Affinage

RAN

GTP-binding nuclear protein Ran · UniProt P62826

Length
216 aa
Mass
24.4 kDa
Annotated
2026-06-10
100 papers in source corpus 40 papers cited in narrative 40 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RAN is a small GTPase whose nucleotide-state cycling — driven by the chromatin-associated exchange factor RCC1 generating Ran-GTP and a Ran-specific GAP promoting GTP hydrolysis — establishes a directional switch that governs nucleocytoplasmic transport and mitotic organization (PMID:8255297, PMID:7988569). Ran was first identified as the essential transport factor required for NLS-dependent protein import through the nuclear pore, with GTP hydrolysis necessary for translocation (PMID:8413630, PMID:8276887); its nucleotide state directs sequential interactions with the import machinery, GTP-bound Ran binding importin-β (p97) and GDP-bound Ran binding NTF2, the latter interaction itself being required to import Ran-GDP into the nucleus and to maintain the gradient (PMID:8755535, PMID:9199309, PMID:10930458). The acidic C-terminal DEDDDL tail stabilizes GDP binding, mediates high-affinity engagement with RanBP1-family Ran-binding domains that coactivate RanGAP, and undergoes a nucleotide-dependent conformational change (PMID:7782302, PMID:7724562). Beyond transport, Ran-GTP generated around chromatin patterns mitosis by releasing importin-bound spindle assembly factors: it liberates TPX2 to activate Aurora A kinase, spatially controls the Kinesin-14 XCTK2 across the spindle, restricts anillin to the equator during cytokinesis, and is required for chromosome alignment and nuclear envelope reassembly (PMID:12577065, PMID:25981788, PMID:28931593, PMID:11909538). Ran activity is further tuned by lysine acetylation (by CBP/p300 and TIP60, reversed by sirtuins), which modulates nucleotide cycling, localization, and receptor binding, with TIP60 acetylation of Lys134 switching Ran from Mog1 to RCC1 to raise mitotic Ran-GTP (PMID:26124124, PMID:29040603). Non-canonical roles include Ran-GTP accumulation at basal bodies during ciliogenesis and a plasma-membrane pool that stabilizes RhoA to promote cancer cell invasion (PMID:21998203, PMID:31209254).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1993 High

    Established that Ran is the diffusible GTPase required for nuclear protein import, defining its core cellular function rather than leaving it an orphan GTP-binding protein.

    Evidence Biochemical reconstitution of NLS-dependent import with purified Ran in digitonin-permeabilized cells, plus GTPγS inhibition with bacterially expressed Ran

    PMID:8276887 PMID:8413630

    Open questions at the time
    • Did not define the receptors Ran acts upon during transport
    • Mechanism of how GTP hydrolysis confers directionality unresolved
  2. 1993 High

    Defined the regulatory circuit of the Ran GTPase switch — RCC1 as exchange factor and a Ran-specific GAP — and tied disruption of GTP hydrolysis to cell cycle arrest.

    Evidence Biochemical identification of RanGAP, in vitro GTPase and binding assays, and GTP-hydrolysis-deficient mutant characterization in cells

    PMID:8255297 PMID:8421051 PMID:8455603

    Open questions at the time
    • Spatial segregation of RCC1 and RanGAP not yet shown to generate a gradient
    • Direct effectors of Ran-GTP not identified
  3. 1994 High

    Showed RCC1's essential interphase role is solely as a Ran GEF and that GDP-bound Ran couples nuclear assembly and DNA replication to mitotic entry via cdc2 phosphorylation.

    Evidence Xenopus egg extract nuclear assembly/DNA replication assays with mutant Ran proteins, RCC1 rescue, and cdc2 phospho-immunoblotting

    PMID:7988569 PMID:8188741 PMID:8196659

    Open questions at the time
    • Molecular link between Ran nucleotide state and cdc2 regulation indirect
    • C-terminal DEDDDL requirement for cell cycle function mechanistically unexplained at the time
  4. 1995 High

    Identified the Ran-binding effectors and partners at the pore (RanBP2, RanBP1/HTF9A, the RanBD module) and confirmed RanGAP/Rna1p as both GTPase activator and import requirement.

    Evidence Yeast two-hybrid, overlay/binding assays, in vitro RanGAP coactivation, and semi-intact yeast import add-back of purified Rna1p

    PMID:7603572 PMID:7657689 PMID:7724562 PMID:7744835 PMID:7782302 PMID:7816822

    Open questions at the time
    • Species-specific GAP recognition determinants not mapped
    • How RanBD coactivation integrates with cargo release left open
  5. 1996 High

    Demonstrated that Ran nucleotide state directs sequential receptor interactions (GTP→importin-β, GDP→NTF2) and that Ran has an essential function beyond import.

    Evidence Nucleotide-preloaded recombinant binding assays with p97/NTF2; effector-domain L43E mutant separating growth from import; mutant localization in BHK21 cells

    PMID:8636225 PMID:8655589 PMID:8755535 PMID:8955121

    Open questions at the time
    • Identity of the import-independent essential function unresolved at the time
    • Shared snRNP/protein import step mechanistically conflated
  6. 1997 High

    Provided reciprocal genetic proof that the Ran–NTF2 interaction is physiologically essential for nuclear transport, not merely an in vitro binding event.

    Evidence Conditional gsp1 alleles with reduced Ntf2p binding suppressed by NTF2 overexpression but not by a binding-deficient NTF2 mutant

    PMID:9199309

    Open questions at the time
    • Did not quantify gradient consequences of disrupted import in vivo
  7. 2000 High

    Linked nuclear Ran concentration directly to spindle-assembly-checkpoint-dependent cell cycle control.

    Evidence Temperature-sensitive NTF2 mutant depleting nuclear Ran, with G2 arrest abolished by mad2 deletion in yeast

    PMID:10930458

    Open questions at the time
    • Mechanism connecting nuclear Ran level to checkpoint signaling not defined
  8. 2001 High

    Identified Mog1 as a nucleotide-release factor that forms a stable nucleotide-free complex with Ran required for import.

    Evidence In vitro nucleotide release assays, charge-reversal interface mutants, in vivo import assay, and synthetic lethality with prp20

    PMID:11509570

    Open questions at the time
    • Physiological trigger regulating Mog1–Ran engagement unknown at the time
  9. 2002 High

    Established the chromatin Ran-GTP gradient as the master spatial cue for mitotic spindle assembly, including the TPX2–Aurora A activation module and Ran-binding kinase Nercc1.

    Evidence C. elegans Ran RNAi with mitotic/NE phenotypes; Xenopus egg extract reconstitution of TPX2 release and Aurora A activation; Nercc1 Co-IP and kinase assays; karyopherin-β2 loop coupling Ran binding to cargo release

    PMID:11909538 PMID:12033928 PMID:12101123 PMID:12577065

    Open questions at the time
    • Full repertoire of spindle assembly factors released by Ran-GTP incomplete
    • How discrete gradient thresholds map to distinct factors unresolved
  10. 2002 Medium

    Defined RanBP3 as a scaffold that stimulates RCC1 activity and promotes Crm1-based export complex assembly.

    Evidence In vitro binding, RCC1 activity, and three-component complex formation assays

    PMID:11932251

    Open questions at the time
    • In vivo significance of RanBP3-stimulated export not established in this study
  11. 2008 Medium

    Connected the Ran gradient to upstream growth signaling and revealed an unexpected role of Ran as an androgen receptor coactivator.

    Evidence RSK/Akt phosphorylation of RanBP3 with transport readouts; reciprocal interaction and reporter assays linking ARA24/Ran to AR poly-Q

    PMID:10400640 PMID:18280241 PMID:18565325

    Open questions at the time
    • AR coactivation mechanism distinct from transport function not mechanistically integrated
    • RanBP3 phospho-control quantitative effect on gradient single-lab
  12. 2009 Medium

    Provided structural and dynamic detail of Ran's interactions at the pore and its cell-cycle-dependent mobility.

    Evidence Crystal structures of Nup153 zinc fingers with Ran plus ITC; live-cell FRAP of GFP-Ran and nucleotide-state mutants

    PMID:19505478 PMID:19765287

    Open questions at the time
    • Functional consequence of Nup153 ZnF differential affinity in transport not directly tested
  13. 2015 High

    Established acetylation as a post-translational layer controlling the entire Ran nucleotide cycle and demonstrated spatial gradient control of a spindle kinesin.

    Evidence In vitro CBP/p300/Tip60 acetylation with MS site mapping and nucleotide/transport assays; Xenopus extract FRAP of XCTK2 across the Ran-GTP gradient

    PMID:25458009 PMID:25981788 PMID:26124124

    Open questions at the time
    • In vivo dynamics of acetylation cycling not quantified
    • Which acetylation sites dominate which functions only partially resolved
  14. 2018 High

    Resolved how mitotic acetylation reroutes Ran partner choice, with TIP60 Lys134 acetylation releasing Mog1 to favor RCC1 and raise Ran-GTP for chromosome alignment.

    Evidence Crystal structure of Ran–Mog1, in vitro TIP60 acetylation, competition binding, and acetyl-mimic mutant chromosome alignment assays; lamina-chromatin-Ran axis controlling import of large cargoes

    PMID:29040603 PMID:30565836

    Open questions at the time
    • Temporal regulation of TIP60 toward Ran during mitosis not fully defined
    • Lamina-Ran axis evidence relies on chemical perturbation in single lab
  15. 2019 Medium

    Revealed non-nuclear Ran functions: a plasma-membrane pool stabilizing RhoA to drive invasion, and Ran-GTP control of cytokinesis and ciliogenesis.

    Evidence Co-IP and domain mapping of Ran–RhoA with invasion assays; Ran-GTP manipulation affecting anillin localization and basal-body ciliogenesis

    PMID:21998203 PMID:28931593 PMID:31209254

    Open questions at the time
    • How Ran reaches the plasma membrane mechanistically unexplained
    • GTPase-independent vs. -dependent contributions to RhoA stabilization unresolved
  16. 2022 Medium

    Connected Ran acetylation control to disease signaling, with RSL1D1 blocking Sirt7-mediated deacetylation to suppress STAT3 import and autophagy in cancer.

    Evidence Co-IP, competition binding, acetylation, and STAT3 localization/autophagy assays in colorectal cancer cells

    PMID:35013134

    Open questions at the time
    • Single-lab Co-IP-based competition without structural validation
    • Generality beyond colorectal cancer context untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple post-translational and partner-based regulatory layers (acetylation, RanBP1/RanBP3 phosphorylation, Mog1 switching) are integrated in space and time to tune the Ran gradient for distinct transport, mitotic, and membrane functions remains unresolved.
  • No unified quantitative model coupling acetylation cycling to gradient dynamics
  • Mechanism targeting Ran to the plasma membrane unknown
  • Disease-relevant Ran functions lack in vivo genetic validation in the corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003924 GTPase activity 4 GO:0098772 molecular function regulator activity 4 GO:0060089 molecular transducer activity 3
Localization
GO:0005634 nucleus 4 GO:0000228 nuclear chromosome 3 GO:0005635 nuclear envelope 3 GO:0005815 microtubule organizing center 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-1640170 Cell Cycle 4 R-HSA-9609507 Protein localization 4 R-HSA-162582 Signal Transduction 2
Partners
KPNB1MOG1NTF2RANBP1RANBP2RANBP3RANGAP1RCC1
Complex memberships
RCC1/Ran/RanBP1 complex

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 Ran/TC4 GTP-binding protein is required for protein import into the nucleus; it is a component of the cytosolic fraction B activity that mediates translocation of NLS-bearing substrates through the nuclear pore, acting downstream of NLS recognition. Biochemical reconstitution using Xenopus oocyte cytosolic fractions in digitonin-permeabilized cell import assay; protein purification to homogeneity Nature High 8413630
1993 Ran/TC4 is an essential GTP-binding transport factor for nuclear import; nonhydrolyzable GTP analogues (GTPγS) block nuclear import in a Ran-dependent manner, demonstrating that GTP hydrolysis by Ran is required for transport. In vitro nuclear import assay in digitonin-permeabilized cells; GTPγS inhibition; biochemical complementation with bacterially expressed Ran/TC4 The Journal of cell biology High 8276887
1993 Ran/TC4 undergoes GTP/GDP cycling regulated by RCC1 (guanine nucleotide exchange factor) and a Ran-specific GTPase-activating protein (RanGAP); GTP-bound form preferentially interacts with putative effectors, and GDP-bound form interacts with RCC1. Disruption of GTP hydrolysis (Q69L-like mutant) inhibits cell cycle progression. Identification of RanGAP by biochemical screen; in vitro GTPase assays; characterization of Ran mutant proteins; yeast two-hybrid and binding assays for GTP-bound effectors Nature High 8255297
1993 Ran/TC4 nuclear localization requires the presence of RCC1; expression of a GTP hydrolysis-deficient Ran mutant disrupts DNA synthesis, placing Ran in a GTPase switch that monitors progress of DNA synthesis and couples it to onset of mitosis. Transient expression of Ran mutants defective in GTP hydrolysis in mammalian cells; indirect immunofluorescence for localization; [3H]-thymidine incorporation assay for DNA synthesis The Journal of cell biology Medium 8421051
1994 A mutant Ran (T24N, GDP-bound state) inhibits nuclear assembly and DNA replication in Xenopus egg extracts by binding tightly to RCC1 and inactivating it as a GEF; supplementing with excess RCC1 rescues nuclear assembly and DNA replication, demonstrating RCC1's essential function is solely as a GEF for Ran in interphase. Xenopus egg extract nuclear assembly and DNA replication assays; addition of bacterially expressed mutant Ran proteins; rescue with purified RCC1; in vitro GEF activity assay The EMBO journal High 7988569
1994 TC4/Ran has distinct roles in nuclear assembly and cell cycle progression; GDP-bound TC4 suppresses nuclear growth and prevents DNA replication, and blocks entry into mitosis by promoting inhibitory phosphorylation of p34(cdc2) on tyrosine and threonine residues in cell-free Xenopus egg extracts. Xenopus egg extract nuclear assembly assay; cell-free cycling extract; immunoblotting for p34(cdc2) phosphorylation; addition of wild-type and mutant TC4 proteins The Journal of cell biology High 8188741
1994 Expression of a Ran/TC4 GTP hydrolysis-deficient mutant arrests cells predominantly in G2 (also G1); deletion of the acidic C-terminal hexapeptide (DEDDDL) does not alter nuclear localization but abrogates the cell cycle inhibitory effect, indicating this domain is essential for mediating Ran's cell cycle function. Transient expression in 293/Tag cells; flow cytometry cell cycle analysis; nuclear localization assessed by subcellular fractionation Molecular and cellular biology Medium 8196659
1995 RanBP2 (a giant nuclear pore protein of 3,224 residues) binds Ran/TC4; it contains four RanBP1-homologous domains, XFXFG nucleoporin motifs, and localizes to the NPC. Antibodies against RanBP2 inhibit NLS-mediated nuclear import, implicating it as a functional Ran effector at the NPC. Yeast two-hybrid screen using Ran/TC4 as bait; sequence analysis; immunolocalization; antibody inhibition of nuclear import in permeabilized cells Nature Medium 7603572
1995 The acidic C-terminal DEDDDL sequence of Ran stabilizes GDP binding and is required for high-affinity interaction with the Ran-binding protein HTF9A/RanBP1; HTF9A functions as a co-stimulator of RanGAP activity on wild-type Ran but acts as a RanGAP inhibitor when the C-terminus is absent. An antibody against the C-terminal region preferentially recognizes GTP-bound Ran, indicating nucleotide-dependent conformational change in this domain. In vitro GDP/GTP binding assays with truncation mutants; in vitro RanGAP co-stimulation assays; antibody specificity experiments The Journal of biological chemistry High 7782302
1995 The yeast RNA1 gene product (Rna1p) is the GTPase-activating protein (GAP) for Gsp1p (yeast Ran/TC4 homolog), stimulating GTP hydrolysis ~10^7-fold; human RanGAP1 and S. pombe rna1p also activate Gsp1p GTPase, but Rna1p does not activate human Ran GTP hydrolysis, revealing species-specific GAP activity. Bacterial expression and purification of recombinant Gsp1p and Rna1p; in vitro GTPase activity assay; cross-species complementation biochemistry The Journal of biological chemistry High 7744835
1995 Rna1p (yeast RanGAP) is directly required for nuclear import; cytosol from rna1-1 mutant cells is unable to support nuclear import in semi-intact yeast cells, and adding back purified Rna1p restores import in a dose-dependent manner. Indirect immunofluorescence; GFP-fusion protein import in living cells; semi-intact yeast cell in vitro import assay; add-back of purified Rna1p The Journal of cell biology High 7657689
1995 The GTP-bound form of Gsp1p (yeast Ran) blocks nuclear protein import and retains poly(A)+ RNA in the nucleus; GTP hydrolysis by Ran is therefore necessary for proper nuclear import of proteins and cytoplasmic appearance of mRNA. Overexpression of wild-type and GTP-locked (G21V) Gsp1p in S. cerevisiae; indirect immunofluorescence for nuclear protein localization; in situ hybridization for poly(A)+ RNA Proceedings of the National Academy of Sciences of the United States of America High 7816822
1995 A conserved ~150-residue Ran-binding domain (RanBD) present in multiple Ran-binding proteins stabilizes the GTP-bound state of Ran and acts as a coactivator of RanGAP; mutation of a conserved residue in the RanBD of HTF9a drastically reduces Ran binding. Expression cloning overlay assay; sequence analysis; in vitro binding assays; RanGAP coactivation assay; site-directed mutagenesis; co-immunoprecipitation from cell lysates Proceedings of the National Academy of Sciences of the United States of America Medium 7724562
1996 Both protein import and U snRNP import require a GTPase activity (Ran); both are sensitive to nonhydrolyzable GTP analogues and to dominant-negative Ran mutants (Q69L defective in hydrolysis; T24N defective in GTP binding), demonstrating a shared Ran-dependent step for these two distinct import pathways. In vitro nuclear import assays in permeabilized cells; comparison of effects of two mechanistically distinct Ran mutants on protein vs. snRNP import The Journal of cell biology Medium 8636225
1996 Ran/TC4 interacts directly with the 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, establishing that Ran nucleotide state directs sequential interactions with import machinery. Solution and solid-phase binding assays using [γ-32P]GTP- or [3H]GDP-preloaded recombinant Ran/TC4 with purified p97 and NTF2 Proceedings of the National Academy of Sciences of the United States of America High 8755535
1996 Multiple Ran mutants (G19V, T24N, L43E, E46G) that affect interaction with regulatory proteins (RCC1, RanGAP/Fug1) or Ran-binding proteins disrupt normal nuclear localization of Ran, causing accumulation at the nuclear envelope; G19V Ran is insensitive to RCC1-stimulated exchange and is ~50% GTP-bound in cells. Expression of epitope-tagged Ran mutants in BHK21 cells; immunofluorescence; nucleotide-binding assays from immunoprecipitated Ran; permeabilized cell import assay The Journal of biological chemistry Medium 8955121
1996 Ran L43E mutant (effector domain mutant) does not affect nuclear import of GR-GFP but strongly inhibits cell growth, providing evidence that Ran mediates at least one essential cell function independent of nuclear protein import. Transfection and microinjection of Ran mutants into BHK21 cells expressing GR-GFP; live-cell fluorescence microscopy for nuclear import; colony formation/cell growth assay The Journal of cell biology Medium 8655589
1997 The interaction between Gsp1p (yeast Ran) and Ntf2p is critical for nuclear transport; temperature-sensitive gsp1 mutations that reduce Ntf2p binding cause nuclear transport defects that are suppressed by NTF2 overexpression, but not by a NTF2 mutant with reduced Gsp1p binding. Genetic screen for conditional gsp1 alleles; biochemical binding assays; in vivo nuclear transport assays; genetic suppression analysis Molecular and cellular biology High 9199309
1995 GSP1 (yeast Ran) is nuclear, binds GTP in vitro, and is an essential gene; a GTP-stabilizing activating mutation in Gsp1p causes dominant lethality, and GSP1 and GSP2 are multicopy suppressors of prp20 (RCC1 homolog) mutants, placing GSP1 downstream of PRP20/RCC1. Multicopy suppressor screen; GTP-binding assay with purified protein; indirect immunofluorescence; dominant lethal mutant analysis Molecular and cellular biology Medium 8455603
1999 Ran (as ARA24) functions as a coactivator of the androgen receptor (AR) that binds differentially to AR N-terminal polyglutamine (poly-Q) regions of different lengths; longer poly-Q expansions diminish AR-ARA24 interaction and coactivation; deletion of DEDDDL at ARA24 C-terminus enhances coactivation. Yeast two-hybrid and mammalian reciprocal interaction assays; transcriptional reporter assays; deletion mutagenesis The Journal of biological chemistry Medium 10400640
2000 Disrupting the Ran-NTF2 interaction by a temperature-sensitive NTF2 mutation prevents nuclear import of RanGDP in vivo, depleting nuclear Ran; this depletion arrests cells in G2 in a MAD2 (spindle assembly checkpoint)-dependent manner, linking nuclear Ran concentration to spindle checkpoint control. Temperature-sensitive NTF2 mutant in S. cerevisiae; live-cell and indirect immunofluorescence for Ran localization; cell cycle analysis; genetic epistasis with mad2 deletion Molecular biology of the cell High 10930458
2001 Mog1 binds nucleotide-free Ran (after stimulating GTP release from Ran-GTP or Ran-GDP) and forms a stable complex; disruption of the Mog1-Ran interface (using engineered charge-reversal mutants Mog1-E65K / Ran-K136E) causes temperature-sensitive growth and nuclear import defects in yeast. In vitro nucleotide release assay; engineering of charge-reversal interaction-disrupting mutants; in vivo import assay with fluorescent reporter; synthetic lethality with prp20 The Journal of biological chemistry High 11509570
2002 Ran-GTP generated around chromatin directs mitotic spindle assembly; in C. elegans, RNAi depletion of Ran causes metaphase chromosome misalignment and failure of nuclear envelope assembly at telophase. Ran localizes to kinetochore regions during mitosis and to the nuclear envelope during interphase/telophase. RNAi depletion in C. elegans embryos; immunofluorescence for chromosome alignment, astral microtubules, and Ran localization; comparison with RCC1 and RanGAP RNAi Current biology High 11909538
2002 Nercc1 (NIMA-like kinase) binds specifically to the Ran GTPase through both its catalytic domain and RCC1-like domain, preferring RanGDP in vivo; Nercc1 autoactivates by autophosphorylation in vitro and is phosphorylated by active p34(Cdc2); its inhibition causes spindle abnormalities and chromosomal misalignment. Co-immunoprecipitation; in vitro kinase assays; microinjection of anti-Nercc1 antibodies; nucleotide-binding preference assays Genes & development Medium 12101123
2002 Ran-GTP promotes spindle assembly by releasing TPX2 from inhibitory importin-α/β binding; Ran-GTP stimulates the interaction between TPX2 and Aurora A kinase (Eg2/Xenopus Aurora A), causing TPX2 to stimulate Aurora A phosphorylation and kinase activity in a microtubule-dependent manner; importin-α/β block this activation and Ran-GTP overcomes this inhibition both in egg extracts and with purified proteins. Reconstitution in Xenopus egg extracts; in vitro kinase assays with purified proteins; immunoprecipitation; dominant-negative and constitutively active Ran constructs Nature cell biology High 12577065
2008 Ran-binding protein 3 (RanBP3) links the Ras/ERK (via RSK) and PI3-kinase (via Akt) pathways to the Ran gradient and nucleocytoplasmic transport; RSK and Akt phosphorylate RanBP3, which modulates its interaction with Ran and Crm1, thereby regulating the nuclear:cytoplasmic Ran gradient. In vitro kinase assays; mass spectrometry phosphosite mapping; nuclear transport assays; interaction studies with RanBP3 mutants Molecular cell Medium 18280241
2008 ARA24/Ran (as AR coactivator) enhances the androgen-dependent N-C terminal interaction of the androgen receptor (AR); constitutively GTP- or GDP-bound forms of ARA24/Ran repress the AR N-C interaction; ARA24/Ran forms an endogenous complex with nuclear AR but not cytoplasmic AR. Co-immunoprecipitation; transcriptional reporter assays; AR N-C interaction assay; subcellular fractionation Biochemical and biophysical research communications Medium 18565325
2009 Crystal structures of Nup153 zinc fingers in complex with Ran show that each of the four zinc finger modules of Nup153 binds one Ran molecule independently and with measurably higher affinity for RanGDP than RanGTP; microcalorimetric analysis identified one specific hydrogen bond accounting for affinity differences between individual zinc fingers. X-ray crystallography (six complex structures plus 1.48 Å RanGDP structure); isothermal titration calorimetry; site-directed mutagenesis Journal of molecular biology High 19505478
2009 Ran-GFP is nuclear during interphase; GTP-locked Ran (Q69L) is less concentrated in the nucleus and associates with nuclear pore complexes; GDP/nucleotide-free Ran (T24N) associates relatively stably with chromatin throughout the cell cycle and is highly concentrated on mitotic chromosomes; wild-type Ran-GTP generated at chromatin is highly mobile and interacts dynamically with NPCs and spindle. Live-cell fluorescence microscopy and FRAP of GFP-Ran and mutant fusions during cell cycle in human cells BMC cell biology Medium 19765287
2011 Ran-GTP accumulation at basal bodies is coordinated with ciliogenesis initiation; RanBP1 knockdown increases Ran-GTP concentration at basal bodies and promotes primary cilia formation, while RanBP1 overexpression inhibits it; Ran-GTP is required for proper KIF17 localization at distal tips of primary cilia. RanBP1 siRNA knockdown and overexpression; immunofluorescence for Ran-GTP and cilia markers; quantification of ciliogenesis; analysis of KIF17 localization Molecular biology of the cell Medium 21998203
2014 RanBP1 controls spindle assembly by modulating RCC1 activity and its chromatin partitioning: the heterotrimeric RCC1/Ran/RanBP1 complex controls both RCC1 enzymatic activity and distribution between chromatin-bound and soluble pools; RanBP1 phosphorylation drives changes in chromatin-bound RCC1 at the metaphase-anaphase transition. Reconstitution in M-phase Xenopus egg extracts; biochemical fractionation; RanBP1 phospho-mutants; spindle assembly assays Developmental cell High 25458009
2015 Ran is acetylated at multiple lysine residues by CBP/p300 and Tip60 in vitro and in vivo; lysine acetylation interferes with nucleotide exchange, GTP hydrolysis, subcellular Ran localization, and interaction with import and export receptors; specific sirtuin deacetylases remove acetyl groups from two Ran acetylation sites in vitro. In vitro acetylation assays with CBP/p300 and Tip60; mass spectrometry identification of acetylation sites; nucleotide exchange and GTPase assays on acetylated Ran; nuclear transport assays; sirtuin deacetylation assays Proceedings of the National Academy of Sciences of the United States of America High 26124124
2015 The Ran-GTP gradient spatially regulates XCTK2 (Kinesin-14) localization and motility within the spindle; a flattened Ran-GTP gradient blocks XCTK2-stimulated bipolar spindle assembly; XCTK2 turnover kinetics are faster near spindle poles (low Ran-GTP) than near chromatin (high Ran-GTP), dependent on importin α/β binding to the XCTK2 NLS. Xenopus egg extract spindle assembly assays; FRAP analysis of XCTK2 with constitutively active Ran mutant; XCTK2 NLS mutants; importin binding assays Current biology High 25981788
2018 Ran is a substrate of TIP60 acetyltransferase; acetylation of Lys134 by TIP60 during mitosis liberates Mog1 from Ran binding, switching Ran to bind RCC1 and promoting high Ran-GTP levels required for chromosome alignment; structural analysis revealed that Mog1 competes with RCC1 for Ran binding in a GTP/GDP-dependent manner. Crystal structure of Ran-Mog1 complex; in vitro acetyltransferase assay with TIP60; structure-guided mutagenesis; competition binding assays between Mog1 and RCC1; chromosome alignment assays in cells expressing acetylation-mimicking Ran mutants Journal of molecular cell biology High 29040603
2018 A nuclear lamina-chromatin-Ran axis controls the Ran gradient and nuclear import; chemical inhibition or depletion of histone methyltransferases G9a/GLP reduces heterochromatin and disrupts the Ran gradient, causing nuclear import defects for large cargoes including ATM; disruption of the Ran gradient in HGPS impairs ATM nuclear import and reduces γ-H2AX generation after ionizing radiation. HMT inhibitor treatment and siRNA depletion; nuclear:cytoplasmic ratio measurements of Ran and import cargoes; DNA damage assays (γ-H2AX immunofluorescence) after ionizing radiation; comparison with HGPS patient fibroblasts Aging cell Medium 30565836
2019 Ran localizes specifically to the plasma membrane/ruffles of ovarian cancer cells in addition to its nucleocytoplasmic distribution; Ran interacts with RhoA via its DEDDDL C-terminal domain (binding serine 188 of RhoA), preventing RhoA proteasomal degradation and promoting RhoA membrane localization and activity; Ran depletion inhibits ovarian cancer cell invasion by impairing RhoA signaling. Subcellular fractionation and immunofluorescence for Ran localization; Co-immunoprecipitation; RhoA stability assays (proteasome inhibition); RhoA activity assays; invasion assays with Ran knockdown; mapping of interaction domains by deletion mutagenesis Nature communications High 31209254
2017 Active Ran-GTP spatially restricts anillin (a cytokinesis regulator) to the cell equator during cytokinesis; anillin contains a conserved NLS at its C-terminus that binds importin-β and is required for cortical polarity; decreasing Ran-GTP levels or ectopically activating Ran affects anillin localization and causes cytokinesis failure. Manipulation of Ran-GTP levels in cells; live-cell imaging; localization of anillin NLS mutants; importin-β binding assays; cytokinesis phenotype quantification Molecular biology of the cell Medium 28931593
2002 Karyopherinβ2 (Kapβ2) releases import substrates in the nucleus upon RanGTP binding; an internal acidic loop in Kapβ2 physically couples the Ran-binding N-terminal arch to the substrate-binding C-terminal arch; proteolytic cleavage or truncation of this loop uncouples Ran binding from substrate dissociation without reducing affinity for either Ran or substrate, and abolishes Ran-mediated nuclear import of fluorescent substrate. Proteolytic cleavage and truncation mutagenesis of Kapβ2; NMR mapping of substrate-binding site; quantitative binding affinity measurements; nuclear import assay in permeabilized HeLa cells Biochemistry High 12033928
2002 RanBP3 associates with RCC1 in a Ran-stimulated manner (Ran-GDP, -GTP, and nucleotide-free Ran all stimulate complex formation); RanBP3 increases RCC1 catalytic activity toward Ran and also promotes Crm1 binding to RCC1, acting as a scaffold to promote efficient nuclear export complex assembly. Binding assays (solid-phase and pull-down); RCC1 activity assays in presence of RanBP3; three-component complex formation assays The Journal of biological chemistry Medium 11932251
2022 RSL1D1 interacts with Ran and inhibits its deacetylation by competing with Sirt7 for binding; RSL1D1-mediated hyperacetylation of Ran inhibits nuclear accumulation of STAT3 and the STAT3-regulated autophagic program in colorectal cancer cells. Co-immunoprecipitation; acetylation assays; STAT3 nuclear localization assays; autophagy markers; competition binding assays between RSL1D1 and Sirt7 for Ran Cell death & disease Medium 35013134

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 The GTP-binding protein Ran/TC4 is required for protein import into the nucleus. Nature 697 8413630
2013 RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia. Proceedings of the National Academy of Sciences of the United States of America 658 24248382
1993 Inhibition of nuclear protein import by nonhydrolyzable analogues of GTP and identification of the small GTPase Ran/TC4 as an essential transport factor. The Journal of cell biology 519 8276887
1995 A giant nucleopore protein that binds Ran/TC4. Nature 447 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
2015 RAN Translation in Huntington Disease. Neuron 271 26590344
1993 Characterization of proteins that interact with the cell-cycle regulatory protein Ran/TC4. Nature 250 8255297
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
2011 Ran-dependent nuclear export mediators: a structural perspective. The EMBO journal 179 21878989
1995 The GTP-bound form of the yeast Ran/TC4 homologue blocks nuclear protein import and appearance of poly(A)+ RNA in the cytoplasm. Proceedings of the National Academy of Sciences of the United States of America 178 7816822
2002 The Ran GTPase: theme and variations. Current biology : CB 172 12176353
2002 The Ran GTPase as a marker of chromosome position in spindle formation and nuclear envelope assembly. Nature cell biology 171 12105431
1993 Ran/TC4: a small nuclear GTP-binding protein that regulates DNA synthesis. The Journal of cell biology 168 8421051
1995 Rna1p, a Ran/TC4 GTPase activating protein, is required for nuclear import. The Journal of cell biology 155 7657689
1993 GSP1 and GSP2, genetic suppressors of the prp20-1 mutant in Saccharomyces cerevisiae: GTP-binding proteins involved in the maintenance of nuclear organization. Molecular and cellular biology 142 8455603
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
1994 A mutant form of the Ran/TC4 protein disrupts nuclear function in Xenopus laevis egg extracts by inhibiting the RCC1 protein, a regulator of chromosome condensation. The EMBO journal 131 7988569
1996 Evidence using a green fluorescent protein-glucocorticoid receptor chimera that the Ran/TC4 GTPase mediates an essential function independent of nuclear protein import. The Journal of cell biology 128 8655589
1994 Evidence for a dual role for TC4 protein in regulating nuclear structure and cell cycle progression. The Journal of cell biology 125 8188741
2013 Repeat-associated non-ATG (RAN) translation in neurological disease. Human molecular genetics 122 23918658
2002 Nercc1, a mammalian NIMA-family kinase, binds the Ran GTPase and regulates mitotic progression. Genes & development 122 12101123
1996 RAN/TC4 mutants identify a common requirement for snRNP and protein import into the nucleus. The Journal of cell biology 116 8636225
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
2017 RAN Translation Regulated by Muscleblind Proteins in Myotonic Dystrophy Type 2. Neuron 112 28910618
1995 RNA1 encodes a GTPase-activating protein specific for Gsp1p, the Ran/TC4 homologue of Saccharomyces cerevisiae. The Journal of biological chemistry 111 7744835
1995 The C terminus of the nuclear RAN/TC4 GTPase stabilizes the GDP-bound state and mediates interactions with RCC1, RAN-GAP, and HTF9A/RANBP1. The Journal of biological chemistry 109 7782302
1995 The Ran/TC4 GTPase-binding domain: identification by expression cloning and characterization of a conserved sequence motif. Proceedings of the National Academy of Sciences of the United States of America 102 7724562
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 96 26481147
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 94 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
2001 The Ran-GTPase and cell-cycle control. BioEssays : news and reviews in molecular, cellular and developmental biology 85 11135312
2020 Ran GTPase: A Key Player in Tumor Progression and Metastasis. Frontiers in cell and developmental biology 82 32528950
2008 Tumor cell dependence on Ran-GTP-directed mitosis. Cancer research 82 18339863
2019 Antibody Therapy Targeting RAN Proteins Rescues C9 ALS/FTD Phenotypes in C9orf72 Mouse Model. Neuron 80 31831332
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
1996 Mutations within the Ran/TC4 GTPase. Effects on regulatory factor interactions and subcellular localization. The Journal of biological chemistry 78 8955121
2016 RAN translation-What makes it run? Brain research 77 27060770
2009 Ran on tracks--cytoplasmic roles for a nuclear regulator. Journal of cell science 74 19225125
1999 Nucleocytoplasmic protein transport and recycling of Ran. Cell structure and function 73 10698256
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 70 26124124
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
2008 Ran-binding protein 3 phosphorylation links the Ras and PI3-kinase pathways to nucleocytoplasmic transport. Molecular cell 68 18280241
2013 Reduced RAN expression and disrupted transport between cytoplasm and nucleus; a key event in Alzheimer's disease pathophysiology. PloS one 66 23308199
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 65 30206144
2020 A native function for RAN translation and CGG repeats in regulating fragile X protein synthesis. Nature neuroscience 64 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
2018 Repeat-Associated Non-ATG (RAN) Translation in Fuchs' Endothelial Corneal Dystrophy. Investigative ophthalmology & visual science 56 29677349
2003 Closing the (Ran)GAP on segregation distortion in Drosophila. BioEssays : news and reviews in molecular, cellular and developmental biology 56 12539236
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
2002 Uncoupling Kapbeta2 substrate dissociation and ran binding. Biochemistry 48 12033928
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
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 43 24563355
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
2014 A pathway linking oxidative stress and the Ran GTPase system in progeria. Molecular biology of the cell 39 24523287
2005 Loading and unloading: orchestrating centrosome duplication and spindle assembly by Ran/Crm1. Cell cycle (Georgetown, Tex.) 39 16294017
2014 RAN translation and frameshifting as translational challenges at simple repeats of human neurodegenerative disorders. Nucleic acids research 37 25217582
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
1995 RanBP1, a Ras-like nuclear G protein binding to Ran/TC4, inhibits RCC1 via Ran/TC4. Molecular & general genetics : MGG 34 7616957
2018 Knockdown of Ran GTPase expression inhibits the proliferation and migration of breast cancer cells. Molecular medicine reports 33 29750309
2007 Coordination of chromosome alignment and mitotic progression by the chromosome-based Ran signal. Cell cycle (Georgetown, Tex.) 33 17671426
1999 A new role of ran GTPase. Biochemical and biophysical research communications 33 10471364
2000 Upstream and downstream of ran GTPase. Biological chemistry 32 10937870
2021 CCG•CGG interruptions in high-penetrance SCA8 families increase RAN translation and protein toxicity. EMBO molecular medicine 31 34632710
2006 Interaction between methyl CpG-binding protein and ran GTPase during cell division in tobacco cultured cells. Annals of botany 30 17008347
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
2022 RSL1D1 promotes the progression of colorectal cancer through RAN-mediated autophagy suppression. Cell death & disease 27 35013134
2017 EGFR feedback-inhibition by Ran-binding protein 6 is disrupted in cancer. Nature communications 27 29229958
2015 The Ran-GTP gradient spatially regulates XCTK2 in the spindle. Current biology : CB 27 25981788
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
2021 SRSF protein kinase 1 modulates RAN translation and suppresses CGG repeat toxicity. EMBO molecular medicine 26 34542927
2017 Active Ran regulates anillin function during cytokinesis. Molecular biology of the cell 26 28931593
2016 Ran GTPase promotes cancer progression via Met recepto-rmediated downstream signaling. Oncotarget 26 27716616
2008 ARA24/Ran enhances the androgen-dependent NH2- and COOH-terminal interaction of the androgen receptor. Biochemical and biophysical research communications 26 18565325
2020 RAN Translation of the Expanded CAG Repeats in the SCA3 Disease Context. Journal of molecular biology 25 33157084
2019 Ran pathway-independent regulation of mitotic Golgi disassembly by Importin-α. Nature communications 24 31541088
2001 Interaction between Ran and Mog1 is required for efficient nuclear protein import. The Journal of biological chemistry 24 11509570

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