Affinage

Showing XPO1 — CRM1 is a alias.

XPO1

Exportin-1 · UniProt O14980

Length
1071 aa
Mass
123.4 kDa
Annotated
2026-06-11
100 papers in source corpus 34 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1999 High

    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

    PMID:10209022

    Open questions at the time
    • Single-lab study
    • Generality of substrate-coupled affinity switching to other cargoes not established
  2. 2000 Medium

    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

    PMID:10639332

    Open questions at the time
    • Molecular trigger for activation at gastrula-neurula transition unidentified
    • Single model system
  3. 2001 High

    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

    PMID:11425870 PMID:11571268

    Open questions at the time
    • Quantitative contribution relative to other cofactors unresolved
  4. 2007 High

    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

    PMID:17891139

    Open questions at the time
    • Whether modification acts directly on the NES or sterically remains incompletely defined
  5. 2008 Medium

    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

    PMID:18573877

    Open questions at the time
    • Whether the role is export-dependent or a moonlighting scaffolding function unclear
    • Yeast only
  6. 2009 Medium

    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

    PMID:19525230

    Open questions at the time
    • Kinase responsible for S14 phosphorylation not identified here
    • Single model organism
  7. 2014 High

    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

    PMID:23034282 PMID:24631835 PMID:24823279 PMID:25579209

    Open questions at the time
    • Structures do not capture dynamic transit through the pore
    • Cargo-specific recognition determinants beyond the consensus NES incompletely modeled
  8. 2014 Medium

    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

    PMID:25486595

    Open questions at the time
    • Single-lab EM without independent replication
    • Whether dimerization occurs for endogenous cellular cargoes unknown
  9. 2015 High

    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

    PMID:23782956 PMID:25895666

    Open questions at the time
    • How the nucleolar/rRNA-processing role relates mechanistically to bulk export incompletely defined
    • Human Slx9 ortholog role not directly tested here
  10. 2018 High

    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

    PMID:29927350

    Open questions at the time
    • Predictivity for cargoes with non-canonical binding modes not established
  11. 2019 Medium

    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

    PMID:31755865 PMID:37801604

    Open questions at the time
    • Whether chromatin recruitment requires active export or is a static scaffold unresolved
    • Selectivity of repair-mRNA cargo loading not fully defined
  12. 2020 High

    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

    PMID:32520643 PMID:32585100

    Open questions at the time
    • Full repertoire of E571K-affected cargoes incomplete
    • In vivo oncogenic consequences of specific cargo shifts not enumerated
  13. 2021 High

    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

    PMID:33451349 PMID:33974430

    Open questions at the time
    • In vivo efficacy and selectivity of noncovalent inhibitors not addressed
  14. 2022 High

    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

    PMID:35668193 PMID:36731340

    Open questions at the time
    • Generality of P2RY2/AKT resistance beyond AML uncertain
    • Direct ASB8-XPO1 ubiquitination chemistry not structurally resolved
  15. 2023 Medium

    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

    PMID:36791564

    Open questions at the time
    • Whether XPO1 directly catalyzes or merely scaffolds NPM1 acetylation unclear
    • Single-lab study
  16. 2024 Medium

    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

    PMID:39443736

    Open questions at the time
    • Mechanism distinguishing chromatin recruitment from canonical export incompletely defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • No unified model linking export-independent and export-dependent functions
  • Cargo-selectivity determinants for oncogenic mutants only partially mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140104 molecular carrier activity 4 GO:0005215 transporter activity 3 GO:0008092 cytoskeletal protein binding 3 GO:0003723 RNA binding 1
Localization
GO:0005634 nucleus 3 GO:0000228 nuclear chromosome 2 GO:0005635 nuclear envelope 2 GO:0005815 microtubule organizing center 2 GO:0005829 cytosol 2 GO:0005730 nucleolus 1
Pathway
R-HSA-1643685 Disease 4 R-HSA-9609507 Protein localization 4 R-HSA-8953854 Metabolism of RNA 3 R-HSA-1640170 Cell Cycle 2 R-HSA-74160 Gene expression (Transcription) 2
Partners
EIF4ENMD3NPM1NUP214NUPL2RANRANBP1RANBP3
Complex memberships
CRM1–RanBP3–NES–RanGTP quaternary complexCRM1–RanGTP–NES export complexnuclear pore complex (transit)

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 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. X-ray crystallography, CRISPR/Cas9 genome editing with functional resistance assays (cytotoxicity, apoptosis, cell cycle, direct drug binding) Chemistry & Biology / Blood / Seminars in Cancer Biology High 23034282 24631835 25579209
2014 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. X-ray crystallography of CRM1 complexes with RanGTP, cargo NES peptides, RanBP1, leptomycin B, and SINE inhibitors Seminars in Cancer Biology High 24631835 24823279
2001 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. Permeabilized cell nuclear export assay, GST pulldown, co-immunoprecipitation, nucleoporin binding assay Journal of Cell Biology / EMBO Reports High 11425870 11571268
1999 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. In vitro binding assays, permeabilized-cell export reconstitution, affinity measurements Journal of Cell Biology High 10209022
2007 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. 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 Nature Cell Biology High 17891139
2018 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. 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 Molecular Biology of the Cell High 29927350
2020 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. 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 Molecular Biology of the Cell High 32520643
2021 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. X-ray crystallography of XPO1(WT) and XPO1(E571K) bound to three SINE compounds Journal of Hematology & Oncology High 33451349
2014 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. Single-particle electron microscopy of assembled HIV Rev–RRE–CRM1–RanGTP export complex, biochemical assembly assays eLife Medium 25486595
2006 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. Co-immunoprecipitation, leptomycin B inhibition with subcellular fractionation and immunofluorescence Journal of Cellular Biochemistry Medium 16552725
2019 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. ChIP-seq, co-immunoprecipitation, loss-of-function with selinexor, chromatin fractionation, CRM1 knockdown in human leukemia cell lines eLife Medium 31755865
2015 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. Immunofluorescence and confocal imaging, subcellular fractionation, siRNA knockdown, leptomycin B inhibition, rRNA synthesis rate measurement (pulse labeling) Nucleus Medium 23782956
2000 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. Leptomycin B sensitivity assays at defined developmental stages, GFP-NES reporter localization in embryos, pulldown assays for RanGTP-CRM1 interaction, subcellular immunofluorescence Journal of Cell Science Medium 10639332
2015 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. In vitro reconstitution of complex assembly, co-immunoprecipitation, yeast genetics (mutant phenotypes), sucrose gradient sedimentation, nuclear export assay eLife High 25895666
2008 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. Two-hybrid, co-immunoprecipitation, NES mutagenesis, fluorescence microscopy of spindle morphology in yeast mutants Molecular and Cellular Biology Medium 18573877
2009 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. Co-immunoprecipitation of Hxk2–Xpo1, NES mutagenesis, phosphomimetic/phospho-dead mutants, nuclear fractionation, leptomycin B inhibition in yeast Journal of Biological Chemistry Medium 19525230
2017 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. Single-particle tracking, super-resolution microscopy, leptomycin B treatment, Nup214 binding assay, quantification of virion motility near nuclear membrane Journal of Cell Science Medium 28515232
2017 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. Proximity ligation assays, inducible CRM1 and importin-β overexpression cell lines, immunofluorescence, kinetochore fibre stability assay Journal of Cell Science Medium 28600321
2017 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. Cell fractionation, immunofluorescence, microinjection of GFP-CRM1 into nucleus or cytoplasm, LMB treatment, C528S mutant comparison Biochemical and Biophysical Research Communications Medium 28412356
2020 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. XPO1 inhibitor treatment of primary human erythroblasts from β-thalassemia patients, subcellular fractionation/immunofluorescence for HSP70 localization, GATA-1 expression assays, differentiation markers Haematologica Medium 33054049
2015 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). FBXL5 siRNA knockdown, CRM1-C528S mutant overexpression, immunofluorescence/fractionation for FBXL5 and snail localization, Western blotting, xenograft tumor models Scientific Reports Medium 26536918
2019 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. 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 Cancer Research Medium 37801604
2023 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. CRISPR-Cas9 loss-of-function chemogenetic screen, ASB8 knockout/overexpression with selinexor sensitivity assays, proteasome inhibitor rescue experiments confirming proteasomal degradation pathway Biomedicine & Pharmacotherapy Medium 36731340
2022 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. 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 Nature Cancer High 35668193
2023 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. Co-immunoprecipitation, mass spectrometry identification of NPM1 acetylation site, immunofluorescence colocalization, CRISPR/Cas9 knockin, RNA-seq, functional proliferation/migration assays Biomedicine & Pharmacotherapy Medium 36791564
2010 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. Immunofluorescence, Western blotting, MEK/ERK inhibitor (U0126), CRM1 expression analysis, HMGB1 subcellular fractionation in primary rat astrocytes Glia Low 20222144
2024 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. ChIP-seq, subcellular localization imaging, mouse bone marrow transplantation AML model, selinexor treatment with HOX reporter and colony formation assays Leukemia Medium 39443736
2021 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. SINE compound treatment (KPT-335, KPT-185) of RSV-infected cells, immunofluorescence for M protein localization, viral titer measurement, cell cycle analysis Scientific Reports Medium 34584169
2021 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. 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 of Medicinal Chemistry High 33974430
2012 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. Fluorescence microscopy, pulldown assays for CRM1–RanGTP–NLP1 complexes, siRNA depletion with nuclear export assay, overexpression experiments, RanBP1/Nup214 dissociation assays Journal of Cell Science Medium 22250199
2020 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. X-ray crystallography of hCRM1–RanGTP–leptomycin B complex, quantitative binding assays for multiple inhibitors and NES peptides Journal of Medicinal Chemistry High 32585100

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia. Blood 259 23034282
2020 The nuclear export protein XPO1 - from biology to targeted therapy. Nature reviews. Clinical oncology 222 33173198
2020 XPO1-dependent nuclear export as a target for cancer therapy. Journal of hematology & oncology 200 32487143
2006 Nuclear-cytoplasmic transport of EGFR involves receptor endocytosis, importin beta1 and CRM1. Journal of cellular biochemistry 197 16552725
2007 Inhibition of Crm1-p53 interaction and nuclear export of p53 by poly(ADP-ribosyl)ation. Nature cell biology 176 17891139
1999 CRM1-mediated recycling of snurportin 1 to the cytoplasm. The Journal of cell biology 147 10209022
2008 CRM1-mediated nuclear export of proteins and drug resistance in cancer. Current medicinal chemistry 141 18991627
2014 Atomic basis of CRM1-cargo recognition, release and inhibition. Seminars in cancer biology 133 24631835
2018 Nuclear egress of TDP-43 and FUS occurs independently of Exportin-1/CRM1. Scientific reports 128 29728564
2013 Preclinical and clinical efficacy of XPO1/CRM1 inhibition by the karyopherin inhibitor KPT-330 in Ph+ leukemias. Blood 124 23970380
2012 The CRM1 nuclear export protein in normal development and disease. International journal of biochemistry and molecular biology 124 22773955
2001 Ran-binding protein 3 is a cofactor for Crm1-mediated nuclear protein export. The Journal of cell biology 118 11425870
2015 Expression, function, and targeting of the nuclear exporter chromosome region maintenance 1 (CRM1) protein. Pharmacology & therapeutics 112 26048327
2015 Identifying drug-target selectivity of small-molecule CRM1/XPO1 inhibitors by CRISPR/Cas9 genome editing. Chemistry & biology 109 25579209
2001 CRM1- and Ran-independent nuclear export of beta-catenin. Current biology : CB 96 11166175
2001 RanBP3 influences interactions between CRM1 and its nuclear protein export substrates. EMBO reports 95 11571268
2014 XPO1 (CRM1) inhibition represses STAT3 activation to drive a survivin-dependent oncogenic switch in triple-negative breast cancer. Molecular cancer therapeutics 92 24431073
2019 The past, present, and future of CRM1/XPO1 inhibitors. Stem cell investigation 90 30976603
2018 Clinical Implications of Targeting XPO1-mediated Nuclear Export in Multiple Myeloma. Clinical lymphoma, myeloma & leukemia 90 29610030
2014 Inhibition of CRM1-dependent nuclear export sensitizes malignant cells to cytotoxic and targeted agents. Seminars in cancer biology 82 24631834
2014 Induction of p53-mediated transcription and apoptosis by exportin-1 (XPO1) inhibition in mantle cell lymphoma. Cancer science 77 24766216
2017 XPO1 in B cell hematological malignancies: from recurrent somatic mutations to targeted therapy. Journal of hematology & oncology 71 28196522
2014 The export receptor Crm1 forms a dimer to promote nuclear export of HIV RNA. eLife 66 25486595
2000 Epstein-Barr virus EB2 protein exports unspliced RNA via a Crm-1-independent pathway. Journal of virology 61 10846090
2016 CRM1/XPO1 is associated with clinical outcome in glioma and represents a therapeutic target by perturbing multiple core pathways. Journal of hematology & oncology 60 27733172
2010 Role of ERK map kinase and CRM1 in IL-1beta-stimulated release of HMGB1 from cortical astrocytes. Glia 59 20222144
2019 Chromatin-bound CRM1 recruits SET-Nup214 and NPM1c onto HOX clusters causing aberrant HOX expression in leukemia cells. eLife 58 31755865
2017 CRM1 Inhibitors for Antiviral Therapy. Frontiers in microbiology 58 28702009
2013 CRM1 and BRAF inhibition synergize and induce tumor regression in BRAF-mutant melanoma. Molecular cancer therapeutics 57 23615632
2015 Structural Basis of Targeting the Exportin CRM1 in Cancer. Cells 54 26402707
2018 Inhibition of XPO1 enhances cell death induced by ABT-199 in acute myeloid leukaemia via Mcl-1. Journal of cellular and molecular medicine 53 30596398
2020 Small Molecule Inhibitors of CRM1. Frontiers in pharmacology 50 32574233
2018 Correlation of CRM1-NES affinity with nuclear export activity. Molecular biology of the cell 47 29927350
2021 Inhibition of XPO1 Sensitizes Small Cell Lung Cancer to First- and Second-Line Chemotherapy. Cancer research 45 34815254
2021 Recurrent XPO1 mutations alter pathogenesis of chronic lymphocytic leukemia. Journal of hematology & oncology 43 33451349
2021 Gluten-induced RNA methylation changes regulate intestinal inflammation via allele-specific XPO1 translation in epithelial cells. Gut 43 33526437
2024 Dual Inhibition of CDK4/6 and XPO1 Induces Senescence With Acquired Vulnerability to CRBN-Based PROTAC Drugs. Gastroenterology 42 38262581
2015 XPO1/CRM1 Inhibition Causes Antitumor Effects by Mitochondrial Accumulation of eIF5A. Clinical cancer research : an official journal of the American Association for Cancer Research 41 25878333
2014 Novel small molecule XPO1/CRM1 inhibitors induce nuclear accumulation of TP53, phosphorylated MAPK and apoptosis in human melanoma cells. PloS one 41 25057921
2000 Developmentally regulated activity of CRM1/XPO1 during early Xenopus embryogenesis. Journal of cell science 40 10639332
2017 Therapeutic Effects of XPO1 Inhibition in Thymic Epithelial Tumors. Cancer research 39 28819023
2005 Loading and unloading: orchestrating centrosome duplication and spindle assembly by Ran/Crm1. Cell cycle (Georgetown, Tex.) 39 16294017
2019 Association of XPO1 Overexpression with NF-κB and Ki67 in Colorectal Cancer. Asian Pacific journal of cancer prevention : APJCP 38 31870117
2022 P2RY2-AKT activation is a therapeutically actionable consequence of XPO1 inhibition in acute myeloid leukemia. Nature cancer 37 35668193
2013 CRM1 and its ribosome export adaptor NMD3 localize to the nucleolus and affect rRNA synthesis. Nucleus (Austin, Tex.) 36 23782956
2015 A non-canonical mechanism for Crm1-export cargo complex assembly. eLife 35 25895666
2021 Sequential Administration of XPO1 and ATR Inhibitors Enhances Therapeutic Response in TP53-mutated Colorectal Cancer. Gastroenterology 34 33745946
2019 Targeting Nuclear Exporter Protein XPO1/CRM1 in Gastric Cancer. International journal of molecular sciences 34 31569391
2017 The nuclear export factor CRM1 controls juxta-nuclear microtubule-dependent virus transport. Journal of cell science 32 28515232
2015 Targeting the Nuclear Export Protein XPO1/CRM1 Reverses Epithelial to Mesenchymal Transition. Scientific reports 32 26536918
2022 The efficacy of selinexor (KPT-330), an XPO1 inhibitor, on non-hematologic cancers: a comprehensive review. Journal of cancer research and clinical oncology 31 35941226
2014 Allosteric control of the exportin CRM1 unraveled by crystal structure analysis. The FEBS journal 29 24823279
2020 XPO1 regulates erythroid differentiation and is a new target for the treatment of β-thalassemia. Haematologica 28 33054049
2019 CRD1, an Xpo1 domain protein, regulates miRNA accumulation and crown root development in rice. The Plant journal : for cell and molecular biology 28 31257621
2023 E3 ubiquitin ligase ASB8 promotes selinexor-induced proteasomal degradation of XPO1. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 27 36731340
2023 Impacting T-cell fitness in multiple myeloma: potential roles for selinexor and XPO1 inhibitors. Frontiers in immunology 27 37954586
2021 Specific inhibition of the Survivin-CRM1 interaction by peptide-modified molecular tweezers. Nature communications 27 33686072
2020 Recognition of nuclear export signals by CRM1 carrying the oncogenic E571K mutation. Molecular biology of the cell 27 32520643
2015 Pharmacodynamic and genomic markers associated with response to the XPO1/CRM1 inhibitor selinexor (KPT-330): A report from the pediatric preclinical testing program. Pediatric blood & cancer 27 26398108
2009 Nuclear export of the yeast hexokinase 2 protein requires the Xpo1 (Crm1)-dependent pathway. The Journal of biological chemistry 25 19525230
2019 Simultaneous targeting of XPO1 and BCL2 as an effective treatment strategy for double-hit lymphoma. Journal of hematology & oncology 24 31752970
2018 Verdinexor Targeting of CRM1 is a Promising Therapeutic Approach against RSV and Influenza Viruses. Viruses 24 29361733
2018 CRM1/XPO1 expression in pancreatic adenocarcinoma correlates with survivin expression and the proliferative activity. Oncotarget 24 29765539
2016 Clinical and molecular characteristics of XPO1 mutations in patients with chronic lymphocytic leukemia. American journal of hematology 24 27468087
2024 XPO1 Enables Adaptive Regulation of mRNA Export Required for Genotoxic Stress Tolerance in Cancer Cells. Cancer research 23 37801604
2020 The XPO1 Inhibitor KPT-8602 Synergizes with Dexamethasone in Acute Lymphoblastic Leukemia. Clinical cancer research : an official journal of the American Association for Cancer Research 23 32826328
2020 IFI27/ISG12 Downregulates Estrogen Receptor α Transactivation by Facilitating Its Interaction With CRM1/XPO1 in Breast Cancer Cells. Frontiers in endocrinology 23 33117284
2012 The nucleoporin-like protein NLP1 (hCG1) promotes CRM1-dependent nuclear protein export. Journal of cell science 23 22250199
2008 Modulation of integrin-linked kinase nucleo-cytoplasmic shuttling by ILKAP and CRM1. Cell cycle (Georgetown, Tex.) 22 18635968
2023 XPO1 intensifies sorafenib resistance by stabilizing acetylation of NPM1 and enhancing epithelial-mesenchymal transition in hepatocellular carcinoma. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 21 36791564
2022 CRM1-spike-mediated nuclear export of hepatitis B virus encapsidated viral RNA. Cell reports 21 35263598
2019 miR-412-5p targets Xpo1 to regulate angiogenesis in hemorrhoid tissue. Gene 21 31026569
2012 CRM1 plays a nuclear role in transporting snoRNPs to nucleoli in higher eukaryotes. Nucleus (Austin, Tex.) 21 22555597
2023 Azacitidine Is Synergistically Lethal with XPO1 Inhibitor Selinexor in Acute Myeloid Leukemia by Targeting XPO1/eIF4E/c-MYC Signaling. International journal of molecular sciences 20 37047788
2023 XPO1 inhibition sensitises CLL cells to NK cell mediated cytotoxicity and overcomes HLA-E expression. Leukemia 20 37528310
2021 Structure-Guided Design of the First Noncovalent Small-Molecule Inhibitor of CRM1. Journal of medicinal chemistry 20 33974430
2020 Circ-XPO1 upregulates XPO1 expression by sponging multiple miRNAs to facilitate osteosarcoma cell progression. Experimental and molecular pathology 20 33091396
2014 CRM1 as a new therapeutic target for non-Hodgkin lymphoma. Leukemia research 20 25466285
2020 The STK38-XPO1 axis, a new actor in physiology and cancer. Cellular and molecular life sciences : CMLS 19 33145612
2022 The XPO1 Inhibitor KPT-8602 Ameliorates Parkinson's Disease by Inhibiting the NF-κB/NLRP3 Pathway. Frontiers in pharmacology 18 35721113
2021 Chromosome Region Maintenance 1 (XPO1/CRM1) as an Anticancer Target and Discovery of Its Inhibitor. Journal of medicinal chemistry 18 34669417
2020 Characterization of Inhibition Reveals Distinctive Properties for Human and Saccharomyces cerevisiae CRM1. Journal of medicinal chemistry 18 32585100
2022 MiR-483-3p improves learning and memory abilities via XPO1 in Alzheimer's disease. Brain and behavior 17 35833267
2017 Leptomycin B alters the subcellular distribution of CRM1 (Exportin 1). Biochemical and biophysical research communications 17 28412356
2017 Importin-β and CRM1 control a RANBP2 spatiotemporal switch essential for mitotic kinetochore function. Journal of cell science 17 28600321
2005 Insights into a CRM1-mediated RNA-nuclear export pathway in Trypanosoma cruzi. Molecular and biochemical parasitology 17 15610815
2014 Understanding XPO1 target networks using systems biology and mathematical modeling. Current pharmaceutical design 16 23530499
2023 Protein biomarkers for response to XPO1 inhibition in haematologic malignancies. Journal of cellular and molecular medicine 15 36722323
2023 Molecular analysis of XPO1 inhibitor and gemcitabine-nab-paclitaxel combination in KPC pancreatic cancer mouse model. Clinical and translational medicine 15 38131168
2021 Reversible disruption of XPO1-mediated nuclear export inhibits respiratory syncytial virus (RSV) replication. Scientific reports 14 34584169
2014 The interaction of CRM1 and the nuclear pore protein Tpr. PloS one 14 24722547
2008 Nuclear export receptor Xpo1/Crm1 is physically and functionally linked to the spindle pole body in budding yeast. Molecular and cellular biology 14 18573877
2024 Hepatitis B virus RNAs co-opt ELAVL1 for stabilization and CRM1-dependent nuclear export. PLoS pathogens 12 38306394
2024 XPO1 blockade with KPT-330 promotes apoptosis in cutaneous T-cell lymphoma by activating the p53-p21 and p27 pathways. Scientific reports 12 38653804
2024 NPM1-fusion proteins promote myeloid leukemogenesis through XPO1-dependent HOX activation. Leukemia 12 39443736
2022 Inhibition of XPO1 impairs cholangiocarcinoma cell proliferation by triggering p53 intranuclear accumulation. Cancer medicine 12 36200270
2022 XPO1-Mediated EIF1AX Cytoplasmic Relocation Promotes Tumor Migration and Invasion in Endometrial Carcinoma. Oxidative medicine and cellular longevity 11 36589683
2023 Nuclear Export in Non-Hodgkin Lymphoma and Implications for Targeted XPO1 Inhibitors. Biomolecules 10 36671496
2022 Targeting XPO1-Dependent Nuclear Export in Cancer. Biochemistry. Biokhimiia 10 35501995
2022 The molecular mechanism and challenge of targeting XPO1 in treatment of relapsed and refractory myeloma. Translational oncology 10 35660848

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