{"gene":"TNPO2","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2020,"finding":"TNPO2 is involved in E2-dependent cytoplasmic retention of oestrogen receptor-α (ERα) via the proline/tyrosine (PY) motifs of ERα. TNPO2 does not mediate nuclear export of ERα but instead competitively binds to the basic nuclear localisation signal (NLS) of ERα with importin-α to inhibit importin-α/β-dependent ERα nuclear import. TNPO2 knockdown enhances nuclear localisation of ERα and reduces PI3K/AKT phosphorylation in the presence of E2.","method":"Co-immunoprecipitation, siRNA knockdown with nuclear/cytoplasmic fractionation, phosphorylation assays; PY-motif mutant ERα constructs","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assays with mutant constructs and functional readouts (localization + signaling), single lab, multiple orthogonal methods","pmids":["33122699"],"is_preprint":false},{"year":2021,"finding":"Drosophila dTnpo (ortholog of TNPO2) is expressed in a subset of neurons and is essential for neuronal maintenance and function; RNAi-mediated downregulation in mature neurons disrupts neuronal activity and survival. Both loss and gain of dTnpo activity cause developmental defects (eye/wing deformities, lethality) in a dosage-dependent manner. Human TNPO2 variants associated with neurodevelopmental delay cause more or less severe developmental abnormalities in flies compared to wild-type TNPO2 when ectopically expressed, with severity correlating with variant position: RAN-binding domain variants are most toxic, acidic loop variants least toxic, and cargo-binding domain variants show tissue-dependent effects.","method":"Drosophila RNAi knockdown, mutant alleles, ectopic expression of wild-type and variant TNPO2; phenotypic readouts (lethality, eye/wing morphology, neuronal activity/survival)","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple alleles, RNAi, and ectopic expression with domain-specific functional dissection; multiple orthogonal phenotypic readouts, replicated across multiple variant alleles","pmids":["34314705"],"is_preprint":false},{"year":2019,"finding":"TNPO2 operates downstream of DYNC1I1 in gastric cancer cells. DYNC1I1 upregulates TNPO2 expression by upregulating SP1, which recruits and binds to P300-acetylated TNPO2 promoter region histones to promote TNPO2 expression. TNPO2 in turn promotes gastric cancer cell proliferation and inhibits apoptosis through a mechanism potentially dependent on functional expression of P21.","method":"Expression profiling chip, siRNA knockdown, chromatin immunoprecipitation (ChIP) for SP1 and P300-acetylated histones at TNPO2 promoter, cell proliferation and apoptosis assays","journal":"Cancer medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and knockdown experiments with functional readouts, single lab, multiple methods but P21 mechanism not fully dissected","pmids":["31605449"],"is_preprint":false},{"year":2023,"finding":"TNPO2 was identified as an interacting partner of MAB21L2 in yeast two-hybrid screens using human adult retina and zebrafish embryo libraries, suggesting TNPO2 can bind to this developmental/eye protein.","method":"Yeast two-hybrid (Y2H) screen","journal":"Developmental dynamics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Y2H screen with no follow-up validation for TNPO2-MAB21L2 interaction specifically; interaction not confirmed by Co-IP or pulldown for this pair","pmids":["36576422"],"is_preprint":false},{"year":2026,"finding":"TNPO2 mRNA does not localize to the nuclear envelope in human U2OS, HeLa, or pluripotent stem cells (negative finding), in contrast to its C. elegans ortholog IMB-2. TNPO1 protein (but not specifically TNPO2 protein) localizes to the nucleus and its periphery.","method":"smiFISH and fluorescence microscopy in multiple human cell lines","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct imaging with smiFISH across three human cell types; negative result for mRNA localization is robust; preprint, single lab","pmids":["42239225"],"is_preprint":true}],"current_model":"TNPO2 (Transportin-2) is a non-classical nuclear import receptor that mediates nucleocytoplasmic shuttling of diverse cargoes including developmental and neuronal proteins; it retains ERα in the cytoplasm by binding its NLS and competing with importin-α/β to inhibit nuclear import, is transcriptionally regulated downstream of DYNC1I1/SP1/P300 to promote cancer cell proliferation via P21, and is essential for neuronal maintenance and development as demonstrated by dosage-sensitive phenotypes in Drosophila, with pathogenic variant severity mapping to functional domains (RAN-binding, acidic loop, cargo-binding)."},"narrative":{"mechanistic_narrative":"TNPO2 (Transportin-2) is a non-classical nuclear transport receptor whose dosage and cargo interactions govern nucleocytoplasmic distribution of developmental and neuronal proteins [PMID:34314705]. It controls subcellular localization of estrogen receptor-α (ERα) by competitively binding the basic NLS of ERα against importin-α, thereby inhibiting importin-α/β-dependent ERα nuclear import rather than exporting it; this retention engages PY motifs of ERα and modulates downstream PI3K/AKT phosphorylation, with TNPO2 knockdown enhancing ERα nuclear localization [PMID:33122699]. In neurons, TNPO2 is required for maintenance and survival, and both loss and gain of activity produce dosage-dependent developmental defects; pathogenic human variants confer graded severity that maps to functional domains, with RAN-binding-domain variants most deleterious, acidic-loop variants least, and cargo-binding-domain variants showing tissue-dependent effects [PMID:34314705]. In gastric cancer cells, TNPO2 acts downstream of a DYNC1I1→SP1→P300 transcriptional axis to drive proliferation and suppress apoptosis via P21 [PMID:31605449]. Additional binding partners and cargoes beyond these contexts have not been characterized in the available corpus.","teleology":[{"year":2019,"claim":"Established a transcriptional and pro-tumorigenic role for TNPO2 by placing it downstream of a defined regulatory cascade in cancer cells.","evidence":"Expression profiling, siRNA knockdown, ChIP for SP1 and P300-acetylated histones at the TNPO2 promoter, and proliferation/apoptosis assays in gastric cancer cells","pmids":["31605449"],"confidence":"Medium","gaps":["The P21-dependent mechanism downstream of TNPO2 is not fully dissected","Whether TNPO2's transport function contributes to the proliferative phenotype is untested"]},{"year":2020,"claim":"Defined a specific molecular mechanism by which TNPO2 retains a cargo in the cytoplasm, showing it competes with importin-α at the cargo NLS rather than mediating export.","evidence":"Co-IP, siRNA knockdown with nuclear/cytoplasmic fractionation, phosphorylation assays, and PY-motif mutant ERα constructs","pmids":["33122699"],"confidence":"Medium","gaps":["Demonstrated for ERα in one cell system; generality to other cargoes unknown","Direct competition kinetics with importin-α not quantified"]},{"year":2021,"claim":"Connected TNPO2 dosage and domain architecture to neuronal maintenance and human neurodevelopmental disease, mapping variant severity to specific functional domains.","evidence":"Drosophila RNAi, mutant alleles, and ectopic expression of wild-type and patient-variant TNPO2 with lethality, eye/wing morphology, and neuronal activity/survival readouts","pmids":["34314705"],"confidence":"High","gaps":["Molecular cargoes underlying the neuronal requirement are not identified","Mechanistic link between domain-specific transport defects and fly phenotypes is inferred, not biochemically resolved"]},{"year":2023,"claim":"Nominated a candidate developmental cargo/partner (MAB21L2) for TNPO2.","evidence":"Yeast two-hybrid screens using human adult retina and zebrafish embryo libraries","pmids":["36576422"],"confidence":"Low","gaps":["Single Y2H screen with no Co-IP or pulldown validation for the TNPO2-MAB21L2 pair","Functional consequence of any interaction untested"]},{"year":2026,"claim":"Tested whether TNPO2 mRNA shares the nuclear-envelope localization of its C. elegans ortholog, establishing a species-specific difference.","evidence":"smiFISH and fluorescence microscopy in U2OS, HeLa, and pluripotent stem cells (preprint)","pmids":["42239225"],"confidence":"Medium","gaps":["Preprint, single lab","Negative mRNA-localization result does not address TNPO2 protein localization"]},{"year":null,"claim":"The full cargo repertoire of TNPO2 and how cargo selectivity, RAN-binding, and the acidic loop coordinate to drive its transport cycle remain undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of TNPO2-cargo or TNPO2-RAN complexes in the corpus","Direct biochemical validation of most candidate cargoes absent"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[0]}],"localization":[],"pathway":[],"complexes":[],"partners":["ESR1","MAB21L2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O14787","full_name":"Transportin-2","aliases":["Karyopherin beta-2b"],"length_aa":897,"mass_kda":101.4,"function":"Probably functions in nuclear protein import as nuclear transport receptor. Serves as receptor for nuclear localization signals (NLS) in cargo substrates. Is thought to mediate docking of the importin/substrate complex to the nuclear pore complex (NPC) through binding to nucleoporin and the complex is subsequently translocated through the pore by an energy requiring, Ran-dependent mechanism. At the nucleoplasmic side of the NPC, Ran binds to the importin, the importin/substrate complex dissociates and importin is re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran. The directionality of nuclear import is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus (By similarity)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/O14787/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TNPO2","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"NUP153","stoichiometry":4.0},{"gene":"KPNB1","stoichiometry":0.2},{"gene":"RAN","stoichiometry":0.2},{"gene":"RANBP1","stoichiometry":0.2},{"gene":"SNF8","stoichiometry":0.2},{"gene":"TMA16","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TNPO2","total_profiled":1310},"omim":[{"mim_id":"619556","title":"INTELLECTUAL DEVELOPMENTAL DISORDER WITH HYPOTONIA, IMPAIRED SPEECH, AND DYSMORPHIC FACIES; IDDHISD","url":"https://www.omim.org/entry/619556"},{"mim_id":"603002","title":"TRANSPORTIN 2; TNPO2","url":"https://www.omim.org/entry/603002"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Nucleoli","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TNPO2"},"hgnc":{"alias_symbol":["IPO3","KPNB2B","FLJ12155","TRN2"],"prev_symbol":[]},"alphafold":{"accession":"O14787","domains":[{"cath_id":"1.25.10.10","chopping":"6-239","consensus_level":"medium","plddt":94.3418,"start":6,"end":239},{"cath_id":"1.25.40","chopping":"748-897","consensus_level":"medium","plddt":85.8167,"start":748,"end":897}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O14787","model_url":"https://alphafold.ebi.ac.uk/files/AF-O14787-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O14787-F1-predicted_aligned_error_v6.png","plddt_mean":91.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TNPO2","jax_strain_url":"https://www.jax.org/strain/search?query=TNPO2"},"sequence":{"accession":"O14787","fasta_url":"https://rest.uniprot.org/uniprotkb/O14787.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O14787/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O14787"}},"corpus_meta":[{"pmid":"34314705","id":"PMC_34314705","title":"TNPO2 variants associate with human developmental delays, neurologic deficits, and dysmorphic features and alter TNPO2 activity in Drosophila.","date":"2021","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34314705","citation_count":36,"is_preprint":false},{"pmid":"25771974","id":"PMC_25771974","title":"Expression status of candidate genes in mesothelioma tissues and cell lines.","date":"2014","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/25771974","citation_count":29,"is_preprint":false},{"pmid":"37372363","id":"PMC_37372363","title":"Identifying Candidate Genes for Litter Size and Three Morphological Traits in Youzhou Dark Goats Based on Genome-Wide SNP Markers.","date":"2023","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/37372363","citation_count":26,"is_preprint":false},{"pmid":"31341054","id":"PMC_31341054","title":"Interferon-Inducible MicroRNA miR-128 Modulates HIV-1 Replication by Targeting TNPO3 mRNA.","date":"2019","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/31341054","citation_count":25,"is_preprint":false},{"pmid":"33122699","id":"PMC_33122699","title":"Transportin-2 plays a critical role in nucleocytoplasmic shuttling of oestrogen receptor-α.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/33122699","citation_count":17,"is_preprint":false},{"pmid":"21452213","id":"PMC_21452213","title":"Transportin 1 in the mouse brain: appearance in regions of neurogenesis, cerebrospinal fluid production/sensing, and circadian clock.","date":"2011","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/21452213","citation_count":15,"is_preprint":false},{"pmid":"37866126","id":"PMC_37866126","title":"Enlightening the path to NSCLC biomarkers: Utilizing the power of XAI-guided deep learning.","date":"2023","source":"Computer methods and programs in biomedicine","url":"https://pubmed.ncbi.nlm.nih.gov/37866126","citation_count":14,"is_preprint":false},{"pmid":"31605449","id":"PMC_31605449","title":"TNPO2 operates downstream of DYNC1I1 and promotes gastric cancer cell proliferation and inhibits apoptosis.","date":"2019","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/31605449","citation_count":12,"is_preprint":false},{"pmid":"31633246","id":"PMC_31633246","title":"Development of a novel gene signature in patients without Helicobacter pylori infection gastric cancer.","date":"2019","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31633246","citation_count":9,"is_preprint":false},{"pmid":"37219934","id":"PMC_37219934","title":"Identification of Distinct Genetic Profiles of Palindromic Rheumatism Using Whole-Exome Sequencing.","date":"2023","source":"Arthritis & rheumatology (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/37219934","citation_count":7,"is_preprint":false},{"pmid":"36576422","id":"PMC_36576422","title":"Identification of HSPA8 as an interacting partner of MAB21L2 and an important factor in eye development.","date":"2023","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/36576422","citation_count":5,"is_preprint":false},{"pmid":"38196148","id":"PMC_38196148","title":"Integration of the cancer cell secretome and transcriptome reveals potential noninvasive diagnostic markers for bladder cancer.","date":"2024","source":"Proteomics. Clinical applications","url":"https://pubmed.ncbi.nlm.nih.gov/38196148","citation_count":3,"is_preprint":false},{"pmid":"35361823","id":"PMC_35361823","title":"NeuroSCORE is a genome-wide omics-based model that identifies candidate disease genes of the central nervous system.","date":"2022","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/35361823","citation_count":1,"is_preprint":false},{"pmid":"41311105","id":"PMC_41311105","title":"A Rare Missense Variant in TNPO2 in an Individual With a Neurodevelopmental Disability.","date":"2025","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/41311105","citation_count":0,"is_preprint":false},{"pmid":"41013606","id":"PMC_41013606","title":"High-throughput behavioural phenotyping of 25 C. elegans disease models including patient-specific mutations.","date":"2025","source":"BMC biology","url":"https://pubmed.ncbi.nlm.nih.gov/41013606","citation_count":0,"is_preprint":false},{"pmid":"42239225","id":"PMC_42239225","title":"Differential mRNA localization of karyopherin-β2 homologs in C. elegans and humans.","date":"2026","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/42239225","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10788,"output_tokens":1504,"usd":0.027462,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8319,"output_tokens":1952,"usd":0.045198,"stage2_stop_reason":"end_turn"},"total_usd":0.07266,"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\": 2020,\n      \"finding\": \"TNPO2 is involved in E2-dependent cytoplasmic retention of oestrogen receptor-α (ERα) via the proline/tyrosine (PY) motifs of ERα. TNPO2 does not mediate nuclear export of ERα but instead competitively binds to the basic nuclear localisation signal (NLS) of ERα with importin-α to inhibit importin-α/β-dependent ERα nuclear import. TNPO2 knockdown enhances nuclear localisation of ERα and reduces PI3K/AKT phosphorylation in the presence of E2.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown with nuclear/cytoplasmic fractionation, phosphorylation assays; PY-motif mutant ERα constructs\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assays with mutant constructs and functional readouts (localization + signaling), single lab, multiple orthogonal methods\",\n      \"pmids\": [\"33122699\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Drosophila dTnpo (ortholog of TNPO2) is expressed in a subset of neurons and is essential for neuronal maintenance and function; RNAi-mediated downregulation in mature neurons disrupts neuronal activity and survival. Both loss and gain of dTnpo activity cause developmental defects (eye/wing deformities, lethality) in a dosage-dependent manner. Human TNPO2 variants associated with neurodevelopmental delay cause more or less severe developmental abnormalities in flies compared to wild-type TNPO2 when ectopically expressed, with severity correlating with variant position: RAN-binding domain variants are most toxic, acidic loop variants least toxic, and cargo-binding domain variants show tissue-dependent effects.\",\n      \"method\": \"Drosophila RNAi knockdown, mutant alleles, ectopic expression of wild-type and variant TNPO2; phenotypic readouts (lethality, eye/wing morphology, neuronal activity/survival)\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple alleles, RNAi, and ectopic expression with domain-specific functional dissection; multiple orthogonal phenotypic readouts, replicated across multiple variant alleles\",\n      \"pmids\": [\"34314705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TNPO2 operates downstream of DYNC1I1 in gastric cancer cells. DYNC1I1 upregulates TNPO2 expression by upregulating SP1, which recruits and binds to P300-acetylated TNPO2 promoter region histones to promote TNPO2 expression. TNPO2 in turn promotes gastric cancer cell proliferation and inhibits apoptosis through a mechanism potentially dependent on functional expression of P21.\",\n      \"method\": \"Expression profiling chip, siRNA knockdown, chromatin immunoprecipitation (ChIP) for SP1 and P300-acetylated histones at TNPO2 promoter, cell proliferation and apoptosis assays\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and knockdown experiments with functional readouts, single lab, multiple methods but P21 mechanism not fully dissected\",\n      \"pmids\": [\"31605449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TNPO2 was identified as an interacting partner of MAB21L2 in yeast two-hybrid screens using human adult retina and zebrafish embryo libraries, suggesting TNPO2 can bind to this developmental/eye protein.\",\n      \"method\": \"Yeast two-hybrid (Y2H) screen\",\n      \"journal\": \"Developmental dynamics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Y2H screen with no follow-up validation for TNPO2-MAB21L2 interaction specifically; interaction not confirmed by Co-IP or pulldown for this pair\",\n      \"pmids\": [\"36576422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TNPO2 mRNA does not localize to the nuclear envelope in human U2OS, HeLa, or pluripotent stem cells (negative finding), in contrast to its C. elegans ortholog IMB-2. TNPO1 protein (but not specifically TNPO2 protein) localizes to the nucleus and its periphery.\",\n      \"method\": \"smiFISH and fluorescence microscopy in multiple human cell lines\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct imaging with smiFISH across three human cell types; negative result for mRNA localization is robust; preprint, single lab\",\n      \"pmids\": [\"42239225\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"TNPO2 (Transportin-2) is a non-classical nuclear import receptor that mediates nucleocytoplasmic shuttling of diverse cargoes including developmental and neuronal proteins; it retains ERα in the cytoplasm by binding its NLS and competing with importin-α/β to inhibit nuclear import, is transcriptionally regulated downstream of DYNC1I1/SP1/P300 to promote cancer cell proliferation via P21, and is essential for neuronal maintenance and development as demonstrated by dosage-sensitive phenotypes in Drosophila, with pathogenic variant severity mapping to functional domains (RAN-binding, acidic loop, cargo-binding).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TNPO2 (Transportin-2) is a non-classical nuclear transport receptor whose dosage and cargo interactions govern nucleocytoplasmic distribution of developmental and neuronal proteins [#1]. It controls subcellular localization of estrogen receptor-\\u03b1 (ER\\u03b1) by competitively binding the basic NLS of ER\\u03b1 against importin-\\u03b1, thereby inhibiting importin-\\u03b1/\\u03b2-dependent ER\\u03b1 nuclear import rather than exporting it; this retention engages PY motifs of ER\\u03b1 and modulates downstream PI3K/AKT phosphorylation, with TNPO2 knockdown enhancing ER\\u03b1 nuclear localization [#0]. In neurons, TNPO2 is required for maintenance and survival, and both loss and gain of activity produce dosage-dependent developmental defects; pathogenic human variants confer graded severity that maps to functional domains, with RAN-binding-domain variants most deleterious, acidic-loop variants least, and cargo-binding-domain variants showing tissue-dependent effects [#1]. In gastric cancer cells, TNPO2 acts downstream of a DYNC1I1\\u2192SP1\\u2192P300 transcriptional axis to drive proliferation and suppress apoptosis via P21 [#2]. Additional binding partners and cargoes beyond these contexts have not been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"Established a transcriptional and pro-tumorigenic role for TNPO2 by placing it downstream of a defined regulatory cascade in cancer cells.\",\n      \"evidence\": \"Expression profiling, siRNA knockdown, ChIP for SP1 and P300-acetylated histones at the TNPO2 promoter, and proliferation/apoptosis assays in gastric cancer cells\",\n      \"pmids\": [\"31605449\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The P21-dependent mechanism downstream of TNPO2 is not fully dissected\", \"Whether TNPO2's transport function contributes to the proliferative phenotype is untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined a specific molecular mechanism by which TNPO2 retains a cargo in the cytoplasm, showing it competes with importin-\\u03b1 at the cargo NLS rather than mediating export.\",\n      \"evidence\": \"Co-IP, siRNA knockdown with nuclear/cytoplasmic fractionation, phosphorylation assays, and PY-motif mutant ER\\u03b1 constructs\",\n      \"pmids\": [\"33122699\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Demonstrated for ER\\u03b1 in one cell system; generality to other cargoes unknown\", \"Direct competition kinetics with importin-\\u03b1 not quantified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected TNPO2 dosage and domain architecture to neuronal maintenance and human neurodevelopmental disease, mapping variant severity to specific functional domains.\",\n      \"evidence\": \"Drosophila RNAi, mutant alleles, and ectopic expression of wild-type and patient-variant TNPO2 with lethality, eye/wing morphology, and neuronal activity/survival readouts\",\n      \"pmids\": [\"34314705\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular cargoes underlying the neuronal requirement are not identified\", \"Mechanistic link between domain-specific transport defects and fly phenotypes is inferred, not biochemically resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Nominated a candidate developmental cargo/partner (MAB21L2) for TNPO2.\",\n      \"evidence\": \"Yeast two-hybrid screens using human adult retina and zebrafish embryo libraries\",\n      \"pmids\": [\"36576422\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Y2H screen with no Co-IP or pulldown validation for the TNPO2-MAB21L2 pair\", \"Functional consequence of any interaction untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Tested whether TNPO2 mRNA shares the nuclear-envelope localization of its C. elegans ortholog, establishing a species-specific difference.\",\n      \"evidence\": \"smiFISH and fluorescence microscopy in U2OS, HeLa, and pluripotent stem cells (preprint)\",\n      \"pmids\": [\"42239225\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single lab\", \"Negative mRNA-localization result does not address TNPO2 protein localization\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The full cargo repertoire of TNPO2 and how cargo selectivity, RAN-binding, and the acidic loop coordinate to drive its transport cycle remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of TNPO2-cargo or TNPO2-RAN complexes in the corpus\", \"Direct biochemical validation of most candidate cargoes absent\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [\"ESR1\", \"MAB21L2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}