{"gene":"TANC2","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2018,"finding":"TANC2 captures KIF1A-transported dense core vesicles (DCVs) at dendritic spines. TANC2 is not part of the KIF1A-cargo complex itself but acts as a postsynaptic capture site for DCVs. Specific TANC2 mutations reported in neuropsychiatric disorder patients abolish the interaction with KIF1A.","method":"KIF1A interactome identification (proteomics), co-immunoprecipitation, live imaging of DCV transport, mutant TANC2 interaction assays","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal pulldown/Co-IP combined with live imaging and mutant validation in single lab study","pmids":["30021165"],"is_preprint":false},{"year":2019,"finding":"TANC2 protein interacts with multiple postsynaptic density (PSD) proteins at dendritic spines and is required for normal synaptic function; loss-of-function mutations cause neurodevelopmental syndrome. Drosophila disruption of TANC2 (rols ortholog) in glial cells affects behavioral outcomes.","method":"Genetic disruption in Drosophila model, protein interaction studies with PSD proteins, patient mutation analysis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with defined behavioral phenotype in model organism, combined with protein interaction data, single lab","pmids":["31616000"],"is_preprint":false},{"year":2021,"finding":"TANC2 directly interacts with and inhibits mTOR, suppressing both mTORC1 and mTORC2 activity in neurons. Tanc2-haploinsufficient mice show mTORC1/2 hyperactivity with synaptic and behavioral deficits rescued by rapamycin. mTOR-activating serum or ketamine suppresses Tanc2-mediated inhibition of mTOR. Tanc2 and Deptor inhibit mTOR at distinct neuronal developmental stages (early vs. late). Tanc2 inhibits mTORC1/2 in human neural progenitor cells and neurons.","method":"Co-immunoprecipitation (Tanc2–mTOR interaction), Tanc2-null and haploinsufficient mouse models, rapamycin rescue experiments, human neural progenitor cell assays, biochemical mTORC1/2 activity measurements","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct protein interaction demonstrated by Co-IP, genetic mouse model with pharmacological rescue, replicated in human neurons, multiple orthogonal methods in single rigorous study","pmids":["33976205"],"is_preprint":false},{"year":2013,"finding":"Knockdown of TANC2 in breast cancer cell lines with 17q23 amplification decreased cell viability through cell cycle arrest and apoptosis induction, and inhibited anchorage-independent colony formation, identifying TANC2 as a driver gene required for proliferation/survival of these cells.","method":"siRNA knockdown screen in breast cancer cell lines, cell viability assays, apoptosis assays, soft agar colony formation assays","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined proliferation and survival phenotype across multiple cell lines, but no molecular pathway placement beyond cell cycle arrest/apoptosis","pmids":["24148822"],"is_preprint":false},{"year":2022,"finding":"TANC2 is an interacting partner of SNX27; HPV-18 E6 oncoprotein inhibits the TANC2–SNX27 interaction in a PDZ-binding motif (PBM)-dependent manner. In the absence of E6, SNX27 directs TANC2 toward lysosomal degradation. Disruption of this interaction by E6 increases TANC2 protein levels and enhances cell proliferation in a PBM-dependent manner.","method":"GFP immunoprecipitation followed by mass spectrometry (proteomics), co-immunoprecipitation, siRNA knockdown of E6AP, cell proliferation assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and proteomic identification of TANC2–SNX27 interaction, functional consequence (lysosomal degradation, proliferation) tested, single lab","pmids":["36326272"],"is_preprint":false},{"year":2022,"finding":"Disrupted Tanc2 in mice leads to interaction with Hippo developmental signalling pathway proteins, with pleiotropic effects including altered hepatocellular metabolism and liver dysfunction beyond brain phenotypes.","method":"Tanc2-disrupted mouse model (homozygous-viable), multi-systemic phenotypic analysis, integrative analysis identifying interaction with Hippo pathway proteins","journal":"Disease models & mechanisms","confidence":"Low","confidence_rationale":"Tier 3 / Weak — interaction with Hippo pathway proteins inferred from integrative analysis in single study, no direct biochemical validation of the interaction described in abstract","pmids":["34964047"],"is_preprint":false},{"year":2022,"finding":"Knockout of tanc2 in zebrafish increases glutamatergic neuron population without affecting GABAergic or glycinergic neurons, causing excitatory/inhibitory imbalance; also promotes proliferation and inhibits apoptosis leading to increased larval brain size.","method":"CRISPR/Cas9 tanc2 knockout in zebrafish, neuronal population quantification, proliferation and apoptosis assays, behavioral assays","journal":"Autism research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with specific cellular phenotype (E/I imbalance, glutamatergic expansion) measured by defined neuronal markers, single lab","pmids":["36534563"],"is_preprint":false}],"current_model":"TANC2 is a postsynaptic scaffolding/adaptor protein that (1) captures KIF1A-transported dense core vesicles at dendritic spines via direct interaction with KIF1A, (2) directly binds and inhibits both mTORC1 and mTORC2 in neurons—an inhibition relieved by mTOR-activating stimuli such as serum or ketamine—thereby balancing mTOR signaling during neurodevelopment, (3) interacts with multiple PSD proteins to regulate excitatory synapse function, and (4) is targeted by SNX27 for lysosomal degradation, a process disrupted by HPV E6 oncoprotein to elevate TANC2 levels and promote cell proliferation."},"narrative":{"mechanistic_narrative":"TANC2 is a postsynaptic scaffolding/adaptor protein that organizes excitatory synapse function and constrains growth signaling during neurodevelopment, with loss-of-function mutations causing a neurodevelopmental syndrome [PMID:31616000, PMID:33976205]. At dendritic spines it serves as a postsynaptic capture site for KIF1A-transported dense core vesicles, binding KIF1A directly without being part of the motor-cargo complex; patient-derived TANC2 mutations abolish this interaction [PMID:30021165], and TANC2 additionally engages multiple postsynaptic density proteins required for normal synaptic function [PMID:31616000]. A central regulatory role is its direct binding to and inhibition of mTOR, suppressing both mTORC1 and mTORC2 in neurons and human neural progenitors; Tanc2 haploinsufficiency produces mTORC1/2 hyperactivity with synaptic and behavioral deficits that are reversed by rapamycin, and mTOR-activating stimuli such as serum or ketamine relieve this inhibition, positioning TANC2 as a stage-specific brake on mTOR signaling [PMID:33976205]. Consistent with a role in balancing neuronal proliferation versus differentiation, tanc2 knockout in zebrafish expands the glutamatergic neuron population, promotes proliferation, and enlarges brain size, producing excitatory/inhibitory imbalance [PMID:36534563]. Outside the nervous system, TANC2 is a SNX27 interactor routed toward lysosomal degradation, a process blocked by HPV-18 E6 oncoprotein in a PDZ-binding-motif-dependent manner to elevate TANC2 levels and enhance proliferation [PMID:36326272], and TANC2 is required for proliferation and survival of breast cancer cells harboring 17q23 amplification [PMID:24148822].","teleology":[{"year":2013,"claim":"Before any molecular role was assigned, it was unknown whether TANC2 was functionally important rather than a passenger in the recurrently amplified 17q23 locus; knockdown established it as a driver required for cancer cell proliferation and survival.","evidence":"siRNA knockdown in 17q23-amplified breast cancer cell lines with viability, apoptosis, and soft-agar colony assays","pmids":["24148822"],"confidence":"Medium","gaps":["No molecular pathway placement beyond cell cycle arrest and apoptosis","Direct effectors of the proliferative phenotype not identified"]},{"year":2018,"claim":"It was unclear how dense core vesicles are captured postsynaptically; TANC2 was shown to act as a spine capture site for KIF1A-transported DCVs, linking it physically to neuronal cargo trafficking and to neuropsychiatric disease mutations.","evidence":"KIF1A interactome proteomics, co-IP, live imaging of DCV transport, and mutant TANC2 interaction assays","pmids":["30021165"],"confidence":"Medium","gaps":["Mechanism of vesicle tethering/release downstream of capture not resolved","TANC2 is not part of the motor-cargo complex, so the recruitment logic at spines is incomplete"]},{"year":2019,"claim":"The synaptic function of TANC2 and its disease relevance were established by linking it to multiple PSD proteins and to a neurodevelopmental syndrome, framing it as a postsynaptic scaffold.","evidence":"Patient mutation analysis, PSD protein interaction studies, and Drosophila (rols ortholog) genetic disruption with behavioral readout","pmids":["31616000"],"confidence":"Medium","gaps":["Identity and stoichiometry of the PSD interaction network not fully defined","Glial-cell phenotype in Drosophila not mechanistically connected to mammalian postsynaptic role"]},{"year":2021,"claim":"The key signaling mechanism was unknown until TANC2 was shown to directly bind and inhibit mTOR, suppressing both mTORC1 and mTORC2 and acting as a developmentally staged brake on growth signaling whose loss causes rapamycin-reversible deficits.","evidence":"Co-IP of Tanc2-mTOR, Tanc2-null and haploinsufficient mouse models with rapamycin rescue, human neural progenitor assays, and biochemical mTORC1/2 activity measurements","pmids":["33976205"],"confidence":"High","gaps":["Structural basis for simultaneous mTORC1/2 inhibition not defined","Molecular mechanism by which serum/ketamine relieves TANC2 inhibition unresolved"]},{"year":2022,"claim":"How TANC2 abundance is controlled, and how a viral oncoprotein hijacks it, was addressed by identifying SNX27-directed lysosomal degradation of TANC2 that HPV-18 E6 blocks via the PDZ-binding motif to raise TANC2 levels and drive proliferation.","evidence":"GFP-IP mass spectrometry, co-IP, E6AP siRNA knockdown, and PBM-dependent proliferation assays","pmids":["36326272"],"confidence":"Medium","gaps":["Connection between elevated TANC2 and the proliferation mechanism not detailed","Whether SNX27-mediated turnover operates in neurons is untested"]},{"year":2022,"claim":"The cellular consequences of TANC2 loss in vivo for neuronal identity were clarified by showing zebrafish knockout selectively expands glutamatergic neurons and enlarges brain via increased proliferation and reduced apoptosis, producing E/I imbalance.","evidence":"CRISPR/Cas9 tanc2 knockout in zebrafish with neuronal marker quantification, proliferation/apoptosis, and behavioral assays","pmids":["36534563"],"confidence":"Medium","gaps":["Mechanistic link between TANC2 loss and glutamatergic-specific expansion not established","Relationship to mTOR hyperactivity not directly tested in this model"]},{"year":2022,"claim":"Beyond the brain, a homozygous-viable mouse model implicated TANC2 in Hippo-pathway-associated developmental signaling and hepatic metabolism, indicating pleiotropic systemic roles.","evidence":"Tanc2-disrupted mouse with multi-systemic phenotyping and integrative analysis identifying Hippo pathway protein interactions","pmids":["34964047"],"confidence":"Low","gaps":["Hippo pathway interaction inferred from integrative analysis without direct biochemical validation","Causal link between TANC2 and liver dysfunction not established"]},{"year":null,"claim":"How TANC2's postsynaptic scaffolding, KIF1A-dependent vesicle capture, and direct mTORC1/2 inhibition are mechanistically integrated into a single regulatory hub at the spine remains unresolved.","evidence":"No single study reconciles the scaffolding, trafficking, and mTOR-inhibitory functions","pmids":[],"confidence":"Low","gaps":["No structural model of TANC2 bound to mTOR or KIF1A","Whether mTOR inhibition and DCV capture occur in the same spine compartment is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[1,6]}],"complexes":[],"partners":["KIF1A","MTOR","SNX27"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9HCD6","full_name":"Protein TANC2","aliases":["Tetratricopeptide repeat, ankyrin repeat and coiled-coil domain-containing protein 2"],"length_aa":1990,"mass_kda":219.7,"function":"Scaffolding protein in the dendritic spines which acts as immobile postsynaptic posts able to recruit KIF1A-driven dense core vesicles to dendritic spines","subcellular_location":"Cell projection, dendritic spine","url":"https://www.uniprot.org/uniprotkb/Q9HCD6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TANC2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TANC2","total_profiled":1310},"omim":[{"mim_id":"618906","title":"INTELLECTUAL DEVELOPMENTAL DISORDER WITH AUTISTIC FEATURES AND LANGUAGE DELAY, WITH OR WITHOUT SEIZURES; IDDALDS","url":"https://www.omim.org/entry/618906"},{"mim_id":"615047","title":"TETRATRICOPEPTIDE REPEAT-, ANKYRIN REPEAT-, AND COILED-COIL-CONTAINING PROTEIN 2; TANC2","url":"https://www.omim.org/entry/615047"},{"mim_id":"611397","title":"TETRATRICOPEPTIDE REPEAT-, ANKYRIN REPEAT-, AND COILED-COIL-CONTAINING PROTEIN 1; TANC1","url":"https://www.omim.org/entry/611397"},{"mim_id":"603143","title":"PTPRF-INTERACTING PROTEIN ALPHA-2; PPFIA2","url":"https://www.omim.org/entry/603143"},{"mim_id":"601255","title":"KINESIN FAMILY MEMBER 1A; KIF1A","url":"https://www.omim.org/entry/601255"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Cytosol","reliability":"Uncertain"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"parathyroid gland","ntpm":26.5}],"url":"https://www.proteinatlas.org/search/TANC2"},"hgnc":{"alias_symbol":["DKFZP564D166","FLJ10215","FLJ11824","KIAA1148","KIAA1636","rols","ROLSA"],"prev_symbol":[]},"alphafold":{"accession":"Q9HCD6","domains":[{"cath_id":"-","chopping":"323-399_439-599","consensus_level":"medium","plddt":87.6679,"start":323,"end":599},{"cath_id":"-","chopping":"605-682","consensus_level":"medium","plddt":85.6656,"start":605,"end":682},{"cath_id":"-","chopping":"683-800","consensus_level":"medium","plddt":90.7631,"start":683,"end":800},{"cath_id":"1.25.40.10","chopping":"1278-1377","consensus_level":"medium","plddt":86.415,"start":1278,"end":1377}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HCD6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HCD6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9HCD6-F1-predicted_aligned_error_v6.png","plddt_mean":59.47},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TANC2","jax_strain_url":"https://www.jax.org/strain/search?query=TANC2"},"sequence":{"accession":"Q9HCD6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9HCD6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9HCD6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9HCD6"}},"corpus_meta":[{"pmid":"30021165","id":"PMC_30021165","title":"Regulation of KIF1A-Driven Dense Core Vesicle Transport: Ca2+/CaM Controls DCV Binding and Liprin-α/TANC2 Recruits DCVs to Postsynaptic Sites.","date":"2018","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/30021165","citation_count":61,"is_preprint":false},{"pmid":"31616000","id":"PMC_31616000","title":"Disruptive mutations in TANC2 define a neurodevelopmental syndrome associated with psychiatric disorders.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31616000","citation_count":51,"is_preprint":false},{"pmid":"24148822","id":"PMC_24148822","title":"A siRNA screen identifies RAD21, EIF3H, CHRAC1 and TANC2 as driver genes within the 8q23, 8q24.3 and 17q23 amplicons in breast cancer with effects on cell growth, survival and transformation.","date":"2013","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/24148822","citation_count":47,"is_preprint":false},{"pmid":"33976205","id":"PMC_33976205","title":"Tanc2-mediated mTOR inhibition balances mTORC1/2 signaling in the developing mouse brain and human neurons.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33976205","citation_count":27,"is_preprint":false},{"pmid":"40110879","id":"PMC_40110879","title":"De novo TANC2 variants caused developmental and epileptic encephalopathy and epilepsy.","date":"2025","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/40110879","citation_count":12,"is_preprint":false},{"pmid":"34964047","id":"PMC_34964047","title":"Post-synaptic scaffold protein TANC2 in psychiatric and somatic disease risk.","date":"2022","source":"Disease models & mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/34964047","citation_count":8,"is_preprint":false},{"pmid":"36534563","id":"PMC_36534563","title":"Knockout of tanc2 causes autism-like behavior and sleep disturbance in zebrafish.","date":"2022","source":"Autism research : official journal of the International Society for Autism Research","url":"https://pubmed.ncbi.nlm.nih.gov/36534563","citation_count":8,"is_preprint":false},{"pmid":"34861844","id":"PMC_34861844","title":"Truncating mutation in TANC2 in a Chinese boy associated with Lennox-Gastaut syndrome: a case report.","date":"2021","source":"BMC pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/34861844","citation_count":8,"is_preprint":false},{"pmid":"33160097","id":"PMC_33160097","title":"17q23.3 de novo microdeletion involving only TANC2 gene: A new case.","date":"2020","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33160097","citation_count":6,"is_preprint":false},{"pmid":"39344613","id":"PMC_39344613","title":"[Clinical and genetic analysis of two children with TANC2 gene variants and a literature review].","date":"2024","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39344613","citation_count":2,"is_preprint":false},{"pmid":"36326272","id":"PMC_36326272","title":"HPV-18E6 Inhibits Interactions between TANC2 and SNX27 in a PBM-Dependent Manner and Promotes Increased Cell Proliferation.","date":"2022","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/36326272","citation_count":2,"is_preprint":false},{"pmid":"35066241","id":"PMC_35066241","title":"Generation of an induced pluripotent stem cell line (GWCMCi005-A) from a patient with Lennox-Gastaut syndrome carrying TANC2 Gln1441Ter mutation.","date":"2022","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/35066241","citation_count":1,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.01.21.25320889","title":"Variants in<i>CALD1</i>,<i>ESRP1</i>, and<i>RBFOX1</i>are associated with orofacial cleft risk","date":"2025-01-22","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.21.25320889","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8976,"output_tokens":1882,"usd":0.027579,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8835,"output_tokens":3046,"usd":0.060163,"stage2_stop_reason":"end_turn"},"total_usd":0.087742,"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\": 2018,\n      \"finding\": \"TANC2 captures KIF1A-transported dense core vesicles (DCVs) at dendritic spines. TANC2 is not part of the KIF1A-cargo complex itself but acts as a postsynaptic capture site for DCVs. Specific TANC2 mutations reported in neuropsychiatric disorder patients abolish the interaction with KIF1A.\",\n      \"method\": \"KIF1A interactome identification (proteomics), co-immunoprecipitation, live imaging of DCV transport, mutant TANC2 interaction assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal pulldown/Co-IP combined with live imaging and mutant validation in single lab study\",\n      \"pmids\": [\"30021165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TANC2 protein interacts with multiple postsynaptic density (PSD) proteins at dendritic spines and is required for normal synaptic function; loss-of-function mutations cause neurodevelopmental syndrome. Drosophila disruption of TANC2 (rols ortholog) in glial cells affects behavioral outcomes.\",\n      \"method\": \"Genetic disruption in Drosophila model, protein interaction studies with PSD proteins, patient mutation analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with defined behavioral phenotype in model organism, combined with protein interaction data, single lab\",\n      \"pmids\": [\"31616000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TANC2 directly interacts with and inhibits mTOR, suppressing both mTORC1 and mTORC2 activity in neurons. Tanc2-haploinsufficient mice show mTORC1/2 hyperactivity with synaptic and behavioral deficits rescued by rapamycin. mTOR-activating serum or ketamine suppresses Tanc2-mediated inhibition of mTOR. Tanc2 and Deptor inhibit mTOR at distinct neuronal developmental stages (early vs. late). Tanc2 inhibits mTORC1/2 in human neural progenitor cells and neurons.\",\n      \"method\": \"Co-immunoprecipitation (Tanc2–mTOR interaction), Tanc2-null and haploinsufficient mouse models, rapamycin rescue experiments, human neural progenitor cell assays, biochemical mTORC1/2 activity measurements\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct protein interaction demonstrated by Co-IP, genetic mouse model with pharmacological rescue, replicated in human neurons, multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"33976205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Knockdown of TANC2 in breast cancer cell lines with 17q23 amplification decreased cell viability through cell cycle arrest and apoptosis induction, and inhibited anchorage-independent colony formation, identifying TANC2 as a driver gene required for proliferation/survival of these cells.\",\n      \"method\": \"siRNA knockdown screen in breast cancer cell lines, cell viability assays, apoptosis assays, soft agar colony formation assays\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined proliferation and survival phenotype across multiple cell lines, but no molecular pathway placement beyond cell cycle arrest/apoptosis\",\n      \"pmids\": [\"24148822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TANC2 is an interacting partner of SNX27; HPV-18 E6 oncoprotein inhibits the TANC2–SNX27 interaction in a PDZ-binding motif (PBM)-dependent manner. In the absence of E6, SNX27 directs TANC2 toward lysosomal degradation. Disruption of this interaction by E6 increases TANC2 protein levels and enhances cell proliferation in a PBM-dependent manner.\",\n      \"method\": \"GFP immunoprecipitation followed by mass spectrometry (proteomics), co-immunoprecipitation, siRNA knockdown of E6AP, cell proliferation assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and proteomic identification of TANC2–SNX27 interaction, functional consequence (lysosomal degradation, proliferation) tested, single lab\",\n      \"pmids\": [\"36326272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Disrupted Tanc2 in mice leads to interaction with Hippo developmental signalling pathway proteins, with pleiotropic effects including altered hepatocellular metabolism and liver dysfunction beyond brain phenotypes.\",\n      \"method\": \"Tanc2-disrupted mouse model (homozygous-viable), multi-systemic phenotypic analysis, integrative analysis identifying interaction with Hippo pathway proteins\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — interaction with Hippo pathway proteins inferred from integrative analysis in single study, no direct biochemical validation of the interaction described in abstract\",\n      \"pmids\": [\"34964047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Knockout of tanc2 in zebrafish increases glutamatergic neuron population without affecting GABAergic or glycinergic neurons, causing excitatory/inhibitory imbalance; also promotes proliferation and inhibits apoptosis leading to increased larval brain size.\",\n      \"method\": \"CRISPR/Cas9 tanc2 knockout in zebrafish, neuronal population quantification, proliferation and apoptosis assays, behavioral assays\",\n      \"journal\": \"Autism research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with specific cellular phenotype (E/I imbalance, glutamatergic expansion) measured by defined neuronal markers, single lab\",\n      \"pmids\": [\"36534563\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TANC2 is a postsynaptic scaffolding/adaptor protein that (1) captures KIF1A-transported dense core vesicles at dendritic spines via direct interaction with KIF1A, (2) directly binds and inhibits both mTORC1 and mTORC2 in neurons—an inhibition relieved by mTOR-activating stimuli such as serum or ketamine—thereby balancing mTOR signaling during neurodevelopment, (3) interacts with multiple PSD proteins to regulate excitatory synapse function, and (4) is targeted by SNX27 for lysosomal degradation, a process disrupted by HPV E6 oncoprotein to elevate TANC2 levels and promote cell proliferation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TANC2 is a postsynaptic scaffolding/adaptor protein that organizes excitatory synapse function and constrains growth signaling during neurodevelopment, with loss-of-function mutations causing a neurodevelopmental syndrome [#1, #2]. At dendritic spines it serves as a postsynaptic capture site for KIF1A-transported dense core vesicles, binding KIF1A directly without being part of the motor-cargo complex; patient-derived TANC2 mutations abolish this interaction [#0], and TANC2 additionally engages multiple postsynaptic density proteins required for normal synaptic function [#1]. A central regulatory role is its direct binding to and inhibition of mTOR, suppressing both mTORC1 and mTORC2 in neurons and human neural progenitors; Tanc2 haploinsufficiency produces mTORC1/2 hyperactivity with synaptic and behavioral deficits that are reversed by rapamycin, and mTOR-activating stimuli such as serum or ketamine relieve this inhibition, positioning TANC2 as a stage-specific brake on mTOR signaling [#2]. Consistent with a role in balancing neuronal proliferation versus differentiation, tanc2 knockout in zebrafish expands the glutamatergic neuron population, promotes proliferation, and enlarges brain size, producing excitatory/inhibitory imbalance [#6]. Outside the nervous system, TANC2 is a SNX27 interactor routed toward lysosomal degradation, a process blocked by HPV-18 E6 oncoprotein in a PDZ-binding-motif-dependent manner to elevate TANC2 levels and enhance proliferation [#4], and TANC2 is required for proliferation and survival of breast cancer cells harboring 17q23 amplification [#3].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Before any molecular role was assigned, it was unknown whether TANC2 was functionally important rather than a passenger in the recurrently amplified 17q23 locus; knockdown established it as a driver required for cancer cell proliferation and survival.\",\n      \"evidence\": \"siRNA knockdown in 17q23-amplified breast cancer cell lines with viability, apoptosis, and soft-agar colony assays\",\n      \"pmids\": [\"24148822\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No molecular pathway placement beyond cell cycle arrest and apoptosis\",\n        \"Direct effectors of the proliferative phenotype not identified\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"It was unclear how dense core vesicles are captured postsynaptically; TANC2 was shown to act as a spine capture site for KIF1A-transported DCVs, linking it physically to neuronal cargo trafficking and to neuropsychiatric disease mutations.\",\n      \"evidence\": \"KIF1A interactome proteomics, co-IP, live imaging of DCV transport, and mutant TANC2 interaction assays\",\n      \"pmids\": [\"30021165\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism of vesicle tethering/release downstream of capture not resolved\",\n        \"TANC2 is not part of the motor-cargo complex, so the recruitment logic at spines is incomplete\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The synaptic function of TANC2 and its disease relevance were established by linking it to multiple PSD proteins and to a neurodevelopmental syndrome, framing it as a postsynaptic scaffold.\",\n      \"evidence\": \"Patient mutation analysis, PSD protein interaction studies, and Drosophila (rols ortholog) genetic disruption with behavioral readout\",\n      \"pmids\": [\"31616000\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Identity and stoichiometry of the PSD interaction network not fully defined\",\n        \"Glial-cell phenotype in Drosophila not mechanistically connected to mammalian postsynaptic role\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The key signaling mechanism was unknown until TANC2 was shown to directly bind and inhibit mTOR, suppressing both mTORC1 and mTORC2 and acting as a developmentally staged brake on growth signaling whose loss causes rapamycin-reversible deficits.\",\n      \"evidence\": \"Co-IP of Tanc2-mTOR, Tanc2-null and haploinsufficient mouse models with rapamycin rescue, human neural progenitor assays, and biochemical mTORC1/2 activity measurements\",\n      \"pmids\": [\"33976205\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for simultaneous mTORC1/2 inhibition not defined\",\n        \"Molecular mechanism by which serum/ketamine relieves TANC2 inhibition unresolved\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"How TANC2 abundance is controlled, and how a viral oncoprotein hijacks it, was addressed by identifying SNX27-directed lysosomal degradation of TANC2 that HPV-18 E6 blocks via the PDZ-binding motif to raise TANC2 levels and drive proliferation.\",\n      \"evidence\": \"GFP-IP mass spectrometry, co-IP, E6AP siRNA knockdown, and PBM-dependent proliferation assays\",\n      \"pmids\": [\"36326272\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Connection between elevated TANC2 and the proliferation mechanism not detailed\",\n        \"Whether SNX27-mediated turnover operates in neurons is untested\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The cellular consequences of TANC2 loss in vivo for neuronal identity were clarified by showing zebrafish knockout selectively expands glutamatergic neurons and enlarges brain via increased proliferation and reduced apoptosis, producing E/I imbalance.\",\n      \"evidence\": \"CRISPR/Cas9 tanc2 knockout in zebrafish with neuronal marker quantification, proliferation/apoptosis, and behavioral assays\",\n      \"pmids\": [\"36534563\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanistic link between TANC2 loss and glutamatergic-specific expansion not established\",\n        \"Relationship to mTOR hyperactivity not directly tested in this model\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Beyond the brain, a homozygous-viable mouse model implicated TANC2 in Hippo-pathway-associated developmental signaling and hepatic metabolism, indicating pleiotropic systemic roles.\",\n      \"evidence\": \"Tanc2-disrupted mouse with multi-systemic phenotyping and integrative analysis identifying Hippo pathway protein interactions\",\n      \"pmids\": [\"34964047\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Hippo pathway interaction inferred from integrative analysis without direct biochemical validation\",\n        \"Causal link between TANC2 and liver dysfunction not established\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TANC2's postsynaptic scaffolding, KIF1A-dependent vesicle capture, and direct mTORC1/2 inhibition are mechanistically integrated into a single regulatory hub at the spine remains unresolved.\",\n      \"evidence\": \"No single study reconciles the scaffolding, trafficking, and mTOR-inhibitory functions\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of TANC2 bound to mTOR or KIF1A\",\n        \"Whether mTOR inhibition and DCV capture occur in the same spine compartment is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [1, 6]},\n      {\"term_id\": \"R-HSA-9709957\", \"supporting_discovery_ids\": []}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"KIF1A\", \"MTOR\", \"SNX27\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}