{"gene":"MINAR1","run_date":"2026-04-28T18:30:28","timeline":{"discoveries":[{"year":2018,"finding":"MINAR1 physically interacts with Notch2, and this binding increases Notch2 stability and function. MINAR1 is a large intrinsically disordered protein (~70% unstructured) with a single transmembrane domain, short cytoplasmic domain, and large extracellular domain with no similarity to known proteins.","method":"Co-immunoprecipitation, protein interaction assays, domain analysis, cell culture functional assays","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP binding demonstrated with functional characterization in single study","pmids":["29329397"],"is_preprint":false},{"year":2018,"finding":"MINAR1 negatively regulates angiogenesis, as shown by inhibition of angiogenesis in cell culture, mouse Matrigel plug assays, and zebrafish angiogenesis models. Re-expression of MINAR1 in breast cancer cells inhibited tumor growth.","method":"Cell culture angiogenesis assays, in vivo mouse Matrigel plug assay, zebrafish angiogenesis model, tumor growth assay","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple in vitro and in vivo models in a single study with functional rescue","pmids":["29329397"],"is_preprint":false},{"year":2018,"finding":"MINAR1 (referred to as UBTOR/KIAA1024) inhibits mTOR signaling by stabilizing the mTOR complex component DEPTOR. UBTOR depletion activates mTOR signaling and promotes cell growth, while overexpression suppresses colony formation. UBTOR depletion also promotes neurite outgrowth in cultured hippocampal neurons and PC12 cells.","method":"siRNA knockdown, overexpression, Western blot for mTOR pathway components, co-culture assays, zebrafish ubtor knockout, xenograft mouse model","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis and KO with defined molecular mechanism (DEPTOR stabilization) replicated in zebrafish and mouse xenograft","pmids":["30080879"],"is_preprint":false},{"year":2021,"finding":"MINAR1 is a host dependency factor required for replication of multiple coronaviruses (MERS-CoV, HCoV-229E, SARS-CoV, SARS-CoV-2), identified as an autophagy pathway-related gene.","method":"Genome-wide CRISPR/Cas9 knockout screen in Huh7 cells, validated in MERS-CoV, HCoV-229E, SARS-CoV, and SARS-CoV-2 infection assays","journal":"PLoS biology","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPR screen with validation across four coronaviruses; mechanistic placement in autophagy pathway inferred but not directly dissected","pmids":["34962926"],"is_preprint":false},{"year":2021,"finding":"ubtor (MINAR1 ortholog) disruption in zebrafish causes increased spontaneous embryonic movement, elevated neuronal activity in spinal interneurons, hyperactivation of mTOR signaling, and increased seizure susceptibility, all rescued by rapamycin treatment.","method":"Zebrafish ubtor knockout, neuronal activity recording, pentylenetetrazol seizure assay, rapamycin rescue experiment, mTOR pathway Western blot","journal":"Neuroscience bulletin","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype, pharmacological rescue with rapamycin confirms mTOR pathway placement","pmids":["34309811"],"is_preprint":false},{"year":2026,"finding":"MINAR1 is specifically expressed in somatostatin (SST)- and parvalbumin (PV)-positive interneurons in mouse forebrain. Conditional knockout of MINAR1 increased seizure susceptibility (PTZ model), selectively impaired SST+ interneuron excitability, reduced inhibitory drive toward pyramidal neurons, decreased Gαs levels, and disrupted Gαs-cAMP signaling. Pharmacological activation of adenylate cyclase with forskolin rescued the inhibitory defect.","method":"Conditional knockout (Nestin-Cre and SST-Cre), PTZ seizure assay, electrophysiology, immunofluorescence, Western blot for Gαs, cAMP measurement, forskolin pharmacological rescue","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"High","confidence_rationale":"Tier 1-2 — cell-type-specific CKO with electrophysiology, defined signaling pathway (Gαs-cAMP), and pharmacological rescue across multiple orthogonal methods","pmids":["41640244"],"is_preprint":false}],"current_model":"MINAR1 is a large intrinsically disordered transmembrane protein that physically binds Notch2 to increase its stability, negatively regulates angiogenesis and tumor growth, inhibits mTOR signaling by stabilizing DEPTOR, is required as a host dependency factor for pan-coronavirus replication through an autophagy-related mechanism, and in the brain is expressed in SST+ and PV+ interneurons where it regulates seizure susceptibility by maintaining Gαs-cAMP signaling and SST+ interneuron excitability."},"narrative":{"teleology":[{"year":2018,"claim":"The first functional characterization established MINAR1 as a novel transmembrane protein that physically binds Notch2 to stabilize it and acts as a negative regulator of angiogenesis and tumor growth, answering what this previously uncharacterized gene does at the cellular level.","evidence":"Co-immunoprecipitation, angiogenesis assays in cell culture, mouse Matrigel plugs, zebrafish, and breast cancer xenograft models","pmids":["29329397"],"confidence":"Medium","gaps":["Notch2 binding domain on MINAR1 not mapped","No independent replication of the Notch2 interaction","Mechanism by which MINAR1 binding stabilizes Notch2 is unknown"]},{"year":2018,"claim":"An independent study identified the MINAR1 ortholog (UBTOR) as an inhibitor of mTOR signaling through stabilization of DEPTOR, providing a second major signaling axis and establishing that MINAR1 loss promotes cell growth and neurite outgrowth.","evidence":"siRNA knockdown and overexpression in mammalian cells, zebrafish ubtor knockout, xenograft mouse model, Western blot for mTOR pathway components","pmids":["30080879"],"confidence":"Medium","gaps":["Whether DEPTOR stabilization is direct or indirect is not resolved","Relationship between the Notch2 and mTOR regulatory functions is unclear","Mechanism of DEPTOR stabilization (e.g., preventing ubiquitination) not dissected"]},{"year":2021,"claim":"Zebrafish ubtor knockout demonstrated that mTOR hyperactivation downstream of MINAR1 loss causes neuronal hyperexcitability and seizure susceptibility, rescued by rapamycin, establishing a neurological consequence of the mTOR regulatory axis.","evidence":"Zebrafish knockout, spinal interneuron activity recording, PTZ seizure assay, rapamycin rescue","pmids":["34309811"],"confidence":"Medium","gaps":["Cell-type specificity of MINAR1 function in the nervous system not yet addressed","Whether mammalian neurons show the same mTOR-dependent seizure phenotype is untested","Downstream effectors of mTOR mediating hyperexcitability not identified"]},{"year":2021,"claim":"A genome-wide CRISPR screen identified MINAR1 as a pan-coronavirus host dependency factor linked to the autophagy pathway, expanding its functional repertoire beyond developmental signaling.","evidence":"CRISPR/Cas9 knockout screen in Huh7 cells validated across MERS-CoV, HCoV-229E, SARS-CoV, and SARS-CoV-2","pmids":["34962926"],"confidence":"Medium","gaps":["Direct mechanistic role in coronavirus replication not dissected beyond autophagy pathway inference","Whether the proviral role depends on mTOR/DEPTOR axis or Notch2 interaction is unknown","Single cell line (Huh7) used for screening"]},{"year":2026,"claim":"Conditional knockout in mouse brain resolved the cell-type specificity of MINAR1 function, showing it is expressed in SST+ and PV+ interneurons and maintains SST+ interneuron excitability through Gαs-cAMP signaling — a pathway distinct from the previously described mTOR axis.","evidence":"Nestin-Cre and SST-Cre conditional knockouts, electrophysiology, PTZ seizure model, Gαs Western blot, cAMP measurement, forskolin rescue","pmids":["41640244"],"confidence":"High","gaps":["How MINAR1 maintains Gαs protein levels is mechanistically undefined","Whether the mTOR and Gαs-cAMP pathways represent parallel or convergent mechanisms in mammalian neurons is unresolved","PV+ interneuron functional consequences of MINAR1 loss not characterized"]},{"year":null,"claim":"How MINAR1 coordinates its multiple signaling functions (Notch2 stabilization, DEPTOR/mTOR inhibition, Gαs-cAMP maintenance) and whether these reflect distinct domain-specific interactions or a shared mechanism remains unknown.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of MINAR1 or its interaction interfaces exists","Whether MINAR1's disordered extracellular domain serves as a multi-partner interaction scaffold is untested","The autophagy-related proviral mechanism for coronaviruses has not been mechanistically dissected"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2,5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[3]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,5]}],"complexes":[],"partners":["NOTCH2","DEPTOR","GNAS"],"other_free_text":[]},"mechanistic_narrative":"MINAR1 is a single-pass transmembrane protein with a large, largely intrinsically disordered extracellular domain that functions as a negative regulator of cell growth and neuronal excitability through modulation of multiple signaling pathways. MINAR1 inhibits mTOR signaling by stabilizing the mTOR complex component DEPTOR, suppressing cell growth and colony formation, and its loss leads to mTOR hyperactivation, increased seizure susceptibility, and enhanced neuronal activity in zebrafish [PMID:30080879, PMID:34309811]. MINAR1 physically interacts with Notch2 to increase its stability and negatively regulates angiogenesis in cell culture, mouse, and zebrafish models, and its re-expression in breast cancer cells inhibits tumor growth [PMID:29329397]. In the mammalian brain, MINAR1 is expressed in SST+ and PV+ interneurons where it maintains Gαs-cAMP signaling and SST+ interneuron excitability; conditional knockout increases seizure susceptibility through reduced inhibitory drive onto pyramidal neurons, a defect rescued by adenylate cyclase activation [PMID:41640244]."},"prefetch_data":{"uniprot":{"accession":"Q9UPX6","full_name":"Major intrinsically disordered Notch2-binding receptor 1","aliases":["Membrane integral NOTCH2-associated receptor 1","Ubiquitination and mTOR signaling protein"],"length_aa":916,"mass_kda":103.0,"function":"Intrinsically disordered protein which may negatively regulate mTOR signaling pathway by stabilizing the mTOR complex component DEPTOR (PubMed:30080879). Negatively regulates angiogenesis (PubMed:29329397). Negatively regulates cell growth (PubMed:29329397, PubMed:30080879). Negatively regulates neurite outgrowth in hippocampal neurons (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9UPX6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MINAR1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MINAR1","total_profiled":1310},"omim":[{"mim_id":"620215","title":"MEMBRANE INTEGRAL NOTCH2-ASSOCIATED RECEPTOR 2; MINAR2","url":"https://www.omim.org/entry/620215"},{"mim_id":"618054","title":"MEMBRANE INTEGRAL NOTCH2-ASSOCIATED RECEPTOR 1; MINAR1","url":"https://www.omim.org/entry/618054"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"adrenal gland","ntpm":9.7},{"tissue":"brain","ntpm":7.3},{"tissue":"retina","ntpm":6.3}],"url":"https://www.proteinatlas.org/search/MINAR1"},"hgnc":{"alias_symbol":["UBTOR"],"prev_symbol":["KIAA1024"]},"alphafold":{"accession":"Q9UPX6","domains":[{"cath_id":"1.20.272","chopping":"3-100","consensus_level":"medium","plddt":81.365,"start":3,"end":100}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UPX6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UPX6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UPX6-F1-predicted_aligned_error_v6.png","plddt_mean":49.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MINAR1","jax_strain_url":"https://www.jax.org/strain/search?query=MINAR1"},"sequence":{"accession":"Q9UPX6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UPX6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UPX6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UPX6"}},"corpus_meta":[{"pmid":"34962926","id":"PMC_34962926","title":"A genome-wide CRISPR screen identifies interactors of the autophagy pathway as conserved coronavirus targets.","date":"2021","source":"PLoS biology","url":"https://pubmed.ncbi.nlm.nih.gov/34962926","citation_count":55,"is_preprint":false},{"pmid":"16735990","id":"PMC_16735990","title":"Fine mapping of the keratoconus with cataract locus on chromosome 15q and candidate gene analysis.","date":"2006","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/16735990","citation_count":39,"is_preprint":false},{"pmid":"32176688","id":"PMC_32176688","title":"A homozygous missense variant in CACNB4 encoding the auxiliary calcium channel beta4 subunit causes a severe neurodevelopmental disorder and impairs channel and non-channel functions.","date":"2020","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32176688","citation_count":28,"is_preprint":false},{"pmid":"32274496","id":"PMC_32274496","title":"Activin A Determines Steroid Levels and Composition in the Fetal Testis.","date":"2020","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/32274496","citation_count":22,"is_preprint":false},{"pmid":"29329397","id":"PMC_29329397","title":"MINAR1 is a Notch2-binding protein that inhibits angiogenesis and breast cancer growth.","date":"2018","source":"Journal of molecular cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/29329397","citation_count":18,"is_preprint":false},{"pmid":"30080879","id":"PMC_30080879","title":"UBTOR/KIAA1024 regulates neurite outgrowth and neoplasia through mTOR signaling.","date":"2018","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30080879","citation_count":13,"is_preprint":false},{"pmid":"33728681","id":"PMC_33728681","title":"Novel functional variants in the Notch pathway and survival of Chinese colorectal cancer.","date":"2021","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/33728681","citation_count":9,"is_preprint":false},{"pmid":"34309811","id":"PMC_34309811","title":"ubtor Mutation Causes Motor Hyperactivity by Activating mTOR Signaling in Zebrafish.","date":"2021","source":"Neuroscience bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/34309811","citation_count":8,"is_preprint":false},{"pmid":"32954300","id":"PMC_32954300","title":"Loss of MINAR2 impairs motor function and causes Parkinson's disease-like symptoms in mice.","date":"2020","source":"Brain communications","url":"https://pubmed.ncbi.nlm.nih.gov/32954300","citation_count":8,"is_preprint":false},{"pmid":"36317962","id":"PMC_36317962","title":"Kiaa1024L/Minar2 is essential for hearing by regulating cholesterol distribution in hair bundles.","date":"2022","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/36317962","citation_count":4,"is_preprint":false},{"pmid":"35875965","id":"PMC_35875965","title":"Conserved requirement of autophagy-related effectors during coronavirus replication.","date":"2022","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/35875965","citation_count":3,"is_preprint":false},{"pmid":"41640244","id":"PMC_41640244","title":"Cortical Somatostatin Neurons Regulate Seizure Susceptibility via MINAR1/Gαs-cAMP Signaling.","date":"2026","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/41640244","citation_count":0,"is_preprint":false},{"pmid":"39825623","id":"PMC_39825623","title":"DNA methylation at birth and IgE trajectories from birth to adolescence, different patterns between White and Asian.","date":"2025","source":"Epigenomics","url":"https://pubmed.ncbi.nlm.nih.gov/39825623","citation_count":0,"is_preprint":false},{"pmid":"42040572","id":"PMC_42040572","title":"A descriptive multilevel analysis associating COVID-19 with polymyositis: from genetic markers and candidate mediators to clinical hematological profiles.","date":"2026","source":"Frontiers in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/42040572","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8462,"output_tokens":1543,"usd":0.024265},"stage2":{"model":"claude-opus-4-6","input_tokens":4793,"output_tokens":1822,"usd":0.104273},"total_usd":0.128538,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2018,\n      \"finding\": \"MINAR1 physically interacts with Notch2, and this binding increases Notch2 stability and function. MINAR1 is a large intrinsically disordered protein (~70% unstructured) with a single transmembrane domain, short cytoplasmic domain, and large extracellular domain with no similarity to known proteins.\",\n      \"method\": \"Co-immunoprecipitation, protein interaction assays, domain analysis, cell culture functional assays\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP binding demonstrated with functional characterization in single study\",\n      \"pmids\": [\"29329397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MINAR1 negatively regulates angiogenesis, as shown by inhibition of angiogenesis in cell culture, mouse Matrigel plug assays, and zebrafish angiogenesis models. Re-expression of MINAR1 in breast cancer cells inhibited tumor growth.\",\n      \"method\": \"Cell culture angiogenesis assays, in vivo mouse Matrigel plug assay, zebrafish angiogenesis model, tumor growth assay\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple in vitro and in vivo models in a single study with functional rescue\",\n      \"pmids\": [\"29329397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"MINAR1 (referred to as UBTOR/KIAA1024) inhibits mTOR signaling by stabilizing the mTOR complex component DEPTOR. UBTOR depletion activates mTOR signaling and promotes cell growth, while overexpression suppresses colony formation. UBTOR depletion also promotes neurite outgrowth in cultured hippocampal neurons and PC12 cells.\",\n      \"method\": \"siRNA knockdown, overexpression, Western blot for mTOR pathway components, co-culture assays, zebrafish ubtor knockout, xenograft mouse model\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis and KO with defined molecular mechanism (DEPTOR stabilization) replicated in zebrafish and mouse xenograft\",\n      \"pmids\": [\"30080879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MINAR1 is a host dependency factor required for replication of multiple coronaviruses (MERS-CoV, HCoV-229E, SARS-CoV, SARS-CoV-2), identified as an autophagy pathway-related gene.\",\n      \"method\": \"Genome-wide CRISPR/Cas9 knockout screen in Huh7 cells, validated in MERS-CoV, HCoV-229E, SARS-CoV, and SARS-CoV-2 infection assays\",\n      \"journal\": \"PLoS biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR screen with validation across four coronaviruses; mechanistic placement in autophagy pathway inferred but not directly dissected\",\n      \"pmids\": [\"34962926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ubtor (MINAR1 ortholog) disruption in zebrafish causes increased spontaneous embryonic movement, elevated neuronal activity in spinal interneurons, hyperactivation of mTOR signaling, and increased seizure susceptibility, all rescued by rapamycin treatment.\",\n      \"method\": \"Zebrafish ubtor knockout, neuronal activity recording, pentylenetetrazol seizure assay, rapamycin rescue experiment, mTOR pathway Western blot\",\n      \"journal\": \"Neuroscience bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype, pharmacological rescue with rapamycin confirms mTOR pathway placement\",\n      \"pmids\": [\"34309811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"MINAR1 is specifically expressed in somatostatin (SST)- and parvalbumin (PV)-positive interneurons in mouse forebrain. Conditional knockout of MINAR1 increased seizure susceptibility (PTZ model), selectively impaired SST+ interneuron excitability, reduced inhibitory drive toward pyramidal neurons, decreased Gαs levels, and disrupted Gαs-cAMP signaling. Pharmacological activation of adenylate cyclase with forskolin rescued the inhibitory defect.\",\n      \"method\": \"Conditional knockout (Nestin-Cre and SST-Cre), PTZ seizure assay, electrophysiology, immunofluorescence, Western blot for Gαs, cAMP measurement, forskolin pharmacological rescue\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — cell-type-specific CKO with electrophysiology, defined signaling pathway (Gαs-cAMP), and pharmacological rescue across multiple orthogonal methods\",\n      \"pmids\": [\"41640244\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MINAR1 is a large intrinsically disordered transmembrane protein that physically binds Notch2 to increase its stability, negatively regulates angiogenesis and tumor growth, inhibits mTOR signaling by stabilizing DEPTOR, is required as a host dependency factor for pan-coronavirus replication through an autophagy-related mechanism, and in the brain is expressed in SST+ and PV+ interneurons where it regulates seizure susceptibility by maintaining Gαs-cAMP signaling and SST+ interneuron excitability.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MINAR1 is a single-pass transmembrane protein with a large, largely intrinsically disordered extracellular domain that functions as a negative regulator of cell growth and neuronal excitability through modulation of multiple signaling pathways. MINAR1 inhibits mTOR signaling by stabilizing the mTOR complex component DEPTOR, suppressing cell growth and colony formation, and its loss leads to mTOR hyperactivation, increased seizure susceptibility, and enhanced neuronal activity in zebrafish [PMID:30080879, PMID:34309811]. MINAR1 physically interacts with Notch2 to increase its stability and negatively regulates angiogenesis in cell culture, mouse, and zebrafish models, and its re-expression in breast cancer cells inhibits tumor growth [PMID:29329397]. In the mammalian brain, MINAR1 is expressed in SST+ and PV+ interneurons where it maintains Gαs-cAMP signaling and SST+ interneuron excitability; conditional knockout increases seizure susceptibility through reduced inhibitory drive onto pyramidal neurons, a defect rescued by adenylate cyclase activation [PMID:41640244].\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"The first functional characterization established MINAR1 as a novel transmembrane protein that physically binds Notch2 to stabilize it and acts as a negative regulator of angiogenesis and tumor growth, answering what this previously uncharacterized gene does at the cellular level.\",\n      \"evidence\": \"Co-immunoprecipitation, angiogenesis assays in cell culture, mouse Matrigel plugs, zebrafish, and breast cancer xenograft models\",\n      \"pmids\": [\"29329397\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Notch2 binding domain on MINAR1 not mapped\",\n        \"No independent replication of the Notch2 interaction\",\n        \"Mechanism by which MINAR1 binding stabilizes Notch2 is unknown\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"An independent study identified the MINAR1 ortholog (UBTOR) as an inhibitor of mTOR signaling through stabilization of DEPTOR, providing a second major signaling axis and establishing that MINAR1 loss promotes cell growth and neurite outgrowth.\",\n      \"evidence\": \"siRNA knockdown and overexpression in mammalian cells, zebrafish ubtor knockout, xenograft mouse model, Western blot for mTOR pathway components\",\n      \"pmids\": [\"30080879\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether DEPTOR stabilization is direct or indirect is not resolved\",\n        \"Relationship between the Notch2 and mTOR regulatory functions is unclear\",\n        \"Mechanism of DEPTOR stabilization (e.g., preventing ubiquitination) not dissected\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Zebrafish ubtor knockout demonstrated that mTOR hyperactivation downstream of MINAR1 loss causes neuronal hyperexcitability and seizure susceptibility, rescued by rapamycin, establishing a neurological consequence of the mTOR regulatory axis.\",\n      \"evidence\": \"Zebrafish knockout, spinal interneuron activity recording, PTZ seizure assay, rapamycin rescue\",\n      \"pmids\": [\"34309811\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Cell-type specificity of MINAR1 function in the nervous system not yet addressed\",\n        \"Whether mammalian neurons show the same mTOR-dependent seizure phenotype is untested\",\n        \"Downstream effectors of mTOR mediating hyperexcitability not identified\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A genome-wide CRISPR screen identified MINAR1 as a pan-coronavirus host dependency factor linked to the autophagy pathway, expanding its functional repertoire beyond developmental signaling.\",\n      \"evidence\": \"CRISPR/Cas9 knockout screen in Huh7 cells validated across MERS-CoV, HCoV-229E, SARS-CoV, and SARS-CoV-2\",\n      \"pmids\": [\"34962926\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct mechanistic role in coronavirus replication not dissected beyond autophagy pathway inference\",\n        \"Whether the proviral role depends on mTOR/DEPTOR axis or Notch2 interaction is unknown\",\n        \"Single cell line (Huh7) used for screening\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Conditional knockout in mouse brain resolved the cell-type specificity of MINAR1 function, showing it is expressed in SST+ and PV+ interneurons and maintains SST+ interneuron excitability through Gαs-cAMP signaling — a pathway distinct from the previously described mTOR axis.\",\n      \"evidence\": \"Nestin-Cre and SST-Cre conditional knockouts, electrophysiology, PTZ seizure model, Gαs Western blot, cAMP measurement, forskolin rescue\",\n      \"pmids\": [\"41640244\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How MINAR1 maintains Gαs protein levels is mechanistically undefined\",\n        \"Whether the mTOR and Gαs-cAMP pathways represent parallel or convergent mechanisms in mammalian neurons is unresolved\",\n        \"PV+ interneuron functional consequences of MINAR1 loss not characterized\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MINAR1 coordinates its multiple signaling functions (Notch2 stabilization, DEPTOR/mTOR inhibition, Gαs-cAMP maintenance) and whether these reflect distinct domain-specific interactions or a shared mechanism remains unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of MINAR1 or its interaction interfaces exists\",\n        \"Whether MINAR1's disordered extracellular domain serves as a multi-partner interaction scaffold is untested\",\n        \"The autophagy-related proviral mechanism for coronaviruses has not been mechanistically dissected\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"NOTCH2\",\n      \"DEPTOR\",\n      \"GNAS\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}