{"gene":"TNS3","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2013,"finding":"TNS3 haploinsufficiency in patient-derived fibroblasts (carrying t(2;7)(p13;p12) translocation) resulted in reduced Tensin3 mRNA and protein levels, broader/shorter cell morphology, loss of Tensin3 localization along cytoskeletal filaments and cell periphery, and a significantly higher cell migration rate compared to control fibroblasts, establishing a role for Tensin3 in cytoskeletal organisation and cell motility.","method":"Quantitative RT-PCR, western blot, immunofluorescent confocal microscopy, scratch wound assay with live cell imaging in patient-derived vs. control fibroblasts","journal":"BMC medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (western blot, immunofluorescence, live migration assay) in a single lab using a natural loss-of-function model","pmids":["23809228"],"is_preprint":false},{"year":2021,"finding":"MLL3 (histone H3K4 methyltransferase) activates TNS3 expression by depositing H3K4me1 and H3K27ac marks on an enhancer ~7 kb upstream of TNS3; this enhancer physically interacts with the TNS3 promoter (confirmed by 3C assay), and loss of MLL3 suppresses TNS3 expression, leading to enhanced cell migration that is fully rescued by exogenous TNS3 re-expression.","method":"CRISPR/sgRNA MLL3 depletion, RNA-Seq, ChIP-Seq (H3K4me1, H3K27ac), 3C chromatin conformation assay, dCas9-KRAB enhancer repression, rescue by TNS3 overexpression","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ChIP-Seq, 3C, CRISPR KO, rescue experiment) in a single rigorous study establishing the MLL3→TNS3 enhancer regulatory axis and functional epistasis","pmids":["33824309"],"is_preprint":false},{"year":2013,"finding":"The TNS3 gene promoter contains a CpG island with functional minimal promoter activity (demonstrated by luciferase reporter assay); CpG-specific hypermethylation at positions 2 and 8 of this region correlates with reduced TNS3 expression in renal cell carcinoma, and pharmacological demethylation of cultured kidney cells causes ~3-fold upregulation of Tensin3 expression.","method":"Luciferase reporter assay for promoter activity, pyrosequencing for CpG methylation quantification, pharmacological demethylation treatment with expression measurement","journal":"Epigenetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional promoter assay plus demethylation rescue, multiple orthogonal methods in a single lab","pmids":["23803643"],"is_preprint":false},{"year":2014,"finding":"A t(7;17)(p13;q23) chromosomal translocation in multicystic mesothelioma generates a chimeric TNS3-MAP3K3 fusion gene encoding a chimeric protein kinase, and the reciprocal MAP3K3-TNS3 fusion places the SH2_Tensin_like and phosphotyrosine-binding domains of TNS3 under MAP3K3 promoter control.","method":"RNA-sequencing, RT-PCR, Sanger sequencing of fusion transcripts from tumor-derived cell culture","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — fusion transcript identification confirmed by RT-PCR and Sanger sequencing, single lab, no functional reconstitution of the chimeric kinase","pmids":["25484136"],"is_preprint":false},{"year":2021,"finding":"Silencing TNS3 in esophageal squamous cell carcinoma (ESCC) cells significantly inhibited cell proliferation in vitro and in vivo, and sensitized cells to the HDAC inhibitor LMK-235, establishing TNS3 as a pro-proliferative factor in ESCC whose expression is regulated by histone acetylation.","method":"TNS3 siRNA knockdown, in vitro proliferation assay, in vivo xenograft model, LMK-235 HDAC inhibitor treatment","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined proliferative phenotype confirmed in both in vitro and in vivo settings, single lab","pmids":["34047714"],"is_preprint":false},{"year":2026,"finding":"IRF1 directly targets TNS3 as a transcriptional regulator, placing TNS3 downstream of IRF1 in a pathway relevant to renal stress, fibrosis, and aging; a mechanistic parallel is proposed and supported by current data between the IRF1-TLR3 antiviral axis and the IRF1-TNS3 renal stress axis.","method":"Chromatin/gene regulation analysis (described as 'current data' linking IRF1 to TNS3 targeting in renal context)","journal":"Current medicinal chemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single paper, abstract provides limited methodological detail about how IRF1 targeting of TNS3 was experimentally established","pmids":["41863168"],"is_preprint":false}],"current_model":"TNS3 (Tensin3) is a cytoskeletal regulatory protein whose expression is controlled epigenetically (via MLL3-dependent enhancer H3K4me1/H3K27ac deposition and CpG promoter methylation) and transcriptionally (by IRF1); loss of TNS3 increases cell migration and cytoskeletal disorganization, while its overexpression promotes proliferation in certain cancer contexts, and chromosomal translocations can generate oncogenic TNS3 fusion proteins (e.g., TNS3-MAP3K3 chimeric kinase)."},"narrative":{"mechanistic_narrative":"TNS3 (Tensin3) is a cytoskeletal regulatory protein that organizes the actin cytoskeleton and restrains cell motility, with haploinsufficiency in patient-derived fibroblasts producing broader, shorter cells, loss of Tensin3 localization along cytoskeletal filaments and the cell periphery, and elevated migration [PMID:23809228]. Its expression is set epigenetically: the histone H3K4 methyltransferase MLL3 deposits H3K4me1 and H3K27ac on an enhancer ~7 kb upstream that physically loops to the TNS3 promoter, and loss of this enhancer regulation enhances migration in a manner fully rescued by re-expressing TNS3 [PMID:33824309], while CpG-island hypermethylation of the TNS3 promoter silences expression and correlates with reduced TNS3 in renal cell carcinoma [PMID:23803643]. In an esophageal squamous cell carcinoma context TNS3 acts as a pro-proliferative factor whose loss impairs growth in vitro and in vivo and sensitizes cells to HDAC inhibition [PMID:34047714]. A t(7;17) translocation in multicystic mesothelioma fuses TNS3 to MAP3K3 to generate a chimeric protein kinase [PMID:25484136]. Beyond these regulatory and phenotypic findings, the biochemical activities of the Tensin3 SH2 and phosphotyrosine-binding domains have not been characterized in the available corpus.","teleology":[{"year":2013,"claim":"Established that Tensin3 is functionally required for normal cytoskeletal organization and for restraining cell migration, rather than being a passive structural marker.","evidence":"RT-PCR, western blot, immunofluorescence and live-cell scratch-wound migration assays in translocation patient-derived fibroblasts versus controls","pmids":["23809228"],"confidence":"Medium","gaps":["Does not identify the molecular partners through which Tensin3 organizes filaments","Loss-of-function based on a single translocation patient line","No biochemical activity assigned to Tensin3 domains"]},{"year":2013,"claim":"Showed that TNS3 expression is controlled by promoter CpG methylation, explaining how the gene is silenced in renal cell carcinoma.","evidence":"Luciferase minimal-promoter assay, pyrosequencing of CpG methylation, and pharmacological demethylation with expression readout in kidney cells","pmids":["23803643"],"confidence":"Medium","gaps":["Correlative link between methylation and cancer phenotype not causally tested","Specific methyltransferases/demethylases not identified","Functional consequence of TNS3 loss in renal cells not assayed here"]},{"year":2014,"claim":"Identified a recurrent oncogenic mechanism in which TNS3 is recombined into a chimeric kinase, implicating the locus in tumorigenic fusion events.","evidence":"RNA-seq, RT-PCR and Sanger sequencing of TNS3-MAP3K3 fusion transcripts from multicystic mesothelioma cells","pmids":["25484136"],"confidence":"Medium","gaps":["Chimeric kinase activity not reconstituted or functionally validated","Contribution of the fusion to transformation untested","Single tumor sample"]},{"year":2021,"claim":"Defined the upstream enhancer logic of TNS3, demonstrating that MLL3-deposited active chromatin marks at a looping enhancer drive TNS3 expression and that this axis controls migration.","evidence":"CRISPR MLL3 depletion, RNA-seq, H3K4me1/H3K27ac ChIP-seq, 3C looping assay, dCas9-KRAB enhancer repression and TNS3 rescue","pmids":["33824309"],"confidence":"High","gaps":["Does not connect enhancer regulation to the methylation-based silencing seen elsewhere","Downstream effectors of TNS3 in migration not resolved"]},{"year":2021,"claim":"Demonstrated a context-dependent pro-proliferative role for TNS3 in cancer, contrasting with its migration-restraining role in fibroblasts.","evidence":"siRNA knockdown of TNS3 with in vitro and xenograft proliferation assays and LMK-235 HDAC inhibitor sensitization in ESCC cells","pmids":["34047714"],"confidence":"Medium","gaps":["Mechanism linking TNS3 to proliferation not defined","Tissue specificity of the pro-proliferative versus migration phenotype unexplained"]},{"year":2026,"claim":"Placed TNS3 downstream of the transcription factor IRF1, extending its regulation into renal stress, fibrosis and aging pathways.","evidence":"Gene-regulation analysis linking IRF1 to TNS3 targeting in a renal context","pmids":["41863168"],"confidence":"Low","gaps":["Limited methodological detail on how IRF1 occupancy/targeting was established","Direct binding versus indirect regulation not distinguished","Functional consequence of the IRF1-TNS3 axis not demonstrated"]},{"year":null,"claim":"The intrinsic biochemical activity of Tensin3 — what its SH2 and phosphotyrosine-binding domains engage to organize the cytoskeleton — remains undefined.","evidence":"No discovery in the corpus assigns a direct molecular partner or catalytic/binding activity to Tensin3 domains","pmids":[],"confidence":"Low","gaps":["No direct binding partners identified","No structural model","Mechanism connecting Tensin3 to actin filaments unknown"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0]}],"pathway":[],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q68CZ2","full_name":"Tensin-3","aliases":["Tensin-like SH2 domain-containing protein 1","Tumor endothelial marker 6"],"length_aa":1445,"mass_kda":155.3,"function":"May act as a protein phosphatase and/or a lipid phosphatase (Probable). Involved in the dissociation of the integrin-tensin-actin complex (PubMed:17643115). EGF activates TNS4 and down-regulates TNS3 which results in capping the tail of ITGB1 (PubMed:17643115). Increases DOCK5 guanine nucleotide exchange activity towards Rac and plays a role in osteoclast podosome organization (By similarity). Enhances RHOA activation in the presence of DLC1 (PubMed:26427649). Required for growth factor-induced epithelial cell migration; growth factor stimulation induces TNS3 phosphorylation which changes its binding preference from DLC1 to the p85 regulatory subunit of the PI3K kinase complex, displacing PI3K inhibitor PTEN and resulting in translocation of the TNS3-p85 complex to the leading edge of migrating cells to promote RAC1 activation (PubMed:26166433). Meanwhile, PTEN switches binding preference from p85 to DLC1 and the PTEN-DLC1 complex translocates to the posterior of migrating cells to activate RHOA (PubMed:26166433). Acts as an adapter protein by bridging the association of scaffolding protein PEAK1 with integrins ITGB1, ITGB3 and ITGB5 which contributes to the promotion of cell migration (PubMed:35687021). Controls tonsil-derived mesenchymal stem cell proliferation and differentiation by regulating the activity of integrin ITGB1 (PubMed:31905841)","subcellular_location":"Cell junction, focal adhesion; Cell projection, podosome","url":"https://www.uniprot.org/uniprotkb/Q68CZ2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TNS3","classification":"Not Classified","n_dependent_lines":152,"n_total_lines":1208,"dependency_fraction":0.12582781456953643},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CSK","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TNS3","total_profiled":1310},"omim":[{"mim_id":"608385","title":"TENSIN 4; TNS4","url":"https://www.omim.org/entry/608385"},{"mim_id":"606825","title":"TENSIN 3; TNS3","url":"https://www.omim.org/entry/606825"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Focal adhesion sites","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TNS3"},"hgnc":{"alias_symbol":["TEM6","H_NH0549I23.2","FLJ13732"],"prev_symbol":["TENS1"]},"alphafold":{"accession":"Q68CZ2","domains":[{"cath_id":"3.90.190.10","chopping":"9-169","consensus_level":"high","plddt":92.6127,"start":9,"end":169},{"cath_id":"2.60.40.1110","chopping":"179-330","consensus_level":"high","plddt":89.3007,"start":179,"end":330},{"cath_id":"3.30.505.10","chopping":"1171-1216_1230-1288","consensus_level":"high","plddt":85.8258,"start":1171,"end":1288},{"cath_id":"2.30.29.30","chopping":"1306-1441","consensus_level":"high","plddt":87.5992,"start":1306,"end":1441}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q68CZ2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q68CZ2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q68CZ2-F1-predicted_aligned_error_v6.png","plddt_mean":56.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TNS3","jax_strain_url":"https://www.jax.org/strain/search?query=TNS3"},"sequence":{"accession":"Q68CZ2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q68CZ2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q68CZ2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q68CZ2"}},"corpus_meta":[{"pmid":"1665171","id":"PMC_1665171","title":"An IS1-like element is responsible for high-level synthesis of extended-spectrum beta-lactamase TEM-6 in Enterobacteriaceae.","date":"1991","source":"Journal of general microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/1665171","citation_count":40,"is_preprint":false},{"pmid":"16251281","id":"PMC_16251281","title":"TEM-109 (CMT-5), a natural complex mutant of TEM-1 beta-lactamase combining the amino acid substitutions of TEM-6 and TEM-33 (IRT-5).","date":"2005","source":"Antimicrobial agents and chemotherapy","url":"https://pubmed.ncbi.nlm.nih.gov/16251281","citation_count":24,"is_preprint":false},{"pmid":"23803643","id":"PMC_23803643","title":"CpG dinucleotide-specific hypermethylation of the TNS3 gene promoter in human renal cell carcinoma.","date":"2013","source":"Epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/23803643","citation_count":22,"is_preprint":false},{"pmid":"33824309","id":"PMC_33824309","title":"MLL3 suppresses tumorigenesis through regulating TNS3 enhancer activity.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/33824309","citation_count":20,"is_preprint":false},{"pmid":"18424204","id":"PMC_18424204","title":"Cytogenetic and molecular characterization of a de-novo t(2p;7p) translocation involving TNS3 and EXOC6B genes in a boy with a complex syndromic phenotype.","date":"2008","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18424204","citation_count":19,"is_preprint":false},{"pmid":"33926026","id":"PMC_33926026","title":"Immunohistochemical Analysis of the Expression of Adhesion Proteins: TNS1, TNS2 and TNS3 in Correlation with Clinicopathological Parameters in Gastric Cancer.","date":"2021","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/33926026","citation_count":17,"is_preprint":false},{"pmid":"25484136","id":"PMC_25484136","title":"Novel TNS3-MAP3K3 and ZFPM2-ELF5 fusion genes identified by RNA sequencing in multicystic mesothelioma with t(7;17)(p12;q23) and t(8;11)(q23;p13).","date":"2014","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/25484136","citation_count":17,"is_preprint":false},{"pmid":"30928649","id":"PMC_30928649","title":"3'UTR variants of TNS3, PHLDB1, NTN4, and GNG2 genes are associated with IgA nephropathy risk in Chinese Han population.","date":"2019","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/30928649","citation_count":16,"is_preprint":false},{"pmid":"34002017","id":"PMC_34002017","title":"A multi-omics study links TNS3 and SEPT7 to long-term former smoking NSCLC survival.","date":"2021","source":"NPJ precision oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34002017","citation_count":12,"is_preprint":false},{"pmid":"39382613","id":"PMC_39382613","title":"EIF4A3-mediated oncogenic circRNA hsa_circ_0001165 advances esophageal squamous cell carcinoma progression through the miR-381-3p/TNS3 pathway.","date":"2024","source":"Cell biology and toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/39382613","citation_count":11,"is_preprint":false},{"pmid":"35987623","id":"PMC_35987623","title":"Abnormal TNS3 gene methylation in patients with congenital scoliosis.","date":"2022","source":"BMC musculoskeletal disorders","url":"https://pubmed.ncbi.nlm.nih.gov/35987623","citation_count":7,"is_preprint":false},{"pmid":"34047714","id":"PMC_34047714","title":"Pharmacological targeting of TNS3 with histone deacetylase inhibitor as a therapeutic strategy in esophageal squamous cell carcinoma.","date":"2021","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/34047714","citation_count":7,"is_preprint":false},{"pmid":"23809228","id":"PMC_23809228","title":"Functional characterisation of human cells harbouring a novel t(2p;7p) translocation involving TNS3 and EXOC6B genes.","date":"2013","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23809228","citation_count":4,"is_preprint":false},{"pmid":"39888120","id":"PMC_39888120","title":"Analysis of TNS3-203 and LRRFIP1-211 Transcripts as Oral Cancer Biomarkers.","date":"2025","source":"Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology","url":"https://pubmed.ncbi.nlm.nih.gov/39888120","citation_count":1,"is_preprint":false},{"pmid":"41923376","id":"PMC_41923376","title":"TNS1 and TNS4 play a potential role in development of pancreatic ductal adenocarcinoma but not TNS2 and TNS3.","date":"2026","source":"Cell adhesion & migration","url":"https://pubmed.ncbi.nlm.nih.gov/41923376","citation_count":0,"is_preprint":false},{"pmid":"41863168","id":"PMC_41863168","title":"IRF1-TNS3 Axis in Renal Injury: Extending Insights from IRF1/IRF2 Antiviral Regulation to Kidney Stress Responses.","date":"2026","source":"Current medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41863168","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.11.25.24317869","title":"Genomic predictors of response to antidepressants in Major depressive disorder (MDD): A GWAS-Based Study on Indian cohort","date":"2024-11-26","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.25.24317869","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.17.24312688","title":"Causal associations between plasma proteins and prostate cancer: a Proteome-Wide Mendelian Randomization","date":"2024-09-18","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.17.24312688","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11128,"output_tokens":1694,"usd":0.029397,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8518,"output_tokens":2232,"usd":0.049195,"stage2_stop_reason":"end_turn"},"total_usd":0.078592,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"TNS3 haploinsufficiency in patient-derived fibroblasts (carrying t(2;7)(p13;p12) translocation) resulted in reduced Tensin3 mRNA and protein levels, broader/shorter cell morphology, loss of Tensin3 localization along cytoskeletal filaments and cell periphery, and a significantly higher cell migration rate compared to control fibroblasts, establishing a role for Tensin3 in cytoskeletal organisation and cell motility.\",\n      \"method\": \"Quantitative RT-PCR, western blot, immunofluorescent confocal microscopy, scratch wound assay with live cell imaging in patient-derived vs. control fibroblasts\",\n      \"journal\": \"BMC medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (western blot, immunofluorescence, live migration assay) in a single lab using a natural loss-of-function model\",\n      \"pmids\": [\"23809228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MLL3 (histone H3K4 methyltransferase) activates TNS3 expression by depositing H3K4me1 and H3K27ac marks on an enhancer ~7 kb upstream of TNS3; this enhancer physically interacts with the TNS3 promoter (confirmed by 3C assay), and loss of MLL3 suppresses TNS3 expression, leading to enhanced cell migration that is fully rescued by exogenous TNS3 re-expression.\",\n      \"method\": \"CRISPR/sgRNA MLL3 depletion, RNA-Seq, ChIP-Seq (H3K4me1, H3K27ac), 3C chromatin conformation assay, dCas9-KRAB enhancer repression, rescue by TNS3 overexpression\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ChIP-Seq, 3C, CRISPR KO, rescue experiment) in a single rigorous study establishing the MLL3→TNS3 enhancer regulatory axis and functional epistasis\",\n      \"pmids\": [\"33824309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The TNS3 gene promoter contains a CpG island with functional minimal promoter activity (demonstrated by luciferase reporter assay); CpG-specific hypermethylation at positions 2 and 8 of this region correlates with reduced TNS3 expression in renal cell carcinoma, and pharmacological demethylation of cultured kidney cells causes ~3-fold upregulation of Tensin3 expression.\",\n      \"method\": \"Luciferase reporter assay for promoter activity, pyrosequencing for CpG methylation quantification, pharmacological demethylation treatment with expression measurement\",\n      \"journal\": \"Epigenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional promoter assay plus demethylation rescue, multiple orthogonal methods in a single lab\",\n      \"pmids\": [\"23803643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A t(7;17)(p13;q23) chromosomal translocation in multicystic mesothelioma generates a chimeric TNS3-MAP3K3 fusion gene encoding a chimeric protein kinase, and the reciprocal MAP3K3-TNS3 fusion places the SH2_Tensin_like and phosphotyrosine-binding domains of TNS3 under MAP3K3 promoter control.\",\n      \"method\": \"RNA-sequencing, RT-PCR, Sanger sequencing of fusion transcripts from tumor-derived cell culture\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — fusion transcript identification confirmed by RT-PCR and Sanger sequencing, single lab, no functional reconstitution of the chimeric kinase\",\n      \"pmids\": [\"25484136\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Silencing TNS3 in esophageal squamous cell carcinoma (ESCC) cells significantly inhibited cell proliferation in vitro and in vivo, and sensitized cells to the HDAC inhibitor LMK-235, establishing TNS3 as a pro-proliferative factor in ESCC whose expression is regulated by histone acetylation.\",\n      \"method\": \"TNS3 siRNA knockdown, in vitro proliferation assay, in vivo xenograft model, LMK-235 HDAC inhibitor treatment\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined proliferative phenotype confirmed in both in vitro and in vivo settings, single lab\",\n      \"pmids\": [\"34047714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"IRF1 directly targets TNS3 as a transcriptional regulator, placing TNS3 downstream of IRF1 in a pathway relevant to renal stress, fibrosis, and aging; a mechanistic parallel is proposed and supported by current data between the IRF1-TLR3 antiviral axis and the IRF1-TNS3 renal stress axis.\",\n      \"method\": \"Chromatin/gene regulation analysis (described as 'current data' linking IRF1 to TNS3 targeting in renal context)\",\n      \"journal\": \"Current medicinal chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single paper, abstract provides limited methodological detail about how IRF1 targeting of TNS3 was experimentally established\",\n      \"pmids\": [\"41863168\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TNS3 (Tensin3) is a cytoskeletal regulatory protein whose expression is controlled epigenetically (via MLL3-dependent enhancer H3K4me1/H3K27ac deposition and CpG promoter methylation) and transcriptionally (by IRF1); loss of TNS3 increases cell migration and cytoskeletal disorganization, while its overexpression promotes proliferation in certain cancer contexts, and chromosomal translocations can generate oncogenic TNS3 fusion proteins (e.g., TNS3-MAP3K3 chimeric kinase).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TNS3 (Tensin3) is a cytoskeletal regulatory protein that organizes the actin cytoskeleton and restrains cell motility, with haploinsufficiency in patient-derived fibroblasts producing broader, shorter cells, loss of Tensin3 localization along cytoskeletal filaments and the cell periphery, and elevated migration [#0]. Its expression is set epigenetically: the histone H3K4 methyltransferase MLL3 deposits H3K4me1 and H3K27ac on an enhancer ~7 kb upstream that physically loops to the TNS3 promoter, and loss of this enhancer regulation enhances migration in a manner fully rescued by re-expressing TNS3 [#1], while CpG-island hypermethylation of the TNS3 promoter silences expression and correlates with reduced TNS3 in renal cell carcinoma [#2]. In an esophageal squamous cell carcinoma context TNS3 acts as a pro-proliferative factor whose loss impairs growth in vitro and in vivo and sensitizes cells to HDAC inhibition [#4]. A t(7;17) translocation in multicystic mesothelioma fuses TNS3 to MAP3K3 to generate a chimeric protein kinase [#3]. Beyond these regulatory and phenotypic findings, the biochemical activities of the Tensin3 SH2 and phosphotyrosine-binding domains have not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established that Tensin3 is functionally required for normal cytoskeletal organization and for restraining cell migration, rather than being a passive structural marker.\",\n      \"evidence\": \"RT-PCR, western blot, immunofluorescence and live-cell scratch-wound migration assays in translocation patient-derived fibroblasts versus controls\",\n      \"pmids\": [\"23809228\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not identify the molecular partners through which Tensin3 organizes filaments\", \"Loss-of-function based on a single translocation patient line\", \"No biochemical activity assigned to Tensin3 domains\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed that TNS3 expression is controlled by promoter CpG methylation, explaining how the gene is silenced in renal cell carcinoma.\",\n      \"evidence\": \"Luciferase minimal-promoter assay, pyrosequencing of CpG methylation, and pharmacological demethylation with expression readout in kidney cells\",\n      \"pmids\": [\"23803643\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Correlative link between methylation and cancer phenotype not causally tested\", \"Specific methyltransferases/demethylases not identified\", \"Functional consequence of TNS3 loss in renal cells not assayed here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified a recurrent oncogenic mechanism in which TNS3 is recombined into a chimeric kinase, implicating the locus in tumorigenic fusion events.\",\n      \"evidence\": \"RNA-seq, RT-PCR and Sanger sequencing of TNS3-MAP3K3 fusion transcripts from multicystic mesothelioma cells\",\n      \"pmids\": [\"25484136\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Chimeric kinase activity not reconstituted or functionally validated\", \"Contribution of the fusion to transformation untested\", \"Single tumor sample\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined the upstream enhancer logic of TNS3, demonstrating that MLL3-deposited active chromatin marks at a looping enhancer drive TNS3 expression and that this axis controls migration.\",\n      \"evidence\": \"CRISPR MLL3 depletion, RNA-seq, H3K4me1/H3K27ac ChIP-seq, 3C looping assay, dCas9-KRAB enhancer repression and TNS3 rescue\",\n      \"pmids\": [\"33824309\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not connect enhancer regulation to the methylation-based silencing seen elsewhere\", \"Downstream effectors of TNS3 in migration not resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated a context-dependent pro-proliferative role for TNS3 in cancer, contrasting with its migration-restraining role in fibroblasts.\",\n      \"evidence\": \"siRNA knockdown of TNS3 with in vitro and xenograft proliferation assays and LMK-235 HDAC inhibitor sensitization in ESCC cells\",\n      \"pmids\": [\"34047714\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking TNS3 to proliferation not defined\", \"Tissue specificity of the pro-proliferative versus migration phenotype unexplained\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Placed TNS3 downstream of the transcription factor IRF1, extending its regulation into renal stress, fibrosis and aging pathways.\",\n      \"evidence\": \"Gene-regulation analysis linking IRF1 to TNS3 targeting in a renal context\",\n      \"pmids\": [\"41863168\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Limited methodological detail on how IRF1 occupancy/targeting was established\", \"Direct binding versus indirect regulation not distinguished\", \"Functional consequence of the IRF1-TNS3 axis not demonstrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The intrinsic biochemical activity of Tensin3 — what its SH2 and phosphotyrosine-binding domains engage to organize the cytoskeleton — remains undefined.\",\n      \"evidence\": \"No discovery in the corpus assigns a direct molecular partner or catalytic/binding activity to Tensin3 domains\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct binding partners identified\", \"No structural model\", \"Mechanism connecting Tensin3 to actin filaments unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}