Affinage

RAN

GTP-binding nuclear protein Ran · UniProt P62826

Round 2 corrected
Length
216 aa
Mass
24.4 kDa
Annotated
2026-04-28
130 papers in source corpus 61 papers cited in narrative 61 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RAN is a small GTPase whose asymmetric nucleotide cycle—GTP loading by chromatin-bound RCC1 in the nucleus and GTP hydrolysis stimulated by cytoplasmic RanGAP1—creates a steep RanGTP/RanGDP gradient across the nuclear envelope that powers nucleocytoplasmic transport of proteins and RNAs by controlling the assembly and disassembly of importin/exportin–cargo complexes (PMID:8146159, PMID:7937864, PMID:8896452, PMID:9323133). During mitosis, chromosome-generated RanGTP liberates spindle assembly factors (TPX2, Aurora A, HURP, hKid) from importin inhibition, driving microtubule nucleation, kinetochore-fiber organization, and spindle pole formation, with CRM1 recruiting RanGAP1/RanBP2 to kinetochores for local gradient shaping (PMID:12577065, PMID:15908946, PMID:16631581, PMID:18268099). RAN activity is tuned by post-translational modifications—PAK4-mediated Ser-135 phosphorylation modulates RCC1/RanGAP1 interactions, CBP/p300- and TIP60-mediated lysine acetylation regulates nucleotide exchange and Mog1 displacement, and RanBP2-complex-mediated SUMOylation targets RanGDP at the NPC—while RanGTP also functions outside the nucleus at centrosomes (via AKAP450), basal bodies during ciliogenesis, and the plasma membrane where it stabilizes RhoA to promote cell invasion (PMID:20805321, PMID:26124124, PMID:29040603, PMID:26251516, PMID:14517334, PMID:21998203, PMID:31209254).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1994 High

    Identification of the core enzymatic regulators of Ran established the GTPase cycle: RanGAP1 stimulates Ran GTPase activity >1000-fold, and effector proteins stabilize the GTP-bound state via the C-terminal DEDDDL motif, while a GTPase-deficient mutant arrests cell cycle progression, linking the Ran GTPase cycle to both nuclear transport and cell division.

    Evidence In vitro GTPase assays with purified RanGAP1 and Q69L mutant from HeLa cells; effector binding by nitrocellulose overlay; dominant-negative mutant expression with flow cytometry

    PMID:8146159 PMID:8157660 PMID:8196659

    Open questions at the time
    • Identity of the 28 kDa and 86–300 kDa effector proteins was not resolved
    • Whether RanGAP1 acts at a specific subcellular site was unknown
    • How the GTPase cycle mechanistically connects to nuclear transport was not established
  2. 1995 High

    Reconstitution experiments demonstrated that Ran is an essential cytosolic factor for both nuclear protein import and export, functioning downstream of NLS recognition and requiring GTP hydrolysis for export, while detailed kinetic measurements defined the quantitative parameters of the GTPase cycle (RCC1 and RanGAP1 each accelerate their respective reactions ~10^5-fold).

    Evidence Biochemical fractionation and reconstitution in permeabilized Xenopus cells; stopped-flow fluorescence kinetics with mant-nucleotides; permeabilized cell export assay with GTP analogs

    PMID:7627554 PMID:7753805 PMID:7819259 PMID:7937864

    Open questions at the time
    • Whether Ran-GDP and Ran-GTP played distinct mechanistic roles in import vs. export was unclear
    • The identity of export receptors was unknown
    • How Ran interfaces with the NPC was not defined
  3. 1995 High

    Identification of RanBP1 and RanBP2 as essential Ran-binding partners placed the GTPase cycle at specific subcellular locations: RanBP2 at the NPC and RanBP1 as a cytosolic cofactor required for both protein import and RNA export, while yeast genetic studies confirmed the conserved requirement for Rna1p (RanGAP) and Yrb1p (RanBP1) in transport.

    Evidence Yeast two-hybrid and antibody inhibition of import for RanBP2; genetic ts mutants and GST pull-downs for yeast Yrb1p; biochemical complementation with purified Rna1p in yeast import assay

    PMID:7489726 PMID:7603572 PMID:7657689 PMID:7836422

    Open questions at the time
    • How RanBP2 at the NPC mechanistically contributes to translocation was not resolved
    • The SUMO modification of RanGAP1 and its functional relevance were not yet discovered
  4. 1996 High

    The directional logic of Ran-dependent transport was resolved: cytoplasmic RanGDP promotes NPC docking/translocation while nucleoplasmic RanGTP triggers cargo release from importin-β; nucleotide-specific interactions with NTF2 (GDP-bound) and importin-β (GTP-bound) establish vectorial transport; SUMOylation of RanGAP1 anchors it to the NPC cytoplasmic face.

    Evidence Permeabilized cell import with importin-β Ran-binding mutants; solution binding assays with radiolabeled Ran; immunolocalization and biochemical identification of SUMO-modified RanGAP1

    PMID:8755535 PMID:8896452 PMID:8955121 PMID:8978815

    Open questions at the time
    • How RanGDP is recycled back to the nucleus was not fully understood
    • The structural basis for nucleotide-dependent receptor switching was unavailable
  5. 1997 High

    Export receptor mechanisms were elucidated: CRM1/exportin forms a cooperative RanGTP-dependent complex with leucine-rich NES cargoes, and CAS mediates importin-α re-export as a RanGTP-dependent trimeric complex; cytoplasmic RanBP1 and RanGAP1 together disassemble export complexes, completing the Ran-driven transport cycle.

    Evidence In vitro binding of purified CRM1 with RanGTP and NES peptides; Xenopus oocyte export assay with leptomycin B; reconstitution of importin-α/CAS/RanGTP complex with permeabilized cell export assay

    PMID:9323133 PMID:9323134

    Open questions at the time
    • Whether all export pathways require RanGTP was unknown (later shown that β-catenin does not)
    • The full repertoire of exportins was not catalogued
  6. 1999 Medium

    A transport-independent role for Ran in microtubule/centrosome organization was discovered: RanGTP (but not RanGDP) induces microtubule self-organization in Xenopus egg extracts lacking nuclei, and the Ran-binding protein RanBPM localizes to the centrosome, opening a new field of Ran function in mitosis.

    Evidence Xenopus egg extract microtubule assembly assay; RanBPM immunolocalization

    PMID:10471364

    Open questions at the time
    • The molecular targets released by RanGTP to drive microtubule assembly were unknown
    • Whether RanBPM is a true effector of Ran-dependent MT nucleation was unclear
    • Confirmation in mammalian mitotic cells was needed
  7. 2002 High

    In vivo validation of Ran's mitotic roles came from C. elegans RNAi (chromosome alignment, segregation, and nuclear envelope assembly defects) and from identification of Ran-interacting kinase Nercc1, whose inhibition causes spindle abnormalities; separately, the mechanism by which RanGTP triggers cargo release from transportin was structurally dissected.

    Evidence C. elegans RNAi of Ran/RCC1/RanGAP with live imaging; Nercc1 co-IP and antibody microinjection; Kap-β2 proteolytic cleavage and ITC with permeabilized cell import

    PMID:11909538 PMID:12033928 PMID:12101123

    Open questions at the time
    • Identity of mitotic Ran effectors beyond Nercc1 was incomplete
    • Whether Ran's mitotic functions are separable from its transport functions was unresolved
  8. 2003 High

    The Ran-GTP→TPX2→Aurora A spindle assembly axis was reconstituted: RanGTP releases TPX2 from importin-α/β inhibition, whereupon TPX2 activates Aurora A kinase and protects it from PP1 dephosphorylation on microtubules; a larger Ran-dependent complex (HURP, XMAP215, Eg5, Aurora A) drives aster-to-spindle conversion; exportin-5 exports pre-miRNAs in a Ran-GTP-dependent manner; Ran localizes to centrosomes via AKAP450.

    Evidence Xenopus egg extract reconstitution with purified TPX2/Aurora A; immunodepletion and MS identification of HURP complex; exportin-5 binding assay with pre-miRNA; immunoEM of centrosomal Ran

    PMID:12577065 PMID:14517334 PMID:14681208 PMID:16631581

    Open questions at the time
    • How the mitotic Ran gradient is shaped in space and time was not quantitatively understood
    • The centrosomal Ran pool's precise substrates were not identified
  9. 2005 High

    CRM1 was shown to have a direct mitotic function at kinetochores: it recruits RanGAP1/RanBP2 to kinetochores, and its inhibition disrupts kinetochore-fiber organization and chromosome segregation, demonstrating that the Ran pathway operates at kinetochores to organize spindle microtubule attachments.

    Evidence Immunofluorescence of kinetochore components; leptomycin B inhibition; tsBN2 Ran pathway mutant analysis

    PMID:15908946

    Open questions at the time
    • The kinetochore-specific cargo(es) of CRM1 regulated by Ran were not fully identified
    • Whether Ran-dependent kinetochore regulation is direct or indirect through gradient effects was unclear
  10. 2008 High

    Survivin was identified as a direct RanGTP-binding partner that delivers TPX2 to spindle microtubules; tumor cells are differentially dependent on Ran for spindle formation and survival compared to normal cells, revealing Ran as a potential oncology target.

    Evidence Proteomics screening; survivin E65A mutagenesis; Xenopus and mammalian spindle assays; siRNA in tumor vs. normal cells

    PMID:18339863 PMID:18591255

    Open questions at the time
    • Why tumor cells are selectively dependent on Ran was mechanistically unresolved
    • Whether survivin–Ran interaction is therapeutically targetable was unknown
  11. 2010 High

    PAK4 phosphorylation of Ran at Ser-135 during mitosis was identified as a regulatory switch: phosphorylation of GDP-bound Ran blocks RCC1-mediated nucleotide exchange while GTP-bound phospho-Ran promotes aster nucleation, and phosphorylation impedes binding to both RCC1 and RanGAP1.

    Evidence In vitro kinase assay with MS site identification; Xenopus egg extract aster assay; co-IP with RCC1/RanGAP1

    PMID:20805321

    Open questions at the time
    • Whether other kinases phosphorylate Ran at additional sites during mitosis was unknown
    • The phosphatase(s) that reverse Ser-135 phosphorylation were not identified
  12. 2011 High

    RanGTP was shown to accumulate at basal bodies and to regulate primary ciliogenesis: RanBP1 depletion increases local RanGTP and promotes cilia formation, while overexpression antagonizes it; Ran is also required for ciliary localization of KIF17, extending Ran's transport paradigm to the cilium.

    Evidence Bidirectional RanBP1 manipulation (siRNA and overexpression) in MDCK cells; immunofluorescence of Ran-GTP and cilia markers

    PMID:21998203

    Open questions at the time
    • The ciliary import/export receptors regulated by Ran were not fully characterized
    • Whether the ciliary Ran gradient is distinct from the nuclear gradient was not addressed
  13. 2015 High

    Two major post-translational modifications of Ran were biochemically characterized: SUMOylation by the RanBP2/RanGAP1*SUMO1/Ubc9 complex targets exclusively RanGDP at the NPC and is antagonized by transport receptors, while acetylation at multiple lysines (by CBP/p300 and TIP60) and deacetylation (by sirtuins) regulate nucleotide exchange, GTP hydrolysis, receptor binding, and subcellular localization.

    Evidence Reconstituted in vitro sumoylation with purified RanBP2 complex and ITC; acetylation/deacetylation assays with identified enzymes; nucleotide exchange/hydrolysis assays on modified Ran

    PMID:26124124 PMID:26251516

    Open questions at the time
    • The functional consequences of Ran SUMOylation for transport in vivo were not demonstrated
    • Site-specific effects of individual acetylation marks were not fully dissected
  14. 2018 High

    Structural and mechanistic integration: the crystal structure of the Ran–Mog1 complex revealed that Mog1 competes with RCC1 for Ran binding; TIP60-mediated Lys-134 acetylation releases Mog1, enabling RCC1 binding and RanGTP production essential for chromosome alignment; separately, disruption of the Ran gradient (via heterochromatin loss in HGPS) impairs nuclear import of large proteins including ATM, linking Ran function to DNA damage responses.

    Evidence X-ray crystallography of Ran–Mog1; in vitro TIP60 acetylation; chromosome alignment assays; HMT inhibition and siRNA in HGPS fibroblasts with γ-H2AX readout

    PMID:29040603 PMID:30565836

    Open questions at the time
    • Whether Mog1 displacement by acetylation occurs at specific cell cycle stages was not fully resolved
    • The quantitative contribution of Ran gradient disruption to HGPS pathology vs. other mechanisms was unclear
  15. 2019 High

    An unexpected non-nuclear function of Ran was demonstrated: Ran localizes to the plasma membrane and stabilizes RhoA by preventing its proteasomal degradation through a direct DEDDDL–Ser188 interaction, promoting cancer cell invasion via RhoA signaling.

    Evidence siRNA knockdown; co-IP; RhoA activity assay; proteasome inhibition rescue; DEDDDL deletion and RhoA S188A mutagenesis; invasion assays in ovarian cancer cells

    PMID:31209254

    Open questions at the time
    • Whether RhoA stabilization requires GTP- or GDP-bound Ran was not determined
    • Generalizability beyond ovarian cancer cells was not tested
    • The mechanism by which Ran reaches the plasma membrane is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: (1) how the ciliary, centrosomal, and plasma-membrane pools of Ran are established and regulated independently of the nuclear gradient; (2) the structural basis for nucleotide-state-specific recognition across the full set of Ran effectors; (3) whether site-specific combinations of phosphorylation, acetylation, and SUMOylation create a 'Ran code' with distinct functional outputs; and (4) why tumor cells are selectively dependent on Ran for mitotic spindle assembly.
  • Integrated structural view of modified Ran with multiple effectors is lacking
  • In vivo significance of Ran SUMOylation remains untested
  • Therapeutic targeting of Ran in cancer lacks tool compounds

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0003924 GTPase activity 3
Localization
GO:0005635 nuclear envelope 4 GO:0005634 nucleus 3 GO:0005694 chromosome 3 GO:0005829 cytosol 2 GO:0005815 microtubule organizing center 1 GO:0005886 plasma membrane 1 GO:0005929 cilium 1
Pathway
R-HSA-9609507 Protein localization 7 R-HSA-1640170 Cell Cycle 6 R-HSA-392499 Metabolism of proteins 2 R-HSA-8953854 Metabolism of RNA 1
Partners
BIRC5NUTF2RANBP1RANBP2RANGAP1RCC1TPX2XPO1
Complex memberships
CAS/importin-α/RanGTP export complexCRM1/RanGTP/NES export complexRanBP2/RanGAP1*SUMO1/Ubc9 SUMO E3 compleximportin-β/RanGTP transport complex

Evidence

Reading pass · 61 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 RanGAP1 (a 65-kDa homodimeric protein purified from HeLa cells) stimulates the GTPase activity of Ran by more than 1000-fold, but has no effect on Ras; the Ran mutant Q69L (analogous to RasQ61L) is insensitive to RanGAP1, establishing RanGAP1 as the principal GTPase activator for Ran. Biochemical purification from HeLa lysates; in vitro GTPase assay; mutagenesis (Q69L) Proceedings of the National Academy of Sciences of the United States of America High 8146159
1994 Ran (Ras-related nuclear protein) is required as part of 'fraction B' cytosolic activity for nuclear protein import in Xenopus permeabilized cell assays, functioning downstream of NLS recognition; a second 10-kDa protein (later identified as NTF2/pp15) is also required for fraction B activity. Biochemical fractionation and reconstitution in permeabilized Xenopus cell nuclear import assay; peptide sequencing Proceedings of the National Academy of Sciences of the United States of America High 7937864
1994 A GTP-hydrolysis-deficient mutant of Ran/TC4 blocks DNA replication and arrests cells predominantly in G2 (also G1), demonstrating that a functional Ran GTPase cycle is required for normal cell cycle progression; the inhibitory effect requires the C-terminal acidic hexapeptide (DEDDDL) of Ran. Transient expression of GTPase-deficient Ran mutants in 293/Tag cells; cell cycle analysis by flow cytometry; deletion mutagenesis Molecular and cellular biology High 8196659
1994 GTP-bound Ran specifically binds a family of effector proteins (28 kDa cytosolic and 86–300 kDa nuclear) that potently inhibit GTP release from Ran, thereby stabilizing the GTP-on state; binding requires the C-terminal DEDDDL acidic sequence and intact N-terminus of Ran. Nitrocellulose overlay assay; GTP release inhibition assay; deletion mutagenesis of Ran The Journal of biological chemistry Medium 8157660
1995 RanBP2 (a 3,224-residue nuclear pore complex protein) binds Ran/TC4 via four RanBP1-homologous domains; it contains leucine-rich repeats, zinc fingers (similar to NUP153), and a cyclophilin-homologous C-terminus; antibodies against RanBP2 inhibit NLS-mediated nuclear import, establishing a functional role for this nucleoporin in protein import. Yeast two-hybrid screen; immunolocalization; antibody inhibition of nuclear import in permeabilized cells Nature High 7603572
1995 Rna1p (the yeast RanGAP ortholog) is required for nuclear protein import in S. cerevisiae; rna1-1 mutant extracts cannot support import, and adding back purified Rna1p rescues import activity in a dose-dependent manner, demonstrating a direct role in nuclear transport. Indirect immunofluorescence; in vitro import assay with semi-intact yeast cells; biochemical complementation with purified Rna1p The Journal of cell biology High 7657689
1995 The yeast Ran homolog Gsp1p (in GTP-bound form) co-purifies with Yrb1p (yeast RanBP1 homolog); Yrb1p stimulates GTP hydrolysis by Gsp1p in the presence of Rna1p (RanGAP); temperature-sensitive yrb1 mutants are defective in both nuclear protein import and RNA export, establishing Yrb1p as an essential component of the Ran/RCC1 transport system. GST pull-down with GTP-locked Gsp1p; GTPase assay; indirect immunofluorescence; nuclear transport assays in ts mutant yeast The EMBO journal High 7489726
1995 The intrinsic GTPase of Ran is ~10-fold slower than p21ras; RanGAP1 stimulates this rate ~10^5-fold (rate constant 2.1 s⁻¹ at 25°C); RCC1 (GEF) stimulates guanine nucleotide dissociation ~10^5-fold; the T24N mutant (dominant-negative analog) has decreased GTP/GDP affinity, favors GDP, but interacts nearly normally with RCC1, causing depletion of free RCC1 in vivo. Fluorescence kinetic assays (mant-nucleotide); stopped-flow measurements; mutagenesis (Q69L, T24N) Biochemistry High 7819259
1995 RNA1 (yeast gene) encodes the GTPase-activating protein for Gsp1p (yeast Ran); recombinant Rna1p stimulates Gsp1p GTPase ~10^7-fold; human RanGAP1 and S. pombe rna1p cross-react with Gsp1p but yeast Rna1p does not stimulate human Ran GTP hydrolysis, revealing species specificity. Recombinant protein expression in E. coli; in vitro GTPase assay; cross-species biochemistry The Journal of biological chemistry High 7744835
1995 Several proteins including S. cerevisiae Nup2p and a putative yeast RanBP contain RanBP1-like domains and bind Ran; Nup2p is identified as a direct Ran target within the NPC, suggesting a direct role in nuclear-cytoplasmic transport; yeast two-hybrid analysis also reveals Ran–Ran self-interaction. Sequence homology analysis; in vitro Ran-binding assays; yeast two-hybrid Proceedings of the National Academy of Sciences of the United States of America Medium 7638224
1995 Overexpression of RanBP1 (CST20) causes chromosome non-disjunction and benomyl sensitivity in yeast; RanBP1 interacts with Ran-GTP in vitro and forms a complex with Ran in vivo (co-immunoprecipitation); deletion of RanBP1 is lethal, establishing it as an essential functional component of the Ran/RCC1 molecular switch. Genetic screen for chromosome instability; in vitro Ran-GTP binding; co-immunoprecipitation; gene deletion/overexpression in yeast The Journal of biological chemistry High 7836422
1995 Protein export from the nucleus requires Ran and GTP hydrolysis (but not ATP hydrolysis): recombinant Ran + GTP drives up to 80% export of imported substrate in permeabilized cells; non-hydrolyzable GTP analogs and a GTPase-deficient Ran mutant inhibit export; fluorescently labeled Ran docks at the nuclear rim (NPC) in a punctate pattern. Permeabilized cell export assay; GTP analog inhibition; GTPase-deficient Ran mutant; fluorescence microscopy Proceedings of the National Academy of Sciences of the United States of America High 7753805
1995 Importin (importin-α/60kDa and importin-β/90kDa heterodimer) constitutes the cytosolic NLS receptor; importin-β is required for transit through the NPC and Ran/TC4 is required for the second (translocation) step of nuclear import, downstream of NLS binding. Biochemical reconstitution in Xenopus egg extracts; permeabilized cell import assay; peptide sequencing Current biology : CB High 7627554
1996 RanBP1 stabilizes the interaction of Ran-GDP with p97 (importin-β): Ran-GTP alone binds p97 with high affinity; Ran-GDP requires RanBP1 to bind p97. A trimeric Ran-GDP/RanBP1/p97 complex can be reconstituted from recombinant proteins; RanBP1 stimulates nuclear transport in permeabilized cells. Gel filtration chromatography; immunoadsorption from HeLa extracts; solution and solid-phase binding assays; reconstitution from recombinant proteins; permeabilized cell import assay The Journal of cell biology High 8909533
1996 Nuclear import depends on cytoplasmic RanGDP (not RanGTP) and free GTP; RanGDP binds to the NPC; nucleoplasmic RanGTP binding to importin-β triggers cargo release into the nucleoplasm (termination step); a Ran-binding-deficient importin-β mutant delivers cargo to the nucleoplasmic face of the NPC but cannot release it, defining two mechanistically distinct roles for RanGDP (docking/translocation) and RanGTP (substrate release). Permeabilized cell nuclear import assay; importin-β mutants deficient in Ran binding; subcellular fractionation; fluorescence microscopy The EMBO journal High 8896452
1996 Ran/TC4 interacts directly with cytosolic transport factors p97 (importin-β) and NTF2 in a nucleotide-specific manner: GTP-bound Ran interacts with p97, while GDP-bound Ran interacts with NTF2; this defines a directionality mechanism where RanGDP/NTF2 association helps establish vectorial transport. Solution and solid-phase binding assays with [γ-³²P]GTP- or [³H]GDP-preloaded recombinant Ran Proceedings of the National Academy of Sciences of the United States of America High 8755535
1996 The modified (90-kDa) form of RanGAP1 is associated with the cytoplasmic fibers of the NPC and the mitotic spindle, while unmodified (70-kDa) RanGAP1 is exclusively cytoplasmic; the modification is conjugation to a ubiquitin-like protein (SUMO-1), establishing the first example of SUMO modification controlling protein localization. Peptide sequence analysis; specific monoclonal antibodies; immunoblot; immunolocalization by light and electron microscopy The Journal of cell biology High 8978815
1996 Gain-of-function (G19V) and effector-domain (L43E, E46G) Ran mutants that are insensitive to RCC1 or RanGAP accumulate at the nuclear envelope rather than the nucleus; C-terminal DEDDDL deletion causes cytosolic mislocalization; wild-type Ran is predominantly nuclear and GDP-bound; these results link Ran's regulatory protein interactions to its subcellular localization. Site-directed mutagenesis; epitope-tagged protein expression in BHK21 cells; nucleotide-bound state analysis; permeabilized cell assays The Journal of biological chemistry High 8955121
1996 RCC1 is the chromatin-bound GEF for Ran, and together with cytoplasmic RanGAP1/Rna1p creates the Ran-GTP/GDP gradient; RanBP proteins (possessing conserved Ran-binding motifs) are found in species from yeast to mammals; loss of RCC1 induces premature mitosis with micronuclei, linking the Ran pathway to cell cycle control. Biochemical and genetic analysis; review of RCC1/Ran pathway components; genetic studies in RCC1-deficient cells Journal of biochemistry Medium 8889801
1996 The wild-type yeast Rna1p (RanGAP) is found predominantly in the cytosol but a small pool localizes at both the cytosolic surface and within the nucleoplasm of HeLa nuclei; the mutant Rna1-1p is restricted to the outer nuclear surface, suggesting that active RanGAP operates on both sides of the nuclear membrane to regulate the Ran GTPase cycle. Subnuclear fractionation of yeast nuclei; indirect immunofluorescence in HeLa cells Proceedings of the National Academy of Sciences of the United States of America Medium 8755533
1997 Two distinct but overlapping binding domains for Ran-GTP and Ran-GDP/RanBP1 exist on p97 (importin-β); an acidic sequence in p97 is part of the Ran-GDP/RanBP1 binding domain; Cys-158 in p97 is required for Ran-GDP/RanBP1 binding but not Ran-GTP binding; a C158A mutant p97 cannot support nuclear import, establishing both nucleotide forms of Ran as active participants in the import cycle. Site-directed mutagenesis; deletion analysis; solid-phase binding assays; permeabilized cell import assay The Journal of biological chemistry High 9045717
1997 CRM1 forms a leptomycin B-sensitive cooperative complex with RanGTP and leucine-rich nuclear export signals (NES from Rev or PKI); overexpression of CRM1 in Xenopus oocytes stimulates Rev and U snRNA export; leptomycin B (which binds CRM1) specifically inhibits these exports, establishing CRM1 as the export receptor for leucine-rich NES and RanGTP as its cofactor. In vitro binding assay with purified CRM1, RanGTP, and NES peptides; Xenopus oocyte microinjection export assay; leptomycin B inhibition Cell High 9323133
1997 CAS protein mediates importin-α re-export: CAS binds importin-α strongly only in the presence of RanGTP, forming an importin-α/CAS/RanGTP trimeric export complex; in the cytoplasm, RanBP1 and RanGAP1 together disassemble this complex; CAS preferentially binds NLS-free importin-α, explaining nuclear retention of import substrates. Biochemical binding assays; nuclear export assay in permeabilized cells; in vitro complex reconstitution Cell High 9323134
1997 High-level expression of yeast Ran homolog Gsp1p suppresses deletion of NTF2 (scNTF2), and high levels of vertebrate Ran/TC4 can substitute for NTF2 in a mammalian permeabilized cell import assay; deletion of scNTF2 is lethal and causes gross nuclear envelope distortions, establishing that NTF2 and Ran have closely linked functions. High-copy suppressor screen; gene deletion in yeast; regulated promoter repression; mammalian permeabilized cell import assay The Journal of biological chemistry High 9261173
1997 Interaction between Ran/Gsp1p and Ntf2p is critical for nuclear transport: two temperature-sensitive gsp1 alleles (gsp1-1, gsp1-2) reduce interaction with Ntf2p; overexpression of NTF2 suppresses the ts phenotype and transport defects; a NTF2 mutant with reduced Gsp1p binding fails to suppress, establishing the Ran–NTF2 interaction as essential for import. Genetic screen for conditional gsp1 alleles; biochemical binding assays; genetic suppression analysis; nuclear transport assays Molecular and cellular biology High 9199309
1999 ARA24/Ran (the nuclear G-protein Ran) was identified as the first androgen receptor (AR) coactivator that binds differentially to different poly-glutamine (poly-Q) lengths within AR; interaction of the AR N-terminal domain with ARA24/Ran diminishes as poly-Q length increases, and coactivation activity likewise diminishes; deletion of the C-terminal DEDDDL of ARA24/Ran further enhances its AR coactivation. Yeast two-hybrid; mammalian reciprocal interaction assays; transactivation assays with poly-Q length series; deletion mutagenesis The Journal of biological chemistry Medium 10400640
1999 A novel Ran-binding protein, RanBPM, localizes to the centrosome; separately, RanGTP (but not RanGDP) induces microtubule self-organization in Xenopus egg extracts lacking nuclear membrane, establishing a transport-independent role for Ran in microtubule/centrosome organization. Immunolocalization; Xenopus egg extract microtubule assembly assay; biochemical fractionation Biochemical and biophysical research communications Medium 10471364
2001 Interaction between Ran and Mog1 is required for efficient nuclear protein import in vivo: Mog1 binds nucleotide-free Ran and stimulates nucleotide release; mog1Δ and specific point mutants (E65K-Mog1 and K136E-Ran) that disrupt the Mog1–Ran interaction cause temperature-sensitive growth and nuclear import defects in yeast; MOG1 shows synthetic lethality with PRP20 (RanGEF). Biochemical binding assays; nucleotide release assay; site-directed mutagenesis; yeast genetics (synthetic lethality, ts phenotype); nuclear import reporter assay The Journal of biological chemistry High 11509570
2001 Beta-catenin export from the nucleus is independent of CRM1 and does not require nuclear RanGTP, and can be reconstituted without soluble factors, consistent with non-directional translocation; this distinguishes beta-catenin transport from classical Ran-dependent export pathways. Permeabilized cell export assay; leptomycin B inhibition; RanGTP manipulation; fluorescence microscopy Current biology : CB Medium 11166175
2002 Ran is indispensable for correct chromosome positioning and nuclear envelope assembly in C. elegans in vivo: RNAi depletion of Ran causes metaphase chromosome misalignment and aberrant segregation; depletion of RCC1 or RanGAP phenocopies this; Ran localizes to kinetochore regions during metaphase/anaphase and to the nuclear envelope at telophase. C. elegans RNAi knockdown; immunofluorescence localization; live imaging Current biology : CB High 11909538
2002 Efficient nuclear import of large cargo proteins (but not small ones) requires hydrolyzable GTP and Ran in the importin-α/β and transportin pathways; RanGTP functions in part by directly binding importin-β and transportin to promote passage of large cargo through diffusionally restricted regions of the NPC. In vitro nuclear import assay with size-varied cargo; GTP analog inhibition; morphological analysis (electron microscopy); biochemical fractionation The Journal of cell biology High 12370244
2002 Karyopherin-β2 (Kapβ2/transportin) releases import substrates upon RanGTP binding via an internal acidic loop that physically couples the Ran-binding site (N-terminal arch) to the substrate-binding site (C-terminal arch); cleavage or truncation of this loop uncouples Ran binding from substrate dissociation without altering binding affinities, and abolishes Ran-mediated nuclear uptake in permeabilized cells. Proteolytic cleavage of Kapβ2; deletion mutagenesis; NMR mapping of substrate-binding interface; isothermal titration calorimetry; permeabilized HeLa cell import assay Biochemistry High 12033928
2002 Nercc1, a new mammalian NIMA-like kinase, binds Ran GTPase preferring RanGDP in vivo through both its catalytic and RCC1-like domains; Nercc1 also binds Nek6, forms homooligomers, autoactivates by autophosphorylation in vitro, and is phosphorylated by Cdc2; microinjection of anti-Nercc1 antibodies causes spindle abnormalities, chromosome misalignment, and aneuploidy, defining a Ran-interacting mitotic kinase pathway. Biochemical binding/pull-down; co-immunoprecipitation; in vitro kinase autophosphorylation assay; Cdc2 phosphorylation assay; microinjection of antibodies in Ptk2 and CFPAC-1 cells Genes & development High 12101123
2003 Ran-GTP stimulates the interaction between TPX2 and Aurora A kinase (Eg2/Xenopus), causing TPX2 to stimulate Aurora A phosphorylation and kinase activity in a microtubule-dependent manner; TPX2 and microtubules prevent PP1-mediated dephosphorylation of Aurora A; importin-α/β inhibit this activation, which is overcome by Ran-GTP, defining a Ran-GTP → TPX2 → Aurora A signaling axis essential for spindle assembly. Xenopus egg extract spindle assembly assay; in vitro kinase assay; phosphatase inhibition assay; immunodepletion; purified protein reconstitution Nature cell biology High 12577065
2003 A fraction of Ran associates with the centrosome throughout the cell cycle, mediated by the centrosomal scaffold protein AKAP450; when AKAP450 is delocalized, centrosomal Ran is also lost and microtubule regrowth/anchoring is impaired despite intact γ-tubulin; Ran is recruited to sperm centrosomes during microtubule nucleation activation. Immunofluorescence; immunoelectron microscopy; biochemical fractionation; Xenopus sperm centrosome activation assay; AKAP450 delocalization experiment Molecular biology of the cell High 14517334
2003 The mutant RanGAP encoded by the Segregation Distorter (Sd) locus in Drosophila is enzymatically active but mislocalized to the nucleus (instead of cytoplasm), apparently reducing intranuclear Ran-GTP levels and disrupting Ran signaling/nuclear transport, causing spermatid dysfunction and meiotic drive. Genetic analysis; biochemical characterization of Sd-encoded RanGAP; localization studies in Drosophila BioEssays : news and reviews in molecular, cellular and developmental biology Medium 12539236
2005 Crm1 localizes to kinetochores and is required for Ran-GTP-dependent recruitment of RanGAP1 and RanBP2 to kinetochores; Crm1 inhibition by leptomycin B disrupts mitotic progression, increases centromere tension, causes continuous microtubule bundles spanning centromeres (loss of discrete end-on kinetochore fiber attachments), and impairs chromosome segregation; similar defects occur in tsBN2 Ran-pathway mutant cells. Immunofluorescence of kinetochore components; leptomycin B inhibition; analysis of ts Ran pathway mutant (tsBN2) cells; spindle morphology analysis Nature cell biology High 15908946
2006 A picornavirus cardiovirus Leader protein (L) binds directly to Ran and blocks nuclear mRNA export; in Xenopus egg extracts, recombinant L also inhibits Ran-GTP-dependent mitotic spindle assembly; L is proposed to disrupt the RanGDP/GTP gradient, triggering nuclear protein efflux to suppress interferon responses. Direct binding assay (recombinant L protein with Ran); Xenopus egg extract spindle assembly assay; nuclear export assay Proceedings of the National Academy of Sciences of the United States of America Medium 16888036
2006 BRCA1/BARD1 is required for mitotic spindle-pole assembly downstream of Ran GTPase: in mammalian cells and Xenopus egg extracts, BRCA1/BARD1 is needed for TPX2 accumulation at spindle poles; this function depends on BRCA1/BARD1 E3 ubiquitin ligase activity; BRCA1/BARD1 forms endogenous complexes with TPX2, NuMA, and XRHAMM and attenuates XRHAMM function. Xenopus egg extract spindle assembly; immunodepletion; co-immunoprecipitation; mammalian cell mitosis analysis; E3 ligase activity assays Cell High 17081976
2006 HURP is part of a Ran-dependent complex containing TPX2, XMAP215, Eg5, and Aurora A required for conversion of aster-like to spindle-like structures; the complex's formation and function depend on Aurora A activity; HURP binds microtubules and affects their organization; anti-HURP antibodies disrupt both Ran-dependent and chromatin/centrosome-induced spindles in egg extracts and in HeLa cells. Xenopus egg extract spindle assembly; immunodepletion; mass spectrometry identification of complex; in vitro microtubule binding; antibody inhibition in HeLa cells Current biology : CB High 16631581
2002 RanBP3 associates with the Ran GEF RCC1 in a Ran-stimulated manner; RanBP3 increases RCC1's catalytic exchange activity toward Ran; RanBP3 also promotes Crm1 binding to RCC1 in the presence of Ran, suggesting RanBP3 acts as a scaffold to link Crm1 to RCC1 and enhance export complex assembly at the site of Ran-GTP production. Co-immunoprecipitation; in vitro binding assays; GEF activity assay with RCC1; biochemical reconstitution The Journal of biological chemistry Medium 11932251
2008 Ran is required for mitotic spindle formation in tumor cells: acute Ran silencing in tumor cell types causes aberrant spindle formation, mitochondrial dysfunction, and apoptosis via a pathway controlled by survivin (a novel Ran target); loss of Ran in normal cells is well tolerated and does not cause mitotic defects, suggesting tumor cells are differentially dependent on Ran signaling. siRNA knockdown of Ran in tumor vs. normal cells; mitotic spindle analysis; cell viability/apoptosis assays; survivin pathway analysis Cancer research High 18339863
2008 Survivin associates with Ran-GTP (not GDP) in an evolutionarily conserved complex in mammalian cells and Xenopus extracts; the interaction is cell-cycle regulated, requires Glu65 in survivin, and is independent of Crm1; disruption of the survivin–Ran complex does not affect chromosomal passenger complex assembly but inhibits TPX2 delivery to microtubules, causing aberrant spindle formation and chromosome missegregation specifically in tumor cells. High-throughput proteomics screening; co-immunoprecipitation; mutagenesis (survivin E65A); Xenopus egg extract spindle assay; live-cell imaging Molecular and cellular biology High 18591255
2008 Ran-GTP locally generated at mitotic chromosomes promotes importin-β-mediated chromosome loading of the chromokinesin hKid; importin-α/β bound to hKid (via NLS) enables initial chromosome targeting, and local Ran-GTP-mediated cargo release promotes hKid accumulation on chromosomes; NLS-deficient hKid has reduced chromosome association in living cells. Permeabilized mitotic cell chromosome-binding assay; Ran-GDP/GTP manipulation; live-cell imaging with NLS mutants; co-immunoprecipitation The Journal of cell biology High 18268099
2009 Crystal structures of Nup153 zinc fingers (ZnF) in complex with Ran reveal that each of four ZnF modules binds one Ran molecule independently and with modestly higher affinity for RanGDP than RanGTP; a specific hydrogen bond accounts for most of the affinity variation between individual zinc fingers; these Ran-binding ZnFs are found only in animal NPCs, suggesting an animal-specific mechanism to maintain high local Ran concentration near the NPC. X-ray crystallography (six ZnF-Ran complex structures; 1.48 Å RanGDP structure); isothermal titration calorimetry; mutational analysis Journal of molecular biology High 19505478
2009 Ran-GFP dynamics during the cell cycle in live human cells: Ran-GFP is nuclear during interphase; GFP-RanQ69L (GTP-locked) is less nuclear, associates with NPCs, and localizes to the spindle during mitosis; GFP-RanT24N (low nucleotide affinity) interacts stably with chromatin throughout the cell cycle, including being highly concentrated on mitotic chromosomes; these nucleotide-state-dependent interactions are demonstrated in living cells. Live-cell fluorescence imaging of GFP-tagged Ran and mutants (RanQ69L, RanT24N); FRAP; cell-cycle-staged analysis BMC cell biology High 19765287
2010 PAK4 (subgroup II p21-activated kinase) phosphorylates Ran on Ser-135 during mitosis; a GDP-bound Ran phosphomimetic (Ser135Asp) cannot undergo RCC1-mediated GDP/GTP exchange and fails to induce microtubule asters in Xenopus egg extracts; GTP-bound phosphorylated Ran facilitates aster nucleation; Ser-135 phosphorylation impedes Ran binding to both RCC1 and RanGAP1. In vitro kinase assay; mass spectrometry identification of phosphosite; Xenopus egg extract aster assay; co-immunoprecipitation with RCC1/RanGAP1; immunofluorescence of endogenous p-Ran and PAK4 in mitotic cells The Journal of cell biology High 20805321
2011 Ran-GTP accumulates at basal bodies coordinately with ciliogenesis initiation; RanBP1 localizes to basal bodies and cilia; RanBP1 knockdown increases Ran-GTP concentration at basal bodies and promotes primary cilia formation, while RanBP1 overexpression antagonizes ciliogenesis; RanBP1 knockdown also disrupts proper localization of KIF17 kinesin at distal cilia tips, demonstrating a role for Ran-GTP in ciliary protein transport. RanBP1 siRNA knockdown and overexpression; immunofluorescence of Ran-GTP and cilia markers; measurement of primary cilia formation; KIF17 localization analysis in MDCK cells Molecular biology of the cell High 21998203
2013 The N17 domain of huntingtin contains a CRM1/exportin-dependent nuclear export signal (NES) whose activity is dependent on the Ran-GTP/GDP gradient; serine phosphorylation of N17 prevents nuclear export and increases nuclear huntingtin; N17 phospho-mimetic mutants also distinguish basal body from ciliary stalk localization of huntingtin, revealing N17 as a multifunctional localization signal regulated by both Ran and phosphorylation. CRM1 interaction assays; nuclear localization in cells with Ran gradient manipulation; phospho-mimetic and phospho-dead mutagenesis; live-cell imaging; leptomycin B inhibition Human molecular genetics Medium 23297360
2014 RanBP1 governs mitotic Ran-GTP production: in M-phase Xenopus egg extracts, a heterotrimeric RCC1/Ran/RanBP1 complex controls both RCC1's enzymatic activity and its partitioning between chromatin-bound and soluble pools; RanBP1 phosphorylation drives changes in chromatin-bound RCC1 dynamics at the metaphase-anaphase transition, thereby controlling the spatial distribution and magnitude of Ran-GTP gradients for spindle assembly. Xenopus egg extract biochemical analysis; immunodepletion and add-back; chromatin fractionation; RCC1 exchange activity assay; cell cycle staging Developmental cell High 25458009
2014 Ran expression is reduced in progranulin-deficient retinal neurons, leading to impaired nuclear import of TDP-43; TDP-43 regulates Ran expression by binding its 3'-UTR; augmented Ran expression in progranulin-deficient neurons restores nuclear TDP-43 levels and improves neuronal survival, establishing a pathological reciprocal loop between Ran and nuclear TDP-43. Mouse model (Grn-KO); Ran overexpression rescue; qRT-PCR; immunofluorescence; nuclear fractionation; TDP-43 3'-UTR binding assay The Journal of experimental medicine Medium 25155018
2015 Ran is SUMOylated by the RanBP2/RanGAP1*SUMO1/Ubc9 E3 ligase complex at the NPC cytoplasmic fibers; only RanGDP (not RanGTP) is the physiological substrate; transport receptors (Crm1, importin-β, transportin, NTF2) inhibit Ran sumoylation; NTF2 prevents sumoylation by reducing RanGDP's affinity for RanBP2's RBDs; SENP1 desumoylates Ran. Reconstituted sumoylation assay with purified RanBP2 complex; semi-permeabilized cell assay; isothermal titration calorimetry; SUMO isopeptidase inhibition; SENP1 depletion The Journal of biological chemistry High 26251516
2015 Ran is regulated by lysine acetylation at five sites in human cells (eleven in mouse/rat), including sites in switch I and switch II; acetylation (by CBP/p300 and Tip60) interferes with nucleotide exchange, GTP hydrolysis, subcellular localization, and interaction with import/export receptors; deacetylation is performed by certain sirtuins; all effects demonstrated both in vitro and in vivo. In vitro acetylation assay (CBP/p300, Tip60); sirtuin deacetylation assay; nucleotide exchange/hydrolysis assays on acetylated Ran; co-immunoprecipitation with import/export receptors; immunofluorescence for Ran localization; proteomics identification of acetylation sites Proceedings of the National Academy of Sciences of the United States of America High 26124124
2015 LIN28B promotes RAN expression by binding RAN mRNA directly and by promoting RanBP2 expression; RAN is identified as a LIN28B target oncogene in neuroblastoma; LIN28B and RAN signaling converge on Aurora kinase A activity; RAN gain (via chromosome 12q24 amplification) is a somatic alteration in high-risk neuroblastoma. RNA-IP for LIN28B-RAN mRNA binding; genomic copy number analysis; Aurora A activity assays; neuroblastoma cell/mouse model functional studies Cancer cell Medium 26481147
2016 The spatial distribution of Ran pathway components on the mitotic spindle is determined by their interactions with microtubules, creating a feedback loop where microtubule nucleators are localized by the microtubules they stimulate; this feedback makes spindle length insensitive to the Ran gradient length scale and allows spindle assembly outside the gradient peak, explaining spindle-cell size scaling. Multipoint fluorescence fluctuation spectroscopy (novel technique); mathematical modeling; perturbation experiments in mitotic cells Proceedings of the National Academy of Sciences of the United States of America Medium 27439876
2018 TIP60 acetylates Ran at Lys134 during mitosis; crystal structure of the Ran–Mog1 complex reveals that Mog1 competes with RCC1 for Ran binding in a GTP/GDP-dependent manner; Mog1-bound Ran prevents RCC1 binding and GTP loading; TIP60-mediated Lys134 acetylation releases Mog1 from Ran, allowing RCC1 binding and high Ran-GTP levels essential for chromosome alignment. X-ray crystallography of Ran–Mog1 complex; in vitro acetylation assay (TIP60); biochemical binding competition assays; structure-guided mutagenesis; chromosome alignment assays in cells Journal of molecular cell biology High 29040603
2018 Disruption of the nuclear lamina–chromatin–Ran axis in Hutchinson-Gilford progeria syndrome: chemical inhibition or depletion of histone methyltransferases G9a and GLP reduces heterochromatin and disrupts the Ran gradient comparably to progerin; Ran gradient disruption impairs nuclear import of large proteins (TPR) and prevents nuclear import of ATM, causing a defect in nuclear γ-H2AX generation in response to ionizing radiation. HMT inhibitors and siRNA depletion; immunofluorescence of Ran gradient; nuclear fractionation; ionizing radiation and γ-H2AX assays in normal vs. HGPS fibroblasts Aging cell Medium 30565836
2019 Ran promotes membrane targeting and stabilization of RhoA in ovarian cancer cells: Ran localizes to the plasma membrane/ruffles in addition to the nucleus; Ran depletion reduces RhoA stability and membrane localization, and decreases RhoA activity; the DEDDDL domain of Ran interacts with Ser188 of RhoA to prevent proteasomal degradation of RhoA; Ran knockdown impairs cancer cell invasion via RhoA signaling. siRNA knockdown of Ran; immunofluorescence and fractionation for plasma membrane localization; co-immunoprecipitation; RhoA activity assay (RBD pull-down); proteasome inhibition; invasion assay; mutagenesis (DEDDDL deletion, RhoA S188A) Nature communications High 31209254
2003 Exportin-5 exports pre-miRNA hairpins from the nucleus in a Ran-GTP-dependent manner: Exportin-5 binds pre-miRNAs specifically in vitro only in the presence of Ran-GTP cofactor; pre-miRNA export and miRNA function are dependent on Exportin-5 in human cells. In vitro binding assay with purified Exportin-5 and Ran-GTP; Exportin-5 knockdown in human cells; nuclear export assay Genes & development High 14681208
2008 ARA24/Ran enhances the androgen-dependent N-terminal/C-terminal (N-C) interaction of the androgen receptor (AR) in the nucleus; wild-type Ran (but not constitutively GTP- or GDP-bound forms) potentiates the N-C interaction; Ran forms an endogenous complex with nuclear AR but not cytoplasmic AR; Ran does not enhance AR mutants that disrupt N-C interaction, confirming N-C interaction dependence. Mammalian two-hybrid N-C interaction assay; co-immunoprecipitation of endogenous Ran with AR; transactivation assays with AR mutants; subcellular fractionation Biochemical and biophysical research communications Medium 18565325
2022 RSL1D1 interacts with Ran and inhibits its deacetylation by competing with Sirt7 for Ran binding; by maintaining Ran acetylation, RSL1D1 inhibits nuclear accumulation of STAT3 and STAT3-regulated autophagy, thereby promoting colorectal cancer progression. Co-immunoprecipitation; acetylation assays; STAT3 nuclear fractionation; autophagy flux assays; siRNA knockdown; colorectal cancer mouse model Cell death & disease Medium 35013134

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Exportin-5 mediates the nuclear export of pre-microRNAs and short hairpin RNAs. Genes & development 2168 14681208
1997 CRM1 is an export receptor for leucine-rich nuclear export signals. Cell 1775 9323133
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
1997 The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants. Science (New York, N.Y.) 1276 9219684
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
1996 A novel ubiquitin-like modification modulates the partitioning of the Ran-GTPase-activating protein RanGAP1 between the cytosol and the nuclear pore complex. The Journal of cell biology 979 8978815
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2012 The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. Molecular cell 973 22681889
2005 Nucleolar proteome dynamics. Nature 934 15635413
2004 Immunoaffinity profiling of tyrosine phosphorylation in cancer cells. Nature biotechnology 916 15592455
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
2015 The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature 804 26308891
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2008 Large-scale proteomics and phosphoproteomics of urinary exosomes. Journal of the American Society of Nephrology : JASN 607 19056867
2002 ALL-1 is a histone methyltransferase that assembles a supercomplex of proteins involved in transcriptional regulation. Molecular cell 576 12453419
1996 Identification of different roles for RanGDP and RanGTP in nuclear protein import. The EMBO journal 562 8896452
2005 High-throughput mapping of a dynamic signaling network in mammalian cells. Science (New York, N.Y.) 553 15761153
2017 Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science (New York, N.Y.) 533 28302793
1997 Export of importin alpha from the nucleus is mediated by a specific nuclear transport factor. Cell 532 9323134
2010 Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Science (New York, N.Y.) 524 20847263
2006 Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis. Cell 517 17110338
1994 RanGAP1 induces GTPase activity of nuclear Ras-related Ran. Proceedings of the National Academy of Sciences of the United States of America 456 8146159
1995 Two different subunits of importin cooperate to recognize nuclear localization signals and bind them to the nuclear envelope. Current biology : CB 447 7627554
1995 A giant nucleopore protein that binds Ran/TC4. Nature 446 7603572
2008 Spatial and temporal coordination of mitosis by Ran GTPase. Nature reviews. Molecular cell biology 333 18478030
1994 Purification of a Ran-interacting protein that is required for protein import into the nucleus. Proceedings of the National Academy of Sciences of the United States of America 317 7937864
2003 A Ran signalling pathway mediated by the mitotic kinase Aurora A in spindle assembly. Nature cell biology 304 12577065
1995 Interaction of the nuclear GTP-binding protein Ran with its regulatory proteins RCC1 and RanGAP1. Biochemistry 289 7819259
2006 The BRCA1/BARD1 heterodimer modulates ran-dependent mitotic spindle assembly. Cell 227 17081976
2006 HURP is part of a Ran-dependent complex involved in spindle formation. Current biology : CB 223 16631581
2015 Nucleolar stress and impaired stress granule formation contribute to C9orf72 RAN translation-induced cytotoxicity. Human molecular genetics 204 25575510
1999 The linkage of Kennedy's neuron disease to ARA24, the first identified androgen receptor polyglutamine region-associated coactivator. The Journal of biological chemistry 181 10400640
2005 Crm1 is a mitotic effector of Ran-GTP in somatic cells. Nature cell biology 171 15908946
2002 The Ran GTPase as a marker of chromosome position in spindle formation and nuclear envelope assembly. Nature cell biology 171 12105431
2002 The Ran GTPase: theme and variations. Current biology : CB 171 12176353
1996 RanBP1 stabilizes the interaction of Ran with p97 nuclear protein import. The Journal of cell biology 164 8909533
1995 Rna1p, a Ran/TC4 GTPase activating protein, is required for nuclear import. The Journal of cell biology 155 7657689
1995 Mutants in a yeast Ran binding protein are defective in nuclear transport. The EMBO journal 136 7489726
2000 The ran decathlon: multiple roles of Ran. Journal of cell science 132 10704362
1998 Two-way trafficking with Ran. Trends in cell biology 132 9695834
2002 Nercc1, a mammalian NIMA-family kinase, binds the Ran GTPase and regulates mitotic progression. Genes & development 122 12101123
2013 Repeat-associated non-ATG (RAN) translation in neurological disease. Human molecular genetics 120 23918658
2020 Metformin inhibits RAN translation through PKR pathway and mitigates disease in C9orf72 ALS/FTD mice. Proceedings of the National Academy of Sciences of the United States of America 113 32690681
1995 RNA1 encodes a GTPase-activating protein specific for Gsp1p, the Ran/TC4 homologue of Saccharomyces cerevisiae. The Journal of biological chemistry 111 7744835
2003 Part of Ran is associated with AKAP450 at the centrosome: involvement in microtubule-organizing activity. Molecular biology of the cell 110 14517334
2013 The huntingtin N17 domain is a multifunctional CRM1 and Ran-dependent nuclear and cilial export signal. Human molecular genetics 104 23297360
1994 A family of proteins that stabilize the Ran/TC4 GTPase in its GTP-bound conformation. The Journal of biological chemistry 100 8157660
2014 Repeat associated non-ATG (RAN) translation: new starts in microsatellite expansion disorders. Current opinion in genetics & development 97 24852074
2015 A LIN28B-RAN-AURKA Signaling Network Promotes Neuroblastoma Tumorigenesis. Cancer cell 95 26481147
2001 CRM1- and Ran-independent nuclear export of beta-catenin. Current biology : CB 95 11166175
2006 A picornavirus protein interacts with Ran-GTPase and disrupts nucleocytoplasmic transport. Proceedings of the National Academy of Sciences of the United States of America 93 16888036
1996 The small nuclear GTPase Ran: how much does it run? BioEssays : news and reviews in molecular, cellular and developmental biology 93 8851043
1997 Interaction between the small GTPase Ran/Gsp1p and Ntf2p is required for nuclear transport. Molecular and cellular biology 91 9199309
2002 The GTPase Ran regulates chromosome positioning and nuclear envelope assembly in vivo. Current biology : CB 88 11909538
2014 Early retinal neurodegeneration and impaired Ran-mediated nuclear import of TDP-43 in progranulin-deficient FTLD. The Journal of experimental medicine 86 25155018
2001 The Ran-GTPase and cell-cycle control. BioEssays : news and reviews in molecular, cellular and developmental biology 85 11135312
2008 Tumor cell dependence on Ran-GTP-directed mitosis. Cancer research 82 18339863
2007 Spatial control of mitosis by the GTPase Ran. Cellular and molecular life sciences : CMLS 82 17483873
1997 Different binding domains for Ran-GTP and Ran-GDP/RanBP1 on nuclear import factor p97. The Journal of biological chemistry 82 9045717
2020 Ran GTPase: A Key Player in Tumor Progression and Metastasis. Frontiers in cell and developmental biology 80 32528950
2002 Influence of cargo size on Ran and energy requirements for nuclear protein import. The Journal of cell biology 80 12370244
1998 RagA is a functional homologue of S. cerevisiae Gtr1p involved in the Ran/Gsp1-GTPase pathway. Journal of cell science 80 9394008
2018 Repeat-associated non-ATG (RAN) translation. The Journal of biological chemistry 78 30213863
1996 Nucleotide-specific interaction of Ran/TC4 with nuclear transport factors NTF2 and p97. Proceedings of the National Academy of Sciences of the United States of America 78 8755535
2019 Antibody Therapy Targeting RAN Proteins Rescues C9 ALS/FTD Phenotypes in C9orf72 Mouse Model. Neuron 77 31831332
1996 Mutations within the Ran/TC4 GTPase. Effects on regulatory factor interactions and subcellular localization. The Journal of biological chemistry 77 8955121
1995 A family of Ran binding proteins that includes nucleoporins. Proceedings of the National Academy of Sciences of the United States of America 77 7638224
1995 Ran-binding protein-1 is an essential component of the Ran/RCC1 molecular switch system in budding yeast. The Journal of biological chemistry 75 7836422
1999 Nucleocytoplasmic protein transport and recycling of Ran. Cell structure and function 73 10698256
1998 Functions of the GTPase Ran in RNA export from the nucleus. Current opinion in cell biology 70 9640542
1996 RCC1 in the Ran pathway. Journal of biochemistry 70 8889801
2017 New developments in RAN translation: insights from multiple diseases. Current opinion in genetics & development 69 28365506
2015 Small GTP-binding protein Ran is regulated by posttranslational lysine acetylation. Proceedings of the National Academy of Sciences of the United States of America 68 26124124
1994 Effects of mutant Ran/TC4 proteins on cell cycle progression. Molecular and cellular biology 66 8196659
2018 SCA8 RAN polySer protein preferentially accumulates in white matter regions and is regulated by eIF3F. The EMBO journal 64 30206144
1995 Protein export from the nucleus requires the GTPase Ran and GTP hydrolysis. Proceedings of the National Academy of Sciences of the United States of America 64 7753805
2020 A native function for RAN translation and CGG repeats in regulating fragile X protein synthesis. Nature neuroscience 63 32066985
2018 Repeat-associated non-AUG (RAN) translation and other molecular mechanisms in Fragile X Tremor Ataxia Syndrome. Brain research 61 29453961
2000 The role of Ran in nuclear function. Current opinion in cell biology 61 10801459
2011 Induction of Ran GTP drives ciliogenesis. Molecular biology of the cell 59 21998203
2021 Improved activity of MC3T3-E1 cells by the exciting piezoelectric BaTiO3/TC4 using low-intensity pulsed ultrasound. Bioactive materials 57 33997494
2003 Closing the (Ran)GAP on segregation distortion in Drosophila. BioEssays : news and reviews in molecular, cellular and developmental biology 56 12539236
2018 Repeat-Associated Non-ATG (RAN) Translation in Fuchs' Endothelial Corneal Dystrophy. Investigative ophthalmology & visual science 55 29677349
2002 Regulation of nuclear import and export by the GTPase Ran. International review of cytology 55 12019565
1996 Ran, a GTPase involved in nuclear processes: its regulators and effectors. Journal of cell science 55 8923203
2010 Subgroup II PAK-mediated phosphorylation regulates Ran activity during mitosis. The Journal of cell biology 49 20805321
2002 Uncoupling Kapbeta2 substrate dissociation and ran binding. Biochemistry 48 12033928
1999 Identification and characterization of a ran gene promoter in the protozoan pathogen Giardia lamblia. The Journal of biological chemistry 48 10391910
2007 Characterization of a ras-related nuclear protein (Ran protein) up-regulated in shrimp antiviral immunity. Fish & shellfish immunology 47 17703953
2002 Ran-binding protein 3 links Crm1 to the Ran guanine nucleotide exchange factor. The Journal of biological chemistry 45 11932251
2019 Repeat-associated non-AUG (RAN) translation: insights from pathology. Laboratory investigation; a journal of technical methods and pathology 44 30918326
2008 Importin-beta and the small guanosine triphosphatase Ran mediate chromosome loading of the human chromokinesin Kid. The Journal of cell biology 44 18268099
2019 Ran promotes membrane targeting and stabilization of RhoA to orchestrate ovarian cancer cell invasion. Nature communications 43 31209254
2016 Spatial organization of the Ran pathway by microtubules in mitosis. Proceedings of the National Academy of Sciences of the United States of America 43 27439876
2014 Ran GTPase in nuclear envelope formation and cancer metastasis. Advances in experimental medicine and biology 42 24563355
2021 CLTRN, Regulated by NRF1/RAN/DLD Protein Complex, Enhances Radiation Sensitivity of Hepatocellular Carcinoma Cells Through Ferroptosis Pathway. International journal of radiation oncology, biology, physics 40 33508374
2014 RanBP1 governs spindle assembly by defining mitotic Ran-GTP production. Developmental cell 40 25458009
2004 TOR kinase and Ran are downstream from PI3K/Akt in H2O2-induced mitosis. Journal of cellular biochemistry 40 15048882
2023 Ran GTPase and Its Importance in Cellular Signaling and Malignant Phenotype. International journal of molecular sciences 39 36834476
2008 A survivin-ran complex regulates spindle formation in tumor cells. Molecular and cellular biology 39 18591255
2005 Loading and unloading: orchestrating centrosome duplication and spindle assembly by Ran/Crm1. Cell cycle (Georgetown, Tex.) 39 16294017
2014 A pathway linking oxidative stress and the Ran GTPase system in progeria. Molecular biology of the cell 38 24523287
2015 Sumoylation of the GTPase Ran by the RanBP2 SUMO E3 Ligase Complex. The Journal of biological chemistry 36 26251516
1997 High levels of the GTPase Ran/TC4 relieve the requirement for nuclear protein transport factor 2. The Journal of biological chemistry 36 9261173
2018 Mitosis-specific acetylation tunes Ran effector binding for chromosome segregation. Journal of molecular cell biology 35 29040603
2018 A nuclear lamina-chromatin-Ran GTPase axis modulates nuclear import and DNA damage signaling. Aging cell 35 30565836
2009 Crystallographic and biochemical analysis of the Ran-binding zinc finger domain. Journal of molecular biology 35 19505478
2018 Knockdown of Ran GTPase expression inhibits the proliferation and migration of breast cancer cells. Molecular medicine reports 33 29750309
1999 A new role of ran GTPase. Biochemical and biophysical research communications 33 10471364
2000 Upstream and downstream of ran GTPase. Biological chemistry 31 10937870
2021 CCG•CGG interruptions in high-penetrance SCA8 families increase RAN translation and protein toxicity. EMBO molecular medicine 30 34632710
2008 Low expression of ZHX2, but not RCBTB2 or RAN, is associated with poor outcome in multiple myeloma. British journal of haematology 30 18353163
2006 The Ran binding protein RanBPM interacts with TrkA receptor. Neuroscience letters 29 16959415
2000 Identification of a novel putative Ran-binding protein and its close homologue. Biochemical and biophysical research communications 29 11071879
2006 Cell biology: Ran, mitosis and the cancer connection. Current biology : CB 28 16782004
2022 RSL1D1 promotes the progression of colorectal cancer through RAN-mediated autophagy suppression. Cell death & disease 27 35013134
2009 Dynamic localisation of Ran GTPase during the cell cycle. BMC cell biology 27 19765287
2000 The interaction between Ran and NTF2 is required for cell cycle progression. Molecular biology of the cell 27 10930458
2017 EGFR feedback-inhibition by Ran-binding protein 6 is disrupted in cancer. Nature communications 26 29229958
2008 ARA24/Ran enhances the androgen-dependent NH2- and COOH-terminal interaction of the androgen receptor. Biochemical and biophysical research communications 26 18565325
2001 Interaction between Ran and Mog1 is required for efficient nuclear protein import. The Journal of biological chemistry 24 11509570
1996 Nucleus-associated pools of Rna1p, the Saccharomyces cerevisiae Ran/TC4 GTPse activating protein involved in nucleus/cytosol transit. Proceedings of the National Academy of Sciences of the United States of America 24 8755533
2020 RAN training in dyslexia: Behavioral and brain correlates. Neuropsychologia 23 32707164