{"gene":"TANC2","run_date":"2026-04-28T21:42:58","timeline":{"discoveries":[{"year":2018,"finding":"TANC2 captures KIF1A-transported dense core vesicles (DCVs) at dendritic spines postsynaptically; TANC2 is not part of the KIF1A-cargo complex but acts as a postsynaptic capture site, and specific TANC2 mutations reported in neuropsychiatric patients abolish the interaction with KIF1A.","method":"KIF1A interactome identification, Co-IP/pulldown, live imaging of DCV transport in neurons, patient mutation analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — reciprocal interactome, functional imaging, and mutagenesis in a single study with multiple orthogonal methods","pmids":["30021165"],"is_preprint":false},{"year":2021,"finding":"TANC2 directly interacts with and inhibits mTOR, suppressing both mTORC1 and mTORC2 activity in neurons; this inhibition is relieved by mTOR-activating serum or ketamine. Tanc2-haploinsufficient mice show mTORC1/2 hyperactivity with synaptic and behavioral deficits reversed by rapamycin, and TANC2 inhibits mTORC1/2 in human neural progenitor cells and neurons.","method":"Co-IP (Tanc2-mTOR interaction), Tanc2-null and haploinsufficient mouse models, rapamycin rescue experiment, phospho-mTOR substrate assays, human neural progenitor cell experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, genetic epistasis via haploinsufficient mouse, pharmacological rescue, replicated in human cells","pmids":["33976205"],"is_preprint":false},{"year":2022,"finding":"TANC2 interacts with SNX27; in the absence of HPV-18 E6, SNX27 directs TANC2 toward lysosomal degradation. HPV-18 E6 inhibits the SNX27-TANC2 interaction in a PDZ-binding motif (PBM)-dependent manner, leading to increased TANC2 protein levels and enhanced cell proliferation.","method":"GFP-immunoprecipitation mass spectrometry (proteomics), siRNA knockdown, Co-IP, cell proliferation assays, PBM mutant constructs","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 — proteomic identification plus functional validation with mutagenesis, single lab","pmids":["36326272"],"is_preprint":false},{"year":2022,"finding":"TANC2 disruption is associated with Hippo developmental signalling pathway protein interactions, with pleiotropic systemic effects including aberrant hepatocellular metabolism in a mouse model.","method":"Homozygous-viable Tanc2-disrupted mouse model, multi-systemic phenotypic analysis, integrative pathway analysis","journal":"Disease models & mechanisms","confidence":"Low","confidence_rationale":"Tier 3 — pathway association by integrative analysis without direct biochemical reconstitution of Hippo interaction","pmids":["34964047"],"is_preprint":false},{"year":2022,"finding":"Loss of tanc2 in zebrafish increases larval brain size and body length by promoting cell proliferation and inhibiting apoptosis, and selectively increases the glutamatergic neuron population without affecting GABAergic or glycinergic neurons, indicating a role in excitatory/inhibitory balance.","method":"tanc2 knockout zebrafish, neuronal population quantification, behavioral assays","journal":"Autism research","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO in vertebrate model with specific cellular phenotype readouts across multiple neuronal subtypes","pmids":["36534563"],"is_preprint":false},{"year":2019,"finding":"TANC2 protein interacts with multiple postsynaptic density (PSD) proteins, and its disruption in Drosophila glial cells affects behavioral outcomes, supporting a role in postsynaptic scaffolding and synaptic function.","method":"Genetic disruption in Drosophila, behavioral assays, expression analysis in human developing brain single-cell data","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — functional genetic disruption in model organism with behavioral readout, corroborated by human brain expression data","pmids":["31616000"],"is_preprint":false},{"year":2013,"finding":"Knockdown of TANC2 in breast cancer cell lines with 17q23 amplification decreases cell viability through cell cycle arrest and apoptosis induction, and inhibits anchorage-independent colony formation, identifying TANC2 as a driver gene for breast cancer cell survival/proliferation in this amplicon.","method":"siRNA screen, cell viability assays, soft agar colony formation assay, apoptosis and cell cycle analysis","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 — functional loss-of-function screen with specific cellular phenotype readouts in multiple cell lines","pmids":["24148822"],"is_preprint":false}],"current_model":"TANC2 is a postsynaptic scaffolding/adaptor protein that captures KIF1A-transported dense core vesicles at dendritic spines, directly interacts with and inhibits both mTORC1 and mTORC2 to regulate neural development, interacts with SNX27 (with lysosomal degradation as a consequence), and is required for excitatory/inhibitory balance in neurons, with loss-of-function causing mTOR hyperactivity, synaptic defects, and neurodevelopmental abnormalities reversible by rapamycin."},"narrative":{"teleology":[{"year":2013,"claim":"Before any neuronal mechanism was known, TANC2 was identified as a proliferation-promoting gene amplified in breast cancer, establishing that its loss causes cell cycle arrest and apoptosis in cancer cells.","evidence":"siRNA knockdown in 17q23-amplified breast cancer cell lines with viability, colony formation, and cell cycle assays","pmids":["24148822"],"confidence":"Medium","gaps":["Mechanism of TANC2-driven proliferation not identified","Not tested whether mTOR or other signaling pathways mediate the effect","Relevance to non-amplified contexts unclear"]},{"year":2018,"claim":"The question of how postsynaptic sites capture cargo was addressed by showing TANC2 acts as a stationary postsynaptic receptor for KIF1A-transported dense core vesicles, with neuropsychiatric patient mutations disrupting this interaction.","evidence":"KIF1A interactome, Co-IP, live DCV imaging in cultured neurons, patient mutation analysis","pmids":["30021165"],"confidence":"High","gaps":["Identity of DCV cargoes captured by TANC2 not determined","How TANC2 is itself anchored at the PSD not resolved","Whether DCV capture defect underlies patient phenotypes not tested in vivo"]},{"year":2019,"claim":"TANC2's broader postsynaptic scaffolding role was supported by showing it interacts with multiple PSD proteins and that its disruption in Drosophila glia alters behavior, linking its scaffolding function to neural circuit outcomes.","evidence":"Genetic disruption in Drosophila, behavioral assays, human developing brain single-cell expression analysis","pmids":["31616000"],"confidence":"Medium","gaps":["Specific PSD binding partners not individually validated biochemically","Glial versus neuronal cell-autonomous contributions not dissected","Drosophila homolog function may diverge from mammalian TANC2"]},{"year":2021,"claim":"A central mechanistic question — how TANC2 loss causes neurodevelopmental disease — was answered by demonstrating that TANC2 directly binds and inhibits mTORC1/2, and that haploinsufficiency-driven mTOR hyperactivation underlies synaptic and behavioral deficits reversible by rapamycin.","evidence":"Reciprocal Co-IP of Tanc2-mTOR, Tanc2-haploinsufficient and null mice, rapamycin rescue, phospho-substrate assays, human neural progenitor cell experiments","pmids":["33976205"],"confidence":"High","gaps":["Structural basis of TANC2-mTOR interaction not determined","How mTOR-activating signals (serum, ketamine) relieve TANC2 inhibition mechanistically unclear","Relative contributions of mTORC1 vs mTORC2 deregulation to specific phenotypes not separated"]},{"year":2022,"claim":"TANC2's role in excitatory/inhibitory balance was established by showing that its loss in zebrafish selectively expands glutamatergic but not GABAergic or glycinergic neurons, linking TANC2 to neuron-type-specific proliferation control.","evidence":"tanc2 knockout zebrafish, neuronal subtype quantification, behavioral assays","pmids":["36534563"],"confidence":"Medium","gaps":["Whether E/I imbalance is driven by mTOR hyperactivation not directly tested","Not determined if the phenotype is cell-autonomous to glutamatergic progenitors","Relevance to mammalian cortical neuron subtype specification not confirmed"]},{"year":2022,"claim":"TANC2 protein turnover was linked to the endosomal sorting pathway through its PDZ-dependent interaction with SNX27, which directs TANC2 to lysosomal degradation — a process hijacked by HPV-18 E6 to stabilize TANC2 and promote proliferation.","evidence":"GFP-IP mass spectrometry, Co-IP, siRNA, PBM mutant constructs, cell proliferation assays","pmids":["36326272"],"confidence":"Medium","gaps":["Whether SNX27-mediated degradation of TANC2 regulates mTOR signaling not tested","Physiological relevance of TANC2 stabilization in non-HPV contexts unknown","Lysosomal degradation pathway for TANC2 not reconstituted with purified components"]},{"year":null,"claim":"Key unresolved questions include the structural basis of the TANC2-mTOR interaction, whether DCV capture and mTOR inhibition are functionally coupled at the synapse, and which specific TANC2 domains mediate each of its scaffolding interactions.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural or cryo-EM model of TANC2 or its complexes","Functional relationship between DCV capture and mTOR inhibition not explored","Domain-resolved interaction map for TANC2's PSD, KIF1A, and mTOR binding not available"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,5]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,5]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,4]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,1,4,5]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0]}],"complexes":[],"partners":["KIF1A","MTOR","SNX27"],"other_free_text":[]},"mechanistic_narrative":"TANC2 is a postsynaptic scaffolding protein that integrates vesicle capture, mTOR signaling, and synaptic balance to regulate neural development and function. At dendritic spines, TANC2 serves as a postsynaptic capture site for KIF1A-transported dense core vesicles, and patient-derived neuropsychiatric mutations abolish this KIF1A interaction [PMID:30021165]. TANC2 directly binds and inhibits both mTORC1 and mTORC2; haploinsufficiency in mice causes mTOR hyperactivation with synaptic and behavioral deficits that are rescued by rapamycin, and this inhibitory function is conserved in human neural progenitor cells [PMID:33976205]. Loss of TANC2 in zebrafish selectively expands the glutamatergic neuron population without affecting inhibitory neurons, establishing a role in excitatory/inhibitory balance [PMID:36534563]."},"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":60,"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":48,"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":23,"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":11,"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":7,"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":7,"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":"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":5,"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":8182,"output_tokens":1638,"usd":0.024558},"stage2":{"model":"claude-opus-4-6","input_tokens":4891,"output_tokens":1976,"usd":0.110783},"total_usd":0.135341,"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\": 2018,\n      \"finding\": \"TANC2 captures KIF1A-transported dense core vesicles (DCVs) at dendritic spines postsynaptically; TANC2 is not part of the KIF1A-cargo complex but acts as a postsynaptic capture site, and specific TANC2 mutations reported in neuropsychiatric patients abolish the interaction with KIF1A.\",\n      \"method\": \"KIF1A interactome identification, Co-IP/pulldown, live imaging of DCV transport in neurons, patient mutation analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal interactome, functional imaging, and mutagenesis in a single study with multiple orthogonal methods\",\n      \"pmids\": [\"30021165\"],\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; this inhibition is relieved by mTOR-activating serum or ketamine. Tanc2-haploinsufficient mice show mTORC1/2 hyperactivity with synaptic and behavioral deficits reversed by rapamycin, and TANC2 inhibits mTORC1/2 in human neural progenitor cells and neurons.\",\n      \"method\": \"Co-IP (Tanc2-mTOR interaction), Tanc2-null and haploinsufficient mouse models, rapamycin rescue experiment, phospho-mTOR substrate assays, human neural progenitor cell experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, genetic epistasis via haploinsufficient mouse, pharmacological rescue, replicated in human cells\",\n      \"pmids\": [\"33976205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TANC2 interacts with SNX27; in the absence of HPV-18 E6, SNX27 directs TANC2 toward lysosomal degradation. HPV-18 E6 inhibits the SNX27-TANC2 interaction in a PDZ-binding motif (PBM)-dependent manner, leading to increased TANC2 protein levels and enhanced cell proliferation.\",\n      \"method\": \"GFP-immunoprecipitation mass spectrometry (proteomics), siRNA knockdown, Co-IP, cell proliferation assays, PBM mutant constructs\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — proteomic identification plus functional validation with mutagenesis, single lab\",\n      \"pmids\": [\"36326272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TANC2 disruption is associated with Hippo developmental signalling pathway protein interactions, with pleiotropic systemic effects including aberrant hepatocellular metabolism in a mouse model.\",\n      \"method\": \"Homozygous-viable Tanc2-disrupted mouse model, multi-systemic phenotypic analysis, integrative pathway analysis\",\n      \"journal\": \"Disease models & mechanisms\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — pathway association by integrative analysis without direct biochemical reconstitution of Hippo interaction\",\n      \"pmids\": [\"34964047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Loss of tanc2 in zebrafish increases larval brain size and body length by promoting cell proliferation and inhibiting apoptosis, and selectively increases the glutamatergic neuron population without affecting GABAergic or glycinergic neurons, indicating a role in excitatory/inhibitory balance.\",\n      \"method\": \"tanc2 knockout zebrafish, neuronal population quantification, behavioral assays\",\n      \"journal\": \"Autism research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO in vertebrate model with specific cellular phenotype readouts across multiple neuronal subtypes\",\n      \"pmids\": [\"36534563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TANC2 protein interacts with multiple postsynaptic density (PSD) proteins, and its disruption in Drosophila glial cells affects behavioral outcomes, supporting a role in postsynaptic scaffolding and synaptic function.\",\n      \"method\": \"Genetic disruption in Drosophila, behavioral assays, expression analysis in human developing brain single-cell data\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional genetic disruption in model organism with behavioral readout, corroborated by human brain expression data\",\n      \"pmids\": [\"31616000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Knockdown of TANC2 in breast cancer cell lines with 17q23 amplification decreases cell viability through cell cycle arrest and apoptosis induction, and inhibits anchorage-independent colony formation, identifying TANC2 as a driver gene for breast cancer cell survival/proliferation in this amplicon.\",\n      \"method\": \"siRNA screen, cell viability assays, soft agar colony formation assay, apoptosis and cell cycle analysis\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional loss-of-function screen with specific cellular phenotype readouts in multiple cell lines\",\n      \"pmids\": [\"24148822\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TANC2 is a postsynaptic scaffolding/adaptor protein that captures KIF1A-transported dense core vesicles at dendritic spines, directly interacts with and inhibits both mTORC1 and mTORC2 to regulate neural development, interacts with SNX27 (with lysosomal degradation as a consequence), and is required for excitatory/inhibitory balance in neurons, with loss-of-function causing mTOR hyperactivity, synaptic defects, and neurodevelopmental abnormalities reversible by rapamycin.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TANC2 is a postsynaptic scaffolding protein that integrates vesicle capture, mTOR signaling, and synaptic balance to regulate neural development and function. At dendritic spines, TANC2 serves as a postsynaptic capture site for KIF1A-transported dense core vesicles, and patient-derived neuropsychiatric mutations abolish this KIF1A interaction [PMID:30021165]. TANC2 directly binds and inhibits both mTORC1 and mTORC2; haploinsufficiency in mice causes mTOR hyperactivation with synaptic and behavioral deficits that are rescued by rapamycin, and this inhibitory function is conserved in human neural progenitor cells [PMID:33976205]. Loss of TANC2 in zebrafish selectively expands the glutamatergic neuron population without affecting inhibitory neurons, establishing a role in excitatory/inhibitory balance [PMID:36534563].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Before any neuronal mechanism was known, TANC2 was identified as a proliferation-promoting gene amplified in breast cancer, establishing that its loss causes cell cycle arrest and apoptosis in cancer cells.\",\n      \"evidence\": \"siRNA knockdown in 17q23-amplified breast cancer cell lines with viability, colony formation, and cell cycle assays\",\n      \"pmids\": [\"24148822\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism of TANC2-driven proliferation not identified\",\n        \"Not tested whether mTOR or other signaling pathways mediate the effect\",\n        \"Relevance to non-amplified contexts unclear\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The question of how postsynaptic sites capture cargo was addressed by showing TANC2 acts as a stationary postsynaptic receptor for KIF1A-transported dense core vesicles, with neuropsychiatric patient mutations disrupting this interaction.\",\n      \"evidence\": \"KIF1A interactome, Co-IP, live DCV imaging in cultured neurons, patient mutation analysis\",\n      \"pmids\": [\"30021165\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Identity of DCV cargoes captured by TANC2 not determined\",\n        \"How TANC2 is itself anchored at the PSD not resolved\",\n        \"Whether DCV capture defect underlies patient phenotypes not tested in vivo\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"TANC2's broader postsynaptic scaffolding role was supported by showing it interacts with multiple PSD proteins and that its disruption in Drosophila glia alters behavior, linking its scaffolding function to neural circuit outcomes.\",\n      \"evidence\": \"Genetic disruption in Drosophila, behavioral assays, human developing brain single-cell expression analysis\",\n      \"pmids\": [\"31616000\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Specific PSD binding partners not individually validated biochemically\",\n        \"Glial versus neuronal cell-autonomous contributions not dissected\",\n        \"Drosophila homolog function may diverge from mammalian TANC2\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A central mechanistic question — how TANC2 loss causes neurodevelopmental disease — was answered by demonstrating that TANC2 directly binds and inhibits mTORC1/2, and that haploinsufficiency-driven mTOR hyperactivation underlies synaptic and behavioral deficits reversible by rapamycin.\",\n      \"evidence\": \"Reciprocal Co-IP of Tanc2-mTOR, Tanc2-haploinsufficient and null mice, rapamycin rescue, phospho-substrate assays, human neural progenitor cell experiments\",\n      \"pmids\": [\"33976205\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of TANC2-mTOR interaction not determined\",\n        \"How mTOR-activating signals (serum, ketamine) relieve TANC2 inhibition mechanistically unclear\",\n        \"Relative contributions of mTORC1 vs mTORC2 deregulation to specific phenotypes not separated\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"TANC2's role in excitatory/inhibitory balance was established by showing that its loss in zebrafish selectively expands glutamatergic but not GABAergic or glycinergic neurons, linking TANC2 to neuron-type-specific proliferation control.\",\n      \"evidence\": \"tanc2 knockout zebrafish, neuronal subtype quantification, behavioral assays\",\n      \"pmids\": [\"36534563\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether E/I imbalance is driven by mTOR hyperactivation not directly tested\",\n        \"Not determined if the phenotype is cell-autonomous to glutamatergic progenitors\",\n        \"Relevance to mammalian cortical neuron subtype specification not confirmed\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"TANC2 protein turnover was linked to the endosomal sorting pathway through its PDZ-dependent interaction with SNX27, which directs TANC2 to lysosomal degradation — a process hijacked by HPV-18 E6 to stabilize TANC2 and promote proliferation.\",\n      \"evidence\": \"GFP-IP mass spectrometry, Co-IP, siRNA, PBM mutant constructs, cell proliferation assays\",\n      \"pmids\": [\"36326272\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether SNX27-mediated degradation of TANC2 regulates mTOR signaling not tested\",\n        \"Physiological relevance of TANC2 stabilization in non-HPV contexts unknown\",\n        \"Lysosomal degradation pathway for TANC2 not reconstituted with purified components\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of the TANC2-mTOR interaction, whether DCV capture and mTOR inhibition are functionally coupled at the synapse, and which specific TANC2 domains mediate each of its scaffolding interactions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural or cryo-EM model of TANC2 or its complexes\",\n        \"Functional relationship between DCV capture and mTOR inhibition not explored\",\n        \"Domain-resolved interaction map for TANC2's PSD, KIF1A, and mTOR binding not available\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 5]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 1, 4, 5]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"KIF1A\",\n      \"MTOR\",\n      \"SNX27\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}