{"gene":"RANBP1","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1995,"finding":"RanBP1 (23 kDa) binds tightly to Ran-GTP but not Ran-GDP, co-activates RanGAP1-induced GTP hydrolysis by ~10-fold, inhibits RCC1-stimulated nucleotide exchange on Ran, and forms a stable complex with nucleotide-free RCC1-Ran. It defines a new class of GTPase regulators distinct from GDIs.","method":"In vitro GTPase and nucleotide exchange assays with purified recombinant proteins; biochemical fractionation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple in vitro enzymatic assays with purified proteins, foundational study replicated by many subsequent labs","pmids":["7882974"],"is_preprint":false},{"year":1995,"finding":"The acidic C-terminal -DEDDDL sequence of Ran is required for high-affinity interaction with RanBP1 (HTF9A); deletion of this domain reduces RanBP1 affinity to ~10 µM and converts RanBP1 from a RanGAP co-activator to a RanGAP inhibitor.","method":"In vitro binding assays, GTPase activity assays with C-terminal deletion mutants of Ran","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with defined mutants and multiple biochemical readouts, replicated in later structural studies","pmids":["7782302"],"is_preprint":false},{"year":1995,"finding":"RanBP1 binds RCC1 only in the presence of Ran (forming a trimeric complex) and inhibits RCC1-stimulated guanine nucleotide release from Ran in vitro. Overexpression of RanBP1 is detrimental in RCC1-deficient cells, establishing it as a negative regulator of RCC1.","method":"Two-hybrid interaction screen, in vitro GST pulldown, in vitro nucleotide exchange assay, yeast genetics (rcc1 mutant complementation/suppression)","journal":"Molecular & general genetics : MGG","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro enzymatic assay plus yeast genetic epistasis, replicated by independent labs","pmids":["7616957"],"is_preprint":false},{"year":1996,"finding":"RanBP1 forms a trimeric complex with p97 (importin-β) and Ran, stabilizes the interaction of Ran-GDP with p97, promotes nuclear import by stabilizing receptor docking at the pore, and stimulates translocation in a permeabilized cell import assay.","method":"Immunoadsorption from HeLa cell extracts, gel filtration, recombinant protein reconstitution, permeabilized cell import assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reconstituted trimeric complex, functional import assay, multiple orthogonal methods","pmids":["8909533"],"is_preprint":false},{"year":1996,"finding":"RanBP1 contains a leucine-rich nuclear export signal (NES) C-terminal to its Ran-binding domain that is necessary for its cytoplasmic localization; the isolated RBD lacking the NES accumulates in the nucleus. The cytoplasmic localization of RanBP1 is important for nuclear protein import.","method":"Subcellular fractionation, transfection of deletion/domain-swap constructs, permeabilized cell assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization experiments with functional consequence, replicated by subsequent studies","pmids":["8794858"],"is_preprint":false},{"year":1997,"finding":"RanBP1 forms a ternary complex with Ran-GTP and karyopherin beta (importin-β) and partially relieves the complete inhibition of RanGAP activity imposed by karyopherin beta, acting through competitive and non-competitive kinetic mechanisms at distinct sites on Ran.","method":"Solution binding assays, kinetic analysis of RanGAP activity in the presence of purified components","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with kinetic dissection; single lab but multiple orthogonal biochemical readouts","pmids":["8995296"],"is_preprint":false},{"year":1997,"finding":"RanBP1 acts as a key disassembly intermediate for importin-β-related transport receptor–RanGTP complexes: RanBP1 stimulates the off-rate of RanGTP from the receptor by >100-fold, transiently releasing RanGTP·RanBP1 which is then driven by RanGAP to hydrolyze GTP. Release of importin-β additionally requires importin-α.","method":"In vitro binding and dissociation kinetics with purified transport receptors, RanGTP, and RanBP1; functional nuclear transport assays","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Strong — kinetic reconstitution with multiple transport receptors, replicated conceptually across multiple labs","pmids":["9428644"],"is_preprint":false},{"year":1997,"finding":"RanBP1 NES mutations that abolish cytoplasmic localization block Rev-mediated HIV-1 nuclear export, demonstrating that RanBP1 competes with or shares the CRM1-dependent nuclear export pathway used by Rev. This inhibitory effect is independent of RanBP1's ability to bind Ran.","method":"Mutational analysis of NES; reporter assays for Rev-mediated and CTE-mediated HIV-1 expression in transfected cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional cell-based assay with defined mutants; single lab","pmids":["9111043"],"is_preprint":false},{"year":1997,"finding":"RanBP1 binds Ran-GTP with nanomolar affinity and Ran-GDP with ~10 µM affinity; the difference is primarily due to a dramatically faster dissociation rate constant for the GDP-bound form. The C-terminal five residues of Ran are required for high-affinity RanBP1 binding to the GTP form.","method":"Fluorescence spectroscopy with nucleotide analogues, surface plasmon resonance (BIAcore), circular dichroism","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — two independent biophysical methods (fluorescence + SPR) in a single rigorous study","pmids":["9315840"],"is_preprint":false},{"year":1997,"finding":"RanBP5, identified through a two-hybrid screen using RanBP1 as bait, binds RanBP1 as part of a trimeric RanBP1–Ran–RanBP5 complex; RanBP1 can relieve GAP-resistance of the RanBP5–RanGTP complex.","method":"Yeast two-hybrid, overlay assay, in vitro GAP assay with purified components","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two-hybrid plus in vitro biochemical confirmation; single lab","pmids":["9271386"],"is_preprint":false},{"year":1997,"finding":"Two distinct but overlapping binding domains for Ran-GTP and Ran-GDP/RanBP1 exist on p97 (importin-β); Cys-158 of p97 is required for Ran-GDP/RanBP1 binding but not Ran-GTP binding, and a Cys158Ala mutant p97 cannot support nuclear import.","method":"Site-directed mutagenesis and deletion analysis of p97; permeabilized cell import assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis with functional import readout; single lab with rigorous controls","pmids":["9045717"],"is_preprint":false},{"year":1997,"finding":"The balance between RanBP1 and RCC1 is critical: restoring only one of these two proteins to co-depleted Xenopus egg extracts causes abnormal nuclear assembly and inhibits transport and DNA replication, rescued by addition of the other protein. The GTP/GDP-Ran balance is the essential functional parameter.","method":"Immunodepletion from Xenopus egg extracts, recombinant protein add-back, nuclear assembly and import assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — immunodepletion/reconstitution in Xenopus extracts with multiple functional readouts","pmids":["9348536"],"is_preprint":false},{"year":1997,"finding":"Both mRNA species from the bidirectional Htf9-a/RanBP1 and Htf9-c promoter peak in S phase; cell cycle-dependent transcription is controlled at the transcriptional level by an S-phase-activated bidirectional promoter containing E2F and Sp1 recognition sites.","method":"Northern blotting of cell cycle fractions, transient reporter assays with promoter deletion constructs","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter dissection with reporter assays; single lab","pmids":["9224656"],"is_preprint":false},{"year":1997,"finding":"Deregulated (forced) expression of RanBP1 in murine fibroblasts disrupts cell cycle progression: it inhibits DNA replication, causes defective mitotic exit, and impairs chromatin decondensation at telophase-to-interphase transition.","method":"Stable transfection, BrdU incorporation, FACS analysis, microscopy","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression with multiple defined cellular phenotypes; single lab","pmids":["9410874"],"is_preprint":false},{"year":1998,"finding":"The RanBP1 Ran-binding domain (RBD) belongs structurally to the EVH1/WH1 domain superfamily shared by VASP, WASP, and Homer proteins.","method":"Computational sequence/structural analysis (domain recognition)","journal":"FEBS letters","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational prediction only, no experimental validation described in the abstract","pmids":["9883880"],"is_preprint":false},{"year":1998,"finding":"The distal E2F-b site plus a neighboring Sp1 element actively drive RanBP1 transcriptional upregulation in S phase, while the proximal E2F-c site mediates repression upon growth arrest; each site interacts with distinct E2F family members.","method":"Site-directed mutagenesis of promoter E2F sites, transient reporter assays, protein-binding assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis combined with binding and reporter assays; single lab","pmids":["10187822"],"is_preprint":false},{"year":1999,"finding":"RanBP1 restores nuclear export of NFAT after RanQ69L-induced accumulation of CRM1 at the cytoplasmic face of the NPC, and both RanBP1 and the Ran-binding domains of RanBP2 promote release of CRM1 from the NPC. RanGTP is required for targeting export complexes to the cytoplasmic face of the NPC.","method":"Permeabilized cell export reconstitution assay, biochemical fractionation, in vitro reconstitution of CRM1-nucleoporin interactions","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reconstitution assay plus biochemical fractionation, multiple orthogonal approaches, replicated conceptually","pmids":["10330396"],"is_preprint":false},{"year":1999,"finding":"RanGTP bound to RanBP1 adopts a specific conformational state (state 2) distinct from free Ran-GTP; the RCC1–Ran–nucleotide ternary complex intermediate is detectable by 31P NMR, providing structural evidence for the exchange mechanism.","method":"31P NMR spectroscopy of purified Ran complexes; conformational analysis","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — NMR structural analysis with multiple complexes; single lab","pmids":["10471274"],"is_preprint":false},{"year":1999,"finding":"Isolated RBD from mammalian RanBP1 or S. pombe sbp1p is sufficient to rescue growth of sbp1-null fission yeast, and the RBD localizes to the nucleus rather than cytoplasm, indicating that cytoplasmic confinement is not required for essential RanBP1 function in yeast.","method":"Genetic complementation of sbp1 null yeast, subcellular localization of exogenous constructs","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic rescue in yeast plus localization; single lab","pmids":["10397757"],"is_preprint":false},{"year":2000,"finding":"RanBP1 shuttles actively through the nuclear pore: it accumulates in nuclei upon leptomycin B treatment (CRM1 inhibition), its import requires nuclear Ran-GTP (but not classical importin pathway), and an E37K mutation abolishes nuclear accumulation despite preserving ternary complex formation with Ran and importin-β.","method":"Leptomycin B treatment, cytoplasmic microinjection, permeabilized cell accumulation assay, nuclear import with exogenous karyopherins and RCC1","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (drug inhibition, microinjection, permeabilized cells, mutant analysis) in a single comprehensive study","pmids":["10779340"],"is_preprint":false},{"year":2000,"finding":"The essential biological activity of RanBP1 in yeast correlates specifically with its capacity to potentiate RanGAP activity toward Ran-GTP within karyopherin complexes, not with Ran-GTP binding per se or ternary complex formation. Mutants crippled for RanGAP co-activation cannot rescue growth even if they form ternary complexes.","method":"Random mutagenesis, in vitro biochemical assays (Ran binding, RanGAP stimulation, ternary complex formation), complementation of temperature-sensitive yrb1 yeast","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — systematic mutagenesis correlated across multiple in vitro assays and in vivo genetic readout","pmids":["10660567"],"is_preprint":false},{"year":2001,"finding":"Importin-β binding to Ran-GTP disrupts an intramolecular interaction between the basic patch (HRKK142) and the C-terminal DEDDDL motif of Ran, exposing the C-terminus and stimulating RanBP1 binding. Mutating the basic patch increases RanBP1 affinity and enables importin-β release without importin-α. CRM1 binding requires the basic patch but uses different Ran determinants than importin-β.","method":"Limited proteolysis protection assays, solution binding measurements with Ran mutants, in vitro dissociation assays","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — proteolytic protection plus functional binding assays; mechanistically detailed single study","pmids":["11124902"],"is_preprint":false},{"year":2001,"finding":"XMog1 (Xenopus Mog1) co-operates with RanBP1 to promote selective GTP loading onto Ran from GDP, and to facilitate RCC1-catalyzed generation of Ran-GTP in the nucleus; alone, neither protein is sufficient for this activity.","method":"Two-hybrid screening, in vitro nucleotide exchange and GTPase assays with purified components, yeast genetic rescue","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro reconstitution plus genetic rescue; single lab","pmids":["11686304"],"is_preprint":false},{"year":2002,"finding":"FRET measurements show that binding of RanGTP to importin-β, RanBP1, or CRM1 all extend the C-terminal tail of Ran (reduced FRET between N-terminal GFP and C-terminal Alexa546). A Ran-GDP·RanBP1·importin-β ternary complex with extended tail is detected both in vitro and in intact cells via cytoplasmic FRET.","method":"FRET using Ran-GFP labeled with Alexa546; co-injection into living cells; in vitro reconstitution","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — FRET in vitro and in living cells; multiple complexes tested; single lab","pmids":["12034733"],"is_preprint":false},{"year":2003,"finding":"RanBP1 overexpression specifically in mitosis induces splitting of mother and daughter centrioles at spindle poles, generating multipolar spindles; this requires microtubule integrity and Eg5 activity. A fraction of RanBP1 localizes at the centrosome during mitosis.","method":"Overexpression in mammalian cells, microscopy (centrosome and spindle staining), drug treatments (nocodazole, monastrol)","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization plus functional epistasis with Eg5 inhibitor; single lab","pmids":["12840069"],"is_preprint":false},{"year":2005,"finding":"RanGAP1 is phosphorylated in vivo at Ser-358 by casein kinase II (CK2); this phosphorylation does not alter GAP catalytic activity but stabilizes formation of the ternary RanGAP1·Ran·RanBP1 complex in vivo.","method":"MALDI-TOF-MS phosphosite identification, site-directed mutagenesis at S358, in vitro kinase assay with CK2, co-immunoprecipitation of ternary complex","journal":"Cell structure and function","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS + mutagenesis + kinase assay + co-IP; single lab","pmids":["16428860"],"is_preprint":false},{"year":2007,"finding":"RANBP1 depletion in human cells causes prolonged prometaphase, hyperstable spindle microtubules, failure to recruit cyclin B1 to spindles, mislocalization of HURP (DLG7) away from plus-ends, and frequent lagging chromosomes in anaphase, indicating roles in microtubule dynamics regulation and prevention of merotelic attachments.","method":"siRNA knockdown in human cells, immunofluorescence microscopy, spindle stability assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — siRNA knockdown with multiple defined molecular and phenotypic readouts, replicated across cell lines","pmids":["17940066"],"is_preprint":false},{"year":2009,"finding":"RanBP1 downregulation by RNAi activates caspase-3-dependent apoptosis in multiple transformed cell lines and increases their apoptotic response to taxol; this effect is absent in caspase-3-deficient MCF-7 cells, placing RanBP1 upstream of caspase-3 in the apoptotic pathway.","method":"siRNA knockdown, flow cytometry for apoptosis, taxol treatment, caspase-3 activity/deficiency comparison across cell lines","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA with multiple cell lines and caspase-3 epistasis; single lab","pmids":["19270727"],"is_preprint":false},{"year":2010,"finding":"RanBP1 protein abundance peaks in mitosis and must decline in mid-to-late telophase for nuclear reformation. Mild RanBP1 overexpression persisting into late mitosis blocks chromatin decondensation, nuclear expansion, nuclear lamina reorganization, and NPC reassembly, with associated failure of importin-β-dependent NLS cargo reimport. Co-expression of importin-β mitigates these defects.","method":"Stable transfection with inducible overexpression, immunofluorescence, quantitative microscopy across cell cycle stages, importin-β co-expression rescue","journal":"Chromosoma","confidence":"High","confidence_rationale":"Tier 2 / Strong — overexpression with temporal dissection and importin-β epistasis rescue; multiple orthogonal phenotypic readouts","pmids":["20658144"],"is_preprint":false},{"year":2014,"finding":"RanBP1 controls RCC1 enzymatic activity and partitioning between chromatin-bound and soluble pools in M-phase Xenopus egg extracts by forming a heterotrimeric RCC1/Ran/RanBP1 complex. This mechanism governs the spatial Ran-GTP gradient that guides spindle assembly. Additionally, phosphorylation of RanBP1 drives changes in chromatin-bound RCC1 dynamics at the metaphase-anaphase transition.","method":"Xenopus egg extract biochemistry, chromatin fractionation, in vitro exchange assays, immunodepletion/reconstitution, phosphorylation analysis","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reconstitution in Xenopus extracts with multiple functional and biochemical assays; detailed mechanistic dissection","pmids":["25458009"],"is_preprint":false},{"year":2014,"finding":"Loss of Ranbp1 in mice selectively disrupts M phase of the cell cycle in cortical progenitors (both apical at E10.5 and basal at E14.5), resulting in microcephaly and specific reduction of layer 2/3 cortical projection neurons; Ranbp1-/- mice are not recovered live at birth and >60% are exencephalic.","method":"Targeted mouse knockout, BrdU/Ki67 proliferation assays, M-phase immunostaining (phospho-H3), cortical layer marker analysis","journal":"Cerebral cortex","confidence":"High","confidence_rationale":"Tier 2 / Moderate — knockout mouse with multiple defined phenotypic readouts across developmental stages; single lab","pmids":["25452572"],"is_preprint":false},{"year":2018,"finding":"RanBP1 regulates cortical neuron axon specification by controlling the cytoplasmic levels of the polarity kinase LKB1/Par4 through the nuclear export machinery; downstream of RanBP1, LKB1 acts via the STK25-GM130 pathway to regulate Golgi organization and promote axonogenesis.","method":"shRNA knockdown in cultured cortical neurons and in vivo, LKB1 localization assay, Golgi morphology analysis, epistasis with STK25 and GM130","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi with epistasis experiments identifying LKB1-STK25-GM130 pathway; single lab","pmids":["30184488"],"is_preprint":false},{"year":2019,"finding":"In animal cells (in contrast to fungi), RanBP1 dissociates nuclear export complexes by sequestering RanGTP away from the CRM1 export receptor, rather than via RanBP1-CRM1-RanGTP sequestration as in fungi. Animal RanBP1 forms a 1:1:2 (RanBP1:CRM1:RanGTP) nuclear export complex, whereas fungal RanBP1 forms a 1:1:1 complex; this mechanistic divergence is due to loss of affinity between animal RanBP1-RanGTP and CRM1, caused by non-conservation of key residues.","method":"In vitro reconstitution of export complexes, stoichiometry determination, mutational analysis of interface residues, biochemical binding assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with mutational analysis; detailed mechanistic dissection; single lab","pmids":["31021318"],"is_preprint":false},{"year":2020,"finding":"RanBP1 controls mitotic RCC1 dynamics in human somatic cells: RanBP1 degradation (auxin-inducible degron) alters metaphase chromatin-bound RCC1 exchange rates (FRAP/FLIP) and causes re-localization of the spindle assembly factor HURP, consistent with altered Ran-GTP gradients.","method":"Auxin-inducible degron (AID) depletion, FRAP and FLIP of RCC1-GFP, HURP immunolocalization in metaphase cells","journal":"Cell cycle (Georgetown, Tex.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — acute conditional depletion (AID) plus live-cell FRAP/FLIP; extends Xenopus findings to human somatic cells","pmids":["32594833"],"is_preprint":false},{"year":2022,"finding":"CD147 interacts with RanBP1 via its intracellular domain (CD147ICD) binding to the C-terminal tail of RanBP1; this interaction mediates CD147-regulated microtubule stability/dynamics and paclitaxel sensitivity in cancer cells.","method":"Co-immunoprecipitation, FRET, surface plasmon resonance (SPR), FRAP of microtubule dynamics, truncation analysis, xenograft models","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — SPR + FRET + Co-IP for interaction, FRAP for functional consequence; multiple orthogonal methods; single lab","pmids":["34974521"],"is_preprint":false},{"year":2022,"finding":"RanBP1 is required for directional chemotaxis and front-to-rear polarity of migrating neural crest cells during development; this function involves LKB1/PAR4 regulated export downstream of Ran/RanBP1.","method":"Morpholino/RNAi knockdown in Xenopus neural crest cells, live cell chemotaxis assays, epistasis with LKB1","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with directional migration readout and LKB1 epistasis; single lab","pmids":["36206829"],"is_preprint":false},{"year":2023,"finding":"Oxidative stress concentrates RanBP1 in the nucleus through EGFR and PKA signaling pathways; pharmacological inhibition of EGFR or PKA reduces this relocalization, and mutational analysis identifies Ser-60 and Tyr-103 as critical residues for oxidant-induced nuclear accumulation.","method":"Subcellular fractionation, pharmacological inhibitors (EGFR/PKA), site-directed mutagenesis (S60A, Y103F), fluorescence microscopy","journal":"European journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological epistasis + mutagenesis; single lab, multiple methods","pmids":["38011756"],"is_preprint":false}],"current_model":"RanBP1 is a conserved cytoplasmic Ran-GTP-binding protein that orchestrates the Ran GTPase cycle: it co-activates RanGAP1-mediated GTP hydrolysis (~10-fold), inhibits RCC1-catalyzed nucleotide exchange on Ran, forms transient trimeric complexes with importin-β/karyopherins and Ran-GTP to drive disassembly of nuclear import and export complexes, promotes release of CRM1 from the cytoplasmic face of the NPC, and—in mitosis—controls the spatial Ran-GTP gradient by regulating RCC1 chromatin dynamics (via a RCC1/Ran/RanBP1 heterotrimer and RanBP1 phosphorylation at the metaphase-anaphase transition), thereby governing spindle assembly, centrosome cohesion, microtubule stability, chromosome segregation, and nuclear reformation after mitosis; in neurons it additionally regulates LKB1 nuclear export to control axon specification and directed migration."},"narrative":{"mechanistic_narrative":"RanBP1 is a conserved cytoplasmic Ran-GTP-binding protein that defines a distinct class of Ran GTPase regulators governing the directionality of the Ran nucleotide cycle and, through it, nucleocytoplasmic transport and mitotic spindle assembly [PMID:7882974]. It binds Ran-GTP with nanomolar affinity through a Ran-binding domain that recognizes the acidic C-terminal -DEDDDL tail of Ran, co-activates RanGAP1-mediated GTP hydrolysis ~10-fold, and inhibits RCC1-catalyzed nucleotide exchange, forming a stable RCC1/Ran/RanBP1 ternary complex [PMID:7882974, PMID:7782302, PMID:7616957, PMID:9315840]. Mechanistically RanBP1 acts as a disassembly factor: it forms transient trimeric complexes with importin-β-family receptors and Ran-GTP, accelerating release of Ran-GTP from transport receptors by >100-fold to be handed to RanGAP for hydrolysis, and in animal cells it dismantles CRM1 export complexes by sequestering Ran-GTP away from CRM1 and promoting CRM1 release from the cytoplasmic face of the nuclear pore [PMID:9428644, PMID:10330396, PMID:31021318]. A leucine-rich NES confines RanBP1 to the cytoplasm where it supports nuclear import, and the protein shuttles through the pore via a Ran-GTP-dependent, importin-independent route [PMID:8794858, PMID:10779340]. In mitosis RanBP1 controls the spatial Ran-GTP gradient by regulating the activity and chromatin partitioning of RCC1 through the RCC1/Ran/RanBP1 heterotrimer and through phosphorylation at the metaphase-anaphase transition, thereby governing spindle microtubule dynamics, centrosome cohesion, chromosome segregation, and nuclear reformation after mitosis [PMID:17940066, PMID:20658144, PMID:25458009, PMID:32594833, PMID:12840069]. RanBP1 abundance is cell-cycle regulated by an S-phase-activated E2F/Sp1 bidirectional promoter, and its level must decline in late mitosis to permit nuclear envelope and NPC reassembly [PMID:9224656, PMID:10187822, PMID:20658144]. In the developing nervous system RanBP1 is required for M-phase progression of cortical progenitors and for axon specification and directed migration via nuclear-export control of the polarity kinase LKB1 acting through the STK25-GM130 pathway [PMID:25452572, PMID:30184488, PMID:36206829].","teleology":[{"year":1995,"claim":"Established the foundational biochemical identity of RanBP1 as a novel Ran regulator that both potentiates RanGAP and antagonizes RCC1, resolving how Ran's GTP/GDP state is biased.","evidence":"In vitro GTPase and nucleotide exchange assays with purified recombinant proteins; two-hybrid and yeast genetics for RCC1 interaction","pmids":["7882974","7616957","7782302"],"confidence":"High","gaps":["Did not resolve how these opposing activities are coordinated in cells","Structural basis of the Ran C-terminal tail recognition not yet defined"]},{"year":1996,"claim":"Showed RanBP1 is not merely a GAP cofactor but a transport-cycle component that forms trimeric complexes with importin-β and Ran and is held cytoplasmic by an NES, linking its biochemistry to nuclear import.","evidence":"Immunoadsorption, gel filtration, recombinant reconstitution, permeabilized cell import assays, and NES deletion/domain-swap localization","pmids":["8909533","8794858"],"confidence":"High","gaps":["Whether trimer formation drives complex assembly or disassembly was not yet distinguished","Kinetics of receptor release not quantified"]},{"year":1997,"claim":"Defined RanBP1's core mechanistic role as a disassembly catalyst that strips Ran-GTP from transport receptors and as a thermodynamic switch tuned by Ran's C-terminus.","evidence":"Kinetic dissociation assays with multiple transport receptors, fluorescence/SPR affinity measurements, and ternary-complex reconstitutions including RanBP5 and karyopherin-β","pmids":["9428644","8995296","9315840","9271386","9045717"],"confidence":"High","gaps":["In vivo confirmation of >100-fold off-rate enhancement was indirect","How disassembly is spatially restricted to the cytoplasmic NPC face unaddressed"]},{"year":1997,"claim":"Connected RanBP1 dosage to cell-cycle physiology, showing its balance with RCC1 and its S-phase-regulated expression are essential for proper nuclear assembly, replication, and mitotic exit.","evidence":"Xenopus egg extract immunodepletion/add-back, promoter dissection with reporter assays, and overexpression phenotyping in fibroblasts","pmids":["9348536","9224656","9410874"],"confidence":"Medium","gaps":["Molecular cause of mitotic-exit defects upon overexpression not yet mechanistic","Promoter studies did not link expression timing to functional demand"]},{"year":1997,"claim":"Extended RanBP1's reach to CRM1-dependent export by showing its NES-dependent cytoplasmic localization intersects the Rev/CRM1 export pathway.","evidence":"NES mutational analysis and Rev/CTE reporter assays in transfected cells","pmids":["9111043"],"confidence":"Medium","gaps":["Single lab, cell-based assay only","Direct biochemical competition with CRM1 not yet demonstrated"]},{"year":1999,"claim":"Provided structural and reconstitution evidence that RanBP1 promotes CRM1 release from the NPC and induces a defined Ran conformational state, mechanizing its export-terminating role.","evidence":"Permeabilized cell export reconstitution, biochemical fractionation of CRM1-nucleoporin complexes, and 31P NMR of Ran complexes","pmids":["10330396","10471274"],"confidence":"Medium","gaps":["Stoichiometry of the RanBP1-CRM1-RanGTP species not yet determined","NMR state assignment from a single lab"]},{"year":2000,"claim":"Resolved which RanBP1 activity is essential and showed RanBP1 itself shuttles through the pore, separating Ran binding from the catalytically essential GAP-co-activation function.","evidence":"Random mutagenesis correlated across binding/GAP/ternary assays with yeast complementation, plus leptomycin B, microinjection, and permeabilized-cell shuttling assays","pmids":["10660567","10779340","10397757"],"confidence":"High","gaps":["Why RanBP1 needs to enter the nucleus mechanistically unclear","Discrepancy with yeast (cytoplasmic confinement dispensable) not reconciled"]},{"year":2001,"claim":"Clarified the allosteric logic of RanBP1 recruitment, showing importin-β binding exposes Ran's C-terminus to stimulate RanBP1 association and that CRM1 uses distinct Ran determinants.","evidence":"Limited proteolysis protection, solution binding with Ran basic-patch and tail mutants, and FRET tail-extension measurements in vitro and in living cells","pmids":["11124902","12034733","11686304"],"confidence":"High","gaps":["In vivo physiological relevance of XMog1 cooperation in mammals untested","Quantitative contribution of each Ran determinant to in vivo flux unmeasured"]},{"year":2007,"claim":"Established RanBP1's mitotic spindle function, linking its loss to hyperstable microtubules, spindle-factor mislocalization, and chromosome mis-segregation.","evidence":"siRNA knockdown with immunofluorescence and spindle stability assays in human cells; centrosome overexpression phenotyping with Eg5 inhibitor epistasis","pmids":["17940066","12840069"],"confidence":"High","gaps":["Whether spindle defects derive solely from Ran-GTP gradient disruption not isolated","Direct centrosome targets of RanBP1 unknown"]},{"year":2010,"claim":"Demonstrated that timely decline of RanBP1 in late mitosis is required for nuclear envelope and NPC reassembly via restoration of importin-β cargo import.","evidence":"Inducible overexpression with temporal microscopy across cell-cycle stages and importin-β co-expression rescue","pmids":["20658144"],"confidence":"High","gaps":["Mechanism degrading RanBP1 at telophase not identified","Direct importin-β cargo set affected not enumerated"]},{"year":2014,"claim":"Mechanized RanBP1's mitotic role as control of RCC1 chromatin dynamics and the spatial Ran-GTP gradient, and showed organismal requirement in cortical neurogenesis.","evidence":"Xenopus extract heterotrimer reconstitution, chromatin fractionation and phosphorylation analysis; targeted mouse knockout with M-phase and cortical-layer readouts","pmids":["25458009","25452572"],"confidence":"High","gaps":["Kinase responsible for metaphase-anaphase RanBP1 phosphorylation not identified","Link between gradient control and specific spindle assembly factors incomplete"]},{"year":2019,"claim":"Revealed an animal-specific export-disassembly mechanism in which RanBP1 sequesters Ran-GTP from CRM1 rather than co-binding CRM1 as in fungi, redefining cross-species mechanistic models.","evidence":"In vitro reconstitution with stoichiometry determination and mutational analysis of interface residues","pmids":["31021318"],"confidence":"High","gaps":["In vivo consequence of the 1:1:2 complex in animal cells not tested","Whether divergence affects export cargo selectivity unknown"]},{"year":2020,"claim":"Confirmed in human somatic cells via acute depletion that RanBP1 directly governs mitotic RCC1 exchange dynamics and downstream spindle-factor localization.","evidence":"Auxin-inducible degron depletion with FRAP/FLIP of RCC1-GFP and HURP immunolocalization","pmids":["32594833"],"confidence":"High","gaps":["Quantitative Ran-GTP gradient changes inferred, not directly imaged","Phosphoregulation in human cells not yet dissected"]},{"year":2022,"claim":"Identified new physical partners and disease-relevant functions, linking RanBP1 to CD147-regulated microtubule dynamics and to caspase-3-dependent apoptosis and chemosensitivity.","evidence":"Co-IP, FRET, SPR, FRAP and xenografts for CD147; siRNA with caspase-3 epistasis and taxol response across cell lines","pmids":["34974521","19270727"],"confidence":"Medium","gaps":["How CD147 binding to the RanBP1 C-terminus alters Ran-cycle activity unresolved","Molecular link from RanBP1 loss to caspase-3 activation undefined"]},{"year":2023,"claim":"Showed RanBP1 localization is signal-regulated, with oxidative stress driving nuclear accumulation through EGFR/PKA signaling and specific phosphosites.","evidence":"Subcellular fractionation, EGFR/PKA pharmacological inhibition, and S60A/Y103F mutational analysis with microscopy","pmids":["38011756"],"confidence":"Medium","gaps":["Functional consequence of stress-induced nuclear RanBP1 not determined","Direct kinase acting on S60/Y103 not identified"]},{"year":null,"claim":"How RanBP1's distinct activities—transport-complex disassembly, mitotic RCC1/Ran-GTP gradient control, and neuronal LKB1 export—are differentially deployed and post-translationally switched in space and time remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["The mitotic kinase and degradation machinery acting on RanBP1 are unidentified","Whether a single biochemical activity underlies all phenotypes or separable functions exist is unclear","No high-resolution structure of the animal RanBP1-CRM1-RanGTP export complex"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,2,6,20]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[6,16,32]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,6,16]},{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[0,5,20]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,19,23]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[19,36,18]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[24]},{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[16,19]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[3,6,16,32]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[26,28,29,33]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[30,31,35]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[27]}],"complexes":["RCC1/Ran/RanBP1 heterotrimer","RanBP1/Ran-GTP/importin-β ternary complex","RanBP1/CRM1/Ran-GTP export complex","RanGAP1/Ran/RanBP1 ternary complex"],"partners":["RAN","RCC1","RANGAP1","IMPORTIN-Β (KPNB1)","CRM1 (XPO1)","RANBP5 (IPO5)","LKB1 (STK11)","BSG (CD147)"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P43487","full_name":"Ran-specific GTPase-activating protein","aliases":["Ran-binding protein 1","RanBP1"],"length_aa":201,"mass_kda":23.3,"function":"Plays a role in RAN-dependent nucleocytoplasmic transport. Alleviates the TNPO1-dependent inhibition of RAN GTPase activity and mediates the dissociation of RAN from proteins involved in transport into the nucleus (By similarity). Induces a conformation change in the complex formed by XPO1 and RAN that triggers the release of the nuclear export signal of cargo proteins (PubMed:20485264). Promotes the disassembly of the complex formed by RAN and importin beta. Promotes dissociation of RAN from a complex with KPNA2 and CSE1L (By similarity). Required for normal mitotic spindle assembly and normal progress through mitosis via its effect on RAN (PubMed:17671426). Does not increase the RAN GTPase activity by itself, but increases GTP hydrolysis mediated by RANGAP1 (PubMed:7882974). Inhibits RCC1-dependent exchange of RAN-bound GDP by GTP (PubMed:7616957, PubMed:7882974)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/P43487/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/RANBP1","classification":"Common Essential","n_dependent_lines":521,"n_total_lines":1208,"dependency_fraction":0.43129139072847683},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000099901","cell_line_id":"CID000264","localizations":[{"compartment":"cytoplasmic","grade":3}],"interactors":[{"gene":"KPNB1","stoichiometry":10.0},{"gene":"RAN","stoichiometry":10.0},{"gene":"RCC1","stoichiometry":10.0},{"gene":"RANGAP1","stoichiometry":10.0},{"gene":"KPNA3","stoichiometry":4.0},{"gene":"ACTR2","stoichiometry":0.2},{"gene":"CTNNB1","stoichiometry":0.2},{"gene":"EEA1","stoichiometry":0.2},{"gene":"FDPS","stoichiometry":0.2},{"gene":"IPO5","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000264","total_profiled":1310},"omim":[{"mim_id":"611151","title":"tRNA METHYLTRANSFERASE 2 HOMOLOG A; TRMT2A","url":"https://www.omim.org/entry/611151"},{"mim_id":"610778","title":"GUANINE NUCLEOTIDE-BINDING PROTEIN, BETA-1-LIKE; GNB1L","url":"https://www.omim.org/entry/610778"},{"mim_id":"610352","title":"PROTEIN PHOSPHATASE 4, REGULATORY SUBUNIT 3, BETA; PPP4R3B","url":"https://www.omim.org/entry/610352"},{"mim_id":"610351","title":"PROTEIN PHOSPHATASE 4, REGULATORY SUBUNIT 3, ALPHA; PPP4R3A","url":"https://www.omim.org/entry/610351"},{"mim_id":"607954","title":"RAN GUANINE NUCLEOTIDE RELEASE FACTOR; RANGRF","url":"https://www.omim.org/entry/607954"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Cytosol","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RANBP1"},"hgnc":{"alias_symbol":["HTF9A"],"prev_symbol":[]},"alphafold":{"accession":"P43487","domains":[{"cath_id":"2.30.29.30","chopping":"44-177","consensus_level":"high","plddt":93.4788,"start":44,"end":177}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P43487","model_url":"https://alphafold.ebi.ac.uk/files/AF-P43487-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P43487-F1-predicted_aligned_error_v6.png","plddt_mean":83.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RANBP1","jax_strain_url":"https://www.jax.org/strain/search?query=RANBP1"},"sequence":{"accession":"P43487","fasta_url":"https://rest.uniprot.org/uniprotkb/P43487.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P43487/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P43487"}},"corpus_meta":[{"pmid":"7882974","id":"PMC_7882974","title":"Co-activation of RanGTPase and inhibition of GTP dissociation by Ran-GTP binding protein RanBP1.","date":"1995","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/7882974","citation_count":342,"is_preprint":false},{"pmid":"9428644","id":"PMC_9428644","title":"RanBP1 is crucial for the release of RanGTP from importin beta-related nuclear transport factors.","date":"1997","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/9428644","citation_count":223,"is_preprint":false},{"pmid":"10330396","id":"PMC_10330396","title":"A role for RanBP1 in the release of CRM1 from the nuclear pore complex in a terminal step of nuclear export.","date":"1999","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/10330396","citation_count":181,"is_preprint":false},{"pmid":"8909533","id":"PMC_8909533","title":"RanBP1 stabilizes the interaction of Ran with p97 nuclear protein import.","date":"1996","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/8909533","citation_count":164,"is_preprint":false},{"pmid":"8794858","id":"PMC_8794858","title":"A nuclear export signal is essential for the cytosolic localization of the Ran binding protein, RanBP1.","date":"1996","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/8794858","citation_count":135,"is_preprint":false},{"pmid":"8995296","id":"PMC_8995296","title":"Ran-binding protein 1 (RanBP1) forms a ternary complex with Ran and karyopherin beta and reduces Ran GTPase-activating protein (RanGAP) inhibition by karyopherin beta.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8995296","citation_count":123,"is_preprint":false},{"pmid":"7782302","id":"PMC_7782302","title":"The C terminus of the nuclear RAN/TC4 GTPase stabilizes the GDP-bound state and mediates interactions with RCC1, RAN-GAP, and HTF9A/RANBP1.","date":"1995","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7782302","citation_count":109,"is_preprint":false},{"pmid":"9045717","id":"PMC_9045717","title":"Different binding domains for Ran-GTP and Ran-GDP/RanBP1 on nuclear import factor p97.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9045717","citation_count":82,"is_preprint":false},{"pmid":"9271386","id":"PMC_9271386","title":"Ran-binding protein 5 (RanBP5) is related to the nuclear transport factor importin-beta but interacts differently with RanBP1.","date":"1997","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/9271386","citation_count":75,"is_preprint":false},{"pmid":"12840069","id":"PMC_12840069","title":"Mammalian RanBP1 regulates centrosome cohesion during mitosis.","date":"2003","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/12840069","citation_count":73,"is_preprint":false},{"pmid":"10779340","id":"PMC_10779340","title":"Facilitated nucleocytoplasmic shuttling of the Ran binding protein RanBP1.","date":"2000","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/10779340","citation_count":70,"is_preprint":false},{"pmid":"9111043","id":"PMC_9111043","title":"Mutations in the nuclear export signal of human ran-binding protein RanBP1 block the Rev-mediated posttranscriptional regulation of human immunodeficiency virus type 1.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9111043","citation_count":56,"is_preprint":false},{"pmid":"23108393","id":"PMC_23108393","title":"Sgk1 enhances RANBP1 transcript levels and decreases taxol sensitivity in RKO colon carcinoma cells.","date":"2012","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/23108393","citation_count":54,"is_preprint":false},{"pmid":"9315840","id":"PMC_9315840","title":"Dynamic and equilibrium studies on the interaction of Ran with its effector, RanBP1.","date":"1997","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9315840","citation_count":54,"is_preprint":false},{"pmid":"17940066","id":"PMC_17940066","title":"RANBP1 localizes a subset of mitotic regulatory factors on spindle microtubules and regulates chromosome segregation in human cells.","date":"2007","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/17940066","citation_count":52,"is_preprint":false},{"pmid":"9224656","id":"PMC_9224656","title":"Expression of the murine RanBP1 and Htf9-c genes is regulated from a shared bidirectional promoter during cell cycle progression.","date":"1997","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/9224656","citation_count":49,"is_preprint":false},{"pmid":"25452572","id":"PMC_25452572","title":"Ranbp1, Deleted in DiGeorge/22q11.2 Deletion Syndrome, is a Microcephaly Gene That Selectively Disrupts Layer 2/3 Cortical Projection Neuron Generation.","date":"2014","source":"Cerebral cortex (New York, N.Y. : 1991)","url":"https://pubmed.ncbi.nlm.nih.gov/25452572","citation_count":46,"is_preprint":false},{"pmid":"9883880","id":"PMC_9883880","title":"EVH1/WH1 domains of VASP and WASP proteins belong to a large family including Ran-binding domains of the RanBP1 family.","date":"1998","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/9883880","citation_count":42,"is_preprint":false},{"pmid":"25458009","id":"PMC_25458009","title":"RanBP1 governs spindle assembly by defining mitotic Ran-GTP production.","date":"2014","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/25458009","citation_count":40,"is_preprint":false},{"pmid":"9348536","id":"PMC_9348536","title":"The balance of RanBP1 and RCC1 is critical for nuclear assembly and nuclear transport.","date":"1997","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/9348536","citation_count":36,"is_preprint":false},{"pmid":"10471274","id":"PMC_10471274","title":"Conformational states of the nuclear GTP-binding protein Ran and its complexes with the exchange factor RCC1 and the effector protein RanBP1.","date":"1999","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10471274","citation_count":36,"is_preprint":false},{"pmid":"12034733","id":"PMC_12034733","title":"Fluorescence resonance energy transfer biosensors that detect Ran conformational changes and a Ran x GDP-importin-beta -RanBP1 complex in vitro and in intact cells.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12034733","citation_count":35,"is_preprint":false},{"pmid":"7616957","id":"PMC_7616957","title":"RanBP1, a Ras-like nuclear G protein binding to Ran/TC4, inhibits RCC1 via Ran/TC4.","date":"1995","source":"Molecular & general genetics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/7616957","citation_count":34,"is_preprint":false},{"pmid":"9410874","id":"PMC_9410874","title":"Deregulated expression of the RanBP1 gene alters cell cycle progression in murine fibroblasts.","date":"1997","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/9410874","citation_count":34,"is_preprint":false},{"pmid":"19270727","id":"PMC_19270727","title":"RanBP1 downregulation sensitizes cancer cells to taxol in a caspase-3-dependent manner.","date":"2009","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/19270727","citation_count":32,"is_preprint":false},{"pmid":"7738003","id":"PMC_7738003","title":"The RCC1 protein interacts with Ran, RanBP1, hsc70, and a 340-kDa protein in Xenopus extracts.","date":"1995","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7738003","citation_count":31,"is_preprint":false},{"pmid":"28358001","id":"PMC_28358001","title":"SGK1 affects RAN/RANBP1/RANGAP1 via SP1 to play a critical role in pre-miRNA nuclear export: a new route of epigenomic regulation.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28358001","citation_count":30,"is_preprint":false},{"pmid":"10187822","id":"PMC_10187822","title":"Two E2F sites control growth-regulated and cell cycle-regulated transcription of the Htf9-a/RanBP1 gene through functionally distinct mechanisms.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10187822","citation_count":26,"is_preprint":false},{"pmid":"9770360","id":"PMC_9770360","title":"A RanBP1 mutation which does not visibly affect nuclear import may reveal additional functions of the ran GTPase system.","date":"1998","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/9770360","citation_count":25,"is_preprint":false},{"pmid":"10660567","id":"PMC_10660567","title":"Random mutagenesis and functional analysis of the Ran-binding protein, RanBP1.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10660567","citation_count":20,"is_preprint":false},{"pmid":"20658144","id":"PMC_20658144","title":"Nuclear reformation after mitosis requires downregulation of the Ran GTPase effector RanBP1 in mammalian cells.","date":"2010","source":"Chromosoma","url":"https://pubmed.ncbi.nlm.nih.gov/20658144","citation_count":20,"is_preprint":false},{"pmid":"11804793","id":"PMC_11804793","title":"RanBP1, a velocardiofacial/DiGeorge syndrome candidate gene, is expressed at sites of mesenchymal/epithelial induction.","date":"2002","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/11804793","citation_count":20,"is_preprint":false},{"pmid":"30184488","id":"PMC_30184488","title":"RanBP1 Couples Nuclear Export and Golgi Regulation through LKB1 to Promote Cortical Neuron Polarity.","date":"2018","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/30184488","citation_count":18,"is_preprint":false},{"pmid":"36672435","id":"PMC_36672435","title":"RANBP1 (RAN Binding Protein 1): The Missing Genetic Piece in Cancer Pathophysiology and Other Complex Diseases.","date":"2023","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/36672435","citation_count":17,"is_preprint":false},{"pmid":"34615998","id":"PMC_34615998","title":"RANBP1 promotes colorectal cancer progression by regulating pre-miRNA nuclear export via a positive feedback loop with YAP.","date":"2021","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/34615998","citation_count":17,"is_preprint":false},{"pmid":"32594833","id":"PMC_32594833","title":"RanBP1 controls the Ran pathway in mammalian cells through regulation of mitotic RCC1 dynamics.","date":"2020","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/32594833","citation_count":16,"is_preprint":false},{"pmid":"11424209","id":"PMC_11424209","title":"Ran binding protein RanBP1 in zebrafish embryonic development.","date":"2001","source":"Molecular reproduction and development","url":"https://pubmed.ncbi.nlm.nih.gov/11424209","citation_count":16,"is_preprint":false},{"pmid":"11124902","id":"PMC_11124902","title":"A role for the basic patch and the C terminus of RanGTP in regulating the dynamic interactions with importin beta, CRM1 and RanBP1.","date":"2001","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11124902","citation_count":16,"is_preprint":false},{"pmid":"16428860","id":"PMC_16428860","title":"Phosphorylation of RanGAP1 stabilizes its interaction with Ran and RanBP1.","date":"2005","source":"Cell structure and function","url":"https://pubmed.ncbi.nlm.nih.gov/16428860","citation_count":16,"is_preprint":false},{"pmid":"11686304","id":"PMC_11686304","title":"XMog1, a nuclear ran-binding protein in Xenopus, is a functional homologue of Schizosaccharomyces pombe mog1p that co-operates with RanBP1 to control generation of Ran-GTP.","date":"2001","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/11686304","citation_count":16,"is_preprint":false},{"pmid":"31021318","id":"PMC_31021318","title":"Distinct RanBP1 nuclear export and cargo dissociation mechanisms between fungi and animals.","date":"2019","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/31021318","citation_count":15,"is_preprint":false},{"pmid":"9417108","id":"PMC_9417108","title":"Interactions with single-stranded and double-stranded DNA-binding factors and alternative promoter conformation upon transcriptional activation of the Htf9-a/RanBP1 and Htf9-c genes.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9417108","citation_count":14,"is_preprint":false},{"pmid":"34974521","id":"PMC_34974521","title":"CD147 supports paclitaxel resistance via interacting with RanBP1.","date":"2022","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/34974521","citation_count":12,"is_preprint":false},{"pmid":"36206829","id":"PMC_36206829","title":"RanBP1 plays an essential role in directed migration of neural crest cells during development.","date":"2022","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/36206829","citation_count":10,"is_preprint":false},{"pmid":"37047826","id":"PMC_37047826","title":"RanBP1: A Potential Therapeutic Target for Cancer Stem Cells in Lung Cancer and Glioma.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37047826","citation_count":9,"is_preprint":false},{"pmid":"30906303","id":"PMC_30906303","title":"Nicotiana benthamiana RanBP1-1 Is Involved in the Induction of Disease Resistance via Regulation of Nuclear-Cytoplasmic Transport of Small GTPase Ran.","date":"2019","source":"Frontiers in plant science","url":"https://pubmed.ncbi.nlm.nih.gov/30906303","citation_count":9,"is_preprint":false},{"pmid":"10397757","id":"PMC_10397757","title":"Isolated mammalian and Schizosaccharomyces pombe ran-binding domains rescue S. pombe sbp1 (RanBP1) genomic mutants.","date":"1999","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/10397757","citation_count":8,"is_preprint":false},{"pmid":"37441077","id":"PMC_37441077","title":"RANBP1, a member of the nuclear-cytoplasmic trafficking-regulator complex, is the terminal-striking point of the SGK1-dependent Th17+ pathological differentiation.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37441077","citation_count":7,"is_preprint":false},{"pmid":"38011756","id":"PMC_38011756","title":"Oxidative stress and signaling through EGFR and PKA pathways converge on the nuclear transport factor RanBP1.","date":"2023","source":"European journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/38011756","citation_count":5,"is_preprint":false},{"pmid":"40018934","id":"PMC_40018934","title":"RANBP1 Regulates NOTCH3-Mediated Autophagy in High Glucose-Induced Vascular Smooth Muscle Cells.","date":"2025","source":"Frontiers in bioscience (Landmark edition)","url":"https://pubmed.ncbi.nlm.nih.gov/40018934","citation_count":4,"is_preprint":false},{"pmid":"36790128","id":"PMC_36790128","title":"Ranbp1 modulates morphogenesis of the craniofacial midline in mouse models of 22q11.2 deletion syndrome.","date":"2023","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36790128","citation_count":3,"is_preprint":false},{"pmid":"11447597","id":"PMC_11447597","title":"Molecular cloning of CaYRB1, the Candida albicans RanBP1/YRB1 homologue.","date":"2001","source":"Yeast (Chichester, England)","url":"https://pubmed.ncbi.nlm.nih.gov/11447597","citation_count":2,"is_preprint":false},{"pmid":"40839321","id":"PMC_40839321","title":"The role of RANBP1 in regulating MiRNA expression and apoptosis in breast cancer cells.","date":"2025","source":"Genes & genomics","url":"https://pubmed.ncbi.nlm.nih.gov/40839321","citation_count":1,"is_preprint":false},{"pmid":"39795905","id":"PMC_39795905","title":"Unveiling the Movement of RanBP1 During the Cell Cycle and Its Interaction with a Cyclin-Dependent Kinase (CDK) in Plants.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39795905","citation_count":1,"is_preprint":false},{"pmid":"41186818","id":"PMC_41186818","title":"RANBP1 promotes immune evasion in triple-negative breast cancer by suppressing T cell infiltration via the miR-769-5p/PRUNE2 axis.","date":"2025","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/41186818","citation_count":0,"is_preprint":false},{"pmid":"42206511","id":"PMC_42206511","title":"Serum- and Glucocorticoid-Regulated Kinase 1 Regulates Spindle Assembly Through RanBP1 During Oocyte Meiosis.","date":"2026","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/42206511","citation_count":0,"is_preprint":false},{"pmid":"39662555","id":"PMC_39662555","title":"Quantitative proteomic landscape of the pathophysiology of adhesive arachnoiditis and its clinical significance: Structure and mechanism of TNC and RANBP1 proteins.","date":"2024","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/39662555","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":28112,"output_tokens":8379,"usd":0.105011,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":18112,"output_tokens":5475,"usd":0.113717,"stage2_stop_reason":"end_turn"},"total_usd":0.218728,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"RanBP1 (23 kDa) binds tightly to Ran-GTP but not Ran-GDP, co-activates RanGAP1-induced GTP hydrolysis by ~10-fold, inhibits RCC1-stimulated nucleotide exchange on Ran, and forms a stable complex with nucleotide-free RCC1-Ran. It defines a new class of GTPase regulators distinct from GDIs.\",\n      \"method\": \"In vitro GTPase and nucleotide exchange assays with purified recombinant proteins; biochemical fractionation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple in vitro enzymatic assays with purified proteins, foundational study replicated by many subsequent labs\",\n      \"pmids\": [\"7882974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The acidic C-terminal -DEDDDL sequence of Ran is required for high-affinity interaction with RanBP1 (HTF9A); deletion of this domain reduces RanBP1 affinity to ~10 µM and converts RanBP1 from a RanGAP co-activator to a RanGAP inhibitor.\",\n      \"method\": \"In vitro binding assays, GTPase activity assays with C-terminal deletion mutants of Ran\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with defined mutants and multiple biochemical readouts, replicated in later structural studies\",\n      \"pmids\": [\"7782302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"RanBP1 binds RCC1 only in the presence of Ran (forming a trimeric complex) and inhibits RCC1-stimulated guanine nucleotide release from Ran in vitro. Overexpression of RanBP1 is detrimental in RCC1-deficient cells, establishing it as a negative regulator of RCC1.\",\n      \"method\": \"Two-hybrid interaction screen, in vitro GST pulldown, in vitro nucleotide exchange assay, yeast genetics (rcc1 mutant complementation/suppression)\",\n      \"journal\": \"Molecular & general genetics : MGG\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro enzymatic assay plus yeast genetic epistasis, replicated by independent labs\",\n      \"pmids\": [\"7616957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"RanBP1 forms a trimeric complex with p97 (importin-β) and Ran, stabilizes the interaction of Ran-GDP with p97, promotes nuclear import by stabilizing receptor docking at the pore, and stimulates translocation in a permeabilized cell import assay.\",\n      \"method\": \"Immunoadsorption from HeLa cell extracts, gel filtration, recombinant protein reconstitution, permeabilized cell import assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reconstituted trimeric complex, functional import assay, multiple orthogonal methods\",\n      \"pmids\": [\"8909533\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"RanBP1 contains a leucine-rich nuclear export signal (NES) C-terminal to its Ran-binding domain that is necessary for its cytoplasmic localization; the isolated RBD lacking the NES accumulates in the nucleus. The cytoplasmic localization of RanBP1 is important for nuclear protein import.\",\n      \"method\": \"Subcellular fractionation, transfection of deletion/domain-swap constructs, permeabilized cell assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization experiments with functional consequence, replicated by subsequent studies\",\n      \"pmids\": [\"8794858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"RanBP1 forms a ternary complex with Ran-GTP and karyopherin beta (importin-β) and partially relieves the complete inhibition of RanGAP activity imposed by karyopherin beta, acting through competitive and non-competitive kinetic mechanisms at distinct sites on Ran.\",\n      \"method\": \"Solution binding assays, kinetic analysis of RanGAP activity in the presence of purified components\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with kinetic dissection; single lab but multiple orthogonal biochemical readouts\",\n      \"pmids\": [\"8995296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"RanBP1 acts as a key disassembly intermediate for importin-β-related transport receptor–RanGTP complexes: RanBP1 stimulates the off-rate of RanGTP from the receptor by >100-fold, transiently releasing RanGTP·RanBP1 which is then driven by RanGAP to hydrolyze GTP. Release of importin-β additionally requires importin-α.\",\n      \"method\": \"In vitro binding and dissociation kinetics with purified transport receptors, RanGTP, and RanBP1; functional nuclear transport assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — kinetic reconstitution with multiple transport receptors, replicated conceptually across multiple labs\",\n      \"pmids\": [\"9428644\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"RanBP1 NES mutations that abolish cytoplasmic localization block Rev-mediated HIV-1 nuclear export, demonstrating that RanBP1 competes with or shares the CRM1-dependent nuclear export pathway used by Rev. This inhibitory effect is independent of RanBP1's ability to bind Ran.\",\n      \"method\": \"Mutational analysis of NES; reporter assays for Rev-mediated and CTE-mediated HIV-1 expression in transfected cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional cell-based assay with defined mutants; single lab\",\n      \"pmids\": [\"9111043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"RanBP1 binds Ran-GTP with nanomolar affinity and Ran-GDP with ~10 µM affinity; the difference is primarily due to a dramatically faster dissociation rate constant for the GDP-bound form. The C-terminal five residues of Ran are required for high-affinity RanBP1 binding to the GTP form.\",\n      \"method\": \"Fluorescence spectroscopy with nucleotide analogues, surface plasmon resonance (BIAcore), circular dichroism\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — two independent biophysical methods (fluorescence + SPR) in a single rigorous study\",\n      \"pmids\": [\"9315840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"RanBP5, identified through a two-hybrid screen using RanBP1 as bait, binds RanBP1 as part of a trimeric RanBP1–Ran–RanBP5 complex; RanBP1 can relieve GAP-resistance of the RanBP5–RanGTP complex.\",\n      \"method\": \"Yeast two-hybrid, overlay assay, in vitro GAP assay with purified components\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two-hybrid plus in vitro biochemical confirmation; single lab\",\n      \"pmids\": [\"9271386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Two distinct but overlapping binding domains for Ran-GTP and Ran-GDP/RanBP1 exist on p97 (importin-β); Cys-158 of p97 is required for Ran-GDP/RanBP1 binding but not Ran-GTP binding, and a Cys158Ala mutant p97 cannot support nuclear import.\",\n      \"method\": \"Site-directed mutagenesis and deletion analysis of p97; permeabilized cell import assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis with functional import readout; single lab with rigorous controls\",\n      \"pmids\": [\"9045717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The balance between RanBP1 and RCC1 is critical: restoring only one of these two proteins to co-depleted Xenopus egg extracts causes abnormal nuclear assembly and inhibits transport and DNA replication, rescued by addition of the other protein. The GTP/GDP-Ran balance is the essential functional parameter.\",\n      \"method\": \"Immunodepletion from Xenopus egg extracts, recombinant protein add-back, nuclear assembly and import assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — immunodepletion/reconstitution in Xenopus extracts with multiple functional readouts\",\n      \"pmids\": [\"9348536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Both mRNA species from the bidirectional Htf9-a/RanBP1 and Htf9-c promoter peak in S phase; cell cycle-dependent transcription is controlled at the transcriptional level by an S-phase-activated bidirectional promoter containing E2F and Sp1 recognition sites.\",\n      \"method\": \"Northern blotting of cell cycle fractions, transient reporter assays with promoter deletion constructs\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter dissection with reporter assays; single lab\",\n      \"pmids\": [\"9224656\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Deregulated (forced) expression of RanBP1 in murine fibroblasts disrupts cell cycle progression: it inhibits DNA replication, causes defective mitotic exit, and impairs chromatin decondensation at telophase-to-interphase transition.\",\n      \"method\": \"Stable transfection, BrdU incorporation, FACS analysis, microscopy\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression with multiple defined cellular phenotypes; single lab\",\n      \"pmids\": [\"9410874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The RanBP1 Ran-binding domain (RBD) belongs structurally to the EVH1/WH1 domain superfamily shared by VASP, WASP, and Homer proteins.\",\n      \"method\": \"Computational sequence/structural analysis (domain recognition)\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational prediction only, no experimental validation described in the abstract\",\n      \"pmids\": [\"9883880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The distal E2F-b site plus a neighboring Sp1 element actively drive RanBP1 transcriptional upregulation in S phase, while the proximal E2F-c site mediates repression upon growth arrest; each site interacts with distinct E2F family members.\",\n      \"method\": \"Site-directed mutagenesis of promoter E2F sites, transient reporter assays, protein-binding assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis combined with binding and reporter assays; single lab\",\n      \"pmids\": [\"10187822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"RanBP1 restores nuclear export of NFAT after RanQ69L-induced accumulation of CRM1 at the cytoplasmic face of the NPC, and both RanBP1 and the Ran-binding domains of RanBP2 promote release of CRM1 from the NPC. RanGTP is required for targeting export complexes to the cytoplasmic face of the NPC.\",\n      \"method\": \"Permeabilized cell export reconstitution assay, biochemical fractionation, in vitro reconstitution of CRM1-nucleoporin interactions\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reconstitution assay plus biochemical fractionation, multiple orthogonal approaches, replicated conceptually\",\n      \"pmids\": [\"10330396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"RanGTP bound to RanBP1 adopts a specific conformational state (state 2) distinct from free Ran-GTP; the RCC1–Ran–nucleotide ternary complex intermediate is detectable by 31P NMR, providing structural evidence for the exchange mechanism.\",\n      \"method\": \"31P NMR spectroscopy of purified Ran complexes; conformational analysis\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structural analysis with multiple complexes; single lab\",\n      \"pmids\": [\"10471274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Isolated RBD from mammalian RanBP1 or S. pombe sbp1p is sufficient to rescue growth of sbp1-null fission yeast, and the RBD localizes to the nucleus rather than cytoplasm, indicating that cytoplasmic confinement is not required for essential RanBP1 function in yeast.\",\n      \"method\": \"Genetic complementation of sbp1 null yeast, subcellular localization of exogenous constructs\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic rescue in yeast plus localization; single lab\",\n      \"pmids\": [\"10397757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"RanBP1 shuttles actively through the nuclear pore: it accumulates in nuclei upon leptomycin B treatment (CRM1 inhibition), its import requires nuclear Ran-GTP (but not classical importin pathway), and an E37K mutation abolishes nuclear accumulation despite preserving ternary complex formation with Ran and importin-β.\",\n      \"method\": \"Leptomycin B treatment, cytoplasmic microinjection, permeabilized cell accumulation assay, nuclear import with exogenous karyopherins and RCC1\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (drug inhibition, microinjection, permeabilized cells, mutant analysis) in a single comprehensive study\",\n      \"pmids\": [\"10779340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The essential biological activity of RanBP1 in yeast correlates specifically with its capacity to potentiate RanGAP activity toward Ran-GTP within karyopherin complexes, not with Ran-GTP binding per se or ternary complex formation. Mutants crippled for RanGAP co-activation cannot rescue growth even if they form ternary complexes.\",\n      \"method\": \"Random mutagenesis, in vitro biochemical assays (Ran binding, RanGAP stimulation, ternary complex formation), complementation of temperature-sensitive yrb1 yeast\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — systematic mutagenesis correlated across multiple in vitro assays and in vivo genetic readout\",\n      \"pmids\": [\"10660567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Importin-β binding to Ran-GTP disrupts an intramolecular interaction between the basic patch (HRKK142) and the C-terminal DEDDDL motif of Ran, exposing the C-terminus and stimulating RanBP1 binding. Mutating the basic patch increases RanBP1 affinity and enables importin-β release without importin-α. CRM1 binding requires the basic patch but uses different Ran determinants than importin-β.\",\n      \"method\": \"Limited proteolysis protection assays, solution binding measurements with Ran mutants, in vitro dissociation assays\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — proteolytic protection plus functional binding assays; mechanistically detailed single study\",\n      \"pmids\": [\"11124902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"XMog1 (Xenopus Mog1) co-operates with RanBP1 to promote selective GTP loading onto Ran from GDP, and to facilitate RCC1-catalyzed generation of Ran-GTP in the nucleus; alone, neither protein is sufficient for this activity.\",\n      \"method\": \"Two-hybrid screening, in vitro nucleotide exchange and GTPase assays with purified components, yeast genetic rescue\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro reconstitution plus genetic rescue; single lab\",\n      \"pmids\": [\"11686304\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"FRET measurements show that binding of RanGTP to importin-β, RanBP1, or CRM1 all extend the C-terminal tail of Ran (reduced FRET between N-terminal GFP and C-terminal Alexa546). A Ran-GDP·RanBP1·importin-β ternary complex with extended tail is detected both in vitro and in intact cells via cytoplasmic FRET.\",\n      \"method\": \"FRET using Ran-GFP labeled with Alexa546; co-injection into living cells; in vitro reconstitution\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — FRET in vitro and in living cells; multiple complexes tested; single lab\",\n      \"pmids\": [\"12034733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"RanBP1 overexpression specifically in mitosis induces splitting of mother and daughter centrioles at spindle poles, generating multipolar spindles; this requires microtubule integrity and Eg5 activity. A fraction of RanBP1 localizes at the centrosome during mitosis.\",\n      \"method\": \"Overexpression in mammalian cells, microscopy (centrosome and spindle staining), drug treatments (nocodazole, monastrol)\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization plus functional epistasis with Eg5 inhibitor; single lab\",\n      \"pmids\": [\"12840069\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"RanGAP1 is phosphorylated in vivo at Ser-358 by casein kinase II (CK2); this phosphorylation does not alter GAP catalytic activity but stabilizes formation of the ternary RanGAP1·Ran·RanBP1 complex in vivo.\",\n      \"method\": \"MALDI-TOF-MS phosphosite identification, site-directed mutagenesis at S358, in vitro kinase assay with CK2, co-immunoprecipitation of ternary complex\",\n      \"journal\": \"Cell structure and function\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS + mutagenesis + kinase assay + co-IP; single lab\",\n      \"pmids\": [\"16428860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"RANBP1 depletion in human cells causes prolonged prometaphase, hyperstable spindle microtubules, failure to recruit cyclin B1 to spindles, mislocalization of HURP (DLG7) away from plus-ends, and frequent lagging chromosomes in anaphase, indicating roles in microtubule dynamics regulation and prevention of merotelic attachments.\",\n      \"method\": \"siRNA knockdown in human cells, immunofluorescence microscopy, spindle stability assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — siRNA knockdown with multiple defined molecular and phenotypic readouts, replicated across cell lines\",\n      \"pmids\": [\"17940066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RanBP1 downregulation by RNAi activates caspase-3-dependent apoptosis in multiple transformed cell lines and increases their apoptotic response to taxol; this effect is absent in caspase-3-deficient MCF-7 cells, placing RanBP1 upstream of caspase-3 in the apoptotic pathway.\",\n      \"method\": \"siRNA knockdown, flow cytometry for apoptosis, taxol treatment, caspase-3 activity/deficiency comparison across cell lines\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA with multiple cell lines and caspase-3 epistasis; single lab\",\n      \"pmids\": [\"19270727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RanBP1 protein abundance peaks in mitosis and must decline in mid-to-late telophase for nuclear reformation. Mild RanBP1 overexpression persisting into late mitosis blocks chromatin decondensation, nuclear expansion, nuclear lamina reorganization, and NPC reassembly, with associated failure of importin-β-dependent NLS cargo reimport. Co-expression of importin-β mitigates these defects.\",\n      \"method\": \"Stable transfection with inducible overexpression, immunofluorescence, quantitative microscopy across cell cycle stages, importin-β co-expression rescue\",\n      \"journal\": \"Chromosoma\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — overexpression with temporal dissection and importin-β epistasis rescue; multiple orthogonal phenotypic readouts\",\n      \"pmids\": [\"20658144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"RanBP1 controls RCC1 enzymatic activity and partitioning between chromatin-bound and soluble pools in M-phase Xenopus egg extracts by forming a heterotrimeric RCC1/Ran/RanBP1 complex. This mechanism governs the spatial Ran-GTP gradient that guides spindle assembly. Additionally, phosphorylation of RanBP1 drives changes in chromatin-bound RCC1 dynamics at the metaphase-anaphase transition.\",\n      \"method\": \"Xenopus egg extract biochemistry, chromatin fractionation, in vitro exchange assays, immunodepletion/reconstitution, phosphorylation analysis\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reconstitution in Xenopus extracts with multiple functional and biochemical assays; detailed mechanistic dissection\",\n      \"pmids\": [\"25458009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Loss of Ranbp1 in mice selectively disrupts M phase of the cell cycle in cortical progenitors (both apical at E10.5 and basal at E14.5), resulting in microcephaly and specific reduction of layer 2/3 cortical projection neurons; Ranbp1-/- mice are not recovered live at birth and >60% are exencephalic.\",\n      \"method\": \"Targeted mouse knockout, BrdU/Ki67 proliferation assays, M-phase immunostaining (phospho-H3), cortical layer marker analysis\",\n      \"journal\": \"Cerebral cortex\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mouse with multiple defined phenotypic readouts across developmental stages; single lab\",\n      \"pmids\": [\"25452572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RanBP1 regulates cortical neuron axon specification by controlling the cytoplasmic levels of the polarity kinase LKB1/Par4 through the nuclear export machinery; downstream of RanBP1, LKB1 acts via the STK25-GM130 pathway to regulate Golgi organization and promote axonogenesis.\",\n      \"method\": \"shRNA knockdown in cultured cortical neurons and in vivo, LKB1 localization assay, Golgi morphology analysis, epistasis with STK25 and GM130\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi with epistasis experiments identifying LKB1-STK25-GM130 pathway; single lab\",\n      \"pmids\": [\"30184488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In animal cells (in contrast to fungi), RanBP1 dissociates nuclear export complexes by sequestering RanGTP away from the CRM1 export receptor, rather than via RanBP1-CRM1-RanGTP sequestration as in fungi. Animal RanBP1 forms a 1:1:2 (RanBP1:CRM1:RanGTP) nuclear export complex, whereas fungal RanBP1 forms a 1:1:1 complex; this mechanistic divergence is due to loss of affinity between animal RanBP1-RanGTP and CRM1, caused by non-conservation of key residues.\",\n      \"method\": \"In vitro reconstitution of export complexes, stoichiometry determination, mutational analysis of interface residues, biochemical binding assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with mutational analysis; detailed mechanistic dissection; single lab\",\n      \"pmids\": [\"31021318\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"RanBP1 controls mitotic RCC1 dynamics in human somatic cells: RanBP1 degradation (auxin-inducible degron) alters metaphase chromatin-bound RCC1 exchange rates (FRAP/FLIP) and causes re-localization of the spindle assembly factor HURP, consistent with altered Ran-GTP gradients.\",\n      \"method\": \"Auxin-inducible degron (AID) depletion, FRAP and FLIP of RCC1-GFP, HURP immunolocalization in metaphase cells\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — acute conditional depletion (AID) plus live-cell FRAP/FLIP; extends Xenopus findings to human somatic cells\",\n      \"pmids\": [\"32594833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CD147 interacts with RanBP1 via its intracellular domain (CD147ICD) binding to the C-terminal tail of RanBP1; this interaction mediates CD147-regulated microtubule stability/dynamics and paclitaxel sensitivity in cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, FRET, surface plasmon resonance (SPR), FRAP of microtubule dynamics, truncation analysis, xenograft models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — SPR + FRET + Co-IP for interaction, FRAP for functional consequence; multiple orthogonal methods; single lab\",\n      \"pmids\": [\"34974521\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"RanBP1 is required for directional chemotaxis and front-to-rear polarity of migrating neural crest cells during development; this function involves LKB1/PAR4 regulated export downstream of Ran/RanBP1.\",\n      \"method\": \"Morpholino/RNAi knockdown in Xenopus neural crest cells, live cell chemotaxis assays, epistasis with LKB1\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with directional migration readout and LKB1 epistasis; single lab\",\n      \"pmids\": [\"36206829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Oxidative stress concentrates RanBP1 in the nucleus through EGFR and PKA signaling pathways; pharmacological inhibition of EGFR or PKA reduces this relocalization, and mutational analysis identifies Ser-60 and Tyr-103 as critical residues for oxidant-induced nuclear accumulation.\",\n      \"method\": \"Subcellular fractionation, pharmacological inhibitors (EGFR/PKA), site-directed mutagenesis (S60A, Y103F), fluorescence microscopy\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological epistasis + mutagenesis; single lab, multiple methods\",\n      \"pmids\": [\"38011756\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RanBP1 is a conserved cytoplasmic Ran-GTP-binding protein that orchestrates the Ran GTPase cycle: it co-activates RanGAP1-mediated GTP hydrolysis (~10-fold), inhibits RCC1-catalyzed nucleotide exchange on Ran, forms transient trimeric complexes with importin-β/karyopherins and Ran-GTP to drive disassembly of nuclear import and export complexes, promotes release of CRM1 from the cytoplasmic face of the NPC, and—in mitosis—controls the spatial Ran-GTP gradient by regulating RCC1 chromatin dynamics (via a RCC1/Ran/RanBP1 heterotrimer and RanBP1 phosphorylation at the metaphase-anaphase transition), thereby governing spindle assembly, centrosome cohesion, microtubule stability, chromosome segregation, and nuclear reformation after mitosis; in neurons it additionally regulates LKB1 nuclear export to control axon specification and directed migration.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RanBP1 is a conserved cytoplasmic Ran-GTP-binding protein that defines a distinct class of Ran GTPase regulators governing the directionality of the Ran nucleotide cycle and, through it, nucleocytoplasmic transport and mitotic spindle assembly [#0]. It binds Ran-GTP with nanomolar affinity through a Ran-binding domain that recognizes the acidic C-terminal -DEDDDL tail of Ran, co-activates RanGAP1-mediated GTP hydrolysis ~10-fold, and inhibits RCC1-catalyzed nucleotide exchange, forming a stable RCC1/Ran/RanBP1 ternary complex [#0, #1, #2, #8]. Mechanistically RanBP1 acts as a disassembly factor: it forms transient trimeric complexes with importin-\\u03b2-family receptors and Ran-GTP, accelerating release of Ran-GTP from transport receptors by >100-fold to be handed to RanGAP for hydrolysis, and in animal cells it dismantles CRM1 export complexes by sequestering Ran-GTP away from CRM1 and promoting CRM1 release from the cytoplasmic face of the nuclear pore [#6, #16, #32]. A leucine-rich NES confines RanBP1 to the cytoplasm where it supports nuclear import, and the protein shuttles through the pore via a Ran-GTP-dependent, importin-independent route [#4, #19]. In mitosis RanBP1 controls the spatial Ran-GTP gradient by regulating the activity and chromatin partitioning of RCC1 through the RCC1/Ran/RanBP1 heterotrimer and through phosphorylation at the metaphase-anaphase transition, thereby governing spindle microtubule dynamics, centrosome cohesion, chromosome segregation, and nuclear reformation after mitosis [#26, #28, #29, #33, #24]. RanBP1 abundance is cell-cycle regulated by an S-phase-activated E2F/Sp1 bidirectional promoter, and its level must decline in late mitosis to permit nuclear envelope and NPC reassembly [#12, #15, #28]. In the developing nervous system RanBP1 is required for M-phase progression of cortical progenitors and for axon specification and directed migration via nuclear-export control of the polarity kinase LKB1 acting through the STK25-GM130 pathway [#30, #31, #35].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established the foundational biochemical identity of RanBP1 as a novel Ran regulator that both potentiates RanGAP and antagonizes RCC1, resolving how Ran's GTP/GDP state is biased.\",\n      \"evidence\": \"In vitro GTPase and nucleotide exchange assays with purified recombinant proteins; two-hybrid and yeast genetics for RCC1 interaction\",\n      \"pmids\": [\"7882974\", \"7616957\", \"7782302\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how these opposing activities are coordinated in cells\", \"Structural basis of the Ran C-terminal tail recognition not yet defined\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Showed RanBP1 is not merely a GAP cofactor but a transport-cycle component that forms trimeric complexes with importin-\\u03b2 and Ran and is held cytoplasmic by an NES, linking its biochemistry to nuclear import.\",\n      \"evidence\": \"Immunoadsorption, gel filtration, recombinant reconstitution, permeabilized cell import assays, and NES deletion/domain-swap localization\",\n      \"pmids\": [\"8909533\", \"8794858\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether trimer formation drives complex assembly or disassembly was not yet distinguished\", \"Kinetics of receptor release not quantified\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Defined RanBP1's core mechanistic role as a disassembly catalyst that strips Ran-GTP from transport receptors and as a thermodynamic switch tuned by Ran's C-terminus.\",\n      \"evidence\": \"Kinetic dissociation assays with multiple transport receptors, fluorescence/SPR affinity measurements, and ternary-complex reconstitutions including RanBP5 and karyopherin-\\u03b2\",\n      \"pmids\": [\"9428644\", \"8995296\", \"9315840\", \"9271386\", \"9045717\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo confirmation of >100-fold off-rate enhancement was indirect\", \"How disassembly is spatially restricted to the cytoplasmic NPC face unaddressed\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Connected RanBP1 dosage to cell-cycle physiology, showing its balance with RCC1 and its S-phase-regulated expression are essential for proper nuclear assembly, replication, and mitotic exit.\",\n      \"evidence\": \"Xenopus egg extract immunodepletion/add-back, promoter dissection with reporter assays, and overexpression phenotyping in fibroblasts\",\n      \"pmids\": [\"9348536\", \"9224656\", \"9410874\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular cause of mitotic-exit defects upon overexpression not yet mechanistic\", \"Promoter studies did not link expression timing to functional demand\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Extended RanBP1's reach to CRM1-dependent export by showing its NES-dependent cytoplasmic localization intersects the Rev/CRM1 export pathway.\",\n      \"evidence\": \"NES mutational analysis and Rev/CTE reporter assays in transfected cells\",\n      \"pmids\": [\"9111043\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, cell-based assay only\", \"Direct biochemical competition with CRM1 not yet demonstrated\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Provided structural and reconstitution evidence that RanBP1 promotes CRM1 release from the NPC and induces a defined Ran conformational state, mechanizing its export-terminating role.\",\n      \"evidence\": \"Permeabilized cell export reconstitution, biochemical fractionation of CRM1-nucleoporin complexes, and 31P NMR of Ran complexes\",\n      \"pmids\": [\"10330396\", \"10471274\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry of the RanBP1-CRM1-RanGTP species not yet determined\", \"NMR state assignment from a single lab\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Resolved which RanBP1 activity is essential and showed RanBP1 itself shuttles through the pore, separating Ran binding from the catalytically essential GAP-co-activation function.\",\n      \"evidence\": \"Random mutagenesis correlated across binding/GAP/ternary assays with yeast complementation, plus leptomycin B, microinjection, and permeabilized-cell shuttling assays\",\n      \"pmids\": [\"10660567\", \"10779340\", \"10397757\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why RanBP1 needs to enter the nucleus mechanistically unclear\", \"Discrepancy with yeast (cytoplasmic confinement dispensable) not reconciled\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Clarified the allosteric logic of RanBP1 recruitment, showing importin-\\u03b2 binding exposes Ran's C-terminus to stimulate RanBP1 association and that CRM1 uses distinct Ran determinants.\",\n      \"evidence\": \"Limited proteolysis protection, solution binding with Ran basic-patch and tail mutants, and FRET tail-extension measurements in vitro and in living cells\",\n      \"pmids\": [\"11124902\", \"12034733\", \"11686304\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo physiological relevance of XMog1 cooperation in mammals untested\", \"Quantitative contribution of each Ran determinant to in vivo flux unmeasured\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Established RanBP1's mitotic spindle function, linking its loss to hyperstable microtubules, spindle-factor mislocalization, and chromosome mis-segregation.\",\n      \"evidence\": \"siRNA knockdown with immunofluorescence and spindle stability assays in human cells; centrosome overexpression phenotyping with Eg5 inhibitor epistasis\",\n      \"pmids\": [\"17940066\", \"12840069\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether spindle defects derive solely from Ran-GTP gradient disruption not isolated\", \"Direct centrosome targets of RanBP1 unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated that timely decline of RanBP1 in late mitosis is required for nuclear envelope and NPC reassembly via restoration of importin-\\u03b2 cargo import.\",\n      \"evidence\": \"Inducible overexpression with temporal microscopy across cell-cycle stages and importin-\\u03b2 co-expression rescue\",\n      \"pmids\": [\"20658144\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism degrading RanBP1 at telophase not identified\", \"Direct importin-\\u03b2 cargo set affected not enumerated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mechanized RanBP1's mitotic role as control of RCC1 chromatin dynamics and the spatial Ran-GTP gradient, and showed organismal requirement in cortical neurogenesis.\",\n      \"evidence\": \"Xenopus extract heterotrimer reconstitution, chromatin fractionation and phosphorylation analysis; targeted mouse knockout with M-phase and cortical-layer readouts\",\n      \"pmids\": [\"25458009\", \"25452572\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinase responsible for metaphase-anaphase RanBP1 phosphorylation not identified\", \"Link between gradient control and specific spindle assembly factors incomplete\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Revealed an animal-specific export-disassembly mechanism in which RanBP1 sequesters Ran-GTP from CRM1 rather than co-binding CRM1 as in fungi, redefining cross-species mechanistic models.\",\n      \"evidence\": \"In vitro reconstitution with stoichiometry determination and mutational analysis of interface residues\",\n      \"pmids\": [\"31021318\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo consequence of the 1:1:2 complex in animal cells not tested\", \"Whether divergence affects export cargo selectivity unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Confirmed in human somatic cells via acute depletion that RanBP1 directly governs mitotic RCC1 exchange dynamics and downstream spindle-factor localization.\",\n      \"evidence\": \"Auxin-inducible degron depletion with FRAP/FLIP of RCC1-GFP and HURP immunolocalization\",\n      \"pmids\": [\"32594833\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative Ran-GTP gradient changes inferred, not directly imaged\", \"Phosphoregulation in human cells not yet dissected\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified new physical partners and disease-relevant functions, linking RanBP1 to CD147-regulated microtubule dynamics and to caspase-3-dependent apoptosis and chemosensitivity.\",\n      \"evidence\": \"Co-IP, FRET, SPR, FRAP and xenografts for CD147; siRNA with caspase-3 epistasis and taxol response across cell lines\",\n      \"pmids\": [\"34974521\", \"19270727\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How CD147 binding to the RanBP1 C-terminus alters Ran-cycle activity unresolved\", \"Molecular link from RanBP1 loss to caspase-3 activation undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed RanBP1 localization is signal-regulated, with oxidative stress driving nuclear accumulation through EGFR/PKA signaling and specific phosphosites.\",\n      \"evidence\": \"Subcellular fractionation, EGFR/PKA pharmacological inhibition, and S60A/Y103F mutational analysis with microscopy\",\n      \"pmids\": [\"38011756\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of stress-induced nuclear RanBP1 not determined\", \"Direct kinase acting on S60/Y103 not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RanBP1's distinct activities\\u2014transport-complex disassembly, mitotic RCC1/Ran-GTP gradient control, and neuronal LKB1 export\\u2014are differentially deployed and post-translationally switched in space and time remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The mitotic kinase and degradation machinery acting on RanBP1 are unidentified\", \"Whether a single biochemical activity underlies all phenotypes or separable functions exist is unclear\", \"No high-resolution structure of the animal RanBP1-CRM1-RanGTP export complex\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 2, 6, 20]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [6, 16, 32]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 6, 16]},\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [0, 5, 20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 19, 23]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [19, 36, 18]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [24]},\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [16, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [3, 6, 16, 32]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [26, 28, 29, 33]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [30, 31, 35]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [27]}\n    ],\n    \"complexes\": [\n      \"RCC1/Ran/RanBP1 heterotrimer\",\n      \"RanBP1/Ran-GTP/importin-\\u03b2 ternary complex\",\n      \"RanBP1/CRM1/Ran-GTP export complex\",\n      \"RanGAP1/Ran/RanBP1 ternary complex\"\n    ],\n    \"partners\": [\n      \"RAN\",\n      \"RCC1\",\n      \"RANGAP1\",\n      \"importin-\\u03b2 (KPNB1)\",\n      \"CRM1 (XPO1)\",\n      \"RanBP5 (IPO5)\",\n      \"LKB1 (STK11)\",\n      \"BSG (CD147)\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}