{"gene":"KPNA4","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":1997,"finding":"KPNA4 (Qip1) was identified as a novel importin-alpha homologue that directly binds DNA helicase Q1/RecQL via its putative NLS; this interaction was confirmed by GST-pulldown from human cell lysates and two-hybrid assays. Qip1 and Rch1, but not hSrp1, could interact with the NLS of DNA helicase Q1, demonstrating isoform selectivity among importin-alpha family members.","method":"GST pulldown from human cell lysates, yeast two-hybrid","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal pulldown and two-hybrid, two orthogonal methods, single lab","pmids":["9168958"],"is_preprint":false},{"year":1997,"finding":"KPNA4 (Qip1) binds the NLS of SV40 T antigen, analogous to Rch1 and hSrp1, confirming its role as a classical NLS receptor.","method":"Yeast two-hybrid","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — two-hybrid only, but consistent with known importin-alpha function and replicated for multiple NLS substrates in same study","pmids":["9168958"],"is_preprint":false},{"year":2013,"finding":"KPNA4 (Qip1/importin alpha3) participates in influenza A virus NP nuclear import: the N-terminal 110-aa region of NP containing the unconventional NLS preferentially bound Qip1. Silencing of Qip1 decreased vRNA transcription and replication of the S9A NP mutant virus without altering NP nuclear localization, indicating a role for KPNA4 in viral replication beyond nuclear transport.","method":"siRNA knockdown of Qip1 in cells infected with NP mutant virus; viral growth assay; vRNA transcription measurement; NP binding assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional KD with defined viral replication phenotype plus binding specificity, single lab","pmids":["23383277"],"is_preprint":false},{"year":2016,"finding":"KPNA4 mediates cytoplasm-to-nucleus translocation of NF-κB in prostate cancer cells; knockdown of KPNA4 reduces cell migration, invasion, and distant metastasis in mouse models, and modulates TNF-α and TNF-β production to alter macrophage polarization and osteoclastogenesis. KPNA4 was also established as a direct target of miR-708.","method":"Stable shRNA knockdown, mouse xenograft/metastasis models, cytokine measurement, luciferase reporter assay for miR-708 targeting","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined in vivo metastasis phenotype and downstream molecular readouts, single lab","pmids":["27941876"],"is_preprint":false},{"year":2015,"finding":"KPNA4 is a direct target of miR-181b; miR-181b suppresses EMT (epithelial-mesenchymal transition) in glioblastoma by targeting KPNA4, and restoration of KPNA4 expression abrogates the EMT-inhibitory effect of miR-181b.","method":"miRNA overexpression, KPNA4 rescue experiments, in vitro invasion assays, in vivo tumor models","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rescue experiment with defined EMT phenotype, single lab, multiple orthogonal assays","pmids":["26283154"],"is_preprint":false},{"year":2020,"finding":"KPNA4 promotes NF-κB nuclear translocation in papillary thyroid cancer cells; overexpression of KPNA4 increased nuclear p65 and NF-κB luciferase reporter activity, while KPNA4 silencing reduced nuclear p65 and induced apoptosis. KPNA4 is negatively regulated by miR-548b-3p.","method":"KPNA4 overexpression/knockdown, NF-κB luciferase reporter assay, nuclear p65 immunodetection, xenograft mouse model","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay plus nuclear fractionation plus in vivo model, single lab","pmids":["33188837"],"is_preprint":false},{"year":2021,"finding":"KPNA4 is required for p53 nuclear import in lens epithelial cells; kpna4 knockout zebrafish (CRISPR/Cas9) develop lens defects resembling cataracts, and loss of Kpna4 causes accumulation of p53 in the center of the lens. In hydrogen peroxide-induced apoptosis, KPNA4 and p53 protein levels increase coordinately in human lens epithelial cells.","method":"CRISPR/Cas9 kpna4 knockout in zebrafish, transmission electron microscopy, immunostaining of p53 in lens, H2O2 stress assay in human lens epithelial cells","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined cellular phenotype and p53 localization readout, single lab","pmids":["33798680"],"is_preprint":false},{"year":2022,"finding":"KPNA4 knockdown in pancreatic ductal adenocarcinoma cells suppresses proliferation, colony formation, and migration, and is associated with decreased expression of FAK (focal adhesion kinase) and PD-L1, placing KPNA4 upstream of FAK signaling in PDAC progression.","method":"siRNA knockdown, CCK-8, colony formation, wound-healing assays, western blot for FAK and PD-L1","journal":"Frontiers in oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, correlative functional knockdown with western blot readouts, no direct mechanistic demonstration of KPNA4-FAK interaction","pmids":["35425701"],"is_preprint":false},{"year":2025,"finding":"Kpna4-deficient mice display a hypermotoric, ADHD-like behavioral phenotype, supporting a neuronal function for KPNA4 in regulating locomotor behavior; no motor neuron deficits were detected.","method":"Kpna4 knockout mouse model, behavioral locomotion assays at multiple time points","journal":"Genes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined behavioral phenotype, but single lab and phenotype does not yet resolve molecular mechanism","pmids":["40565582"],"is_preprint":false},{"year":2026,"finding":"SV40 (polyomavirus) exploits KPNA4 as an NPC-associated importin receptor for nuclear entry: after Nesprin-2/SUN1-dependent targeting to the nuclear membrane, SV40 binds KPNA4 which translocates the virus into the nucleus.","method":"Functional knockdown/overexpression, co-immunoprecipitation, nuclear entry assays in cell culture (preprint)","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — preprint, single lab, mechanistic detail limited to abstract description","pmids":["41959248"],"is_preprint":true}],"current_model":"KPNA4 (importin alpha3/Qip1) is a classical NLS receptor that mediates nuclear import of cargo proteins including NF-κB (p65), p53, and viral proteins (influenza NP, SV40) by recognizing their NLS and bridging them to the importin-beta pathway; beyond transport, KPNA4 promotes cancer cell migration/invasion and EMT via NF-κB nuclear translocation, regulates p53-dependent lens homeostasis, and is required for normal neuronal function, as Kpna4-deficient mice display ADHD-like hyperactivity."},"narrative":{"mechanistic_narrative":"KPNA4 (Qip1/importin alpha3) is a classical nuclear localization signal (NLS) receptor of the importin-alpha family that recognizes NLS-bearing cargo and bridges it to the nuclear import machinery [PMID:9168958]. It displays isoform selectivity among importin-alpha members, binding the NLS of DNA helicase Q1/RecQL and of SV40 T antigen in a manner distinct from related receptors such as hSrp1 [PMID:9168958]. Through this transport activity KPNA4 controls the nuclear access of regulatory cargoes: it mediates cytoplasm-to-nucleus translocation of the NF-κB subunit p65 [PMID:27941876, PMID:33188837] and is required for p53 nuclear import, with loss of Kpna4 in zebrafish causing p53 accumulation in the lens and cataract-like lens defects [PMID:33798680]. By driving NF-κB nuclear translocation, KPNA4 promotes cancer cell migration, invasion, EMT, and metastasis across prostate, glioblastoma, thyroid, and pancreatic models, where it is held in check by tumor-suppressive microRNAs including miR-708, miR-181b, and miR-548b-3p [PMID:27941876, PMID:26283154, PMID:33188837]. KPNA4 is also exploited by viruses, contributing to influenza A NP-dependent viral replication beyond simple NP nuclear localization [PMID:23383277]. In vivo, Kpna4-deficient mice show an ADHD-like hypermotoric phenotype, indicating a role in neuronal regulation of locomotor behavior [PMID:40565582].","teleology":[{"year":1997,"claim":"Established KPNA4 as a bona fide importin-alpha family NLS receptor and showed it is not redundant with other family members, answering whether a newly identified importin-alpha homologue had cargo-binding specificity.","evidence":"GST-pulldown from human cell lysates and yeast two-hybrid against DNA helicase Q1/RecQL and SV40 T antigen NLS","pmids":["9168958"],"confidence":"Medium","gaps":["No structural basis for isoform selectivity defined","Import competence not demonstrated in a reconstituted transport assay","Full cargo repertoire unresolved"]},{"year":2013,"claim":"Showed KPNA4 contributes to influenza A virus replication through preferential binding to the unconventional NP NLS, indicating a transport-linked role in viral RNA synthesis beyond bulk NP nuclear localization.","evidence":"siRNA knockdown of Qip1 in cells infected with NP mutant virus, viral growth and vRNA transcription assays, NP binding assays","pmids":["23383277"],"confidence":"Medium","gaps":["Mechanism linking KPNA4 to vRNA transcription not defined","Does not separate import-dependent from import-independent contributions","Single virus mutant system"]},{"year":2015,"claim":"Identified KPNA4 as a direct miR-181b target whose restoration reverses miR-181b suppression of EMT, connecting KPNA4 levels to invasive phenotype control.","evidence":"miRNA overexpression with KPNA4 rescue, in vitro invasion and in vivo tumor models in glioblastoma","pmids":["26283154"],"confidence":"Medium","gaps":["Molecular cargo driving EMT not pinned down in this study","Single tumor type","Does not establish transport mechanism"]},{"year":2016,"claim":"Demonstrated that KPNA4-mediated NF-κB nuclear translocation drives cancer cell migration, invasion, and metastasis, and that KPNA4 is repressed by miR-708, linking the transport function to a defined in vivo malignant phenotype.","evidence":"Stable shRNA knockdown, mouse xenograft/metastasis models, cytokine measurement, miR-708 luciferase reporter in prostate cancer","pmids":["27941876"],"confidence":"Medium","gaps":["Direct p65-KPNA4 binding not structurally resolved","Contribution of macrophage/osteoclast effects vs tumor-intrinsic effects not separated","Single lab"]},{"year":2020,"claim":"Confirmed KPNA4 controls nuclear p65 abundance and NF-κB transcriptional activity in a second cancer type, reinforcing the NF-κB transport axis and adding miR-548b-3p as a regulator.","evidence":"KPNA4 overexpression/knockdown, NF-κB luciferase reporter, nuclear p65 immunodetection, xenograft in papillary thyroid cancer","pmids":["33188837"],"confidence":"Medium","gaps":["Direct NLS recognition of p65 not shown biochemically here","Apoptosis link to NF-κB loss correlative","Single lab"]},{"year":2021,"claim":"Established KPNA4 as the import receptor required for p53 nuclear localization in lens epithelium, giving a developmental/homeostatic cargo and phenotype distinct from cancer NF-κB roles.","evidence":"CRISPR/Cas9 kpna4 knockout zebrafish, electron microscopy, p53 immunostaining, H2O2 stress assay in human lens epithelial cells","pmids":["33798680"],"confidence":"Medium","gaps":["Direct KPNA4-p53 NLS binding not demonstrated biochemically","Whether cataract phenotype is fully p53-dependent unresolved","Single model organism"]},{"year":2022,"claim":"Linked KPNA4 to FAK and PD-L1 expression in pancreatic adenocarcinoma, extending its pro-tumor role but without a defined transport mechanism.","evidence":"siRNA knockdown with CCK-8, colony formation, wound-healing assays, western blot for FAK and PD-L1","pmids":["35425701"],"confidence":"Low","gaps":["No direct KPNA4-FAK interaction shown; correlative only","Cargo mediating FAK/PD-L1 changes unidentified","Single lab western-blot readouts"]},{"year":2025,"claim":"Revealed a physiological neuronal requirement for KPNA4 by showing loss causes ADHD-like hyperactivity, indicating a behavioral role independent of motor neuron integrity.","evidence":"Kpna4 knockout mouse with behavioral locomotion assays at multiple timepoints","pmids":["40565582"],"confidence":"Medium","gaps":["Molecular cargo/pathway underlying behavior unknown","No cellular or circuit mechanism defined","Single lab"]},{"year":2026,"claim":"Positioned KPNA4 as an NPC-associated receptor for SV40 nuclear entry downstream of Nesprin-2/SUN1 targeting, expanding its role to viral genome delivery.","evidence":"Knockdown/overexpression, co-immunoprecipitation, nuclear entry assays in cell culture (preprint)","pmids":["41959248"],"confidence":"Low","gaps":["Preprint, single lab, mechanistic detail limited","Direct virus-KPNA4 binding interface undefined","No reciprocal validation reported"]},{"year":null,"claim":"How KPNA4 selects among its many cargoes (NF-κB, p53, viral proteins) in a cell-type- and signal-specific manner, and what molecular cargo underlies its neuronal phenotype, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of KPNA4-cargo NLS recognition","Cargo specificity determinants vs other importin-alpha members unmapped","Neuronal cargo/pathway unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[0,1,3,5,6]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,5]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,5,6]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,1,3,6]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,4,5]}],"complexes":[],"partners":["RECQL","RELA","TP53","NP"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O00629","full_name":"Importin subunit alpha-3","aliases":["Importin alpha Q1","Qip1","Karyopherin subunit alpha-4"],"length_aa":521,"mass_kda":57.9,"function":"Functions in nuclear protein import as an adapter protein for nuclear receptor KPNB1 (PubMed:10567565, PubMed:20818336, PubMed:28760339, PubMed:29042532, PubMed:38512451). Binds specifically and directly to substrates containing either a simple or bipartite NLS motif (PubMed:20818336, PubMed:28760339, PubMed:29042532, PubMed:38512451). Docking of the importin/substrate complex to the nuclear pore complex (NPC) is mediated by KPNB1 through binding to nucleoporin FxFG repeats and the complex is subsequently translocated through the pore by an energy requiring, Ran-dependent mechanism (PubMed:20818336, PubMed:28760339, PubMed:29042532, PubMed:38512451). At the nucleoplasmic side of the NPC, Ran binds to importin-beta and the three components separate and importin-alpha and -beta are re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran from importin (PubMed:20818336, PubMed:28760339, PubMed:29042532, PubMed:38512451). 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 (PubMed:20818336, PubMed:28760339, PubMed:29042532, PubMed:38512451). Mediates nuclear import of AARS1, MRTFA and RANBP3 (PubMed:10567565, PubMed:20818336, PubMed:28760339, PubMed:38512451) (Microbial infection) In vitro, mediates the nuclear import of human cytomegalovirus UL84 by recognizing a non-classical NLS. In vitro, mediates the nuclear import of human cytomegalovirus UL84 by recognizing a non-classical NLS","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/O00629/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/KPNA4","classification":"Not Classified","n_dependent_lines":67,"n_total_lines":1208,"dependency_fraction":0.055463576158940396},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000186432","cell_line_id":"CID001561","localizations":[{"compartment":"big_aggregates","grade":3},{"compartment":"nuclear_membrane","grade":3},{"compartment":"cytoplasmic","grade":2},{"compartment":"nucleoplasm","grade":2}],"interactors":[{"gene":"NOLC1","stoichiometry":10.0},{"gene":"NUP50","stoichiometry":10.0},{"gene":"RCC1","stoichiometry":10.0},{"gene":"KPNA3","stoichiometry":10.0},{"gene":"KPNB1","stoichiometry":4.0},{"gene":"RBBP4","stoichiometry":4.0},{"gene":"RAN","stoichiometry":4.0},{"gene":"DDX21","stoichiometry":0.2},{"gene":"HDAC1","stoichiometry":0.2},{"gene":"HDAC2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001561","total_profiled":1310},"omim":[{"mim_id":"610563","title":"KARYOPHERIN ALPHA-6; KPNA6","url":"https://www.omim.org/entry/610563"},{"mim_id":"608626","title":"STE20-RELATED KINASE ADAPTOR ALPHA; STRADA","url":"https://www.omim.org/entry/608626"},{"mim_id":"602970","title":"KARYOPHERIN ALPHA-4; KPNA4","url":"https://www.omim.org/entry/602970"},{"mim_id":"602738","title":"KARYOPHERIN BETA-1; KPNB1","url":"https://www.omim.org/entry/602738"},{"mim_id":"601892","title":"KARYOPHERIN ALPHA-3; KPNA3","url":"https://www.omim.org/entry/601892"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Nuclear membrane","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":116.7},{"tissue":"tongue","ntpm":56.0}],"url":"https://www.proteinatlas.org/search/KPNA4"},"hgnc":{"alias_symbol":["QIP1","SRP3","IPOA3","MGC12217","MGC26703"],"prev_symbol":[]},"alphafold":{"accession":"O00629","domains":[{"cath_id":"1.25.10.10","chopping":"75-198","consensus_level":"medium","plddt":95.3717,"start":75,"end":198},{"cath_id":"1.25.10.10","chopping":"204-325","consensus_level":"medium","plddt":95.2125,"start":204,"end":325}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O00629","model_url":"https://alphafold.ebi.ac.uk/files/AF-O00629-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O00629-F1-predicted_aligned_error_v6.png","plddt_mean":86.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=KPNA4","jax_strain_url":"https://www.jax.org/strain/search?query=KPNA4"},"sequence":{"accession":"O00629","fasta_url":"https://rest.uniprot.org/uniprotkb/O00629.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O00629/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O00629"}},"corpus_meta":[{"pmid":"9168958","id":"PMC_9168958","title":"Cloning of a cDNA encoding a novel importin-alpha homologue, Qip1: discrimination of Qip1 and Rch1 from hSrp1 by their ability to interact with DNA helicase Q1/RecQL.","date":"1997","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/9168958","citation_count":82,"is_preprint":false},{"pmid":"31693222","id":"PMC_31693222","title":"YY1-mediated overexpression of long noncoding RNA MCM3AP-AS1 accelerates angiogenesis and progression in lung cancer by targeting miR-340-5p/KPNA4 axis.","date":"2019","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31693222","citation_count":62,"is_preprint":false},{"pmid":"26283154","id":"PMC_26283154","title":"Upregulation of miR-181s reverses mesenchymal transition by targeting KPNA4 in glioblastoma.","date":"2015","source":"Scientific 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surgery and research","url":"https://pubmed.ncbi.nlm.nih.gov/34930332","citation_count":19,"is_preprint":false},{"pmid":"33327962","id":"PMC_33327962","title":"LncRNA ST7-AS1, by regulating miR-181b-5p/KPNA4 axis, promotes the malignancy of lung adenocarcinoma.","date":"2020","source":"Cancer cell international","url":"https://pubmed.ncbi.nlm.nih.gov/33327962","citation_count":18,"is_preprint":false},{"pmid":"35781593","id":"PMC_35781593","title":"Long noncoding RNA SNHG14 knockdown exerts a neuroprotective role in MPP+-induced Parkinson's disease cell model through mediating miR-135b-5p/KPNA4 axis.","date":"2022","source":"Metabolic brain disease","url":"https://pubmed.ncbi.nlm.nih.gov/35781593","citation_count":17,"is_preprint":false},{"pmid":"23383277","id":"PMC_23383277","title":"Importin α3/Qip1 is involved in multiplication of mutant influenza virus with alanine mutation at amino acid 9 independently of nuclear transport function.","date":"2013","source":"PloS 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age","date":"2025-11-13","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.13.688005","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16914,"output_tokens":2372,"usd":0.043161,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9443,"output_tokens":3299,"usd":0.064845,"stage2_stop_reason":"end_turn"},"total_usd":0.108006,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"KPNA4 (Qip1) was identified as a novel importin-alpha homologue that directly binds DNA helicase Q1/RecQL via its putative NLS; this interaction was confirmed by GST-pulldown from human cell lysates and two-hybrid assays. Qip1 and Rch1, but not hSrp1, could interact with the NLS of DNA helicase Q1, demonstrating isoform selectivity among importin-alpha family members.\",\n      \"method\": \"GST pulldown from human cell lysates, yeast two-hybrid\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal pulldown and two-hybrid, two orthogonal methods, single lab\",\n      \"pmids\": [\"9168958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"KPNA4 (Qip1) binds the NLS of SV40 T antigen, analogous to Rch1 and hSrp1, confirming its role as a classical NLS receptor.\",\n      \"method\": \"Yeast two-hybrid\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — two-hybrid only, but consistent with known importin-alpha function and replicated for multiple NLS substrates in same study\",\n      \"pmids\": [\"9168958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"KPNA4 (Qip1/importin alpha3) participates in influenza A virus NP nuclear import: the N-terminal 110-aa region of NP containing the unconventional NLS preferentially bound Qip1. Silencing of Qip1 decreased vRNA transcription and replication of the S9A NP mutant virus without altering NP nuclear localization, indicating a role for KPNA4 in viral replication beyond nuclear transport.\",\n      \"method\": \"siRNA knockdown of Qip1 in cells infected with NP mutant virus; viral growth assay; vRNA transcription measurement; NP binding assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional KD with defined viral replication phenotype plus binding specificity, single lab\",\n      \"pmids\": [\"23383277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"KPNA4 mediates cytoplasm-to-nucleus translocation of NF-κB in prostate cancer cells; knockdown of KPNA4 reduces cell migration, invasion, and distant metastasis in mouse models, and modulates TNF-α and TNF-β production to alter macrophage polarization and osteoclastogenesis. KPNA4 was also established as a direct target of miR-708.\",\n      \"method\": \"Stable shRNA knockdown, mouse xenograft/metastasis models, cytokine measurement, luciferase reporter assay for miR-708 targeting\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined in vivo metastasis phenotype and downstream molecular readouts, single lab\",\n      \"pmids\": [\"27941876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"KPNA4 is a direct target of miR-181b; miR-181b suppresses EMT (epithelial-mesenchymal transition) in glioblastoma by targeting KPNA4, and restoration of KPNA4 expression abrogates the EMT-inhibitory effect of miR-181b.\",\n      \"method\": \"miRNA overexpression, KPNA4 rescue experiments, in vitro invasion assays, in vivo tumor models\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rescue experiment with defined EMT phenotype, single lab, multiple orthogonal assays\",\n      \"pmids\": [\"26283154\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"KPNA4 promotes NF-κB nuclear translocation in papillary thyroid cancer cells; overexpression of KPNA4 increased nuclear p65 and NF-κB luciferase reporter activity, while KPNA4 silencing reduced nuclear p65 and induced apoptosis. KPNA4 is negatively regulated by miR-548b-3p.\",\n      \"method\": \"KPNA4 overexpression/knockdown, NF-κB luciferase reporter assay, nuclear p65 immunodetection, xenograft mouse model\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay plus nuclear fractionation plus in vivo model, single lab\",\n      \"pmids\": [\"33188837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"KPNA4 is required for p53 nuclear import in lens epithelial cells; kpna4 knockout zebrafish (CRISPR/Cas9) develop lens defects resembling cataracts, and loss of Kpna4 causes accumulation of p53 in the center of the lens. In hydrogen peroxide-induced apoptosis, KPNA4 and p53 protein levels increase coordinately in human lens epithelial cells.\",\n      \"method\": \"CRISPR/Cas9 kpna4 knockout in zebrafish, transmission electron microscopy, immunostaining of p53 in lens, H2O2 stress assay in human lens epithelial cells\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined cellular phenotype and p53 localization readout, single lab\",\n      \"pmids\": [\"33798680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KPNA4 knockdown in pancreatic ductal adenocarcinoma cells suppresses proliferation, colony formation, and migration, and is associated with decreased expression of FAK (focal adhesion kinase) and PD-L1, placing KPNA4 upstream of FAK signaling in PDAC progression.\",\n      \"method\": \"siRNA knockdown, CCK-8, colony formation, wound-healing assays, western blot for FAK and PD-L1\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, correlative functional knockdown with western blot readouts, no direct mechanistic demonstration of KPNA4-FAK interaction\",\n      \"pmids\": [\"35425701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Kpna4-deficient mice display a hypermotoric, ADHD-like behavioral phenotype, supporting a neuronal function for KPNA4 in regulating locomotor behavior; no motor neuron deficits were detected.\",\n      \"method\": \"Kpna4 knockout mouse model, behavioral locomotion assays at multiple time points\",\n      \"journal\": \"Genes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined behavioral phenotype, but single lab and phenotype does not yet resolve molecular mechanism\",\n      \"pmids\": [\"40565582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SV40 (polyomavirus) exploits KPNA4 as an NPC-associated importin receptor for nuclear entry: after Nesprin-2/SUN1-dependent targeting to the nuclear membrane, SV40 binds KPNA4 which translocates the virus into the nucleus.\",\n      \"method\": \"Functional knockdown/overexpression, co-immunoprecipitation, nuclear entry assays in cell culture (preprint)\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — preprint, single lab, mechanistic detail limited to abstract description\",\n      \"pmids\": [\"41959248\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"KPNA4 (importin alpha3/Qip1) is a classical NLS receptor that mediates nuclear import of cargo proteins including NF-κB (p65), p53, and viral proteins (influenza NP, SV40) by recognizing their NLS and bridging them to the importin-beta pathway; beyond transport, KPNA4 promotes cancer cell migration/invasion and EMT via NF-κB nuclear translocation, regulates p53-dependent lens homeostasis, and is required for normal neuronal function, as Kpna4-deficient mice display ADHD-like hyperactivity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"KPNA4 (Qip1/importin alpha3) is a classical nuclear localization signal (NLS) receptor of the importin-alpha family that recognizes NLS-bearing cargo and bridges it to the nuclear import machinery [#0, #1]. It displays isoform selectivity among importin-alpha members, binding the NLS of DNA helicase Q1/RecQL and of SV40 T antigen in a manner distinct from related receptors such as hSrp1 [#0, #1]. Through this transport activity KPNA4 controls the nuclear access of regulatory cargoes: it mediates cytoplasm-to-nucleus translocation of the NF-\\u03baB subunit p65 [#3, #5] and is required for p53 nuclear import, with loss of Kpna4 in zebrafish causing p53 accumulation in the lens and cataract-like lens defects [#6]. By driving NF-\\u03baB nuclear translocation, KPNA4 promotes cancer cell migration, invasion, EMT, and metastasis across prostate, glioblastoma, thyroid, and pancreatic models, where it is held in check by tumor-suppressive microRNAs including miR-708, miR-181b, and miR-548b-3p [#3, #4, #5]. KPNA4 is also exploited by viruses, contributing to influenza A NP-dependent viral replication beyond simple NP nuclear localization [#2]. In vivo, Kpna4-deficient mice show an ADHD-like hypermotoric phenotype, indicating a role in neuronal regulation of locomotor behavior [#8].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established KPNA4 as a bona fide importin-alpha family NLS receptor and showed it is not redundant with other family members, answering whether a newly identified importin-alpha homologue had cargo-binding specificity.\",\n      \"evidence\": \"GST-pulldown from human cell lysates and yeast two-hybrid against DNA helicase Q1/RecQL and SV40 T antigen NLS\",\n      \"pmids\": [\"9168958\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural basis for isoform selectivity defined\", \"Import competence not demonstrated in a reconstituted transport assay\", \"Full cargo repertoire unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed KPNA4 contributes to influenza A virus replication through preferential binding to the unconventional NP NLS, indicating a transport-linked role in viral RNA synthesis beyond bulk NP nuclear localization.\",\n      \"evidence\": \"siRNA knockdown of Qip1 in cells infected with NP mutant virus, viral growth and vRNA transcription assays, NP binding assays\",\n      \"pmids\": [\"23383277\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking KPNA4 to vRNA transcription not defined\", \"Does not separate import-dependent from import-independent contributions\", \"Single virus mutant system\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified KPNA4 as a direct miR-181b target whose restoration reverses miR-181b suppression of EMT, connecting KPNA4 levels to invasive phenotype control.\",\n      \"evidence\": \"miRNA overexpression with KPNA4 rescue, in vitro invasion and in vivo tumor models in glioblastoma\",\n      \"pmids\": [\"26283154\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular cargo driving EMT not pinned down in this study\", \"Single tumor type\", \"Does not establish transport mechanism\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated that KPNA4-mediated NF-\\u03baB nuclear translocation drives cancer cell migration, invasion, and metastasis, and that KPNA4 is repressed by miR-708, linking the transport function to a defined in vivo malignant phenotype.\",\n      \"evidence\": \"Stable shRNA knockdown, mouse xenograft/metastasis models, cytokine measurement, miR-708 luciferase reporter in prostate cancer\",\n      \"pmids\": [\"27941876\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct p65-KPNA4 binding not structurally resolved\", \"Contribution of macrophage/osteoclast effects vs tumor-intrinsic effects not separated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Confirmed KPNA4 controls nuclear p65 abundance and NF-\\u03baB transcriptional activity in a second cancer type, reinforcing the NF-\\u03baB transport axis and adding miR-548b-3p as a regulator.\",\n      \"evidence\": \"KPNA4 overexpression/knockdown, NF-\\u03baB luciferase reporter, nuclear p65 immunodetection, xenograft in papillary thyroid cancer\",\n      \"pmids\": [\"33188837\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct NLS recognition of p65 not shown biochemically here\", \"Apoptosis link to NF-\\u03baB loss correlative\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established KPNA4 as the import receptor required for p53 nuclear localization in lens epithelium, giving a developmental/homeostatic cargo and phenotype distinct from cancer NF-\\u03baB roles.\",\n      \"evidence\": \"CRISPR/Cas9 kpna4 knockout zebrafish, electron microscopy, p53 immunostaining, H2O2 stress assay in human lens epithelial cells\",\n      \"pmids\": [\"33798680\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct KPNA4-p53 NLS binding not demonstrated biochemically\", \"Whether cataract phenotype is fully p53-dependent unresolved\", \"Single model organism\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked KPNA4 to FAK and PD-L1 expression in pancreatic adenocarcinoma, extending its pro-tumor role but without a defined transport mechanism.\",\n      \"evidence\": \"siRNA knockdown with CCK-8, colony formation, wound-healing assays, western blot for FAK and PD-L1\",\n      \"pmids\": [\"35425701\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No direct KPNA4-FAK interaction shown; correlative only\", \"Cargo mediating FAK/PD-L1 changes unidentified\", \"Single lab western-blot readouts\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a physiological neuronal requirement for KPNA4 by showing loss causes ADHD-like hyperactivity, indicating a behavioral role independent of motor neuron integrity.\",\n      \"evidence\": \"Kpna4 knockout mouse with behavioral locomotion assays at multiple timepoints\",\n      \"pmids\": [\"40565582\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular cargo/pathway underlying behavior unknown\", \"No cellular or circuit mechanism defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Positioned KPNA4 as an NPC-associated receptor for SV40 nuclear entry downstream of Nesprin-2/SUN1 targeting, expanding its role to viral genome delivery.\",\n      \"evidence\": \"Knockdown/overexpression, co-immunoprecipitation, nuclear entry assays in cell culture (preprint)\",\n      \"pmids\": [\"41959248\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint, single lab, mechanistic detail limited\", \"Direct virus-KPNA4 binding interface undefined\", \"No reciprocal validation reported\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How KPNA4 selects among its many cargoes (NF-\\u03baB, p53, viral proteins) in a cell-type- and signal-specific manner, and what molecular cargo underlies its neuronal phenotype, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of KPNA4-cargo NLS recognition\", \"Cargo specificity determinants vs other importin-alpha members unmapped\", \"Neuronal cargo/pathway unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [0, 1, 3, 5, 6]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 5]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 5, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 1, 3, 6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 4, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RECQL\", \"RELA\", \"TP53\", \"NP\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}