{"gene":"LAMTOR3","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2013,"finding":"LAMTOR3 (MP1) forms a heterodimer with LAMTOR2 (p14) as part of the larger Ragulator complex at late endosomes/lysosomes, where it is required for MAPK and mTORC1 signaling. Loss of LAMTOR2 results in monomeric cytosolic LAMTOR3 that is rapidly degraded in a proteasome-dependent, lysosome-independent manner. Mutational analyses showed the turnover depends on ubiquitination of several lysine residues.","method":"Mutational analysis of lysine residues, proteasome inhibitor treatment, subcellular fractionation, loss-of-function (LAMTOR2 depletion)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal loss-of-function with multiple orthogonal methods (mutagenesis, proteasome inhibitors, fractionation) in a single focused study","pmids":["23653355"],"is_preprint":false},{"year":2013,"finding":"PAF transcriptionally activates LAMTOR3 expression, and elevated LAMTOR3 hyperphosphorylates MEK and ERK independently of Ras or Raf mutations, driving pancreatic cancer cell proliferation. LAMTOR3 depletion is necessary for PAF-induced MAPK hyperactivation.","method":"Transcriptional reporter assays, ERK/MEK phosphorylation assays, siRNA knockdown of LAMTOR3 in pancreatic cancer cells, mouse pancreatic intraepithelial neoplasia models","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with phosphorylation readouts and in vivo model, single lab, multiple orthogonal methods","pmids":["24209743"],"is_preprint":false},{"year":2017,"finding":"In mesenchymal lung cancer cells, LAMTOR3 (MP1) acts as a scaffold for the MEK1/ERK1 axis; depletion of LAMTOR3 represses ERK1 activity and downstream BCL2 expression, sensitizing cells to chemoradiotherapy.","method":"siRNA knockdown of LAMTOR3 (MP1), Western blot for ERK1 phosphorylation and BCL2, MEK1 inhibitor treatment, cell viability assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KD with defined signaling phenotype but single lab and single approach for mechanistic placement","pmids":["28606806"],"is_preprint":false},{"year":2022,"finding":"miR-8485 directly targets the 3'-UTR of LAMTOR3 (confirmed by dual-luciferase reporter assay), and downregulation of LAMTOR3 by miR-8485 reduces mTOR activity and upregulates ATG13 and LC3-II, promoting autophagy in ovarian cancer cells.","method":"Dual-luciferase reporter assay, qRT-PCR, Western blot for LAMTOR3/mTOR/ATG13/LC3-II, autophagy inhibitor rescue experiment, overexpression and knockdown","journal":"Frontiers in pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct target validation by luciferase assay plus rescue experiments with multiple pathway markers, single lab","pmids":["35959437"],"is_preprint":false},{"year":2025,"finding":"miR-1287-5p directly targets the 3'-UTR of LAMTOR3 (confirmed by dual-luciferase reporter assay), and overexpression of LAMTOR3 rescues the suppression of proliferation, migration, and invasion caused by miR-1287-5p in gastric cancer cells.","method":"Dual-luciferase reporter assay, qRT-PCR, Western blot, rescue overexpression experiments, CCK-8, wound-healing, transwell invasion, flow cytometry","journal":"World journal of surgical oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct target validation by luciferase assay with rescue experiments confirming LAMTOR3 as effector, single lab","pmids":["41088225"],"is_preprint":false}],"current_model":"LAMTOR3 (MP1) functions as part of the Ragulator complex at late endosomes/lysosomes, where it heterodimerizes with LAMTOR2 (p14) to scaffold MEK1/ERK1 signaling and support mTORC1 activation; monomeric LAMTOR3 is unstable and degraded via proteasome-dependent ubiquitination, and elevated LAMTOR3 can hyperactivate MEK/ERK to drive proliferation and BCL2-mediated chemoradioresistance, while its expression is post-transcriptionally regulated by miRNAs including miR-8485 and miR-1287-5p that target its 3'-UTR."},"narrative":{"mechanistic_narrative":"LAMTOR3 (MP1) is a scaffold subunit of the Ragulator complex at late endosomes/lysosomes, where it couples MAPK and mTORC1 signaling to cell proliferation and survival [PMID:23653355, PMID:28606806]. It is stabilized through obligate heterodimerization with LAMTOR2 (p14); when LAMTOR2 is lost, monomeric LAMTOR3 is mislocalized to the cytosol and rapidly destroyed by proteasome-dependent ubiquitination of multiple lysine residues, establishing complex assembly as the determinant of its stability [PMID:23653355]. Functionally, LAMTOR3 scaffolds the MEK1/ERK1 axis: elevated LAMTOR3 hyperphosphorylates MEK and ERK independently of Ras or Raf mutations to drive proliferation, and in mesenchymal cancer cells it sustains ERK1 activity and downstream BCL2 expression to confer chemoradioresistance [PMID:24209743, PMID:28606806]. LAMTOR3 abundance is set post-transcriptionally by miRNAs targeting its 3'-UTR—miR-8485 and miR-1287-5p—whose loss-of-LAMTOR3 effects reduce mTOR activity, promote autophagy, and suppress proliferation, migration, and invasion [PMID:35959437, PMID:41088225].","teleology":[{"year":2013,"claim":"Established that LAMTOR3 stability is governed by its incorporation into the Ragulator complex rather than being intrinsic, defining heterodimerization with LAMTOR2 as the gatekeeper of its function in MAPK and mTORC1 signaling.","evidence":"Lysine mutagenesis, proteasome inhibition, subcellular fractionation, and LAMTOR2 depletion at late endosomes/lysosomes","pmids":["23653355"],"confidence":"High","gaps":["E3 ligase mediating LAMTOR3 ubiquitination not identified","structural basis of the LAMTOR2-LAMTOR3 interface not resolved here"]},{"year":2013,"claim":"Showed that transcriptional upregulation of LAMTOR3 can drive MEK/ERK hyperactivation and tumor cell proliferation without canonical Ras/Raf mutations, positioning LAMTOR3 dosage as an oncogenic input to the MAPK pathway.","evidence":"Transcriptional reporter assays, MEK/ERK phosphorylation readouts, siRNA knockdown in pancreatic cancer cells, and PanIN mouse models","pmids":["24209743"],"confidence":"Medium","gaps":["mechanism by which LAMTOR3 scaffolds and amplifies MEK/ERK phosphorylation not detailed","single lab"]},{"year":2017,"claim":"Connected LAMTOR3 scaffolding of MEK1/ERK1 to a survival output (BCL2), explaining how LAMTOR3 supports chemoradioresistance in mesenchymal cancer cells.","evidence":"siRNA knockdown, phospho-ERK1 and BCL2 Western blots, MEK1 inhibitor treatment, and cell viability assays","pmids":["28606806"],"confidence":"Medium","gaps":["single approach for mechanistic placement","direct LAMTOR3-MEK1 binding not demonstrated in this context"]},{"year":2022,"claim":"Identified LAMTOR3 as a direct miRNA target whose suppression lowers mTOR activity and induces autophagy, linking LAMTOR3 dosage control to the mTORC1 arm of Ragulator signaling.","evidence":"Dual-luciferase 3'-UTR reporter assay, qRT-PCR, autophagy marker (ATG13, LC3-II) Western blots, and autophagy inhibitor rescue in ovarian cancer cells","pmids":["35959437"],"confidence":"Medium","gaps":["whether miR-8485 effects are entirely LAMTOR3-dependent not fully isolated","single lab"]},{"year":2025,"claim":"Confirmed a second miRNA (miR-1287-5p) controlling LAMTOR3 and demonstrated by rescue that LAMTOR3 is the effector driving proliferation, migration, and invasion downstream of this regulatory axis.","evidence":"Dual-luciferase reporter assay, qRT-PCR, rescue overexpression, CCK-8, wound-healing, transwell, and flow cytometry in gastric cancer cells","pmids":["41088225"],"confidence":"Medium","gaps":["downstream signaling pathway not dissected in this study","single lab"]},{"year":null,"claim":"How LAMTOR3 mechanistically distinguishes and partitions its MEK1/ERK1 scaffolding function from its mTORC1-activating function within the Ragulator remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["no structural model of LAMTOR3 engaging MEK1 versus mTORC1 machinery","E3 ligase and full ubiquitination code controlling monomer turnover unknown","physiological (non-cancer) roles uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[3]}],"complexes":["Ragulator"],"partners":["LAMTOR2","MEK1","ERK1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UHA4","full_name":"Ragulator complex protein LAMTOR3","aliases":["Late endosomal/lysosomal adaptor and MAPK and MTOR activator 3","MEK-binding partner 1","Mp1","Mitogen-activated protein kinase kinase 1-interacting protein 1","Mitogen-activated protein kinase scaffold protein 1"],"length_aa":124,"mass_kda":13.6,"function":"As part of the Ragulator complex it is involved in amino acid sensing and activation of mTORC1, a signaling complex promoting cell growth in response to growth factors, energy levels, and amino acids (PubMed:20381137, PubMed:22980980, PubMed:28935770, PubMed:29107538, PubMed:29123114, PubMed:29158492, PubMed:30181260). Activated by amino acids through a mechanism involving the lysosomal V-ATPase, the Ragulator plays a dual role for the small GTPases Rag (RagA/RRAGA, RagB/RRAGB, RagC/RRAGC and/or RagD/RRAGD): it (1) acts as a guanine nucleotide exchange factor (GEF), activating the small GTPases Rag and (2) mediates recruitment of Rag GTPases to the lysosome membrane (PubMed:22980980, PubMed:28935770, PubMed:29107538, PubMed:29123114, PubMed:29158492, PubMed:30181260). Activated Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated (PubMed:22980980, PubMed:28935770, PubMed:29107538, PubMed:29123114, PubMed:29158492, PubMed:30181260). Adapter protein that enhances the efficiency of the MAP kinase cascade facilitating the activation of MAPK2 (By similarity)","subcellular_location":"Late endosome membrane","url":"https://www.uniprot.org/uniprotkb/Q9UHA4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/LAMTOR3","classification":"Common Essential","n_dependent_lines":746,"n_total_lines":1208,"dependency_fraction":0.6175496688741722},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"LAMTOR2","stoichiometry":10.0},{"gene":"PIP4P1","stoichiometry":10.0},{"gene":"LAMP1","stoichiometry":4.0},{"gene":"RAB7A","stoichiometry":0.2},{"gene":"STX7","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/LAMTOR3","total_profiled":1310},"omim":[{"mim_id":"618834","title":"LATE ENDOSOMAL/LYSOSOMAL ADAPTOR, MAPK AND MTOR ACTIVATOR 4; LAMTOR4","url":"https://www.omim.org/entry/618834"},{"mim_id":"616850","title":"WD REPEAT-CONTAINING PROTEIN 83; WDR83","url":"https://www.omim.org/entry/616850"},{"mim_id":"616203","title":"SOLUTE CARRIER FAMILY 38, MEMBER 9; SLC38A9","url":"https://www.omim.org/entry/616203"},{"mim_id":"608521","title":"LATE ENDOSOMAL/LYSOSOMAL ADAPTOR, MAPK AND MTOR ACTIVATOR 5; LAMTOR5","url":"https://www.omim.org/entry/608521"},{"mim_id":"603296","title":"LATE ENDOSOMAL/LYSOSOMAL ADAPTOR, MAPK AND MTOR ACTIVATOR 3; LAMTOR3","url":"https://www.omim.org/entry/603296"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LAMTOR3"},"hgnc":{"alias_symbol":["MP1","MAPBP","Ragulator3"],"prev_symbol":["MAP2K1IP1","MAPKSP1"]},"alphafold":{"accession":"Q9UHA4","domains":[{"cath_id":"3.30.450.30","chopping":"1-124","consensus_level":"medium","plddt":95.4094,"start":1,"end":124}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UHA4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UHA4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UHA4-F1-predicted_aligned_error_v6.png","plddt_mean":95.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LAMTOR3","jax_strain_url":"https://www.jax.org/strain/search?query=LAMTOR3"},"sequence":{"accession":"Q9UHA4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UHA4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UHA4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UHA4"}},"corpus_meta":[{"pmid":"24209743","id":"PMC_24209743","title":"PAF-mediated MAPK signaling hyperactivation via LAMTOR3 induces pancreatic tumorigenesis.","date":"2013","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/24209743","citation_count":46,"is_preprint":false},{"pmid":"33184989","id":"PMC_33184989","title":"Circ_0075829 facilitates the progression of pancreatic carcinoma by sponging miR-1287-5p and activating LAMTOR3 signalling.","date":"2020","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33184989","citation_count":31,"is_preprint":false},{"pmid":"23653355","id":"PMC_23653355","title":"Stability of the endosomal scaffold protein LAMTOR3 depends on heterodimer assembly and proteasomal degradation.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23653355","citation_count":28,"is_preprint":false},{"pmid":"28606806","id":"PMC_28606806","title":"BCL2 induced by LAMTOR3/MAPK is a druggable target of chemoradioresistance in mesenchymal lung cancer.","date":"2017","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/28606806","citation_count":25,"is_preprint":false},{"pmid":"35959437","id":"PMC_35959437","title":"Brucea javanica Oil Emulsion Promotes Autophagy in Ovarian Cancer Cells Through the miR-8485/LAMTOR3/mTOR/ATG13 Signaling Axis.","date":"2022","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/35959437","citation_count":18,"is_preprint":false},{"pmid":"23341997","id":"PMC_23341997","title":"Polymorphisms in the gene regions of the adaptor complex LAMTOR2/LAMTOR3 and their association with breast cancer risk.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23341997","citation_count":9,"is_preprint":false},{"pmid":"25661340","id":"PMC_25661340","title":"A miR-29c binding site genetic variant in the 3'-untranslated region of LAMTOR3 gene is associated with gastric cancer risk.","date":"2014","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/25661340","citation_count":7,"is_preprint":false},{"pmid":"41088225","id":"PMC_41088225","title":"miR-1287-5p suppresses proliferation, migration, invasion and promotes apoptosis in gastric cancer cells through targeting LAMTOR3.","date":"2025","source":"World journal of surgical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41088225","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6654,"output_tokens":1398,"usd":0.020466,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8096,"output_tokens":2249,"usd":0.048352,"stage2_stop_reason":"end_turn"},"total_usd":0.068818,"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\": 2013,\n      \"finding\": \"LAMTOR3 (MP1) forms a heterodimer with LAMTOR2 (p14) as part of the larger Ragulator complex at late endosomes/lysosomes, where it is required for MAPK and mTORC1 signaling. Loss of LAMTOR2 results in monomeric cytosolic LAMTOR3 that is rapidly degraded in a proteasome-dependent, lysosome-independent manner. Mutational analyses showed the turnover depends on ubiquitination of several lysine residues.\",\n      \"method\": \"Mutational analysis of lysine residues, proteasome inhibitor treatment, subcellular fractionation, loss-of-function (LAMTOR2 depletion)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal loss-of-function with multiple orthogonal methods (mutagenesis, proteasome inhibitors, fractionation) in a single focused study\",\n      \"pmids\": [\"23653355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PAF transcriptionally activates LAMTOR3 expression, and elevated LAMTOR3 hyperphosphorylates MEK and ERK independently of Ras or Raf mutations, driving pancreatic cancer cell proliferation. LAMTOR3 depletion is necessary for PAF-induced MAPK hyperactivation.\",\n      \"method\": \"Transcriptional reporter assays, ERK/MEK phosphorylation assays, siRNA knockdown of LAMTOR3 in pancreatic cancer cells, mouse pancreatic intraepithelial neoplasia models\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with phosphorylation readouts and in vivo model, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"24209743\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In mesenchymal lung cancer cells, LAMTOR3 (MP1) acts as a scaffold for the MEK1/ERK1 axis; depletion of LAMTOR3 represses ERK1 activity and downstream BCL2 expression, sensitizing cells to chemoradiotherapy.\",\n      \"method\": \"siRNA knockdown of LAMTOR3 (MP1), Western blot for ERK1 phosphorylation and BCL2, MEK1 inhibitor treatment, cell viability assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KD with defined signaling phenotype but single lab and single approach for mechanistic placement\",\n      \"pmids\": [\"28606806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"miR-8485 directly targets the 3'-UTR of LAMTOR3 (confirmed by dual-luciferase reporter assay), and downregulation of LAMTOR3 by miR-8485 reduces mTOR activity and upregulates ATG13 and LC3-II, promoting autophagy in ovarian cancer cells.\",\n      \"method\": \"Dual-luciferase reporter assay, qRT-PCR, Western blot for LAMTOR3/mTOR/ATG13/LC3-II, autophagy inhibitor rescue experiment, overexpression and knockdown\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct target validation by luciferase assay plus rescue experiments with multiple pathway markers, single lab\",\n      \"pmids\": [\"35959437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"miR-1287-5p directly targets the 3'-UTR of LAMTOR3 (confirmed by dual-luciferase reporter assay), and overexpression of LAMTOR3 rescues the suppression of proliferation, migration, and invasion caused by miR-1287-5p in gastric cancer cells.\",\n      \"method\": \"Dual-luciferase reporter assay, qRT-PCR, Western blot, rescue overexpression experiments, CCK-8, wound-healing, transwell invasion, flow cytometry\",\n      \"journal\": \"World journal of surgical oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct target validation by luciferase assay with rescue experiments confirming LAMTOR3 as effector, single lab\",\n      \"pmids\": [\"41088225\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LAMTOR3 (MP1) functions as part of the Ragulator complex at late endosomes/lysosomes, where it heterodimerizes with LAMTOR2 (p14) to scaffold MEK1/ERK1 signaling and support mTORC1 activation; monomeric LAMTOR3 is unstable and degraded via proteasome-dependent ubiquitination, and elevated LAMTOR3 can hyperactivate MEK/ERK to drive proliferation and BCL2-mediated chemoradioresistance, while its expression is post-transcriptionally regulated by miRNAs including miR-8485 and miR-1287-5p that target its 3'-UTR.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LAMTOR3 (MP1) is a scaffold subunit of the Ragulator complex at late endosomes/lysosomes, where it couples MAPK and mTORC1 signaling to cell proliferation and survival [#0, #2]. It is stabilized through obligate heterodimerization with LAMTOR2 (p14); when LAMTOR2 is lost, monomeric LAMTOR3 is mislocalized to the cytosol and rapidly destroyed by proteasome-dependent ubiquitination of multiple lysine residues, establishing complex assembly as the determinant of its stability [#0]. Functionally, LAMTOR3 scaffolds the MEK1/ERK1 axis: elevated LAMTOR3 hyperphosphorylates MEK and ERK independently of Ras or Raf mutations to drive proliferation, and in mesenchymal cancer cells it sustains ERK1 activity and downstream BCL2 expression to confer chemoradioresistance [#1, #2]. LAMTOR3 abundance is set post-transcriptionally by miRNAs targeting its 3'-UTR—miR-8485 and miR-1287-5p—whose loss-of-LAMTOR3 effects reduce mTOR activity, promote autophagy, and suppress proliferation, migration, and invasion [#3, #4].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established that LAMTOR3 stability is governed by its incorporation into the Ragulator complex rather than being intrinsic, defining heterodimerization with LAMTOR2 as the gatekeeper of its function in MAPK and mTORC1 signaling.\",\n      \"evidence\": \"Lysine mutagenesis, proteasome inhibition, subcellular fractionation, and LAMTOR2 depletion at late endosomes/lysosomes\",\n      \"pmids\": [\"23653355\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase mediating LAMTOR3 ubiquitination not identified\", \"structural basis of the LAMTOR2-LAMTOR3 interface not resolved here\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed that transcriptional upregulation of LAMTOR3 can drive MEK/ERK hyperactivation and tumor cell proliferation without canonical Ras/Raf mutations, positioning LAMTOR3 dosage as an oncogenic input to the MAPK pathway.\",\n      \"evidence\": \"Transcriptional reporter assays, MEK/ERK phosphorylation readouts, siRNA knockdown in pancreatic cancer cells, and PanIN mouse models\",\n      \"pmids\": [\"24209743\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mechanism by which LAMTOR3 scaffolds and amplifies MEK/ERK phosphorylation not detailed\", \"single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected LAMTOR3 scaffolding of MEK1/ERK1 to a survival output (BCL2), explaining how LAMTOR3 supports chemoradioresistance in mesenchymal cancer cells.\",\n      \"evidence\": \"siRNA knockdown, phospho-ERK1 and BCL2 Western blots, MEK1 inhibitor treatment, and cell viability assays\",\n      \"pmids\": [\"28606806\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"single approach for mechanistic placement\", \"direct LAMTOR3-MEK1 binding not demonstrated in this context\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified LAMTOR3 as a direct miRNA target whose suppression lowers mTOR activity and induces autophagy, linking LAMTOR3 dosage control to the mTORC1 arm of Ragulator signaling.\",\n      \"evidence\": \"Dual-luciferase 3'-UTR reporter assay, qRT-PCR, autophagy marker (ATG13, LC3-II) Western blots, and autophagy inhibitor rescue in ovarian cancer cells\",\n      \"pmids\": [\"35959437\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"whether miR-8485 effects are entirely LAMTOR3-dependent not fully isolated\", \"single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Confirmed a second miRNA (miR-1287-5p) controlling LAMTOR3 and demonstrated by rescue that LAMTOR3 is the effector driving proliferation, migration, and invasion downstream of this regulatory axis.\",\n      \"evidence\": \"Dual-luciferase reporter assay, qRT-PCR, rescue overexpression, CCK-8, wound-healing, transwell, and flow cytometry in gastric cancer cells\",\n      \"pmids\": [\"41088225\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"downstream signaling pathway not dissected in this study\", \"single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How LAMTOR3 mechanistically distinguishes and partitions its MEK1/ERK1 scaffolding function from its mTORC1-activating function within the Ragulator remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no structural model of LAMTOR3 engaging MEK1 versus mTORC1 machinery\", \"E3 ligase and full ubiquitination code controlling monomer turnover unknown\", \"physiological (non-cancer) roles uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\"Ragulator\"],\n    \"partners\": [\"LAMTOR2\", \"MEK1\", \"ERK1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}