{"gene":"AGK","run_date":"2026-06-09T22:02:42","timeline":{"discoveries":[{"year":2004,"finding":"AGK (MuLK) is a novel 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 despite being predicted soluble; activity is inhibited by sphingosine, enhanced by cardiolipin, stimulated by calcium at low magnesium, and inhibited by calcium at high magnesium.","method":"Recombinant protein in vitro kinase assays with multiple substrates, subcellular fractionation, immunolocalization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro enzymatic reconstitution with multiple substrates, fractionation, and systematic pharmacological characterization in a single focused study","pmids":["15252046"],"is_preprint":false},{"year":2020,"finding":"AGK binds JAK2 in megakaryocytes/platelets independent of its kinase activity; the JAK2 V617F mutation dramatically enhances AGK-JAK2 binding and facilitates JAK2/Stat3 signaling in response to thrombopoietin; AGK-specific deletion causes thrombocytopenia and inefficient thrombocytopoiesis, while the kinase-dead G126E mutation does not affect platelet counts, demonstrating that AGK's role in megakaryocyte development is kinase-independent.","method":"Co-immunoprecipitation, megakaryocyte/platelet-specific knockout mice, AGK G126E kinase-dead knock-in mice, platelet count analysis, JAK2/Stat3 signaling assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP combined with genetic mouse models (KO and kinase-dead knock-in) with clear cellular phenotype and 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 to maintain complex I function and hepatic mitochondrial integrity; this function is kinase-independent, as AGK G126E kinase-dead mice do not develop NASH, while hepatic AGK knockout mice develop severe NASH with mitochondrial dysfunction.","method":"Hepatocyte-specific AGK knockout mice, AGK G126E knock-in mice, co-immunoprecipitation, high-fat diet NASH models, mitochondrial function assays","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, domain mapping, two genetic mouse models (KO vs kinase-dead knock-in) with orthogonal phenotypic readouts establishing kinase-independent mechanism","pmids":["35547757"],"is_preprint":false},{"year":2023,"finding":"ZDHHC2-mediated S-palmitoylation of AGK promotes its translocation from mitochondria to the plasma membrane and activates PI3K-AKT-mTOR signaling in clear cell renal cell carcinoma, contributing to sunitinib resistance.","method":"Palmitoylation assays, subcellular fractionation, PI3K-AKT-mTOR pathway analysis, cell-based sunitinib resistance models, mouse xenograft models","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct palmitoylation assay and fractionation showing membrane translocation linked to signaling, single lab with two orthogonal methods","pmids":["37078777"],"is_preprint":false},{"year":2023,"finding":"AGK promotes Talin-1 Ser425 phosphorylation through its kinase activity, affecting αIIbβ3-mediated bidirectional signaling in platelets, thereby potentiating platelet activation and arterial thrombus formation; AGK does not affect phosphatidic acid/lysophosphatidic acid lipid synthesis in platelets.","method":"Co-immunoprecipitation, mass spectrometry, immunofluorescence, Western blot for pTalin-1, platelet aggregation assays, in vivo thrombosis models, AGK-deficient and G126E knock-in mice","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus mass spectrometry identifying Talin-1 as substrate, kinase-dead knock-in separating kinase-dependent from independent functions, single lab","pmids":["37051931"],"is_preprint":false},{"year":2025,"finding":"In CLL cells, aberrantly expressed AGK forms a complex with HSP90 and JAK2, activating JAK2 independent of cytokine stimulation; AGK-activated JAK2 phosphorylates histone H3 at Y41 (a non-canonical substrate) rather than STAT3, activating diverse gene transcription programs; AGK also shows nuclear localization in association with JAK2 in CLL cells.","method":"Co-immunoprecipitation, biochemical fractionation (nuclear localization), Western blot for pHistone H3(Y41), JAK2 inhibition experiments, apoptosis assays in primary CLL cells","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP showing AGK-HSP90-JAK2 complex with functional readout of H3Y41 phosphorylation; single lab with multiple biochemical methods","pmids":["39636206"],"is_preprint":false},{"year":2023,"finding":"AGK is present in a proximal complex with the ROMK2 potassium channel in mitochondria, confirmed by co-immunoprecipitation; the AGK product lysophosphatidic acid (LPA) stimulates ROMK2 channel activity in artificial lipid bilayers, suggesting localized lipid synthesis by 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 / Moderate — proximity labeling plus Co-IP confirming complex, plus in vitro bilayer functional assay with LPA product; single lab","pmids":["38056763"],"is_preprint":false},{"year":2020,"finding":"AGK expression is transcriptionally induced by YAP1/TEAD binding to the AGK promoter; in turn, AGK inhibits Hippo pathway kinases and promotes YAP1 nuclear localization, forming a positive feedback loop in gastric cancer cells.","method":"Luciferase reporter assay with TEAD binding site in AGK promoter, ChIP or promoter analysis, YAP1 nuclear localization imaging, knockdown/overexpression with Hippo pathway readouts","journal":"Journal of cellular and molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, promoter reporter and localization assay but limited mechanistic detail in abstract; mechanism of AGK inhibiting Hippo kinases not directly established","pmids":["32827244"],"is_preprint":false},{"year":2015,"finding":"AGK directly activates PI3K-AKT-FoxO3a signaling in oral squamous cell carcinoma cells; miR-194 suppresses OSCC proliferation by directly targeting AGK and reducing this pathway, decreasing cyclin D1 and increasing p21 expression.","method":"miRNA overexpression/inhibition, Western blot for PI3K/AKT/FoxO3a pathway components, cell proliferation assays","journal":"Biomedicine & pharmacotherapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, indirect pathway readout without direct biochemical demonstration of AGK-PI3K interaction","pmids":["25960215"],"is_preprint":false},{"year":2014,"finding":"AGK overexpression enhances angiogenesis and inhibits apoptosis in hepatocellular carcinoma cells in part via activation of NF-κB signaling; AGK knockdown has the opposite effects.","method":"AGK overexpression/knockdown in HCC cell lines, in vitro angiogenesis assays, apoptosis assays, NF-κB reporter/pathway analysis, in vivo xenograft","journal":"Oncotarget","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway activation inferred from downstream readouts without direct biochemical demonstration of AGK-NF-κB interaction","pmids":["25474138"],"is_preprint":false},{"year":2024,"finding":"Netupitant binds the ATP-binding region of AGK (confirmed by molecular dynamics simulation and biolayer interferometry), inhibits AGK kinase activity, and reduces PTEN phosphorylation, thereby suppressing PI3K/AKT/mTOR pathway activation and inducing apoptosis in breast cancer cells.","method":"Molecular dynamics simulation, biolayer interferometry (BIL) binding assay, siRNA knockdown, cell viability assays, xenograft mouse model, Western blot for PI3K/AKT/mTOR pathway","journal":"Cancers","confidence":"Low","confidence_rationale":"Tier 3 / Weak — binding assay and in vitro/in vivo pharmacology but mechanism of PTEN phosphorylation by AGK not directly demonstrated; single lab","pmids":["39594764"],"is_preprint":false}],"current_model":"AGK is a mitochondrial multi-substrate lipid kinase that phosphorylates diacylglycerol, monoacylglycerol, and ceramide to produce phosphatidic acid and lysophosphatidic acid; beyond its enzymatic role, AGK functions as a kinase-independent structural component of the TIM22 mitochondrial import complex and interacts with complex I subunits (NDUFS2, NDUFA10) to maintain mitochondrial respiratory chain integrity; AGK also binds JAK2 to regulate megakaryocyte differentiation and platelet biogenesis (kinase-independent), promotes Talin-1 Ser425 phosphorylation to potentiate platelet activation (kinase-dependent), can be S-palmitoylated by ZDHHC2 to translocate to the plasma membrane and activate PI3K-AKT-mTOR signaling, and in CLL cells forms a complex with HSP90-JAK2 to drive non-canonical histone H3(Y41) phosphorylation and gene transcription."},"narrative":{"mechanistic_narrative":"AGK is a mitochondrial multi-substrate lipid kinase that phosphorylates diacylglycerol, ceramide, and monoacylglycerol—but not sphingosine—to generate phosphatidic and lysophosphatidic acid, with activity modulated by cardiolipin, sphingosine, and calcium/magnesium ratios [PMID:15252046]. A defining feature emerging across genetic models is that AGK exerts several of its physiological roles independently of this catalytic activity, dissected through paired knockout and kinase-dead (G126E) mouse alleles: it stabilizes mitochondrial respiratory chain complex I by binding the NDUFS2 and NDUFA10 subunits through its DGK domain, with loss of AGK—but not loss of kinase activity—causing mitochondrial dysfunction and hepatic NASH [PMID:35547757], and it binds JAK2 to support thrombopoietin-driven megakaryocyte differentiation and platelet production, a role abolished by AGK deletion but preserved in kinase-dead animals [PMID:32202634]. AGK's kinase activity is separately deployed in platelets to phosphorylate Talin-1 at Ser425 and potentiate αIIbβ3 integrin signaling and thrombus formation, without affecting bulk platelet lipid synthesis [PMID:37051931]. In disease contexts AGK is co-opted to drive oncogenic signaling: ZDHHC2-mediated S-palmitoylation relocates AGK from mitochondria to the plasma membrane to activate PI3K-AKT-mTOR signaling [PMID:37078777], and in CLL cells aberrant AGK assembles with HSP90 and JAK2 to activate JAK2 in a cytokine-independent manner, directing non-canonical histone H3(Y41) phosphorylation and transcriptional reprogramming [PMID:39636206]. Additional functions—local regulation of the mitochondrial ROMK2 channel via LPA production [PMID:38056763]—extend its role at the interface of mitochondrial lipid metabolism and membrane signaling.","teleology":[{"year":2004,"claim":"Established AGK's fundamental biochemical identity—answering whether it was an enzyme and on what substrates—by defining it as a membrane-associated multi-substrate lipid kinase.","evidence":"Recombinant in vitro kinase assays across multiple lipid substrates with fractionation and pharmacological profiling","pmids":["15252046"],"confidence":"High","gaps":["Did not resolve the physiological in vivo substrate(s)","Internal membrane compartment identity not precisely defined","No structural basis for substrate selectivity"]},{"year":2020,"claim":"Revealed that AGK has a kinase-independent function, binding JAK2 to drive megakaryocyte development, separating its enzymatic role from a structural/signaling role.","evidence":"Reciprocal Co-IP plus megakaryocyte/platelet-specific knockout and G126E kinase-dead knock-in mice with platelet phenotyping","pmids":["32202634"],"confidence":"High","gaps":["Structural basis of AGK-JAK2 interaction not defined","How JAK2 V617F enhances binding mechanistically unresolved","Whether mitochondrial localization is required for JAK2 binding unclear"]},{"year":2022,"claim":"Demonstrated AGK maintains respiratory chain complex I integrity through direct, kinase-independent binding to NDUFS2 and NDUFA10, explaining its mitochondrial structural role.","evidence":"Reciprocal Co-IP with DGK-domain mapping plus hepatocyte-specific knockout vs kinase-dead knock-in mice in NASH models","pmids":["35547757"],"confidence":"High","gaps":["Stoichiometry and assembly step of AGK within complex I biogenesis not defined","No structural model of the AGK-NDUFS2/NDUFA10 interface","Tissue-specificity of the complex I requirement unresolved"]},{"year":2023,"claim":"Identified a kinase-dependent substrate of AGK—Talin-1 Ser425—linking its catalytic activity to integrin-mediated platelet activation rather than bulk lipid synthesis.","evidence":"Co-IP and mass spectrometry substrate identification with G126E knock-in mice and in vivo thrombosis models","pmids":["37051931"],"confidence":"Medium","gaps":["Direct phosphotransfer to Talin-1 not reconstituted in vitro","Whether AGK acts as a protein kinase or via a lipid intermediate unclear","Single-lab finding"]},{"year":2023,"claim":"Showed that post-translational palmitoylation can reroute AGK out of mitochondria to the plasma membrane to engage PI3K-AKT-mTOR signaling, establishing regulated relocalization as a functional switch.","evidence":"Palmitoylation assays, subcellular fractionation, and pathway analysis in ccRCC cells and xenografts","pmids":["37078777"],"confidence":"Medium","gaps":["Direct molecular link between membrane AGK and PI3K activation not defined","Whether kinase activity is required at the plasma membrane unclear","Single-lab finding"]},{"year":2023,"claim":"Connected AGK's lipid product to ion channel regulation, showing localized LPA synthesis modulates the mitochondrial ROMK2 channel.","evidence":"TurboID proximity labeling and Co-IP with artificial bilayer electrophysiology and docking","pmids":["38056763"],"confidence":"Medium","gaps":["In situ requirement of AGK for ROMK2 activity not shown genetically","Physiological consequence of ROMK2 modulation undefined","Single-lab finding"]},{"year":2025,"claim":"Defined a pathological non-canonical signaling axis in which AGK-HSP90-JAK2 complexes activate JAK2 to phosphorylate histone H3(Y41) and reprogram transcription, extending AGK's JAK2 partnership into the nucleus.","evidence":"Co-IP, nuclear fractionation, pH3(Y41) Western blots, and JAK2 inhibition/apoptosis assays in primary CLL cells","pmids":["39636206"],"confidence":"Medium","gaps":["Mechanism of AGK nuclear translocation not established","Whether AGK kinase activity contributes is unclear","Generality beyond CLL unknown"]},{"year":null,"claim":"It remains unresolved how AGK partitions between its kinase-dependent and kinase-independent functions and how its subcellular localization (mitochondria, plasma membrane, nucleus) is coordinated across cell types.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model linking lipid-kinase and scaffold functions","Regulators governing AGK relocalization incompletely mapped","Direct vs indirect nature of several signaling outputs (PI3K, NF-κB, Hippo) not biochemically established"]}],"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]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,2,3,6]},{"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-1430728","term_label":"Metabolism","supporting_discovery_ids":[0]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,3,5]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[1,4]}],"complexes":["TIM22 mitochondrial import complex","respiratory chain complex I","AGK-HSP90-JAK2 complex"],"partners":["JAK2","NDUFS2","NDUFA10","TLN1","HSP90","ZDHHC2","ROMK2"],"other_free_text":[]}},"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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Response to MEK Inhibition in an AGK-BRAF Gene Fusion Driven Carcinoma: Case Report and Literature Review.","date":"2022","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/34969747","citation_count":7,"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) axis.","date":"2022","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/35635053","citation_count":6,"is_preprint":false},{"pmid":"34773510","id":"PMC_34773510","title":"Complete genome sequence of a novel mitovirus from binucleate Rhizoctonia AG-K strain 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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":3,"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":"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":"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":"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":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":"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":"42100208","id":"PMC_42100208","title":"Genomic profiling of a DICER1-wildtype thyroblastoma reveals AGK-BRAF fusion, EIF1AX duplication, and TERT promoter mutations: integrated genomic and pathway analysis.","date":"2026","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/42100208","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":19964,"output_tokens":2985,"usd":0.052333,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10426,"output_tokens":3170,"usd":0.06569,"stage2_stop_reason":"end_turn"},"total_usd":0.118023,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"AGK (MuLK) is a novel 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 despite being predicted soluble; activity is inhibited by sphingosine, enhanced by cardiolipin, stimulated by calcium at low magnesium, and inhibited by calcium at high magnesium.\",\n      \"method\": \"Recombinant protein in vitro kinase assays with multiple substrates, subcellular fractionation, immunolocalization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro enzymatic reconstitution with multiple substrates, fractionation, and systematic pharmacological characterization in a single focused study\",\n      \"pmids\": [\"15252046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"AGK binds JAK2 in megakaryocytes/platelets independent of its kinase activity; the JAK2 V617F mutation dramatically enhances AGK-JAK2 binding and facilitates JAK2/Stat3 signaling in response to thrombopoietin; AGK-specific deletion causes thrombocytopenia and inefficient thrombocytopoiesis, while the kinase-dead G126E mutation does not affect platelet counts, demonstrating that AGK's role in megakaryocyte development is kinase-independent.\",\n      \"method\": \"Co-immunoprecipitation, megakaryocyte/platelet-specific knockout mice, AGK G126E kinase-dead knock-in mice, platelet count analysis, JAK2/Stat3 signaling assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP combined with genetic mouse models (KO and kinase-dead knock-in) with clear cellular phenotype and 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 to maintain complex I function and hepatic mitochondrial integrity; this function is kinase-independent, as AGK G126E kinase-dead mice do not develop NASH, while hepatic AGK knockout mice develop severe NASH with mitochondrial dysfunction.\",\n      \"method\": \"Hepatocyte-specific AGK knockout mice, AGK G126E knock-in mice, co-immunoprecipitation, high-fat diet NASH models, mitochondrial function assays\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, domain mapping, two genetic mouse models (KO vs kinase-dead knock-in) with orthogonal phenotypic readouts establishing kinase-independent mechanism\",\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 and activates PI3K-AKT-mTOR signaling in clear cell renal cell carcinoma, contributing to sunitinib resistance.\",\n      \"method\": \"Palmitoylation assays, subcellular fractionation, PI3K-AKT-mTOR pathway analysis, cell-based sunitinib resistance models, mouse xenograft models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct palmitoylation assay and fractionation showing membrane translocation linked to signaling, single lab with two orthogonal methods\",\n      \"pmids\": [\"37078777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"AGK promotes Talin-1 Ser425 phosphorylation through its kinase activity, affecting αIIbβ3-mediated bidirectional signaling in platelets, thereby potentiating platelet activation and arterial thrombus formation; AGK does not affect phosphatidic acid/lysophosphatidic acid lipid synthesis in platelets.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, immunofluorescence, Western blot for pTalin-1, platelet aggregation assays, in vivo thrombosis models, AGK-deficient and G126E knock-in mice\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus mass spectrometry identifying Talin-1 as substrate, kinase-dead knock-in separating kinase-dependent from independent functions, single lab\",\n      \"pmids\": [\"37051931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In CLL cells, aberrantly expressed AGK forms a complex with HSP90 and JAK2, activating JAK2 independent of cytokine stimulation; AGK-activated JAK2 phosphorylates histone H3 at Y41 (a non-canonical substrate) rather than STAT3, activating diverse gene transcription programs; AGK also shows nuclear localization in association with JAK2 in CLL cells.\",\n      \"method\": \"Co-immunoprecipitation, biochemical fractionation (nuclear localization), Western blot for pHistone H3(Y41), JAK2 inhibition experiments, apoptosis assays in primary CLL cells\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP showing AGK-HSP90-JAK2 complex with functional readout of H3Y41 phosphorylation; single lab with multiple biochemical methods\",\n      \"pmids\": [\"39636206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"AGK is present in a proximal complex with the ROMK2 potassium channel in mitochondria, confirmed by co-immunoprecipitation; the AGK product lysophosphatidic acid (LPA) stimulates ROMK2 channel activity in artificial lipid bilayers, suggesting localized lipid synthesis by 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 / Moderate — proximity labeling plus Co-IP confirming complex, plus in vitro bilayer functional assay with LPA product; single lab\",\n      \"pmids\": [\"38056763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"AGK expression is transcriptionally induced by YAP1/TEAD binding to the AGK promoter; in turn, AGK inhibits Hippo pathway kinases and promotes YAP1 nuclear localization, forming a positive feedback loop in gastric cancer cells.\",\n      \"method\": \"Luciferase reporter assay with TEAD binding site in AGK promoter, ChIP or promoter analysis, YAP1 nuclear localization imaging, knockdown/overexpression with Hippo pathway readouts\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, promoter reporter and localization assay but limited mechanistic detail in abstract; mechanism of AGK inhibiting Hippo kinases not directly established\",\n      \"pmids\": [\"32827244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"AGK directly activates PI3K-AKT-FoxO3a signaling in oral squamous cell carcinoma cells; miR-194 suppresses OSCC proliferation by directly targeting AGK and reducing this pathway, decreasing cyclin D1 and increasing p21 expression.\",\n      \"method\": \"miRNA overexpression/inhibition, Western blot for PI3K/AKT/FoxO3a pathway components, cell proliferation assays\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, indirect pathway readout without direct biochemical demonstration of AGK-PI3K interaction\",\n      \"pmids\": [\"25960215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"AGK overexpression enhances angiogenesis and inhibits apoptosis in hepatocellular carcinoma cells in part via activation of NF-κB signaling; AGK knockdown has the opposite effects.\",\n      \"method\": \"AGK overexpression/knockdown in HCC cell lines, in vitro angiogenesis assays, apoptosis assays, NF-κB reporter/pathway analysis, in vivo xenograft\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway activation inferred from downstream readouts without direct biochemical demonstration of AGK-NF-κB interaction\",\n      \"pmids\": [\"25474138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Netupitant binds the ATP-binding region of AGK (confirmed by molecular dynamics simulation and biolayer interferometry), inhibits AGK kinase activity, and reduces PTEN phosphorylation, thereby suppressing PI3K/AKT/mTOR pathway activation and inducing apoptosis in breast cancer cells.\",\n      \"method\": \"Molecular dynamics simulation, biolayer interferometry (BIL) binding assay, siRNA knockdown, cell viability assays, xenograft mouse model, Western blot for PI3K/AKT/mTOR pathway\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — binding assay and in vitro/in vivo pharmacology but mechanism of PTEN phosphorylation by AGK not directly demonstrated; single lab\",\n      \"pmids\": [\"39594764\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AGK is a mitochondrial multi-substrate lipid kinase that phosphorylates diacylglycerol, monoacylglycerol, and ceramide to produce phosphatidic acid and lysophosphatidic acid; beyond its enzymatic role, AGK functions as a kinase-independent structural component of the TIM22 mitochondrial import complex and interacts with complex I subunits (NDUFS2, NDUFA10) to maintain mitochondrial respiratory chain integrity; AGK also binds JAK2 to regulate megakaryocyte differentiation and platelet biogenesis (kinase-independent), promotes Talin-1 Ser425 phosphorylation to potentiate platelet activation (kinase-dependent), can be S-palmitoylated by ZDHHC2 to translocate to the plasma membrane and activate PI3K-AKT-mTOR signaling, and in CLL cells forms a complex with HSP90-JAK2 to drive non-canonical histone H3(Y41) phosphorylation and gene transcription.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"AGK is a mitochondrial multi-substrate lipid kinase that phosphorylates diacylglycerol, ceramide, and monoacylglycerol—but not sphingosine—to generate phosphatidic and lysophosphatidic acid, with activity modulated by cardiolipin, sphingosine, and calcium/magnesium ratios [#0]. A defining feature emerging across genetic models is that AGK exerts several of its physiological roles independently of this catalytic activity, dissected through paired knockout and kinase-dead (G126E) mouse alleles: it stabilizes mitochondrial respiratory chain complex I by binding the NDUFS2 and NDUFA10 subunits through its DGK domain, with loss of AGK—but not loss of kinase activity—causing mitochondrial dysfunction and hepatic NASH [#2], and it binds JAK2 to support thrombopoietin-driven megakaryocyte differentiation and platelet production, a role abolished by AGK deletion but preserved in kinase-dead animals [#1]. AGK's kinase activity is separately deployed in platelets to phosphorylate Talin-1 at Ser425 and potentiate αIIbβ3 integrin signaling and thrombus formation, without affecting bulk platelet lipid synthesis [#4]. In disease contexts AGK is co-opted to drive oncogenic signaling: ZDHHC2-mediated S-palmitoylation relocates AGK from mitochondria to the plasma membrane to activate PI3K-AKT-mTOR signaling [#3], and in CLL cells aberrant AGK assembles with HSP90 and JAK2 to activate JAK2 in a cytokine-independent manner, directing non-canonical histone H3(Y41) phosphorylation and transcriptional reprogramming [#5]. Additional functions—local regulation of the mitochondrial ROMK2 channel via LPA production [#6]—extend its role at the interface of mitochondrial lipid metabolism and membrane signaling.\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established AGK's fundamental biochemical identity—answering whether it was an enzyme and on what substrates—by defining it as a membrane-associated multi-substrate lipid kinase.\",\n      \"evidence\": \"Recombinant in vitro kinase assays across multiple lipid substrates with fractionation and pharmacological profiling\",\n      \"pmids\": [\"15252046\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the physiological in vivo substrate(s)\", \"Internal membrane compartment identity not precisely defined\", \"No structural basis for substrate selectivity\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed that AGK has a kinase-independent function, binding JAK2 to drive megakaryocyte development, separating its enzymatic role from a structural/signaling role.\",\n      \"evidence\": \"Reciprocal Co-IP plus megakaryocyte/platelet-specific knockout and G126E kinase-dead knock-in mice with platelet phenotyping\",\n      \"pmids\": [\"32202634\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of AGK-JAK2 interaction not defined\", \"How JAK2 V617F enhances binding mechanistically unresolved\", \"Whether mitochondrial localization is required for JAK2 binding unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated AGK maintains respiratory chain complex I integrity through direct, kinase-independent binding to NDUFS2 and NDUFA10, explaining its mitochondrial structural role.\",\n      \"evidence\": \"Reciprocal Co-IP with DGK-domain mapping plus hepatocyte-specific knockout vs kinase-dead knock-in mice in NASH models\",\n      \"pmids\": [\"35547757\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and assembly step of AGK within complex I biogenesis not defined\", \"No structural model of the AGK-NDUFS2/NDUFA10 interface\", \"Tissue-specificity of the complex I requirement unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a kinase-dependent substrate of AGK—Talin-1 Ser425—linking its catalytic activity to integrin-mediated platelet activation rather than bulk lipid synthesis.\",\n      \"evidence\": \"Co-IP and mass spectrometry substrate identification with G126E knock-in mice and in vivo thrombosis models\",\n      \"pmids\": [\"37051931\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct phosphotransfer to Talin-1 not reconstituted in vitro\", \"Whether AGK acts as a protein kinase or via a lipid intermediate unclear\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed that post-translational palmitoylation can reroute AGK out of mitochondria to the plasma membrane to engage PI3K-AKT-mTOR signaling, establishing regulated relocalization as a functional switch.\",\n      \"evidence\": \"Palmitoylation assays, subcellular fractionation, and pathway analysis in ccRCC cells and xenografts\",\n      \"pmids\": [\"37078777\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between membrane AGK and PI3K activation not defined\", \"Whether kinase activity is required at the plasma membrane unclear\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected AGK's lipid product to ion channel regulation, showing localized LPA synthesis modulates the mitochondrial ROMK2 channel.\",\n      \"evidence\": \"TurboID proximity labeling and Co-IP with artificial bilayer electrophysiology and docking\",\n      \"pmids\": [\"38056763\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In situ requirement of AGK for ROMK2 activity not shown genetically\", \"Physiological consequence of ROMK2 modulation undefined\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a pathological non-canonical signaling axis in which AGK-HSP90-JAK2 complexes activate JAK2 to phosphorylate histone H3(Y41) and reprogram transcription, extending AGK's JAK2 partnership into the nucleus.\",\n      \"evidence\": \"Co-IP, nuclear fractionation, pH3(Y41) Western blots, and JAK2 inhibition/apoptosis assays in primary CLL cells\",\n      \"pmids\": [\"39636206\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of AGK nuclear translocation not established\", \"Whether AGK kinase activity contributes is unclear\", \"Generality beyond CLL unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how AGK partitions between its kinase-dependent and kinase-independent functions and how its subcellular localization (mitochondria, plasma membrane, nucleus) is coordinated across cell types.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model linking lipid-kinase and scaffold functions\", \"Regulators governing AGK relocalization incompletely mapped\", \"Direct vs indirect nature of several signaling outputs (PI3K, NF-κB, Hippo) not biochemically established\"]\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]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 2, 3, 6]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [1, 3, 5]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 3, 5]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"complexes\": [\n      \"TIM22 mitochondrial import complex\",\n      \"respiratory chain complex I\",\n      \"AGK-HSP90-JAK2 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}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}