{"gene":"IPO11","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2020,"finding":"IPO11 (Importin-11) is required for β-catenin nuclear import in APC-mutant colorectal cancer cells. IPO11 knockout reduces nuclear β-catenin protein levels and decreases β-catenin target gene activation, establishing IPO11 as a nuclear import factor for β-catenin in cells with high Wnt activity.","method":"Genome-wide CRISPR screen (DEADPOOL), IPO11 knockout cell lines, nuclear fractionation/western blot for β-catenin levels, target gene expression analysis, colony formation assay, patient-derived CRC organoid proliferation assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR knockout with multiple orthogonal functional readouts (nuclear fractionation, transcriptional target gene assays, organoid proliferation), supported by genome-wide unbiased screen identification","pmids":["31881079"],"is_preprint":false},{"year":2022,"finding":"IPO11 mediates nuclear import of RPRM (Reprimo) upon X-irradiation. RPRM phosphorylation at serine 98 by CDK4/6 is required for its nuclear translocation, and this translocation depends on IPO11. Once nuclear, RPRM interacts with ATM and promotes its nuclear export and proteasomal degradation, thereby downregulating ATM levels and impairing DNA repair.","method":"IPO11 knockdown/knockout, co-immunoprecipitation (RPRM–ATM interaction), nuclear fractionation to track RPRM translocation, phosphorylation site mutagenesis (S98), CDK4/6 inhibitor treatment, in vitro and in vivo radiosensitivity assays","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus loss-of-function with multiple cellular phenotypes in a single lab, but not independently replicated","pmids":["36185355"],"is_preprint":false}],"current_model":"IPO11 (Importin-11) functions as a nuclear import receptor that shuttles specific cargo proteins into the nucleus: it facilitates β-catenin nuclear import in APC-mutant colorectal cancer cells to sustain Wnt transcriptional programs, and it mediates the irradiation-induced, CDK4/6-phosphorylation-dependent nuclear import of RPRM, which subsequently promotes ATM nuclear export and proteasomal degradation to modulate DNA damage response."},"narrative":{"mechanistic_narrative":"IPO11 (Importin-11) functions as a nuclear import receptor that delivers specific cargo proteins into the nucleus to control transcriptional and DNA-damage signaling programs [PMID:31881079]. In APC-mutant colorectal cancer cells with high Wnt activity, IPO11 is required for nuclear import of β-catenin; its loss reduces nuclear β-catenin and dampens β-catenin target gene activation, sustaining the proliferative Wnt transcriptional program [PMID:31881079]. IPO11 also mediates the irradiation-induced nuclear translocation of RPRM, which depends on CDK4/6 phosphorylation of RPRM at serine 98; once nuclear, RPRM binds ATM and promotes its nuclear export and proteasomal degradation, thereby downregulating ATM and impairing DNA repair [PMID:36185355]. Beyond these two cargo relationships, no further mechanistic detail on IPO11 has been characterized in the available corpus.","teleology":[{"year":2020,"claim":"Established IPO11 as the nuclear import factor required to sustain β-catenin-driven Wnt transcription in APC-mutant cancer, identifying a previously unknown node controlling oncogenic Wnt signaling.","evidence":"Genome-wide CRISPR screen with IPO11 knockout, nuclear fractionation/western blot for β-catenin, target gene expression, and patient-derived CRC organoid proliferation assays","pmids":["31881079"],"confidence":"High","gaps":["No direct biochemical demonstration that IPO11 binds β-catenin or a recognition motif","Cargo specificity and breadth beyond β-catenin not defined","No structural model of the IPO11–cargo interaction"]},{"year":2022,"claim":"Showed IPO11 imports phospho-RPRM into the nucleus to trigger ATM downregulation, linking IPO11 cargo transport to the DNA damage response and radiosensitivity.","evidence":"IPO11 knockdown/knockout, reciprocal RPRM–ATM co-immunoprecipitation, nuclear fractionation, S98 phosphosite mutagenesis, CDK4/6 inhibitor treatment, and in vitro/in vivo radiosensitivity assays","pmids":["36185355"],"confidence":"Medium","gaps":["Not independently replicated outside a single lab","Direct IPO11–RPRM binding not biochemically reconstituted","Mechanism by which IPO11 recognizes phospho-S98 RPRM is unresolved"]},{"year":null,"claim":"Whether IPO11 has a general import recognition mechanism unifying its diverse cargoes remains unknown.","evidence":"","pmids":[],"confidence":"Low","gaps":["No consensus cargo-recognition signal identified","No structural or RanGTP-dependence data in the corpus","Full cargo repertoire uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[0,1]}],"localization":[],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,1]}],"complexes":[],"partners":["CTNNB1","RPRM"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UI26","full_name":"Importin-11","aliases":["Ran-binding protein 11","RanBP11"],"length_aa":975,"mass_kda":112.5,"function":"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). Mediates the nuclear import of UBE2E3, and of RPL12 (By similarity)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9UI26/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/IPO11","classification":"Common Essential","n_dependent_lines":1179,"n_total_lines":1208,"dependency_fraction":0.9759933774834437},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000086200","cell_line_id":"CID001551","localizations":[{"compartment":"nucleoplasm","grade":3},{"compartment":"cytoplasmic","grade":2}],"interactors":[{"gene":"DDX5","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001551","total_profiled":1310},"omim":[{"mim_id":"610889","title":"IMPORTIN 11; IPO11","url":"https://www.omim.org/entry/610889"},{"mim_id":"175100","title":"FAMILIAL ADENOMATOUS POLYPOSIS 1; FAP1","url":"https://www.omim.org/entry/175100"},{"mim_id":"135290","title":"DESMOID DISEASE, HEREDITARY; DESMD","url":"https://www.omim.org/entry/135290"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/IPO11"},"hgnc":{"alias_symbol":["RanBP11"],"prev_symbol":[]},"alphafold":{"accession":"Q9UI26","domains":[{"cath_id":"1.25.10,1.25.40","chopping":"2-161","consensus_level":"medium","plddt":94.1843,"start":2,"end":161},{"cath_id":"-","chopping":"874-973","consensus_level":"high","plddt":85.1987,"start":874,"end":973}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UI26","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UI26-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UI26-F1-predicted_aligned_error_v6.png","plddt_mean":93.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IPO11","jax_strain_url":"https://www.jax.org/strain/search?query=IPO11"},"sequence":{"accession":"Q9UI26","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UI26.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UI26/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UI26"}},"corpus_meta":[{"pmid":"23216389","id":"PMC_23216389","title":"Genome-wide significant association signals in IPO11-HTR1A region specific for alcohol and nicotine codependence.","date":"2012","source":"Alcoholism, clinical and experimental research","url":"https://pubmed.ncbi.nlm.nih.gov/23216389","citation_count":36,"is_preprint":false},{"pmid":"28736931","id":"PMC_28736931","title":"Genetic Variants in HSD17B3, SMAD3, and IPO11 Impact Circulating Lipids in Response to Fenofibrate in Individuals With Type 2 Diabetes.","date":"2017","source":"Clinical pharmacology and therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/28736931","citation_count":34,"is_preprint":false},{"pmid":"31881079","id":"PMC_31881079","title":"IPO11 mediates βcatenin nuclear import in a subset of colorectal cancers.","date":"2020","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/31881079","citation_count":32,"is_preprint":false},{"pmid":"30906303","id":"PMC_30906303","title":"Nicotiana benthamiana RanBP1-1 Is Involved in the Induction of Disease Resistance via Regulation of Nuclear-Cytoplasmic Transport of Small GTPase Ran.","date":"2019","source":"Frontiers in plant science","url":"https://pubmed.ncbi.nlm.nih.gov/30906303","citation_count":9,"is_preprint":false},{"pmid":"19819847","id":"PMC_19819847","title":"[Influence of Tripterygium wilfordii on the expression of spermiogenesis related genes Herc4, Ipo11 and Mrto4 in mice].","date":"2009","source":"Yi chuan = Hereditas","url":"https://pubmed.ncbi.nlm.nih.gov/19819847","citation_count":8,"is_preprint":false},{"pmid":"26079129","id":"PMC_26079129","title":"Significant association between rare IPO11-HTR1A variants and attention deficit hyperactivity disorder in Caucasians.","date":"2015","source":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26079129","citation_count":6,"is_preprint":false},{"pmid":"36185355","id":"PMC_36185355","title":"RPRM negatively regulates ATM levels through its nuclear translocation on irradiation mediated by CDK4/6 and IPO11.","date":"2022","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/36185355","citation_count":4,"is_preprint":false},{"pmid":"37195868","id":"PMC_37195868","title":"Protocol for IPO11 deletion and re-expression in H460 lung cancer cells using CRISPR-Cas9 and plasmid transfection.","date":"2023","source":"STAR protocols","url":"https://pubmed.ncbi.nlm.nih.gov/37195868","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6134,"output_tokens":701,"usd":0.014459,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7122,"output_tokens":1316,"usd":0.034255,"stage2_stop_reason":"end_turn"},"total_usd":0.048714,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"IPO11 (Importin-11) is required for β-catenin nuclear import in APC-mutant colorectal cancer cells. IPO11 knockout reduces nuclear β-catenin protein levels and decreases β-catenin target gene activation, establishing IPO11 as a nuclear import factor for β-catenin in cells with high Wnt activity.\",\n      \"method\": \"Genome-wide CRISPR screen (DEADPOOL), IPO11 knockout cell lines, nuclear fractionation/western blot for β-catenin levels, target gene expression analysis, colony formation assay, patient-derived CRC organoid proliferation assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR knockout with multiple orthogonal functional readouts (nuclear fractionation, transcriptional target gene assays, organoid proliferation), supported by genome-wide unbiased screen identification\",\n      \"pmids\": [\"31881079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IPO11 mediates nuclear import of RPRM (Reprimo) upon X-irradiation. RPRM phosphorylation at serine 98 by CDK4/6 is required for its nuclear translocation, and this translocation depends on IPO11. Once nuclear, RPRM interacts with ATM and promotes its nuclear export and proteasomal degradation, thereby downregulating ATM levels and impairing DNA repair.\",\n      \"method\": \"IPO11 knockdown/knockout, co-immunoprecipitation (RPRM–ATM interaction), nuclear fractionation to track RPRM translocation, phosphorylation site mutagenesis (S98), CDK4/6 inhibitor treatment, in vitro and in vivo radiosensitivity assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus loss-of-function with multiple cellular phenotypes in a single lab, but not independently replicated\",\n      \"pmids\": [\"36185355\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IPO11 (Importin-11) functions as a nuclear import receptor that shuttles specific cargo proteins into the nucleus: it facilitates β-catenin nuclear import in APC-mutant colorectal cancer cells to sustain Wnt transcriptional programs, and it mediates the irradiation-induced, CDK4/6-phosphorylation-dependent nuclear import of RPRM, which subsequently promotes ATM nuclear export and proteasomal degradation to modulate DNA damage response.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IPO11 (Importin-11) functions as a nuclear import receptor that delivers specific cargo proteins into the nucleus to control transcriptional and DNA-damage signaling programs [#0]. In APC-mutant colorectal cancer cells with high Wnt activity, IPO11 is required for nuclear import of \\u03b2-catenin; its loss reduces nuclear \\u03b2-catenin and dampens \\u03b2-catenin target gene activation, sustaining the proliferative Wnt transcriptional program [#0]. IPO11 also mediates the irradiation-induced nuclear translocation of RPRM, which depends on CDK4/6 phosphorylation of RPRM at serine 98; once nuclear, RPRM binds ATM and promotes its nuclear export and proteasomal degradation, thereby downregulating ATM and impairing DNA repair [#1]. Beyond these two cargo relationships, no further mechanistic detail on IPO11 has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2020,\n      \"claim\": \"Established IPO11 as the nuclear import factor required to sustain \\u03b2-catenin-driven Wnt transcription in APC-mutant cancer, identifying a previously unknown node controlling oncogenic Wnt signaling.\",\n      \"evidence\": \"Genome-wide CRISPR screen with IPO11 knockout, nuclear fractionation/western blot for \\u03b2-catenin, target gene expression, and patient-derived CRC organoid proliferation assays\",\n      \"pmids\": [\"31881079\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No direct biochemical demonstration that IPO11 binds \\u03b2-catenin or a recognition motif\",\n        \"Cargo specificity and breadth beyond \\u03b2-catenin not defined\",\n        \"No structural model of the IPO11\\u2013cargo interaction\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed IPO11 imports phospho-RPRM into the nucleus to trigger ATM downregulation, linking IPO11 cargo transport to the DNA damage response and radiosensitivity.\",\n      \"evidence\": \"IPO11 knockdown/knockout, reciprocal RPRM\\u2013ATM co-immunoprecipitation, nuclear fractionation, S98 phosphosite mutagenesis, CDK4/6 inhibitor treatment, and in vitro/in vivo radiosensitivity assays\",\n      \"pmids\": [\"36185355\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Not independently replicated outside a single lab\",\n        \"Direct IPO11\\u2013RPRM binding not biochemically reconstituted\",\n        \"Mechanism by which IPO11 recognizes phospho-S98 RPRM is unresolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether IPO11 has a general import recognition mechanism unifying its diverse cargoes remains unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No consensus cargo-recognition signal identified\",\n        \"No structural or RanGTP-dependence data in the corpus\",\n        \"Full cargo repertoire uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CTNNB1\", \"RPRM\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}