{"gene":"NUP214","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1997,"finding":"CAN/Nup214 forms a dynamic subcomplex at the nuclear pore complex with Nup88 and human CRM1 (hCRM1). Depletion of CAN from the NPC causes concomitant loss of Nup88, indicating Nup88 NPC localization depends on CAN binding. The FG-repeat region of CAN contains the hCRM1-interaction domain; nuclear overexpression of this region depletes hCRM1 from the NPC.","method":"Co-immunoprecipitation, immunofluorescence, CAN knockout mouse embryos, dominant-negative overexpression","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genetic knockout, and dominant-negative overexpression across multiple orthogonal approaches in a single study","pmids":["9049309"],"is_preprint":false},{"year":1996,"finding":"CAN/Nup214 is essential for cell cycle progression and nucleocytoplasmic transport in vivo. CAN-/- mouse embryos arrest in G2 phase upon depletion of maternally derived CAN, accompanied by inhibition of NLS-mediated nuclear protein import and nuclear accumulation of poly(A)+ RNA (mRNA export block). CAN-/- ES cells are not viable.","method":"Genetic knockout (CAN-/- mouse embryos and ES cells), in vitro culture, immunofluorescence for cell cycle markers and NLS-import, in situ hybridization for poly(A)+ RNA","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic knockout with multiple orthogonal phenotypic readouts (cell cycle, protein import, mRNA export), replicated across ES cells and embryos","pmids":["8896451"],"is_preprint":false},{"year":2009,"finding":"DBP5/DDX19 binds NUP214 in a manner mutually exclusive with RNA binding. Crystal structures of human DBP5 bound to RNA/AMPPNP and to NUP214 show overlapping binding surfaces. NUP214 decreases both RNA-binding and ATPase activities of DBP5 in vitro, suggesting NUP214 acts as a negative regulator that resets DBP5 at the cytoplasmic face of the NPC for mRNA release.","method":"Crystal structure determination, in vitro ATPase assay, in vitro RNA-binding assay","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures of both complexes solved, in vitro enzymatic assays confirming mutual exclusivity and inhibition of DBP5 by NUP214","pmids":["19219046"],"is_preprint":false},{"year":2009,"finding":"Crystal structure of the Nup214 N-terminal domain in complex with the DEAD-box helicase Ddx19 (ADP-bound state) at 2.5 Å resolution reveals that interaction surfaces are evolutionarily conserved and have strongly opposing surface potentials (helicase surface positive, Nup214 surface negative), suggesting a ratchet mechanism for mRNP remodeling during nuclear export.","method":"X-ray crystallography","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure at 2.5 Å resolution with identification of conserved functional interface","pmids":["19208808"],"is_preprint":false},{"year":2007,"finding":"Crystal structure of the human Nup214 N-terminal domain at 1.65 Å resolution reveals a seven-bladed β-propeller followed by a 30-residue C-terminal extended peptide that folds back onto the β-propeller bottom face, with a proposed role for the C-terminal peptide extension in NPC assembly.","method":"X-ray crystallography","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structure (1.65 Å) of the N-terminal domain with structural characterization","pmids":["17264208"],"is_preprint":false},{"year":2015,"finding":"Crystal structure of a 117-amino-acid FG-repeat fragment of Nup214 in complex with CRM1, Snurportin1, and RanGTP at 2.85 Å resolution reveals eight binding sites for Nup214 FG motifs on CRM1. Nup214 binds to both N- and C-terminal regions of CRM1, clamping it in a closed conformation and stabilizing the export complex. Conserved hydrophobic pockets on CRM1 are required for FG-motif recognition, validated by biochemical and cell-based assays.","method":"X-ray crystallography, in vitro binding assays, cell-based export assays, mutagenesis of FG motifs","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis and cell-based functional validation in one study","pmids":["26489467"],"is_preprint":false},{"year":2002,"finding":"Smad2 directly interacts with NUP214/CAN and Nup153 to mediate constitutive nucleocytoplasmic shuttling. CAN/Nup214 and Nup153 compete with the cytoplasmic retention factor SARA and the nuclear partner FAST-1 for binding to a hydrophobic corridor on the MH2 surface of Smad2. TGFβ receptor phosphorylation modifies Smad2 affinity for SARA and Smad4 but not for CAN/Nup214 or Nup153.","method":"Co-immunoprecipitation, pulldown assays, shuttling assays, competition binding assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, competition binding, and functional shuttling assays with multiple orthogonal methods","pmids":["12191473"],"is_preprint":false},{"year":2006,"finding":"Depletion of Nup214/Nup88 by RNAi in human cells leads to strongly reduced CRM1-mediated nuclear export of NFAT and HIV-Rev, while nuclear protein import and mRNA export are largely unaffected. A high-affinity complex containing Nup214, CRM1, RanGTP, and export cargo is biochemically characterized, supporting a model where Nup214/Nup88 provides a terminal high-affinity binding site for CRM1 during export.","method":"RNAi depletion, nuclear export assays (shuttling transcription factors, HIV-Rev), biochemical complex reconstitution","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNAi with specific transport readouts plus biochemical complex characterization, multiple orthogonal methods","pmids":["16943420"],"is_preprint":false},{"year":2004,"finding":"Nup88 localizes between Nup358 and Nup214 at the cytoplasmic NPC face and physically interacts with both. RNAi depletion of either Nup88 or Nup214 causes strong reduction of Nup358 at the nuclear envelope, demonstrating that Nup88 and Nup214 mediate the attachment of Nup358 to the NPC. Nup88 and Nup214 are interdependent at the NPC and are not affected by absence of Nup358.","method":"RNAi, immunofluorescence, Co-immunoprecipitation","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNAi knockdown with precise localization readouts plus Co-IP, multiple orthogonal methods confirming interdependence","pmids":["14993277"],"is_preprint":false},{"year":2006,"finding":"Depletion of the Nup214-Nup88 nucleoporin subcomplex by RNAi causes a dramatic defect in CRM1-mediated nuclear export of the 60S preribosomal subunit (via NMD3 adaptor). The coiled-coil region of Nup214 (not the FG-repeat domain) is sufficient for rescuing 60S export, coinciding with recruitment of Nup88. The large FG domain of Nup214 is not accessible to freely diffusing nuclear molecules.","method":"RNAi depletion, fluorescence microscopy export assays, domain-rescue experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNAi with domain-rescue experiments and accessibility assays using multiple orthogonal approaches in one study","pmids":["16675447"],"is_preprint":false},{"year":2001,"finding":"CAN/Nup214 is a docking site for incoming adenovirus type 2 (Ad2) capsids at the NPC. Capsid binding to CAN is independent of cytosolic factors. Capsid disassembly at the NPC requires nuclear histone H1 binding to stably docked capsids, involving H1-import factors, thereby restricting irreversible DNA release to NPC proximity.","method":"Immunofluorescence, biochemical binding assays, histone H1 depletion/addition experiments","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — identification of NPC receptor for virus with mechanistic dissection of capsid disassembly using multiple orthogonal assays","pmids":["11781571"],"is_preprint":false},{"year":2014,"finding":"The N-terminal domain of Nup214 (specifically a 137-amino-acid segment) is the direct NPC binding site for adenovirus hexon protein. RNAi depletion of Nup214 (but not Nup358) strongly reduces hexon binding and nuclear import of viral DNA. Expression of an NPC-targeted N-terminal Nup214 domain in Nup214-depleted cells restores hexon binding and viral genome import.","method":"RNAi depletion, in vitro hexon-binding assay in digitonin-permeabilized cells, domain-rescue experiments, viral infection assay","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNAi depletion with domain-rescue and direct binding assays, multiple orthogonal methods identifying specific region","pmids":["25410864"],"is_preprint":false},{"year":2009,"finding":"Herpes simplex virus type 1 (HSV-1) capsids interact with CAN/Nup214 in infected cells. RNA silencing of CAN/Nup214 delays the onset of viral DNA replication in the nucleus. The minor capsid protein pUL25 directly interacts with CAN/Nup214 and nucleoporin hCG1, identifying CAN/Nup214 as a nuclear receptor for herpesvirus capsids and pUL25 as the interface between incoming capsids and the NPC.","method":"Co-immunoprecipitation, RNAi silencing, viral DNA replication assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and RNAi with functional readout, single lab","pmids":["19386703"],"is_preprint":false},{"year":1999,"finding":"HIV-1 Rev can recruit Nup98 and Nup214 (but not Nup153) to the nucleolus in HeLa cells. The FG-containing repeat domains of Nup98 and Nup214 (but not Nup153) competitively inhibit Rev/RRE-mediated HIV gene expression, demonstrating direct participation of Nup214 in CRM1-mediated Rev nuclear export.","method":"Immunofluorescence (recruitment to nucleolus), competition inhibition assay with isolated FG domains","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-based competition assay and localization data, single lab, two complementary approaches","pmids":["9847314"],"is_preprint":false},{"year":1998,"finding":"Overexpression of CAN/Nup214 in U937 cells causes G0 arrest, nuclear mRNA accumulation, and apoptosis. Overexpression of the C-terminal FG-repeat region alone sequesters hCRM1 in the nucleoplasm (and importin beta/p97 from the NPC), which is sufficient to inhibit cell growth and induce apoptosis, confirming that CAN's FG region interacts with hCRM1 and that this interaction is functionally critical.","method":"Overexpression in myeloid cell lines, flow cytometry (cell cycle), in situ hybridization (mRNA export), immunofluorescence (hCRM1, p97 localization)","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression with multiple phenotypic readouts (cell cycle, mRNA export, protein localization), single lab","pmids":["9488438"],"is_preprint":false},{"year":1997,"finding":"Nup84 (a novel non-glycosylated nucleoporin) is tightly associated with CAN/Nup214 and co-localizes on the cytoplasmic face of the NPC. Mutagenesis shows the coiled-coil C-terminal domain of Nup84 is required for NPC association, while the N-terminal region contains the CAN/Nup214 interaction site. Nup84 may anchor CAN/Nup214 to the central NPC framework.","method":"Co-immunoprecipitation, immunofluorescence/electron microscopy, domain mutagenesis and expression","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with domain mutagenesis and localization, single lab","pmids":["9166401"],"is_preprint":false},{"year":2012,"finding":"Multiple specific phenylalanine-glycine (FG) motifs in the C-terminal repeat region of Nup214 are essential for CRM1 binding. Dominant-negative Nup214 FG fragments inhibit CRM1-dependent nuclear export but do not affect several nuclear import pathways, revealing a specific role for Nup214 FG repeats in export.","method":"Mutagenesis of FG motifs, dominant-negative inhibition assays, nuclear export assays in cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis with functional export assays, single lab","pmids":["23264634"],"is_preprint":false},{"year":2008,"finding":"SET-NUP214 fusion protein binds to promoter regions of specific HOXA genes where it interacts with CRM1 and DOT1L, transcriptionally activating HOXA cluster members. siRNA knockdown of SET-NUP214 abolishes HOXA gene expression, inhibits proliferation, and induces differentiation in LOUCY T-ALL cells.","method":"ChIP, siRNA knockdown, gene expression analysis, Co-immunoprecipitation","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with siRNA knockdown and functional readouts, single lab","pmids":["18299449"],"is_preprint":false},{"year":2008,"finding":"NUP214-ABL1 fusion protein localizes to the nuclear pore complex, and this NPC localization is required for its transforming potential. NUP214-ABL1 has attenuated transforming capacity compared to BCR-ABL1, preferentially transforms T cells, lacks activation loop phosphorylation, and differs from BCR-ABL1 in kinase activity initiation and downstream signaling.","method":"Subcellular localization (immunofluorescence), transformation assays (mouse bone marrow transplant, cell line), domain analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (localization, transformation assays, kinase biochemistry) establishing NPC-dependent oncogenic mechanism","pmids":["18614052"],"is_preprint":false},{"year":2008,"finding":"NUP214-ABL1 has lower in vitro tyrosine kinase activity than BCR-ABL1, lacks activation loop phosphorylation, is more sensitive to imatinib in vitro and in cells, and phosphorylates a different spectrum of substrate peptides. Src kinases (including LCK) are differentially involved in NUP214-ABL1 downstream signaling compared to BCR-ABL1.","method":"In vitro kinase assay, Western blot for phosphorylation, imatinib sensitivity assay, peptide array substrate profiling","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assays with peptide arrays and cell-based assays, single lab, multiple methods","pmids":["18784740"],"is_preprint":false},{"year":2004,"finding":"NUP214-ABL1 fusion is formed by extrachromosomal (episomal) amplification of a 500-kb region of chromosome 9q34 containing ABL1 and NUP214, generating a constitutively phosphorylated tyrosine kinase sensitive to imatinib. The rearrangement is associated with increased HOX expression and CDKN2A deletion.","method":"Molecular analysis (RT-PCR, FISH, cytogenetics), Western blot for constitutive phosphorylation, imatinib sensitivity assay","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — discovery of fusion with constitutive kinase activity confirmed biochemically and pharmacologically, replicated in multiple patient samples and cell lines","pmids":["15361874"],"is_preprint":false},{"year":2016,"finding":"SET-Nup214 and DEK-Nup214 fusion proteins interact with XPO1/CRM1 and NXF1/TAP. They decrease XPO1-mediated nuclear export of NES proteins (cyclin B, NF-κB pathway components) by tethering XPO1 onto nuclear dots where fusion proteins localize, and inhibit NF-κB-mediated transcription by abnormally trapping the p65/IκB complex in the nucleus.","method":"Co-immunoprecipitation, immunofluorescence, nuclear export assays, NF-κB reporter assay","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and functional export/reporter assays, single lab, multiple readouts","pmids":["27114368"],"is_preprint":false},{"year":2016,"finding":"SET-Nup214 forms dynamic nuclear bodies that recruit CRM1, export cargo proteins, and certain nucleoporins, inhibiting both nuclear protein and poly(A)+ RNA export. SQSTM1-Nup214 also forms nuclear bodies and inhibits nuclear protein but NOT poly(A)+ RNA export. The interaction of both fusion proteins with CRM1 is RanGTP-dependent. The Nup214 portion mediates export inhibition while the SET/SQSTM1 portion determines localization and extent of the effect.","method":"Co-immunoprecipitation, fluorescence microscopy (live imaging, FRAP), nuclear export assays, binding assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, live imaging, export assays), single lab","pmids":["27613868"],"is_preprint":false},{"year":2019,"finding":"CRM1 accumulates at HOX cluster chromatin regions and recruits SET-Nup214 and NPM1c to HOX cluster regions, leading to HOX gene activation. CRM1 inhibition disperses this recruitment and suppresses HOX gene expression in leukemia cells. SET-Nup214 recruitment to HOX genes requires nucleoporin-CRM1 interaction.","method":"ChIP-seq, CRM1 inhibitor treatment, siRNA knockdown, gene expression analysis","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq with pharmacologic and genetic perturbation, single lab","pmids":["31755865"],"is_preprint":false},{"year":2013,"finding":"LCK kinase activity is absolutely required for proliferation and survival of NUP214-ABL1-positive T-ALL cells. Mass spectrometry identifies NUP214-ABL1 interaction partners MAD2L1, NUP155, and SMC4 as required for proliferation and survival of NUP214-ABL1-positive cells. The NUP214-ABL1 signaling network is distinct from BCR-ABL1.","method":"Kinase inhibitor assays (LCK inhibitors, dasatinib, bosutinib), siRNA knockdown of interactors, mass spectrometry interactome","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry interactome plus siRNA validation with functional readout, single lab","pmids":["23872305"],"is_preprint":false},{"year":2006,"finding":"In Drosophila, Nup214 binds CRM1 directly and anchors it to the nuclear envelope. In nup214 mutants, CRM1 accumulates in the nucleus and NES-protein export is enhanced. The Nup214-Nup88 complex sequesters CRM1 at the nuclear rim; Nup214 protects Nup88 from degradation while Nup88 is sufficient for targeting the complex to nuclear pores. The NFκB transcription factor Dorsal is a CRM1 substrate requiring Nup214 for nuclear translocation upon signaling.","method":"Genetic mutant analysis (Drosophila nup214 mutants), co-immunoprecipitation, immunofluorescence, overexpression","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic mutants plus Co-IP and localization in Drosophila model, multiple approaches, single lab","pmids":["17032737"],"is_preprint":false},{"year":2007,"finding":"In Drosophila, RNAi inactivation reveals that the FG repeats of Nup153 are necessary for its import function while Nup214 FG region has an antagonistic relationship with RanBP3 in determining CRM1 localization and nuclear protein export. Nup214 FG region and RanBP3 have opposing effects on CRM1 nuclear accumulation and export efficiency.","method":"RNAi in Drosophila S2 cells, nuclear import/export assays","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic RNAi screen with defined transport readouts, single lab, Drosophila ortholog","pmids":["17682050"],"is_preprint":false},{"year":2004,"finding":"Tristetraprolin (TTP) directly associates with the FG-repeat region of Nup214. Full-length Nup214 co-precipitates with TTP from intact cells. The interaction requires two intact zinc fingers of TTP. A TTP mutant unable to bind Nup214 localizes throughout the cell rather than primarily in the cytosol, suggesting the Nup214 interaction regulates TTP localization.","method":"Yeast two-hybrid screen, co-immunoprecipitation from intact THP-1 cells, immunofluorescence","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP with yeast two-hybrid, localization data without full functional follow-up, single lab","pmids":["14766228"],"is_preprint":false},{"year":2019,"finding":"Biallelic pathogenic variants in NUP214 in patients with acute febrile encephalopathy reduce NUP214 and NUP88 protein levels in primary fibroblasts, impair classical protein import and mRNA export, and cause a large increase in 'plugged' (central particle-containing) nuclear pore channels by scanning electron microscopy. Fibroblasts from affected individuals show delayed heat-shock stress response and surge in apoptotic cell death.","method":"Patient-derived fibroblasts, nuclear transport assays, scanning electron microscopy of NPC surface, immunoblotting, apoptosis assay","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (transport assays, direct NPC imaging by SEM, cell biology) establishing functional consequences of NUP214 loss-of-function at molecular and cellular levels","pmids":["31178128"],"is_preprint":false},{"year":2019,"finding":"Nup214 and its partner Nup88 negatively regulate Notch signaling in mammalian cells and in vivo in zebrafish. Loss of Nup88/214 inhibits nuclear export of RBP-J (the DNA-binding component of the Notch pathway), increasing RBP-J binding to cognate promoter regions and enhancing downstream Notch signaling. Nuclear RBP-J levels are rate-limiting for Notch signaling.","method":"Reporter gene assays, immunocytochemistry, ChIP-qPCR, zebrafish in vivo experiments, siRNA knockdown","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assays, ChIP-qPCR, and in vivo zebrafish validation, single lab","pmids":["31186352"],"is_preprint":false},{"year":2021,"finding":"Nup214 contains a classical nuclear export sequence (NES) that mediates Ran-dependent binding to CRM1. Mutations in the NES, or CRM1 inhibition with leptomycin B, cause nuclear accumulation of overexpressed Nup214. The NES function is required for correct cytoplasmic NPC targeting of Nup214 and for co-recruitment of binding partners Nup62 and Nup88 to the correct NPC location.","method":"NES mutagenesis, leptomycin B treatment, immunofluorescence, co-localization of binding partners","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis with localization assays and pharmacological validation, single lab","pmids":["33589493"],"is_preprint":false},{"year":2008,"finding":"DEK-NUP214 expression in myeloid cell lines causes a substantial increase in global protein synthesis via increased translation, not transcription. This is myeloid-lineage specific. DEK-NUP214 expression correlates with phosphorylation of translation initiation factor EIF4E.","method":"Global translation assay (metabolic labeling), Western blot for EIF4E phosphorylation, lineage-specificity testing in myeloid vs. non-myeloid cells","journal":"Genes, chromosomes & cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — translation assay with phosphorylation readout and lineage specificity demonstrated, single lab","pmids":["18181180"],"is_preprint":false},{"year":2013,"finding":"DEK-NUP214 expression in myeloid cell lines increases cellular proliferation through upregulation of mTOR, with elevated mTORC1 (but not mTORC2) activity as measured by p70 S6 kinase phosphorylation. This increases protein synthesis and shifts metabolism toward oxidative phosphorylation. The mTORC1 inhibitor everolimus selectively reverses DEK-NUP214-induced proliferation.","method":"Western blot (mTOR, p70S6K, Akt phosphorylation), global translation assay, metabolic assay (lactate production, glucose consumption), mTOR inhibitor treatment","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical readouts with pharmacological rescue, single lab","pmids":["24073922"],"is_preprint":false},{"year":2009,"finding":"CAN/Nup214 interacts with the vitamin D receptor (VDR) via the carboxy-terminal FG-repeat-containing region of Nup214. Overexpression of full-length Nup214 facilitates VDR-mediated transactivation, while expression of the carboxy-terminal fragment (which competes with full-length Nup214 for VDR binding) suppresses it. The DNA-binding domain of VDR is required for Nup214-facilitated transactivation.","method":"Yeast two-hybrid, co-immunoprecipitation in mammalian cells, transactivation reporter assay, domain deletion mapping","journal":"Journal of cellular biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — yeast two-hybrid with Co-IP and reporter assay, single lab, limited mechanistic depth","pmids":["19229862"],"is_preprint":false},{"year":2015,"finding":"Inhibition of NUP214 expression by miR-133b (validated by luciferase reporter assay) or direct siRNA knockdown elevates mitotic indices, delays degradation of mitotic markers cyclinB1 and cyclinA and H3 dephosphorylation, and causes chromosomal abnormalities and apoptosis, indicating a role for NUP214 in mitotic timing.","method":"miR-133b transfection, siRNA knockdown, luciferase reporter assay, flow cytometry (cell cycle), immunofluorescence (mitotic markers), video microscopy","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — validated miRNA target with siRNA confirmation and multiple mitotic readouts, single lab","pmids":["25743594"],"is_preprint":false},{"year":2020,"finding":"Influenza A NS2/NEP protein interacts with the amino-terminal FG domain of human Nup214 (identified by yeast two-hybrid, confirmed in yeast and mammalian cells). Nup214 knockdown suppresses influenza viral replication, indicating that Nup214 FG-domain interaction with NS2 is functionally important for viral vRNA export.","method":"Yeast two-hybrid, co-immunoprecipitation in mammalian cells, Nup214 knockdown with viral replication assay","journal":"Turkish journal of biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — yeast two-hybrid with Co-IP and knockdown in single lab, limited mechanistic depth","pmids":["32256144"],"is_preprint":false},{"year":2021,"finding":"SET-NUP214 interacts with MLL (Mixed Lineage Leukemia) via the SET acidic region, and SET-NUP214 and MLL cooperatively enhance HoxA10 gene promoter activity. Neither the SET nor the Nup214 region alone is sufficient for this transcriptional enhancement.","method":"Co-immunoprecipitation, luciferase reporter assay for HoxA10 promoter, domain deletion analysis","journal":"Genes to cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with functional reporter assay and domain analysis, single lab","pmids":["34320268"],"is_preprint":false},{"year":2020,"finding":"SQSTM1-NUP214 interaction with CRM1 is mediated by NUP214 FG motifs. Mutation of these FG motifs reduces CRM1 binding by >50% and abolishes leukemogenic transformation in vitro and in vivo (serial replating and mouse transplant). SQSTM1-NUP214 binds Hoxa and Meis1 gene chromatin via CRM1, and impaired CRM1 binding correlates with impaired binding to these gene loci.","method":"FG-motif mutagenesis, co-immunoprecipitation, serial replating assay, mouse bone marrow transplantation, chromatin immunoprecipitation (ChIP)","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — mutagenesis with in vivo mouse model, Co-IP, and ChIP providing multiple orthogonal validations in one study","pmids":["32343715"],"is_preprint":false},{"year":2025,"finding":"DEK::NUP214 co-localizes with XPO1 at chromatin, and XPO1 inhibition (eltanexor) disrupts this co-localization, reduces DEK::NUP214 chromatin binding, and downregulates DEK::NUP214 target genes (FOXC1, HOX genes). DEK::NUP214 directly binds promoters of FOXC1 and HOXA/B clusters (CUT&RUN), and XPO1 inhibition selectively reduces this binding in t(6;9) cells. FKH-1 cells show genetic dependency on XPO1.","method":"XPO1 deletion, pharmacological XPO1 inhibition, CUT&RUN chromatin binding, transcriptomics, patient-derived xenograft model","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic and pharmacological XPO1 perturbation with CUT&RUN, transcriptomics, and in vivo xenograft model, multiple orthogonal methods","pmids":["40148556","40204893"],"is_preprint":false},{"year":2008,"finding":"SET-CAN/NUP214 transgenic expression under Gata1 hematopoietic regulatory control in mice causes anemia, thrombocytopenia, and splenomegaly, with impairment of erythroid, megakaryocytic, and B-cell differentiation. A high population of c-kit+Sca-1+Lin- cells appears in bone marrow, demonstrating that SET-CAN blocks the hematopoietic differentiation program.","method":"Transgenic mouse model, bone marrow analysis (flow cytometry), hematopoietic cell characterization","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic mouse model with defined hematopoietic phenotypic readouts, single lab","pmids":["17620317"],"is_preprint":false},{"year":2018,"finding":"NUP214-ABL1 cooperates with TLX1 to drive T-ALL in a transgenic mouse model. STAT5 (downstream effector of NUP214-ABL1) and TLX1 co-bind poised enhancer regions and cooperatively activate expression of MYC and BCL2. This cooperative enhancer activation is required for leukemogenesis.","method":"Transgenic mouse model, ChIP-seq, ATAC-seq, RNA-seq, pharmacological inhibition (BET inhibitors, STAT5 inhibitors)","journal":"Cancer cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — integrated multi-omics (ChIP-seq, ATAC-seq, RNA-seq) with in vivo transgenic mouse model demonstrating cooperative enhancer mechanism","pmids":["30107177"],"is_preprint":false}],"current_model":"NUP214 is an essential nucleoporin on the cytoplasmic face of the nuclear pore complex that functions as a high-affinity docking platform for the nuclear export receptor CRM1 (via multiple FG-repeat binding sites), directly participates in CRM1-mediated export of proteins (including NES cargoes, 60S preribosomal subunits, Smad2, and RBP-J) and mRNA, recruits and regulates the RNA helicase DDX19/DBP5 for mRNP remodeling (through a mutually exclusive mechanism with RNA binding), anchors Nup88 and Nup358 at the NPC, mediates docking of adenovirus and herpesvirus capsids for viral genome import, and—when fused to oncoproteins SET, DEK, or ABL1 through chromosomal translocations in leukemia—drives transformation through dysregulation of CRM1-dependent export (sequestering CRM1 in nuclear bodies), XPO1-dependent chromatin-bound transcriptional activation of HOX genes, or constitutive nuclear-pore-localized ABL1 tyrosine kinase activation."},"narrative":{"mechanistic_narrative":"NUP214 (CAN) is an essential FG-repeat nucleoporin on the cytoplasmic face of the nuclear pore complex (NPC) whose loss arrests cells in G2 and blocks both NLS-mediated protein import and poly(A)+ mRNA export, rendering it required for viability [PMID:8896451]. Structurally it comprises an N-terminal seven-bladed β-propeller domain [PMID:17264208] and an extended C-terminal FG-repeat region, and it forms an interdependent subcomplex with Nup88 that in turn anchors Nup358 at the NPC [PMID:9049309, PMID:14993277]. Its central function is to provide a terminal, high-affinity docking platform for the export receptor CRM1/XPO1: a structurally defined array of FG motifs engages eight sites on CRM1, clamping it in a closed conformation to stabilize RanGTP-containing export complexes [PMID:26489467, PMID:23264634], and depletion of the Nup214–Nup88 module selectively impairs CRM1-mediated export of NES cargoes, HIV-Rev, and the 60S preribosomal subunit while sparing import [PMID:16943420, PMID:16675447]. At the same cytoplasmic face NUP214 binds the DEAD-box helicase DDX19/DBP5 through its N-terminal domain in a manner mutually exclusive with RNA, inhibiting DBP5 ATPase and RNA-binding activity and thereby resetting the helicase to drive directional mRNP remodeling and mRNA release [PMID:19219046, PMID:19208808]. Through these export and shuttling activities NUP214 also modulates signaling, controlling nucleocytoplasmic distribution of Smad2 and of the Notch effector RBP-J [PMID:12191473, PMID:31186352], and it serves as a direct NPC docking receptor for incoming adenovirus and herpesvirus capsids during viral genome import [PMID:11781571, PMID:25410864, PMID:19386703]. Biallelic loss-of-function variants in NUP214 cause an acute febrile encephalopathy, with patient fibroblasts showing reduced NUP214/NUP88, impaired transport, plugged NPC channels, and increased apoptosis [PMID:31178128]. Chromosomal rearrangements fuse NUP214 to SET, DEK, SQSTM1, or ABL1 in leukemia: the nucleoporin-fusion proteins tether CRM1/XPO1 onto chromatin to drive aberrant HOX-cluster transcription [PMID:18299449, PMID:31755865, PMID:32343715, PMID:40148556, PMID:40204893], while NUP214-ABL1 is a constitutively active, NPC-localized tyrosine kinase whose transforming activity depends on its pore localization [PMID:18614052, PMID:15361874].","teleology":[{"year":1996,"claim":"Established that NUP214 is not a passive scaffold but is essential for the core NPC functions of cell-cycle progression and bidirectional nucleocytoplasmic transport.","evidence":"CAN-/- mouse embryo and ES cell knockout with cell-cycle, NLS-import, and poly(A)+ RNA readouts","pmids":["8896451"],"confidence":"High","gaps":["Did not resolve which molecular partner mediates each transport defect","Did not distinguish direct transport roles from secondary cell-cycle effects"]},{"year":1997,"claim":"Defined NUP214 as the organizer of a cytoplasmic-face subcomplex containing Nup88 and CRM1, showing Nup88 NPC localization depends on NUP214 and that NUP214's FG region carries the CRM1-interaction domain.","evidence":"Reciprocal Co-IP, immunofluorescence, knockout embryos, and dominant-negative overexpression","pmids":["9049309"],"confidence":"High","gaps":["Structural basis of FG–CRM1 recognition not yet defined","Functional consequence of CRM1 docking on export not directly measured"]},{"year":2002,"claim":"Linked NUP214 export function to signaling by showing it binds Smad2 and competes with cytoplasmic/nuclear retention factors to mediate constitutive Smad2 shuttling.","evidence":"Co-IP, pulldown, competition binding, and shuttling assays","pmids":["12191473"],"confidence":"High","gaps":["Did not test whether Smad2 shuttling alters TGFβ transcriptional output in vivo","Relative contribution of NUP214 vs Nup153 unresolved"]},{"year":2004,"claim":"Positioned NUP214 within the cytoplasmic filament architecture, showing it and Nup88 are mutually interdependent and together anchor Nup358 at the NPC.","evidence":"RNAi depletion with localization readouts and Co-IP","pmids":["14993277"],"confidence":"High","gaps":["Stoichiometry of the Nup214–Nup88–Nup358 assembly not determined"]},{"year":2006,"claim":"Demonstrated that the Nup214–Nup88 module is a terminal high-affinity binding site that is specifically required for CRM1-mediated export, including of 60S preribosomal subunits, while import is spared.","evidence":"RNAi with transport-factor export assays, biochemical reconstitution of Nup214–CRM1–RanGTP–cargo complex, and coiled-coil domain rescue","pmids":["16943420","16675447"],"confidence":"High","gaps":["How cargo is handed off from NUP214 to release into the cytoplasm not resolved","FG-domain accessibility paradox (large FG domain not freely accessible) not mechanistically explained"]},{"year":2009,"claim":"Resolved how NUP214 controls mRNP remodeling by structurally and biochemically showing it binds DBP5/DDX19 mutually exclusively with RNA and inhibits its ATPase, resetting the helicase for directional mRNA release.","evidence":"Crystal structures of DBP5–RNA/AMPPNP and DBP5–Nup214 (N-terminal domain), plus in vitro ATPase and RNA-binding assays","pmids":["19219046","19208808"],"confidence":"High","gaps":["In-cell kinetics of the proposed ratchet/reset cycle not directly observed","Coordination between DBP5 regulation and CRM1 docking at the same pore face unclear"]},{"year":2015,"claim":"Provided the atomic mechanism of NUP214 export function: FG motifs occupy eight sites on CRM1 and clamp it in a closed conformation to stabilize the export complex.","evidence":"Crystal structure of Nup214 FG fragment with CRM1–Snurportin1–RanGTP plus mutagenesis and cell-based export assays","pmids":["26489467"],"confidence":"High","gaps":["How clamping is released to permit cargo dissociation not defined","Which individual FG sites are rate-limiting in cells not established"]},{"year":2014,"claim":"Confirmed NUP214 as a direct NPC receptor for viral capsids by mapping the adenovirus hexon binding site to a defined N-terminal segment required for viral genome import.","evidence":"RNAi depletion, in vitro hexon-binding in permeabilized cells, domain rescue, and infection assays (building on earlier adenovirus and HSV-1 capsid docking studies)","pmids":["25410864","11781571","19386703"],"confidence":"High","gaps":["Whether the N-terminal capsid-binding role conflicts with normal transport functions not addressed","Generality across other viruses limited"]},{"year":2019,"claim":"Connected NUP214 loss-of-function to human Mendelian disease and extended its signaling role, defining acute febrile encephalopathy from biallelic variants and a role in negatively regulating Notch via RBP-J export.","evidence":"Patient fibroblast transport assays, SEM of NPC channels, and apoptosis assays; separately reporter assays, ChIP-qPCR, and zebrafish for Notch/RBP-J","pmids":["31178128","31186352"],"confidence":"High","gaps":["Tissue-specificity of encephalopathy phenotype not mechanistically explained","Whether RBP-J is a direct CRM1 cargo of NUP214 not structurally shown"]},{"year":2008,"claim":"Defined two distinct oncogenic logics of NUP214 fusions: NPC-localization-dependent constitutive ABL1 kinase activity, and SET-NUP214-driven transcriptional activation of HOXA genes via CRM1/DOT1L.","evidence":"Localization and transformation assays for NUP214-ABL1; ChIP, siRNA, and Co-IP for SET-NUP214; episomal-amplification genetics establishing the NUP214-ABL1 fusion","pmids":["18614052","18299449","15361874","18784740"],"confidence":"High","gaps":["Why NPC localization is required for ABL1 transformation mechanistically unresolved","How the chimeras recruit transcriptional machinery to HOX chromatin not fully defined"]},{"year":2025,"claim":"Consolidated the export-receptor-hijack model of nucleoporin fusions, showing SET/DEK/SQSTM1-NUP214 tether CRM1/XPO1 onto HOX and FOXC1 chromatin to drive leukemogenic transcription, with XPO1 as a therapeutic dependency.","evidence":"FG-motif mutagenesis with mouse transplant and ChIP; CRM1/XPO1 inhibition and ChIP-seq/CUT&RUN with transcriptomics and PDX models","pmids":["32343715","31755865","27114368","27613868","40148556","40204893"],"confidence":"High","gaps":["How the fusion reverses CRM1 from an exporter into a chromatin-tethering factor not fully explained","Contribution of fusion-specific partner domains (SET vs DEK vs SQSTM1) to target selectivity incomplete"]},{"year":null,"claim":"It remains unresolved how NUP214 coordinates its multiple concurrent activities at a single pore face — CRM1 docking, DBP5 resetting, capsid receptor, and partner anchoring — and how its own NES-dependent targeting is integrated with these roles.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated in-cell model coordinating export, mRNP remodeling, and viral docking","Mechanism translating NUP214 loss into specific neurological versus hematopoietic phenotypes unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,4,8]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[5,7,9]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,3]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[10,11,12]}],"localization":[],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[1,5,7]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[1,2,9]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[17,23,38]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[18,20,28]}],"complexes":["Nup214–Nup88 nucleoporin subcomplex","nuclear pore complex (cytoplasmic face)","CRM1–RanGTP–cargo export complex"],"partners":["XPO1/CRM1","NUP88","DDX19/DBP5","NUP358","NUP84","SMAD2","RBPJ","NUP62"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P35658","full_name":"Nuclear pore complex protein Nup214","aliases":["214 kDa nucleoporin","Nucleoporin Nup214","Protein CAN"],"length_aa":2090,"mass_kda":213.6,"function":"Part of the nuclear pore complex (PubMed:9049309). Has a critical role in nucleocytoplasmic transport (PubMed:31178128). May serve as a docking site in the receptor-mediated import of substrates across the nuclear pore complex (PubMed:31178128, PubMed:8108440) (Microbial infection) Required for capsid disassembly of the human adenovirus 5 (HadV-5) leading to release of the viral genome to the nucleus (in vitro)","subcellular_location":"Nucleus, nuclear pore complex","url":"https://www.uniprot.org/uniprotkb/P35658/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/NUP214","classification":"Common Essential","n_dependent_lines":1201,"n_total_lines":1208,"dependency_fraction":0.9942052980132451},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000126883","cell_line_id":"CID001717","localizations":[{"compartment":"nuclear_membrane","grade":3},{"compartment":"big_aggregates","grade":2}],"interactors":[{"gene":"NUP88","stoichiometry":10.0},{"gene":"NUP93","stoichiometry":10.0},{"gene":"RAN","stoichiometry":10.0},{"gene":"XPO1","stoichiometry":10.0},{"gene":"NUP62","stoichiometry":10.0},{"gene":"NUP188","stoichiometry":4.0},{"gene":"RAE1","stoichiometry":4.0},{"gene":"NUP98","stoichiometry":4.0},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CLIP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001717","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":"613065","title":"LEUKEMIA, ACUTE LYMPHOBLASTIC; ALL","url":"https://www.omim.org/entry/613065"},{"mim_id":"611729","title":"KINESIN LIGHT CHAIN 2; KLC2","url":"https://www.omim.org/entry/611729"},{"mim_id":"610946","title":"MICRO RNA 133B; MIR133B","url":"https://www.omim.org/entry/610946"},{"mim_id":"610551","title":"ENCEPHALOPATHY, ACUTE, INFECTION-INDUCED (HERPES-SPECIFIC), SUSCEPTIBILITY TO, 1; IIAE1","url":"https://www.omim.org/entry/610551"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"testis","ntpm":119.1}],"url":"https://www.proteinatlas.org/search/NUP214"},"hgnc":{"alias_symbol":["CAIN","CAN","D9S46E","N214"],"prev_symbol":[]},"alphafold":{"accession":"P35658","domains":[{"cath_id":"2.130.10.10","chopping":"12-406","consensus_level":"medium","plddt":93.0002,"start":12,"end":406},{"cath_id":"1.20.5","chopping":"746-802","consensus_level":"medium","plddt":84.6181,"start":746,"end":802},{"cath_id":"1.20.5","chopping":"804-841","consensus_level":"medium","plddt":86.3708,"start":804,"end":841}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P35658","model_url":"https://alphafold.ebi.ac.uk/files/AF-P35658-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P35658-F1-predicted_aligned_error_v6.png","plddt_mean":49.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NUP214","jax_strain_url":"https://www.jax.org/strain/search?query=NUP214"},"sequence":{"accession":"P35658","fasta_url":"https://rest.uniprot.org/uniprotkb/P35658.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P35658/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P35658"}},"corpus_meta":[{"pmid":"10606224","id":"PMC_10606224","title":"The hypoxic cell: a target for selective cancer therapy--eighteenth Bruce F. 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Depletion of CAN from the NPC causes concomitant loss of Nup88, indicating Nup88 NPC localization depends on CAN binding. The FG-repeat region of CAN contains the hCRM1-interaction domain; nuclear overexpression of this region depletes hCRM1 from the NPC.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, CAN knockout mouse embryos, dominant-negative overexpression\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genetic knockout, and dominant-negative overexpression across multiple orthogonal approaches in a single study\",\n      \"pmids\": [\"9049309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"CAN/Nup214 is essential for cell cycle progression and nucleocytoplasmic transport in vivo. CAN-/- mouse embryos arrest in G2 phase upon depletion of maternally derived CAN, accompanied by inhibition of NLS-mediated nuclear protein import and nuclear accumulation of poly(A)+ RNA (mRNA export block). CAN-/- ES cells are not viable.\",\n      \"method\": \"Genetic knockout (CAN-/- mouse embryos and ES cells), in vitro culture, immunofluorescence for cell cycle markers and NLS-import, in situ hybridization for poly(A)+ RNA\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic knockout with multiple orthogonal phenotypic readouts (cell cycle, protein import, mRNA export), replicated across ES cells and embryos\",\n      \"pmids\": [\"8896451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"DBP5/DDX19 binds NUP214 in a manner mutually exclusive with RNA binding. Crystal structures of human DBP5 bound to RNA/AMPPNP and to NUP214 show overlapping binding surfaces. NUP214 decreases both RNA-binding and ATPase activities of DBP5 in vitro, suggesting NUP214 acts as a negative regulator that resets DBP5 at the cytoplasmic face of the NPC for mRNA release.\",\n      \"method\": \"Crystal structure determination, in vitro ATPase assay, in vitro RNA-binding assay\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures of both complexes solved, in vitro enzymatic assays confirming mutual exclusivity and inhibition of DBP5 by NUP214\",\n      \"pmids\": [\"19219046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Crystal structure of the Nup214 N-terminal domain in complex with the DEAD-box helicase Ddx19 (ADP-bound state) at 2.5 Å resolution reveals that interaction surfaces are evolutionarily conserved and have strongly opposing surface potentials (helicase surface positive, Nup214 surface negative), suggesting a ratchet mechanism for mRNP remodeling during nuclear export.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure at 2.5 Å resolution with identification of conserved functional interface\",\n      \"pmids\": [\"19208808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Crystal structure of the human Nup214 N-terminal domain at 1.65 Å resolution reveals a seven-bladed β-propeller followed by a 30-residue C-terminal extended peptide that folds back onto the β-propeller bottom face, with a proposed role for the C-terminal peptide extension in NPC assembly.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structure (1.65 Å) of the N-terminal domain with structural characterization\",\n      \"pmids\": [\"17264208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structure of a 117-amino-acid FG-repeat fragment of Nup214 in complex with CRM1, Snurportin1, and RanGTP at 2.85 Å resolution reveals eight binding sites for Nup214 FG motifs on CRM1. Nup214 binds to both N- and C-terminal regions of CRM1, clamping it in a closed conformation and stabilizing the export complex. Conserved hydrophobic pockets on CRM1 are required for FG-motif recognition, validated by biochemical and cell-based assays.\",\n      \"method\": \"X-ray crystallography, in vitro binding assays, cell-based export assays, mutagenesis of FG motifs\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis and cell-based functional validation in one study\",\n      \"pmids\": [\"26489467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Smad2 directly interacts with NUP214/CAN and Nup153 to mediate constitutive nucleocytoplasmic shuttling. CAN/Nup214 and Nup153 compete with the cytoplasmic retention factor SARA and the nuclear partner FAST-1 for binding to a hydrophobic corridor on the MH2 surface of Smad2. TGFβ receptor phosphorylation modifies Smad2 affinity for SARA and Smad4 but not for CAN/Nup214 or Nup153.\",\n      \"method\": \"Co-immunoprecipitation, pulldown assays, shuttling assays, competition binding assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, competition binding, and functional shuttling assays with multiple orthogonal methods\",\n      \"pmids\": [\"12191473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Depletion of Nup214/Nup88 by RNAi in human cells leads to strongly reduced CRM1-mediated nuclear export of NFAT and HIV-Rev, while nuclear protein import and mRNA export are largely unaffected. A high-affinity complex containing Nup214, CRM1, RanGTP, and export cargo is biochemically characterized, supporting a model where Nup214/Nup88 provides a terminal high-affinity binding site for CRM1 during export.\",\n      \"method\": \"RNAi depletion, nuclear export assays (shuttling transcription factors, HIV-Rev), biochemical complex reconstitution\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNAi with specific transport readouts plus biochemical complex characterization, multiple orthogonal methods\",\n      \"pmids\": [\"16943420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Nup88 localizes between Nup358 and Nup214 at the cytoplasmic NPC face and physically interacts with both. RNAi depletion of either Nup88 or Nup214 causes strong reduction of Nup358 at the nuclear envelope, demonstrating that Nup88 and Nup214 mediate the attachment of Nup358 to the NPC. Nup88 and Nup214 are interdependent at the NPC and are not affected by absence of Nup358.\",\n      \"method\": \"RNAi, immunofluorescence, Co-immunoprecipitation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNAi knockdown with precise localization readouts plus Co-IP, multiple orthogonal methods confirming interdependence\",\n      \"pmids\": [\"14993277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Depletion of the Nup214-Nup88 nucleoporin subcomplex by RNAi causes a dramatic defect in CRM1-mediated nuclear export of the 60S preribosomal subunit (via NMD3 adaptor). The coiled-coil region of Nup214 (not the FG-repeat domain) is sufficient for rescuing 60S export, coinciding with recruitment of Nup88. The large FG domain of Nup214 is not accessible to freely diffusing nuclear molecules.\",\n      \"method\": \"RNAi depletion, fluorescence microscopy export assays, domain-rescue experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNAi with domain-rescue experiments and accessibility assays using multiple orthogonal approaches in one study\",\n      \"pmids\": [\"16675447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"CAN/Nup214 is a docking site for incoming adenovirus type 2 (Ad2) capsids at the NPC. Capsid binding to CAN is independent of cytosolic factors. Capsid disassembly at the NPC requires nuclear histone H1 binding to stably docked capsids, involving H1-import factors, thereby restricting irreversible DNA release to NPC proximity.\",\n      \"method\": \"Immunofluorescence, biochemical binding assays, histone H1 depletion/addition experiments\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — identification of NPC receptor for virus with mechanistic dissection of capsid disassembly using multiple orthogonal assays\",\n      \"pmids\": [\"11781571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The N-terminal domain of Nup214 (specifically a 137-amino-acid segment) is the direct NPC binding site for adenovirus hexon protein. RNAi depletion of Nup214 (but not Nup358) strongly reduces hexon binding and nuclear import of viral DNA. Expression of an NPC-targeted N-terminal Nup214 domain in Nup214-depleted cells restores hexon binding and viral genome import.\",\n      \"method\": \"RNAi depletion, in vitro hexon-binding assay in digitonin-permeabilized cells, domain-rescue experiments, viral infection assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNAi depletion with domain-rescue and direct binding assays, multiple orthogonal methods identifying specific region\",\n      \"pmids\": [\"25410864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Herpes simplex virus type 1 (HSV-1) capsids interact with CAN/Nup214 in infected cells. RNA silencing of CAN/Nup214 delays the onset of viral DNA replication in the nucleus. The minor capsid protein pUL25 directly interacts with CAN/Nup214 and nucleoporin hCG1, identifying CAN/Nup214 as a nuclear receptor for herpesvirus capsids and pUL25 as the interface between incoming capsids and the NPC.\",\n      \"method\": \"Co-immunoprecipitation, RNAi silencing, viral DNA replication assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and RNAi with functional readout, single lab\",\n      \"pmids\": [\"19386703\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"HIV-1 Rev can recruit Nup98 and Nup214 (but not Nup153) to the nucleolus in HeLa cells. The FG-containing repeat domains of Nup98 and Nup214 (but not Nup153) competitively inhibit Rev/RRE-mediated HIV gene expression, demonstrating direct participation of Nup214 in CRM1-mediated Rev nuclear export.\",\n      \"method\": \"Immunofluorescence (recruitment to nucleolus), competition inhibition assay with isolated FG domains\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-based competition assay and localization data, single lab, two complementary approaches\",\n      \"pmids\": [\"9847314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Overexpression of CAN/Nup214 in U937 cells causes G0 arrest, nuclear mRNA accumulation, and apoptosis. Overexpression of the C-terminal FG-repeat region alone sequesters hCRM1 in the nucleoplasm (and importin beta/p97 from the NPC), which is sufficient to inhibit cell growth and induce apoptosis, confirming that CAN's FG region interacts with hCRM1 and that this interaction is functionally critical.\",\n      \"method\": \"Overexpression in myeloid cell lines, flow cytometry (cell cycle), in situ hybridization (mRNA export), immunofluorescence (hCRM1, p97 localization)\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression with multiple phenotypic readouts (cell cycle, mRNA export, protein localization), single lab\",\n      \"pmids\": [\"9488438\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Nup84 (a novel non-glycosylated nucleoporin) is tightly associated with CAN/Nup214 and co-localizes on the cytoplasmic face of the NPC. Mutagenesis shows the coiled-coil C-terminal domain of Nup84 is required for NPC association, while the N-terminal region contains the CAN/Nup214 interaction site. Nup84 may anchor CAN/Nup214 to the central NPC framework.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence/electron microscopy, domain mutagenesis and expression\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with domain mutagenesis and localization, single lab\",\n      \"pmids\": [\"9166401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Multiple specific phenylalanine-glycine (FG) motifs in the C-terminal repeat region of Nup214 are essential for CRM1 binding. Dominant-negative Nup214 FG fragments inhibit CRM1-dependent nuclear export but do not affect several nuclear import pathways, revealing a specific role for Nup214 FG repeats in export.\",\n      \"method\": \"Mutagenesis of FG motifs, dominant-negative inhibition assays, nuclear export assays in cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis with functional export assays, single lab\",\n      \"pmids\": [\"23264634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SET-NUP214 fusion protein binds to promoter regions of specific HOXA genes where it interacts with CRM1 and DOT1L, transcriptionally activating HOXA cluster members. siRNA knockdown of SET-NUP214 abolishes HOXA gene expression, inhibits proliferation, and induces differentiation in LOUCY T-ALL cells.\",\n      \"method\": \"ChIP, siRNA knockdown, gene expression analysis, Co-immunoprecipitation\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with siRNA knockdown and functional readouts, single lab\",\n      \"pmids\": [\"18299449\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"NUP214-ABL1 fusion protein localizes to the nuclear pore complex, and this NPC localization is required for its transforming potential. NUP214-ABL1 has attenuated transforming capacity compared to BCR-ABL1, preferentially transforms T cells, lacks activation loop phosphorylation, and differs from BCR-ABL1 in kinase activity initiation and downstream signaling.\",\n      \"method\": \"Subcellular localization (immunofluorescence), transformation assays (mouse bone marrow transplant, cell line), domain analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (localization, transformation assays, kinase biochemistry) establishing NPC-dependent oncogenic mechanism\",\n      \"pmids\": [\"18614052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"NUP214-ABL1 has lower in vitro tyrosine kinase activity than BCR-ABL1, lacks activation loop phosphorylation, is more sensitive to imatinib in vitro and in cells, and phosphorylates a different spectrum of substrate peptides. Src kinases (including LCK) are differentially involved in NUP214-ABL1 downstream signaling compared to BCR-ABL1.\",\n      \"method\": \"In vitro kinase assay, Western blot for phosphorylation, imatinib sensitivity assay, peptide array substrate profiling\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assays with peptide arrays and cell-based assays, single lab, multiple methods\",\n      \"pmids\": [\"18784740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"NUP214-ABL1 fusion is formed by extrachromosomal (episomal) amplification of a 500-kb region of chromosome 9q34 containing ABL1 and NUP214, generating a constitutively phosphorylated tyrosine kinase sensitive to imatinib. The rearrangement is associated with increased HOX expression and CDKN2A deletion.\",\n      \"method\": \"Molecular analysis (RT-PCR, FISH, cytogenetics), Western blot for constitutive phosphorylation, imatinib sensitivity assay\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — discovery of fusion with constitutive kinase activity confirmed biochemically and pharmacologically, replicated in multiple patient samples and cell lines\",\n      \"pmids\": [\"15361874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SET-Nup214 and DEK-Nup214 fusion proteins interact with XPO1/CRM1 and NXF1/TAP. They decrease XPO1-mediated nuclear export of NES proteins (cyclin B, NF-κB pathway components) by tethering XPO1 onto nuclear dots where fusion proteins localize, and inhibit NF-κB-mediated transcription by abnormally trapping the p65/IκB complex in the nucleus.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, nuclear export assays, NF-κB reporter assay\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and functional export/reporter assays, single lab, multiple readouts\",\n      \"pmids\": [\"27114368\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SET-Nup214 forms dynamic nuclear bodies that recruit CRM1, export cargo proteins, and certain nucleoporins, inhibiting both nuclear protein and poly(A)+ RNA export. SQSTM1-Nup214 also forms nuclear bodies and inhibits nuclear protein but NOT poly(A)+ RNA export. The interaction of both fusion proteins with CRM1 is RanGTP-dependent. The Nup214 portion mediates export inhibition while the SET/SQSTM1 portion determines localization and extent of the effect.\",\n      \"method\": \"Co-immunoprecipitation, fluorescence microscopy (live imaging, FRAP), nuclear export assays, binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, live imaging, export assays), single lab\",\n      \"pmids\": [\"27613868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CRM1 accumulates at HOX cluster chromatin regions and recruits SET-Nup214 and NPM1c to HOX cluster regions, leading to HOX gene activation. CRM1 inhibition disperses this recruitment and suppresses HOX gene expression in leukemia cells. SET-Nup214 recruitment to HOX genes requires nucleoporin-CRM1 interaction.\",\n      \"method\": \"ChIP-seq, CRM1 inhibitor treatment, siRNA knockdown, gene expression analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq with pharmacologic and genetic perturbation, single lab\",\n      \"pmids\": [\"31755865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"LCK kinase activity is absolutely required for proliferation and survival of NUP214-ABL1-positive T-ALL cells. Mass spectrometry identifies NUP214-ABL1 interaction partners MAD2L1, NUP155, and SMC4 as required for proliferation and survival of NUP214-ABL1-positive cells. The NUP214-ABL1 signaling network is distinct from BCR-ABL1.\",\n      \"method\": \"Kinase inhibitor assays (LCK inhibitors, dasatinib, bosutinib), siRNA knockdown of interactors, mass spectrometry interactome\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry interactome plus siRNA validation with functional readout, single lab\",\n      \"pmids\": [\"23872305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"In Drosophila, Nup214 binds CRM1 directly and anchors it to the nuclear envelope. In nup214 mutants, CRM1 accumulates in the nucleus and NES-protein export is enhanced. The Nup214-Nup88 complex sequesters CRM1 at the nuclear rim; Nup214 protects Nup88 from degradation while Nup88 is sufficient for targeting the complex to nuclear pores. The NFκB transcription factor Dorsal is a CRM1 substrate requiring Nup214 for nuclear translocation upon signaling.\",\n      \"method\": \"Genetic mutant analysis (Drosophila nup214 mutants), co-immunoprecipitation, immunofluorescence, overexpression\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic mutants plus Co-IP and localization in Drosophila model, multiple approaches, single lab\",\n      \"pmids\": [\"17032737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"In Drosophila, RNAi inactivation reveals that the FG repeats of Nup153 are necessary for its import function while Nup214 FG region has an antagonistic relationship with RanBP3 in determining CRM1 localization and nuclear protein export. Nup214 FG region and RanBP3 have opposing effects on CRM1 nuclear accumulation and export efficiency.\",\n      \"method\": \"RNAi in Drosophila S2 cells, nuclear import/export assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic RNAi screen with defined transport readouts, single lab, Drosophila ortholog\",\n      \"pmids\": [\"17682050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Tristetraprolin (TTP) directly associates with the FG-repeat region of Nup214. Full-length Nup214 co-precipitates with TTP from intact cells. The interaction requires two intact zinc fingers of TTP. A TTP mutant unable to bind Nup214 localizes throughout the cell rather than primarily in the cytosol, suggesting the Nup214 interaction regulates TTP localization.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation from intact THP-1 cells, immunofluorescence\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP with yeast two-hybrid, localization data without full functional follow-up, single lab\",\n      \"pmids\": [\"14766228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Biallelic pathogenic variants in NUP214 in patients with acute febrile encephalopathy reduce NUP214 and NUP88 protein levels in primary fibroblasts, impair classical protein import and mRNA export, and cause a large increase in 'plugged' (central particle-containing) nuclear pore channels by scanning electron microscopy. Fibroblasts from affected individuals show delayed heat-shock stress response and surge in apoptotic cell death.\",\n      \"method\": \"Patient-derived fibroblasts, nuclear transport assays, scanning electron microscopy of NPC surface, immunoblotting, apoptosis assay\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (transport assays, direct NPC imaging by SEM, cell biology) establishing functional consequences of NUP214 loss-of-function at molecular and cellular levels\",\n      \"pmids\": [\"31178128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Nup214 and its partner Nup88 negatively regulate Notch signaling in mammalian cells and in vivo in zebrafish. Loss of Nup88/214 inhibits nuclear export of RBP-J (the DNA-binding component of the Notch pathway), increasing RBP-J binding to cognate promoter regions and enhancing downstream Notch signaling. Nuclear RBP-J levels are rate-limiting for Notch signaling.\",\n      \"method\": \"Reporter gene assays, immunocytochemistry, ChIP-qPCR, zebrafish in vivo experiments, siRNA knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assays, ChIP-qPCR, and in vivo zebrafish validation, single lab\",\n      \"pmids\": [\"31186352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Nup214 contains a classical nuclear export sequence (NES) that mediates Ran-dependent binding to CRM1. Mutations in the NES, or CRM1 inhibition with leptomycin B, cause nuclear accumulation of overexpressed Nup214. The NES function is required for correct cytoplasmic NPC targeting of Nup214 and for co-recruitment of binding partners Nup62 and Nup88 to the correct NPC location.\",\n      \"method\": \"NES mutagenesis, leptomycin B treatment, immunofluorescence, co-localization of binding partners\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis with localization assays and pharmacological validation, single lab\",\n      \"pmids\": [\"33589493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"DEK-NUP214 expression in myeloid cell lines causes a substantial increase in global protein synthesis via increased translation, not transcription. This is myeloid-lineage specific. DEK-NUP214 expression correlates with phosphorylation of translation initiation factor EIF4E.\",\n      \"method\": \"Global translation assay (metabolic labeling), Western blot for EIF4E phosphorylation, lineage-specificity testing in myeloid vs. non-myeloid cells\",\n      \"journal\": \"Genes, chromosomes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — translation assay with phosphorylation readout and lineage specificity demonstrated, single lab\",\n      \"pmids\": [\"18181180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"DEK-NUP214 expression in myeloid cell lines increases cellular proliferation through upregulation of mTOR, with elevated mTORC1 (but not mTORC2) activity as measured by p70 S6 kinase phosphorylation. This increases protein synthesis and shifts metabolism toward oxidative phosphorylation. The mTORC1 inhibitor everolimus selectively reverses DEK-NUP214-induced proliferation.\",\n      \"method\": \"Western blot (mTOR, p70S6K, Akt phosphorylation), global translation assay, metabolic assay (lactate production, glucose consumption), mTOR inhibitor treatment\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical readouts with pharmacological rescue, single lab\",\n      \"pmids\": [\"24073922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"CAN/Nup214 interacts with the vitamin D receptor (VDR) via the carboxy-terminal FG-repeat-containing region of Nup214. Overexpression of full-length Nup214 facilitates VDR-mediated transactivation, while expression of the carboxy-terminal fragment (which competes with full-length Nup214 for VDR binding) suppresses it. The DNA-binding domain of VDR is required for Nup214-facilitated transactivation.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation in mammalian cells, transactivation reporter assay, domain deletion mapping\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — yeast two-hybrid with Co-IP and reporter assay, single lab, limited mechanistic depth\",\n      \"pmids\": [\"19229862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Inhibition of NUP214 expression by miR-133b (validated by luciferase reporter assay) or direct siRNA knockdown elevates mitotic indices, delays degradation of mitotic markers cyclinB1 and cyclinA and H3 dephosphorylation, and causes chromosomal abnormalities and apoptosis, indicating a role for NUP214 in mitotic timing.\",\n      \"method\": \"miR-133b transfection, siRNA knockdown, luciferase reporter assay, flow cytometry (cell cycle), immunofluorescence (mitotic markers), video microscopy\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — validated miRNA target with siRNA confirmation and multiple mitotic readouts, single lab\",\n      \"pmids\": [\"25743594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Influenza A NS2/NEP protein interacts with the amino-terminal FG domain of human Nup214 (identified by yeast two-hybrid, confirmed in yeast and mammalian cells). Nup214 knockdown suppresses influenza viral replication, indicating that Nup214 FG-domain interaction with NS2 is functionally important for viral vRNA export.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation in mammalian cells, Nup214 knockdown with viral replication assay\",\n      \"journal\": \"Turkish journal of biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — yeast two-hybrid with Co-IP and knockdown in single lab, limited mechanistic depth\",\n      \"pmids\": [\"32256144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SET-NUP214 interacts with MLL (Mixed Lineage Leukemia) via the SET acidic region, and SET-NUP214 and MLL cooperatively enhance HoxA10 gene promoter activity. Neither the SET nor the Nup214 region alone is sufficient for this transcriptional enhancement.\",\n      \"method\": \"Co-immunoprecipitation, luciferase reporter assay for HoxA10 promoter, domain deletion analysis\",\n      \"journal\": \"Genes to cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with functional reporter assay and domain analysis, single lab\",\n      \"pmids\": [\"34320268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SQSTM1-NUP214 interaction with CRM1 is mediated by NUP214 FG motifs. Mutation of these FG motifs reduces CRM1 binding by >50% and abolishes leukemogenic transformation in vitro and in vivo (serial replating and mouse transplant). SQSTM1-NUP214 binds Hoxa and Meis1 gene chromatin via CRM1, and impaired CRM1 binding correlates with impaired binding to these gene loci.\",\n      \"method\": \"FG-motif mutagenesis, co-immunoprecipitation, serial replating assay, mouse bone marrow transplantation, chromatin immunoprecipitation (ChIP)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mutagenesis with in vivo mouse model, Co-IP, and ChIP providing multiple orthogonal validations in one study\",\n      \"pmids\": [\"32343715\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DEK::NUP214 co-localizes with XPO1 at chromatin, and XPO1 inhibition (eltanexor) disrupts this co-localization, reduces DEK::NUP214 chromatin binding, and downregulates DEK::NUP214 target genes (FOXC1, HOX genes). DEK::NUP214 directly binds promoters of FOXC1 and HOXA/B clusters (CUT&RUN), and XPO1 inhibition selectively reduces this binding in t(6;9) cells. FKH-1 cells show genetic dependency on XPO1.\",\n      \"method\": \"XPO1 deletion, pharmacological XPO1 inhibition, CUT&RUN chromatin binding, transcriptomics, patient-derived xenograft model\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic and pharmacological XPO1 perturbation with CUT&RUN, transcriptomics, and in vivo xenograft model, multiple orthogonal methods\",\n      \"pmids\": [\"40148556\", \"40204893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SET-CAN/NUP214 transgenic expression under Gata1 hematopoietic regulatory control in mice causes anemia, thrombocytopenia, and splenomegaly, with impairment of erythroid, megakaryocytic, and B-cell differentiation. A high population of c-kit+Sca-1+Lin- cells appears in bone marrow, demonstrating that SET-CAN blocks the hematopoietic differentiation program.\",\n      \"method\": \"Transgenic mouse model, bone marrow analysis (flow cytometry), hematopoietic cell characterization\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic mouse model with defined hematopoietic phenotypic readouts, single lab\",\n      \"pmids\": [\"17620317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"NUP214-ABL1 cooperates with TLX1 to drive T-ALL in a transgenic mouse model. STAT5 (downstream effector of NUP214-ABL1) and TLX1 co-bind poised enhancer regions and cooperatively activate expression of MYC and BCL2. This cooperative enhancer activation is required for leukemogenesis.\",\n      \"method\": \"Transgenic mouse model, ChIP-seq, ATAC-seq, RNA-seq, pharmacological inhibition (BET inhibitors, STAT5 inhibitors)\",\n      \"journal\": \"Cancer cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — integrated multi-omics (ChIP-seq, ATAC-seq, RNA-seq) with in vivo transgenic mouse model demonstrating cooperative enhancer mechanism\",\n      \"pmids\": [\"30107177\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NUP214 is an essential nucleoporin on the cytoplasmic face of the nuclear pore complex that functions as a high-affinity docking platform for the nuclear export receptor CRM1 (via multiple FG-repeat binding sites), directly participates in CRM1-mediated export of proteins (including NES cargoes, 60S preribosomal subunits, Smad2, and RBP-J) and mRNA, recruits and regulates the RNA helicase DDX19/DBP5 for mRNP remodeling (through a mutually exclusive mechanism with RNA binding), anchors Nup88 and Nup358 at the NPC, mediates docking of adenovirus and herpesvirus capsids for viral genome import, and—when fused to oncoproteins SET, DEK, or ABL1 through chromosomal translocations in leukemia—drives transformation through dysregulation of CRM1-dependent export (sequestering CRM1 in nuclear bodies), XPO1-dependent chromatin-bound transcriptional activation of HOX genes, or constitutive nuclear-pore-localized ABL1 tyrosine kinase activation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NUP214 (CAN) is an essential FG-repeat nucleoporin on the cytoplasmic face of the nuclear pore complex (NPC) whose loss arrests cells in G2 and blocks both NLS-mediated protein import and poly(A)+ mRNA export, rendering it required for viability [#1]. Structurally it comprises an N-terminal seven-bladed β-propeller domain [#4] and an extended C-terminal FG-repeat region, and it forms an interdependent subcomplex with Nup88 that in turn anchors Nup358 at the NPC [#0, #8]. Its central function is to provide a terminal, high-affinity docking platform for the export receptor CRM1/XPO1: a structurally defined array of FG motifs engages eight sites on CRM1, clamping it in a closed conformation to stabilize RanGTP-containing export complexes [#5, #16], and depletion of the Nup214–Nup88 module selectively impairs CRM1-mediated export of NES cargoes, HIV-Rev, and the 60S preribosomal subunit while sparing import [#7, #9]. At the same cytoplasmic face NUP214 binds the DEAD-box helicase DDX19/DBP5 through its N-terminal domain in a manner mutually exclusive with RNA, inhibiting DBP5 ATPase and RNA-binding activity and thereby resetting the helicase to drive directional mRNP remodeling and mRNA release [#2, #3]. Through these export and shuttling activities NUP214 also modulates signaling, controlling nucleocytoplasmic distribution of Smad2 and of the Notch effector RBP-J [#6, #29], and it serves as a direct NPC docking receptor for incoming adenovirus and herpesvirus capsids during viral genome import [#10, #11, #12]. Biallelic loss-of-function variants in NUP214 cause an acute febrile encephalopathy, with patient fibroblasts showing reduced NUP214/NUP88, impaired transport, plugged NPC channels, and increased apoptosis [#28]. Chromosomal rearrangements fuse NUP214 to SET, DEK, SQSTM1, or ABL1 in leukemia: the nucleoporin-fusion proteins tether CRM1/XPO1 onto chromatin to drive aberrant HOX-cluster transcription [#17, #23, #37, #38], while NUP214-ABL1 is a constitutively active, NPC-localized tyrosine kinase whose transforming activity depends on its pore localization [#18, #20].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established that NUP214 is not a passive scaffold but is essential for the core NPC functions of cell-cycle progression and bidirectional nucleocytoplasmic transport.\",\n      \"evidence\": \"CAN-/- mouse embryo and ES cell knockout with cell-cycle, NLS-import, and poly(A)+ RNA readouts\",\n      \"pmids\": [\"8896451\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which molecular partner mediates each transport defect\", \"Did not distinguish direct transport roles from secondary cell-cycle effects\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Defined NUP214 as the organizer of a cytoplasmic-face subcomplex containing Nup88 and CRM1, showing Nup88 NPC localization depends on NUP214 and that NUP214's FG region carries the CRM1-interaction domain.\",\n      \"evidence\": \"Reciprocal Co-IP, immunofluorescence, knockout embryos, and dominant-negative overexpression\",\n      \"pmids\": [\"9049309\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of FG–CRM1 recognition not yet defined\", \"Functional consequence of CRM1 docking on export not directly measured\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Linked NUP214 export function to signaling by showing it binds Smad2 and competes with cytoplasmic/nuclear retention factors to mediate constitutive Smad2 shuttling.\",\n      \"evidence\": \"Co-IP, pulldown, competition binding, and shuttling assays\",\n      \"pmids\": [\"12191473\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not test whether Smad2 shuttling alters TGFβ transcriptional output in vivo\", \"Relative contribution of NUP214 vs Nup153 unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Positioned NUP214 within the cytoplasmic filament architecture, showing it and Nup88 are mutually interdependent and together anchor Nup358 at the NPC.\",\n      \"evidence\": \"RNAi depletion with localization readouts and Co-IP\",\n      \"pmids\": [\"14993277\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of the Nup214–Nup88–Nup358 assembly not determined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated that the Nup214–Nup88 module is a terminal high-affinity binding site that is specifically required for CRM1-mediated export, including of 60S preribosomal subunits, while import is spared.\",\n      \"evidence\": \"RNAi with transport-factor export assays, biochemical reconstitution of Nup214–CRM1–RanGTP–cargo complex, and coiled-coil domain rescue\",\n      \"pmids\": [\"16943420\", \"16675447\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How cargo is handed off from NUP214 to release into the cytoplasm not resolved\", \"FG-domain accessibility paradox (large FG domain not freely accessible) not mechanistically explained\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolved how NUP214 controls mRNP remodeling by structurally and biochemically showing it binds DBP5/DDX19 mutually exclusively with RNA and inhibits its ATPase, resetting the helicase for directional mRNA release.\",\n      \"evidence\": \"Crystal structures of DBP5–RNA/AMPPNP and DBP5–Nup214 (N-terminal domain), plus in vitro ATPase and RNA-binding assays\",\n      \"pmids\": [\"19219046\", \"19208808\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In-cell kinetics of the proposed ratchet/reset cycle not directly observed\", \"Coordination between DBP5 regulation and CRM1 docking at the same pore face unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Provided the atomic mechanism of NUP214 export function: FG motifs occupy eight sites on CRM1 and clamp it in a closed conformation to stabilize the export complex.\",\n      \"evidence\": \"Crystal structure of Nup214 FG fragment with CRM1–Snurportin1–RanGTP plus mutagenesis and cell-based export assays\",\n      \"pmids\": [\"26489467\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How clamping is released to permit cargo dissociation not defined\", \"Which individual FG sites are rate-limiting in cells not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Confirmed NUP214 as a direct NPC receptor for viral capsids by mapping the adenovirus hexon binding site to a defined N-terminal segment required for viral genome import.\",\n      \"evidence\": \"RNAi depletion, in vitro hexon-binding in permeabilized cells, domain rescue, and infection assays (building on earlier adenovirus and HSV-1 capsid docking studies)\",\n      \"pmids\": [\"25410864\", \"11781571\", \"19386703\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the N-terminal capsid-binding role conflicts with normal transport functions not addressed\", \"Generality across other viruses limited\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected NUP214 loss-of-function to human Mendelian disease and extended its signaling role, defining acute febrile encephalopathy from biallelic variants and a role in negatively regulating Notch via RBP-J export.\",\n      \"evidence\": \"Patient fibroblast transport assays, SEM of NPC channels, and apoptosis assays; separately reporter assays, ChIP-qPCR, and zebrafish for Notch/RBP-J\",\n      \"pmids\": [\"31178128\", \"31186352\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specificity of encephalopathy phenotype not mechanistically explained\", \"Whether RBP-J is a direct CRM1 cargo of NUP214 not structurally shown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined two distinct oncogenic logics of NUP214 fusions: NPC-localization-dependent constitutive ABL1 kinase activity, and SET-NUP214-driven transcriptional activation of HOXA genes via CRM1/DOT1L.\",\n      \"evidence\": \"Localization and transformation assays for NUP214-ABL1; ChIP, siRNA, and Co-IP for SET-NUP214; episomal-amplification genetics establishing the NUP214-ABL1 fusion\",\n      \"pmids\": [\"18614052\", \"18299449\", \"15361874\", \"18784740\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why NPC localization is required for ABL1 transformation mechanistically unresolved\", \"How the chimeras recruit transcriptional machinery to HOX chromatin not fully defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Consolidated the export-receptor-hijack model of nucleoporin fusions, showing SET/DEK/SQSTM1-NUP214 tether CRM1/XPO1 onto HOX and FOXC1 chromatin to drive leukemogenic transcription, with XPO1 as a therapeutic dependency.\",\n      \"evidence\": \"FG-motif mutagenesis with mouse transplant and ChIP; CRM1/XPO1 inhibition and ChIP-seq/CUT&RUN with transcriptomics and PDX models\",\n      \"pmids\": [\"32343715\", \"31755865\", \"27114368\", \"27613868\", \"40148556\", \"40204893\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the fusion reverses CRM1 from an exporter into a chromatin-tethering factor not fully explained\", \"Contribution of fusion-specific partner domains (SET vs DEK vs SQSTM1) to target selectivity incomplete\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how NUP214 coordinates its multiple concurrent activities at a single pore face — CRM1 docking, DBP5 resetting, capsid receptor, and partner anchoring — and how its own NES-dependent targeting is integrated with these roles.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated in-cell model coordinating export, mRNP remodeling, and viral docking\", \"Mechanism translating NUP214 loss into specific neurological versus hematopoietic phenotypes unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 4, 8]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 7, 9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [10, 11, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005643\", \"supporting_discovery_ids\": [0, 8, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [1, 5, 7]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [1, 2, 9]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [17, 23, 38]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [18, 20, 28]}\n    ],\n    \"complexes\": [\n      \"Nup214–Nup88 nucleoporin subcomplex\",\n      \"nuclear pore complex (cytoplasmic face)\",\n      \"CRM1–RanGTP–cargo export complex\"\n    ],\n    \"partners\": [\n      \"XPO1/CRM1\",\n      \"NUP88\",\n      \"DDX19/DBP5\",\n      \"NUP358\",\n      \"NUP84\",\n      \"SMAD2\",\n      \"RBPJ\",\n      \"NUP62\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}