{"gene":"LAGE3","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2024,"finding":"LAGE3, as a component of the EKC/KEOPS complex (involved in threonylcarbamoylation of adenosine at position 37 in tRNAs), is required for VEGFA mRNA stability; increased LAGE3 expression leads to upregulated VEGFA secretion and angiogenesis in hepatocellular carcinoma cells.","method":"Knockdown/overexpression experiments in HCC cell lines with western blot and mRNA stability assays","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single lab, mechanistic follow-up linking LAGE3 to mRNA stability, but abstract lacks detail on orthogonal methods or rescue experiments","pmids":["38653358"],"is_preprint":false},{"year":2021,"finding":"LAGE3 promotes proliferation, migration, and invasion of hepatocellular carcinoma cells and inhibits apoptosis by activating the JNK and ERK signaling pathways; pharmacological inhibition of ERK (SCH772984) or JNK (SP600125) reversed LAGE3 overexpression-induced malignant phenotypes.","method":"siRNA knockdown and overexpression in HCC cell lines (Hep3B, SK-HEP1), xenograft mouse model, western blot for p-JNK/JNK and p-ERK/ERK, pharmacological inhibitor rescue experiments","journal":"Cellular & molecular biology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro KD/OE with defined phenotype plus pathway inhibitor rescue, single lab","pmids":["34837962"],"is_preprint":false},{"year":2023,"finding":"LAGE3 promotes cell metastasis and stemness in non-small cell lung cancer by activating the AKT/PI3K signaling pathway; LAGE3 knockdown suppressed stemness-related proteins (Nanog, SOX2, OCT4) and reduced tumor growth in vivo.","method":"siRNA knockdown in NSCLC cell lines (A549, H1975), xenograft nude mouse model, western blotting for AKT/PI3K pathway components and stemness proteins","journal":"Pathology, research and practice","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — KD with defined phenotype and pathway placement, single lab, no rescue or mutagenesis","pmids":["37473499"],"is_preprint":false},{"year":2018,"finding":"LAGE3 physically interacts with orf virus protein ORFV024; this interaction was confirmed by yeast two-hybrid screening, His-tag pull-down assay, and co-immunoprecipitation.","method":"Yeast two-hybrid, His-tag pull-down assay, co-immunoprecipitation, confocal microscopy","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction confirmed by three orthogonal methods (Y2H, pull-down, Co-IP) in a single study","pmids":["29605601"],"is_preprint":false}],"current_model":"LAGE3 is a component of the EKC/KEOPS complex that participates in threonylcarbamoylation of tRNA adenosine-37; it stabilizes VEGFA mRNA to promote angiogenesis, and activates JNK/ERK and AKT/PI3K signaling pathways to drive tumor cell proliferation, migration, invasion, and stemness, while also physically interacting with viral immunomodulatory proteins such as ORFV024."},"narrative":{"mechanistic_narrative":"LAGE3 is a component of the EKC/KEOPS complex implicated in threonylcarbamoylation of adenosine at position 37 in tRNAs, and it functions as a pro-tumorigenic factor across multiple cancer contexts [PMID:38653358]. In hepatocellular carcinoma, LAGE3 is required for VEGFA mRNA stability, and its elevated expression increases VEGFA secretion and angiogenesis [PMID:38653358]; it further drives proliferation, migration, invasion, and apoptosis resistance through activation of the JNK and ERK signaling pathways, as pharmacological ERK or JNK inhibition reverses LAGE3-induced malignant phenotypes [PMID:34837962]. In non-small cell lung cancer, LAGE3 promotes metastasis and stemness via AKT/PI3K signaling, with its knockdown suppressing the stemness factors Nanog, SOX2, and OCT4 and reducing tumor growth in vivo [PMID:37473499]. LAGE3 also physically interacts with the orf virus immunomodulatory protein ORFV024 [PMID:29605601]. Beyond these signaling and interaction findings, the biochemical mechanism by which LAGE3 stabilizes VEGFA mRNA or engages upstream kinase activation has not been characterized in the available corpus.","teleology":[{"year":2018,"claim":"Establishing a physical binding partner for LAGE3 provided the first direct interaction-level evidence for the protein, linking it to viral immunomodulation.","evidence":"Yeast two-hybrid screen, His-tag pull-down, and co-immunoprecipitation with confocal microscopy identifying orf virus ORFV024 as a binding partner","pmids":["29605601"],"confidence":"Medium","gaps":["Functional consequence of the LAGE3-ORFV024 interaction for host immunity is undefined","No mapping of the interaction interface or binding domain","Relevance to endogenous LAGE3 cellular function unclear"]},{"year":2021,"claim":"Placed LAGE3 within defined kinase cascades by showing it activates JNK and ERK to drive HCC malignant phenotypes, moving from correlation toward mechanism.","evidence":"siRNA knockdown and overexpression in Hep3B and SK-HEP1 cells, xenograft model, phospho-JNK/ERK western blots, and inhibitor (SCH772984, SP600125) rescue","pmids":["34837962"],"confidence":"Medium","gaps":["How LAGE3 connects to upstream JNK/ERK activation is unknown","No structural or biochemical basis for pathway engagement","Single lab, no orthogonal genetic rescue"]},{"year":2023,"claim":"Extended LAGE3's oncogenic role beyond liver cancer to NSCLC and to a distinct pathway, implicating AKT/PI3K in metastasis and stemness control.","evidence":"siRNA knockdown in A549 and H1975 cells, xenograft nude mouse model, western blotting of AKT/PI3K components and stemness markers Nanog/SOX2/OCT4","pmids":["37473499"],"confidence":"Medium","gaps":["No rescue or mutagenesis to confirm causality","Mechanistic link between LAGE3 and AKT/PI3K activation unresolved","Whether different pathways in HCC vs NSCLC reflect tissue context is untested"]},{"year":2024,"claim":"Connected LAGE3's EKC/KEOPS complex membership to a specific molecular output by showing it is required for VEGFA mRNA stability and angiogenesis.","evidence":"Knockdown/overexpression in HCC cell lines with western blot and mRNA stability assays","pmids":["38653358"],"confidence":"Medium","gaps":["Direct biochemical mechanism linking LAGE3 or tRNA modification to VEGFA mRNA stability not defined","No orthogonal method or rescue reported","Whether tRNA threonylcarbamoylation activity underlies the mRNA effect is untested"]},{"year":null,"claim":"How LAGE3's role in the EKC/KEOPS tRNA-modification complex mechanistically gives rise to its diverse oncogenic signaling and mRNA-stabilizing activities remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of LAGE3 within the EKC/KEOPS complex from the corpus","No demonstration that catalytic tRNA modification activity is required for the cancer phenotypes","Unifying mechanism across angiogenesis, JNK/ERK, and AKT/PI3K pathways not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0]}],"localization":[],"pathway":[],"complexes":["EKC/KEOPS complex"],"partners":["ORFV024"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14657","full_name":"EKC/KEOPS complex subunit LAGE3","aliases":["L antigen family member 3","Protein ESO-3","Protein ITBA2"],"length_aa":143,"mass_kda":14.8,"function":"Component of the EKC/KEOPS complex that is required for the formation of a threonylcarbamoyl group on adenosine at position 37 (t(6)A37) in tRNAs that read codons beginning with adenine (PubMed:22912744, PubMed:27903914). The complex is probably involved in the transfer of the threonylcarbamoyl moiety of threonylcarbamoyl-AMP (TC-AMP) to the N6 group of A37 (PubMed:22912744, PubMed:27903914). LAGE3 functions as a dimerization module for the complex (PubMed:22912744, PubMed:27903914)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q14657/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LAGE3","classification":"Not Classified","n_dependent_lines":183,"n_total_lines":1208,"dependency_fraction":0.15149006622516556},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LAGE3","total_profiled":1310},"omim":[{"mim_id":"617731","title":"GALLOWAY-MOWAT SYNDROME 5; GAMOS5","url":"https://www.omim.org/entry/617731"},{"mim_id":"617730","title":"GALLOWAY-MOWAT SYNDROME 4; GAMOS4","url":"https://www.omim.org/entry/617730"},{"mim_id":"617729","title":"GALLOWAY-MOWAT SYNDROME 3; GAMOS3","url":"https://www.omim.org/entry/617729"},{"mim_id":"617436","title":"GON7 SUBUNIT OF KEOPS COMPLEX; GON7","url":"https://www.omim.org/entry/617436"},{"mim_id":"610107","title":"O-SIALOGLYCOPROTEIN ENDOPEPTIDASE; OSGEP","url":"https://www.omim.org/entry/610107"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nuclear bodies","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LAGE3"},"hgnc":{"alias_symbol":["ITBA2","CVG5","DXS9951E","DXS9879E","ESO3","Pcc1"],"prev_symbol":[]},"alphafold":{"accession":"Q14657","domains":[{"cath_id":"3.30.310.50","chopping":"60-136","consensus_level":"high","plddt":89.1797,"start":60,"end":136}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14657","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14657-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14657-F1-predicted_aligned_error_v6.png","plddt_mean":74.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LAGE3","jax_strain_url":"https://www.jax.org/strain/search?query=LAGE3"},"sequence":{"accession":"Q14657","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14657.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14657/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14657"}},"corpus_meta":[{"pmid":"34837962","id":"PMC_34837962","title":"LAGE3 promoted cell proliferation, migration, and invasion and inhibited cell apoptosis of hepatocellular carcinoma by facilitating the JNK and ERK signaling pathway.","date":"2021","source":"Cellular & molecular biology letters","url":"https://pubmed.ncbi.nlm.nih.gov/34837962","citation_count":24,"is_preprint":false},{"pmid":"32683301","id":"PMC_32683301","title":"LAGE3 correlates with tumorigenic immune infiltrates in the clear cell renal cell carcinoma microenvironment.","date":"2020","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/32683301","citation_count":14,"is_preprint":false},{"pmid":"29605601","id":"PMC_29605601","title":"Identification of host cellular proteins LAGE3 and IGFBP6 that interact with orf virus protein ORFV024.","date":"2018","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/29605601","citation_count":9,"is_preprint":false},{"pmid":"36755238","id":"PMC_36755238","title":"Diagnosis delay a family of Galloway-Mowat Syndrome caused by a classical splicing mutation of Lage3.","date":"2023","source":"BMC nephrology","url":"https://pubmed.ncbi.nlm.nih.gov/36755238","citation_count":7,"is_preprint":false},{"pmid":"37900929","id":"PMC_37900929","title":"Novel LAGE3 Pathogenic Variants Combined with TRPC6 and NUP160 Variants in Galloway-Mowat Syndrome: A Case Report.","date":"2023","source":"Case reports in nephrology and dialysis","url":"https://pubmed.ncbi.nlm.nih.gov/37900929","citation_count":2,"is_preprint":false},{"pmid":"38653358","id":"PMC_38653358","title":"LAGE3 promotes angiogenesis on hepatocellular carcinoma by stabilizing VEGFA mRNA.","date":"2024","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/38653358","citation_count":1,"is_preprint":false},{"pmid":"37473499","id":"PMC_37473499","title":"LAGE3 promotes cell metastasis and stemness in non-small cell lung cancer companied with AKT/PI3K signaling pathway activation.","date":"2023","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/37473499","citation_count":1,"is_preprint":false},{"pmid":"40490705","id":"PMC_40490705","title":"Two brothers presented with rare clinical characteristics with a novel LAGE3 variant: a case report and literature review.","date":"2025","source":"BMC pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/40490705","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6143,"output_tokens":1037,"usd":0.016992,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7561,"output_tokens":1919,"usd":0.04289,"stage2_stop_reason":"end_turn"},"total_usd":0.059882,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2024,\n      \"finding\": \"LAGE3, as a component of the EKC/KEOPS complex (involved in threonylcarbamoylation of adenosine at position 37 in tRNAs), is required for VEGFA mRNA stability; increased LAGE3 expression leads to upregulated VEGFA secretion and angiogenesis in hepatocellular carcinoma cells.\",\n      \"method\": \"Knockdown/overexpression experiments in HCC cell lines with western blot and mRNA stability assays\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single lab, mechanistic follow-up linking LAGE3 to mRNA stability, but abstract lacks detail on orthogonal methods or rescue experiments\",\n      \"pmids\": [\"38653358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LAGE3 promotes proliferation, migration, and invasion of hepatocellular carcinoma cells and inhibits apoptosis by activating the JNK and ERK signaling pathways; pharmacological inhibition of ERK (SCH772984) or JNK (SP600125) reversed LAGE3 overexpression-induced malignant phenotypes.\",\n      \"method\": \"siRNA knockdown and overexpression in HCC cell lines (Hep3B, SK-HEP1), xenograft mouse model, western blot for p-JNK/JNK and p-ERK/ERK, pharmacological inhibitor rescue experiments\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro KD/OE with defined phenotype plus pathway inhibitor rescue, single lab\",\n      \"pmids\": [\"34837962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LAGE3 promotes cell metastasis and stemness in non-small cell lung cancer by activating the AKT/PI3K signaling pathway; LAGE3 knockdown suppressed stemness-related proteins (Nanog, SOX2, OCT4) and reduced tumor growth in vivo.\",\n      \"method\": \"siRNA knockdown in NSCLC cell lines (A549, H1975), xenograft nude mouse model, western blotting for AKT/PI3K pathway components and stemness proteins\",\n      \"journal\": \"Pathology, research and practice\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — KD with defined phenotype and pathway placement, single lab, no rescue or mutagenesis\",\n      \"pmids\": [\"37473499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"LAGE3 physically interacts with orf virus protein ORFV024; this interaction was confirmed by yeast two-hybrid screening, His-tag pull-down assay, and co-immunoprecipitation.\",\n      \"method\": \"Yeast two-hybrid, His-tag pull-down assay, co-immunoprecipitation, confocal microscopy\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction confirmed by three orthogonal methods (Y2H, pull-down, Co-IP) in a single study\",\n      \"pmids\": [\"29605601\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LAGE3 is a component of the EKC/KEOPS complex that participates in threonylcarbamoylation of tRNA adenosine-37; it stabilizes VEGFA mRNA to promote angiogenesis, and activates JNK/ERK and AKT/PI3K signaling pathways to drive tumor cell proliferation, migration, invasion, and stemness, while also physically interacting with viral immunomodulatory proteins such as ORFV024.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LAGE3 is a component of the EKC/KEOPS complex implicated in threonylcarbamoylation of adenosine at position 37 in tRNAs, and it functions as a pro-tumorigenic factor across multiple cancer contexts [#0]. In hepatocellular carcinoma, LAGE3 is required for VEGFA mRNA stability, and its elevated expression increases VEGFA secretion and angiogenesis [#0]; it further drives proliferation, migration, invasion, and apoptosis resistance through activation of the JNK and ERK signaling pathways, as pharmacological ERK or JNK inhibition reverses LAGE3-induced malignant phenotypes [#1]. In non-small cell lung cancer, LAGE3 promotes metastasis and stemness via AKT/PI3K signaling, with its knockdown suppressing the stemness factors Nanog, SOX2, and OCT4 and reducing tumor growth in vivo [#2]. LAGE3 also physically interacts with the orf virus immunomodulatory protein ORFV024 [#3]. Beyond these signaling and interaction findings, the biochemical mechanism by which LAGE3 stabilizes VEGFA mRNA or engages upstream kinase activation has not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"Establishing a physical binding partner for LAGE3 provided the first direct interaction-level evidence for the protein, linking it to viral immunomodulation.\",\n      \"evidence\": \"Yeast two-hybrid screen, His-tag pull-down, and co-immunoprecipitation with confocal microscopy identifying orf virus ORFV024 as a binding partner\",\n      \"pmids\": [\"29605601\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\n        \"Functional consequence of the LAGE3-ORFV024 interaction for host immunity is undefined\",\n        \"No mapping of the interaction interface or binding domain\",\n        \"Relevance to endogenous LAGE3 cellular function unclear\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed LAGE3 within defined kinase cascades by showing it activates JNK and ERK to drive HCC malignant phenotypes, moving from correlation toward mechanism.\",\n      \"evidence\": \"siRNA knockdown and overexpression in Hep3B and SK-HEP1 cells, xenograft model, phospho-JNK/ERK western blots, and inhibitor (SCH772984, SP600125) rescue\",\n      \"pmids\": [\"34837962\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"How LAGE3 connects to upstream JNK/ERK activation is unknown\",\n        \"No structural or biochemical basis for pathway engagement\",\n        \"Single lab, no orthogonal genetic rescue\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended LAGE3's oncogenic role beyond liver cancer to NSCLC and to a distinct pathway, implicating AKT/PI3K in metastasis and stemness control.\",\n      \"evidence\": \"siRNA knockdown in A549 and H1975 cells, xenograft nude mouse model, western blotting of AKT/PI3K components and stemness markers Nanog/SOX2/OCT4\",\n      \"pmids\": [\"37473499\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No rescue or mutagenesis to confirm causality\",\n        \"Mechanistic link between LAGE3 and AKT/PI3K activation unresolved\",\n        \"Whether different pathways in HCC vs NSCLC reflect tissue context is untested\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected LAGE3's EKC/KEOPS complex membership to a specific molecular output by showing it is required for VEGFA mRNA stability and angiogenesis.\",\n      \"evidence\": \"Knockdown/overexpression in HCC cell lines with western blot and mRNA stability assays\",\n      \"pmids\": [\"38653358\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct biochemical mechanism linking LAGE3 or tRNA modification to VEGFA mRNA stability not defined\",\n        \"No orthogonal method or rescue reported\",\n        \"Whether tRNA threonylcarbamoylation activity underlies the mRNA effect is untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LAGE3's role in the EKC/KEOPS tRNA-modification complex mechanistically gives rise to its diverse oncogenic signaling and mRNA-stabilizing activities remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model of LAGE3 within the EKC/KEOPS complex from the corpus\",\n        \"No demonstration that catalytic tRNA modification activity is required for the cancer phenotypes\",\n        \"Unifying mechanism across angiogenesis, JNK/ERK, and AKT/PI3K pathways not established\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [],\n    \"pathway\": [],\n    \"complexes\": [\"EKC/KEOPS complex\"],\n    \"partners\": [\"ORFV024\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":4,"faith_total":4,"faith_pct":100.0}}