{"gene":"XPO6","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2017,"finding":"Laminin-111 (LN1) attenuates the PI3K pathway, leading to upregulation of XPO6 activity, which shuttles actin out of the nucleus. Silencing XPO6 prevents LN1-induced epithelial quiescence. FRAP assays showed nuclear actin exit begins within 30 min of LN1 treatment, defining a LN1/PI3K/XPO6/N-actin axis in growth control.","method":"siRNA knockdown, photobleaching (FRAP) assays, PI3K pathway inhibitor experiments in mammary epithelial cells","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined cellular phenotype (quiescence), FRAP for localization dynamics, PI3K inhibitor orthogonal approach; single lab","pmids":["28591581"],"is_preprint":false},{"year":2019,"finding":"RASSF1A localizes to the nuclear envelope and is required for XPO6 to bind RAN GTPase, thereby supporting nuclear actin export. Loss of RASSF1A in cancer cells impairs the XPO6/RAN interaction, reduces nuclear actin export, and deregulates MRTF-A/SRF transcriptional activity, causing cell adhesion defects.","method":"Co-immunoprecipitation (endogenous RASSF1A–XPO6–RAN), subcellular fractionation/immunofluorescence, RASSF1A knockdown/knockout with MRTF-A reporter and adhesion assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP showing RASSF1A supports XPO6–RAN binding, multiple orthogonal functional readouts (actin transport, MRTF-A activity, adhesion), independently consistent with prior XPO6 literature","pmids":["31414556"],"is_preprint":false},{"year":2019,"finding":"MST2 (Hippo pathway kinase) also plays a pivotal role in regulating XPO6 association with RAN GTPase for nucleocytoplasmic actin shuttling, acting downstream of or in concert with RASSF1A.","method":"Genetic/biochemical follow-up described in companion commentary referencing data from PMID:31414556","journal":"Molecular & cellular oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — commentary paper, single-method inference from primary data; no independent experimental detail provided in this abstract","pmids":["31528703"],"is_preprint":false},{"year":2021,"finding":"XPO6 exports profilin-1 from the nucleus; reducing XPO6 accumulates nuclear profilin-1, which then interacts with the ENL subunit of the super elongation complex (SEC) and inhibits SEC-driven transcription of pro-cancer genes including MYC.","method":"XPO6 knockdown/overexpression in breast cancer cells, Co-IP of nuclear profilin-1 with ENL, transcriptional reporter and ChIP-seq for SEC target genes, rescue experiments","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP (profilin-1/ENL), KD with defined transcriptional and oncogenic phenotype, multiple orthogonal methods (Co-IP, reporter, ChIP-seq, rescue) in single rigorous study","pmids":["33596420"],"is_preprint":false},{"year":2020,"finding":"XPO6 is required for the release of HSV-1 glycoprotein M (gM) from nuclear membranes to the trans-Golgi network late in infection. This was an unexpected cargo, as XPO6 was previously known only for actin/profilin export.","method":"BioID proximity-ligation proteomics to identify gM interacting partners, followed by siRNA/KD validation of XPO6 requirement for gM nuclear release, immunofluorescence tracking of gM localization","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — BioID proteomics plus siRNA KD with defined localization phenotype; single lab, novel cargo claim requires further validation","pmids":["32817212"],"is_preprint":false},{"year":2022,"finding":"Overexpression of XPO6 (nuclear actin export complex) reduces nuclear actin monomer levels and rescues RelA/p65 protein levels and NF-κB reporter activity that were suppressed by elevated cAMP, demonstrating that XPO6-mediated nuclear actin export opposes cAMP-induced proteasomal degradation of RelA/p65.","method":"XPO6 overexpression in forskolin-stimulated cells, NF-κB reporter assays, RelA/p65 half-life measurements, proteasome inhibitor (MG132) rescue, ubiquitin affinity bead pull-down","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression rescue with multiple functional readouts (reporter, protein half-life, ubiquitination assay); single lab, XPO6 used as a tool to modulate nuclear actin rather than as primary subject","pmids":["35563720"],"is_preprint":false},{"year":2023,"finding":"XPO6 promotes YAP1 protein expression and nuclear translocation in prostate cancer cells, activating the Hippo pathway effector YAP1; blocking YAP1 with an inhibitor abrogates XPO6-mediated effects on proliferation, migration, and docetaxel resistance.","method":"XPO6 knockdown/overexpression in PCa cell lines, YAP1 protein expression and nuclear translocation assays, YAP1 inhibitor rescue, xenograft mouse experiments","journal":"Discover oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single Co-IP/immunofluorescence approach for YAP1 translocation; mechanistic link between XPO6 (an exportin) and YAP1 nuclear import is not biochemically explained","pmids":["37243787"],"is_preprint":false},{"year":2024,"finding":"XPO6 facilitates nuclear export of TLR2 mRNA in pulmonary monocytes, stabilizing TLR2 mRNA and increasing TLR2 protein levels, which activates the MyD88/NF-κB inflammatory signaling pathway and promotes secretion of TNFα, IL-6, and IL-1β in COPD.","method":"XPO6 knockdown/overexpression in monocytes, TLR2 mRNA nuclear export assay, TLR2 protein expression measurements, cytokine ELISA, NF-κB reporter in COPD mouse model and human samples","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined mechanistic readout (mRNA nuclear export, downstream signaling), multiple functional assays; single lab, mRNA export is non-canonical for XPO6","pmids":["38788453"],"is_preprint":false},{"year":2025,"finding":"miR-3613-5p directly targets the 3′UTR of XPO6 mRNA (verified by dual-luciferase reporter assay), reducing XPO6 expression and thereby promoting lung cancer cell proliferation, migration, and invasion; restoring XPO6 offsets these effects.","method":"Dual-luciferase reporter assay for miR-3613-5p/XPO6 interaction, qRT-PCR, CCK-8 proliferation assay, Transwell migration/invasion assay, rescue experiments","journal":"Discover oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, luciferase assay confirms targeting but provides no mechanistic insight into XPO6 protein function beyond being a downstream effector","pmids":["41379264"],"is_preprint":false}],"current_model":"XPO6 (Exportin-6) is a nuclear export receptor that, in complex with RAN GTPase, exports actin monomers and profilin-1 from the nucleus; its activity is regulated by RASSF1A and MST2 (which support XPO6–RAN binding), and by the PI3K pathway downstream of laminin-111 signaling; nuclear profilin-1 retained upon XPO6 loss suppresses the super elongation complex (SEC)/MYC transcriptional program, while nuclear actin levels modulated by XPO6 further regulate NF-κB (RelA/p65) stability and MRTF-A/SRF activity; XPO6 also mediates HSV-1 glycoprotein M nuclear release and, non-canonically, facilitates TLR2 mRNA nuclear export in monocytes."},"narrative":{"mechanistic_narrative":"XPO6 (Exportin-6) is a RAN-dependent nuclear export receptor that controls nuclear levels of actin and the actin-binding protein profilin-1, thereby coupling cytoskeletal monomer trafficking to transcriptional programs governing cell growth and adhesion [PMID:31414556, PMID:33596420]. Its export activity is set by upstream regulators: laminin-111 signaling attenuates the PI3K pathway to upregulate XPO6-mediated nuclear actin efflux and impose epithelial quiescence [PMID:28591581], while RASSF1A localizes to the nuclear envelope and is required for XPO6 to engage RAN GTPase, sustaining nuclear actin export that supports MRTF-A/SRF transcriptional activity and proper cell adhesion [PMID:31414556]. By exporting profilin-1, XPO6 limits nuclear profilin-1 available to bind the ENL subunit of the super elongation complex (SEC); loss of XPO6 accumulates nuclear profilin-1, which inhibits SEC-driven transcription of pro-cancer genes including MYC [PMID:33596420]. XPO6-dependent depletion of nuclear actin monomers also opposes cAMP-induced proteasomal degradation of NF-κB RelA/p65, linking its transport activity to inflammatory signaling stability [PMID:35563720]. Beyond its canonical actin/profilin cargo, XPO6 is required for nuclear release of HSV-1 glycoprotein M toward the trans-Golgi network during late infection [PMID:32817212].","teleology":[{"year":2017,"claim":"Established that XPO6-mediated nuclear actin export is an actively regulated node in growth control, placing it downstream of an extracellular matrix/PI3K signal rather than acting constitutively.","evidence":"siRNA knockdown, FRAP nuclear-actin dynamics, and PI3K inhibition in mammary epithelial cells","pmids":["28591581"],"confidence":"Medium","gaps":["Does not define how PI3K signaling biochemically alters XPO6 activity","Single cell-type model (mammary epithelium)"]},{"year":2019,"claim":"Identified RASSF1A as a required cofactor for XPO6–RAN engagement, explaining how nuclear actin export is licensed and linking its loss to MRTF-A/SRF deregulation and adhesion defects in cancer.","evidence":"Endogenous reciprocal Co-IP of RASSF1A–XPO6–RAN, fractionation/IF, knockdown with MRTF-A reporter and adhesion assays","pmids":["31414556"],"confidence":"High","gaps":["Structural basis of how RASSF1A promotes XPO6–RAN binding not resolved","Whether RASSF1A regulates profilin-1 export equally is untested"]},{"year":2019,"claim":"Extended the regulatory model by implicating the Hippo kinase MST2 in controlling XPO6–RAN association alongside RASSF1A.","evidence":"Commentary inferring from primary data of PMID:31414556","pmids":["31528703"],"confidence":"Low","gaps":["Commentary with no independent experimental data","MST2's direct biochemical contribution to XPO6–RAN binding undefined"]},{"year":2020,"claim":"Revealed a non-canonical cargo by showing XPO6 is required for nuclear release of HSV-1 glycoprotein M, expanding its role beyond actin/profilin to viral protein egress.","evidence":"BioID proximity proteomics for gM partners plus siRNA validation and IF localization tracking","pmids":["32817212"],"confidence":"Medium","gaps":["Direct XPO6–gM binding and RAN-dependence not demonstrated","Single lab; novel cargo not independently replicated"]},{"year":2021,"claim":"Provided the transcriptional consequence of profilin-1 export: nuclear profilin-1 retained upon XPO6 loss binds SEC component ENL and suppresses SEC-driven oncogenic transcription including MYC.","evidence":"XPO6 KD/overexpression in breast cancer cells, profilin-1/ENL Co-IP, reporter, ChIP-seq, rescue","pmids":["33596420"],"confidence":"High","gaps":["Whether nuclear actin and nuclear profilin-1 act independently on SEC not separated","Stoichiometry of profilin-1–ENL inhibition unknown"]},{"year":2022,"claim":"Connected XPO6-controlled nuclear actin levels to NF-κB stability, showing actin export opposes cAMP-induced proteasomal degradation of RelA/p65.","evidence":"XPO6 overexpression in forskolin-stimulated cells, NF-κB reporter, RelA/p65 half-life, MG132 rescue, ubiquitin pull-down","pmids":["35563720"],"confidence":"Medium","gaps":["XPO6 used as a tool to lower nuclear actin rather than primary subject","Mechanism linking nuclear actin to RelA/p65 ubiquitination not defined"]},{"year":2023,"claim":"Reported that XPO6 promotes YAP1 expression and nuclear translocation to drive prostate cancer proliferation, migration and drug resistance.","evidence":"XPO6 KD/overexpression in PCa lines, YAP1 translocation assays, YAP1 inhibitor rescue, xenografts","pmids":["37243787"],"confidence":"Low","gaps":["Mechanistic link between an exportin and YAP1 nuclear import not biochemically explained","Single-lab, single approach for translocation"]},{"year":2024,"claim":"Demonstrated a non-canonical mRNA-export role, with XPO6 facilitating nuclear export of TLR2 mRNA to amplify MyD88/NF-κB inflammatory signaling in COPD monocytes.","evidence":"XPO6 KD/overexpression, TLR2 mRNA nuclear export assay, cytokine ELISA, NF-κB reporter in mouse model and human samples","pmids":["38788453"],"confidence":"Medium","gaps":["Direct XPO6–TLR2 mRNA association mechanism not shown","mRNA export is non-canonical for XPO6 and not independently confirmed"]},{"year":2025,"claim":"Placed XPO6 under post-transcriptional control by miR-3613-5p, with its downregulation promoting lung cancer aggressiveness.","evidence":"Dual-luciferase 3′UTR reporter, qRT-PCR, CCK-8, Transwell, rescue experiments","pmids":["41379264"],"confidence":"Low","gaps":["Provides no insight into XPO6 protein function beyond being a downstream effector","Single-lab validation"]},{"year":null,"claim":"How XPO6 distinguishes and engages its diverse cargoes (actin, profilin-1, viral gM, specific mRNAs) at the structural and RAN-dependent level remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of XPO6–cargo recognition","Whether non-canonical cargoes share the RAN-dependent mechanism is untested","Cargo-selection determinants unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[1,3]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1,3]}],"localization":[{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[1]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,3]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[1,3]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3]}],"complexes":[],"partners":["RAN","RASSF1A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96QU8","full_name":"Exportin-6","aliases":["Ran-binding protein 20"],"length_aa":1125,"mass_kda":128.9,"function":"Mediates the nuclear export of actin and profilin-actin complexes in somatic cells","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q96QU8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/XPO6","classification":"Not Classified","n_dependent_lines":11,"n_total_lines":1208,"dependency_fraction":0.009105960264900662},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000169180","cell_line_id":"CID001581","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nuclear_membrane","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"ATP2B4","stoichiometry":0.2},{"gene":"PES1","stoichiometry":0.2},{"gene":"ZMAT2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001581","total_profiled":1310},"omim":[{"mim_id":"608411","title":"EXPORTIN 6; XPO6","url":"https://www.omim.org/entry/608411"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/XPO6"},"hgnc":{"alias_symbol":["KIAA0370","FLJ22519"],"prev_symbol":["RANBP20"]},"alphafold":{"accession":"Q96QU8","domains":[{"cath_id":"-","chopping":"970-1116","consensus_level":"high","plddt":92.4646,"start":970,"end":1116},{"cath_id":"1.25.40","chopping":"3-158","consensus_level":"high","plddt":90.7739,"start":3,"end":158}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96QU8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96QU8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96QU8-F1-predicted_aligned_error_v6.png","plddt_mean":86.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=XPO6","jax_strain_url":"https://www.jax.org/strain/search?query=XPO6"},"sequence":{"accession":"Q96QU8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96QU8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96QU8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96QU8"}},"corpus_meta":[{"pmid":"28591581","id":"PMC_28591581","title":"Laminin-111 and the Level of Nuclear Actin Regulate Epithelial Quiescence via Exportin-6.","date":"2017","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/28591581","citation_count":64,"is_preprint":false},{"pmid":"31414556","id":"PMC_31414556","title":"RASSF1A is required for the maintenance of nuclear actin levels.","date":"2019","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/31414556","citation_count":39,"is_preprint":false},{"pmid":"33596420","id":"PMC_33596420","title":"Cancer-associated exportin-6 upregulation inhibits the transcriptionally repressive and anticancer effects of nuclear profilin-1.","date":"2021","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/33596420","citation_count":20,"is_preprint":false},{"pmid":"22127497","id":"PMC_22127497","title":"Genome-wide association and fine mapping of genetic loci predisposing to colon carcinogenesis in mice.","date":"2011","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/22127497","citation_count":20,"is_preprint":false},{"pmid":"26408707","id":"PMC_26408707","title":"Signatures of Adverse Pathological Features, Androgen Insensitivity and Metastatic Potential in Prostate Cancer.","date":"2015","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/26408707","citation_count":15,"is_preprint":false},{"pmid":"32817212","id":"PMC_32817212","title":"The XPO6 Exportin Mediates Herpes Simplex Virus 1 gM Nuclear Release Late in Infection.","date":"2020","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/32817212","citation_count":13,"is_preprint":false},{"pmid":"38788453","id":"PMC_38788453","title":"Exportin XPO6 upregulation activates the TLR2/MyD88/NF-κB signaling by facilitating TLR2 mRNA nuclear export in COPD pulmonary monocytes.","date":"2024","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38788453","citation_count":7,"is_preprint":false},{"pmid":"37243787","id":"PMC_37243787","title":"Targeting XPO6 inhibits prostate cancer progression and enhances the suppressive efficacy of docetaxel.","date":"2023","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37243787","citation_count":6,"is_preprint":false},{"pmid":"35563720","id":"PMC_35563720","title":"Cyclic-AMP Increases Nuclear Actin Monomer Which Promotes Proteasomal Degradation of RelA/p65 Leading to Anti-Inflammatory Effects.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/35563720","citation_count":4,"is_preprint":false},{"pmid":"31528703","id":"PMC_31528703","title":"When Hippo meets actin in the nucleus.","date":"2019","source":"Molecular & cellular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/31528703","citation_count":3,"is_preprint":false},{"pmid":"41379264","id":"PMC_41379264","title":"miR-3613-5p promotes lung cancer progression by targeting and regulating XPO6.","date":"2025","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41379264","citation_count":0,"is_preprint":false},{"pmid":"42051519","id":"PMC_42051519","title":"Identification of key biomarkers for myocardial infarction by multi-omics analysis and machine learning.","date":"2026","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/42051519","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8321,"output_tokens":2496,"usd":0.031202,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9621,"output_tokens":3096,"usd":0.062753,"stage2_stop_reason":"end_turn"},"total_usd":0.093955,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"Laminin-111 (LN1) attenuates the PI3K pathway, leading to upregulation of XPO6 activity, which shuttles actin out of the nucleus. Silencing XPO6 prevents LN1-induced epithelial quiescence. FRAP assays showed nuclear actin exit begins within 30 min of LN1 treatment, defining a LN1/PI3K/XPO6/N-actin axis in growth control.\",\n      \"method\": \"siRNA knockdown, photobleaching (FRAP) assays, PI3K pathway inhibitor experiments in mammary epithelial cells\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined cellular phenotype (quiescence), FRAP for localization dynamics, PI3K inhibitor orthogonal approach; single lab\",\n      \"pmids\": [\"28591581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"RASSF1A localizes to the nuclear envelope and is required for XPO6 to bind RAN GTPase, thereby supporting nuclear actin export. Loss of RASSF1A in cancer cells impairs the XPO6/RAN interaction, reduces nuclear actin export, and deregulates MRTF-A/SRF transcriptional activity, causing cell adhesion defects.\",\n      \"method\": \"Co-immunoprecipitation (endogenous RASSF1A–XPO6–RAN), subcellular fractionation/immunofluorescence, RASSF1A knockdown/knockout with MRTF-A reporter and adhesion assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP showing RASSF1A supports XPO6–RAN binding, multiple orthogonal functional readouts (actin transport, MRTF-A activity, adhesion), independently consistent with prior XPO6 literature\",\n      \"pmids\": [\"31414556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MST2 (Hippo pathway kinase) also plays a pivotal role in regulating XPO6 association with RAN GTPase for nucleocytoplasmic actin shuttling, acting downstream of or in concert with RASSF1A.\",\n      \"method\": \"Genetic/biochemical follow-up described in companion commentary referencing data from PMID:31414556\",\n      \"journal\": \"Molecular & cellular oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — commentary paper, single-method inference from primary data; no independent experimental detail provided in this abstract\",\n      \"pmids\": [\"31528703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"XPO6 exports profilin-1 from the nucleus; reducing XPO6 accumulates nuclear profilin-1, which then interacts with the ENL subunit of the super elongation complex (SEC) and inhibits SEC-driven transcription of pro-cancer genes including MYC.\",\n      \"method\": \"XPO6 knockdown/overexpression in breast cancer cells, Co-IP of nuclear profilin-1 with ENL, transcriptional reporter and ChIP-seq for SEC target genes, rescue experiments\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP (profilin-1/ENL), KD with defined transcriptional and oncogenic phenotype, multiple orthogonal methods (Co-IP, reporter, ChIP-seq, rescue) in single rigorous study\",\n      \"pmids\": [\"33596420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"XPO6 is required for the release of HSV-1 glycoprotein M (gM) from nuclear membranes to the trans-Golgi network late in infection. This was an unexpected cargo, as XPO6 was previously known only for actin/profilin export.\",\n      \"method\": \"BioID proximity-ligation proteomics to identify gM interacting partners, followed by siRNA/KD validation of XPO6 requirement for gM nuclear release, immunofluorescence tracking of gM localization\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — BioID proteomics plus siRNA KD with defined localization phenotype; single lab, novel cargo claim requires further validation\",\n      \"pmids\": [\"32817212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Overexpression of XPO6 (nuclear actin export complex) reduces nuclear actin monomer levels and rescues RelA/p65 protein levels and NF-κB reporter activity that were suppressed by elevated cAMP, demonstrating that XPO6-mediated nuclear actin export opposes cAMP-induced proteasomal degradation of RelA/p65.\",\n      \"method\": \"XPO6 overexpression in forskolin-stimulated cells, NF-κB reporter assays, RelA/p65 half-life measurements, proteasome inhibitor (MG132) rescue, ubiquitin affinity bead pull-down\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression rescue with multiple functional readouts (reporter, protein half-life, ubiquitination assay); single lab, XPO6 used as a tool to modulate nuclear actin rather than as primary subject\",\n      \"pmids\": [\"35563720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"XPO6 promotes YAP1 protein expression and nuclear translocation in prostate cancer cells, activating the Hippo pathway effector YAP1; blocking YAP1 with an inhibitor abrogates XPO6-mediated effects on proliferation, migration, and docetaxel resistance.\",\n      \"method\": \"XPO6 knockdown/overexpression in PCa cell lines, YAP1 protein expression and nuclear translocation assays, YAP1 inhibitor rescue, xenograft mouse experiments\",\n      \"journal\": \"Discover oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single Co-IP/immunofluorescence approach for YAP1 translocation; mechanistic link between XPO6 (an exportin) and YAP1 nuclear import is not biochemically explained\",\n      \"pmids\": [\"37243787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"XPO6 facilitates nuclear export of TLR2 mRNA in pulmonary monocytes, stabilizing TLR2 mRNA and increasing TLR2 protein levels, which activates the MyD88/NF-κB inflammatory signaling pathway and promotes secretion of TNFα, IL-6, and IL-1β in COPD.\",\n      \"method\": \"XPO6 knockdown/overexpression in monocytes, TLR2 mRNA nuclear export assay, TLR2 protein expression measurements, cytokine ELISA, NF-κB reporter in COPD mouse model and human samples\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined mechanistic readout (mRNA nuclear export, downstream signaling), multiple functional assays; single lab, mRNA export is non-canonical for XPO6\",\n      \"pmids\": [\"38788453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"miR-3613-5p directly targets the 3′UTR of XPO6 mRNA (verified by dual-luciferase reporter assay), reducing XPO6 expression and thereby promoting lung cancer cell proliferation, migration, and invasion; restoring XPO6 offsets these effects.\",\n      \"method\": \"Dual-luciferase reporter assay for miR-3613-5p/XPO6 interaction, qRT-PCR, CCK-8 proliferation assay, Transwell migration/invasion assay, rescue experiments\",\n      \"journal\": \"Discover oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, luciferase assay confirms targeting but provides no mechanistic insight into XPO6 protein function beyond being a downstream effector\",\n      \"pmids\": [\"41379264\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"XPO6 (Exportin-6) is a nuclear export receptor that, in complex with RAN GTPase, exports actin monomers and profilin-1 from the nucleus; its activity is regulated by RASSF1A and MST2 (which support XPO6–RAN binding), and by the PI3K pathway downstream of laminin-111 signaling; nuclear profilin-1 retained upon XPO6 loss suppresses the super elongation complex (SEC)/MYC transcriptional program, while nuclear actin levels modulated by XPO6 further regulate NF-κB (RelA/p65) stability and MRTF-A/SRF activity; XPO6 also mediates HSV-1 glycoprotein M nuclear release and, non-canonically, facilitates TLR2 mRNA nuclear export in monocytes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"XPO6 (Exportin-6) is a RAN-dependent nuclear export receptor that controls nuclear levels of actin and the actin-binding protein profilin-1, thereby coupling cytoskeletal monomer trafficking to transcriptional programs governing cell growth and adhesion [#1, #3]. Its export activity is set by upstream regulators: laminin-111 signaling attenuates the PI3K pathway to upregulate XPO6-mediated nuclear actin efflux and impose epithelial quiescence [#0], while RASSF1A localizes to the nuclear envelope and is required for XPO6 to engage RAN GTPase, sustaining nuclear actin export that supports MRTF-A/SRF transcriptional activity and proper cell adhesion [#1]. By exporting profilin-1, XPO6 limits nuclear profilin-1 available to bind the ENL subunit of the super elongation complex (SEC); loss of XPO6 accumulates nuclear profilin-1, which inhibits SEC-driven transcription of pro-cancer genes including MYC [#3]. XPO6-dependent depletion of nuclear actin monomers also opposes cAMP-induced proteasomal degradation of NF-\\u03baB RelA/p65, linking its transport activity to inflammatory signaling stability [#5]. Beyond its canonical actin/profilin cargo, XPO6 is required for nuclear release of HSV-1 glycoprotein M toward the trans-Golgi network during late infection [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Established that XPO6-mediated nuclear actin export is an actively regulated node in growth control, placing it downstream of an extracellular matrix/PI3K signal rather than acting constitutively.\",\n      \"evidence\": \"siRNA knockdown, FRAP nuclear-actin dynamics, and PI3K inhibition in mammary epithelial cells\",\n      \"pmids\": [\"28591581\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not define how PI3K signaling biochemically alters XPO6 activity\", \"Single cell-type model (mammary epithelium)\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified RASSF1A as a required cofactor for XPO6\\u2013RAN engagement, explaining how nuclear actin export is licensed and linking its loss to MRTF-A/SRF deregulation and adhesion defects in cancer.\",\n      \"evidence\": \"Endogenous reciprocal Co-IP of RASSF1A\\u2013XPO6\\u2013RAN, fractionation/IF, knockdown with MRTF-A reporter and adhesion assays\",\n      \"pmids\": [\"31414556\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of how RASSF1A promotes XPO6\\u2013RAN binding not resolved\", \"Whether RASSF1A regulates profilin-1 export equally is untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended the regulatory model by implicating the Hippo kinase MST2 in controlling XPO6\\u2013RAN association alongside RASSF1A.\",\n      \"evidence\": \"Commentary inferring from primary data of PMID:31414556\",\n      \"pmids\": [\"31528703\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Commentary with no independent experimental data\", \"MST2's direct biochemical contribution to XPO6\\u2013RAN binding undefined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed a non-canonical cargo by showing XPO6 is required for nuclear release of HSV-1 glycoprotein M, expanding its role beyond actin/profilin to viral protein egress.\",\n      \"evidence\": \"BioID proximity proteomics for gM partners plus siRNA validation and IF localization tracking\",\n      \"pmids\": [\"32817212\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct XPO6\\u2013gM binding and RAN-dependence not demonstrated\", \"Single lab; novel cargo not independently replicated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided the transcriptional consequence of profilin-1 export: nuclear profilin-1 retained upon XPO6 loss binds SEC component ENL and suppresses SEC-driven oncogenic transcription including MYC.\",\n      \"evidence\": \"XPO6 KD/overexpression in breast cancer cells, profilin-1/ENL Co-IP, reporter, ChIP-seq, rescue\",\n      \"pmids\": [\"33596420\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether nuclear actin and nuclear profilin-1 act independently on SEC not separated\", \"Stoichiometry of profilin-1\\u2013ENL inhibition unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected XPO6-controlled nuclear actin levels to NF-\\u03baB stability, showing actin export opposes cAMP-induced proteasomal degradation of RelA/p65.\",\n      \"evidence\": \"XPO6 overexpression in forskolin-stimulated cells, NF-\\u03baB reporter, RelA/p65 half-life, MG132 rescue, ubiquitin pull-down\",\n      \"pmids\": [\"35563720\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"XPO6 used as a tool to lower nuclear actin rather than primary subject\", \"Mechanism linking nuclear actin to RelA/p65 ubiquitination not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Reported that XPO6 promotes YAP1 expression and nuclear translocation to drive prostate cancer proliferation, migration and drug resistance.\",\n      \"evidence\": \"XPO6 KD/overexpression in PCa lines, YAP1 translocation assays, YAP1 inhibitor rescue, xenografts\",\n      \"pmids\": [\"37243787\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Mechanistic link between an exportin and YAP1 nuclear import not biochemically explained\", \"Single-lab, single approach for translocation\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated a non-canonical mRNA-export role, with XPO6 facilitating nuclear export of TLR2 mRNA to amplify MyD88/NF-\\u03baB inflammatory signaling in COPD monocytes.\",\n      \"evidence\": \"XPO6 KD/overexpression, TLR2 mRNA nuclear export assay, cytokine ELISA, NF-\\u03baB reporter in mouse model and human samples\",\n      \"pmids\": [\"38788453\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct XPO6\\u2013TLR2 mRNA association mechanism not shown\", \"mRNA export is non-canonical for XPO6 and not independently confirmed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed XPO6 under post-transcriptional control by miR-3613-5p, with its downregulation promoting lung cancer aggressiveness.\",\n      \"evidence\": \"Dual-luciferase 3\\u2032UTR reporter, qRT-PCR, CCK-8, Transwell, rescue experiments\",\n      \"pmids\": [\"41379264\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Provides no insight into XPO6 protein function beyond being a downstream effector\", \"Single-lab validation\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How XPO6 distinguishes and engages its diverse cargoes (actin, profilin-1, viral gM, specific mRNAs) at the structural and RAN-dependent level remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of XPO6\\u2013cargo recognition\", \"Whether non-canonical cargoes share the RAN-dependent mechanism is untested\", \"Cargo-selection determinants unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RAN\", \"RASSF1A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}