{"gene":"NUP88","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1997,"finding":"Nup88 is a novel nuclear pore complex (NPC) component that localizes to the NPC dependent on CAN/Nup214 binding; depletion of CAN from the NPC results in concomitant loss of Nup88, establishing that CAN is required for Nup88 NPC localization. Human CRM1 (hCRM1) was identified as part of a dynamic subcomplex with CAN/Nup214 and Nup88.","method":"Co-immunoprecipitation, immunofluorescence, depletion experiments in CAN-/- mouse embryos","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP and genetic depletion (CAN-/- embryos), replicated with multiple orthogonal methods in a focused study","pmids":["9049309"],"is_preprint":false},{"year":2004,"finding":"Nup88 localizes midway between Nup358 and Nup214 on the cytoplasmic face of the NPC, physically interacts with both Nup358 and Nup214, and mediates the attachment of Nup358 to the NPC. RNAi knockdown of Nup88 or Nup214 caused strong reduction of Nup358 at the nuclear envelope, while Nup88 and Nup214 showed mutual interdependence but were not affected by absence of Nup358.","method":"RNA interference, co-immunoprecipitation, immunofluorescence localization","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNAi knockdown with defined phenotypic readout plus reciprocal co-IP, multiple orthogonal methods in a single focused study","pmids":["14993277"],"is_preprint":false},{"year":2006,"finding":"The Nup214-Nup88 subcomplex is specifically required for CRM1-mediated nuclear export of the 60S preribosomal subunit (via NMD3 adaptor), whereas depletion had only minor effects on other CRM1 cargoes. The coiled-coil region of Nup214 (coinciding with Nup88 recruitment to the NPC) is sufficient to rescue the 60S export defect, while the large FG domain of Nup214 is dispensable for this function.","method":"RNA interference, rescue experiments with Nup214 deletion mutants, nuclear export assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNAi depletion with specific phenotypic readout, structure-function rescue using deletion mutants, multiple orthogonal methods","pmids":["16675447"],"is_preprint":false},{"year":2011,"finding":"Nup88 binds lamin A in vitro and in vivo; the interaction is mediated by the N-terminus of Nup88 and the tail domain of lamin A (but not lamins B1 or B2). Laminopathy-associated mutants of lamin A disrupt this interaction in vitro, and immunoelectron microscopy of Xenopus oocyte nuclei revealed that Nup88 localizes to both the cytoplasmic and nuclear faces of the NPC.","method":"In vitro binding assay, co-immunoprecipitation, immunofluorescence (epitope masking assay), immunoelectron microscopy in Xenopus oocytes","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro binding assay plus co-IP plus IEM localization, single lab but multiple orthogonal methods with mutagenesis (laminopathy mutants)","pmids":["21289091"],"is_preprint":false},{"year":2008,"finding":"Nup88 is upregulated by hypertonic/osmotic stress in kidney inner medullary collecting duct (IMCD3) cells, and silencing Nup88 reduces nuclear retention of the transcription factor TonEBP under hypertonic conditions, blunting transcription of osmoprotective genes and reducing cell viability. Under isotonic conditions, TonEBP nuclear export is CRM1-dependent, but under hypertonic stress it is CRM1-independent.","method":"Antibody microarray, Western blot, qPCR, RNAi knockdown with GFP-TonEBP nuclear export reporter assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi knockdown with specific transcriptional readout and live-cell reporter, single lab with multiple methods","pmids":["18606815"],"is_preprint":false},{"year":2016,"finding":"NUP88 overexpression does not alter global nuclear transport but sequesters NUP98-RAE1 away from APC/C-CDH1, triggering premitotic proteolysis of PLK1 (polo-like kinase 1). This premitotic PLK1 destruction disrupts centrosome separation, causes mitotic spindle asymmetry, merotelic microtubule-kinetochore attachments, lagging chromosomes, and aneuploidy. Transgenic mice overexpressing NUP88 are cancer-prone and develop intestinal tumors.","method":"Transgenic mouse model (doxycycline-inducible), co-immunoprecipitation (NUP88-NUP98-RAE1 complex), APC/C activity assays, PLK1 proteolysis assays, live-cell imaging of mitosis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo transgenic model combined with biochemical co-IP of the NUP88-NUP98-RAE1-APC/C axis and multiple functional readouts (PLK1 levels, centrosome separation, aneuploidy)","pmids":["26731471"],"is_preprint":false},{"year":2016,"finding":"NUP88 interacts with MISP (mitotic interactor and substrate of PLK1), and NUP88 overexpression blocks MISP phosphorylation, which is required for normal spindle formation and accurate chromosome segregation during mitosis.","method":"Proteomic interaction screen (subcellular fractionation-based), co-immunoprecipitation, phosphorylation assays","journal":"Genes, chromosomes & cancer","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, co-IP plus phosphorylation readout, limited mechanistic follow-up in abstract","pmids":["27636375"],"is_preprint":false},{"year":2018,"finding":"Biallelic loss-of-function mutations in NUP88 cause lethal fetal akinesia deformation sequence (FADS) in humans. In zebrafish, genetic disruption of nup88 results in locomotor defects and defects at neuromuscular junctions; these phenotypes are rescued by wild-type Nup88 but not by disease-linked mutant forms. NUP88 depletion (in human and mouse cell lines and fetal muscle tissue) reduces levels of rapsyn, a key regulator of the nicotinic acetylcholine receptor at the neuromuscular junction.","method":"Human genetics (biallelic mutations), zebrafish nup88 knockout, rescue experiments (wild-type vs. disease mutants), immunohistochemistry and Western blot for rapsyn in cell lines and fetal tissue","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic disease causation plus zebrafish KO with rescue, mechanistic link to rapsyn via depletion in multiple cell/tissue systems","pmids":["30543681"],"is_preprint":false},{"year":2019,"finding":"Nup88 and Nup214 negatively regulate Notch signaling by promoting nuclear export of RBP-J (the DNA-binding component of the Notch pathway); loss of Nup88/214 inhibits nuclear export of RBP-J, increasing its binding to cognate promoter regions and amplifying downstream Notch target gene expression. This regulation was demonstrated in vitro and in vivo in zebrafish.","method":"Reporter gene assays, immunocytochemistry, ChIP-qPCR, zebrafish in vivo experiments, RNAi knockdown of Nup88/214","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (reporter assay, ChIP-qPCR, in vivo zebrafish), single lab","pmids":["31186352"],"is_preprint":false},{"year":2023,"finding":"Nup88 and Nup62 form a strong interaction independent of Nup O-glycosylation status and cell cycle stage; Nup62 interaction stabilizes overexpressed Nup88 by inhibiting its proteasome-mediated degradation. Stabilized overexpressed Nup88 interacts with NF-κB p65 and sequesters p65 partly into the nucleus of unstimulated cells, leading to induction of NF-κB target genes (Akt, c-Myc, IL-6, BIRC3).","method":"Co-immunoprecipitation, proteasome inhibitor assays, knockdown/overexpression with NF-κB target gene expression readouts (qPCR/Western blot), immunofluorescence","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — co-IP plus proteasome assay plus functional NF-κB target readouts, single lab with multiple methods","pmids":["36845732"],"is_preprint":false},{"year":2021,"finding":"Overexpression of Nup88 in HeLa cells promotes cell migration and invasion, and knockdown suppresses these phenotypes. The invasive phenotype is not mediated by EMT or NF-κB activation, but instead by upregulation of matrix metalloproteinase-12 (MMP-12) at the gene and protein level; a selective MMP-12 inhibitor suppressed the invasive ability induced by Nup88 overexpression.","method":"Nup88 overexpression and RNAi knockdown in HeLa and other cancer cell lines, migration/invasion assays, MMP-12 mRNA/protein quantification, MMP-12 inhibitor treatment","journal":"Histochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss- and gain-of-function with specific pathway exclusion (EMT, NF-κB negative) and pharmacological inhibitor confirmation, single lab","pmids":["34331103"],"is_preprint":false},{"year":2015,"finding":"Flightless I (FLII) physically interacts with Nup88 (and Importin β), with the LRR domain of FLII mediating these interactions, as demonstrated by GST pulldown and co-immunoprecipitation.","method":"GST pulldown, co-immunoprecipitation","journal":"Sheng wu gong cheng xue bao (Chinese journal of biotechnology)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single Co-IP/pulldown method, limited functional follow-up described in abstract","pmids":["26762046"],"is_preprint":false}],"current_model":"NUP88 is a cytoplasmic-face nuclear pore complex component that requires CAN/Nup214 for its NPC localization, forms a Nup214-Nup88 subcomplex essential for CRM1-mediated 60S preribosomal export and RBP-J nuclear export (suppressing Notch signaling), mediates attachment of Nup358 to the NPC, binds lamin A through its N-terminus on the nuclear face, retains TonEBP in the nucleus under osmotic stress, and when overexpressed sequesters the NUP98-RAE1 complex away from APC/C-CDH1 causing premitotic PLK1 degradation, aneuploidy, and tumorigenesis; loss-of-function mutations in NUP88 cause fetal akinesia deformation sequence linked to impaired rapsyn levels at neuromuscular junctions."},"narrative":{"mechanistic_narrative":"NUP88 is a cytoplasmic-face nuclear pore complex (NPC) component whose own incorporation into the pore depends on CAN/Nup214, with which it forms a constitutive subcomplex [PMID:9049309]. Positioned midway between Nup358 and Nup214, NUP88 physically bridges these nucleoporins and is required to anchor Nup358 to the nuclear envelope, while NUP88 and Nup214 show mutual interdependence for their own NPC localization [PMID:14993277]. The Nup214–NUP88 subcomplex provides a docking platform for CRM1-mediated nuclear export, being specifically required for export of the 60S preribosomal subunit via the NMD3 adaptor [PMID:9049309, PMID:16675447]; this export function extends to regulatory cargoes, as NUP88/Nup214 promote nuclear export of the Notch effector RBP-J to restrain Notch target-gene expression [PMID:31186352] and contribute to nuclear retention of the osmoprotective transcription factor TonEBP under hypertonic stress [PMID:18606815]. Beyond the cytoplasmic face, NUP88 also localizes to the nuclear side of the pore and binds the tail domain of lamin A through its N-terminus, an interaction disrupted by laminopathy-associated lamin A mutants [PMID:21289091]. When overexpressed, NUP88 acquires oncogenic activity by sequestering the NUP98–RAE1 complex away from APC/C-CDH1, driving premitotic proteolysis of PLK1, spindle defects, aneuploidy, and tumor formation in mice [PMID:26731471], and it additionally promotes cancer-cell migration and invasion through MMP-12 upregulation [PMID:34331103]. Biallelic loss-of-function mutations in NUP88 cause lethal fetal akinesia deformation sequence, mechanistically linked to reduced levels of rapsyn at the neuromuscular junction [PMID:30543681].","teleology":[{"year":1997,"claim":"Established NUP88 as a bona fide NPC component and defined the hierarchy of its assembly, answering how NUP88 is targeted to the pore.","evidence":"Co-IP, immunofluorescence, and depletion in CAN-/- mouse embryos showing CAN/Nup214-dependent NUP88 localization and a dynamic hCRM1-containing subcomplex","pmids":["9049309"],"confidence":"High","gaps":["Did not resolve the structural basis of the Nup214–NUP88 interaction","Functional role of the CRM1 association not yet defined"]},{"year":2004,"claim":"Defined NUP88's spatial position and connectivity on the cytoplasmic face, showing it bridges Nup214 and Nup358 and is required to anchor Nup358.","evidence":"RNAi knockdown with NE localization readout plus reciprocal co-IP in human cells","pmids":["14993277"],"confidence":"High","gaps":["Stoichiometry of the Nup358–NUP88–Nup214 assembly not determined","Whether anchoring is direct or requires additional factors unresolved"]},{"year":2006,"claim":"Assigned a specific transport function to the Nup214–NUP88 subcomplex, identifying it as the CRM1 platform for 60S preribosomal export rather than a general export factor.","evidence":"RNAi depletion with export assays and structure-function rescue using Nup214 deletion mutants","pmids":["16675447"],"confidence":"High","gaps":["NUP88's own direct contribution versus that of Nup214 not separated","Generality across other ribosomal export cargoes not fully mapped"]},{"year":2008,"claim":"Linked NUP88 to stress-responsive transcription by showing it retains TonEBP in the nucleus under hypertonic conditions, extending its export role to a regulatory transcription factor.","evidence":"Antibody microarray, RNAi knockdown, and GFP-TonEBP nuclear export reporter in IMCD3 cells","pmids":["18606815"],"confidence":"Medium","gaps":["Mechanism of CRM1-independent TonEBP export under stress not defined","Direct NUP88–TonEBP interaction not shown"]},{"year":2011,"claim":"Revealed a nuclear-face function for NUP88 by demonstrating a lamin A interaction with disease relevance, expanding its localization beyond the cytoplasmic face.","evidence":"In vitro binding, co-IP, epitope-masking IF, and IEM in Xenopus oocytes with laminopathy mutant testing","pmids":["21289091"],"confidence":"High","gaps":["Functional consequence of the NUP88–lamin A interaction not established","Relationship to laminopathy pathology not tested in vivo"]},{"year":2016,"claim":"Uncovered an oncogenic gain-of-function: overexpressed NUP88 sequesters NUP98-RAE1 from APC/C-CDH1 to trigger premitotic PLK1 degradation, aneuploidy, and tumors.","evidence":"Doxycycline-inducible transgenic mice, co-IP of the NUP88-NUP98-RAE1-APC/C axis, PLK1 proteolysis and mitosis imaging","pmids":["26731471"],"confidence":"High","gaps":["Whether endogenous NUP88 levels modulate APC/C in normal cells unclear","Threshold of overexpression for the phenotype not quantified"]},{"year":2016,"claim":"Connected NUP88 overexpression to a mitotic substrate by showing it interacts with MISP and blocks its PLK1-dependent phosphorylation.","evidence":"Proteomic interaction screen, co-IP, and phosphorylation assays","pmids":["27636375"],"confidence":"Medium","gaps":["Direct versus PLK1-mediated effect on MISP phosphorylation not separated","Limited mechanistic follow-up beyond interaction"]},{"year":2018,"claim":"Established NUP88 as a Mendelian disease gene, defining biallelic loss-of-function as the cause of fetal akinesia deformation sequence via reduced rapsyn at neuromuscular junctions.","evidence":"Human genetics, zebrafish nup88 knockout with wild-type vs mutant rescue, and rapsyn quantification in cell and fetal tissue","pmids":["30543681"],"confidence":"High","gaps":["Mechanism linking NUP88 to rapsyn levels not defined","Whether the defect reflects transport or non-transport function unresolved"]},{"year":2019,"claim":"Extended NUP88's export role to signaling control, showing NUP88/Nup214 export RBP-J to negatively regulate Notch target-gene expression.","evidence":"Reporter assays, ChIP-qPCR, immunocytochemistry, and in vivo zebrafish with Nup88/214 RNAi","pmids":["31186352"],"confidence":"Medium","gaps":["Direct RBP-J–NUP88 contact not demonstrated","Dependence on CRM1 for RBP-J export not established"]},{"year":2021,"claim":"Defined a pro-invasive activity of NUP88 distinct from its mitotic role, acting through MMP-12 upregulation rather than EMT or NF-κB.","evidence":"Gain- and loss-of-function in HeLa/cancer lines, invasion assays, MMP-12 quantification, and MMP-12 inhibitor rescue","pmids":["34331103"],"confidence":"Medium","gaps":["Transcriptional mechanism of MMP-12 induction unknown","Relationship to the APC/C-PLK1 oncogenic pathway not addressed"]},{"year":2023,"claim":"Identified Nup62 as a stabilizing partner that protects overexpressed NUP88 from proteasomal degradation, enabling NUP88-driven nuclear sequestration of NF-κB p65 and target-gene induction.","evidence":"Co-IP, proteasome inhibitor assays, and NF-κB target gene readouts with IF","pmids":["36845732"],"confidence":"Medium","gaps":["Apparent tension with prior finding that NUP88 invasion is NF-κB-independent not reconciled","Single-lab characterization of the p65 mechanism"]},{"year":null,"claim":"How NUP88's distinct activities — cytoplasmic-face export scaffolding versus overexpression-driven mitotic and signaling oncogenicity — are mechanistically partitioned, and how loss-of-function specifically depletes rapsyn at neuromuscular junctions, remain open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the Nup214–NUP88 subcomplex with CRM1","Mechanism linking NUP88 loss to rapsyn reduction undefined","Reconciliation of NF-κB-dependent and -independent oncogenic models needed"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,2,5]}],"localization":[{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[0,1,3]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3,9]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,2,8]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[5,6]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[2]}],"complexes":["Nup214-Nup88 subcomplex","cytoplasmic-face nuclear pore complex"],"partners":["NUP214","RANBP2","XPO1","LMNA","RAE1","NUP98","MISP","NUP62"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q99567","full_name":"Nuclear pore complex protein Nup88","aliases":["88 kDa nucleoporin","Nucleoporin Nup88"],"length_aa":741,"mass_kda":83.5,"function":"Component of nuclear pore complex","subcellular_location":"Nucleus, nuclear pore complex","url":"https://www.uniprot.org/uniprotkb/Q99567/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/NUP88","classification":"Common Essential","n_dependent_lines":1192,"n_total_lines":1208,"dependency_fraction":0.9867549668874173},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"NUP214","stoichiometry":10.0},{"gene":"DNAJC24","stoichiometry":0.2},{"gene":"FDPS","stoichiometry":0.2},{"gene":"NUMA1","stoichiometry":0.2},{"gene":"NUTF2","stoichiometry":0.2},{"gene":"PMVK","stoichiometry":0.2},{"gene":"RAN","stoichiometry":0.2},{"gene":"RANBP1","stoichiometry":0.2},{"gene":"XPO1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NUP88","total_profiled":1310},"omim":[{"mim_id":"618426","title":"ENCEPHALOPATHY, ACUTE, INFECTION-INDUCED, SUSCEPTIBILITY TO, 9; IIAE9","url":"https://www.omim.org/entry/618426"},{"mim_id":"618393","title":"FETAL AKINESIA DEFORMATION SEQUENCE 4; FADS4","url":"https://www.omim.org/entry/618393"},{"mim_id":"611729","title":"KINESIN LIGHT CHAIN 2; KLC2","url":"https://www.omim.org/entry/611729"},{"mim_id":"602559","title":"EXPORTIN 1; XPO1","url":"https://www.omim.org/entry/602559"},{"mim_id":"602552","title":"NUCLEOPORIN, 88-KD; NUP88","url":"https://www.omim.org/entry/602552"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NUP88"},"hgnc":{"alias_symbol":["MGC8530"],"prev_symbol":[]},"alphafold":{"accession":"Q99567","domains":[{"cath_id":"-","chopping":"12-33_55-197","consensus_level":"medium","plddt":87.0199,"start":12,"end":197},{"cath_id":"-","chopping":"233-343_360-371","consensus_level":"medium","plddt":85.9322,"start":233,"end":371},{"cath_id":"-","chopping":"389-432_439-488_546-557","consensus_level":"medium","plddt":84.7964,"start":389,"end":557}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99567","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q99567-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q99567-F1-predicted_aligned_error_v6.png","plddt_mean":79.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NUP88","jax_strain_url":"https://www.jax.org/strain/search?query=NUP88"},"sequence":{"accession":"Q99567","fasta_url":"https://rest.uniprot.org/uniprotkb/Q99567.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q99567/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q99567"}},"corpus_meta":[{"pmid":"9049309","id":"PMC_9049309","title":"The human homologue of yeast CRM1 is in a dynamic subcomplex with CAN/Nup214 and a novel nuclear pore component Nup88.","date":"1997","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/9049309","citation_count":411,"is_preprint":false},{"pmid":"14993277","id":"PMC_14993277","title":"Nup358/RanBP2 attaches to the nuclear pore complex via association with Nup88 and Nup214/CAN and plays a supporting role in CRM1-mediated nuclear protein export.","date":"2004","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/14993277","citation_count":141,"is_preprint":false},{"pmid":"14999780","id":"PMC_14999780","title":"Nup88 mRNA overexpression is associated with high aggressiveness of breast cancer.","date":"2004","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/14999780","citation_count":81,"is_preprint":false},{"pmid":"16675447","id":"PMC_16675447","title":"Nup214-Nup88 nucleoporin subcomplex is required for CRM1-mediated 60 S preribosomal nuclear export.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16675447","citation_count":74,"is_preprint":false},{"pmid":"10554006","id":"PMC_10554006","title":"The nuclear pore complex protein Nup88 is overexpressed in tumor cells.","date":"1999","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/10554006","citation_count":72,"is_preprint":false},{"pmid":"21289091","id":"PMC_21289091","title":"The nucleoporin Nup88 is interacting with nuclear lamin A.","date":"2011","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/21289091","citation_count":38,"is_preprint":false},{"pmid":"12063548","id":"PMC_12063548","title":"Expression of p16, p27, p53, p73 and Nup88 proteins in matched primary and metastatic melanoma cells.","date":"2002","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/12063548","citation_count":37,"is_preprint":false},{"pmid":"12759533","id":"PMC_12759533","title":"Clinicopathological significance of Nup88 expression in patients with colorectal cancer.","date":"2003","source":"Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/12759533","citation_count":34,"is_preprint":false},{"pmid":"26731471","id":"PMC_26731471","title":"Nuclear pore protein NUP88 activates anaphase-promoting complex to promote aneuploidy.","date":"2016","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/26731471","citation_count":33,"is_preprint":false},{"pmid":"30543681","id":"PMC_30543681","title":"Biallelic mutations in nucleoporin NUP88 cause lethal fetal akinesia deformation sequence.","date":"2018","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30543681","citation_count":28,"is_preprint":false},{"pmid":"17264541","id":"PMC_17264541","title":"Nup88 expression in normal mucosa, adenoma, primary adenocarcinoma and lymph node metastasis in the colorectum.","date":"2007","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/17264541","citation_count":25,"is_preprint":false},{"pmid":"21327081","id":"PMC_21327081","title":"Nucleoporin MOS7/Nup88 contributes to plant immunity and nuclear accumulation of defense regulators.","date":"2010","source":"Nucleus (Austin, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/21327081","citation_count":22,"is_preprint":false},{"pmid":"21863385","id":"PMC_21863385","title":"Increased serum level of Nup88 protein is associated with the development of colorectal cancer.","date":"2011","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/21863385","citation_count":18,"is_preprint":false},{"pmid":"36845732","id":"PMC_36845732","title":"Overexpressed Nup88 stabilized through interaction with Nup62 promotes NF-κB dependent pathways in cancer.","date":"2023","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36845732","citation_count":17,"is_preprint":false},{"pmid":"18606815","id":"PMC_18606815","title":"Nucleoporin 88 (Nup88) is regulated by hypertonic stress in kidney cells to retain the transcription factor tonicity enhancer-binding protein (TonEBP) in the nucleus.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18606815","citation_count":16,"is_preprint":false},{"pmid":"20973273","id":"PMC_20973273","title":"Nup88 expression is associated with myometrial invasion in endometrial carcinoma.","date":"2010","source":"International journal of gynecological cancer : official journal of the International Gynecological Cancer Society","url":"https://pubmed.ncbi.nlm.nih.gov/20973273","citation_count":13,"is_preprint":false},{"pmid":"16174445","id":"PMC_16174445","title":"Deguelin regulates nuclear pore complex proteins Nup98 and Nup88 in U937 cells in vitro.","date":"2005","source":"Acta pharmacologica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/16174445","citation_count":13,"is_preprint":false},{"pmid":"34331103","id":"PMC_34331103","title":"Overexpression of the nucleoporin Nup88 stimulates migration and invasion of HeLa cells.","date":"2021","source":"Histochemistry and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/34331103","citation_count":10,"is_preprint":false},{"pmid":"31186352","id":"PMC_31186352","title":"The nuclear pore proteins Nup88/214 and T-cell acute lymphatic leukemia-associated NUP214 fusion proteins regulate Notch signaling.","date":"2019","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31186352","citation_count":8,"is_preprint":false},{"pmid":"15300515","id":"PMC_15300515","title":"Developing chick embryos express a protein which shares homology with the nuclear pore complex protein Nup88 present in human tumors.","date":"2004","source":"The International journal of developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/15300515","citation_count":8,"is_preprint":false},{"pmid":"27636375","id":"PMC_27636375","title":"Multiple biological processes may be associated with tumorigenesis under NUP88-overexpressed condition.","date":"2016","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/27636375","citation_count":7,"is_preprint":false},{"pmid":"21896994","id":"PMC_21896994","title":"Nup88 mRNA overexpression in colorectal cancers and relationship with p53.","date":"2010","source":"Cancer biomarkers : section A of Disease markers","url":"https://pubmed.ncbi.nlm.nih.gov/21896994","citation_count":6,"is_preprint":false},{"pmid":"18175937","id":"PMC_18175937","title":"Deguelin represses both the expression of nucleophosmin and some nucleoporins: Nup88 and Nup214 in Jurkat cells.","date":"2008","source":"Biological & pharmaceutical bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/18175937","citation_count":6,"is_preprint":false},{"pmid":"17828493","id":"PMC_17828493","title":"Effects of gambogic acid on the regulation of nucleoporin Nup88 in U937 cells.","date":"2007","source":"Journal of Huazhong University of Science and Technology. Medical sciences = Hua zhong ke ji da xue xue bao. Yi xue Ying De wen ban = Huazhong keji daxue xuebao. Yixue Yingdewen ban","url":"https://pubmed.ncbi.nlm.nih.gov/17828493","citation_count":5,"is_preprint":false},{"pmid":"19062711","id":"PMC_19062711","title":"[Effects of gambogic acid on the regulation of nucleoporin Nup88 in HL-60 cells].","date":"2008","source":"Zhonghua zhong liu za zhi [Chinese journal of oncology]","url":"https://pubmed.ncbi.nlm.nih.gov/19062711","citation_count":4,"is_preprint":false},{"pmid":"26839161","id":"PMC_26839161","title":"Can Nup88 expression be associated with atypical endometrial hyperplasia and endometrial cancer? A preliminary study.","date":"2016","source":"Pathology, research and practice","url":"https://pubmed.ncbi.nlm.nih.gov/26839161","citation_count":3,"is_preprint":false},{"pmid":"17650673","id":"PMC_17650673","title":"[Deguelin regulates cell cycle and nuclear pore complex protein Nup98 and Nup88 in U937 cells in vitro].","date":"2007","source":"Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi","url":"https://pubmed.ncbi.nlm.nih.gov/17650673","citation_count":3,"is_preprint":false},{"pmid":"26762046","id":"PMC_26762046","title":"[Interaction of Flightless I with Nup88 and Importin β].","date":"2015","source":"Sheng wu gong cheng xue bao = Chinese journal of biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/26762046","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15577,"output_tokens":3421,"usd":0.049023,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10871,"output_tokens":3809,"usd":0.07479,"stage2_stop_reason":"end_turn"},"total_usd":0.123813,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"Nup88 is a novel nuclear pore complex (NPC) component that localizes to the NPC dependent on CAN/Nup214 binding; depletion of CAN from the NPC results in concomitant loss of Nup88, establishing that CAN is required for Nup88 NPC localization. Human CRM1 (hCRM1) was identified as part of a dynamic subcomplex with CAN/Nup214 and Nup88.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, depletion experiments in CAN-/- mouse embryos\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP and genetic depletion (CAN-/- embryos), replicated with multiple orthogonal methods in a focused study\",\n      \"pmids\": [\"9049309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Nup88 localizes midway between Nup358 and Nup214 on the cytoplasmic face of the NPC, physically interacts with both Nup358 and Nup214, and mediates the attachment of Nup358 to the NPC. RNAi knockdown of Nup88 or Nup214 caused strong reduction of Nup358 at the nuclear envelope, while Nup88 and Nup214 showed mutual interdependence but were not affected by absence of Nup358.\",\n      \"method\": \"RNA interference, co-immunoprecipitation, immunofluorescence localization\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNAi knockdown with defined phenotypic readout plus reciprocal co-IP, multiple orthogonal methods in a single focused study\",\n      \"pmids\": [\"14993277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The Nup214-Nup88 subcomplex is specifically required for CRM1-mediated nuclear export of the 60S preribosomal subunit (via NMD3 adaptor), whereas depletion had only minor effects on other CRM1 cargoes. The coiled-coil region of Nup214 (coinciding with Nup88 recruitment to the NPC) is sufficient to rescue the 60S export defect, while the large FG domain of Nup214 is dispensable for this function.\",\n      \"method\": \"RNA interference, rescue experiments with Nup214 deletion mutants, nuclear export assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNAi depletion with specific phenotypic readout, structure-function rescue using deletion mutants, multiple orthogonal methods\",\n      \"pmids\": [\"16675447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Nup88 binds lamin A in vitro and in vivo; the interaction is mediated by the N-terminus of Nup88 and the tail domain of lamin A (but not lamins B1 or B2). Laminopathy-associated mutants of lamin A disrupt this interaction in vitro, and immunoelectron microscopy of Xenopus oocyte nuclei revealed that Nup88 localizes to both the cytoplasmic and nuclear faces of the NPC.\",\n      \"method\": \"In vitro binding assay, co-immunoprecipitation, immunofluorescence (epitope masking assay), immunoelectron microscopy in Xenopus oocytes\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro binding assay plus co-IP plus IEM localization, single lab but multiple orthogonal methods with mutagenesis (laminopathy mutants)\",\n      \"pmids\": [\"21289091\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Nup88 is upregulated by hypertonic/osmotic stress in kidney inner medullary collecting duct (IMCD3) cells, and silencing Nup88 reduces nuclear retention of the transcription factor TonEBP under hypertonic conditions, blunting transcription of osmoprotective genes and reducing cell viability. Under isotonic conditions, TonEBP nuclear export is CRM1-dependent, but under hypertonic stress it is CRM1-independent.\",\n      \"method\": \"Antibody microarray, Western blot, qPCR, RNAi knockdown with GFP-TonEBP nuclear export reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi knockdown with specific transcriptional readout and live-cell reporter, single lab with multiple methods\",\n      \"pmids\": [\"18606815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NUP88 overexpression does not alter global nuclear transport but sequesters NUP98-RAE1 away from APC/C-CDH1, triggering premitotic proteolysis of PLK1 (polo-like kinase 1). This premitotic PLK1 destruction disrupts centrosome separation, causes mitotic spindle asymmetry, merotelic microtubule-kinetochore attachments, lagging chromosomes, and aneuploidy. Transgenic mice overexpressing NUP88 are cancer-prone and develop intestinal tumors.\",\n      \"method\": \"Transgenic mouse model (doxycycline-inducible), co-immunoprecipitation (NUP88-NUP98-RAE1 complex), APC/C activity assays, PLK1 proteolysis assays, live-cell imaging of mitosis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo transgenic model combined with biochemical co-IP of the NUP88-NUP98-RAE1-APC/C axis and multiple functional readouts (PLK1 levels, centrosome separation, aneuploidy)\",\n      \"pmids\": [\"26731471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NUP88 interacts with MISP (mitotic interactor and substrate of PLK1), and NUP88 overexpression blocks MISP phosphorylation, which is required for normal spindle formation and accurate chromosome segregation during mitosis.\",\n      \"method\": \"Proteomic interaction screen (subcellular fractionation-based), co-immunoprecipitation, phosphorylation assays\",\n      \"journal\": \"Genes, chromosomes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, co-IP plus phosphorylation readout, limited mechanistic follow-up in abstract\",\n      \"pmids\": [\"27636375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Biallelic loss-of-function mutations in NUP88 cause lethal fetal akinesia deformation sequence (FADS) in humans. In zebrafish, genetic disruption of nup88 results in locomotor defects and defects at neuromuscular junctions; these phenotypes are rescued by wild-type Nup88 but not by disease-linked mutant forms. NUP88 depletion (in human and mouse cell lines and fetal muscle tissue) reduces levels of rapsyn, a key regulator of the nicotinic acetylcholine receptor at the neuromuscular junction.\",\n      \"method\": \"Human genetics (biallelic mutations), zebrafish nup88 knockout, rescue experiments (wild-type vs. disease mutants), immunohistochemistry and Western blot for rapsyn in cell lines and fetal tissue\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic disease causation plus zebrafish KO with rescue, mechanistic link to rapsyn via depletion in multiple cell/tissue systems\",\n      \"pmids\": [\"30543681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Nup88 and Nup214 negatively regulate Notch signaling by promoting nuclear export of RBP-J (the DNA-binding component of the Notch pathway); loss of Nup88/214 inhibits nuclear export of RBP-J, increasing its binding to cognate promoter regions and amplifying downstream Notch target gene expression. This regulation was demonstrated in vitro and in vivo in zebrafish.\",\n      \"method\": \"Reporter gene assays, immunocytochemistry, ChIP-qPCR, zebrafish in vivo experiments, RNAi knockdown of Nup88/214\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (reporter assay, ChIP-qPCR, in vivo zebrafish), single lab\",\n      \"pmids\": [\"31186352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Nup88 and Nup62 form a strong interaction independent of Nup O-glycosylation status and cell cycle stage; Nup62 interaction stabilizes overexpressed Nup88 by inhibiting its proteasome-mediated degradation. Stabilized overexpressed Nup88 interacts with NF-κB p65 and sequesters p65 partly into the nucleus of unstimulated cells, leading to induction of NF-κB target genes (Akt, c-Myc, IL-6, BIRC3).\",\n      \"method\": \"Co-immunoprecipitation, proteasome inhibitor assays, knockdown/overexpression with NF-κB target gene expression readouts (qPCR/Western blot), immunofluorescence\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — co-IP plus proteasome assay plus functional NF-κB target readouts, single lab with multiple methods\",\n      \"pmids\": [\"36845732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Overexpression of Nup88 in HeLa cells promotes cell migration and invasion, and knockdown suppresses these phenotypes. The invasive phenotype is not mediated by EMT or NF-κB activation, but instead by upregulation of matrix metalloproteinase-12 (MMP-12) at the gene and protein level; a selective MMP-12 inhibitor suppressed the invasive ability induced by Nup88 overexpression.\",\n      \"method\": \"Nup88 overexpression and RNAi knockdown in HeLa and other cancer cell lines, migration/invasion assays, MMP-12 mRNA/protein quantification, MMP-12 inhibitor treatment\",\n      \"journal\": \"Histochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss- and gain-of-function with specific pathway exclusion (EMT, NF-κB negative) and pharmacological inhibitor confirmation, single lab\",\n      \"pmids\": [\"34331103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Flightless I (FLII) physically interacts with Nup88 (and Importin β), with the LRR domain of FLII mediating these interactions, as demonstrated by GST pulldown and co-immunoprecipitation.\",\n      \"method\": \"GST pulldown, co-immunoprecipitation\",\n      \"journal\": \"Sheng wu gong cheng xue bao (Chinese journal of biotechnology)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single Co-IP/pulldown method, limited functional follow-up described in abstract\",\n      \"pmids\": [\"26762046\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NUP88 is a cytoplasmic-face nuclear pore complex component that requires CAN/Nup214 for its NPC localization, forms a Nup214-Nup88 subcomplex essential for CRM1-mediated 60S preribosomal export and RBP-J nuclear export (suppressing Notch signaling), mediates attachment of Nup358 to the NPC, binds lamin A through its N-terminus on the nuclear face, retains TonEBP in the nucleus under osmotic stress, and when overexpressed sequesters the NUP98-RAE1 complex away from APC/C-CDH1 causing premitotic PLK1 degradation, aneuploidy, and tumorigenesis; loss-of-function mutations in NUP88 cause fetal akinesia deformation sequence linked to impaired rapsyn levels at neuromuscular junctions.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NUP88 is a cytoplasmic-face nuclear pore complex (NPC) component whose own incorporation into the pore depends on CAN/Nup214, with which it forms a constitutive subcomplex [#0]. Positioned midway between Nup358 and Nup214, NUP88 physically bridges these nucleoporins and is required to anchor Nup358 to the nuclear envelope, while NUP88 and Nup214 show mutual interdependence for their own NPC localization [#1]. The Nup214–NUP88 subcomplex provides a docking platform for CRM1-mediated nuclear export, being specifically required for export of the 60S preribosomal subunit via the NMD3 adaptor [#0, #2]; this export function extends to regulatory cargoes, as NUP88/Nup214 promote nuclear export of the Notch effector RBP-J to restrain Notch target-gene expression [#8] and contribute to nuclear retention of the osmoprotective transcription factor TonEBP under hypertonic stress [#4]. Beyond the cytoplasmic face, NUP88 also localizes to the nuclear side of the pore and binds the tail domain of lamin A through its N-terminus, an interaction disrupted by laminopathy-associated lamin A mutants [#3]. When overexpressed, NUP88 acquires oncogenic activity by sequestering the NUP98–RAE1 complex away from APC/C-CDH1, driving premitotic proteolysis of PLK1, spindle defects, aneuploidy, and tumor formation in mice [#5], and it additionally promotes cancer-cell migration and invasion through MMP-12 upregulation [#10]. Biallelic loss-of-function mutations in NUP88 cause lethal fetal akinesia deformation sequence, mechanistically linked to reduced levels of rapsyn at the neuromuscular junction [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established NUP88 as a bona fide NPC component and defined the hierarchy of its assembly, answering how NUP88 is targeted to the pore.\",\n      \"evidence\": \"Co-IP, immunofluorescence, and depletion in CAN-/- mouse embryos showing CAN/Nup214-dependent NUP88 localization and a dynamic hCRM1-containing subcomplex\",\n      \"pmids\": [\"9049309\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of the Nup214–NUP88 interaction\", \"Functional role of the CRM1 association not yet defined\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined NUP88's spatial position and connectivity on the cytoplasmic face, showing it bridges Nup214 and Nup358 and is required to anchor Nup358.\",\n      \"evidence\": \"RNAi knockdown with NE localization readout plus reciprocal co-IP in human cells\",\n      \"pmids\": [\"14993277\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the Nup358–NUP88–Nup214 assembly not determined\", \"Whether anchoring is direct or requires additional factors unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Assigned a specific transport function to the Nup214–NUP88 subcomplex, identifying it as the CRM1 platform for 60S preribosomal export rather than a general export factor.\",\n      \"evidence\": \"RNAi depletion with export assays and structure-function rescue using Nup214 deletion mutants\",\n      \"pmids\": [\"16675447\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"NUP88's own direct contribution versus that of Nup214 not separated\", \"Generality across other ribosomal export cargoes not fully mapped\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Linked NUP88 to stress-responsive transcription by showing it retains TonEBP in the nucleus under hypertonic conditions, extending its export role to a regulatory transcription factor.\",\n      \"evidence\": \"Antibody microarray, RNAi knockdown, and GFP-TonEBP nuclear export reporter in IMCD3 cells\",\n      \"pmids\": [\"18606815\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of CRM1-independent TonEBP export under stress not defined\", \"Direct NUP88–TonEBP interaction not shown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed a nuclear-face function for NUP88 by demonstrating a lamin A interaction with disease relevance, expanding its localization beyond the cytoplasmic face.\",\n      \"evidence\": \"In vitro binding, co-IP, epitope-masking IF, and IEM in Xenopus oocytes with laminopathy mutant testing\",\n      \"pmids\": [\"21289091\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of the NUP88–lamin A interaction not established\", \"Relationship to laminopathy pathology not tested in vivo\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Uncovered an oncogenic gain-of-function: overexpressed NUP88 sequesters NUP98-RAE1 from APC/C-CDH1 to trigger premitotic PLK1 degradation, aneuploidy, and tumors.\",\n      \"evidence\": \"Doxycycline-inducible transgenic mice, co-IP of the NUP88-NUP98-RAE1-APC/C axis, PLK1 proteolysis and mitosis imaging\",\n      \"pmids\": [\"26731471\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether endogenous NUP88 levels modulate APC/C in normal cells unclear\", \"Threshold of overexpression for the phenotype not quantified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected NUP88 overexpression to a mitotic substrate by showing it interacts with MISP and blocks its PLK1-dependent phosphorylation.\",\n      \"evidence\": \"Proteomic interaction screen, co-IP, and phosphorylation assays\",\n      \"pmids\": [\"27636375\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus PLK1-mediated effect on MISP phosphorylation not separated\", \"Limited mechanistic follow-up beyond interaction\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established NUP88 as a Mendelian disease gene, defining biallelic loss-of-function as the cause of fetal akinesia deformation sequence via reduced rapsyn at neuromuscular junctions.\",\n      \"evidence\": \"Human genetics, zebrafish nup88 knockout with wild-type vs mutant rescue, and rapsyn quantification in cell and fetal tissue\",\n      \"pmids\": [\"30543681\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking NUP88 to rapsyn levels not defined\", \"Whether the defect reflects transport or non-transport function unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended NUP88's export role to signaling control, showing NUP88/Nup214 export RBP-J to negatively regulate Notch target-gene expression.\",\n      \"evidence\": \"Reporter assays, ChIP-qPCR, immunocytochemistry, and in vivo zebrafish with Nup88/214 RNAi\",\n      \"pmids\": [\"31186352\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct RBP-J–NUP88 contact not demonstrated\", \"Dependence on CRM1 for RBP-J export not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a pro-invasive activity of NUP88 distinct from its mitotic role, acting through MMP-12 upregulation rather than EMT or NF-\\u03baB.\",\n      \"evidence\": \"Gain- and loss-of-function in HeLa/cancer lines, invasion assays, MMP-12 quantification, and MMP-12 inhibitor rescue\",\n      \"pmids\": [\"34331103\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcriptional mechanism of MMP-12 induction unknown\", \"Relationship to the APC/C-PLK1 oncogenic pathway not addressed\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified Nup62 as a stabilizing partner that protects overexpressed NUP88 from proteasomal degradation, enabling NUP88-driven nuclear sequestration of NF-\\u03baB p65 and target-gene induction.\",\n      \"evidence\": \"Co-IP, proteasome inhibitor assays, and NF-\\u03baB target gene readouts with IF\",\n      \"pmids\": [\"36845732\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Apparent tension with prior finding that NUP88 invasion is NF-\\u03baB-independent not reconciled\", \"Single-lab characterization of the p65 mechanism\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NUP88's distinct activities — cytoplasmic-face export scaffolding versus overexpression-driven mitotic and signaling oncogenicity — are mechanistically partitioned, and how loss-of-function specifically depletes rapsyn at neuromuscular junctions, remain open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the Nup214–NUP88 subcomplex with CRM1\", \"Mechanism linking NUP88 loss to rapsyn reduction undefined\", \"Reconciliation of NF-\\u03baB-dependent and -independent oncogenic models needed\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 2, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 2, 8]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [\n      \"Nup214-Nup88 subcomplex\",\n      \"cytoplasmic-face nuclear pore complex\"\n    ],\n    \"partners\": [\n      \"NUP214\",\n      \"RANBP2\",\n      \"XPO1\",\n      \"LMNA\",\n      \"RAE1\",\n      \"NUP98\",\n      \"MISP\",\n      \"NUP62\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}