{"gene":"XPO1","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2014,"finding":"Crystal structures of CRM1/XPO1 demonstrate that SINE compounds (e.g., KPT-330/selinexor) covalently bind to cysteine 528 (C528) in the NES-binding groove of XPO1, thereby blocking cargo NES binding and inhibiting nuclear export. The active-site C528 was validated as the prime drug-binding residue by CRISPR/Cas9 introduction of C528S mutation, which confers full resistance to selinexor.","method":"X-ray crystallography, CRISPR/Cas9 genome editing with functional resistance assays (cytotoxicity, apoptosis, cell cycle, direct drug binding)","journal":"Chemistry & Biology / Blood / Seminars in Cancer Biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis/genome editing in multiple papers with orthogonal methods confirming covalent C528 binding","pmids":["25579209","23034282","24631835"],"is_preprint":false},{"year":2014,"finding":"Atomic-resolution crystal structures reveal that RanGTP and cargo NES bind CRM1 with positive cooperativity, that RanBP1 triggers release of export cargoes in the cytoplasm, and that leptomycin B and KPT-SINE compounds block export by occupying the hydrophobic NES-binding cleft of CRM1.","method":"X-ray crystallography of CRM1 complexes with RanGTP, cargo NES peptides, RanBP1, leptomycin B, and SINE inhibitors","journal":"Seminars in Cancer Biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple atomic-resolution structures from several independent laboratories establishing cooperative binding mechanism","pmids":["24631835","24823279"],"is_preprint":false},{"year":2001,"finding":"Ran-binding protein 3 (RanBP3) acts as a nuclear cofactor for CRM1-mediated export: it binds directly to CRM1, enhances CRM1 affinity for both RanGTP and NES cargo, and forms a quaternary CRM1–RanBP3–NES–RanGTP complex that can associate with nucleoporins. RanBP3 also modulates the relative affinity of CRM1 for different export substrates.","method":"Permeabilized cell nuclear export assay, GST pulldown, co-immunoprecipitation, nucleoporin binding assay","journal":"Journal of Cell Biology / EMBO Reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — replicated independently in two labs using reciprocal pulldowns, permeabilized cell assays, and functional export reconstitution","pmids":["11425870","11571268"],"is_preprint":false},{"year":1999,"finding":"CRM1 mediates nuclear export of snurportin 1 (the m3G-capped U snRNP import adapter) via a large domain interaction distinct from short NES peptides. Snurportin 1 binds CRM1 with ~50-fold higher affinity than Rev NES and with ~5,000-fold higher affinity than minimum Rev NES. Critically, snurportin 1 has low CRM1 affinity when bound to its import substrate (m3G-cap) and high affinity when substrate-free, coupling import substrate release to CRM1 recycling.","method":"In vitro binding assays, permeabilized-cell export reconstitution, affinity measurements","journal":"Journal of Cell Biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with quantitative affinity measurements and mechanistic mutagenesis, single lab with multiple orthogonal methods","pmids":["10209022"],"is_preprint":false},{"year":2007,"finding":"PARP-1-mediated poly(ADP-ribosyl)ation of p53 at specific sites blocks the interaction between p53 and CRM1, resulting in nuclear accumulation of p53 in response to DNA damage. This provides a mechanism by which DNA damage signals through PARP-1 to retain p53 in the nucleus for transactivation.","method":"Identification of poly(ADP-ribosyl)ation sites by mass spectrometry, in vitro and cellular co-immunoprecipitation of p53-CRM1 interaction, PARP-1 knockout/inhibition with subcellular fractionation and functional reporter assays","journal":"Nature Cell Biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — rigorous mapping of modification sites combined with interaction assays and loss-of-function experiments, published in high-impact journal","pmids":["17891139"],"is_preprint":false},{"year":2018,"finding":"Linear correlation exists between CRM1-NES binding affinity (Kd) and nuclear export activity for NESs with Kds between tens of nanomolar to tens of micromolar; NESs outside this range show reduced activity. An unusually tight-binding MVM NS2 NES was structurally explained by intramolecular contacts stabilizing the CRM1-bound conformation, enabling design of picomolar-affinity CRM1-inhibiting peptides.","method":"Quantitative binding assays (ITC/fluorescence polarization) for 24 NES peptides, cell-based nuclear export assays, X-ray crystal structure of CRM1–MVM NS2 NES complex","journal":"Molecular Biology of the Cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure combined with quantitative binding and functional export assays across many NES sequences in a single rigorous study","pmids":["29927350"],"is_preprint":false},{"year":2020,"finding":"The E571K oncogenic mutation of CRM1 alters NES-binding groove charge, causing altered (increased or decreased >10-fold) binding affinity for select NES-containing cargoes (e.g., eIF4E-transporter, Mek1, RPS2) while leaving most NES affinities unchanged. eIF4E-transporter is mislocalized in tumor cells carrying CRM1(E571K), providing proof-of-concept that E571K confers cargo-selective nuclear export changes driving cancer.","method":"CRISPR/Cas9-generated monoallelic and biallelic CRM1-E571K HEK293 cell lines, quantitative binding assays for 27 NES peptides, X-ray crystal structures, subcellular localization by immunofluorescence, structure-based bioinformatics","journal":"Molecular Biology of the Cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures combined with genome editing, quantitative binding, and functional localization assays in a single comprehensive study","pmids":["32520643"],"is_preprint":false},{"year":2021,"finding":"Crystal structures of wild-type and E571K XPO1 bound to SINE inhibitors (KPT-185, selinexor/KPT-330, eltanexor/KPT-8602) are highly similar, demonstrating that E571K mutations at the CRM1 cargo-binding groove do not structurally interfere with SINE drug binding, explaining why SINE activity is not abrogated by E571 mutations in CLL patients.","method":"X-ray crystallography of XPO1(WT) and XPO1(E571K) bound to three SINE compounds","journal":"Journal of Hematology & Oncology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple crystal structures with direct structural comparison, single study with clear functional implication","pmids":["33451349"],"is_preprint":false},{"year":2014,"finding":"CRM1 forms a dimer (observed by single-particle electron microscopy) when assembled in the HIV Rev–RRE nuclear export complex. The CRM1 dimer interface enhances association with the Rev-RRE oligomer and poises NES-binding sites to interact with multiple Rev NES domains. Differences in dimerization between CRM1 orthologs correlate with altered nuclear export and HIV cellular tropism.","method":"Single-particle electron microscopy of assembled HIV Rev–RRE–CRM1–RanGTP export complex, biochemical assembly assays","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — single-particle EM structure from one lab, no independent replication; novel finding of CRM1 dimerization in this context","pmids":["25486595"],"is_preprint":false},{"year":2006,"finding":"CRM1/XPO1 interacts with EGFR and mediates its nuclear export; co-immunoprecipitation detected EGFR–CRM1 interaction, and leptomycin B (CRM1 inhibitor) caused marked nuclear EGFR accumulation, indicating CRM1-dependent export is required to maintain EGFR nuclear-cytoplasmic balance.","method":"Co-immunoprecipitation, leptomycin B inhibition with subcellular fractionation and immunofluorescence","journal":"Journal of Cellular Biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP plus pharmacological inhibition, replicated with two orthogonal methods in one lab","pmids":["16552725"],"is_preprint":false},{"year":2019,"finding":"Chromatin-bound CRM1 recruits leukemogenic proteins SET-Nup214 (via nucleoporin-CRM1 interaction) and NPM1c (via its NES) to HOX cluster chromatin regions, causing aberrant HOX gene activation in leukemia cells. CRM1 inhibition with selinexor suppresses this HOX activation.","method":"ChIP-seq, co-immunoprecipitation, loss-of-function with selinexor, chromatin fractionation, CRM1 knockdown in human leukemia cell lines","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq and Co-IP combined with functional CRM1 inhibition, single lab with multiple orthogonal methods","pmids":["31755865"],"is_preprint":false},{"year":2015,"finding":"CRM1 and its ribosome export adaptor NMD3 co-localize with nucleolar marker proteins in the nucleolus; CRM1 nucleolar localization is dependent on its own export activity and on NMD3 expression (which provides nucleolar tethering), while NMD3 localization is CRM1-independent. CRM1 inhibition reduces 28S rRNA processing and both CRM1 and NMD3 inactivation reduce the rate of pre-47S rRNA synthesis.","method":"Immunofluorescence and confocal imaging, subcellular fractionation, siRNA knockdown, leptomycin B inhibition, rRNA synthesis rate measurement (pulse labeling)","journal":"Nucleus","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal localization and functional approaches in single lab; direct nucleolar CRM1 role with mechanistic follow-up","pmids":["23782956"],"is_preprint":false},{"year":2000,"finding":"CRM1/XPO1 activity is developmentally regulated during early Xenopus embryogenesis: the protein is present but functionally inactive until the gastrula-neurula transition. CRM1 becomes active (leptomycin B-sensitive) concomitant with a change in its nuclear localization, as demonstrated by pulldown experiments and localization of a GFP–NES reporter.","method":"Leptomycin B sensitivity assays at defined developmental stages, GFP-NES reporter localization in embryos, pulldown assays for RanGTP-CRM1 interaction, subcellular immunofluorescence","journal":"Journal of Cell Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (reporter, pulldown, LMB sensitivity) in Xenopus developmental system, single lab","pmids":["10639332"],"is_preprint":false},{"year":2015,"finding":"A non-canonical stepwise mechanism assembles Crm1 export complexes for 40S pre-ribosome export: the RanGTP-binding protein Slx9 scaffolds Rio2 (NES adaptor) and RanGTP, and this pre-assembled complex directly loads Crm1. A Slx9 mutation impairing Crm1-export complex assembly inhibits 40S pre-ribosome export in vivo.","method":"In vitro reconstitution of complex assembly, co-immunoprecipitation, yeast genetics (mutant phenotypes), sucrose gradient sedimentation, nuclear export assay","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution combined with genetic epistasis and in vivo export assay in a single rigorous study","pmids":["25895666"],"is_preprint":false},{"year":2008,"finding":"Yeast Xpo1/Crm1 physically interacts with spindle pole body component Spc72 in a RanGTP- and NES-dependent manner. Mutations in the Spc72 NES impair mitotic spindle morphology in vivo and xpo1 mutants show reduced cytoplasmic microtubules, establishing a functional link between Xpo1 and spindle pole body/spindle biogenesis.","method":"Two-hybrid, co-immunoprecipitation, NES mutagenesis, fluorescence microscopy of spindle morphology in yeast mutants","journal":"Molecular and Cellular Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and biochemical evidence in yeast with NES mutagenesis and in vivo phenotype, single lab","pmids":["18573877"],"is_preprint":false},{"year":2009,"finding":"Yeast hexokinase 2 (Hxk2) is exported from the nucleus via Xpo1/CRM1 through two leucine-rich NES sequences (NES1: L23–I33; NES2: L310–L318). Phosphorylation of Hxk2 at serine 14 in low-glucose conditions promotes its nuclear export by facilitating Hxk2–Xpo1 association.","method":"Co-immunoprecipitation of Hxk2–Xpo1, NES mutagenesis, phosphomimetic/phospho-dead mutants, nuclear fractionation, leptomycin B inhibition in yeast","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — NES mutagenesis combined with Co-IP and phospho-mutant analysis in a single lab study","pmids":["19525230"],"is_preprint":false},{"year":2017,"finding":"CRM1/XPO1 inhibition by leptomycin B selectively enhances juxta-nuclear adenovirus association with microtubules and boosts virion motions on microtubules near the nuclear membrane, indicating that CRM1 normally provides positional information that facilitates transfer of incoming virions from microtubules to nuclear pore complexes (NPCs). LMB did not compete with adenovirus for nucleoporin Nup214 binding at NPCs.","method":"Single-particle tracking, super-resolution microscopy, leptomycin B treatment, Nup214 binding assay, quantification of virion motility near nuclear membrane","journal":"Journal of Cell Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct live-cell tracking and super-resolution imaging with pharmacological CRM1 inhibition showing clear mechanistic distinction from Nup214 competition","pmids":["28515232"],"is_preprint":false},{"year":2017,"finding":"Importin-β and CRM1 play opposing roles in regulating RANBP2-SUMO-RANGAP1 localization at kinetochores during mitosis: CRM1 promotes deposition of the complex at kinetochores, while importin-β keeps it away. Overexpression of CRM1 or importin-β respectively advances or retards RANBP2 kinetochore localization, affecting accumulation of SUMO-conjugated topoisomerase-IIα and stability of kinetochore fibres.","method":"Proximity ligation assays, inducible CRM1 and importin-β overexpression cell lines, immunofluorescence, kinetochore fibre stability assay","journal":"Journal of Cell Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity ligation assays and inducible overexpression with functional kinetochore readouts, single lab","pmids":["28600321"],"is_preprint":false},{"year":2017,"finding":"LMB alters CRM1 subcellular distribution: upon binding to C528, LMB causes CRM1 to redistribute from the nucleus to the cytoplasm by inhibiting CRM1 nuclear import (not by trapping it in the cytoplasm). CRM1-C528S mutant is insensitive to this redistribution, confirming C528 dependence.","method":"Cell fractionation, immunofluorescence, microinjection of GFP-CRM1 into nucleus or cytoplasm, LMB treatment, C528S mutant comparison","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — microinjection plus fractionation with C528S mutant control, single lab with orthogonal methods","pmids":["28412356"],"is_preprint":false},{"year":2020,"finding":"In normal erythroid progenitors, HSP70 nuclear localization during terminal maturation is regulated by XPO1-mediated export; XPO1 inhibition increases nuclear HSP70 levels, rescues GATA-1 transcription factor expression, and improves terminal differentiation in β-thalassemic erythroblasts where HSP70 is aberrantly sequestered in the cytoplasm by free α-globin chains.","method":"XPO1 inhibitor treatment of primary human erythroblasts from β-thalassemia patients, subcellular fractionation/immunofluorescence for HSP70 localization, GATA-1 expression assays, differentiation markers","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition with functional erythroid differentiation readouts and mechanistic link to GATA-1 and HSP70, single lab","pmids":["33054049"],"is_preprint":false},{"year":2015,"finding":"SINE compound-mediated XPO1 inhibition causes nuclear retention of FBXL5, which in turn suppresses the EMT driver snail and reverses epithelial-to-mesenchymal transition (EMT) in human mammary epithelial cells. This mechanism was confirmed using FBXL5 siRNA (which abrogates SINE activity) and a CRM1-C528S mutant (lacking SINE binding site, resistant to SINE-induced EMT reversal).","method":"FBXL5 siRNA knockdown, CRM1-C528S mutant overexpression, immunofluorescence/fractionation for FBXL5 and snail localization, Western blotting, xenograft tumor models","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic (siRNA, C528S mutant) plus pharmacological inhibition with defined mechanistic pathway, single lab","pmids":["26536918"],"is_preprint":false},{"year":2019,"finding":"XPO1 overexpression upon DNA damage causes export of EIF4E and THOC4 carrying DNA damage repair mRNAs, thereby increasing synthesis of DNA repair proteins and conferring tolerance to genotoxic stress. XPO1 inhibition decreases DNA repair capacity and sensitizes lymphoma cells to DNA-damaging chemotherapy.","method":"RNA immunoprecipitation showing XPO1 binding to EIF4E and THOC4 on DNA damage repair mRNAs, ribosome profiling, XPO1 overexpression and inhibition experiments, patient-derived xenograft models, phase I clinical trial validation","journal":"Cancer Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-IP with functional mRNA export and translation measurements, gain- and loss-of-function approaches, single lab with translational clinical data","pmids":["37801604"],"is_preprint":false},{"year":2023,"finding":"The E3 ubiquitin ligase ASB8 promotes selinexor-induced proteasomal degradation of XPO1. ASB8 loss-of-function (knockout) and overexpression both result in selinexor hypersensitivity, indicating ASB8 modulates drug-induced XPO1 protein turnover as a shared vulnerability across cancer types.","method":"CRISPR-Cas9 loss-of-function chemogenetic screen, ASB8 knockout/overexpression with selinexor sensitivity assays, proteasome inhibitor rescue experiments confirming proteasomal degradation pathway","journal":"Biomedicine & Pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genome-wide CRISPR screen plus mechanistic validation by rescue experiments, single lab","pmids":["36731340"],"is_preprint":false},{"year":2022,"finding":"XPO1 inhibition by selinexor activates PI3Kγ-dependent AKT signaling in AML via upregulation of the purinergic receptor P2RY2. This adaptive resistance mechanism was identified by systematic CRISPR-Cas9 screening and validated in AML cell lines, patient-derived primary cultures, and multiple mouse models. Combined XPO1 + AKT inhibition outperforms standard-of-care chemotherapy in MLL-AF9-driven AML.","method":"CRISPR-Cas9 gain/loss-of-function screens, P2RY2 knockdown/overexpression, PI3K/AKT pathway inhibition rescue experiments, in vivo mouse AML models, patient-derived primary cultures","journal":"Nature Cancer","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic genome-wide screening plus orthogonal genetic and pharmacological validation in multiple models including in vivo, published in high-impact journal","pmids":["35668193"],"is_preprint":false},{"year":2023,"finding":"XPO1 interacts with the C-terminus of NPM1 and mediates acetylation of NPM1 at lysine 54, which contributes to sorafenib resistance in hepatocellular carcinoma. XPO1 also binds Vimentin, promoting EMT progression in sorafenib-resistant cells.","method":"Co-immunoprecipitation, mass spectrometry identification of NPM1 acetylation site, immunofluorescence colocalization, CRISPR/Cas9 knockin, RNA-seq, functional proliferation/migration assays","journal":"Biomedicine & Pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with MS-based PTM identification and CRISPR validation, single lab with multiple orthogonal methods","pmids":["36791564"],"is_preprint":false},{"year":2010,"finding":"IL-1β stimulates CRM1 expression in astrocytes, concurrent with translocation of HMGB1 from nucleus to cytoplasm via a CRM1-dependent pathway. ERK MAP kinase activity is required upstream of CRM1 for this effect: MEK/ERK inhibition reduces CRM1 upregulation and blocks HMGB1 nuclear export.","method":"Immunofluorescence, Western blotting, MEK/ERK inhibitor (U0126), CRM1 expression analysis, HMGB1 subcellular fractionation in primary rat astrocytes","journal":"Glia","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single pharmacological inhibitor without genetic confirmation of CRM1 in HMGB1 export; mechanistic link is indirect","pmids":["20222144"],"is_preprint":false},{"year":2024,"finding":"NPM1-fusion proteins (NPM1::MLF1 and NPM1::CCDC28A) are recruited to HOX gene cluster chromatin via XPO1 (through NES-CRM1 interaction), causing aberrant HOX gene upregulation in AML. XPO1 inhibitor selinexor suppresses fusion-protein-driven HOX activation and colony formation, establishing XPO1 as essential for NPM1-fusion-mediated leukemogenesis.","method":"ChIP-seq, subcellular localization imaging, mouse bone marrow transplantation AML model, selinexor treatment with HOX reporter and colony formation assays","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq and in vivo mouse AML model with pharmacological rescue, single lab","pmids":["39443736"],"is_preprint":false},{"year":2021,"finding":"CRM1 inhibition by leptomycin B or SINE compounds blocks nuclear export of the RSV matrix (M) protein, causing its retention in the nucleus and reducing RSV replication in human respiratory epithelial cells. The effect was reversible within 24 h of compound removal.","method":"SINE compound treatment (KPT-335, KPT-185) of RSV-infected cells, immunofluorescence for M protein localization, viral titer measurement, cell cycle analysis","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pharmacological CRM1 inhibition with localization and functional viral titer readouts, replicated in prior work; mechanistic specificity supported by leptomycin B and two SINE compounds","pmids":["34584169"],"is_preprint":false},{"year":2021,"finding":"Structure-guided design yielded the first noncovalent CRM1 inhibitor (NCI-1), which binds the 'open' NES groove of CRM1 simultaneously occupying two hydrophobic pockets (rather than forming a covalent bond to C528). Crystal structures of yeast CRM1–NCI-1 complex confirmed this binding mode, and NCI-1 inhibited nuclear export in cells carrying the human CRM1-C528S covalent-inhibitor-resistant mutant.","method":"X-ray crystal structure of yeast CRM1–NCI-1 complex, binding affinity assays in presence/absence of RanGTP, cell-based nuclear export assay including CRM1-C528S mutant cells","journal":"Journal of Medicinal Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with quantitative binding and functional export assays including drug-resistant mutant validation, single rigorous study","pmids":["33974430"],"is_preprint":false},{"year":2012,"finding":"NLP1 (NUPL2/hCG1), a nucleoporin-like FG-repeat protein that localizes to the nuclear envelope and is mobile within the nucleus, promotes CRM1–RanGTP complex formation (with or without NES cargo) and facilitates CRM1-dependent nuclear export. NLP1 depletion reduces CRM1-dependent export rates; overexpression enhances export of specific cargoes.","method":"Fluorescence microscopy, pulldown assays for CRM1–RanGTP–NLP1 complexes, siRNA depletion with nuclear export assay, overexpression experiments, RanBP1/Nup214 dissociation assays","journal":"Journal of Cell Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA loss-of-function and overexpression with direct export assays and complex reconstitution, single lab","pmids":["22250199"],"is_preprint":false},{"year":2020,"finding":"Crystal structure of human CRM1 (hCRM1) bound to leptomycin B in complex with RanGTP was solved, revealing that hCRM1 exhibits 16-fold lower NES-binding affinity than yeast CRM1 and significant affinity differences toward various CRM1 inhibitors. A human-adapted CRM1-T539C mutant (analogous to yeast) does not bind all tested inhibitors, establishing species-specific pharmacological distinctions.","method":"X-ray crystallography of hCRM1–RanGTP–leptomycin B complex, quantitative binding assays for multiple inhibitors and NES peptides","journal":"Journal of Medicinal Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure of human CRM1 complex combined with quantitative binding assays revealing mechanistic species differences","pmids":["32585100"],"is_preprint":false}],"current_model":"XPO1/CRM1 is the major nuclear export receptor that recognizes leucine-rich nuclear export signals (NESs) on cargo proteins by forming a cooperative ternary complex with RanGTP in the nucleus; cofactors RanBP3 and NLP1 facilitate complex assembly, the complex translocates through nuclear pore complexes (interacting with nucleoporins), and is disassembled in the cytoplasm by RanBP1 and RanGAP. Its NES-binding groove contains an essential cysteine (C528) that is the covalent target of leptomycin B and SINE inhibitors (e.g., selinexor). Post-translational modifications of cargo (e.g., poly-ADP-ribosylation of p53 by PARP-1, phosphorylation of Hxk2 at S14) regulate CRM1–cargo interactions to control nucleocytoplasmic partitioning in response to cellular signals. Beyond transport, CRM1 plays roles in spindle pole body function/spindle assembly (via interaction with Spc72/RanGTP), nucleolar rRNA biogenesis (with adaptor NMD3), chromatin-associated recruitment of leukemogenic proteins to HOX gene clusters, and regulation of genotoxic stress tolerance through mRNA export of DNA repair transcripts."},"narrative":{"mechanistic_narrative":"XPO1/CRM1 is the major leucine-rich nuclear export receptor that recognizes nuclear export signals (NESs) on cargo proteins and translocates them through nuclear pore complexes, with cargo recognition driven by positive cooperativity between RanGTP and NES binding and cargo release in the cytoplasm triggered by RanBP1 [PMID:24631835, PMID:24823279]. Crystal structures define a hydrophobic NES-binding cleft whose affinity for diverse NES sequences scales linearly with export activity over a defined Kd window, and whose conserved cysteine 528 is the covalent target of leptomycin B and SINE inhibitors such as selinexor [PMID:25579209, PMID:23034282, PMID:24631835, PMID:29927350]. Complex assembly is assisted by the nuclear cofactors RanBP3, which enhances CRM1 affinity for both RanGTP and NES cargo within a quaternary CRM1–RanBP3–NES–RanGTP complex that engages nucleoporins [PMID:11425870, PMID:11571268], and the nucleoporin-like FG-repeat protein NLP1/NUPL2, which promotes CRM1–RanGTP complex formation and export [PMID:22250199]. Beyond canonical peptide cargoes, CRM1 exports large folded substrates such as snurportin 1 in a manner coupled to import-substrate release, and assembles via non-canonical stepwise adaptor mechanisms for ribosomal subunit export, scaffolded by Slx9/Rio2 for the 40S pre-ribosome and by NMD3 in the nucleolus where CRM1 supports rRNA processing [PMID:10209022, PMID:25895666, PMID:23782956]. Cargo partitioning is gated by signal-responsive post-translational modifications: PARP-1-mediated poly(ADP-ribosyl)ation of p53 and phosphorylation of hexokinase 2 at serine 14 modulate cargo–CRM1 association [PMID:17891139, PMID:19525230]. CRM1 also contributes to mitotic spindle and kinetochore organization through RanGTP/NES-dependent interactions with Spc72 and through deposition of the RANBP2–SUMO–RANGAP1 complex at kinetochores [PMID:18573877, PMID:28600321]. In cancer, CRM1 drives leukemogenesis by recruiting NPM1c and NPM1-fusion proteins to HOX cluster chromatin to aberrantly activate HOX genes, and supports genotoxic stress tolerance by exporting EIF4E/THOC4-bound DNA repair mRNAs; the recurrent E571K oncogenic mutation alters the NES-groove charge to confer cargo-selective export changes without abrogating SINE drug binding [PMID:31755865, PMID:39443736, PMID:37801604, PMID:32520643, PMID:33451349].","teleology":[{"year":1999,"claim":"Established that CRM1 exports not only short NES peptides but large folded domains, and that export affinity can be coupled to release of the cargo's own import substrate.","evidence":"In vitro binding and permeabilized-cell export reconstitution of snurportin 1 with quantitative affinity measurements","pmids":["10209022"],"confidence":"High","gaps":["Single-lab study","Generality of substrate-coupled affinity switching to other cargoes not established"]},{"year":2000,"claim":"Showed that CRM1 export activity is not constitutive but developmentally gated, linking the receptor to programmed control of nucleocytoplasmic partitioning.","evidence":"Leptomycin B sensitivity, GFP-NES reporter localization, and RanGTP-CRM1 pulldowns across Xenopus developmental stages","pmids":["10639332"],"confidence":"Medium","gaps":["Molecular trigger for activation at gastrula-neurula transition unidentified","Single model system"]},{"year":2001,"claim":"Identified RanBP3 as a nuclear cofactor that enhances CRM1 affinity for RanGTP and cargo, explaining how stable export complexes form and can tune substrate selectivity.","evidence":"Permeabilized-cell export assays, GST pulldowns, co-IP, and nucleoporin-binding assays in two independent labs","pmids":["11425870","11571268"],"confidence":"High","gaps":["Quantitative contribution relative to other cofactors unresolved"]},{"year":2007,"claim":"Demonstrated that a signal-responsive PTM on cargo controls CRM1 engagement, providing a mechanism for damage-induced nuclear retention of p53.","evidence":"MS mapping of poly(ADP-ribosyl)ation sites with co-IP of p53-CRM1 and PARP-1 loss-of-function/fractionation assays","pmids":["17891139"],"confidence":"High","gaps":["Whether modification acts directly on the NES or sterically remains incompletely defined"]},{"year":2008,"claim":"Linked CRM1 to spindle pole body and spindle biogenesis through a RanGTP/NES-dependent interaction, extending its role beyond bulk export.","evidence":"Two-hybrid, co-IP, Spc72 NES mutagenesis, and spindle morphology imaging in yeast mutants","pmids":["18573877"],"confidence":"Medium","gaps":["Whether the role is export-dependent or a moonlighting scaffolding function unclear","Yeast only"]},{"year":2009,"claim":"Showed that cargo phosphorylation in response to a metabolic signal promotes CRM1 export, connecting nucleocytoplasmic partitioning to nutrient state.","evidence":"Hxk2-Xpo1 co-IP, dual NES mutagenesis, and phosphomimetic/phospho-dead analysis in yeast","pmids":["19525230"],"confidence":"Medium","gaps":["Kinase responsible for S14 phosphorylation not identified here","Single model organism"]},{"year":2014,"claim":"Resolved the atomic mechanism of export-complex assembly and inhibition, defining cooperative RanGTP/NES binding, RanBP1-triggered release, and covalent C528 targeting by leptomycin B and SINE compounds.","evidence":"X-ray crystallography of multiple CRM1 complexes plus CRISPR C528S resistance assays across several studies","pmids":["24631835","24823279","25579209","23034282"],"confidence":"High","gaps":["Structures do not capture dynamic transit through the pore","Cargo-specific recognition determinants beyond the consensus NES incompletely modeled"]},{"year":2014,"claim":"Proposed that CRM1 can dimerize to assemble multivalent export complexes, illustrated by the HIV Rev-RRE system and correlated with viral tropism.","evidence":"Single-particle EM of the assembled Rev-RRE-CRM1-RanGTP complex and biochemical assembly assays","pmids":["25486595"],"confidence":"Medium","gaps":["Single-lab EM without independent replication","Whether dimerization occurs for endogenous cellular cargoes unknown"]},{"year":2015,"claim":"Defined non-canonical, adaptor-scaffolded mechanisms of CRM1 export for ribosomal subunits and placed CRM1 in nucleolar rRNA biogenesis.","evidence":"Slx9/Rio2 in vitro reconstitution with yeast genetics; NMD3 co-localization, siRNA, LMB inhibition, and rRNA synthesis-rate measurements","pmids":["25895666","23782956"],"confidence":"High","gaps":["How the nucleolar/rRNA-processing role relates mechanistically to bulk export incompletely defined","Human Slx9 ortholog role not directly tested here"]},{"year":2018,"claim":"Quantitatively related CRM1-NES binding affinity to export activity, establishing the affinity window governing functional export and enabling rational inhibitor peptide design.","evidence":"ITC/fluorescence-polarization binding for 24 NES peptides, cell-based export assays, and crystal structure of the CRM1-MVM NS2 NES complex","pmids":["29927350"],"confidence":"High","gaps":["Predictivity for cargoes with non-canonical binding modes not established"]},{"year":2019,"claim":"Revealed a chromatin-associated, transport-coupled function in which CRM1 recruits leukemogenic proteins to HOX clusters, and an mRNA-export role supporting genotoxic stress tolerance.","evidence":"ChIP-seq, co-IP, chromatin fractionation, and selinexor rescue for SET-Nup214/NPM1c; RNA-IP, ribosome profiling, and PDX/clinical validation for EIF4E/THOC4 DNA-repair mRNA export","pmids":["31755865","37801604"],"confidence":"Medium","gaps":["Whether chromatin recruitment requires active export or is a static scaffold unresolved","Selectivity of repair-mRNA cargo loading not fully defined"]},{"year":2020,"claim":"Showed that the recurrent oncogenic E571K mutation alters NES-groove electrostatics to produce cargo-selective export changes, and that human CRM1 differs pharmacologically from yeast.","evidence":"CRISPR E571K cell lines with quantitative binding for 27 NES peptides, crystal structures, and immunofluorescence; separate hCRM1-RanGTP-LMB structure with inhibitor binding panel","pmids":["32520643","32585100"],"confidence":"High","gaps":["Full repertoire of E571K-affected cargoes incomplete","In vivo oncogenic consequences of specific cargo shifts not enumerated"]},{"year":2021,"claim":"Established that E571K does not impair covalent SINE binding and that the NES groove can be targeted noncovalently, expanding strategies against drug-resistant CRM1.","evidence":"Crystal structures of WT and E571K XPO1 with three SINE compounds; structure-guided NCI-1 design with crystal structure and export assays in C528S cells","pmids":["33451349","33974430"],"confidence":"High","gaps":["In vivo efficacy and selectivity of noncovalent inhibitors not addressed"]},{"year":2022,"claim":"Identified adaptive resistance and degradation pathways shaping CRM1 inhibitor response, defining combination vulnerabilities and turnover regulators.","evidence":"CRISPR screens with genetic/pharmacological validation in AML models (PI3Kγ/AKT via P2RY2); chemogenetic screen identifying ASB8-mediated proteasomal XPO1 degradation","pmids":["35668193","36731340"],"confidence":"High","gaps":["Generality of P2RY2/AKT resistance beyond AML uncertain","Direct ASB8-XPO1 ubiquitination chemistry not structurally resolved"]},{"year":2023,"claim":"Extended CRM1's tumor roles to direct partner binding and PTM events driving therapy resistance in solid tumors.","evidence":"Co-IP, MS identification of NPM1 K54 acetylation, CRISPR knockin, and migration/proliferation assays in sorafenib-resistant hepatocellular carcinoma","pmids":["36791564"],"confidence":"Medium","gaps":["Whether XPO1 directly catalyzes or merely scaffolds NPM1 acetylation unclear","Single-lab study"]},{"year":2024,"claim":"Confirmed that XPO1 is essential for NPM1-fusion-driven leukemogenesis through NES-dependent recruitment to HOX chromatin, reinforcing CRM1 as a therapeutic target.","evidence":"ChIP-seq, localization imaging, mouse bone marrow transplantation AML model, and selinexor rescue with HOX reporter/colony assays","pmids":["39443736"],"confidence":"Medium","gaps":["Mechanism distinguishing chromatin recruitment from canonical export incompletely defined"]},{"year":null,"claim":"How CRM1's distinct moonlighting activities (chromatin recruitment, spindle/kinetochore organization, nucleolar rRNA processing) mechanistically relate to its canonical export cycle, and what governs cargo selectivity in disease states, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking export-independent and export-dependent functions","Cargo-selectivity determinants for oncogenic mutants only partially mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[1,3,5,2]},{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[1,3,21]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[14,16,17]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[21]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[18,12,11]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[11]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[29,18]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[18,1]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[10,26]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[14,17]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[1,2,3,13]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[13,11,21]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10,26,6,23]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[14,17]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[10,26]}],"complexes":["CRM1–RanGTP–NES export complex","CRM1–RanBP3–NES–RanGTP quaternary complex","nuclear pore complex (transit)"],"partners":["RANBP3","NUPL2","NMD3","RAN","RANBP1","NPM1","EIF4E","NUP214"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O14980","full_name":"Exportin-1","aliases":["Chromosome region maintenance 1 protein homolog"],"length_aa":1071,"mass_kda":123.4,"function":"Mediates the nuclear export of cellular proteins (cargos) bearing a leucine-rich nuclear export signal (NES) and of RNAs. 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Interacts with, and mediates the nuclear export of HIV-1 Rev and HTLV-1 Rex proteins. 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The active-site C528 was validated as the prime drug-binding residue by CRISPR/Cas9 introduction of C528S mutation, which confers full resistance to selinexor.\",\n      \"method\": \"X-ray crystallography, CRISPR/Cas9 genome editing with functional resistance assays (cytotoxicity, apoptosis, cell cycle, direct drug binding)\",\n      \"journal\": \"Chemistry & Biology / Blood / Seminars in Cancer Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis/genome editing in multiple papers with orthogonal methods confirming covalent C528 binding\",\n      \"pmids\": [\"25579209\", \"23034282\", \"24631835\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Atomic-resolution crystal structures reveal that RanGTP and cargo NES bind CRM1 with positive cooperativity, that RanBP1 triggers release of export cargoes in the cytoplasm, and that leptomycin B and KPT-SINE compounds block export by occupying the hydrophobic NES-binding cleft of CRM1.\",\n      \"method\": \"X-ray crystallography of CRM1 complexes with RanGTP, cargo NES peptides, RanBP1, leptomycin B, and SINE inhibitors\",\n      \"journal\": \"Seminars in Cancer Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple atomic-resolution structures from several independent laboratories establishing cooperative binding mechanism\",\n      \"pmids\": [\"24631835\", \"24823279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Ran-binding protein 3 (RanBP3) acts as a nuclear cofactor for CRM1-mediated export: it binds directly to CRM1, enhances CRM1 affinity for both RanGTP and NES cargo, and forms a quaternary CRM1–RanBP3–NES–RanGTP complex that can associate with nucleoporins. RanBP3 also modulates the relative affinity of CRM1 for different export substrates.\",\n      \"method\": \"Permeabilized cell nuclear export assay, GST pulldown, co-immunoprecipitation, nucleoporin binding assay\",\n      \"journal\": \"Journal of Cell Biology / EMBO Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated independently in two labs using reciprocal pulldowns, permeabilized cell assays, and functional export reconstitution\",\n      \"pmids\": [\"11425870\", \"11571268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"CRM1 mediates nuclear export of snurportin 1 (the m3G-capped U snRNP import adapter) via a large domain interaction distinct from short NES peptides. Snurportin 1 binds CRM1 with ~50-fold higher affinity than Rev NES and with ~5,000-fold higher affinity than minimum Rev NES. Critically, snurportin 1 has low CRM1 affinity when bound to its import substrate (m3G-cap) and high affinity when substrate-free, coupling import substrate release to CRM1 recycling.\",\n      \"method\": \"In vitro binding assays, permeabilized-cell export reconstitution, affinity measurements\",\n      \"journal\": \"Journal of Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with quantitative affinity measurements and mechanistic mutagenesis, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"10209022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PARP-1-mediated poly(ADP-ribosyl)ation of p53 at specific sites blocks the interaction between p53 and CRM1, resulting in nuclear accumulation of p53 in response to DNA damage. This provides a mechanism by which DNA damage signals through PARP-1 to retain p53 in the nucleus for transactivation.\",\n      \"method\": \"Identification of poly(ADP-ribosyl)ation sites by mass spectrometry, in vitro and cellular co-immunoprecipitation of p53-CRM1 interaction, PARP-1 knockout/inhibition with subcellular fractionation and functional reporter assays\",\n      \"journal\": \"Nature Cell Biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — rigorous mapping of modification sites combined with interaction assays and loss-of-function experiments, published in high-impact journal\",\n      \"pmids\": [\"17891139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Linear correlation exists between CRM1-NES binding affinity (Kd) and nuclear export activity for NESs with Kds between tens of nanomolar to tens of micromolar; NESs outside this range show reduced activity. An unusually tight-binding MVM NS2 NES was structurally explained by intramolecular contacts stabilizing the CRM1-bound conformation, enabling design of picomolar-affinity CRM1-inhibiting peptides.\",\n      \"method\": \"Quantitative binding assays (ITC/fluorescence polarization) for 24 NES peptides, cell-based nuclear export assays, X-ray crystal structure of CRM1–MVM NS2 NES complex\",\n      \"journal\": \"Molecular Biology of the Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure combined with quantitative binding and functional export assays across many NES sequences in a single rigorous study\",\n      \"pmids\": [\"29927350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The E571K oncogenic mutation of CRM1 alters NES-binding groove charge, causing altered (increased or decreased >10-fold) binding affinity for select NES-containing cargoes (e.g., eIF4E-transporter, Mek1, RPS2) while leaving most NES affinities unchanged. eIF4E-transporter is mislocalized in tumor cells carrying CRM1(E571K), providing proof-of-concept that E571K confers cargo-selective nuclear export changes driving cancer.\",\n      \"method\": \"CRISPR/Cas9-generated monoallelic and biallelic CRM1-E571K HEK293 cell lines, quantitative binding assays for 27 NES peptides, X-ray crystal structures, subcellular localization by immunofluorescence, structure-based bioinformatics\",\n      \"journal\": \"Molecular Biology of the Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures combined with genome editing, quantitative binding, and functional localization assays in a single comprehensive study\",\n      \"pmids\": [\"32520643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Crystal structures of wild-type and E571K XPO1 bound to SINE inhibitors (KPT-185, selinexor/KPT-330, eltanexor/KPT-8602) are highly similar, demonstrating that E571K mutations at the CRM1 cargo-binding groove do not structurally interfere with SINE drug binding, explaining why SINE activity is not abrogated by E571 mutations in CLL patients.\",\n      \"method\": \"X-ray crystallography of XPO1(WT) and XPO1(E571K) bound to three SINE compounds\",\n      \"journal\": \"Journal of Hematology & Oncology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple crystal structures with direct structural comparison, single study with clear functional implication\",\n      \"pmids\": [\"33451349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CRM1 forms a dimer (observed by single-particle electron microscopy) when assembled in the HIV Rev–RRE nuclear export complex. The CRM1 dimer interface enhances association with the Rev-RRE oligomer and poises NES-binding sites to interact with multiple Rev NES domains. Differences in dimerization between CRM1 orthologs correlate with altered nuclear export and HIV cellular tropism.\",\n      \"method\": \"Single-particle electron microscopy of assembled HIV Rev–RRE–CRM1–RanGTP export complex, biochemical assembly assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — single-particle EM structure from one lab, no independent replication; novel finding of CRM1 dimerization in this context\",\n      \"pmids\": [\"25486595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CRM1/XPO1 interacts with EGFR and mediates its nuclear export; co-immunoprecipitation detected EGFR–CRM1 interaction, and leptomycin B (CRM1 inhibitor) caused marked nuclear EGFR accumulation, indicating CRM1-dependent export is required to maintain EGFR nuclear-cytoplasmic balance.\",\n      \"method\": \"Co-immunoprecipitation, leptomycin B inhibition with subcellular fractionation and immunofluorescence\",\n      \"journal\": \"Journal of Cellular Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP plus pharmacological inhibition, replicated with two orthogonal methods in one lab\",\n      \"pmids\": [\"16552725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Chromatin-bound CRM1 recruits leukemogenic proteins SET-Nup214 (via nucleoporin-CRM1 interaction) and NPM1c (via its NES) to HOX cluster chromatin regions, causing aberrant HOX gene activation in leukemia cells. CRM1 inhibition with selinexor suppresses this HOX activation.\",\n      \"method\": \"ChIP-seq, co-immunoprecipitation, loss-of-function with selinexor, chromatin fractionation, CRM1 knockdown in human leukemia cell lines\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq and Co-IP combined with functional CRM1 inhibition, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"31755865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CRM1 and its ribosome export adaptor NMD3 co-localize with nucleolar marker proteins in the nucleolus; CRM1 nucleolar localization is dependent on its own export activity and on NMD3 expression (which provides nucleolar tethering), while NMD3 localization is CRM1-independent. CRM1 inhibition reduces 28S rRNA processing and both CRM1 and NMD3 inactivation reduce the rate of pre-47S rRNA synthesis.\",\n      \"method\": \"Immunofluorescence and confocal imaging, subcellular fractionation, siRNA knockdown, leptomycin B inhibition, rRNA synthesis rate measurement (pulse labeling)\",\n      \"journal\": \"Nucleus\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal localization and functional approaches in single lab; direct nucleolar CRM1 role with mechanistic follow-up\",\n      \"pmids\": [\"23782956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CRM1/XPO1 activity is developmentally regulated during early Xenopus embryogenesis: the protein is present but functionally inactive until the gastrula-neurula transition. CRM1 becomes active (leptomycin B-sensitive) concomitant with a change in its nuclear localization, as demonstrated by pulldown experiments and localization of a GFP–NES reporter.\",\n      \"method\": \"Leptomycin B sensitivity assays at defined developmental stages, GFP-NES reporter localization in embryos, pulldown assays for RanGTP-CRM1 interaction, subcellular immunofluorescence\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (reporter, pulldown, LMB sensitivity) in Xenopus developmental system, single lab\",\n      \"pmids\": [\"10639332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A non-canonical stepwise mechanism assembles Crm1 export complexes for 40S pre-ribosome export: the RanGTP-binding protein Slx9 scaffolds Rio2 (NES adaptor) and RanGTP, and this pre-assembled complex directly loads Crm1. A Slx9 mutation impairing Crm1-export complex assembly inhibits 40S pre-ribosome export in vivo.\",\n      \"method\": \"In vitro reconstitution of complex assembly, co-immunoprecipitation, yeast genetics (mutant phenotypes), sucrose gradient sedimentation, nuclear export assay\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution combined with genetic epistasis and in vivo export assay in a single rigorous study\",\n      \"pmids\": [\"25895666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Yeast Xpo1/Crm1 physically interacts with spindle pole body component Spc72 in a RanGTP- and NES-dependent manner. Mutations in the Spc72 NES impair mitotic spindle morphology in vivo and xpo1 mutants show reduced cytoplasmic microtubules, establishing a functional link between Xpo1 and spindle pole body/spindle biogenesis.\",\n      \"method\": \"Two-hybrid, co-immunoprecipitation, NES mutagenesis, fluorescence microscopy of spindle morphology in yeast mutants\",\n      \"journal\": \"Molecular and Cellular Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and biochemical evidence in yeast with NES mutagenesis and in vivo phenotype, single lab\",\n      \"pmids\": [\"18573877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Yeast hexokinase 2 (Hxk2) is exported from the nucleus via Xpo1/CRM1 through two leucine-rich NES sequences (NES1: L23–I33; NES2: L310–L318). Phosphorylation of Hxk2 at serine 14 in low-glucose conditions promotes its nuclear export by facilitating Hxk2–Xpo1 association.\",\n      \"method\": \"Co-immunoprecipitation of Hxk2–Xpo1, NES mutagenesis, phosphomimetic/phospho-dead mutants, nuclear fractionation, leptomycin B inhibition in yeast\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — NES mutagenesis combined with Co-IP and phospho-mutant analysis in a single lab study\",\n      \"pmids\": [\"19525230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CRM1/XPO1 inhibition by leptomycin B selectively enhances juxta-nuclear adenovirus association with microtubules and boosts virion motions on microtubules near the nuclear membrane, indicating that CRM1 normally provides positional information that facilitates transfer of incoming virions from microtubules to nuclear pore complexes (NPCs). LMB did not compete with adenovirus for nucleoporin Nup214 binding at NPCs.\",\n      \"method\": \"Single-particle tracking, super-resolution microscopy, leptomycin B treatment, Nup214 binding assay, quantification of virion motility near nuclear membrane\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct live-cell tracking and super-resolution imaging with pharmacological CRM1 inhibition showing clear mechanistic distinction from Nup214 competition\",\n      \"pmids\": [\"28515232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Importin-β and CRM1 play opposing roles in regulating RANBP2-SUMO-RANGAP1 localization at kinetochores during mitosis: CRM1 promotes deposition of the complex at kinetochores, while importin-β keeps it away. Overexpression of CRM1 or importin-β respectively advances or retards RANBP2 kinetochore localization, affecting accumulation of SUMO-conjugated topoisomerase-IIα and stability of kinetochore fibres.\",\n      \"method\": \"Proximity ligation assays, inducible CRM1 and importin-β overexpression cell lines, immunofluorescence, kinetochore fibre stability assay\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity ligation assays and inducible overexpression with functional kinetochore readouts, single lab\",\n      \"pmids\": [\"28600321\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LMB alters CRM1 subcellular distribution: upon binding to C528, LMB causes CRM1 to redistribute from the nucleus to the cytoplasm by inhibiting CRM1 nuclear import (not by trapping it in the cytoplasm). CRM1-C528S mutant is insensitive to this redistribution, confirming C528 dependence.\",\n      \"method\": \"Cell fractionation, immunofluorescence, microinjection of GFP-CRM1 into nucleus or cytoplasm, LMB treatment, C528S mutant comparison\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — microinjection plus fractionation with C528S mutant control, single lab with orthogonal methods\",\n      \"pmids\": [\"28412356\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In normal erythroid progenitors, HSP70 nuclear localization during terminal maturation is regulated by XPO1-mediated export; XPO1 inhibition increases nuclear HSP70 levels, rescues GATA-1 transcription factor expression, and improves terminal differentiation in β-thalassemic erythroblasts where HSP70 is aberrantly sequestered in the cytoplasm by free α-globin chains.\",\n      \"method\": \"XPO1 inhibitor treatment of primary human erythroblasts from β-thalassemia patients, subcellular fractionation/immunofluorescence for HSP70 localization, GATA-1 expression assays, differentiation markers\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition with functional erythroid differentiation readouts and mechanistic link to GATA-1 and HSP70, single lab\",\n      \"pmids\": [\"33054049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SINE compound-mediated XPO1 inhibition causes nuclear retention of FBXL5, which in turn suppresses the EMT driver snail and reverses epithelial-to-mesenchymal transition (EMT) in human mammary epithelial cells. This mechanism was confirmed using FBXL5 siRNA (which abrogates SINE activity) and a CRM1-C528S mutant (lacking SINE binding site, resistant to SINE-induced EMT reversal).\",\n      \"method\": \"FBXL5 siRNA knockdown, CRM1-C528S mutant overexpression, immunofluorescence/fractionation for FBXL5 and snail localization, Western blotting, xenograft tumor models\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic (siRNA, C528S mutant) plus pharmacological inhibition with defined mechanistic pathway, single lab\",\n      \"pmids\": [\"26536918\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"XPO1 overexpression upon DNA damage causes export of EIF4E and THOC4 carrying DNA damage repair mRNAs, thereby increasing synthesis of DNA repair proteins and conferring tolerance to genotoxic stress. XPO1 inhibition decreases DNA repair capacity and sensitizes lymphoma cells to DNA-damaging chemotherapy.\",\n      \"method\": \"RNA immunoprecipitation showing XPO1 binding to EIF4E and THOC4 on DNA damage repair mRNAs, ribosome profiling, XPO1 overexpression and inhibition experiments, patient-derived xenograft models, phase I clinical trial validation\",\n      \"journal\": \"Cancer Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-IP with functional mRNA export and translation measurements, gain- and loss-of-function approaches, single lab with translational clinical data\",\n      \"pmids\": [\"37801604\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The E3 ubiquitin ligase ASB8 promotes selinexor-induced proteasomal degradation of XPO1. ASB8 loss-of-function (knockout) and overexpression both result in selinexor hypersensitivity, indicating ASB8 modulates drug-induced XPO1 protein turnover as a shared vulnerability across cancer types.\",\n      \"method\": \"CRISPR-Cas9 loss-of-function chemogenetic screen, ASB8 knockout/overexpression with selinexor sensitivity assays, proteasome inhibitor rescue experiments confirming proteasomal degradation pathway\",\n      \"journal\": \"Biomedicine & Pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide CRISPR screen plus mechanistic validation by rescue experiments, single lab\",\n      \"pmids\": [\"36731340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"XPO1 inhibition by selinexor activates PI3Kγ-dependent AKT signaling in AML via upregulation of the purinergic receptor P2RY2. This adaptive resistance mechanism was identified by systematic CRISPR-Cas9 screening and validated in AML cell lines, patient-derived primary cultures, and multiple mouse models. Combined XPO1 + AKT inhibition outperforms standard-of-care chemotherapy in MLL-AF9-driven AML.\",\n      \"method\": \"CRISPR-Cas9 gain/loss-of-function screens, P2RY2 knockdown/overexpression, PI3K/AKT pathway inhibition rescue experiments, in vivo mouse AML models, patient-derived primary cultures\",\n      \"journal\": \"Nature Cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic genome-wide screening plus orthogonal genetic and pharmacological validation in multiple models including in vivo, published in high-impact journal\",\n      \"pmids\": [\"35668193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"XPO1 interacts with the C-terminus of NPM1 and mediates acetylation of NPM1 at lysine 54, which contributes to sorafenib resistance in hepatocellular carcinoma. XPO1 also binds Vimentin, promoting EMT progression in sorafenib-resistant cells.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry identification of NPM1 acetylation site, immunofluorescence colocalization, CRISPR/Cas9 knockin, RNA-seq, functional proliferation/migration assays\",\n      \"journal\": \"Biomedicine & Pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with MS-based PTM identification and CRISPR validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36791564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"IL-1β stimulates CRM1 expression in astrocytes, concurrent with translocation of HMGB1 from nucleus to cytoplasm via a CRM1-dependent pathway. ERK MAP kinase activity is required upstream of CRM1 for this effect: MEK/ERK inhibition reduces CRM1 upregulation and blocks HMGB1 nuclear export.\",\n      \"method\": \"Immunofluorescence, Western blotting, MEK/ERK inhibitor (U0126), CRM1 expression analysis, HMGB1 subcellular fractionation in primary rat astrocytes\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single pharmacological inhibitor without genetic confirmation of CRM1 in HMGB1 export; mechanistic link is indirect\",\n      \"pmids\": [\"20222144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NPM1-fusion proteins (NPM1::MLF1 and NPM1::CCDC28A) are recruited to HOX gene cluster chromatin via XPO1 (through NES-CRM1 interaction), causing aberrant HOX gene upregulation in AML. XPO1 inhibitor selinexor suppresses fusion-protein-driven HOX activation and colony formation, establishing XPO1 as essential for NPM1-fusion-mediated leukemogenesis.\",\n      \"method\": \"ChIP-seq, subcellular localization imaging, mouse bone marrow transplantation AML model, selinexor treatment with HOX reporter and colony formation assays\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq and in vivo mouse AML model with pharmacological rescue, single lab\",\n      \"pmids\": [\"39443736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CRM1 inhibition by leptomycin B or SINE compounds blocks nuclear export of the RSV matrix (M) protein, causing its retention in the nucleus and reducing RSV replication in human respiratory epithelial cells. The effect was reversible within 24 h of compound removal.\",\n      \"method\": \"SINE compound treatment (KPT-335, KPT-185) of RSV-infected cells, immunofluorescence for M protein localization, viral titer measurement, cell cycle analysis\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological CRM1 inhibition with localization and functional viral titer readouts, replicated in prior work; mechanistic specificity supported by leptomycin B and two SINE compounds\",\n      \"pmids\": [\"34584169\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Structure-guided design yielded the first noncovalent CRM1 inhibitor (NCI-1), which binds the 'open' NES groove of CRM1 simultaneously occupying two hydrophobic pockets (rather than forming a covalent bond to C528). Crystal structures of yeast CRM1–NCI-1 complex confirmed this binding mode, and NCI-1 inhibited nuclear export in cells carrying the human CRM1-C528S covalent-inhibitor-resistant mutant.\",\n      \"method\": \"X-ray crystal structure of yeast CRM1–NCI-1 complex, binding affinity assays in presence/absence of RanGTP, cell-based nuclear export assay including CRM1-C528S mutant cells\",\n      \"journal\": \"Journal of Medicinal Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with quantitative binding and functional export assays including drug-resistant mutant validation, single rigorous study\",\n      \"pmids\": [\"33974430\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NLP1 (NUPL2/hCG1), a nucleoporin-like FG-repeat protein that localizes to the nuclear envelope and is mobile within the nucleus, promotes CRM1–RanGTP complex formation (with or without NES cargo) and facilitates CRM1-dependent nuclear export. NLP1 depletion reduces CRM1-dependent export rates; overexpression enhances export of specific cargoes.\",\n      \"method\": \"Fluorescence microscopy, pulldown assays for CRM1–RanGTP–NLP1 complexes, siRNA depletion with nuclear export assay, overexpression experiments, RanBP1/Nup214 dissociation assays\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA loss-of-function and overexpression with direct export assays and complex reconstitution, single lab\",\n      \"pmids\": [\"22250199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Crystal structure of human CRM1 (hCRM1) bound to leptomycin B in complex with RanGTP was solved, revealing that hCRM1 exhibits 16-fold lower NES-binding affinity than yeast CRM1 and significant affinity differences toward various CRM1 inhibitors. A human-adapted CRM1-T539C mutant (analogous to yeast) does not bind all tested inhibitors, establishing species-specific pharmacological distinctions.\",\n      \"method\": \"X-ray crystallography of hCRM1–RanGTP–leptomycin B complex, quantitative binding assays for multiple inhibitors and NES peptides\",\n      \"journal\": \"Journal of Medicinal Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure of human CRM1 complex combined with quantitative binding assays revealing mechanistic species differences\",\n      \"pmids\": [\"32585100\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"XPO1/CRM1 is the major nuclear export receptor that recognizes leucine-rich nuclear export signals (NESs) on cargo proteins by forming a cooperative ternary complex with RanGTP in the nucleus; cofactors RanBP3 and NLP1 facilitate complex assembly, the complex translocates through nuclear pore complexes (interacting with nucleoporins), and is disassembled in the cytoplasm by RanBP1 and RanGAP. Its NES-binding groove contains an essential cysteine (C528) that is the covalent target of leptomycin B and SINE inhibitors (e.g., selinexor). Post-translational modifications of cargo (e.g., poly-ADP-ribosylation of p53 by PARP-1, phosphorylation of Hxk2 at S14) regulate CRM1–cargo interactions to control nucleocytoplasmic partitioning in response to cellular signals. Beyond transport, CRM1 plays roles in spindle pole body function/spindle assembly (via interaction with Spc72/RanGTP), nucleolar rRNA biogenesis (with adaptor NMD3), chromatin-associated recruitment of leukemogenic proteins to HOX gene clusters, and regulation of genotoxic stress tolerance through mRNA export of DNA repair transcripts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"XPO1/CRM1 is the major leucine-rich nuclear export receptor that recognizes nuclear export signals (NESs) on cargo proteins and translocates them through nuclear pore complexes, with cargo recognition driven by positive cooperativity between RanGTP and NES binding and cargo release in the cytoplasm triggered by RanBP1 [#1]. Crystal structures define a hydrophobic NES-binding cleft whose affinity for diverse NES sequences scales linearly with export activity over a defined Kd window, and whose conserved cysteine 528 is the covalent target of leptomycin B and SINE inhibitors such as selinexor [#0, #5]. Complex assembly is assisted by the nuclear cofactors RanBP3, which enhances CRM1 affinity for both RanGTP and NES cargo within a quaternary CRM1\\u2013RanBP3\\u2013NES\\u2013RanGTP complex that engages nucleoporins [#2], and the nucleoporin-like FG-repeat protein NLP1/NUPL2, which promotes CRM1\\u2013RanGTP complex formation and export [#29]. Beyond canonical peptide cargoes, CRM1 exports large folded substrates such as snurportin 1 in a manner coupled to import-substrate release, and assembles via non-canonical stepwise adaptor mechanisms for ribosomal subunit export, scaffolded by Slx9/Rio2 for the 40S pre-ribosome and by NMD3 in the nucleolus where CRM1 supports rRNA processing [#3, #13, #11]. Cargo partitioning is gated by signal-responsive post-translational modifications: PARP-1-mediated poly(ADP-ribosyl)ation of p53 and phosphorylation of hexokinase 2 at serine 14 modulate cargo\\u2013CRM1 association [#4, #15]. CRM1 also contributes to mitotic spindle and kinetochore organization through RanGTP/NES-dependent interactions with Spc72 and through deposition of the RANBP2\\u2013SUMO\\u2013RANGAP1 complex at kinetochores [#14, #17]. In cancer, CRM1 drives leukemogenesis by recruiting NPM1c and NPM1-fusion proteins to HOX cluster chromatin to aberrantly activate HOX genes, and supports genotoxic stress tolerance by exporting EIF4E/THOC4-bound DNA repair mRNAs; the recurrent E571K oncogenic mutation alters the NES-groove charge to confer cargo-selective export changes without abrogating SINE drug binding [#10, #26, #21, #6, #7].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established that CRM1 exports not only short NES peptides but large folded domains, and that export affinity can be coupled to release of the cargo's own import substrate.\",\n      \"evidence\": \"In vitro binding and permeabilized-cell export reconstitution of snurportin 1 with quantitative affinity measurements\",\n      \"pmids\": [\"10209022\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single-lab study\", \"Generality of substrate-coupled affinity switching to other cargoes not established\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Showed that CRM1 export activity is not constitutive but developmentally gated, linking the receptor to programmed control of nucleocytoplasmic partitioning.\",\n      \"evidence\": \"Leptomycin B sensitivity, GFP-NES reporter localization, and RanGTP-CRM1 pulldowns across Xenopus developmental stages\",\n      \"pmids\": [\"10639332\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular trigger for activation at gastrula-neurula transition unidentified\", \"Single model system\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Identified RanBP3 as a nuclear cofactor that enhances CRM1 affinity for RanGTP and cargo, explaining how stable export complexes form and can tune substrate selectivity.\",\n      \"evidence\": \"Permeabilized-cell export assays, GST pulldowns, co-IP, and nucleoporin-binding assays in two independent labs\",\n      \"pmids\": [\"11425870\", \"11571268\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution relative to other cofactors unresolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated that a signal-responsive PTM on cargo controls CRM1 engagement, providing a mechanism for damage-induced nuclear retention of p53.\",\n      \"evidence\": \"MS mapping of poly(ADP-ribosyl)ation sites with co-IP of p53-CRM1 and PARP-1 loss-of-function/fractionation assays\",\n      \"pmids\": [\"17891139\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether modification acts directly on the NES or sterically remains incompletely defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Linked CRM1 to spindle pole body and spindle biogenesis through a RanGTP/NES-dependent interaction, extending its role beyond bulk export.\",\n      \"evidence\": \"Two-hybrid, co-IP, Spc72 NES mutagenesis, and spindle morphology imaging in yeast mutants\",\n      \"pmids\": [\"18573877\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the role is export-dependent or a moonlighting scaffolding function unclear\", \"Yeast only\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed that cargo phosphorylation in response to a metabolic signal promotes CRM1 export, connecting nucleocytoplasmic partitioning to nutrient state.\",\n      \"evidence\": \"Hxk2-Xpo1 co-IP, dual NES mutagenesis, and phosphomimetic/phospho-dead analysis in yeast\",\n      \"pmids\": [\"19525230\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase responsible for S14 phosphorylation not identified here\", \"Single model organism\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved the atomic mechanism of export-complex assembly and inhibition, defining cooperative RanGTP/NES binding, RanBP1-triggered release, and covalent C528 targeting by leptomycin B and SINE compounds.\",\n      \"evidence\": \"X-ray crystallography of multiple CRM1 complexes plus CRISPR C528S resistance assays across several studies\",\n      \"pmids\": [\"24631835\", \"24823279\", \"25579209\", \"23034282\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structures do not capture dynamic transit through the pore\", \"Cargo-specific recognition determinants beyond the consensus NES incompletely modeled\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Proposed that CRM1 can dimerize to assemble multivalent export complexes, illustrated by the HIV Rev-RRE system and correlated with viral tropism.\",\n      \"evidence\": \"Single-particle EM of the assembled Rev-RRE-CRM1-RanGTP complex and biochemical assembly assays\",\n      \"pmids\": [\"25486595\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab EM without independent replication\", \"Whether dimerization occurs for endogenous cellular cargoes unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined non-canonical, adaptor-scaffolded mechanisms of CRM1 export for ribosomal subunits and placed CRM1 in nucleolar rRNA biogenesis.\",\n      \"evidence\": \"Slx9/Rio2 in vitro reconstitution with yeast genetics; NMD3 co-localization, siRNA, LMB inhibition, and rRNA synthesis-rate measurements\",\n      \"pmids\": [\"25895666\", \"23782956\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the nucleolar/rRNA-processing role relates mechanistically to bulk export incompletely defined\", \"Human Slx9 ortholog role not directly tested here\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Quantitatively related CRM1-NES binding affinity to export activity, establishing the affinity window governing functional export and enabling rational inhibitor peptide design.\",\n      \"evidence\": \"ITC/fluorescence-polarization binding for 24 NES peptides, cell-based export assays, and crystal structure of the CRM1-MVM NS2 NES complex\",\n      \"pmids\": [\"29927350\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Predictivity for cargoes with non-canonical binding modes not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed a chromatin-associated, transport-coupled function in which CRM1 recruits leukemogenic proteins to HOX clusters, and an mRNA-export role supporting genotoxic stress tolerance.\",\n      \"evidence\": \"ChIP-seq, co-IP, chromatin fractionation, and selinexor rescue for SET-Nup214/NPM1c; RNA-IP, ribosome profiling, and PDX/clinical validation for EIF4E/THOC4 DNA-repair mRNA export\",\n      \"pmids\": [\"31755865\", \"37801604\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether chromatin recruitment requires active export or is a static scaffold unresolved\", \"Selectivity of repair-mRNA cargo loading not fully defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed that the recurrent oncogenic E571K mutation alters NES-groove electrostatics to produce cargo-selective export changes, and that human CRM1 differs pharmacologically from yeast.\",\n      \"evidence\": \"CRISPR E571K cell lines with quantitative binding for 27 NES peptides, crystal structures, and immunofluorescence; separate hCRM1-RanGTP-LMB structure with inhibitor binding panel\",\n      \"pmids\": [\"32520643\", \"32585100\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full repertoire of E571K-affected cargoes incomplete\", \"In vivo oncogenic consequences of specific cargo shifts not enumerated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established that E571K does not impair covalent SINE binding and that the NES groove can be targeted noncovalently, expanding strategies against drug-resistant CRM1.\",\n      \"evidence\": \"Crystal structures of WT and E571K XPO1 with three SINE compounds; structure-guided NCI-1 design with crystal structure and export assays in C528S cells\",\n      \"pmids\": [\"33451349\", \"33974430\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo efficacy and selectivity of noncovalent inhibitors not addressed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified adaptive resistance and degradation pathways shaping CRM1 inhibitor response, defining combination vulnerabilities and turnover regulators.\",\n      \"evidence\": \"CRISPR screens with genetic/pharmacological validation in AML models (PI3K\\u03b3/AKT via P2RY2); chemogenetic screen identifying ASB8-mediated proteasomal XPO1 degradation\",\n      \"pmids\": [\"35668193\", \"36731340\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality of P2RY2/AKT resistance beyond AML uncertain\", \"Direct ASB8-XPO1 ubiquitination chemistry not structurally resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended CRM1's tumor roles to direct partner binding and PTM events driving therapy resistance in solid tumors.\",\n      \"evidence\": \"Co-IP, MS identification of NPM1 K54 acetylation, CRISPR knockin, and migration/proliferation assays in sorafenib-resistant hepatocellular carcinoma\",\n      \"pmids\": [\"36791564\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether XPO1 directly catalyzes or merely scaffolds NPM1 acetylation unclear\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Confirmed that XPO1 is essential for NPM1-fusion-driven leukemogenesis through NES-dependent recruitment to HOX chromatin, reinforcing CRM1 as a therapeutic target.\",\n      \"evidence\": \"ChIP-seq, localization imaging, mouse bone marrow transplantation AML model, and selinexor rescue with HOX reporter/colony assays\",\n      \"pmids\": [\"39443736\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism distinguishing chromatin recruitment from canonical export incompletely defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CRM1's distinct moonlighting activities (chromatin recruitment, spindle/kinetochore organization, nucleolar rRNA processing) mechanistically relate to its canonical export cycle, and what governs cargo selectivity in disease states, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking export-independent and export-dependent functions\", \"Cargo-selectivity determinants for oncogenic mutants only partially mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [1, 3, 5, 2]},\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [1, 3, 21]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [14, 16, 17]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [21]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [18, 12, 11]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [29, 18]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [18, 1]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [10, 26]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [14, 17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [1, 2, 3, 13]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [13, 11, 21]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 26, 6, 23]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [14, 17]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [10, 26]}\n    ],\n    \"complexes\": [\n      \"CRM1\\u2013RanGTP\\u2013NES export complex\",\n      \"CRM1\\u2013RanBP3\\u2013NES\\u2013RanGTP quaternary complex\",\n      \"nuclear pore complex (transit)\"\n    ],\n    \"partners\": [\n      \"RANBP3\",\n      \"NUPL2\",\n      \"NMD3\",\n      \"RAN\",\n      \"RANBP1\",\n      \"NPM1\",\n      \"EIF4E\",\n      \"NUP214\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}