":"miRNA overexpression/inhibition, AGK knockdown, PI3K/AKT/FoxO3a pathway signaling analysis in OSCC cell lines","journal":"Biomedicine & pharmacotherapy","confidence":"Low","confidence_rationale":"Tier 3 — signaling pathway placement by KD/OE, no direct biochemical mechanism for AGK-PI3K interaction","pmids":["25960215"],"is_preprint":false},{"year":2024,"finding":"Netupitant binds to the ATP-binding region of AGK (confirmed by molecular dynamics simulations and binding affinity assays), inhibits AGK kinase activity, reduces PTEN phosphorylation, and suppresses PI3K/AKT/mTOR pathway activation in breast cancer cells.","method":"Molecular dynamics simulation, binding affinity (BIL assay), siRNA knockdown, in vitro proliferation/apoptosis assays, xenograft mouse model","journal":"Cancers","confidence":"Low","confidence_rationale":"Tier 4/3 — binding is primarily computational with binding assay; kinase inhibition not directly measured by enzymatic assay","pmids":["39594764"],"is_preprint":false}],"current_model":"AGK is a mitochondrial membrane-associated multi-substrate lipid kinase (phosphorylating diacylglycerol, monoacylglycerol, and ceramide to generate phosphatidic acid and lysophosphatidic acid) that also functions kinase-independently as a structural component of the TIM22 inner mitochondrial membrane protein import complex; it interacts with JAK2 to modulate megakaryocyte/platelet development and JAK2-STAT3 signaling, interacts with mitochondrial complex I subunits NDUFS2/NDUFA10 to maintain respiratory chain integrity, can be palmitoylated by ZDHHC2 to translocate to the plasma membrane and activate AKT-mTOR signaling, and promotes platelet activation by phosphorylating Talin-1 Ser425 to regulate αIIbβ3 bidirectional signaling."},"narrative":{"teleology":[{"year":2004,"claim":"The fundamental enzymatic identity of AGK was established as a multi-substrate lipid kinase with broad specificity toward diacylglycerol, ceramide, and monoacylglycerol, resolving its biochemical activity and membrane association.","evidence":"In vitro enzymatic assay with recombinant AGK, substrate specificity profiling, subcellular fractionation","pmids":["15252046"],"confidence":"High","gaps":["Physiological lipid substrates in vivo not determined","Subcellular membrane compartment identity not resolved beyond 'internal membranes'","No structural model of the active site"]},{"year":2014,"claim":"AGK was linked to oncogenic signaling beyond lipid metabolism, with overexpression in hepatocellular carcinoma activating NF-κB signaling to promote angiogenesis and inhibit apoptosis.","evidence":"AGK overexpression and knockdown in HCC cell lines, xenograft model, NF-κB pathway analysis","pmids":["25474138"],"confidence":"Medium","gaps":["Direct biochemical mechanism linking AGK to NF-κB not established","Unclear whether lipid kinase activity is required for NF-κB activation","Single study without independent replication"]},{"year":2019,"claim":"AGK was shown to regulate CD8+ T cell metabolism and antitumor function through inactivation of PTEN and enhancement of mTOR activity, revealing a role in adaptive immunity.","evidence":"Genetic loss-of-function and overexpression in CD8+ T cells, PTEN/mTOR signaling analysis","pmids":["31390548"],"confidence":"Medium","gaps":["Mechanism of PTEN inactivation by AGK not biochemically defined","Whether lipid kinase products or a kinase-independent function drives the effect is unknown"]},{"year":2020,"claim":"A major conceptual advance established that AGK has kinase-independent scaffolding functions: AGK binds JAK2 in megakaryocytes independent of its kinase activity to support thrombopoiesis, and the JAK2 V617F oncogenic mutation enhances this interaction, linking AGK to myeloproliferative signaling.","evidence":"Reciprocal Co-IP, megakaryocyte/platelet-specific AGK knockout and kinase-dead G126E knock-in mice, platelet functional assays","pmids":["32202634"],"confidence":"High","gaps":["Structural basis of AGK-JAK2 interaction not resolved","Whether AGK-JAK2 interaction is direct or mediated by adaptor proteins not fully excluded","Role in human Sengers syndrome thrombopoiesis not addressed"]},{"year":2021,"claim":"AGK was confirmed as a subunit of the TIM22 mitochondrial protein import complex, and patient-derived AGK mutations were shown to impair OXPHOS complex I and V activity, linking its structural role to mitochondrial bioenergetics.","evidence":"Patient fibroblast OCR/ECAR measurements, spectrophotometric OXPHOS complex activity assays, cDNA splicing validation","pmids":["34948281"],"confidence":"Medium","gaps":["Which TIM22 substrates are specifically affected by AGK loss not catalogued","Relative contribution of lipid kinase versus TIM22 scaffold function to OXPHOS defects not dissected","Single patient variant studied"]},{"year":2022,"claim":"The kinase-independent scaffolding concept was extended to the respiratory chain: AGK interacts with complex I subunits NDUFS2 and NDUFA10 via its DGK domain to maintain complex I function in hepatocytes, with AGK deficiency (but not kinase-dead mutation) causing NASH progression.","evidence":"Hepatocyte-specific AGK knockout and G126E knock-in mice, reciprocal Co-IP, dietary NASH models","pmids":["35547757"],"confidence":"High","gaps":["Whether AGK-complex I interaction is direct or mediated through TIM22 import of complex I subunits is ambiguous","Stoichiometry and stability of AGK-NDUFS2/NDUFA10 complex not characterized","Relevance to human NASH not tested"]},{"year":2023,"claim":"Two discoveries in 2023 expanded AGK's functional repertoire: ZDHHC2-mediated palmitoylation was shown to redirect AGK from mitochondria to the plasma membrane to activate AKT-mTOR signaling, and AGK was found to function as a protein kinase phosphorylating Talin-1 Ser425 to regulate integrin bidirectional signaling in platelets.","evidence":"Palmitoylation assay with subcellular fractionation and sunitinib resistance models (PMID:37078777); Co-IP/MS, phosphosite mapping, platelet-specific KO and kinase-dead KI mice with in vivo thrombosis assays (PMID:37051931)","pmids":["37078777","37051931"],"confidence":"High","gaps":["Talin-1 phosphorylation by AGK not reconstituted with purified components","Palmitoylation-dependent relocalization not confirmed in non-cancer cell types","How AGK switches between lipid kinase and protein kinase activity is unknown"]},{"year":2023,"claim":"AGK lipid products were linked to regulation of mitochondrial ion channels: AGK associates with ROMK2 in a proximity complex, and its products LPA and PA directly stimulate ROMK2 channel activity, suggesting localized lipid synthesis regulates channel function.","evidence":"TurboID proximity labeling, Co-IP, artificial lipid bilayer electrophysiology","pmids":["38056763"],"confidence":"Medium","gaps":["Functional consequence of ROMK2 regulation by AGK-derived lipids in intact mitochondria not shown","Single study without genetic validation in cells","Whether AGK is obligate for ROMK2 activity or merely modulatory is unclear"]},{"year":2025,"claim":"AGK-HSP90-JAK2 complex formation was demonstrated in CLL cells, driving constitutive cytokine-independent JAK2 activation and non-canonical histone H3Y41 phosphorylation with nuclear AGK-JAK2 co-localization, broadening AGK's scaffolding role to hematologic malignancy.","evidence":"Co-IP in primary CLL patient cells, nuclear fractionation, BCR signaling analysis","pmids":["39636206"],"confidence":"Medium","gaps":["AGK-HSP90-JAK2 complex stoichiometry and directness of AGK-HSP90 interaction not resolved","Nuclear AGK localization observed only by fractionation, not by imaging","Single study in primary CLL cells without genetic manipulation of AGK"]},{"year":null,"claim":"How AGK coordinates its dual lipid kinase, protein kinase, and kinase-independent scaffolding activities — and what determines substrate selection and subcellular targeting — remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal structure or cryo-EM structure of AGK available","Mechanism governing switch between lipid and protein kinase activities unknown","Relative contributions of TIM22 scaffold vs. lipid kinase function to Sengers syndrome phenotype not dissected in vivo"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,4]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,6]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[4]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2,5]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,2,6,9]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,3,5,7,8,10]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,6]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[1,4]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[9]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[2,9]}],"complexes":["TIM22 complex"],"partners":["JAK2","NDUFS2","NDUFA10","TLN1","HSP90","ZDHHC2","ROMK2"],"other_free_text":[]},"mechanistic_narrative":"AGK is a mitochondrial membrane-associated lipid kinase with dual kinase-dependent and kinase-independent functions spanning lipid metabolism, mitochondrial protein import, signal transduction, and platelet biology. As a multi-substrate lipid kinase, AGK phosphorylates diacylglycerol, monoacylglycerol, and ceramide to generate phosphatidic acid and lysophosphatidic acid, with activity modulated by cardiolipin and divalent cations [PMID:15252046]; it also serves as a structural subunit of the TIM22 inner mitochondrial membrane protein import complex, where AGK mutations impair OXPHOS complex I and V activity [PMID:34948281]. Independent of its kinase activity, AGK binds JAK2 via a kinase-independent interaction to support megakaryopoiesis and thrombopoietin-driven JAK2/STAT3 signaling, and interacts with complex I subunits NDUFS2/NDUFA10 to maintain mitochondrial respiratory chain integrity [PMID:32202634, PMID:35547757]. AGK also functions as a protein kinase that phosphorylates Talin-1 at Ser425 to regulate αIIbβ3 integrin bidirectional signaling in platelets, and can be palmitoylated by ZDHHC2 to relocalize to the plasma membrane where it activates PI3K-AKT-mTOR signaling [PMID:37051931, PMID:37078777]."},"prefetch_data":{"uniprot":{"accession":"Q53H12","full_name":"Acylglycerol kinase, mitochondrial","aliases":["Multiple substrate lipid kinase","HsMuLK","MuLK","Multi-substrate lipid kinase"],"length_aa":422,"mass_kda":47.1,"function":"Lipid kinase that can phosphorylate both monoacylglycerol and diacylglycerol to form lysophosphatidic acid (LPA) and phosphatidic acid (PA), respectively (PubMed:15939762). Does not phosphorylate sphingosine (PubMed:15939762). Phosphorylates ceramide (By similarity). Phosphorylates 1,2-dioleoylglycerol more rapidly than 2,3-dioleoylglycerol (By similarity). Independently of its lipid kinase activity, acts as a component of the TIM22 complex (PubMed:28712724, PubMed:28712726). The TIM22 complex mediates the import and insertion of multi-pass transmembrane proteins into the mitochondrial inner membrane by forming a twin-pore translocase that uses the membrane potential as the external driving force (PubMed:28712724, PubMed:28712726). In the TIM22 complex, required for the import of a subset of metabolite carriers into mitochondria, such as ANT1/SLC25A4 and SLC25A24, while it is not required for the import of TIMM23 (PubMed:28712724). Overexpression increases the formation and secretion of LPA, resulting in transactivation of EGFR and activation of the downstream MAPK signaling pathway, leading to increased cell growth (PubMed:15939762)","subcellular_location":"Mitochondrion inner membrane; Mitochondrion intermembrane space","url":"https://www.uniprot.org/uniprotkb/Q53H12/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/AGK","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CBX1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/AGK","total_profiled":1310},"omim":[{"mim_id":"621332","title":"WILMS TUMOR 7; WT7","url":"https://www.omim.org/entry/621332"},{"mim_id":"618383","title":"NEURODEVELOPMENTAL DISORDER WITH PROGRESSIVE MOVEMENT ABNORMALITIES, COGNITIVE DECLINE, AND BRAIN ABNORMALITIES; NEDMCB","url":"https://www.omim.org/entry/618383"},{"mim_id":"618181","title":"ZINC FINGER- AND BTB DOMAIN-CONTAINING PROTEIN 11; ZBTB11","url":"https://www.omim.org/entry/618181"},{"mim_id":"614691","title":"CATARACT 38; CTRCT38","url":"https://www.omim.org/entry/614691"},{"mim_id":"610345","title":"ACYLGLYCEROL KINASE; AGK","url":"https://www.omim.org/entry/610345"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Mitochondria","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/AGK"},"hgnc":{"alias_symbol":["FLJ10842"],"prev_symbol":["MULK"]},"alphafold":{"accession":"Q53H12","domains":[{"cath_id":"3.40.50.10330","chopping":"26-185","consensus_level":"high","plddt":92.3704,"start":26,"end":185},{"cath_id":"2.60.200.40","chopping":"207-259_301-401","consensus_level":"high","plddt":88.0825,"start":207,"end":401}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q53H12","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q53H12-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q53H12-F1-predicted_aligned_error_v6.png","plddt_mean":87.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=AGK","jax_strain_url":"https://www.jax.org/strain/search?query=AGK"},"sequence":{"accession":"Q53H12","fasta_url":"https://rest.uniprot.org/uniprotkb/Q53H12.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q53H12/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q53H12"}},"corpus_meta":[{"pmid":"25208612","id":"PMC_25208612","title":"Sengers 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kinase.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15252046","citation_count":53,"is_preprint":false},{"pmid":"25960215","id":"PMC_25960215","title":"miR-194 regulated AGK and inhibited cell proliferation of oral squamous cell carcinoma by reducing PI3K-Akt-FoxO3a signaling.","date":"2015","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/25960215","citation_count":50,"is_preprint":false},{"pmid":"30924609","id":"PMC_30924609","title":"AGK-BRAF is associated with distant metastasis and younger age in pediatric papillary thyroid carcinoma.","date":"2019","source":"Pediatric blood & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30924609","citation_count":37,"is_preprint":false},{"pmid":"32202634","id":"PMC_32202634","title":"The role of AGK in thrombocytopoiesis and possible therapeutic strategies.","date":"2020","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/32202634","citation_count":33,"is_preprint":false},{"pmid":"35547757","id":"PMC_35547757","title":"AGK regulates the progression to NASH by affecting mitochondria complex I function.","date":"2022","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/35547757","citation_count":31,"is_preprint":false},{"pmid":"25474138","id":"PMC_25474138","title":"AGK enhances angiogenesis and inhibits apoptosis via activation of the NF-κB signaling pathway in hepatocellular carcinoma.","date":"2014","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/25474138","citation_count":31,"is_preprint":false},{"pmid":"38750075","id":"PMC_38750075","title":"GPC3-targeted CAR-T cells expressing GLUT1 or AGK exhibit enhanced antitumor activity against hepatocellular carcinoma.","date":"2024","source":"Acta pharmacologica 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biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10632732","citation_count":14,"is_preprint":false},{"pmid":"37354892","id":"PMC_37354892","title":"Sengers syndrome and AGK-related disorders - Minireview of phenotypic variability and clinical outcomes in molecularly confirmed cases.","date":"2023","source":"Molecular genetics and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/37354892","citation_count":12,"is_preprint":false},{"pmid":"31390548","id":"PMC_31390548","title":"AGK Unleashes CD8+ T Cell Glycolysis to Combat Tumor Growth.","date":"2019","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/31390548","citation_count":11,"is_preprint":false},{"pmid":"34948281","id":"PMC_34948281","title":"Characterization of a Novel Splicing Variant in Acylglycerol Kinase (AGK) Associated with Fatal Sengers Syndrome.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34948281","citation_count":10,"is_preprint":false},{"pmid":"34164355","id":"PMC_34164355","title":"Case Report: Two Chinese Infants of Sengers Syndrome Caused by Mutations in AGK Gene.","date":"2021","source":"Frontiers in pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/34164355","citation_count":10,"is_preprint":false},{"pmid":"30657560","id":"PMC_30657560","title":"MiR-610 functions as a tumor suppressor in oral squamous cell carcinoma by directly targeting AGK.","date":"2019","source":"European review for medical and pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30657560","citation_count":7,"is_preprint":false},{"pmid":"35635053","id":"PMC_35635053","title":"Circ_0008068 facilitates the oral squamous cell carcinoma development by microRNA-153-3p/acylgycerol kinase (AGK) 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Case reports","url":"https://pubmed.ncbi.nlm.nih.gov/34316732","citation_count":5,"is_preprint":false},{"pmid":"33562578","id":"PMC_33562578","title":"A Multifocal Pediatric Papillary Thyroid Carcinoma (PTC) Harboring the AGK-BRAF and RET/PTC3 Fusion in a Mutually Exclusive Pattern Reveals Distinct Levels of Genomic Instability and Nuclear Organization.","date":"2021","source":"Biology","url":"https://pubmed.ncbi.nlm.nih.gov/33562578","citation_count":4,"is_preprint":false},{"pmid":"37051931","id":"PMC_37051931","title":"AGK Potentiates Arterial Thrombosis by Affecting Talin-1 and αIIbβ3-Mediated Bidirectional Signaling Pathway.","date":"2023","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/37051931","citation_count":2,"is_preprint":false},{"pmid":"40189647","id":"PMC_40189647","title":"MEK inhibitors for the treatment of immunotherapy-resistant, AGK-BRAF fusion advanced acral melanoma: a case report and literature review.","date":"2025","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40189647","citation_count":2,"is_preprint":false},{"pmid":"38056763","id":"PMC_38056763","title":"Interaction of ROMK2 channel with lipid kinases DGKE and AGK: Potential channel activation by localized anionic lipid synthesis.","date":"2023","source":"Biochimica et biophysica acta. Molecular and cell biology of lipids","url":"https://pubmed.ncbi.nlm.nih.gov/38056763","citation_count":2,"is_preprint":false},{"pmid":"39636206","id":"PMC_39636206","title":"Aberrantly Expressed Mitochondrial Lipid Kinase, AGK, Activates JAK2-Histone H3 Axis and BCR Signal: A Mechanistic Study with Implication in CLL Therapy.","date":"2025","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/39636206","citation_count":1,"is_preprint":false},{"pmid":"39594764","id":"PMC_39594764","title":"Netupitant Inhibits the Proliferation of Breast Cancer Cells by Targeting AGK.","date":"2024","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/39594764","citation_count":0,"is_preprint":false},{"pmid":"41249571","id":"PMC_41249571","title":"A long non-coding RNA SCAMP1 induces pancreatic ductal adenocarcinoma progression through miR-106a-5p/AGK signaling.","date":"2025","source":"Clinical and experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41249571","citation_count":0,"is_preprint":false},{"pmid":"39824030","id":"PMC_39824030","title":"Novel c.221+1dup pathogenic variant in AGK gene linked to Sengers syndrome.","date":"2024","source":"Neuromuscular disorders : NMD","url":"https://pubmed.ncbi.nlm.nih.gov/39824030","citation_count":0,"is_preprint":false},{"pmid":"41995619","id":"PMC_41995619","title":"Effects of AGK-2 treatment on sirtuin-2, oxidative stress and apoptosis in ageing pancreatic tissue of rats.","date":"2026","source":"Archives of physiology and biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41995619","citation_count":0,"is_preprint":false},{"pmid":"41496283","id":"PMC_41496283","title":"Generation of a pluripotent human AGK knockout embryonic stem cell model (WAe009-A-3C) of Sengers syndrome.","date":"2025","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/41496283","citation_count":0,"is_preprint":false},{"pmid":"41695748","id":"PMC_41695748","title":"Case Report: Sengers syndrome caused by a novel 7.6 kb AGK deletion misdiagnosed as isolated congenital cataract.","date":"2026","source":"Frontiers in pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/41695748","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.02.06.636895","title":"Targeting BRAF kinase fusions with pan-RAF and vertical MAPK inhibition","date":"2025-02-08","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.06.636895","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19159,"output_tokens":3222,"usd":0.052903},"stage2":{"model":"claude-opus-4-6","input_tokens":6605,"output_tokens":2967,"usd":0.1608},"total_usd":0.213703,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"AGK (named MuLK) is a multi-substrate lipid kinase that phosphorylates diacylglycerol, ceramide, and 1-acylglycerol but not sphingosine; it co-fractionates with membranes and localizes to an internal membrane compartment; its activity is inhibited by sphingosine, enhanced by cardiolipin, stimulated by calcium at low magnesium, and inhibited by calcium at high magnesium concentrations.\",\n      \"method\": \"In vitro enzymatic assay with recombinant protein, subcellular fractionation, membrane localization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with recombinant enzyme, substrate specificity profiling, and localization by fractionation\",\n      \"pmids\": [\"15252046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"AGK binds to JAK2 in megakaryocytes/platelets independent of its kinase activity (G126E kinase-dead mutation does not affect platelet counts or megakaryocyte differentiation), and JAK2 V617F mutation enhances AGK-JAK2 binding and greatly facilitates JAK2/Stat3 signaling in response to thrombopoietin; AGK-deficient mice develop thrombocytopenia due to defective bone marrow thrombocytopoiesis.\",\n      \"method\": \"Co-immunoprecipitation, megakaryocyte/platelet-specific AGK knockout mice, kinase-dead AGK G126E knock-in mice, platelet functional assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, multiple genetic models (KO + knock-in), defined cellular phenotype with pathway placement\",\n      \"pmids\": [\"32202634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"AGK interacts with mitochondrial respiratory chain complex I subunits NDUFS2 and NDUFA10 via its DGK domain (kinase-independent) to maintain complex I function and hepatic mitochondrial integrity; AGK deficiency (but not kinase-dead G126E mutation) causes mitochondrial dysfunction, fatty acid metabolism dysregulation, and NASH progression.\",\n      \"method\": \"Hepatocyte-specific AGK knockout mice, AGK G126E knock-in mice, co-immunoprecipitation, dietary NASH models (CDAHFD, MCD)\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, multiple genetic models (KO + kinase-dead knock-in), defined pathway with domain mapping\",\n      \"pmids\": [\"35547757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ZDHHC2-mediated S-palmitoylation of AGK promotes its translocation from mitochondria to the plasma membrane, where it activates the PI3K-AKT-mTOR signaling pathway and reduces sunitinib sensitivity in clear cell renal cell carcinoma.\",\n      \"method\": \"Palmitoylation assay, subcellular fractionation, signaling pathway analysis, cell and mouse models of sunitinib resistance\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct palmitoylation assay, localization by fractionation linked to functional signaling outcome, in vivo validation\",\n      \"pmids\": [\"37078777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"AGK promotes Talin-1 Ser425 phosphorylation in a kinase-activity-dependent manner, affecting αIIbβ3-mediated bidirectional signaling in platelets; this is independent of AGK's lipid synthesis (phosphatidic acid/lysophosphatidic acid) activity in platelets, and AGK deficiency or kinase-dead mutation reduces platelet aggregation, granule secretion, and delays arterial thrombus formation.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, immunofluorescence, Western blot, platelet-specific knockout and kinase-dead knock-in mice, in vivo thrombosis models\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP/MS identification of Talin-1, multiple genetic models, phosphorylation site mapping, in vivo thrombosis assays\",\n      \"pmids\": [\"37051931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AGK forms a complex with HSP90 and JAK2 in CLL cells, promoting aberrant constitutive JAK2 activation independent of cytokine signaling; AGK is detected in nuclear localization associated with JAK2 in some CLL cells; JAK2 phosphorylates histone H3(Y41) (non-canonical substrate) but not STAT3, activating gene transcription; JAK2 also activates BCR signaling via LYN/BTK axis.\",\n      \"method\": \"Co-immunoprecipitation, biochemical and molecular biology assays in primary CLL cells, nuclear fractionation\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP in primary patient cells, nuclear localization by fractionation, mechanistic pathway dissection; single study\",\n      \"pmids\": [\"39636206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"AGK (acylglycerol kinase) is present in a proximity complex with the ROMK2 channel in mitochondria, confirmed by co-immunoprecipitation; the AGK products lysophosphatidic acid and phosphatidic acid stimulate ROMK2 channel activity in artificial lipid bilayers, suggesting localized lipid synthesis by channel-bound AGK regulates ROMK2 activity.\",\n      \"method\": \"TurboID proximity labeling, co-immunoprecipitation, artificial lipid bilayer electrophysiology, molecular docking\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular and cell biology of lipids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — proximity labeling + Co-IP + functional bilayer assay; single study with multiple orthogonal methods\",\n      \"pmids\": [\"38056763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"AGK promotes glycolytic metabolism and effector function of CD8+ T cells by inactivating PTEN and boosting mTOR activity, thereby enhancing antitumor CD8+ T cell activity.\",\n      \"method\": \"Genetic loss-of-function and overexpression in CD8+ T cells, signaling pathway analysis (PTEN/mTOR)\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined signaling mechanism (PTEN inactivation, mTOR activation) with functional T cell phenotype; cited as summary of primary work by Hu et al. 2019\",\n      \"pmids\": [\"31390548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"AGK overexpression in hepatocellular carcinoma enhances angiogenesis and inhibits apoptosis via activation of NF-κB signaling; silencing AGK reverses these effects in vitro and reduces tumorigenicity in vivo.\",\n      \"method\": \"AGK overexpression and knockdown in HCC cell lines, in vitro angiogenesis/apoptosis assays, xenograft mouse model, NF-κB pathway analysis\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — defined signaling pathway (NF-κB) with loss- and gain-of-function, but NF-κB mechanism not biochemically dissected\",\n      \"pmids\": [\"25474138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AGK is a component of the TIM22 complex in the inner mitochondrial membrane, mediating import of a subset of membrane proteins; AGK mutations alter both phospholipid metabolism and mitochondrial protein biogenesis; patient fibroblasts with a novel AGK splicing variant show decreased oxygen consumption rate and reduced OXPHOS complex I and V activity.\",\n      \"method\": \"Patient fibroblast functional assays (OCR, ECAR measurements by Seahorse), spectrophotometric OXPHOS complex activity, cDNA splicing analysis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional mitochondrial assays with patient cells, splicing validated in vitro; single study\",\n      \"pmids\": [\"34948281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In gastric cancer, YAP1 transcriptionally induces AGK expression through TEAD binding to the AGK promoter; AGK in turn inhibits Hippo pathway proteins and induces YAP1 nuclear localization, forming a positive feedback loop (YAP1-AGK loop).\",\n      \"method\": \"ChIP/promoter binding assay, knockdown/overexpression in gastric cancer cells, Hippo pathway signaling analysis, nuclear localization assay\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — TEAD-promoter binding shown, feedback loop established by KD/OE with pathway readouts; single study\",\n      \"pmids\": [\"32827244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"AGK directly promotes PI3K/AKT/FoxO3a signaling in oral squamous cell carcinoma cells; miR-194 suppresses AGK and thereby reduces cyclin D1 and increases p21 expression via this pathway.\",\n      \"method\": \"miRNA overexpression/inhibition, AGK knockdown, PI3K/AKT/FoxO3a pathway signaling analysis in OSCC cell lines\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — signaling pathway placement by KD/OE, no direct biochemical mechanism for AGK-PI3K interaction\",\n      \"pmids\": [\"25960215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Netupitant binds to the ATP-binding region of AGK (confirmed by molecular dynamics simulations and binding affinity assays), inhibits AGK kinase activity, reduces PTEN phosphorylation, and suppresses PI3K/AKT/mTOR pathway activation in breast cancer cells.\",\n      \"method\": \"Molecular dynamics simulation, binding affinity (BIL assay), siRNA knockdown, in vitro proliferation/apoptosis assays, xenograft mouse model\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4/3 — binding is primarily computational with binding assay; kinase inhibition not directly measured by enzymatic assay\",\n      \"pmids\": [\"39594764\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AGK is a mitochondrial membrane-associated multi-substrate lipid kinase (phosphorylating diacylglycerol, monoacylglycerol, and ceramide to generate phosphatidic acid and lysophosphatidic acid) that also functions kinase-independently as a structural component of the TIM22 inner mitochondrial membrane protein import complex; it interacts with JAK2 to modulate megakaryocyte/platelet development and JAK2-STAT3 signaling, interacts with mitochondrial complex I subunits NDUFS2/NDUFA10 to maintain respiratory chain integrity, can be palmitoylated by ZDHHC2 to translocate to the plasma membrane and activate AKT-mTOR signaling, and promotes platelet activation by phosphorylating Talin-1 Ser425 to regulate αIIbβ3 bidirectional signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"AGK is a mitochondrial membrane-associated lipid kinase with dual kinase-dependent and kinase-independent functions spanning lipid metabolism, mitochondrial protein import, signal transduction, and platelet biology. As a multi-substrate lipid kinase, AGK phosphorylates diacylglycerol, monoacylglycerol, and ceramide to generate phosphatidic acid and lysophosphatidic acid, with activity modulated by cardiolipin and divalent cations [PMID:15252046]; it also serves as a structural subunit of the TIM22 inner mitochondrial membrane protein import complex, where AGK mutations impair OXPHOS complex I and V activity [PMID:34948281]. Independent of its kinase activity, AGK binds JAK2 via a kinase-independent interaction to support megakaryopoiesis and thrombopoietin-driven JAK2/STAT3 signaling, and interacts with complex I subunits NDUFS2/NDUFA10 to maintain mitochondrial respiratory chain integrity [PMID:32202634, PMID:35547757]. AGK also functions as a protein kinase that phosphorylates Talin-1 at Ser425 to regulate αIIbβ3 integrin bidirectional signaling in platelets, and can be palmitoylated by ZDHHC2 to relocalize to the plasma membrane where it activates PI3K-AKT-mTOR signaling [PMID:37051931, PMID:37078777].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"The fundamental enzymatic identity of AGK was established as a multi-substrate lipid kinase with broad specificity toward diacylglycerol, ceramide, and monoacylglycerol, resolving its biochemical activity and membrane association.\",\n      \"evidence\": \"In vitro enzymatic assay with recombinant AGK, substrate specificity profiling, subcellular fractionation\",\n      \"pmids\": [\"15252046\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Physiological lipid substrates in vivo not determined\",\n        \"Subcellular membrane compartment identity not resolved beyond 'internal membranes'\",\n        \"No structural model of the active site\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"AGK was linked to oncogenic signaling beyond lipid metabolism, with overexpression in hepatocellular carcinoma activating NF-κB signaling to promote angiogenesis and inhibit apoptosis.\",\n      \"evidence\": \"AGK overexpression and knockdown in HCC cell lines, xenograft model, NF-κB pathway analysis\",\n      \"pmids\": [\"25474138\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct biochemical mechanism linking AGK to NF-κB not established\",\n        \"Unclear whether lipid kinase activity is required for NF-κB activation\",\n        \"Single study without independent replication\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"AGK was shown to regulate CD8+ T cell metabolism and antitumor function through inactivation of PTEN and enhancement of mTOR activity, revealing a role in adaptive immunity.\",\n      \"evidence\": \"Genetic loss-of-function and overexpression in CD8+ T cells, PTEN/mTOR signaling analysis\",\n      \"pmids\": [\"31390548\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism of PTEN inactivation by AGK not biochemically defined\",\n        \"Whether lipid kinase products or a kinase-independent function drives the effect is unknown\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"A major conceptual advance established that AGK has kinase-independent scaffolding functions: AGK binds JAK2 in megakaryocytes independent of its kinase activity to support thrombopoiesis, and the JAK2 V617F oncogenic mutation enhances this interaction, linking AGK to myeloproliferative signaling.\",\n      \"evidence\": \"Reciprocal Co-IP, megakaryocyte/platelet-specific AGK knockout and kinase-dead G126E knock-in mice, platelet functional assays\",\n      \"pmids\": [\"32202634\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of AGK-JAK2 interaction not resolved\",\n        \"Whether AGK-JAK2 interaction is direct or mediated by adaptor proteins not fully excluded\",\n        \"Role in human Sengers syndrome thrombopoiesis not addressed\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"AGK was confirmed as a subunit of the TIM22 mitochondrial protein import complex, and patient-derived AGK mutations were shown to impair OXPHOS complex I and V activity, linking its structural role to mitochondrial bioenergetics.\",\n      \"evidence\": \"Patient fibroblast OCR/ECAR measurements, spectrophotometric OXPHOS complex activity assays, cDNA splicing validation\",\n      \"pmids\": [\"34948281\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Which TIM22 substrates are specifically affected by AGK loss not catalogued\",\n        \"Relative contribution of lipid kinase versus TIM22 scaffold function to OXPHOS defects not dissected\",\n        \"Single patient variant studied\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The kinase-independent scaffolding concept was extended to the respiratory chain: AGK interacts with complex I subunits NDUFS2 and NDUFA10 via its DGK domain to maintain complex I function in hepatocytes, with AGK deficiency (but not kinase-dead mutation) causing NASH progression.\",\n      \"evidence\": \"Hepatocyte-specific AGK knockout and G126E knock-in mice, reciprocal Co-IP, dietary NASH models\",\n      \"pmids\": [\"35547757\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether AGK-complex I interaction is direct or mediated through TIM22 import of complex I subunits is ambiguous\",\n        \"Stoichiometry and stability of AGK-NDUFS2/NDUFA10 complex not characterized\",\n        \"Relevance to human NASH not tested\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Two discoveries in 2023 expanded AGK's functional repertoire: ZDHHC2-mediated palmitoylation was shown to redirect AGK from mitochondria to the plasma membrane to activate AKT-mTOR signaling, and AGK was found to function as a protein kinase phosphorylating Talin-1 Ser425 to regulate integrin bidirectional signaling in platelets.\",\n      \"evidence\": \"Palmitoylation assay with subcellular fractionation and sunitinib resistance models (PMID:37078777); Co-IP/MS, phosphosite mapping, platelet-specific KO and kinase-dead KI mice with in vivo thrombosis assays (PMID:37051931)\",\n      \"pmids\": [\"37078777\", \"37051931\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Talin-1 phosphorylation by AGK not reconstituted with purified components\",\n        \"Palmitoylation-dependent relocalization not confirmed in non-cancer cell types\",\n        \"How AGK switches between lipid kinase and protein kinase activity is unknown\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"AGK lipid products were linked to regulation of mitochondrial ion channels: AGK associates with ROMK2 in a proximity complex, and its products LPA and PA directly stimulate ROMK2 channel activity, suggesting localized lipid synthesis regulates channel function.\",\n      \"evidence\": \"TurboID proximity labeling, Co-IP, artificial lipid bilayer electrophysiology\",\n      \"pmids\": [\"38056763\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequence of ROMK2 regulation by AGK-derived lipids in intact mitochondria not shown\",\n        \"Single study without genetic validation in cells\",\n        \"Whether AGK is obligate for ROMK2 activity or merely modulatory is unclear\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"AGK-HSP90-JAK2 complex formation was demonstrated in CLL cells, driving constitutive cytokine-independent JAK2 activation and non-canonical histone H3Y41 phosphorylation with nuclear AGK-JAK2 co-localization, broadening AGK's scaffolding role to hematologic malignancy.\",\n      \"evidence\": \"Co-IP in primary CLL patient cells, nuclear fractionation, BCR signaling analysis\",\n      \"pmids\": [\"39636206\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"AGK-HSP90-JAK2 complex stoichiometry and directness of AGK-HSP90 interaction not resolved\",\n        \"Nuclear AGK localization observed only by fractionation, not by imaging\",\n        \"Single study in primary CLL cells without genetic manipulation of AGK\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How AGK coordinates its dual lipid kinase, protein kinase, and kinase-independent scaffolding activities — and what determines substrate selection and subcellular targeting — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No crystal structure or cryo-EM structure of AGK available\",\n        \"Mechanism governing switch between lipid and protein kinase activities unknown\",\n        \"Relative contributions of TIM22 scaffold vs. lipid kinase function to Sengers syndrome phenotype not dissected in vivo\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 2, 6, 9]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 3, 5, 7, 8, 10]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 6]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [2, 9]}\n    ],\n    \"complexes\": [\n      \"TIM22 complex\"\n    ],\n    \"partners\": [\n      \"JAK2\",\n      \"NDUFS2\",\n      \"NDUFA10\",\n      \"TLN1\",\n      \"HSP90\",\n      \"ZDHHC2\",\n      \"ROMK2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}