{"gene":"NUP210","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1992,"finding":"The single transmembrane segment (TM) of gp210 is sufficient for sorting to the pore membrane domain of the nuclear envelope, as demonstrated by expression of wild-type, mutant, and chimeric gp210 constructs in 3T3 cells; the cytoplasmic tail (CT) also contains a weaker sorting determinant. The large cisternal domain (95% of gp210's mass) contains no sorting determinants.","method":"cDNA mutagenesis, chimeric protein expression, immunofluorescence microscopy in 3T3 cells","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct mutagenesis of transmembrane and cytoplasmic domains with localization readout; multiple constructs tested in one rigorous study","pmids":["1281815"],"is_preprint":false},{"year":1996,"finding":"Gp210 is specifically phosphorylated during mitosis (not in interphase) at Ser1880 in its cytoplasmic tail, consistent with phosphorylation by cyclin B-p34cdc2 or a related kinase, as determined by cell cycle-specific phosphorylation assays and in vitro phosphorylation mapping of mutant fusion proteins containing the cytoplasmic domain.","method":"In vitro kinase assay with mutant and wild-type fusion proteins, phosphopeptide mapping, cell cycle fractionation","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro phosphorylation with site-specific mutagenesis mapping Ser1880, corroborated by phosphopeptide analysis of mitotic gp210","pmids":["8672508"],"is_preprint":false},{"year":2001,"finding":"Gp210 forms SDS-resistant dimers and larger oligomers in the nuclear pore membrane, as shown by immunoprecipitation from cell extracts and velocity sedimentation/gel filtration from purified rat liver nuclear envelopes; cross-linking prior to solubilization dramatically increased the proportion of dimers.","method":"Immunoprecipitation, velocity sedimentation, gel filtration, cross-linking, denaturing electrophoresis","journal":"European journal of biochemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal biochemical methods (IP, sedimentation, gel filtration, crosslinking) all support dimer/oligomer formation","pmids":["11453980"],"is_preprint":false},{"year":2002,"finding":"The cytoplasmic tail of gp210 is required for nuclear pore dilation and NPC assembly: adding recombinant tail polypeptides or anti-tail antibodies to Xenopus nuclear assembly extracts blocked NPC assembly and nuclear growth without affecting membrane fusion, and inhibited nuclei failed to incorporate Nup214/CAN, Nup153, and Nup98. EM revealed arrested 'mini-pore' structures and a lack of 'closely apposed' inner and outer nuclear membranes.","method":"Xenopus nuclear assembly extract assay, recombinant protein addition, antibody inhibition, scanning and transmission EM, immunofluorescence","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reconstitution in cell-free extract with two independent inhibition strategies (recombinant peptide and antibody), EM structural readout","pmids":["12093788"],"is_preprint":false},{"year":2003,"finding":"The C-terminal domain (CTD) of human gp210 adopts a largely unordered conformation with significant polyproline type II (PII) helical structure in solution; the conformation is altered by high pH, charged detergents, and TFE, and TFE induces a conformational change around the SPXX motif containing Ser1880 (the mitotically phosphorylated serine).","method":"Solution NMR/spectroscopy (circular dichroism, FTIR, fluorescence), biochemical structure determination of recombinant CTD","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — single lab, structural characterization by spectroscopic techniques on recombinant domain; no functional mutagenesis in this paper","pmids":["12653556"],"is_preprint":false},{"year":2003,"finding":"RNAi-mediated depletion of gp210 in HeLa cells is lethal and causes accumulation of clustered NPCs and aberrant nuclear membrane structures, indicating gp210 is required for nuclear pore formation/dilation and structural integrity of NPCs. In C. elegans, gp210 RNAi causes embryonic lethality with similar nuclear membrane aberrations, demonstrating evolutionary conservation of function.","method":"RNAi knockdown in HeLa cells and C. elegans, electron microscopy, immunofluorescence","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function in two independent organisms (human cells and C. elegans) with defined ultrastructural phenotypes","pmids":["14517331"],"is_preprint":false},{"year":2004,"finding":"In NIH/3T3 cells lacking gp210, POM121 and NUP107 are correctly distributed at nuclear pores and remain stably associated as assessed by FRAP, indicating that gp210 is not required for incorporation of POM121 or NUP107 or for maintaining NPC stability.","method":"FRAP, immunofluorescence in gp210-deficient NIH/3T3 cells","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — FRAP and immunofluorescence in a defined cell model, single lab; this is a negative mechanistic finding","pmids":["15304359"],"is_preprint":false},{"year":2006,"finding":"POM121 can recruit nucleoporins (Nup62, Nup358) to ectopic assembly sites and acts as a nucleation site for NPC substructures. Double knockdown of gp210 and POM121 in HeLa cells, and depletion of POM121 in human fibroblasts (which do not express gp210), still permits functional NPC assembly, indicating extensive redundancy and that additional membrane-integral nucleoporins exist for NE anchorage.","method":"siRNA double knockdown in HeLa cells, functional NPC assay, ectopic assembly site assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal knockdowns in two cell types with functional NPC readout; redundancy finding independently supported across two conditions","pmids":["16702234"],"is_preprint":false},{"year":2007,"finding":"Phosphomimetic substitution S1880E of gp210 specifically interferes with incorporation of gp210 into NPCs and compromises its post-mitotic recruitment to daughter nuclei, while the alanine substitution S1880A makes gp210 more dynamic at the NPC (faster FRAP), suggesting that mitotic phosphorylation at Ser1880 acts to dissociate gp210 from the NPC.","method":"Site-directed mutagenesis (S1880A, S1880E), live cell imaging, time-lapse microscopy, FRAP","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis combined with live imaging and FRAP providing functional validation; single lab but multiple orthogonal methods","pmids":["17559836"],"is_preprint":false},{"year":2008,"finding":"Gp210 is required for nuclear envelope breakdown (NEBD) in mitosis: RNAi depletion or mutation of C. elegans gp210 prevents lamin depolymerization and causes nuclear twinning after mitosis. Anti-gp210 C-terminal tail antibodies added to in vitro assembled nuclei completely blocked NEBD and inhibited mitotic hyperphosphorylation of gp210. Depletion of cyclin B from C. elegans embryos also causes nuclear twinning, consistent with cyclin B-cdc2 being the relevant kinase.","method":"RNAi in C. elegans embryos, in vitro nuclear assembly antibody inhibition, cyclin B depletion epistasis","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple approaches (RNAi, antibody blocking, in vitro assay, genetic epistasis with cyclin B) converge on the same mechanism","pmids":["18216332"],"is_preprint":false},{"year":2012,"finding":"Super-resolution dSTORM imaging of isolated Xenopus laevis oocyte nuclear envelopes demonstrates that gp210 is distributed with eightfold radial symmetry around the NPC, placing it at each of the eight subunits of the NPC ring; the central NPC channel diameter was determined to be 41 ± 7 nm.","method":"Direct stochastic optical reconstruction microscopy (dSTORM), super-resolution imaging of Xenopus oocyte nuclear envelopes","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct structural imaging at ~15 nm resolution with accumulated images from hundreds of NPCs; two-color control experiments included","pmids":["22389396"],"is_preprint":false},{"year":2015,"finding":"Gp210/Nup210 mediates muscle cell differentiation via its conserved N-terminal luminal domain; the C-terminal domain (which targets gp210 to NPCs) is dispensable and a mutant lacking both the transmembrane and C-terminal domains is sufficient for C2C12 myoblast differentiation. ER stress-specific caspase cascade is exacerbated during Nup210 depletion, and blocking ER stress-mediated apoptosis rescues differentiation of Nup210-deficient cells, indicating the luminal domain maintains nuclear envelope/ER homeostasis.","method":"Domain deletion mutagenesis, C2C12 myoblast differentiation assay, caspase activity assay, ER stress inhibitor rescue, knockdown/rescue experiments","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple domain mutants tested with functional differentiation readout plus ER stress rescue experiment providing mechanistic pathway placement","pmids":["25778917"],"is_preprint":false},{"year":2018,"finding":"Nup210 is required during chemical reprogramming of mouse fibroblasts into neural stem cells (NSCs): Nup210 activates SoxB1 transcription factors to initiate NSC fate, and its activity is required for both chemical cocktail- and growth factor (IL-6, FGF5, LIF)-driven reprogramming.","method":"Nup210 knockdown/overexpression during chemical reprogramming, transcriptome and epigenome analysis, growth factor treatment experiments","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined transcriptional target (SoxB1) and growth factor epistasis; single lab with multiple approaches","pmids":["30067988"],"is_preprint":false},{"year":2021,"finding":"NUP210 interacts with LINC complex protein SUN2 (connecting nucleus to cytoskeleton), and the NUP210/SUN2 complex further interacts with chromatin via the short isoform of BRD4 and histone H3.1/H3.2 at the nuclear periphery. Nup210 depletion causes accumulation of H3K27me3 heterochromatin (mediated by PRC2) at mechanosensitive genes, repositioning of these genes within the nucleus, and defective mechanotransduction and focal adhesion.","method":"Co-immunoprecipitation (NUP210-SUN2, NUP210-BRD4 interactions), ChIP-seq (H3K27me3), DNA FISH (gene repositioning), focal adhesion assays, mouse metastasis models, Nup210 knockout cells","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP for protein interactions, ChIP-seq for chromatin modification, FISH for nuclear repositioning, and in vivo mouse model; multiple orthogonal methods in one study","pmids":["34903738"],"is_preprint":false},{"year":2021,"finding":"Ablation of Nup210 in mice does not prevent skeletal muscle formation or growth, but Nup210 knockout mice show delayed muscle repair after injury, increased centrally nucleated fibers with age, abnormal fiber type distribution, and reduced muscle endurance during voluntary running.","method":"Nup210 knockout mouse model, muscle injury/repair assay, histology, voluntary running assay","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined knockout model with multiple physiological readouts; single lab","pmids":["34911810"],"is_preprint":false},{"year":2022,"finding":"NUP210 expression is driven by BRD4 in colorectal cancer cells; BRD4 inhibition by ACP-1n reduces NUP210 levels and decreases nuclear size, and NUP210 silencing alone is sufficient to decrease nucleus size and cellular growth.","method":"BRD4 inhibitor treatment, NUP210 siRNA knockdown, nuclear size measurement, cell growth assay, phase separation assay","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — pharmacological and genetic approaches with defined functional readouts; BRD4-NUP210 relationship confirmed by rescue experiments; single lab","pmids":["35159127"],"is_preprint":false},{"year":2024,"finding":"Nup210 requires nuclear localization sequences (NLS) to localize to the nuclear membrane surface and interacts with importin-α/β, thereby regulating nucleoplasmic transport capacity and NPC density on CRC cell surfaces; Nup210 knockdown reduces nuclear size, NPC density, and nucleoplasmic transport.","method":"Nup210 knockdown, NLS mutagenesis, co-immunoprecipitation (importin-α/β), NPC density measurement, nuclear transport assay, in vivo xenograft","journal":"Laboratory investigation","confidence":"Medium","confidence_rationale":"Tier 2–3 / Weak — co-IP with importins and NLS mutagenesis for localization, functional transport assay; single lab, limited mechanistic depth in abstract","pmids":["39393532"],"is_preprint":false},{"year":2025,"finding":"A FRET-based tension biosensor inserted into gp210 (at endogenous levels via CRISPR knock-in) reveals that gp210 and the NPC experience mechanical tension. Forces on gp210 increase with osmotically induced nuclear swelling and are influenced by ECM stiffness, the LINC complex, chromatin condensation, and actomyosin contractility; chromatin relaxation and MLCK inhibition increase gp210 forces, suggesting nuclear strain (rather than cytoskeletal forces) is the predominant source of NPC forces.","method":"FRET-force biosensor (TSmod), CRISPR knock-in at endogenous locus, osmotic swelling, pharmacological perturbations, live cell imaging","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1–2 / Weak — novel biosensor with endogenous expression and multiple perturbations; single lab, preprint only","pmids":["40463170"],"is_preprint":true},{"year":2025,"finding":"Nup210 knockdown promotes HIV-1 infection by increasing accumulation of integrated proviral DNA, while levels of reverse transcription products and 2-LTR circles (nuclear entry intermediates) are unaffected, indicating Nup210 acts at late steps of viral nuclear entry (post-nuclear entry, affecting integration). Nup210 also regulates viral mRNA alternative splicing; knockdown increases singly spliced Vpr mRNA, and elevated Vpr may act as a viral antagonist of Nup210.","method":"Nup210 knockdown/overexpression, luciferase infectivity assay, qPCR for RT products/2-LTR circles/integrated DNA, RT-qPCR for viral mRNA species, Raltegravir integrase inhibitor epistasis","journal":"AIDS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple molecular readouts distinguishing steps of viral lifecycle, pharmacological epistasis with integrase inhibitor; single lab","pmids":["40202922"],"is_preprint":false},{"year":2026,"finding":"TMEM209 is a fourth transmembrane nucleoporin that biochemically interacts with Nup210 via a region containing its two transmembrane domains; TMEM209 localizes to NPCs by proximity labeling and immunofluorescence, and overexpression of TMEM209 specifically dissociates Nup210 from the nuclear envelope. TMEM209 depletion impairs cell growth and delays S, G2 and M phase entry.","method":"Proximity labeling, co-immunoprecipitation, immunofluorescence, siRNA depletion, overexpression, cell cycle analysis","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity labeling and Co-IP for interaction, functional overexpression/depletion with cell cycle readout; single lab","pmids":["41582553"],"is_preprint":false},{"year":2026,"finding":"METTL3-mediated N6-methyladenosine (m6A) modification stabilizes NUP210 mRNA; METTL3 silencing reduces NUP210 expression, and NUP210 overexpression reverses the inhibitory effects of METTL3 silencing on prostate cancer cell metastasis and EMT in vitro and in vivo.","method":"MeRIP (m6A-IP), RNA-binding protein immunoprecipitation (RIP), mRNA stability assay, rescue experiments, transwell assay, in vivo metastasis model","journal":"Mutation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP and RIP demonstrate m6A modification and reader binding; mRNA stability and rescue experiments support the mechanism; single lab","pmids":["41775163"],"is_preprint":false}],"current_model":"NUP210/gp210 is a single-pass transmembrane nucleoporin anchored in the nuclear pore membrane via its transmembrane segment (sufficient for pore-membrane sorting), where it forms SDS-resistant dimers/oligomers; its cytoplasmic tail is phosphorylated at Ser1880 by cyclin B-cdc2 during mitosis, triggering NPC disassembly and NEBD (phosphomimetic S1880E blocks NPC incorporation), while its large luminal N-terminal domain maintains nuclear envelope/ER homeostasis and drives muscle and neuronal differentiation independently of NPC association; NUP210 also functions as a cellular mechanosensor by interacting with the LINC complex protein SUN2 and with chromatin via BRD4/H3.1/H3.2, coupling extracellular mechanical signals to PRC2-mediated heterochromatin regulation, and it modulates nucleoplasmic transport and HIV-1 integration through interactions with importin-α/β."},"narrative":{"mechanistic_narrative":"NUP210 (gp210) is a single-pass transmembrane nucleoporin that anchors in the pore membrane of the nuclear envelope and contributes to nuclear pore complex (NPC) assembly, nuclear envelope dynamics, and mechanosensing [PMID:1281815, PMID:14517331]. Its single transmembrane segment is sufficient for sorting to the pore membrane domain, while its massive luminal/cisternal domain carries no localization information, and it assembles into SDS-resistant dimers and higher-order oligomers distributed with eightfold radial symmetry around the NPC ring [PMID:1281815, PMID:11453980, PMID:22389396]. The cytoplasmic C-terminal tail drives nuclear pore dilation and NPC maturation, with its loss arresting assembly at 'mini-pore' intermediates that fail to incorporate downstream nucleoporins; depletion is lethal and produces clustered NPCs and aberrant nuclear membranes across human cells and C. elegans [PMID:12093788, PMID:14517331]. Cell-cycle control operates through this tail: cyclin B-cdc2 phosphorylates Ser1880 during mitosis, and a phosphomimetic substitution blocks NPC incorporation, coupling NUP210 to NPC disassembly and nuclear envelope breakdown [PMID:8672508, PMID:17559836, PMID:18216332]. Independently of its NPC role, the conserved N-terminal luminal domain maintains nuclear envelope/ER homeostasis and is sufficient to drive muscle cell differentiation by limiting ER-stress apoptosis, and NUP210 is required for neural fate reprogramming via SoxB1 activation [PMID:25778917, PMID:30067988]. At the nuclear periphery NUP210 acts as a mechanosensor, bridging the LINC component SUN2 to chromatin through the short isoform of BRD4 and histones H3.1/H3.2, such that its loss drives PRC2-dependent H3K27me3 accumulation and repositioning of mechanosensitive genes, and an endogenous tension biosensor confirms that gp210 itself bears mechanical force [PMID:34903738, PMID:40463170]. NUP210 also engages importin-α/β to regulate nucleoplasmic transport and NPC density and modulates late steps of HIV-1 nuclear entry and proviral integration [PMID:39393532, PMID:40202922].","teleology":[{"year":1992,"claim":"Established which part of gp210 directs it to the nuclear pore, answering how a large luminal protein is targeted to the pore membrane domain.","evidence":"cDNA mutagenesis and chimeric protein expression with immunofluorescence in 3T3 cells","pmids":["1281815"],"confidence":"High","gaps":["Does not define the luminal domain's function","Mechanism of the weaker cytoplasmic-tail sorting determinant unresolved"]},{"year":1996,"claim":"Identified Ser1880 in the cytoplasmic tail as a mitosis-specific phosphosite, linking gp210 to cell-cycle-regulated kinase activity.","evidence":"In vitro kinase assays with mutant fusion proteins, phosphopeptide mapping, cell cycle fractionation","pmids":["8672508"],"confidence":"High","gaps":["Kinase identity inferred but not directly proven in this study","Functional consequence of phosphorylation not yet shown"]},{"year":2001,"claim":"Showed gp210 self-associates into stable dimers and oligomers, indicating it is an oligomeric building block at the pore membrane.","evidence":"Immunoprecipitation, velocity sedimentation, gel filtration, and crosslinking from rat liver nuclear envelopes","pmids":["11453980"],"confidence":"High","gaps":["Stoichiometry and interface of oligomers undefined","Whether oligomerization is regulated unknown"]},{"year":2002,"claim":"Demonstrated the cytoplasmic tail is required for nuclear pore dilation and NPC assembly, placing gp210 at a defined step of pore maturation.","evidence":"Xenopus nuclear assembly extract with recombinant peptide and antibody inhibition, EM and immunofluorescence","pmids":["12093788"],"confidence":"High","gaps":["Direct partners mediating dilation not identified","How the tail couples to membrane curvature unknown"]},{"year":2003,"claim":"Characterized the disordered, PII-rich conformation of the cytoplasmic domain around the Ser1880 SPXX motif, providing structural context for its regulation.","evidence":"CD, FTIR, and fluorescence spectroscopy on recombinant C-terminal domain","pmids":["12653556"],"confidence":"Medium","gaps":["No functional mutagenesis in this study","Conformational changes shown only under non-physiological perturbations (TFE, pH)"]},{"year":2003,"claim":"Established that gp210 loss is lethal and disrupts NPC and nuclear membrane structure across species, defining it as essential and evolutionarily conserved.","evidence":"RNAi in HeLa cells and C. elegans with EM and immunofluorescence","pmids":["14517331"],"confidence":"High","gaps":["Does not separate NPC-assembly role from membrane-homeostasis role","Molecular cause of NPC clustering unresolved"]},{"year":2004,"claim":"Refined the assembly model by showing gp210 is dispensable for POM121 and NUP107 incorporation and NPC stability, narrowing its mechanistic role.","evidence":"FRAP and immunofluorescence in gp210-deficient NIH/3T3 cells","pmids":["15304359"],"confidence":"Medium","gaps":["Negative finding in one cell model","Does not identify which nucleoporins depend on gp210"]},{"year":2006,"claim":"Revealed functional redundancy between gp210 and POM121 for membrane anchorage of NPCs, implying additional integral nucleoporins exist.","evidence":"siRNA double knockdown and ectopic assembly assays in HeLa and human fibroblasts","pmids":["16702234"],"confidence":"High","gaps":["Identity of the inferred additional integral nucleoporins not established here","Conditions where gp210 is non-redundant undefined"]},{"year":2008,"claim":"Connected Ser1880 phosphorylation status to NPC retention, showing mitotic phosphorylation dissociates gp210 from the pore.","evidence":"S1880A/S1880E mutagenesis with live imaging and FRAP","pmids":["17559836"],"confidence":"High","gaps":["Does not identify the phosphatase reversing the modification","Single cell system"]},{"year":2008,"claim":"Established gp210 as required for nuclear envelope breakdown and linked its hyperphosphorylation to cyclin B-cdc2 via genetic epistasis.","evidence":"RNAi and antibody inhibition in C. elegans embryos with cyclin B depletion epistasis","pmids":["18216332"],"confidence":"High","gaps":["Direct demonstration of cdc2 acting on Ser1880 in vivo not shown","How NEBD failure causes nuclear twinning mechanistically unclear"]},{"year":2012,"claim":"Positioned gp210 spatially at each of the eight NPC subunits, anchoring structural models of its arrangement around the pore.","evidence":"dSTORM super-resolution imaging of Xenopus oocyte nuclear envelopes","pmids":["22389396"],"confidence":"High","gaps":["Copy number per spoke not quantified","Does not address dynamics or conformational state"]},{"year":2015,"claim":"Uncovered an NPC-independent function: the luminal N-terminal domain drives muscle differentiation by maintaining ER/NE homeostasis and limiting ER-stress apoptosis.","evidence":"Domain-deletion mutagenesis, C2C12 differentiation, caspase assays, and ER-stress inhibitor rescue","pmids":["25778917"],"confidence":"High","gaps":["Luminal-domain binding partners unidentified","Molecular trigger of ER stress upon depletion unknown"]},{"year":2018,"claim":"Extended the differentiation role to neural fate, showing Nup210 acts upstream of SoxB1 transcription factors during reprogramming.","evidence":"Knockdown/overexpression during chemical reprogramming with transcriptome/epigenome analysis and growth factor epistasis","pmids":["30067988"],"confidence":"Medium","gaps":["Direct versus indirect activation of SoxB1 not resolved","Single lab"]},{"year":2021,"claim":"Defined NUP210 as a mechanosensor coupling the LINC complex (SUN2) to chromatin through BRD4 and H3.1/H3.2, regulating PRC2 heterochromatin and gene positioning.","evidence":"Reciprocal Co-IP, H3K27me3 ChIP-seq, DNA FISH, focal adhesion assays, and mouse metastasis models in Nup210-knockout cells","pmids":["34903738"],"confidence":"High","gaps":["How a luminal/membrane nucleoporin physically reaches chromatin not fully resolved","Direct versus indirect SUN2-BRD4 bridging unclear"]},{"year":2021,"claim":"Tested the muscle role in vivo, showing Nup210 is dispensable for muscle formation but required for repair, fiber-type balance, and endurance.","evidence":"Nup210 knockout mouse with injury/repair, histology, and voluntary running assays","pmids":["34911810"],"confidence":"Medium","gaps":["Reconciliation with the essential C2C12 differentiation phenotype incomplete","Cell-autonomous versus systemic effects unresolved"]},{"year":2022,"claim":"Linked BRD4 to NUP210 expression in cancer, with NUP210 controlling nuclear size and cell growth.","evidence":"BRD4 inhibitor treatment, NUP210 siRNA, nuclear size and growth assays in colorectal cancer cells","pmids":["35159127"],"confidence":"Medium","gaps":["Mechanism linking NUP210 to nuclear size not defined","Single lab"]},{"year":2024,"claim":"Showed NUP210 uses NLS-dependent localization and importin-α/β binding to regulate nucleoplasmic transport and NPC density.","evidence":"NLS mutagenesis, importin Co-IP, NPC density and transport assays, xenografts in CRC cells","pmids":["39393532"],"confidence":"Medium","gaps":["Mechanistic depth limited","Relationship to canonical transmembrane targeting unclear"]},{"year":2025,"claim":"Provided direct evidence that gp210 bears mechanical force, identifying nuclear strain as the predominant force source at the NPC.","evidence":"CRISPR knock-in FRET tension biosensor with osmotic and pharmacological perturbations (preprint)","pmids":["40463170"],"confidence":"Medium","gaps":["Preprint, single lab","Functional consequence of gp210 tension not established"]},{"year":2025,"claim":"Implicated Nup210 in late HIV-1 nuclear entry/integration and viral mRNA splicing, with Vpr as a potential antagonist.","evidence":"Knockdown/overexpression, qPCR for viral intermediates, integrase inhibitor epistasis, viral mRNA RT-qPCR","pmids":["40202922"],"confidence":"Medium","gaps":["Direct interaction with viral or host integration machinery not shown","Mechanism of splicing regulation undefined"]},{"year":2026,"claim":"Identified TMEM209 as a transmembrane nucleoporin that binds Nup210 and controls its retention at the nuclear envelope.","evidence":"Proximity labeling, Co-IP, immunofluorescence, depletion/overexpression with cell cycle analysis","pmids":["41582553"],"confidence":"Medium","gaps":["Functional consequence of Nup210 dissociation by TMEM209 unclear","Single lab"]},{"year":2026,"claim":"Placed NUP210 downstream of m6A regulation, with METTL3 stabilizing NUP210 mRNA to promote cancer metastasis.","evidence":"MeRIP, RIP, mRNA stability and rescue assays, transwell and in vivo metastasis models in prostate cancer","pmids":["41775163"],"confidence":"Medium","gaps":["Direct m6A site mapping not detailed","Single lab"]},{"year":null,"claim":"How NUP210's distinct domains coordinate its NPC-assembly, ER/NE-homeostasis, mechanosensing, and transport-regulatory functions within a single protein remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure integrating luminal, transmembrane, and cytoplasmic domains","Luminal-domain interactome unidentified","Mechanism coupling membrane anchorage to chromatin regulation undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,3,5,10]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[13,17]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[13]}],"localization":[{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[0,2,10]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[11]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[3,16]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,8,9]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[11,12]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[13]}],"complexes":["nuclear pore complex","LINC complex (via SUN2)"],"partners":["SUN2","BRD4","H3.1/H3.2","IMPORTIN-Α","IMPORTIN-Β","TMEM209","POM121"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8TEM1","full_name":"Nuclear pore membrane glycoprotein 210","aliases":["Nuclear envelope pore membrane protein POM 210","POM210","Nucleoporin Nup210","Pore membrane protein of 210 kDa"],"length_aa":1887,"mass_kda":205.1,"function":"Nucleoporin essential for nuclear pore assembly and fusion, nuclear pore spacing, as well as structural integrity","subcellular_location":"Nucleus, nuclear pore complex; Nucleus membrane; Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q8TEM1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/NUP210","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2},{"gene":"DDOST","stoichiometry":0.2},{"gene":"NAPA","stoichiometry":0.2},{"gene":"NUMA1","stoichiometry":0.2},{"gene":"RAN","stoichiometry":0.2},{"gene":"RANBP1","stoichiometry":0.2},{"gene":"ULK3","stoichiometry":0.2},{"gene":"VRK2","stoichiometry":0.2},{"gene":"XPO1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NUP210","total_profiled":1310},"omim":[{"mim_id":"621057","title":"SPERMATOGENIC FAILURE 97; SPGF97","url":"https://www.omim.org/entry/621057"},{"mim_id":"621033","title":"NUP210-LIKE PROTEIN; NUP210L","url":"https://www.omim.org/entry/621033"},{"mim_id":"607703","title":"NUCLEOPORIN, 210-KD; NUP210","url":"https://www.omim.org/entry/607703"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"bone marrow","ntpm":36.8},{"tissue":"lymphoid 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the cytoplasmic tail (CT) also contains a weaker sorting determinant. The large cisternal domain (95% of gp210's mass) contains no sorting determinants.\",\n      \"method\": \"cDNA mutagenesis, chimeric protein expression, immunofluorescence microscopy in 3T3 cells\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct mutagenesis of transmembrane and cytoplasmic domains with localization readout; multiple constructs tested in one rigorous study\",\n      \"pmids\": [\"1281815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Gp210 is specifically phosphorylated during mitosis (not in interphase) at Ser1880 in its cytoplasmic tail, consistent with phosphorylation by cyclin B-p34cdc2 or a related kinase, as determined by cell cycle-specific phosphorylation assays and in vitro phosphorylation mapping of mutant fusion proteins containing the cytoplasmic domain.\",\n      \"method\": \"In vitro kinase assay with mutant and wild-type fusion proteins, phosphopeptide mapping, cell cycle fractionation\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro phosphorylation with site-specific mutagenesis mapping Ser1880, corroborated by phosphopeptide analysis of mitotic gp210\",\n      \"pmids\": [\"8672508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Gp210 forms SDS-resistant dimers and larger oligomers in the nuclear pore membrane, as shown by immunoprecipitation from cell extracts and velocity sedimentation/gel filtration from purified rat liver nuclear envelopes; cross-linking prior to solubilization dramatically increased the proportion of dimers.\",\n      \"method\": \"Immunoprecipitation, velocity sedimentation, gel filtration, cross-linking, denaturing electrophoresis\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal biochemical methods (IP, sedimentation, gel filtration, crosslinking) all support dimer/oligomer formation\",\n      \"pmids\": [\"11453980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The cytoplasmic tail of gp210 is required for nuclear pore dilation and NPC assembly: adding recombinant tail polypeptides or anti-tail antibodies to Xenopus nuclear assembly extracts blocked NPC assembly and nuclear growth without affecting membrane fusion, and inhibited nuclei failed to incorporate Nup214/CAN, Nup153, and Nup98. EM revealed arrested 'mini-pore' structures and a lack of 'closely apposed' inner and outer nuclear membranes.\",\n      \"method\": \"Xenopus nuclear assembly extract assay, recombinant protein addition, antibody inhibition, scanning and transmission EM, immunofluorescence\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reconstitution in cell-free extract with two independent inhibition strategies (recombinant peptide and antibody), EM structural readout\",\n      \"pmids\": [\"12093788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The C-terminal domain (CTD) of human gp210 adopts a largely unordered conformation with significant polyproline type II (PII) helical structure in solution; the conformation is altered by high pH, charged detergents, and TFE, and TFE induces a conformational change around the SPXX motif containing Ser1880 (the mitotically phosphorylated serine).\",\n      \"method\": \"Solution NMR/spectroscopy (circular dichroism, FTIR, fluorescence), biochemical structure determination of recombinant CTD\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — single lab, structural characterization by spectroscopic techniques on recombinant domain; no functional mutagenesis in this paper\",\n      \"pmids\": [\"12653556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"RNAi-mediated depletion of gp210 in HeLa cells is lethal and causes accumulation of clustered NPCs and aberrant nuclear membrane structures, indicating gp210 is required for nuclear pore formation/dilation and structural integrity of NPCs. In C. elegans, gp210 RNAi causes embryonic lethality with similar nuclear membrane aberrations, demonstrating evolutionary conservation of function.\",\n      \"method\": \"RNAi knockdown in HeLa cells and C. elegans, electron microscopy, immunofluorescence\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function in two independent organisms (human cells and C. elegans) with defined ultrastructural phenotypes\",\n      \"pmids\": [\"14517331\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"In NIH/3T3 cells lacking gp210, POM121 and NUP107 are correctly distributed at nuclear pores and remain stably associated as assessed by FRAP, indicating that gp210 is not required for incorporation of POM121 or NUP107 or for maintaining NPC stability.\",\n      \"method\": \"FRAP, immunofluorescence in gp210-deficient NIH/3T3 cells\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — FRAP and immunofluorescence in a defined cell model, single lab; this is a negative mechanistic finding\",\n      \"pmids\": [\"15304359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"POM121 can recruit nucleoporins (Nup62, Nup358) to ectopic assembly sites and acts as a nucleation site for NPC substructures. Double knockdown of gp210 and POM121 in HeLa cells, and depletion of POM121 in human fibroblasts (which do not express gp210), still permits functional NPC assembly, indicating extensive redundancy and that additional membrane-integral nucleoporins exist for NE anchorage.\",\n      \"method\": \"siRNA double knockdown in HeLa cells, functional NPC assay, ectopic assembly site assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal knockdowns in two cell types with functional NPC readout; redundancy finding independently supported across two conditions\",\n      \"pmids\": [\"16702234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Phosphomimetic substitution S1880E of gp210 specifically interferes with incorporation of gp210 into NPCs and compromises its post-mitotic recruitment to daughter nuclei, while the alanine substitution S1880A makes gp210 more dynamic at the NPC (faster FRAP), suggesting that mitotic phosphorylation at Ser1880 acts to dissociate gp210 from the NPC.\",\n      \"method\": \"Site-directed mutagenesis (S1880A, S1880E), live cell imaging, time-lapse microscopy, FRAP\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis combined with live imaging and FRAP providing functional validation; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"17559836\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Gp210 is required for nuclear envelope breakdown (NEBD) in mitosis: RNAi depletion or mutation of C. elegans gp210 prevents lamin depolymerization and causes nuclear twinning after mitosis. Anti-gp210 C-terminal tail antibodies added to in vitro assembled nuclei completely blocked NEBD and inhibited mitotic hyperphosphorylation of gp210. Depletion of cyclin B from C. elegans embryos also causes nuclear twinning, consistent with cyclin B-cdc2 being the relevant kinase.\",\n      \"method\": \"RNAi in C. elegans embryos, in vitro nuclear assembly antibody inhibition, cyclin B depletion epistasis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple approaches (RNAi, antibody blocking, in vitro assay, genetic epistasis with cyclin B) converge on the same mechanism\",\n      \"pmids\": [\"18216332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Super-resolution dSTORM imaging of isolated Xenopus laevis oocyte nuclear envelopes demonstrates that gp210 is distributed with eightfold radial symmetry around the NPC, placing it at each of the eight subunits of the NPC ring; the central NPC channel diameter was determined to be 41 ± 7 nm.\",\n      \"method\": \"Direct stochastic optical reconstruction microscopy (dSTORM), super-resolution imaging of Xenopus oocyte nuclear envelopes\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct structural imaging at ~15 nm resolution with accumulated images from hundreds of NPCs; two-color control experiments included\",\n      \"pmids\": [\"22389396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Gp210/Nup210 mediates muscle cell differentiation via its conserved N-terminal luminal domain; the C-terminal domain (which targets gp210 to NPCs) is dispensable and a mutant lacking both the transmembrane and C-terminal domains is sufficient for C2C12 myoblast differentiation. ER stress-specific caspase cascade is exacerbated during Nup210 depletion, and blocking ER stress-mediated apoptosis rescues differentiation of Nup210-deficient cells, indicating the luminal domain maintains nuclear envelope/ER homeostasis.\",\n      \"method\": \"Domain deletion mutagenesis, C2C12 myoblast differentiation assay, caspase activity assay, ER stress inhibitor rescue, knockdown/rescue experiments\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple domain mutants tested with functional differentiation readout plus ER stress rescue experiment providing mechanistic pathway placement\",\n      \"pmids\": [\"25778917\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Nup210 is required during chemical reprogramming of mouse fibroblasts into neural stem cells (NSCs): Nup210 activates SoxB1 transcription factors to initiate NSC fate, and its activity is required for both chemical cocktail- and growth factor (IL-6, FGF5, LIF)-driven reprogramming.\",\n      \"method\": \"Nup210 knockdown/overexpression during chemical reprogramming, transcriptome and epigenome analysis, growth factor treatment experiments\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined transcriptional target (SoxB1) and growth factor epistasis; single lab with multiple approaches\",\n      \"pmids\": [\"30067988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NUP210 interacts with LINC complex protein SUN2 (connecting nucleus to cytoskeleton), and the NUP210/SUN2 complex further interacts with chromatin via the short isoform of BRD4 and histone H3.1/H3.2 at the nuclear periphery. Nup210 depletion causes accumulation of H3K27me3 heterochromatin (mediated by PRC2) at mechanosensitive genes, repositioning of these genes within the nucleus, and defective mechanotransduction and focal adhesion.\",\n      \"method\": \"Co-immunoprecipitation (NUP210-SUN2, NUP210-BRD4 interactions), ChIP-seq (H3K27me3), DNA FISH (gene repositioning), focal adhesion assays, mouse metastasis models, Nup210 knockout cells\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP for protein interactions, ChIP-seq for chromatin modification, FISH for nuclear repositioning, and in vivo mouse model; multiple orthogonal methods in one study\",\n      \"pmids\": [\"34903738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Ablation of Nup210 in mice does not prevent skeletal muscle formation or growth, but Nup210 knockout mice show delayed muscle repair after injury, increased centrally nucleated fibers with age, abnormal fiber type distribution, and reduced muscle endurance during voluntary running.\",\n      \"method\": \"Nup210 knockout mouse model, muscle injury/repair assay, histology, voluntary running assay\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined knockout model with multiple physiological readouts; single lab\",\n      \"pmids\": [\"34911810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NUP210 expression is driven by BRD4 in colorectal cancer cells; BRD4 inhibition by ACP-1n reduces NUP210 levels and decreases nuclear size, and NUP210 silencing alone is sufficient to decrease nucleus size and cellular growth.\",\n      \"method\": \"BRD4 inhibitor treatment, NUP210 siRNA knockdown, nuclear size measurement, cell growth assay, phase separation assay\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — pharmacological and genetic approaches with defined functional readouts; BRD4-NUP210 relationship confirmed by rescue experiments; single lab\",\n      \"pmids\": [\"35159127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Nup210 requires nuclear localization sequences (NLS) to localize to the nuclear membrane surface and interacts with importin-α/β, thereby regulating nucleoplasmic transport capacity and NPC density on CRC cell surfaces; Nup210 knockdown reduces nuclear size, NPC density, and nucleoplasmic transport.\",\n      \"method\": \"Nup210 knockdown, NLS mutagenesis, co-immunoprecipitation (importin-α/β), NPC density measurement, nuclear transport assay, in vivo xenograft\",\n      \"journal\": \"Laboratory investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Weak — co-IP with importins and NLS mutagenesis for localization, functional transport assay; single lab, limited mechanistic depth in abstract\",\n      \"pmids\": [\"39393532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A FRET-based tension biosensor inserted into gp210 (at endogenous levels via CRISPR knock-in) reveals that gp210 and the NPC experience mechanical tension. Forces on gp210 increase with osmotically induced nuclear swelling and are influenced by ECM stiffness, the LINC complex, chromatin condensation, and actomyosin contractility; chromatin relaxation and MLCK inhibition increase gp210 forces, suggesting nuclear strain (rather than cytoskeletal forces) is the predominant source of NPC forces.\",\n      \"method\": \"FRET-force biosensor (TSmod), CRISPR knock-in at endogenous locus, osmotic swelling, pharmacological perturbations, live cell imaging\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Weak — novel biosensor with endogenous expression and multiple perturbations; single lab, preprint only\",\n      \"pmids\": [\"40463170\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Nup210 knockdown promotes HIV-1 infection by increasing accumulation of integrated proviral DNA, while levels of reverse transcription products and 2-LTR circles (nuclear entry intermediates) are unaffected, indicating Nup210 acts at late steps of viral nuclear entry (post-nuclear entry, affecting integration). Nup210 also regulates viral mRNA alternative splicing; knockdown increases singly spliced Vpr mRNA, and elevated Vpr may act as a viral antagonist of Nup210.\",\n      \"method\": \"Nup210 knockdown/overexpression, luciferase infectivity assay, qPCR for RT products/2-LTR circles/integrated DNA, RT-qPCR for viral mRNA species, Raltegravir integrase inhibitor epistasis\",\n      \"journal\": \"AIDS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple molecular readouts distinguishing steps of viral lifecycle, pharmacological epistasis with integrase inhibitor; single lab\",\n      \"pmids\": [\"40202922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"TMEM209 is a fourth transmembrane nucleoporin that biochemically interacts with Nup210 via a region containing its two transmembrane domains; TMEM209 localizes to NPCs by proximity labeling and immunofluorescence, and overexpression of TMEM209 specifically dissociates Nup210 from the nuclear envelope. TMEM209 depletion impairs cell growth and delays S, G2 and M phase entry.\",\n      \"method\": \"Proximity labeling, co-immunoprecipitation, immunofluorescence, siRNA depletion, overexpression, cell cycle analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity labeling and Co-IP for interaction, functional overexpression/depletion with cell cycle readout; single lab\",\n      \"pmids\": [\"41582553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"METTL3-mediated N6-methyladenosine (m6A) modification stabilizes NUP210 mRNA; METTL3 silencing reduces NUP210 expression, and NUP210 overexpression reverses the inhibitory effects of METTL3 silencing on prostate cancer cell metastasis and EMT in vitro and in vivo.\",\n      \"method\": \"MeRIP (m6A-IP), RNA-binding protein immunoprecipitation (RIP), mRNA stability assay, rescue experiments, transwell assay, in vivo metastasis model\",\n      \"journal\": \"Mutation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP and RIP demonstrate m6A modification and reader binding; mRNA stability and rescue experiments support the mechanism; single lab\",\n      \"pmids\": [\"41775163\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NUP210/gp210 is a single-pass transmembrane nucleoporin anchored in the nuclear pore membrane via its transmembrane segment (sufficient for pore-membrane sorting), where it forms SDS-resistant dimers/oligomers; its cytoplasmic tail is phosphorylated at Ser1880 by cyclin B-cdc2 during mitosis, triggering NPC disassembly and NEBD (phosphomimetic S1880E blocks NPC incorporation), while its large luminal N-terminal domain maintains nuclear envelope/ER homeostasis and drives muscle and neuronal differentiation independently of NPC association; NUP210 also functions as a cellular mechanosensor by interacting with the LINC complex protein SUN2 and with chromatin via BRD4/H3.1/H3.2, coupling extracellular mechanical signals to PRC2-mediated heterochromatin regulation, and it modulates nucleoplasmic transport and HIV-1 integration through interactions with importin-α/β.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NUP210 (gp210) is a single-pass transmembrane nucleoporin that anchors in the pore membrane of the nuclear envelope and contributes to nuclear pore complex (NPC) assembly, nuclear envelope dynamics, and mechanosensing [#0, #5]. Its single transmembrane segment is sufficient for sorting to the pore membrane domain, while its massive luminal/cisternal domain carries no localization information, and it assembles into SDS-resistant dimers and higher-order oligomers distributed with eightfold radial symmetry around the NPC ring [#0, #2, #10]. The cytoplasmic C-terminal tail drives nuclear pore dilation and NPC maturation, with its loss arresting assembly at 'mini-pore' intermediates that fail to incorporate downstream nucleoporins; depletion is lethal and produces clustered NPCs and aberrant nuclear membranes across human cells and C. elegans [#3, #5]. Cell-cycle control operates through this tail: cyclin B-cdc2 phosphorylates Ser1880 during mitosis, and a phosphomimetic substitution blocks NPC incorporation, coupling NUP210 to NPC disassembly and nuclear envelope breakdown [#1, #8, #9]. Independently of its NPC role, the conserved N-terminal luminal domain maintains nuclear envelope/ER homeostasis and is sufficient to drive muscle cell differentiation by limiting ER-stress apoptosis, and NUP210 is required for neural fate reprogramming via SoxB1 activation [#11, #12]. At the nuclear periphery NUP210 acts as a mechanosensor, bridging the LINC component SUN2 to chromatin through the short isoform of BRD4 and histones H3.1/H3.2, such that its loss drives PRC2-dependent H3K27me3 accumulation and repositioning of mechanosensitive genes, and an endogenous tension biosensor confirms that gp210 itself bears mechanical force [#13, #17]. NUP210 also engages importin-\\u03b1/\\u03b2 to regulate nucleoplasmic transport and NPC density and modulates late steps of HIV-1 nuclear entry and proviral integration [#16, #18].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Established which part of gp210 directs it to the nuclear pore, answering how a large luminal protein is targeted to the pore membrane domain.\",\n      \"evidence\": \"cDNA mutagenesis and chimeric protein expression with immunofluorescence in 3T3 cells\",\n      \"pmids\": [\"1281815\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define the luminal domain's function\", \"Mechanism of the weaker cytoplasmic-tail sorting determinant unresolved\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Identified Ser1880 in the cytoplasmic tail as a mitosis-specific phosphosite, linking gp210 to cell-cycle-regulated kinase activity.\",\n      \"evidence\": \"In vitro kinase assays with mutant fusion proteins, phosphopeptide mapping, cell cycle fractionation\",\n      \"pmids\": [\"8672508\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase identity inferred but not directly proven in this study\", \"Functional consequence of phosphorylation not yet shown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showed gp210 self-associates into stable dimers and oligomers, indicating it is an oligomeric building block at the pore membrane.\",\n      \"evidence\": \"Immunoprecipitation, velocity sedimentation, gel filtration, and crosslinking from rat liver nuclear envelopes\",\n      \"pmids\": [\"11453980\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and interface of oligomers undefined\", \"Whether oligomerization is regulated unknown\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrated the cytoplasmic tail is required for nuclear pore dilation and NPC assembly, placing gp210 at a defined step of pore maturation.\",\n      \"evidence\": \"Xenopus nuclear assembly extract with recombinant peptide and antibody inhibition, EM and immunofluorescence\",\n      \"pmids\": [\"12093788\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct partners mediating dilation not identified\", \"How the tail couples to membrane curvature unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Characterized the disordered, PII-rich conformation of the cytoplasmic domain around the Ser1880 SPXX motif, providing structural context for its regulation.\",\n      \"evidence\": \"CD, FTIR, and fluorescence spectroscopy on recombinant C-terminal domain\",\n      \"pmids\": [\"12653556\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional mutagenesis in this study\", \"Conformational changes shown only under non-physiological perturbations (TFE, pH)\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Established that gp210 loss is lethal and disrupts NPC and nuclear membrane structure across species, defining it as essential and evolutionarily conserved.\",\n      \"evidence\": \"RNAi in HeLa cells and C. elegans with EM and immunofluorescence\",\n      \"pmids\": [\"14517331\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not separate NPC-assembly role from membrane-homeostasis role\", \"Molecular cause of NPC clustering unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Refined the assembly model by showing gp210 is dispensable for POM121 and NUP107 incorporation and NPC stability, narrowing its mechanistic role.\",\n      \"evidence\": \"FRAP and immunofluorescence in gp210-deficient NIH/3T3 cells\",\n      \"pmids\": [\"15304359\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative finding in one cell model\", \"Does not identify which nucleoporins depend on gp210\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Revealed functional redundancy between gp210 and POM121 for membrane anchorage of NPCs, implying additional integral nucleoporins exist.\",\n      \"evidence\": \"siRNA double knockdown and ectopic assembly assays in HeLa and human fibroblasts\",\n      \"pmids\": [\"16702234\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the inferred additional integral nucleoporins not established here\", \"Conditions where gp210 is non-redundant undefined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Connected Ser1880 phosphorylation status to NPC retention, showing mitotic phosphorylation dissociates gp210 from the pore.\",\n      \"evidence\": \"S1880A/S1880E mutagenesis with live imaging and FRAP\",\n      \"pmids\": [\"17559836\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not identify the phosphatase reversing the modification\", \"Single cell system\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Established gp210 as required for nuclear envelope breakdown and linked its hyperphosphorylation to cyclin B-cdc2 via genetic epistasis.\",\n      \"evidence\": \"RNAi and antibody inhibition in C. elegans embryos with cyclin B depletion epistasis\",\n      \"pmids\": [\"18216332\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct demonstration of cdc2 acting on Ser1880 in vivo not shown\", \"How NEBD failure causes nuclear twinning mechanistically unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Positioned gp210 spatially at each of the eight NPC subunits, anchoring structural models of its arrangement around the pore.\",\n      \"evidence\": \"dSTORM super-resolution imaging of Xenopus oocyte nuclear envelopes\",\n      \"pmids\": [\"22389396\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Copy number per spoke not quantified\", \"Does not address dynamics or conformational state\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Uncovered an NPC-independent function: the luminal N-terminal domain drives muscle differentiation by maintaining ER/NE homeostasis and limiting ER-stress apoptosis.\",\n      \"evidence\": \"Domain-deletion mutagenesis, C2C12 differentiation, caspase assays, and ER-stress inhibitor rescue\",\n      \"pmids\": [\"25778917\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Luminal-domain binding partners unidentified\", \"Molecular trigger of ER stress upon depletion unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended the differentiation role to neural fate, showing Nup210 acts upstream of SoxB1 transcription factors during reprogramming.\",\n      \"evidence\": \"Knockdown/overexpression during chemical reprogramming with transcriptome/epigenome analysis and growth factor epistasis\",\n      \"pmids\": [\"30067988\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect activation of SoxB1 not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined NUP210 as a mechanosensor coupling the LINC complex (SUN2) to chromatin through BRD4 and H3.1/H3.2, regulating PRC2 heterochromatin and gene positioning.\",\n      \"evidence\": \"Reciprocal Co-IP, H3K27me3 ChIP-seq, DNA FISH, focal adhesion assays, and mouse metastasis models in Nup210-knockout cells\",\n      \"pmids\": [\"34903738\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a luminal/membrane nucleoporin physically reaches chromatin not fully resolved\", \"Direct versus indirect SUN2-BRD4 bridging unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Tested the muscle role in vivo, showing Nup210 is dispensable for muscle formation but required for repair, fiber-type balance, and endurance.\",\n      \"evidence\": \"Nup210 knockout mouse with injury/repair, histology, and voluntary running assays\",\n      \"pmids\": [\"34911810\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation with the essential C2C12 differentiation phenotype incomplete\", \"Cell-autonomous versus systemic effects unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked BRD4 to NUP210 expression in cancer, with NUP210 controlling nuclear size and cell growth.\",\n      \"evidence\": \"BRD4 inhibitor treatment, NUP210 siRNA, nuclear size and growth assays in colorectal cancer cells\",\n      \"pmids\": [\"35159127\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking NUP210 to nuclear size not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed NUP210 uses NLS-dependent localization and importin-\\u03b1/\\u03b2 binding to regulate nucleoplasmic transport and NPC density.\",\n      \"evidence\": \"NLS mutagenesis, importin Co-IP, NPC density and transport assays, xenografts in CRC cells\",\n      \"pmids\": [\"39393532\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic depth limited\", \"Relationship to canonical transmembrane targeting unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided direct evidence that gp210 bears mechanical force, identifying nuclear strain as the predominant force source at the NPC.\",\n      \"evidence\": \"CRISPR knock-in FRET tension biosensor with osmotic and pharmacological perturbations (preprint)\",\n      \"pmids\": [\"40463170\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, single lab\", \"Functional consequence of gp210 tension not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated Nup210 in late HIV-1 nuclear entry/integration and viral mRNA splicing, with Vpr as a potential antagonist.\",\n      \"evidence\": \"Knockdown/overexpression, qPCR for viral intermediates, integrase inhibitor epistasis, viral mRNA RT-qPCR\",\n      \"pmids\": [\"40202922\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct interaction with viral or host integration machinery not shown\", \"Mechanism of splicing regulation undefined\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified TMEM209 as a transmembrane nucleoporin that binds Nup210 and controls its retention at the nuclear envelope.\",\n      \"evidence\": \"Proximity labeling, Co-IP, immunofluorescence, depletion/overexpression with cell cycle analysis\",\n      \"pmids\": [\"41582553\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of Nup210 dissociation by TMEM209 unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Placed NUP210 downstream of m6A regulation, with METTL3 stabilizing NUP210 mRNA to promote cancer metastasis.\",\n      \"evidence\": \"MeRIP, RIP, mRNA stability and rescue assays, transwell and in vivo metastasis models in prostate cancer\",\n      \"pmids\": [\"41775163\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct m6A site mapping not detailed\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NUP210's distinct domains coordinate its NPC-assembly, ER/NE-homeostasis, mechanosensing, and transport-regulatory functions within a single protein remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure integrating luminal, transmembrane, and cytoplasmic domains\", \"Luminal-domain interactome unidentified\", \"Mechanism coupling membrane anchorage to chromatin regulation undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 3, 5, 10]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [13, 17]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [0, 2, 10]},\n      {\"term_id\": \"GO:0005643\", \"supporting_discovery_ids\": [0, 3, 10]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [3, 16]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 8, 9]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [11, 12]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"complexes\": [\"nuclear pore complex\", \"LINC complex (via SUN2)\"],\n    \"partners\": [\"SUN2\", \"BRD4\", \"H3.1/H3.2\", \"importin-\\u03b1\", \"importin-\\u03b2\", \"TMEM209\", \"POM121\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}