{"gene":"IPO11","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":2020,"finding":"IPO11 (Importin-11) was identified as a required factor for β-catenin nuclear import in APC-mutant colorectal cancer cells. A genome-wide CRISPR screen (DEADPOOL) identified IPO11, and IPO11 knockout cells exhibited reduced nuclear β-catenin protein levels and decreased β-catenin target gene activation, demonstrating that IPO11 facilitates β-catenin nucleocytoplasmic shuttling and is required for β-catenin-mediated transcription in cells with high Wnt activity.","method":"Genome-wide CRISPR screen (DEADPOOL positive selection), IPO11 knockout cell lines, nuclear fractionation, β-catenin 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 — clean KO with defined cellular phenotype, multiple orthogonal readouts (nuclear fractionation, transcriptional output, organoid growth), genome-wide unbiased screen identification","pmids":["31881079"],"is_preprint":false},{"year":2022,"finding":"IPO11 (Importin-11) mediates the nuclear import of RPRM (Reprimo) upon X-irradiation. RPRM is primarily cytoplasmic but translocates to the nucleus after irradiation, a process requiring phosphorylation of RPRM at serine 98 by CDK4/6 and requiring IPO11. Once nuclear, RPRM interacts with ATM and promotes its nuclear export and proteasomal degradation, thereby downregulating ATM protein levels and impairing DNA repair. IPO11 deletion abrogated RPRM nuclear import and prevented ATM downregulation.","method":"Co-immunoprecipitation, subcellular fractionation, CRISPR-based IPO11 knockout, site-directed mutagenesis (S98 phospho-site), CDK4/6 inhibitor treatment, in vivo irradiation experiments, proteasome inhibition assay","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, clean KO, mutagenesis of phosphorylation site, multiple orthogonal methods establishing the IPO11→RPRM import→ATM degradation axis","pmids":["36185355"],"is_preprint":false},{"year":2009,"finding":"Ipo11 expression is associated with spermiogenesis in mouse testis; treatment with Tripterygium wilfordii (GTW) caused abnormal expression of Ipo11 (along with Herc4 and Mrto4) in testicular tissue, correlating with disrupted spermatogenic cell populations and infertility, indicating a role for Ipo11 in male germ cell development.","method":"Gene chip (microarray) expression profiling of testis tissue from GTW-treated versus control mice, histological analysis of seminiferous tubules","journal":"Yi chuan = Hereditas","confidence":"Low","confidence_rationale":"Tier 3/4 — expression-based finding from microarray without functional rescue or mechanistic follow-up specific to IPO11","pmids":["19819847"],"is_preprint":false}],"current_model":"IPO11 (Importin-11) functions as a nuclear import receptor that translocates cargo proteins from the cytoplasm to the nucleus: it mediates β-catenin nuclear import in APC-mutant colorectal cancer cells to sustain Wnt/β-catenin transcription, and it mediates CDK4/6-phosphorylated RPRM nuclear import upon irradiation, enabling RPRM to interact with ATM and promote its proteasomal degradation, thereby regulating the DNA damage response."},"narrative":{"teleology":[{"year":2020,"claim":"A genome-wide CRISPR screen resolved how β-catenin reaches the nucleus in APC-mutant colorectal cancer, identifying IPO11 as the import receptor required for β-catenin nuclear accumulation and Wnt target gene transcription.","evidence":"DEADPOOL CRISPR screen in APC-mutant CRC lines, IPO11 knockout, nuclear fractionation, transcriptional reporters, patient-derived organoid proliferation assays","pmids":["31881079"],"confidence":"High","gaps":["Whether IPO11 binds β-catenin directly or through an adaptor has not been established","The nuclear localization signal or recognition motif on β-catenin used by IPO11 is undefined","Relevance of IPO11-mediated β-catenin import in non-APC-mutant Wnt-active contexts is untested"]},{"year":2022,"claim":"Discovery that IPO11 imports phosphorylated RPRM into the nucleus after irradiation established a second cargo and linked IPO11 to the DNA damage response via ATM degradation.","evidence":"Reciprocal co-immunoprecipitation, CRISPR IPO11 knockout, RPRM S98 phosphosite mutagenesis, CDK4/6 inhibitor treatment, subcellular fractionation, in vivo irradiation","pmids":["36185355"],"confidence":"High","gaps":["Structural basis for IPO11 recognition of CDK4/6-phosphorylated RPRM is unknown","Whether IPO11 has additional DNA-damage-responsive cargoes has not been explored","RanGTP-dependent release of RPRM in the nucleus has not been directly demonstrated"]},{"year":null,"claim":"A comprehensive cargo repertoire for IPO11 remains undefined; beyond β-catenin and RPRM, no systematic identification of physiological import substrates has been performed.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unbiased proteomics-based cargo identification has been reported","Structural determinants of cargo specificity (NLS-like motifs recognized by IPO11) are uncharacterized","Physiological roles of IPO11 in normal tissues (e.g., spermatogenesis) lack mechanistic validation"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0]}],"complexes":[],"partners":["CTNNB1","RPRM"],"other_free_text":[]},"mechanistic_narrative":"IPO11 (Importin-11) is a nuclear import receptor that mediates the translocation of specific cargo proteins from the cytoplasm to the nucleus. In APC-mutant colorectal cancer cells, IPO11 is required for β-catenin nuclear import and consequent β-catenin-dependent transcriptional activation; its deletion reduces nuclear β-catenin levels and impairs Wnt-driven proliferation in patient-derived organoids [PMID:31881079]. IPO11 also imports CDK4/6-phosphorylated RPRM (Reprimo) into the nucleus following ionizing radiation, where RPRM promotes ATM nuclear export and proteasomal degradation, thereby attenuating the DNA damage response [PMID:36185355]."},"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,"source_track":"pubmed_title"},{"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":32,"is_preprint":false,"source_track":"pubmed_title"},{"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":31,"is_preprint":false,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"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,"source_track":"pubmed_title"},{"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. 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target gene activation, and loss of IPO11 decreases colony formation of CRC cell lines and proliferation of patient-derived CRC organoids.\",\n      \"method\": \"Genome-wide CRISPR screen (DEADPOOL), IPO11 knockout cell lines, nuclear fractionation, target gene expression analysis, colony formation assay, organoid proliferation assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genome-wide functional screen with orthogonal validation (KO, fractionation, transcriptional readouts, organoid assay) in a single rigorous study\",\n      \"pmids\": [\"31881079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IPO11 is required for the nuclear import of RPRM (Reprimo) upon X-irradiation; CDK4/6-mediated phosphorylation of RPRM at serine 98 enables its interaction with IPO11, which transports RPRM to the nucleus where it promotes ATM nuclear export and proteasomal degradation, thereby negatively regulating ATM protein levels and increasing cellular radiosensitivity.\",\n      \"method\": \"IPO11 knockdown/knockout (CRISPR), co-immunoprecipitation, phosphorylation site mutagenesis (S98), CDK4/6 inhibition, nuclear fractionation, in vivo and in vitro radiosensitivity assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including KO, Co-IP, mutagenesis, fractionation, and in vivo validation in a single study\",\n      \"pmids\": [\"36185355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IPO11 deletion via CRISPR-Cas9 in H460 lung cancer cells confirmed IPO11's essential role in the nuclear translocation of its cargo proteins, validated by re-expression rescue experiments.\",\n      \"method\": \"CRISPR-Cas9 deletion, lentiviral transduction, plasmid-based re-expression, single-clone selection and validation\",\n      \"journal\": \"STAR protocols\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — methodological protocol paper supporting mechanistic findings from Zhang et al. (PMID:36185355); provides functional validation context but limited independent mechanistic data\",\n      \"pmids\": [\"37195868\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IPO11 (Importin-11) is a nuclear import receptor that transports specific cargo proteins — including β-catenin in APC-mutant colorectal cancer cells and phospho-RPRM (phosphorylated at S98 by CDK4/6) in irradiated cells — from the cytoplasm to the nucleus, thereby regulating Wnt/β-catenin transcriptional programs and ATM-mediated DNA damage responses, respectively.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"IPO11 (Importin-11) was identified as a required factor for β-catenin nuclear import in APC-mutant colorectal cancer cells. A genome-wide CRISPR screen (DEADPOOL) identified IPO11, and IPO11 knockout cells exhibited reduced nuclear β-catenin protein levels and decreased β-catenin target gene activation, demonstrating that IPO11 facilitates β-catenin nucleocytoplasmic shuttling and is required for β-catenin-mediated transcription in cells with high Wnt activity.\",\n      \"method\": \"Genome-wide CRISPR screen (DEADPOOL positive selection), IPO11 knockout cell lines, nuclear fractionation, β-catenin 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 — clean KO with defined cellular phenotype, multiple orthogonal readouts (nuclear fractionation, transcriptional output, organoid growth), genome-wide unbiased screen identification\",\n      \"pmids\": [\"31881079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IPO11 (Importin-11) mediates the nuclear import of RPRM (Reprimo) upon X-irradiation. RPRM is primarily cytoplasmic but translocates to the nucleus after irradiation, a process requiring phosphorylation of RPRM at serine 98 by CDK4/6 and requiring IPO11. Once nuclear, RPRM interacts with ATM and promotes its nuclear export and proteasomal degradation, thereby downregulating ATM protein levels and impairing DNA repair. IPO11 deletion abrogated RPRM nuclear import and prevented ATM downregulation.\",\n      \"method\": \"Co-immunoprecipitation, subcellular fractionation, CRISPR-based IPO11 knockout, site-directed mutagenesis (S98 phospho-site), CDK4/6 inhibitor treatment, in vivo irradiation experiments, proteasome inhibition assay\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, clean KO, mutagenesis of phosphorylation site, multiple orthogonal methods establishing the IPO11→RPRM import→ATM degradation axis\",\n      \"pmids\": [\"36185355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Ipo11 expression is associated with spermiogenesis in mouse testis; treatment with Tripterygium wilfordii (GTW) caused abnormal expression of Ipo11 (along with Herc4 and Mrto4) in testicular tissue, correlating with disrupted spermatogenic cell populations and infertility, indicating a role for Ipo11 in male germ cell development.\",\n      \"method\": \"Gene chip (microarray) expression profiling of testis tissue from GTW-treated versus control mice, histological analysis of seminiferous tubules\",\n      \"journal\": \"Yi chuan = Hereditas\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3/4 — expression-based finding from microarray without functional rescue or mechanistic follow-up specific to IPO11\",\n      \"pmids\": [\"19819847\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IPO11 (Importin-11) functions as a nuclear import receptor that translocates cargo proteins from the cytoplasm to the nucleus: it mediates β-catenin nuclear import in APC-mutant colorectal cancer cells to sustain Wnt/β-catenin transcription, and it mediates CDK4/6-phosphorylated RPRM nuclear import upon irradiation, enabling RPRM to interact with ATM and promote its proteasomal degradation, thereby regulating the DNA damage response.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IPO11 (Importin-11) is a nuclear import receptor that transports specific cargo proteins into the nucleus in a context-dependent manner. In APC-mutant colorectal cancer cells, IPO11 mediates the nuclear import of β-catenin, and its loss reduces nuclear β-catenin levels, β-catenin target gene expression, colony formation, and patient-derived organoid proliferation [PMID:31881079]. Upon ionizing radiation, CDK4/6-mediated phosphorylation of RPRM at serine 98 enables RPRM recognition by IPO11 and subsequent nuclear import, where RPRM promotes ATM nuclear export and proteasomal degradation, thereby attenuating the DNA damage response and modulating radiosensitivity [PMID:36185355].\",\n  \"teleology\": [\n    {\n      \"year\": 2020,\n      \"claim\": \"Addressing how β-catenin reaches the nucleus in APC-mutant colorectal cancer independently of classical Wnt-ligand signaling, a genome-wide CRISPR screen identified IPO11 as the dedicated nuclear import receptor for β-catenin in this context, establishing a direct link between a karyopherin family member and oncogenic Wnt pathway output.\",\n      \"evidence\": \"Genome-wide CRISPR screen (DEADPOOL) in APC-mutant CRC cells, validated by IPO11 knockout, nuclear fractionation, transcriptional readouts, colony formation, and patient-derived organoid assays\",\n      \"pmids\": [\"31881079\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether IPO11-mediated β-catenin import operates in APC-wild-type contexts or is restricted to APC-mutant settings\",\n        \"The structural basis of the IPO11–β-catenin interaction and whether RanGTP regulates cargo release\",\n        \"Whether additional cargoes beyond β-catenin contribute to the CRC proliferation phenotype upon IPO11 loss\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealing how the DNA damage response protein RPRM is regulated post-irradiation, CDK4/6-dependent phosphorylation of RPRM at S98 was shown to create a recognition signal for IPO11, which imports RPRM into the nucleus where it drives ATM nuclear export and degradation — establishing IPO11 as a phosphorylation-gated importer linking cell-cycle kinase signaling to the DNA damage response.\",\n      \"evidence\": \"IPO11 KO/knockdown, co-immunoprecipitation, S98 phosphorylation-site mutagenesis, CDK4/6 inhibition, nuclear fractionation, in vivo and in vitro radiosensitivity assays in lung cancer models\",\n      \"pmids\": [\"36185355\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether additional post-translational modifications on RPRM or IPO11 fine-tune this import pathway\",\n        \"The mechanism by which nuclear RPRM promotes ATM export and proteasomal degradation\",\n        \"Whether IPO11–RPRM import operates in non-cancerous cells or other DNA-damaging contexts beyond ionizing radiation\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Independent validation confirmed that CRISPR-mediated IPO11 deletion abolishes nuclear translocation of its cargo and that re-expression rescues the phenotype, reinforcing the specificity and non-redundancy of IPO11 as an import receptor.\",\n      \"evidence\": \"CRISPR-Cas9 deletion and lentiviral re-expression rescue in H460 lung cancer cells\",\n      \"pmids\": [\"37195868\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Protocol paper; limited novel mechanistic data beyond confirming prior findings\",\n        \"No identification of the full repertoire of IPO11 cargoes\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The complete cargo repertoire of IPO11, its structural basis for cargo recognition, the role of RanGTP in cargo release, and whether IPO11 functions are relevant in normal (non-cancerous) physiology remain uncharacterized.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No unbiased proteomics-based identification of the full IPO11 cargo spectrum\",\n        \"No structural or biophysical characterization of IPO11–cargo complexes\",\n        \"No in vivo genetic models (e.g., knockout mice) to assess physiological roles beyond cancer\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CTNNB1\",\n      \"RPRM\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"IPO11 (Importin-11) is a nuclear import receptor that mediates the translocation of specific cargo proteins from the cytoplasm to the nucleus. In APC-mutant colorectal cancer cells, IPO11 is required for β-catenin nuclear import and consequent β-catenin-dependent transcriptional activation; its deletion reduces nuclear β-catenin levels and impairs Wnt-driven proliferation in patient-derived organoids [PMID:31881079]. IPO11 also imports CDK4/6-phosphorylated RPRM (Reprimo) into the nucleus following ionizing radiation, where RPRM promotes ATM nuclear export and proteasomal degradation, thereby attenuating the DNA damage response [PMID:36185355].\",\n  \"teleology\": [\n    {\n      \"year\": 2020,\n      \"claim\": \"A genome-wide CRISPR screen resolved how β-catenin reaches the nucleus in APC-mutant colorectal cancer, identifying IPO11 as the import receptor required for β-catenin nuclear accumulation and Wnt target gene transcription.\",\n      \"evidence\": \"DEADPOOL CRISPR screen in APC-mutant CRC lines, IPO11 knockout, nuclear fractionation, transcriptional reporters, patient-derived organoid proliferation assays\",\n      \"pmids\": [\"31881079\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether IPO11 binds β-catenin directly or through an adaptor has not been established\",\n        \"The nuclear localization signal or recognition motif on β-catenin used by IPO11 is undefined\",\n        \"Relevance of IPO11-mediated β-catenin import in non-APC-mutant Wnt-active contexts is untested\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Discovery that IPO11 imports phosphorylated RPRM into the nucleus after irradiation established a second cargo and linked IPO11 to the DNA damage response via ATM degradation.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, CRISPR IPO11 knockout, RPRM S98 phosphosite mutagenesis, CDK4/6 inhibitor treatment, subcellular fractionation, in vivo irradiation\",\n      \"pmids\": [\"36185355\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for IPO11 recognition of CDK4/6-phosphorylated RPRM is unknown\",\n        \"Whether IPO11 has additional DNA-damage-responsive cargoes has not been explored\",\n        \"RanGTP-dependent release of RPRM in the nucleus has not been directly demonstrated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A comprehensive cargo repertoire for IPO11 remains undefined; beyond β-catenin and RPRM, no systematic identification of physiological import substrates has been performed.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No unbiased proteomics-based cargo identification has been reported\",\n        \"Structural determinants of cargo specificity (NLS-like motifs recognized by IPO11) are uncharacterized\",\n        \"Physiological roles of IPO11 in normal tissues (e.g., spermatogenesis) lack mechanistic validation\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CTNNB1\",\n      \"RPRM\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}