{"gene":"TNS2","run_date":"2026-04-28T21:42:59","timeline":{"discoveries":[{"year":2002,"finding":"TNS2 (C1-TEN) was identified as an intracellular binding partner for the Axl receptor tyrosine kinase (RTK), interacting via both its SH2 and PTB domains with the Axl cytoplasmic domain, as demonstrated by yeast two-hybrid screening and co-immunoprecipitation in mammalian cells.","method":"Yeast two-hybrid screen, co-immunoprecipitation, in vitro translation","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 — reciprocal two-hybrid and Co-IP with domain-level mapping, replicated in two assay systems","pmids":["12470648"],"is_preprint":false},{"year":2005,"finding":"TNS2 (C1-TEN) functions as a phosphatase that negatively regulates Akt/PKB signaling; overexpression reduced Akt phosphorylation and enzymatic activity, reduced GSK3 phosphorylation, inhibited cell proliferation and migration, and increased apoptosis. Mutation of the putative active-site cysteine (C231S) fully restored Akt activation and cell proliferation, confirming phosphatase-dependent activity.","method":"Stable overexpression, active-site mutagenesis (C231S), Akt kinase assay, caspase-3 activity assay, cell proliferation and migration assays","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 1-2 — active-site mutagenesis combined with multiple orthogonal functional readouts in the same study","pmids":["15817639"],"is_preprint":false},{"year":2013,"finding":"TNS2 (C1-TEN) is a protein tyrosine phosphatase (PTPase) that dephosphorylates IRS-1 preferentially at Y612, thereby accelerating IRS-1 proteasomal degradation, reducing PI3K activity, activating FoxO transcription factors, and causing skeletal muscle atrophy. C1-Ten expression is upregulated by glucocorticoids and downregulated by insulin.","method":"In vitro phosphatase assay, site-directed mutagenesis, Western blot, loss-of-function and gain-of-function in cell and mouse models","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 — direct enzymatic substrate identification with site specificity, multiple in vitro and in vivo experiments","pmids":["23401856"],"is_preprint":false},{"year":2013,"finding":"Tenc1 (tensin2/TNS2) is required for normal assembly and maturation of the glomerular basement membrane (GBM) and maintenance of podocyte foot processes; loss of function in a susceptible genetic background (DBA/2J) leads to nephrotic syndrome with GBM abnormalities consistent with disrupted integrin signaling.","method":"Genetic mouse model (Tenc1 mutant ICGN strain on two genetic backgrounds), histological and biochemical analysis","journal":"Nephron. Experimental nephrology","confidence":"Medium","confidence_rationale":"Tier 2 — clean knockout/mutant with defined kidney phenotype and pathway context, but single lab and no in vitro reconstitution","pmids":["23988887"],"is_preprint":false},{"year":2014,"finding":"p62/SQSTM1 sequesters TNS2 (C1-TEN) into cytoplasmic puncta and promotes its ubiquitination and proteasomal degradation; p62 depletion causes C1-Ten to diffuse into the cytoplasm. This regulation is specific to C1-Ten and not to tensin1 or tensin3. p62 expression increases during muscle differentiation, correlating with decreased C1-Ten protein levels.","method":"Co-immunoprecipitation, siRNA knockdown, ubiquitination assay, fluorescence imaging, proteasome inhibitor treatment","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2-3 — direct interaction demonstrated by Co-IP plus functional ubiquitination and degradation assays, single lab","pmids":["25101860"],"is_preprint":false},{"year":2017,"finding":"TNS2 (C1-TEN) acts as a PTPase on nephrin at its PI3K binding site, redirecting PI3K toward IRS-1 and thereby activating mTORC1, leading to podocyte hypertrophy and proteinuria in diabetic kidney disease. C1-Ten levels are elevated in diabetic kidneys and high-glucose-treated podocytes.","method":"In vitro phosphatase assay with nephrin substrate, cell-based mTORC1 activity measurement, in vivo mouse model of diabetic nephropathy, siRNA knockdown","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1-2 — direct enzymatic substrate identification, mechanistic pathway placement, validated in vitro and in vivo","pmids":["28955049"],"is_preprint":false},{"year":2017,"finding":"Pharmacological inhibition of TNS2 (C1-TEN) PTPase activity by 15,16-dihydrotanshinone I (DHTS) increases IRS-1 stability, improves glucose tolerance, and reveals a new function of C1-Ten in AMPK inhibition, suggesting C1-Ten regulates AMPK signaling possibly through IRS-1.","method":"Small-molecule inhibitor treatment, glucose tolerance assay, IRS-1 stability assay, AMPK activity measurement in cell and mouse models","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological inhibitor with mechanistic readouts, but indirect inhibition approach; single lab","pmids":["29259227"],"is_preprint":false},{"year":2018,"finding":"The cellular phosphatase activity of TNS2 (C1-Ten/Tensin2) on IRS-1 is controlled by binding of the C1-Ten SH2 domain to phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3), forming a negative feedback loop in insulin signaling. Three basic residues in the SH2 domain critical for PtdIns(3,4,5)P3 binding (but not phosphotyrosine binding or PTP activity) were identified by mutagenesis; a PtdIns(3,4,5)P3 binding-deficient mutant abolished cellular PTP activity toward IRS-1.","method":"Lipid-binding assay, site-directed mutagenesis, in vitro phosphatase assay, cell-based IRS-1 dephosphorylation assay, PI3K inhibition experiments","journal":"Cellular signalling","confidence":"High","confidence_rationale":"Tier 1 — reconstitution-level binding assay combined with structure-informed mutagenesis and functional validation in cells","pmids":["30092354"],"is_preprint":false},{"year":2018,"finding":"AXL receptor tyrosine kinase phosphorylates TNS2, and this phosphorylation releases TNS2 from interaction with IRS-1, thereby increasing IRS-1 stability. The AXL/TNS2/IRS-1 cross-talk upregulates aerobic glycolysis enzymes Glut4 and PDK1 in cancer cells.","method":"Co-immunoprecipitation, IP-Western blot, Western blot for phosphorylation substrates","journal":"Journal of biomedical science","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP/IP-Western showing phosphorylation and interaction changes, but single lab and no in vitro reconstitution of kinase reaction","pmids":["30419905"],"is_preprint":false},{"year":2011,"finding":"Complete NMR chemical shift assignments of the SH2 domain of human TNS2 (TENC1) were determined, providing a structural basis for understanding its interactions with tyrosine-phosphorylated proteins and DLC1 recruitment to focal adhesions in a phosphotyrosine-independent manner.","method":"Triple-resonance NMR spectroscopy (1H, 15N, 13C chemical shift assignment)","journal":"Biomolecular NMR assignments","confidence":"Low","confidence_rationale":"Tier 1 method (NMR) but no functional validation in this paper; assignments only","pmids":["21461930"],"is_preprint":false}],"current_model":"TNS2 (C1-TEN/Tensin2) is a multi-domain focal adhesion protein with intrinsic protein tyrosine phosphatase (PTPase) activity that negatively regulates Akt/PKB signaling by dephosphorylating IRS-1 (at Y612) and nephrin, with its cellular phosphatase activity controlled by binding of its SH2 domain to PtdIns(3,4,5)P3; it is also a phosphorylation substrate and binding partner of the Axl receptor tyrosine kinase, and its protein levels are regulated by p62/SQSTM1-mediated sequestration and proteasomal degradation, collectively placing TNS2 as a feedback regulator of insulin/PI3K/Akt signaling with roles in muscle atrophy, podocyte function, and cell proliferation/migration."},"narrative":{"teleology":[{"year":2002,"claim":"Identifying TNS2 as a physical partner of the Axl RTK established that this multi-domain protein participates in receptor tyrosine kinase signaling complexes.","evidence":"Yeast two-hybrid screen and co-immunoprecipitation in mammalian cells with domain mapping","pmids":["12470648"],"confidence":"High","gaps":["Functional consequence of TNS2–Axl interaction unknown","Whether Axl phosphorylates TNS2 not tested","Cellular context of interaction (which tissues/cell types) undefined"]},{"year":2005,"claim":"Demonstrating that TNS2 overexpression suppresses Akt phosphorylation and cell proliferation in a catalytic-cysteine-dependent manner established TNS2 as a bona fide phosphatase that negatively regulates PI3K/Akt signaling.","evidence":"Active-site C231S mutagenesis coupled with Akt kinase assays, caspase-3 activity, and proliferation/migration assays","pmids":["15817639"],"confidence":"High","gaps":["Direct phosphatase substrate not identified","Lipid vs. protein phosphatase activity not distinguished","In vivo relevance untested"]},{"year":2011,"claim":"NMR chemical shift assignment of the TNS2 SH2 domain provided the structural foundation for understanding how this domain engages phosphotyrosine-containing ligands and recruits partners such as DLC1.","evidence":"Triple-resonance NMR spectroscopy on recombinant SH2 domain","pmids":["21461930"],"confidence":"Low","gaps":["No functional validation or ligand-bound structure determined","Relevance of DLC1 recruitment to TNS2 biology not tested","No binding affinity measurements"]},{"year":2013,"claim":"Identification of IRS-1 Y612 as a direct TNS2 substrate and demonstration that glucocorticoid-induced TNS2 drives IRS-1 degradation, FoxO activation, and muscle atrophy provided the first substrate-specific mechanism for TNS2 phosphatase activity in metabolic regulation.","evidence":"In vitro phosphatase assay with site-directed mutagenesis, gain/loss-of-function in cell lines and mouse models","pmids":["23401856"],"confidence":"High","gaps":["Whether TNS2 acts on other IRS-1 phosphotyrosine sites not fully resolved","Structural basis of substrate recognition unknown","Contribution relative to other phosphatases in muscle unclear"]},{"year":2013,"claim":"Loss-of-function studies in mice revealed that TNS2 is essential for glomerular basement membrane assembly and podocyte foot process maintenance, linking TNS2 to nephrotic syndrome in a strain-dependent manner.","evidence":"Tenc1-mutant ICGN mice on DBA/2J vs. B6 backgrounds with histological and biochemical analysis","pmids":["23988887"],"confidence":"Medium","gaps":["Molecular mechanism in podocytes not reconstituted in vitro","Modifier genes on permissive background unidentified","No rescue experiment reported"]},{"year":2014,"claim":"Discovery that p62/SQSTM1 sequesters TNS2 into puncta and promotes its ubiquitin-dependent proteasomal degradation revealed a post-translational mechanism controlling TNS2 protein levels, particularly during muscle differentiation.","evidence":"Co-immunoprecipitation, siRNA, ubiquitination assays, proteasome inhibitor treatment, fluorescence imaging","pmids":["25101860"],"confidence":"Medium","gaps":["E3 ubiquitin ligase responsible not identified","Direct vs. indirect p62-mediated ubiquitination not resolved","Physiological consequence of altered TNS2 turnover in muscle not fully demonstrated"]},{"year":2017,"claim":"Identification of nephrin as a second TNS2 PTPase substrate explained how TNS2 upregulation in diabetic kidneys redirects PI3K toward mTORC1, causing podocyte hypertrophy and proteinuria.","evidence":"In vitro phosphatase assay on nephrin, mTORC1 activity measurement, diabetic nephropathy mouse model, siRNA knockdown","pmids":["28955049"],"confidence":"High","gaps":["Specific nephrin phosphotyrosine site targeted not pinpointed","Whether TNS2 inhibition reverses established diabetic nephropathy untested","Contribution of TNS2 vs. other phosphatases in podocytes not quantified"]},{"year":2017,"claim":"Pharmacological inhibition of TNS2 by DHTS improved glucose tolerance and revealed AMPK as a downstream pathway, broadening the metabolic reach of TNS2 beyond Akt.","evidence":"Small-molecule inhibitor treatment with glucose tolerance tests and AMPK activity measurement in cell and mouse models","pmids":["29259227"],"confidence":"Medium","gaps":["DHTS selectivity for TNS2 over other phosphatases not rigorously established","Whether AMPK regulation is direct or via IRS-1 not resolved","Single lab finding"]},{"year":2018,"claim":"Demonstrating that PtdIns(3,4,5)P3 binding to the SH2 domain gates TNS2 cellular phosphatase activity established a lipid-sensing negative feedback loop in insulin/PI3K signaling.","evidence":"Lipid-binding assay, structure-informed mutagenesis of three basic SH2 residues, cell-based IRS-1 dephosphorylation assay","pmids":["30092354"],"confidence":"High","gaps":["Structural model of SH2–PIP3 complex not solved","Whether PIP3 binding also regulates nephrin dephosphorylation untested","In vivo validation of the PIP3 switch not performed"]},{"year":2018,"claim":"Showing that AXL phosphorylates TNS2 and that this dissociates TNS2 from IRS-1 completed a receptor-to-phosphatase regulatory circuit and linked TNS2 to cancer cell glycolytic reprogramming.","evidence":"Co-immunoprecipitation and IP-Western blot in cancer cells","pmids":["30419905"],"confidence":"Medium","gaps":["AXL phosphorylation sites on TNS2 not mapped","No in vitro kinase assay to confirm direct phosphorylation","Generalizability beyond the tested cancer cell lines unclear"]},{"year":null,"claim":"Key unresolved questions include the structural basis of TNS2 substrate selectivity, the identity of the E3 ligase mediating p62-driven TNS2 degradation, whether the PIP3-gating mechanism applies to nephrin dephosphorylation, and whether TNS2 has additional physiological substrates beyond IRS-1 and nephrin.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure of full-length TNS2 or its PTP domain","E3 ligase for TNS2 ubiquitination unidentified","Comprehensive substrate profiling not performed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2,5,7]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,2,5,7,8]}],"complexes":[],"partners":["AXL","IRS1","SQSTM1","NPHS1"],"other_free_text":[]},"mechanistic_narrative":"TNS2 (C1-TEN/Tensin2) is a focal adhesion-associated protein tyrosine phosphatase that functions as a negative feedback regulator of PI3K/Akt signaling. Its PTPase domain dephosphorylates IRS-1 at Y612, accelerating IRS-1 proteasomal degradation and thereby suppressing PI3K activity, Akt phosphorylation, and downstream signaling—effects abolished by active-site mutation (C231S)—leading to FoxO activation and skeletal muscle atrophy under glucocorticoid stimulation [PMID:23401856, PMID:15817639]. TNS2 also dephosphorylates nephrin at its PI3K-binding site, redirecting PI3K toward IRS-1/mTORC1 and contributing to podocyte hypertrophy in diabetic nephropathy, while loss-of-function in mice causes nephrotic syndrome with glomerular basement membrane defects [PMID:28955049, PMID:23988887]. The cellular phosphatase activity of TNS2 is gated by PtdIns(3,4,5)P3 binding to its SH2 domain, and TNS2 protein levels are regulated by p62/SQSTM1-mediated sequestration and proteasomal degradation as well as by AXL-dependent phosphorylation that dissociates TNS2 from IRS-1 [PMID:30092354, PMID:25101860, PMID:30419905]."},"prefetch_data":{"uniprot":{"accession":"Q63HR2","full_name":"Tensin-2","aliases":["C1 domain-containing phosphatase and tensin homolog","C1-TEN","Tensin-like C1 domain-containing phosphatase"],"length_aa":1409,"mass_kda":152.6,"function":"Tyrosine-protein phosphatase which regulates cell motility, proliferation and muscle-response to insulin (PubMed:15817639, PubMed:23401856). Phosphatase activity is mediated by binding to phosphatidylinositol-3,4,5-triphosphate (PtdIns(3,4,5)P3) via the SH2 domain (PubMed:30092354). In muscles and under catabolic conditions, dephosphorylates IRS1 leading to its degradation and muscle atrophy (PubMed:23401856, PubMed:30092354). Negatively regulates PI3K-AKT pathway activation (PubMed:15817639, PubMed:23401856, PubMed:30092354). Dephosphorylates nephrin NPHS1 in podocytes which regulates activity of the mTORC1 complex (PubMed:28955049). Under normal glucose conditions, NPHS1 outcompetes IRS1 for binding to phosphatidylinositol 3-kinase (PI3K) which balances mTORC1 activity but high glucose conditions lead to up-regulation of TNS2, increased NPHS1 dephosphorylation and activation of mTORC1, contributing to podocyte hypertrophy and proteinuria (PubMed:28955049). Required for correct podocyte morphology, podocyte-glomerular basement membrane interaction and integrity of the glomerular filtration barrier (By similarity). Enhances RHOA activation in the presence of DLC1 (PubMed:26427649). Plays a role in promoting DLC1-dependent remodeling of the extracellular matrix (PubMed:20069572)","subcellular_location":"Cell junction, focal adhesion; Cell membrane; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q63HR2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TNS2","classification":"Not Classified","n_dependent_lines":57,"n_total_lines":1208,"dependency_fraction":0.04718543046357616},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TNS2","total_profiled":1310},"omim":[{"mim_id":"607717","title":"TENSIN 2; TNS2","url":"https://www.omim.org/entry/607717"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TNS2"},"hgnc":{"alias_symbol":["KIAA1075","C1-TEN"],"prev_symbol":["TENC1"]},"alphafold":{"accession":"Q63HR2","domains":[{"cath_id":"3.30.60.20","chopping":"35-82","consensus_level":"high","plddt":88.8892,"start":35,"end":82},{"cath_id":"3.90.190.10","chopping":"121-296","consensus_level":"medium","plddt":88.5727,"start":121,"end":296},{"cath_id":"2.60.40.1110","chopping":"299-429","consensus_level":"medium","plddt":89.1792,"start":299,"end":429},{"cath_id":"3.30.505.10","chopping":"1137-1184_1197-1234","consensus_level":"high","plddt":88.8617,"start":1137,"end":1234},{"cath_id":"2.30.29.30","chopping":"1269-1407","consensus_level":"high","plddt":86.7586,"start":1269,"end":1407}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q63HR2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q63HR2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q63HR2-F1-predicted_aligned_error_v6.png","plddt_mean":58.34},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TNS2","jax_strain_url":"https://www.jax.org/strain/search?query=TNS2"},"sequence":{"accession":"Q63HR2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q63HR2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q63HR2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q63HR2"}},"corpus_meta":[{"pmid":"15817639","id":"PMC_15817639","title":"C1-TEN is a negative regulator of the Akt/PKB signal transduction pathway and inhibits cell survival, proliferation, and migration.","date":"2005","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/15817639","citation_count":79,"is_preprint":false},{"pmid":"12470648","id":"PMC_12470648","title":"Interaction of Axl receptor tyrosine kinase with C1-TEN, a novel C1 domain-containing protein with homology to tensin.","date":"2002","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/12470648","citation_count":69,"is_preprint":false},{"pmid":"23401856","id":"PMC_23401856","title":"C1-Ten is a protein tyrosine phosphatase of insulin receptor substrate 1 (IRS-1), regulating IRS-1 stability and muscle atrophy.","date":"2013","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/23401856","citation_count":34,"is_preprint":false},{"pmid":"23988887","id":"PMC_23988887","title":"Tenc1-deficient mice develop glomerular disease in a strain-specific manner.","date":"2013","source":"Nephron. Experimental nephrology","url":"https://pubmed.ncbi.nlm.nih.gov/23988887","citation_count":19,"is_preprint":false},{"pmid":"30419905","id":"PMC_30419905","title":"AXL phosphorylates and up-regulates TNS2 and its implications in IRS-1-associated metabolism in cancer cells.","date":"2018","source":"Journal of biomedical science","url":"https://pubmed.ncbi.nlm.nih.gov/30419905","citation_count":17,"is_preprint":false},{"pmid":"29259227","id":"PMC_29259227","title":"Inhibition of C1-Ten PTPase activity reduces insulin resistance through IRS-1 and AMPK pathways.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29259227","citation_count":17,"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":16,"is_preprint":false},{"pmid":"28955049","id":"PMC_28955049","title":"C1-Ten is a PTPase of nephrin, regulating podocyte hypertrophy through mTORC1 activation.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28955049","citation_count":16,"is_preprint":false},{"pmid":"30092354","id":"PMC_30092354","title":"Cellular phosphatase activity of C1-Ten/Tensin2 is controlled by Phosphatidylinositol-3,4,5-triphosphate binding through the C1-Ten/Tensin2 SH2 domain.","date":"2018","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/30092354","citation_count":13,"is_preprint":false},{"pmid":"25101860","id":"PMC_25101860","title":"Regulation of C1-Ten protein tyrosine phosphatase by p62/SQSTM1-mediated sequestration and degradation.","date":"2014","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/25101860","citation_count":3,"is_preprint":false},{"pmid":"21461930","id":"PMC_21461930","title":"1H, 15N and 13C chemical shift assignments of the SH2 domain of human tensin2 (TENC1).","date":"2011","source":"Biomolecular NMR assignments","url":"https://pubmed.ncbi.nlm.nih.gov/21461930","citation_count":2,"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":"40865979","id":"PMC_40865979","title":"Adult-Onset Nephrotic Syndrome due to a Homozygous TNS2 Truncating Variant: Broadening the Mutational Spectrum.","date":"2025","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/40865979","citation_count":0,"is_preprint":false},{"pmid":"41739851","id":"PMC_41739851","title":"Hypothalamic-Pituitary Deficiency after Radiation in Childhood Cancer Survivors is Associated with Rare Variants in TNS2.","date":"2026","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/41739851","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7731,"output_tokens":2611,"usd":0.031179},"stage2":{"model":"claude-opus-4-6","input_tokens":5913,"output_tokens":2656,"usd":0.143948},"total_usd":0.175127,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"TNS2 (C1-TEN) was identified as an intracellular binding partner for the Axl receptor tyrosine kinase (RTK), interacting via both its SH2 and PTB domains with the Axl cytoplasmic domain, as demonstrated by yeast two-hybrid screening and co-immunoprecipitation in mammalian cells.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, in vitro translation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal two-hybrid and Co-IP with domain-level mapping, replicated in two assay systems\",\n      \"pmids\": [\"12470648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TNS2 (C1-TEN) functions as a phosphatase that negatively regulates Akt/PKB signaling; overexpression reduced Akt phosphorylation and enzymatic activity, reduced GSK3 phosphorylation, inhibited cell proliferation and migration, and increased apoptosis. Mutation of the putative active-site cysteine (C231S) fully restored Akt activation and cell proliferation, confirming phosphatase-dependent activity.\",\n      \"method\": \"Stable overexpression, active-site mutagenesis (C231S), Akt kinase assay, caspase-3 activity assay, cell proliferation and migration assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — active-site mutagenesis combined with multiple orthogonal functional readouts in the same study\",\n      \"pmids\": [\"15817639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TNS2 (C1-TEN) is a protein tyrosine phosphatase (PTPase) that dephosphorylates IRS-1 preferentially at Y612, thereby accelerating IRS-1 proteasomal degradation, reducing PI3K activity, activating FoxO transcription factors, and causing skeletal muscle atrophy. C1-Ten expression is upregulated by glucocorticoids and downregulated by insulin.\",\n      \"method\": \"In vitro phosphatase assay, site-directed mutagenesis, Western blot, loss-of-function and gain-of-function in cell and mouse models\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct enzymatic substrate identification with site specificity, multiple in vitro and in vivo experiments\",\n      \"pmids\": [\"23401856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Tenc1 (tensin2/TNS2) is required for normal assembly and maturation of the glomerular basement membrane (GBM) and maintenance of podocyte foot processes; loss of function in a susceptible genetic background (DBA/2J) leads to nephrotic syndrome with GBM abnormalities consistent with disrupted integrin signaling.\",\n      \"method\": \"Genetic mouse model (Tenc1 mutant ICGN strain on two genetic backgrounds), histological and biochemical analysis\",\n      \"journal\": \"Nephron. Experimental nephrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean knockout/mutant with defined kidney phenotype and pathway context, but single lab and no in vitro reconstitution\",\n      \"pmids\": [\"23988887\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"p62/SQSTM1 sequesters TNS2 (C1-TEN) into cytoplasmic puncta and promotes its ubiquitination and proteasomal degradation; p62 depletion causes C1-Ten to diffuse into the cytoplasm. This regulation is specific to C1-Ten and not to tensin1 or tensin3. p62 expression increases during muscle differentiation, correlating with decreased C1-Ten protein levels.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, ubiquitination assay, fluorescence imaging, proteasome inhibitor treatment\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — direct interaction demonstrated by Co-IP plus functional ubiquitination and degradation assays, single lab\",\n      \"pmids\": [\"25101860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TNS2 (C1-TEN) acts as a PTPase on nephrin at its PI3K binding site, redirecting PI3K toward IRS-1 and thereby activating mTORC1, leading to podocyte hypertrophy and proteinuria in diabetic kidney disease. C1-Ten levels are elevated in diabetic kidneys and high-glucose-treated podocytes.\",\n      \"method\": \"In vitro phosphatase assay with nephrin substrate, cell-based mTORC1 activity measurement, in vivo mouse model of diabetic nephropathy, siRNA knockdown\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct enzymatic substrate identification, mechanistic pathway placement, validated in vitro and in vivo\",\n      \"pmids\": [\"28955049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Pharmacological inhibition of TNS2 (C1-TEN) PTPase activity by 15,16-dihydrotanshinone I (DHTS) increases IRS-1 stability, improves glucose tolerance, and reveals a new function of C1-Ten in AMPK inhibition, suggesting C1-Ten regulates AMPK signaling possibly through IRS-1.\",\n      \"method\": \"Small-molecule inhibitor treatment, glucose tolerance assay, IRS-1 stability assay, AMPK activity measurement in cell and mouse models\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological inhibitor with mechanistic readouts, but indirect inhibition approach; single lab\",\n      \"pmids\": [\"29259227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The cellular phosphatase activity of TNS2 (C1-Ten/Tensin2) on IRS-1 is controlled by binding of the C1-Ten SH2 domain to phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3), forming a negative feedback loop in insulin signaling. Three basic residues in the SH2 domain critical for PtdIns(3,4,5)P3 binding (but not phosphotyrosine binding or PTP activity) were identified by mutagenesis; a PtdIns(3,4,5)P3 binding-deficient mutant abolished cellular PTP activity toward IRS-1.\",\n      \"method\": \"Lipid-binding assay, site-directed mutagenesis, in vitro phosphatase assay, cell-based IRS-1 dephosphorylation assay, PI3K inhibition experiments\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution-level binding assay combined with structure-informed mutagenesis and functional validation in cells\",\n      \"pmids\": [\"30092354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"AXL receptor tyrosine kinase phosphorylates TNS2, and this phosphorylation releases TNS2 from interaction with IRS-1, thereby increasing IRS-1 stability. The AXL/TNS2/IRS-1 cross-talk upregulates aerobic glycolysis enzymes Glut4 and PDK1 in cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, IP-Western blot, Western blot for phosphorylation substrates\",\n      \"journal\": \"Journal of biomedical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP/IP-Western showing phosphorylation and interaction changes, but single lab and no in vitro reconstitution of kinase reaction\",\n      \"pmids\": [\"30419905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Complete NMR chemical shift assignments of the SH2 domain of human TNS2 (TENC1) were determined, providing a structural basis for understanding its interactions with tyrosine-phosphorylated proteins and DLC1 recruitment to focal adhesions in a phosphotyrosine-independent manner.\",\n      \"method\": \"Triple-resonance NMR spectroscopy (1H, 15N, 13C chemical shift assignment)\",\n      \"journal\": \"Biomolecular NMR assignments\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 1 method (NMR) but no functional validation in this paper; assignments only\",\n      \"pmids\": [\"21461930\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TNS2 (C1-TEN/Tensin2) is a multi-domain focal adhesion protein with intrinsic protein tyrosine phosphatase (PTPase) activity that negatively regulates Akt/PKB signaling by dephosphorylating IRS-1 (at Y612) and nephrin, with its cellular phosphatase activity controlled by binding of its SH2 domain to PtdIns(3,4,5)P3; it is also a phosphorylation substrate and binding partner of the Axl receptor tyrosine kinase, and its protein levels are regulated by p62/SQSTM1-mediated sequestration and proteasomal degradation, collectively placing TNS2 as a feedback regulator of insulin/PI3K/Akt signaling with roles in muscle atrophy, podocyte function, and cell proliferation/migration.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TNS2 (C1-TEN/Tensin2) is a focal adhesion-associated protein tyrosine phosphatase that functions as a negative feedback regulator of PI3K/Akt signaling. Its PTPase domain dephosphorylates IRS-1 at Y612, accelerating IRS-1 proteasomal degradation and thereby suppressing PI3K activity, Akt phosphorylation, and downstream signaling—effects abolished by active-site mutation (C231S)—leading to FoxO activation and skeletal muscle atrophy under glucocorticoid stimulation [PMID:23401856, PMID:15817639]. TNS2 also dephosphorylates nephrin at its PI3K-binding site, redirecting PI3K toward IRS-1/mTORC1 and contributing to podocyte hypertrophy in diabetic nephropathy, while loss-of-function in mice causes nephrotic syndrome with glomerular basement membrane defects [PMID:28955049, PMID:23988887]. The cellular phosphatase activity of TNS2 is gated by PtdIns(3,4,5)P3 binding to its SH2 domain, and TNS2 protein levels are regulated by p62/SQSTM1-mediated sequestration and proteasomal degradation as well as by AXL-dependent phosphorylation that dissociates TNS2 from IRS-1 [PMID:30092354, PMID:25101860, PMID:30419905].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Identifying TNS2 as a physical partner of the Axl RTK established that this multi-domain protein participates in receptor tyrosine kinase signaling complexes.\",\n      \"evidence\": \"Yeast two-hybrid screen and co-immunoprecipitation in mammalian cells with domain mapping\",\n      \"pmids\": [\"12470648\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Functional consequence of TNS2–Axl interaction unknown\",\n        \"Whether Axl phosphorylates TNS2 not tested\",\n        \"Cellular context of interaction (which tissues/cell types) undefined\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrating that TNS2 overexpression suppresses Akt phosphorylation and cell proliferation in a catalytic-cysteine-dependent manner established TNS2 as a bona fide phosphatase that negatively regulates PI3K/Akt signaling.\",\n      \"evidence\": \"Active-site C231S mutagenesis coupled with Akt kinase assays, caspase-3 activity, and proliferation/migration assays\",\n      \"pmids\": [\"15817639\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct phosphatase substrate not identified\",\n        \"Lipid vs. protein phosphatase activity not distinguished\",\n        \"In vivo relevance untested\"\n      ]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"NMR chemical shift assignment of the TNS2 SH2 domain provided the structural foundation for understanding how this domain engages phosphotyrosine-containing ligands and recruits partners such as DLC1.\",\n      \"evidence\": \"Triple-resonance NMR spectroscopy on recombinant SH2 domain\",\n      \"pmids\": [\"21461930\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No functional validation or ligand-bound structure determined\",\n        \"Relevance of DLC1 recruitment to TNS2 biology not tested\",\n        \"No binding affinity measurements\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identification of IRS-1 Y612 as a direct TNS2 substrate and demonstration that glucocorticoid-induced TNS2 drives IRS-1 degradation, FoxO activation, and muscle atrophy provided the first substrate-specific mechanism for TNS2 phosphatase activity in metabolic regulation.\",\n      \"evidence\": \"In vitro phosphatase assay with site-directed mutagenesis, gain/loss-of-function in cell lines and mouse models\",\n      \"pmids\": [\"23401856\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether TNS2 acts on other IRS-1 phosphotyrosine sites not fully resolved\",\n        \"Structural basis of substrate recognition unknown\",\n        \"Contribution relative to other phosphatases in muscle unclear\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Loss-of-function studies in mice revealed that TNS2 is essential for glomerular basement membrane assembly and podocyte foot process maintenance, linking TNS2 to nephrotic syndrome in a strain-dependent manner.\",\n      \"evidence\": \"Tenc1-mutant ICGN mice on DBA/2J vs. B6 backgrounds with histological and biochemical analysis\",\n      \"pmids\": [\"23988887\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Molecular mechanism in podocytes not reconstituted in vitro\",\n        \"Modifier genes on permissive background unidentified\",\n        \"No rescue experiment reported\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Discovery that p62/SQSTM1 sequesters TNS2 into puncta and promotes its ubiquitin-dependent proteasomal degradation revealed a post-translational mechanism controlling TNS2 protein levels, particularly during muscle differentiation.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA, ubiquitination assays, proteasome inhibitor treatment, fluorescence imaging\",\n      \"pmids\": [\"25101860\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"E3 ubiquitin ligase responsible not identified\",\n        \"Direct vs. indirect p62-mediated ubiquitination not resolved\",\n        \"Physiological consequence of altered TNS2 turnover in muscle not fully demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of nephrin as a second TNS2 PTPase substrate explained how TNS2 upregulation in diabetic kidneys redirects PI3K toward mTORC1, causing podocyte hypertrophy and proteinuria.\",\n      \"evidence\": \"In vitro phosphatase assay on nephrin, mTORC1 activity measurement, diabetic nephropathy mouse model, siRNA knockdown\",\n      \"pmids\": [\"28955049\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Specific nephrin phosphotyrosine site targeted not pinpointed\",\n        \"Whether TNS2 inhibition reverses established diabetic nephropathy untested\",\n        \"Contribution of TNS2 vs. other phosphatases in podocytes not quantified\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Pharmacological inhibition of TNS2 by DHTS improved glucose tolerance and revealed AMPK as a downstream pathway, broadening the metabolic reach of TNS2 beyond Akt.\",\n      \"evidence\": \"Small-molecule inhibitor treatment with glucose tolerance tests and AMPK activity measurement in cell and mouse models\",\n      \"pmids\": [\"29259227\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"DHTS selectivity for TNS2 over other phosphatases not rigorously established\",\n        \"Whether AMPK regulation is direct or via IRS-1 not resolved\",\n        \"Single lab finding\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrating that PtdIns(3,4,5)P3 binding to the SH2 domain gates TNS2 cellular phosphatase activity established a lipid-sensing negative feedback loop in insulin/PI3K signaling.\",\n      \"evidence\": \"Lipid-binding assay, structure-informed mutagenesis of three basic SH2 residues, cell-based IRS-1 dephosphorylation assay\",\n      \"pmids\": [\"30092354\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural model of SH2–PIP3 complex not solved\",\n        \"Whether PIP3 binding also regulates nephrin dephosphorylation untested\",\n        \"In vivo validation of the PIP3 switch not performed\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showing that AXL phosphorylates TNS2 and that this dissociates TNS2 from IRS-1 completed a receptor-to-phosphatase regulatory circuit and linked TNS2 to cancer cell glycolytic reprogramming.\",\n      \"evidence\": \"Co-immunoprecipitation and IP-Western blot in cancer cells\",\n      \"pmids\": [\"30419905\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"AXL phosphorylation sites on TNS2 not mapped\",\n        \"No in vitro kinase assay to confirm direct phosphorylation\",\n        \"Generalizability beyond the tested cancer cell lines unclear\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of TNS2 substrate selectivity, the identity of the E3 ligase mediating p62-driven TNS2 degradation, whether the PIP3-gating mechanism applies to nephrin dephosphorylation, and whether TNS2 has additional physiological substrates beyond IRS-1 and nephrin.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No crystal or cryo-EM structure of full-length TNS2 or its PTP domain\",\n        \"E3 ligase for TNS2 ubiquitination unidentified\",\n        \"Comprehensive substrate profiling not performed\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2, 5, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 2, 5, 7, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"AXL\", \"IRS1\", \"SQSTM1\", \"NPHS1\"],\n    \"other_free_text\": []\n  }\n}\n```"}