Affinage

RANGAP1

Ran GTPase-activating protein 1 · UniProt P46060

Length
587 aa
Mass
63.5 kDa
Annotated
2026-06-10
53 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RANGAP1 is the GTPase-activating protein that drives Ran GTP hydrolysis to maintain the Ran-GTP/GDP gradient governing nucleocytoplasmic transport, accelerating Ran's intrinsic GTPase rate by more than three orders of magnitude in a manner abolished by the Ran(Q69L) mutant (PMID:8146159, PMID:7819259). Spatially, RANGAP1 is the cytoplasmic arm of the Ran cycle, working antagonistically to nuclear RCC1 (PMID:7878053). A 90-kDa form of RANGAP1 is covalently conjugated to SUMO-1 at Lys526 via an isopeptide bond, a modification carried out by the E2 enzyme Ubc9, and this SUMOylation targets the protein from the cytosol to the cytoplasmic filaments of the nuclear pore complex through binding to the nucleoporin RanBP2/Nup358 (PMID:8978815, PMID:9019411, PMID:9442102, PMID:9456312). SUMO conjugation does not inactivate the GAP but creates a stable RanBP2/RanGAP1*SUMO1/Ubc9 four-protein assembly that constitutes a composite multisubunit SUMO E3 ligase—catalytically silent in free RanBP2 but activated upon complex formation—which modifies substrates such as Borealin (PMID:9108047, PMID:15931224, PMID:22464730). Structural work established that SUMO-1 and RanGAP1 behave as independent beads on a flexible tether recognized bipartitely by RanBP2, and that paralog-selective SUMO-1 modification is enforced at the level of deconjugation through the higher-affinity, isopeptidase-protected SUMO-1–Nup358 complex (PMID:15355965, PMID:19285941, PMID:22194619). This same NPC complex acts as an autonomous disassembly machine for Crm1/CRM1-dependent nuclear export complexes, binding the export receptor through FG-repeat patches and releasing cargo via RanBP2 Ran-binding domains coupled to Ran-GTP hydrolysis (PMID:27160050). During mitosis RANGAP1 is phosphorylated by cyclin B/Cdk1 and, in a SUMO-1- and RanBP2-dependent manner, relocalizes with its partner complex to mitotic spindles and kinetochores, where it stabilizes microtubule-kinetochore attachments and recruits PP1-γ to restrain the spindle-assembly checkpoint and protect TOP2A to safeguard chromatid decatenation; loss of RANGAP1 causes checkpoint hyperactivation, decatenation failure, chromothripsis, and osteosarcoma in mice (PMID:11854305, PMID:15062103, PMID:15037602, PMID:36696903). In immune signaling, TCR-driven PKC-θ phosphorylates RANGAP1 at Ser504/Ser506 to enhance Ubc9 binding and complex assembly, and the SLP-76 adaptor binds SUMO-RanGAP1 at NPC filaments, together promoting nuclear import of AP-1, NFATc1, and NF-κB (PMID:26321253, PMID:34110283).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 1994 High

    Establishing that a dedicated cytoplasmic factor catalyzes Ran GTP hydrolysis defined the enzymatic engine of directional nuclear transport.

    Evidence Biochemical purification from HeLa lysates and in vitro GTPase assays with Ran(Q69L) mutant

    PMID:8146159

    Open questions at the time
    • Did not address how RanGAP1 is positioned relative to the nuclear envelope
    • Cellular regulation of activity unexamined
  2. 1995 High

    Conservation with yeast Rna1p and the cytoplasmic versus nuclear segregation of RanGAP1 and RCC1 established the spatial logic of the Ran GTP/GDP gradient.

    Evidence Sequence homology, recombinant Rna1p GTPase assays, and quantitative stopped-flow kinetics across species

    PMID:7819259 PMID:7878053

    Open questions at the time
    • Mechanism of cytoplasmic confinement not yet defined
    • Did not explain NPC association of a modified form
  3. 1997 High

    Discovery that RanGAP1 is conjugated to SUMO-1 and targeted to the NPC via RanBP2 revealed the first physiological SUMO substrate and the structural basis for localizing Ran GTP hydrolysis at the pore.

    Evidence Immunolocalization, biochemical fractionation, identification of SUMO-1, and import-inhibition antibody assays; Co-IP from Xenopus extracts

    PMID:8978815 PMID:9019411 PMID:9108047 PMID:9427648

    Open questions at the time
    • Exact acceptor lysine and minimal targeting domain not yet mapped
    • Whether SUMOylation alters catalytic activity unresolved at this stage
  4. 1998 High

    Mapping the isopeptide linkage to Lys526 and a 25-kDa C-terminal domain sufficient for both SUMOylation and NPC targeting defined the molecular determinants of pore recruitment.

    Evidence Mass spectrometry, site-directed mutagenesis, heterologous targeting and in vitro SUMOylation assays

    PMID:9442102 PMID:9456312

    Open questions at the time
    • Structural basis of Ubc9 substrate recognition not yet resolved
    • Role of the C-terminal NLS left functionally undefined
  5. 2002 High

    Co-crystal structures of Ubc9 with the RanGAP1 C-terminal domain explained how the SUMO machinery recognizes consensus modification sites.

    Evidence X-ray crystallography at 2.5 Å with structure-based mutagenesis and SUMOylation assays

    PMID:11853669

    Open questions at the time
    • Did not include the RanBP2 E3 component
    • E3-stimulated catalysis mechanism unaddressed
  6. 2002 High

    Demonstrating that SUMO conjugation is required for RanGAP1 association with mitotic spindles and kinetochores extended its role beyond interphase transport into mitosis.

    Evidence Live imaging and immunofluorescence with a SUMO-conjugation-deficient mutant

    PMID:11854305

    Open questions at the time
    • Functional consequence at kinetochores not yet defined
    • Targeting determinants beyond SUMO not identified
  7. 2004 High

    Identifying the RanGAP1-RanBP2 complex as required for stable kinetochore-microtubule attachments and Cdk1 phosphorylation as a mitotic trigger linked Ran cycle machinery to chromosome segregation fidelity.

    Evidence RNAi epistasis with cold-stable MT assays; MS phosphosite mapping and in vitro cyclin B/Cdk1 kinase assays

    PMID:15037602 PMID:15062103

    Open questions at the time
    • Downstream effector recruited to kinetochores not yet identified
    • How phosphorylation controls relocalization unresolved
  8. 2005 High

    NMR and the four-protein crystal structure resolved how RanBP2 acts as E3 by orienting the SUMO-charged Ubc9 thioester rather than by inducing a new RanGAP1 surface.

    Evidence NMR dynamics of the SUMO-1–RanGAP1 conjugate and X-ray structure of the Ubc9/RanBP2(IR1-M)/SUMO-1-RanGAP1 complex with kinetics

    PMID:15355965 PMID:15931224

    Open questions at the time
    • Whether the full IR domain confers paralog specificity unaddressed
    • In vivo substrate scope of the E3 not yet defined
  9. 2005 Medium

    CK2 phosphorylation at Ser358 stabilizing a Ran/RanBP1 ternary complex revealed an additional post-translational layer tuning RanGAP1 partner interactions.

    Evidence MS site mapping, in vitro CK2 kinase assay with inhibitors, and in vivo Co-IP with Ser358Ala mutant

    PMID:16428860

    Open questions at the time
    • Single lab; physiological importance of the ternary complex unclear
    • No effect on GAP activity, leaving functional output uncertain
  10. 2006 Medium

    Establishing a dual role for Ubc9 — as conjugating enzyme and as a stable structural subunit required for NPC association — refined the composition of the targeting complex.

    Evidence Rapamycin-induced heterodimerization to force SUMO-RanGAP1 association in living cells, with immunofluorescence and Co-IP

    PMID:16469311

    Open questions at the time
    • Single lab chemical-genetic system
    • Stoichiometry in endogenous complexes not quantified here
  11. 2008 Medium

    SUMO1-knockout mice showing RanGAP1 mislocalization rescuable by SUMO2/3 demonstrated functional redundancy among SUMO isoforms in vivo.

    Evidence SUMO1 knockout mouse immunofluorescence and immunoblot analysis

    PMID:19033381

    Open questions at the time
    • Quantitative contribution of each isoform unresolved
    • Single study
  12. 2008 Medium

    Identifying mel-18 as a RanGAP1-interacting inhibitor of its SUMOylation introduced a regulator coupling SUMO status to the cell cycle.

    Evidence Co-IP, in vitro SUMOylation assay, and cell cycle synchronization

    PMID:18706886

    Open questions at the time
    • Single lab with limited follow-up
    • Physiological consequence of reduced mitotic SUMOylation not established
  13. 2009 High

    Showing that SUMO-1 paralog selectivity is enforced at deconjugation via a higher-affinity, isopeptidase-protected Nup358 complex explained why RanGAP1 is preferentially SUMO-1 modified in vivo.

    Evidence In vitro SUMOylation, isopeptidase protection, affinity measurements, residue-swap mutagenesis, and siRNA of isopeptidases with in vivo validation

    PMID:19285941

    Open questions at the time
    • Which isopeptidases act in vivo not fully enumerated
    • Structural basis of the affinity difference addressed only later
  14. 2011 High

    Mapping IR1 as the primary E3 and crystallizing hybrid IR complexes provided the structural explanation for SUMO-1 over SUMO-2 specificity.

    Evidence Domain swaps, protease protection, automodification assays, and X-ray crystallography

    PMID:22194619

    Open questions at the time
    • Cellular regulation of IR1 versus IR2 usage not addressed
    • Substrate repertoire of the assembled E3 left for later work
  15. 2012 High

    Reconstituting the RanBP2/RanGAP1*SUMO1/Ubc9 four-protein assembly as a composite E3 that is silent in free RanBP2 and modifies Borealin defined RanGAP1's role as a structural cofactor of a SUMO ligase.

    Evidence Biochemical reconstitution, quantitative Co-IP, and SUMOylation activity assay with Borealin

    PMID:22464730

    Open questions at the time
    • Full endogenous substrate set undefined
    • How the catalytic site is allosterically induced not mechanistically resolved
  16. 2012 Medium

    Demonstrating importin-β and CRM1 control of RanGAP1 kinetochore recruitment after pore disassembly connected the soluble transport receptors to mitotic targeting of the complex.

    Evidence Overexpression of importin-β constructs, immunofluorescence, and CRM1 co-expression rescue

    PMID:22331847

    Open questions at the time
    • Single lab using overexpression rather than endogenous perturbation
    • Quantitative balance of competing receptors unclear
  17. 2015 High

    Defining the NPC complex as an autonomous Crm1 export-complex disassembly machine and identifying SLP-76 binding revealed how RanGAP1 couples Ran hydrolysis to cargo release and immune transcription factor import.

    Evidence In vitro reconstitution of disassembly intermediates; direct binding, EM, GAP and nuclear import assays for SLP-76(K56)

    PMID:26321253 PMID:27160050

    Open questions at the time
    • Generality of disassembly across diverse export cargoes not fully tested
    • In vivo contribution of SLP-76 binding to transport quantification limited
  18. 2015 Medium

    Establishing CRM1-mediated export of RanGAP1, gated by its C-terminal NLS, showed that RanGAP1 itself shuttles and can be SUMOylated in the nucleus.

    Evidence CRM1 RNAi, leptomycin B treatment, time-course immunofluorescence, and NLS deletion

    PMID:26506250

    Open questions at the time
    • Functional role of nuclear RanGAP1 unresolved
    • Single lab
  19. 2021 Medium

    Identifying PKC-θ phosphorylation at Ser504/506 enhancing Ubc9 binding and β-arrestin2 SIM-dependent docking on the SUMO complex extended RanGAP1's transport role to signal-dependent import of specific transcription regulators.

    Evidence In vitro PKC-θ kinase assay with Ser504/506 mutants, Co-IP, nuclear import assays; SIM-mutant β-arr2 import and p53/Mdm2 readouts

    PMID:33649538 PMID:34110283

    Open questions at the time
    • β-arrestin2 study from a single lab
    • Breadth of signal-regulated cargoes not systematically defined
  20. 2023 High

    A RanGAP1 knockout mouse linked kinetochore-anchored RanGAP1, PP1-γ recruitment, and TOP2A protection to checkpoint control and decatenation, establishing a tumor-suppressive role whose loss drives chromothripsis and osteosarcoma.

    Evidence RanGAP1 KO mouse, immunofluorescence, PP1-γ Co-IP, mitotic and chromosome phenotyping, and whole-genome sequencing

    PMID:36696903

    Open questions at the time
    • Direct enzymatic link between GAP activity and PP1-γ recruitment not dissected
    • Whether SUMOylation is required for the PP1-γ function unresolved
  21. 2023 Medium

    Disease-context studies extended the disassembly and stability functions of RanGAP1 to Smad4 export regulation and HBV-driven hepatocarcinogenesis.

    Evidence Co-IP, SUMO1 inhibition, nuclear fractionation in keloid fibroblasts; Co-IP/MS and interaction mapping of HBV core, SYVN1, and KDM2A

    PMID:36916534 PMID:37845585

    Open questions at the time
    • Both single-lab disease models
    • Generalizability beyond the specific contexts untested
  22. 2024 Medium

    Discovery of a perinuclear RAS•GTP–RanGAP1 complex promoting XPO1-dependent cargo export, plus cryo-EM definition of a RanGAP1 NES, refined how RanGAP1 couples Ran hydrolysis to export and revealed a noncanonical oncogenic RAS function.

    Evidence Co-IP of RAS•GTP–RanGAP1 with nuclear export and EZH2/DLC1 readouts; cryo-EM of RanBP2–Crm1–SUMO1-RanGAP1/Ubc9–Ran complex with NES deletion (one source preprint)

    PMID:39528835 PMID:bio_10.1101_2024.10.04.616749

    Open questions at the time
    • RAS-RanGAP1 finding from a single study
    • Cryo-EM NES structure not yet peer-reviewed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RanGAP1's enzymatic GAP activity, its SUMO-E3 cofactor role, and its mitotic PP1-γ recruitment are integrated and selectively engaged in different cellular contexts remains unresolved.
  • No unified model linking catalytic, structural, and mitotic functions
  • Full endogenous substrate and cargo repertoire of the NPC complex undefined
  • Signal-specific selection among competing import/export receptors unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0060090 molecular adaptor activity 2 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005635 nuclear envelope 3 GO:0005634 nucleus 2 GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-1640170 Cell Cycle 2 R-HSA-9609507 Protein localization 2 R-HSA-392499 Metabolism of proteins 1
Partners
CRM1KPNB1PPP1CCRANRANBP2SLP-76SUMO1UBC9
Complex memberships
RanBP2/RanGAP1*SUMO1/Ubc9 SUMO E3 ligase complexkinetochore

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 RanGAP1 is a GTPase-activating protein purified from HeLa cell lysates that stimulates GTP hydrolysis by Ran (but not Ras) by more than 3 orders of magnitude; the Ran Q69L mutant (analogous to RasQ61L) is insensitive to RanGAP1, establishing the catalytic mechanism. Biochemical purification from HeLa lysates, in vitro GTPase assay, mutant analysis Proceedings of the National Academy of Sciences of the United States of America High 8146159
1995 RanGAP1 is homologous to yeast Rna1p; recombinant Rna1p from S. pombe stimulates Ran GTPase activity to the same extent as human RanGAP1, confirming functional conservation; RCC1 (exchange factor) is nuclear while RanGAP1 is cytoplasmic, establishing antagonistic spatial regulation of the Ran GTP/GDP cycle. cDNA sequencing, sequence homology analysis, in vitro GTPase activity assay with recombinant proteins Proceedings of the National Academy of Sciences of the United States of America High 7878053
1995 RanGAP1 stimulates Ran GTPase activity ~10^5-fold under saturating conditions (rate constant 2.1 s⁻¹ at 25°C); has no effect on Ran(Q69L); RCC1 stimulates nucleotide exchange ~10^5-fold; Ran(T24N) interacts nearly normally with RCC1 but favors GDP, stabilizing the Ran(T24N)-RCC1 complex. Fluorescence kinetic assays (stopped-flow, equilibrium fluorescence) Biochemistry High 7819259
1996 Unmodified 70-kDa RanGAP1 is exclusively cytoplasmic, whereas a 90-kDa form conjugated to a ubiquitin-like protein is associated with the cytoplasmic fibers of the nuclear pore complex (NPC) and also with the mitotic spindle apparatus. Peptide sequence analysis, immunoblot with specific mAbs, immunolocalization (light and electron microscopy) The Journal of cell biology High 8978815
1997 RanGAP1 is concentrated at the cytoplasmic periphery of the NPC through ATP-dependent conjugation to SUMO-1 (a novel ubiquitin-related modifier), which promotes its association with the nucleoporin RanBP2/Nup358; antibodies against NPC-associated RanGAP1 inhibit nuclear protein import in a manner not overcome by soluble cytosolic RanGAP1, indicating that Ran GTP hydrolysis at RanBP2 is required for nuclear import. Immunolocalization, biochemical fractionation, in vitro import inhibition with specific antibodies, identification of SUMO-1 Cell High 9019411
1997 RanBP2 associates in a complex with SUMO-modified RanGAP1 and Ubc9 (the Xenopus homolog of yeast Ubc9p, an E2 ubiquitin-conjugating enzyme); the RanBP2-RanGAP1 complex retains GTPase-activating protein activity, showing that SUMO modification does not inactivate RanGAP1. Immunoprecipitation from Xenopus egg extracts, cloning of Xenopus RanGAP1 and Ubc9 homologs, GAP activity assay Proceedings of the National Academy of Sciences of the United States of America High 9108047
1998 SUMO-1 is linked to RanGAP1 via an isopeptide bond at lysine K526 (acceptor site) and the C-terminal glycine 97 of SUMO-1 (after proteolytic removal of the last 4 amino acids); a 25-kDa C-terminal domain of RanGAP1 contains sufficient information for both SUMO-1 modification and NPC targeting; SUMO-1 modification of RanGAP1 leads to nuclear envelope association. Peptide mapping, mass spectrometry, site-directed mutagenesis, in vitro SUMOylation assay The Journal of cell biology High 9442102
1998 SUMO-1 modification targets RanGAP1 to the NPC by exposing or creating a binding site in the C-terminal domain of RanGAP1 for the nucleoporin Nup358 (between its Ran-binding domains 3 and 4); mutations that inhibit SUMO-1 modification also inhibit NPC targeting; the C-terminal domain of RanGAP1 also harbors a nuclear localization signal. Domain mutagenesis, heterologous protein targeting assay, co-immunoprecipitation, nuclear import assay The Journal of cell biology High 9456312
1998 Ubc9 acts as an E2-like enzyme for SUMO-1 conjugation (but not for ubiquitin conjugation); Ubc9 also associates with the internal repeat domain of RanBP2, which is itself a SUMO-1 conjugation substrate in Xenopus egg extracts. In vitro SUMOylation assay with Xenopus egg extracts, ubiquitin conjugation assay, binding assays Current biology : CB High 9427648
2002 Crystal structure of Ubc9 bound to the C-terminal domain of RanGAP1 at 2.5 Å reveals structural determinants for recognition of consensus SUMO modification sequences; structure-based mutagenesis identifies distinct motifs in Ubc9 and RanGAP1 required for substrate binding and SUMO modification. X-ray crystallography at 2.5 Å, structure-based mutagenesis, biochemical SUMOylation assay Cell High 11853669
2002 SUMO-1 conjugation is required for RanGAP1 association with mitotic spindles and kinetochores; a SUMO-1 conjugation-deficient RanGAP1 mutant no longer associates with spindles; RanBP2 co-localizes with RanGAP1 on spindles, suggesting a complex mediates mitotic targeting. Live cell imaging, immunofluorescence, expression of SUMO-1 conjugation-deficient RanGAP1 mutant The Journal of cell biology High 11854305
2004 The RanGAP1-RanBP2 complex is required for stable microtubule-kinetochore interactions; depletion of RanBP2 causes mislocalization of RanGAP1, Mad1, Mad2, CENP-E, and CENP-F, loss of cold-stable kinetochore-MT interactions, and accumulation of mitotic cells with multipolar spindles and unaligned chromosomes; RanGAP1/RanBP2 kinetochore targeting requires Hec1/Ndc80 and Nuf2 (MT-attachment factors) but not CENP-I, Bub1, or CENP-E. RNAi depletion of specific kinetochore proteins, immunofluorescence, cold-stable MT assay, live cell analysis Current biology : CB High 15062103
2004 RanGAP1 is phosphorylated at residues T409, S428, and S442 at the onset of mitosis; cyclin B/Cdk1 phosphorylates RanGAP1 efficiently in vitro; T409 phosphorylation correlates with nuclear cyclin B1 accumulation in vivo; phosphorylated RanGAP1 remains associated with RanBP2/Nup358 and Ubc9 in mitosis. Mass spectrometry phosphorylation mapping, in vitro kinase assay with cyclin B/Cdk1, immunoprecipitation, nocodazole synchronization The Journal of cell biology High 15037602
2004 By NMR spectroscopy, SUMO-1 and RanGAP1 behave as structurally independent 'beads-on-a-string' connected by a flexible isopeptide tether; the overall structure and backbone dynamics of each protein are unchanged upon covalent linkage, suggesting that sumoylation-dependent interaction with RanBP2 arises through bipartite recognition of both proteins rather than a new binding surface. NMR spectroscopy (amide chemical shift, 15N relaxation measurements) on isopeptide-linked SUMO-1-RanGAP1 C-terminal domain complex The Journal of biological chemistry High 15355965
2005 Crystal structure at 3.0 Å of a four-protein complex of Ubc9, Nup358/RanBP2 E3 ligase domain (IR1-M), and SUMO-1 conjugated to the C-terminal domain of RanGAP1; biochemical and kinetic data support a model in which Nup358/RanBP2 acts as E3 by binding both SUMO and Ubc9 to optimally orient the SUMO-E2-thioester for conjugation. X-ray crystallography at 3.0 Å, biochemical SUMOylation kinetics assay Nature High 15931224
2005 Phosphorylation of RanGAP1 at Ser-358 by casein kinase II (CK2) stabilizes formation of a ternary complex with Ran and RanBP1 in vivo without significantly altering GAP activity; a Ser358Ala mutant fails to form this stable complex. MALDI-TOF-MS phosphorylation site identification, site-directed mutagenesis, in vitro kinase assay with purified CK2, specific kinase inhibitors (DRB, apigenin), in vivo co-immunoprecipitation Cell structure and function Medium 16428860
2006 Ubc9 has a dual role in targeting RanGAP1 to NPCs: it conjugates SUMO-1 to RanGAP1 AND is required as part of a stable ternary complex with SUMO-1-modified RanGAP1 and Nup358 for NPC association. Rapamycin heterodimerizer system to selectively induce SUMO-RanGAP1 association in living cells, immunofluorescence, co-immunoprecipitation Experimental cell research Medium 16469311
2008 SUMO-1 loss in mice results in mislocalization of RanGAP1 (detected by immunofluorescence), which can be compensated by SUMO2 or SUMO3 sumoylating RanGAP1; SUMO1 knockout mice are viable, indicating functional redundancy among SUMO isoforms for RanGAP1 modification. SUMO1 knockout mouse model, immunofluorescence localization of RanGAP1, immunoblot analysis Journal of cell science Medium 19033381
2008 The polycomb protein mel-18 interacts with RanGAP1 and inhibits its sumoylation in a RING domain-independent manner; RanGAP1 sumoylation decreases during mitosis, coincident with increased mel-18–RanGAP1 interaction. Co-immunoprecipitation, in vitro SUMOylation assay, cell cycle synchronization Biochemical and biophysical research communications Medium 18706886
2009 Paralog-selective sumoylation of RanGAP1 by SUMO-1 over SUMO-2 in vivo is determined at the level of deconjugation: SUMO-1-modified RanGAP1 forms a more stable, higher-affinity complex with Nup358/RanBP2, which protects it from isopeptidases; swapping SUMO-1/SUMO-2 residues responsible for Nup358 binding or manipulating isopeptidase levels alters paralog-selective modification in vitro and in vivo. In vitro SUMOylation assay, isopeptidase protection assay, affinity measurements, residue swap mutagenesis, siRNA manipulation of isopeptidase levels, in vivo modification analysis Molecular cell High 19285941
2011 RanBP2 IR1 domain is the primary E3 ligase for SUMO1, and both IR1 and IR2 contribute to SUMO1 specificity; crystal structures of hybrid IR1 and IR1 complexes with Ubc9 and RanGAP1-SUMO1/2 reveal more extensive contacts with SUMO1 than SUMO2, explaining specificity. Domain deletion/swap constructs, protease protection assay, automodification assay, X-ray crystallography The Journal of biological chemistry High 22194619
2012 The RanBP2/RanGAP1*SUMO1/Ubc9 complex is a composite multisubunit SUMO E3 ligase; cellular RanBP2 is quantitatively associated with RanGAP1; complex formation induces a catalytic site that shows no activity in free RanBP2; the complex SUMOylates the endogenous substrate Borealin. Biochemical reconstitution of the four-protein complex, quantitative co-immunoprecipitation, SUMOylation activity assay with Borealin substrate Molecular cell High 22464730
2012 Importin-β interacts with NUP358/RANBP2 (which binds SUMO-conjugated RANGAP1) after nuclear pore disassembly; overexpression of importin-β or its nucleoporin-binding region inhibits RANGAP1 recruitment to mitotic kinetochores; co-expression of importin-β-interacting RANBP2 fragments or CRM1 restores RANGAP1 to kinetochores. Overexpression of importin-β constructs, immunofluorescence, domain interaction analysis, CRM1 co-expression rescue The Journal of cell biology Medium 22331847
2015 The immune adaptor SLP-76 binds directly to SUMO-RanGAP1 at cytoplasmic NPC filaments via the N-terminal lysine K56 of SLP-76; this interaction is required for optimal RanGAP1-NPC localization and GAP exchange activity; the SLP-76(K56E) mutant impairs NFATc1 and NF-κB p65 nuclear entry in T cells. Direct binding assay (Co-IP, pulldown), transmission electron microscopy, GAP exchange activity assay, nuclear import assay, mutagenesis, in vivo antigen response assay Molecular cell High 26321253
2015 CRM1-mediated nuclear export regulates RanGAP1 subcellular distribution; inhibition of CRM1 (by RNAi or leptomycin B) causes nuclear accumulation of RanGAP1; the nuclear localization signal at the C-terminus of RanGAP1 is required for this nuclear accumulation; LMB-induced nuclear accumulation correlates with increased SUMO-modified RanGAP1, suggesting nuclear sumoylation. CRM1 RNAi knockdown, leptomycin B treatment, immunofluorescence time-course, NLS deletion mutagenesis PloS one Medium 26506250
2016 The RanBP2/RanGAP1*SUMO1/Ubc9 complex functions as an autonomous disassembly machine with preference for the export receptor Crm1; three in vitro reconstituted disassembly intermediates show binding of a Crm1 export complex via two FG-repeat patches, cargo release by RanBP2's Ran-binding domains, and retention of free Crm1 at RanBP2 after Ran-GTP hydrolysis; all intermediates are compatible with SUMO E3 ligase activity. In vitro reconstitution of disassembly intermediates, biochemical assays for disassembly steps, SUMO E3 ligase activity assay Nature communications High 27160050
2021 TCR stimulation induces PKC-θ translocation to the NPC where it directly phosphorylates RanGAP1 at Ser504 and Ser506; this phosphorylation increases RanGAP1's binding affinity for Ubc9, promoting sumoylation of RanGAP1 and assembly of the RanBP2/RanGAP1-SUMO1/Ubc9 subcomplex, facilitating nuclear import of AP-1 transcription factor. In vitro kinase assay with PKC-θ, site-directed mutagenesis (Ser504/Ser506), Co-IP, nuclear import assay, T cell stimulation eLife High 34110283
2021 β-arrestin2 interacts non-covalently with the RanBP2/RanGAP1-SUMO NPC complex via a SUMO interaction motif (SIM); depletion of RanBP2/RanGAP1-SUMO causes defective β-arr2 nuclear entry; SIM mutation inhibits β-arr2 nuclear import and its ability to delocalize Mdm2 and enhance p53 signaling. Co-IP, RNAi depletion, mutagenesis, nuclear import assay, p53/Mdm2 signaling readout Oncogene Medium 33649538
2023 RanGAP1 anchors to the kinetochore during mitosis where it recruits PP1-γ to counteract spindle-assembly checkpoint (SAC) activity and prevents TOP2A degradation, safeguarding chromatid decatenation; loss of RanGAP1 causes SAC hyperactivation and chromatid decatenation failure, leading to chromothripsis and osteosarcoma tumorigenesis in mice. RanGAP1 knockout mouse model, immunofluorescence, co-immunoprecipitation (PP1-γ), mitotic phenotype analysis, chromosome analysis, whole-genome sequencing Developmental cell High 36696903
2023 SUMOylated RanGAP1 at the NPC functions as a disassembly machine for CRM1-Smad4 nuclear export complexes; RanGAP1*SUMO1 mediates nuclear accumulation of Smad4 by promoting dissociation of the Smad4-CRM1 complex, representing a mechanism by which sumoylation regulates TGF-β/Smad pathway output. Co-IP, SUMO1 inhibition, nuclear fractionation, RanGAP1 manipulation in keloid fibroblasts Journal of cellular and molecular medicine Medium 36916534
2023 HBV core protein (HBC) interacts with RANGAP1 and stabilizes it by disrupting the interaction between RANGAP1 and the E3 ubiquitin ligase SYVN1; stabilized RANGAP1 in turn promotes KDM2A stability by disrupting KDM2A-SYVN1 interaction, facilitating hepatocarcinogenesis. Co-IP combined with mass spectrometry, Western blot, Co-IP interaction mapping Cellular oncology Medium 37845585
2024 RAS•GTP forms a perinuclear complex with RanGAP1 that facilitates hydrolysis of Ran•GTP to Ran•GDP to promote XPO1-dependent release of nuclear protein cargo (including EZH2) into the cytoplasm; this is independent of PI3K/AKT and RAF/MEK signaling and represents a noncanonical oncogenic RAS activity. Co-immunoprecipitation identifying RAS•GTP-RanGAP1 complex, nuclear export assay, KRAS inhibition, functional readout of EZH2/DLC1 pathway Nature cancer Medium 39528835
2024 Cryo-EM structures of a RanBP2 C-terminal fragment in complex with Crm1, SUMO1-RanGAP1/Ubc9, and two Ran(GTP) molecules reveal a nuclear export signal (NES) within RanGAP1; deletion of this NES mislocalizes RanGAP1 and Ran GTPase in cells; RanBP2 E3 ligase activity is dependent on Crm1 and the RanGAP1 NES. Cryo-EM structure determination, NES deletion mutagenesis, immunofluorescence localization in cells, biochemical E3 ligase assay bioRxivpreprint Medium bio_10.1101_2024.10.04.616749

Source papers

Stage 0 corpus · 53 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 A small ubiquitin-related polypeptide involved in targeting RanGAP1 to nuclear pore complex protein RanBP2. Cell 1033 9019411
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 982 8978815
2002 Structural basis for E2-mediated SUMO conjugation revealed by a complex between ubiquitin-conjugating enzyme Ubc9 and RanGAP1. Cell 487 11853669
1994 RanGAP1 induces GTPase activity of nuclear Ras-related Ran. Proceedings of the National Academy of Sciences of the United States of America 458 8146159
2005 Insights into E3 ligase activity revealed by a SUMO-RanGAP1-Ubc9-Nup358 complex. Nature 418 15931224
1998 SUMO-1 modification and its role in targeting the Ran GTPase-activating protein, RanGAP1, to the nuclear pore complex. The Journal of cell biology 395 9456312
1995 Interaction of the nuclear GTP-binding protein Ran with its regulatory proteins RCC1 and RanGAP1. Biochemistry 289 7819259
2004 The RanGAP1-RanBP2 complex is essential for microtubule-kinetochore interactions in vivo. Current biology : CB 244 15062103
1998 Molecular characterization of the SUMO-1 modification of RanGAP1 and its role in nuclear envelope association. The Journal of cell biology 244 9442102
2002 SUMO-1 targets RanGAP1 to kinetochores and mitotic spindles. The Journal of cell biology 238 11854305
1995 Human RanGTPase-activating protein RanGAP1 is a homologue of yeast Rna1p involved in mRNA processing and transport. Proceedings of the National Academy of Sciences of the United States of America 230 7878053
2019 Circular RNA circ-RanGAP1 regulates VEGFA expression by targeting miR-877-3p to facilitate gastric cancer invasion and metastasis. Cancer letters 203 31811909
1997 RanBP2 associates with Ubc9p and a modified form of RanGAP1. Proceedings of the National Academy of Sciences of the United States of America 170 9108047
1998 Ubc9p and the conjugation of SUMO-1 to RanGAP1 and RanBP2. Current biology : CB 167 9427648
2012 The RanBP2/RanGAP1*SUMO1/Ubc9 complex is a multisubunit SUMO E3 ligase. Molecular cell 146 22464730
2008 Loss of SUMO1 in mice affects RanGAP1 localization and formation of PML nuclear bodies, but is not lethal as it can be compensated by SUMO2 or SUMO3. Journal of cell science 127 19033381
2016 The RanBP2/RanGAP1*SUMO1/Ubc9 SUMO E3 ligase is a disassembly machine for Crm1-dependent nuclear export complexes. Nature communications 83 27160050
2011 Determinants of small ubiquitin-like modifier 1 (SUMO1) protein specificity, E3 ligase, and SUMO-RanGAP1 binding activities of nucleoporin RanBP2. The Journal of biological chemistry 67 22194619
2009 Protection from isopeptidase-mediated deconjugation regulates paralog-selective sumoylation of RanGAP1. Molecular cell 64 19285941
2004 RanGAP1*SUMO1 is phosphorylated at the onset of mitosis and remains associated with RanBP2 upon NPC disassembly. The Journal of cell biology 54 15037602
2012 Importin-β negatively regulates multiple aspects of mitosis including RANGAP1 recruitment to kinetochores. The Journal of cell biology 50 22331847
2011 Effect of ON 01910.Na, an anticancer mitotic inhibitor, on cell-cycle progression correlates with RanGAP1 hyperphosphorylation. Cancer research 33 21646468
2017 SGK1 affects RAN/RANBP1/RANGAP1 via SP1 to play a critical role in pre-miRNA nuclear export: a new route of epigenomic regulation. Scientific reports 30 28358001
2016 A gene delivery system containing nuclear localization signal: Increased nucleus import and transfection efficiency with the assistance of RanGAP1. Acta biomaterialia 26 27816620
2004 Structural and dynamic independence of isopeptide-linked RanGAP1 and SUMO-1. The Journal of biological chemistry 25 15355965
2009 WPP-domain proteins mimic the activity of the HSC70-1 chaperone in preventing mistargeting of RanGAP1-anchoring protein WIT1. Plant physiology 24 19617588
2015 The Immune Adaptor SLP-76 Binds to SUMO-RANGAP1 at Nuclear Pore Complex Filaments to Regulate Nuclear Import of Transcription Factors in T Cells. Molecular cell 23 26321253
2023 Loss of RanGAP1 drives chromosome instability and rapid tumorigenesis of osteosarcoma. Developmental cell 21 36696903
2021 The RanBP2/RanGAP1-SUMO complex gates β-arrestin2 nuclear entry to regulate the Mdm2-p53 signaling axis. Oncogene 20 33649538
2016 The novel fungal-specific gene FUG1 has a role in pathogenicity and fumonisin biosynthesis in Fusarium verticillioides. Molecular plant pathology 19 27071505
2016 MicroRNA-1301-Mediated RanGAP1 Downregulation Induces BCR-ABL Nuclear Entrapment to Enhance Imatinib Efficacy in Chronic Myeloid Leukemia Cells. PloS one 19 27228340
2015 Inhibition of RNA transportation induces glioma cell apoptosis via downregulation of RanGAP1 expression. Chemico-biological interactions 19 25746355
2012 The RanBP2/RanGAP1*SUMO1/Ubc9 complex: a multisubunit E3 ligase at the intersection of sumoylation and the RanGTPase cycle. Nucleus (Austin, Tex.) 17 22925898
2006 SUMO modification through rapamycin-mediated heterodimerization reveals a dual role for Ubc9 in targeting RanGAP1 to nuclear pore complexes. Experimental cell research 16 16469311
2005 Phosphorylation of RanGAP1 stabilizes its interaction with Ran and RanBP1. Cell structure and function 16 16428860
2021 T-cell receptor (TCR) signaling promotes the assembly of RanBP2/RanGAP1-SUMO1/Ubc9 nuclear pore subcomplex via PKC-θ-mediated phosphorylation of RanGAP1. eLife 15 34110283
2024 METTL3-mediated RanGAP1 promotes colorectal cancer progression through the MAPK pathway by recruiting YTHDF1. Cancer gene therapy 14 38267624
2021 CircRNA_0079586 and circRNA_RanGAP1 are involved in the pathogenesis of intracranial aneurysms rupture by regulating the expression of MPO. Scientific reports 12 34611229
2023 SUMOylation mediates the disassembly of the Smad4 nuclear export complex via RanGAP1 in KELOIDS. Journal of cellular and molecular medicine 11 36916534
2014 The Ran GTPase-activating protein (RanGAP1) is critically involved in smooth muscle cell differentiation, proliferation and migration following vascular injury: implications for neointima formation and restenosis. PloS one 11 24988324
2015 The Cellular Distribution of RanGAP1 Is Regulated by CRM1-Mediated Nuclear Export in Mammalian Cells. PloS one 9 26506250
2024 The pro-oncogenic noncanonical activity of a RAS•GTP:RanGAP1 complex facilitates nuclear protein export. Nature cancer 8 39528835
2023 Hepatitis B virus core protein stabilizes RANGAP1 to upregulate KDM2A and facilitate hepatocarcinogenesis. Cellular oncology (Dordrecht, Netherlands) 8 37845585
2008 Mel-18 interacts with RanGAP1 and inhibits its sumoylation. Biochemical and biophysical research communications 8 18706886
1996 Ubiquitous expression and testis-specific alternative polyadenylation of mRNA for the human Ran GTPase activator RanGAP1. Gene 7 8973340
2013 Exploring the desumoylation process of SENP1: a study combined MD simulations with QM/MM calculations on SENP1-SUMO1-RanGAP1. Journal of chemical information and modeling 6 23930863
2011 Nuclear translocation of RanGAP1 coincides with virtual nuclear envelope breakdown in fission yeast meiosis. Communicative & integrative biology 6 21980566
2024 RanGAP1 maintains chromosome stability in limb bud mesenchymal cells during bone development. Cellular signalling 5 38729327
2022 circ-RANGAP1/MicroRNA-542-3p/Myosin Regulatory Light Chain Interacting Protein Axis Modulates the Osteosarcoma Cell Progression. Applied bionics and biomechanics 3 35747400
2013 SUMOylated RanGAP1 prepared by click chemistry. Journal of peptide science : an official publication of the European Peptide Society 3 24338848
2026 RanGAP1 plays a vital role in anti-infective functions of macrophages and sepsis progression. Immunology letters 0 42055254
2025 Production and Purification of SUMO-UBC9 and SUMO-RANGAP1CTD. Methods in molecular biology (Clifton, N.J.) 0 40875115
2023 Retracted: circ-RANGAP1/MicroRNA-542-3p/Myosin Regulatory Light Chain Interacting Protein Axis Modulates the Osteosarcoma Cell Progression. Applied bionics and biomechanics 0 37621479

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