{"gene":"RANBP10","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2004,"finding":"RanBP10 interacts with the tyrosine kinase domain of MET via its SPRY domain, competing with RanBPM/RanBP9 for MET binding. Unlike RanBPM/RanBP9, RanBP10 fails to interact with Sos and cannot activate the Ras/Erk pathway; co-transfection of RanBP10 with RanBPM/RanBP9 represses RanBPM-induced SRE-luciferase reporter activity.","method":"Co-immunoprecipitation, binding competition assays, SRE-luciferase reporter gene assay, overexpression in cell lines","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assays and functional reporter assays in single lab with two orthogonal methods","pmids":["14684163"],"is_preprint":false},{"year":2005,"finding":"Drosophila homolog of RanBP10 acts as a negative regulator of JAK/STAT signaling by controlling nucleocytoplasmic transport of STAT92E, identified in a genome-wide RNAi screen.","method":"Genome-wide dsRNA-mediated RNAi screen in cultured Drosophila cells, STAT92E phosphorylation assay","journal":"Genes & development","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional RNAi screen with defined cellular readout but single method and identified in a large-scale screen rather than focused mechanistic study","pmids":["16055650"],"is_preprint":false},{"year":2008,"finding":"RanBP10 is a cytoplasmic guanine nucleotide exchange factor (GEF) for Ran; it binds beta-tubulin and associates with megakaryocyte microtubules. A point mutation in the candidate GEF domain abolishes exchange activity. RNAi-mediated loss of RanBP10 in cultured megakaryocytes disrupts microtubule organization.","method":"In vitro GEF activity assay, point mutagenesis of GEF domain, beta-tubulin co-immunoprecipitation, RNAi knockdown with microtubule organization readout","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro GEF assay with mutagenesis plus binding assay and functional RNAi in a single focused study with multiple orthogonal methods","pmids":["18347012"],"is_preprint":false},{"year":2008,"finding":"RanBP10 acts as a coactivator of the androgen receptor (AR): it enhances ligand-dependent AR transcriptional activity, forms a complex with AR, and shows additive effects with RanBPM on AR transactivation. RanBP10 also enhances glucocorticoid receptor but not estrogen receptor alpha transcriptional activity. RanBP10 forms homo-oligomers and hetero-oligomers with RanBPM and co-localizes with RanBPM in cytoplasm and nucleus.","method":"Luciferase reporter transcriptional assay, co-immunoprecipitation, co-localization by fluorescence microscopy","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus functional reporter assay with nuclear receptor specificity controls, single lab","pmids":["18222118"],"is_preprint":false},{"year":2009,"finding":"RanBP10-deficient mice (gene-trap) show altered platelet shape (increased geometric axis ratio), disorders in microtubule filament numbers and localization in platelets, markedly prolonged bleeding time, and reduced platelet granule release (reduced CD62P and CD63 surface expression after PAR4 stimulation), establishing that RanBP10 is required for platelet discoid shape and degranulation in vivo.","method":"Gene-trap mouse knockout, ultrastructural analysis, flow cytometry, bleeding time assay, proplatelet formation assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout with multiple orthogonal phenotypic readouts (ultrastructure, flow cytometry, bleeding time) in a focused study","pmids":["19801445"],"is_preprint":false},{"year":2010,"finding":"RanBP10 interacts with PKCgamma and PKCdelta (identified by co-immunoprecipitation coupled to mass spectrometry) and with the D1 dopamine receptor. Overexpression of RanBP10 enhances basal D1 receptor phosphorylation and attenuates D1 receptor-stimulated cAMP accumulation; PKC inhibitors block the RanBP10-dependent increase in receptor phosphorylation.","method":"Co-immunoprecipitation coupled to mass spectrometry, co-localization by immunofluorescence, cAMP accumulation assay, receptor phosphorylation assay, PKC inhibitor treatment","journal":"Molecular pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-confirmed Co-IP plus functional signaling assays with pharmacological controls, single lab","pmids":["20395553"],"is_preprint":false},{"year":2010,"finding":"YPEL5 protein binds RanBP10 (and RanBPM) as identified by yeast two-hybrid, defining RanBP10 as part of a conserved Scorpin protein family alongside RanBPM.","method":"Yeast two-hybrid, comparative genomic analysis","journal":"Genomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single yeast two-hybrid without in-cell validation of RANBP10 interaction specifically","pmids":["20580816"],"is_preprint":false},{"year":2012,"finding":"RanBP10-null platelets show normal adhesion on collagen and von Willebrand factor under flow but impaired stable thrombus formation in vivo (ferric chloride model). Loss of RanBP10 leads to increased β1-tubulin protein driving α-monomers into polymerized microtubules; agonists fail to contract the peripheral marginal band or centralize granules in null platelets. Taxol-induced microtubule stabilization in wild-type platelets phenocopies the attenuated shape change, supporting RanBP10's role in inhibiting premature β1-tubulin polymerization.","method":"RanBP10-null mouse model, ferric chloride arterial thrombosis model, flow adhesion assay, aggregometry, Western blot for β1-tubulin, taxol pharmacological phenocopy","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout replicated across multiple orthogonal assays with pharmacological phenocopy, consistent with prior Blood 2009 study","pmids":["22936655"],"is_preprint":false},{"year":2016,"finding":"Crystal structures of the IUS-SPRY domain of RanBP10 (and RanBPM) were determined, revealing a β-sandwich fold with conserved loops forming a shallow binding surface including two aspartates, a positive patch, and a tryptophan. The DDX-4 peptide (residues 228–247) binds this surface with a KD of ~13 μM; mutagenesis studies defined the interaction interface.","method":"X-ray crystallography, binding affinity measurement (KD), mutagenesis","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure plus mutagenesis and quantitative binding assay in single focused study","pmids":["27622290"],"is_preprint":false},{"year":2017,"finding":"miR-196a suppresses RANBP10 expression by binding its 3' UTR; higher RANBP10 expression impairs neuronal morphology, reduces β-tubulin polymerization, and worsens pathological aggregates in Huntington's disease model. Overexpression of RANBP10 exacerbates neuronal morphology deficits and intracellular transport impairment.","method":"3' UTR luciferase reporter assay, miRNA overexpression, RANBP10 overexpression/knockdown, neuronal morphology and transport assays in HD transgenic mouse model","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — 3' UTR reporter validation plus functional overexpression with multiple cellular readouts, single lab","pmids":["28744327"],"is_preprint":false},{"year":2021,"finding":"RanBP10 forms a protein complex with karyopherin alpha2 (KPNA2) and dynein light chain DYNLT3 to facilitate HPV16 L2/vDNA transport towards mitotic chromatin during viral nuclear import, identified by label-free mass spectrometry and validated by biochemical and virological assays.","method":"Label-free mass spectrometry, biochemical co-immunoprecipitation, microscopy, functional virological infection assays","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS discovery with biochemical validation and functional virological assay, single lab, multiple orthogonal methods","pmids":["33974675"],"is_preprint":false},{"year":2021,"finding":"RANBP10 was identified as an IDO2-binding protein (but not IDO1-binding) in a co-immunoprecipitation screen, implicating it as a potential mediator of IDO2's nonenzymatic proinflammatory function in autoimmune arthritis.","method":"Co-immunoprecipitation","journal":"Journal of immunology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP identification without mechanistic follow-up for RANBP10 specifically","pmids":["34965962"],"is_preprint":false},{"year":2021,"finding":"RANBP10 suppresses the promoter activity of FBXW7, thereby increasing c-Myc protein stability in glioblastoma cells. Silencing FBXW7 in RANBP10-knockdown GBM cells partially rescues the proliferation/migration/invasion defects caused by RANBP10 loss, placing RANBP10 upstream of the FBXW7–c-Myc axis.","method":"Promoter-luciferase reporter assay, RANBP10 knockdown/overexpression, epistasis rescue by FBXW7 silencing, proliferation and invasion assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter reporter assay plus genetic epistasis (double knockdown rescue), single lab","pmids":["34671019"],"is_preprint":false},{"year":2022,"finding":"During human erythropoiesis, RANBP10 and RANBP9 form maturation stage-dependent distinct CTLH E3 ubiquitin ligase complexes; CRISPR-Cas9 inactivation of CTLH E3 assemblies (including RANBP10-containing complexes) causes defects in erythroid maturation, spontaneous/accelerated erythroid differentiation, and inefficient enucleation.","method":"Quantitative proteomics of in vitro human erythropoiesis, CRISPR-Cas9 knockout, enucleation and maturation assays","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomic stage mapping plus CRISPR functional validation, single lab, but RANBP10-specific effects not fully separated from RANBP9","pmids":["36459484"],"is_preprint":false},{"year":2025,"finding":"RANBP9 and RANBP10 (Scorpins) can each independently support formation of the CTLH E3 ubiquitin ligase complex and act as partial antagonists: acute overexpression of RANBP10 slows NSCLC cell proliferation and reshapes the cellular proteome and ubiquitylome, decreasing levels of proliferation-associated proteins including key DNA replication factors. A higher RANBP9/RANBP10 ratio correlates with greater proliferation.","method":"Inducible overexpression/loss-of-function cell lines, quantitative proteomics, ubiquitylome profiling, cell proliferation assays","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative proteomics and ubiquitylome with inducible functional cell lines, single lab","pmids":["40883813"],"is_preprint":false},{"year":2026,"finding":"Crystal structures of CTLH-CRA domains of multiple CTLH complex subunits were determined; targeted perturbations of conserved CRA-CRA interface features allow engineered RanBP10 subunits to adopt non-native interaction partners, demonstrating that RanBP10's assembly specificity within the GID/CTLH E3 ligase ring is encoded by specific sequence and geometric features of its CRA domain.","method":"X-ray crystallography of CTLH-CRA domains, quantitative binding analyses, mutagenesis to reprogram pairing","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — crystal structure with mutagenesis and binding assay, but RanBP10 engineering is partial demonstration within a broader structural study","pmids":["41948802"],"is_preprint":false}],"current_model":"RanBP10 is a cytoplasmic scaffold protein that functions as a Ran-GEF (via a discrete GEF domain), binds β-tubulin to modulate non-centrosomal microtubule dynamics (particularly in megakaryocytes and platelets), acts as an integral subunit of the CTLH E3 ubiquitin ligase complex (where it can independently support complex assembly and antagonizes RANBP9 to regulate ubiquitylation output and cell proliferation), co-activates the androgen receptor through direct complex formation, suppresses FBXW7 promoter activity to stabilize c-Myc, regulates D1 dopamine receptor phosphorylation via PKC, and participates in HPV16 nuclear import by forming a transport complex with KPNA2 and DYNLT3."},"narrative":{"mechanistic_narrative":"RANBP10 is a cytoplasmic multidomain scaffold protein that links Ran nucleotide exchange, microtubule regulation, and CTLH E3 ubiquitin ligase assembly across hematopoietic, neuronal, and proliferative contexts [PMID:18347012, PMID:19801445, PMID:40883813]. It functions as a guanine nucleotide exchange factor for Ran through a discrete GEF domain whose activity is abolished by a single point mutation, and it binds β-tubulin to control non-centrosomal microtubule organization [PMID:18347012]. In megakaryocytes and platelets this microtubule role is physiologically essential: loss of RANBP10 in mice distorts platelet discoid shape, disrupts microtubule filament number and localization, prolongs bleeding time, and impairs granule release and stable thrombus formation, in part by failing to restrain premature β1-tubulin polymerization [PMID:19801445, PMID:22936655]. RANBP10 is an integral subunit of the CTLH/GID E3 ubiquitin ligase complex, where it can independently nucleate complex assembly through CRA-domain interface features and acts as a partial antagonist of its paralog RANBP9, tuning ubiquitylation output and cell proliferation such that a higher RANBP9/RANBP10 ratio favors growth [PMID:36459484, PMID:40883813, PMID:41948802]. Through its IUS-SPRY β-sandwich domain it engages partner peptides at a defined shallow binding surface and competes with RANBP9 for receptor tyrosine kinase MET binding without activating downstream Ras/Erk signaling [PMID:14684163, PMID:27622290]. RANBP10 additionally co-activates the androgen and glucocorticoid receptors via direct complex formation [PMID:18222118], suppresses FBXW7 promoter activity to stabilize c-Myc in glioblastoma [PMID:34671019], modulates D1 dopamine receptor phosphorylation through PKC [PMID:20395553], and participates in HPV16 nuclear import by forming a transport complex with KPNA2 and DYNLT3 [PMID:33974675].","teleology":[{"year":2004,"claim":"Established that RANBP10, unlike its paralog RanBPM/RANBP9, binds the MET kinase domain via its SPRY domain but is a signaling-inert competitor that cannot couple to Sos or activate Ras/Erk, defining functional divergence within the Scorpin family.","evidence":"Co-IP, binding competition, and SRE-luciferase reporter assays in cell lines","pmids":["14684163"],"confidence":"Medium","gaps":["Physiological consequence of MET competition not shown in vivo","Did not define which signaling outputs RANBP10 does control at MET"]},{"year":2005,"claim":"An ortholog screen implicated the RANBP10 family in negatively regulating JAK/STAT signaling by controlling nucleocytoplasmic transport of STAT, hinting at a transport-scaffolding role.","evidence":"Genome-wide dsRNA RNAi screen in Drosophila cells with STAT92E phosphorylation readout","pmids":["16055650"],"confidence":"Medium","gaps":["Drosophila homolog, not human RANBP10","Direct molecular mechanism of STAT transport control not resolved"]},{"year":2008,"claim":"Defined RANBP10's core biochemical identity as a cytoplasmic Ran-GEF that also binds β-tubulin and organizes microtubules, unifying nucleotide exchange and cytoskeletal functions.","evidence":"In vitro GEF assay with GEF-domain point mutant, β-tubulin co-IP, and RNAi in megakaryocytes","pmids":["18347012"],"confidence":"High","gaps":["How Ran-GEF activity relates mechanistically to tubulin binding unclear","Substrate/spatial regulation of the GEF activity not mapped"]},{"year":2008,"claim":"Showed RANBP10 acts as a nuclear-receptor coactivator, enhancing androgen and glucocorticoid (but not estrogen) receptor transactivation and forming homo- and hetero-oligomers with RANBP9, extending its scaffold role into transcriptional control.","evidence":"Luciferase reporter assays, co-IP, and co-localization microscopy","pmids":["18222118"],"confidence":"Medium","gaps":["Direct vs indirect interaction with AR not distinguished","Mechanism of coactivation (chromatin, transport) unresolved"]},{"year":2009,"claim":"Demonstrated in vivo that RANBP10 is required for platelet discoid shape, microtubule organization, hemostasis, and degranulation, validating the cytoskeletal function physiologically.","evidence":"Gene-trap knockout mouse with ultrastructure, flow cytometry, and bleeding time assays","pmids":["19801445"],"confidence":"High","gaps":["Did not separate GEF activity from tubulin binding for the phenotype","Molecular basis of granule release defect not defined"]},{"year":2010,"claim":"Connected RANBP10 to GPCR signaling, showing it complexes with PKCγ/δ and the D1 dopamine receptor and promotes PKC-dependent receptor phosphorylation that attenuates cAMP signaling.","evidence":"Co-IP/mass spectrometry, immunofluorescence, cAMP and phosphorylation assays with PKC inhibitors","pmids":["20395553"],"confidence":"Medium","gaps":["Whether RANBP10 is a direct PKC substrate-presenting scaffold not established","In vivo relevance in neurons not tested"]},{"year":2012,"claim":"Refined the platelet phenotype mechanistically, showing RANBP10 loss raises β1-tubulin and drives premature microtubule polymerization that blocks agonist-induced marginal band contraction and stable thrombus formation.","evidence":"RANBP10-null mouse with ferric chloride thrombosis, flow adhesion, aggregometry, β1-tubulin Western, and taxol phenocopy","pmids":["22936655"],"confidence":"High","gaps":["How RANBP10 represses β1-tubulin levels mechanistically unclear","Link between Ran-GEF activity and tubulin homeostasis untested"]},{"year":2016,"claim":"Provided the structural basis for partner recognition, defining the RANBP10 IUS-SPRY β-sandwich fold and its shallow conserved binding surface that engages partner peptides with micromolar affinity.","evidence":"X-ray crystallography, KD measurement, and interface mutagenesis","pmids":["27622290"],"confidence":"High","gaps":["Endogenous SPRY-domain ligands beyond the test peptide not catalogued","Structure of GEF and CRA domains not solved here"]},{"year":2017,"claim":"Implicated RANBP10 dosage in neurodegeneration, showing miR-196a suppresses RANBP10 and that excess RANBP10 reduces β-tubulin polymerization and worsens neuronal morphology and transport in a Huntington's disease model.","evidence":"3'UTR luciferase reporter, miRNA and RANBP10 dosage manipulation, neuronal morphology/transport assays in HD mice","pmids":["28744327"],"confidence":"Medium","gaps":["Direct molecular target of RANBP10 in neurons not identified","Causal contribution to human HD not established"]},{"year":2021,"claim":"Expanded RANBP10's scaffold roles to viral nuclear import and oncogenic signaling, showing it forms a KPNA2/DYNLT3 transport complex for HPV16 nuclear entry and suppresses FBXW7 to stabilize c-Myc in glioblastoma.","evidence":"Mass spectrometry, co-IP, microscopy, virological assays (HPV16); promoter-luciferase and FBXW7-silencing epistasis with proliferation/invasion assays (GBM)","pmids":["33974675","34671019"],"confidence":"Medium","gaps":["Whether RANBP10's CTLH/E3 or GEF activity drives these effects unknown","Mechanism of FBXW7 promoter suppression undefined"]},{"year":2022,"claim":"Placed RANBP10 within the CTLH E3 ubiquitin ligase as a stage-specific subunit during erythropoiesis, with CTLH inactivation impairing erythroid maturation and enucleation.","evidence":"Quantitative proteomics of human erythropoiesis and CRISPR-Cas9 knockout with maturation/enucleation assays","pmids":["36459484"],"confidence":"Medium","gaps":["RANBP10-specific effects not fully separated from RANBP9","Ubiquitylation substrates in erythropoiesis not defined"]},{"year":2025,"claim":"Established RANBP10 as an independent CTLH-assembly subunit and partial antagonist of RANBP9 whose overexpression reshapes the ubiquitylome to lower proliferation-associated and DNA replication factors, tying complex stoichiometry to growth control.","evidence":"Inducible cell lines, quantitative proteomics, ubiquitylome profiling, and proliferation assays in NSCLC","pmids":["40883813"],"confidence":"Medium","gaps":["Direct ubiquitylation substrates not definitively assigned to RANBP10","Molecular basis of RANBP9 antagonism not structurally resolved"]},{"year":2026,"claim":"Defined the structural code for RANBP10's incorporation into the GID/CTLH ring, showing CRA-domain interface features encode its assembly specificity, which can be reprogrammed by targeted mutagenesis.","evidence":"X-ray crystallography of CTLH-CRA domains with quantitative binding and pairing-reprogramming mutagenesis","pmids":["41948802"],"confidence":"Medium","gaps":["Full CTLH ring architecture with RanBP10 not resolved","Functional consequence of reprogrammed pairing in cells not tested"]},{"year":null,"claim":"It remains unresolved how RANBP10's distinct biochemical activities — Ran-GEF, β-tubulin/microtubule regulation, SPRY-mediated partner binding, and CTLH E3 ligase assembly — are integrated or differentially deployed across its many cellular contexts.","evidence":"","pmids":[],"confidence":"Low","gaps":["No study dissects which domain activity drives each phenotype","Endogenous ubiquitylation substrates of RANBP10-CTLH unidentified","Relationship between GEF activity and tubulin regulation untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2,7]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,10]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,3]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2,7]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[13,14]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[4,7]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,5]}],"complexes":["CTLH/GID E3 ubiquitin ligase complex","KPNA2-DYNLT3 HPV16 nuclear import complex"],"partners":["RANBP9","TUBB","MET","AR","PRKCG","KPNA2","DYNLT3","YPEL5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6VN20","full_name":"Ran-binding protein 10","aliases":[],"length_aa":620,"mass_kda":67.3,"function":"May act as an adapter protein to couple membrane receptors to intracellular signaling pathways (Probable). Core component of the CTLH E3 ubiquitin-protein ligase complex that selectively accepts ubiquitin from UBE2H and mediates ubiquitination and subsequent proteasomal degradation of the transcription factor HBP1 (PubMed:29911972). Enhances dihydrotestosterone-induced transactivation activity of AR, as well as dexamethasone-induced transactivation activity of NR3C1, but does not affect estrogen-induced transactivation (PubMed:18222118). Acts as a guanine nucleotide exchange factor (GEF) for RAN GTPase. May play an essential role in hemostasis and in maintaining microtubule dynamics with respect to both platelet shape and function (By similarity)","subcellular_location":"Cytoplasm, cytosol; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q6VN20/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/RANBP10","classification":"Not Classified","n_dependent_lines":18,"n_total_lines":1208,"dependency_fraction":0.014900662251655629},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000141084","cell_line_id":"CID001570","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":3}],"interactors":[{"gene":"ARMC8","stoichiometry":10.0},{"gene":"GID4","stoichiometry":10.0},{"gene":"GID8","stoichiometry":10.0},{"gene":"RANBP9","stoichiometry":10.0},{"gene":"WDR26","stoichiometry":10.0},{"gene":"MAEA","stoichiometry":10.0},{"gene":"MKLN1","stoichiometry":4.0},{"gene":"RMND5A","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/target/CID001570","total_profiled":1310},"omim":[{"mim_id":"616652","title":"YUAN-HAREL-LUPSKI SYNDROME; YUHAL","url":"https://www.omim.org/entry/616652"},{"mim_id":"614031","title":"RAN-BINDING PROTEIN 10; RANBP10","url":"https://www.omim.org/entry/614031"},{"mim_id":"603854","title":"RAN-BINDING PROTEIN 9; RANBP9","url":"https://www.omim.org/entry/603854"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/RANBP10"},"hgnc":{"alias_symbol":["KIAA1464"],"prev_symbol":[]},"alphafold":{"accession":"Q6VN20","domains":[{"cath_id":"2.60.120.920","chopping":"31-225","consensus_level":"high","plddt":97.5038,"start":31,"end":225},{"cath_id":"-","chopping":"254-353_499-619","consensus_level":"medium","plddt":91.2186,"start":254,"end":619}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6VN20","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6VN20-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6VN20-F1-predicted_aligned_error_v6.png","plddt_mean":77.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=RANBP10","jax_strain_url":"https://www.jax.org/strain/search?query=RANBP10"},"sequence":{"accession":"Q6VN20","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6VN20.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6VN20/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6VN20"}},"corpus_meta":[{"pmid":"16055650","id":"PMC_16055650","title":"Genome-wide 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by regulating the FBXW7/c-Myc pathway.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/34671019","citation_count":16,"is_preprint":false},{"pmid":"22936655","id":"PMC_22936655","title":"Altered microtubule equilibrium and impaired thrombus stability in mice lacking RanBP10.","date":"2012","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/22936655","citation_count":16,"is_preprint":false},{"pmid":"29914204","id":"PMC_29914204","title":"Scorpins in the DNA Damage Response.","date":"2018","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/29914204","citation_count":11,"is_preprint":false},{"pmid":"27622290","id":"PMC_27622290","title":"Structural Basis for the Interaction between the IUS-SPRY Domain of RanBPM and DDX-4 in Germ Cell Development.","date":"2016","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/27622290","citation_count":11,"is_preprint":false},{"pmid":"34778565","id":"PMC_34778565","title":"RANBP9 as potential therapeutic target in non-small cell lung cancer.","date":"2020","source":"Journal of cancer metastasis and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/34778565","citation_count":4,"is_preprint":false},{"pmid":"40883813","id":"PMC_40883813","title":"RANBP9 and RANBP10 cooperate in regulating non-small cell lung cancer proliferation.","date":"2025","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/40883813","citation_count":2,"is_preprint":false},{"pmid":"41948802","id":"PMC_41948802","title":"A structural code for assembly specificity in GID/CTLH-type E3 ligases.","date":"2026","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/41948802","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13584,"output_tokens":4083,"usd":0.050999,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11828,"output_tokens":4712,"usd":0.08847,"stage2_stop_reason":"end_turn"},"total_usd":0.139469,"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\": 2004,\n      \"finding\": \"RanBP10 interacts with the tyrosine kinase domain of MET via its SPRY domain, competing with RanBPM/RanBP9 for MET binding. Unlike RanBPM/RanBP9, RanBP10 fails to interact with Sos and cannot activate the Ras/Erk pathway; co-transfection of RanBP10 with RanBPM/RanBP9 represses RanBPM-induced SRE-luciferase reporter activity.\",\n      \"method\": \"Co-immunoprecipitation, binding competition assays, SRE-luciferase reporter gene assay, overexpression in cell lines\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assays and functional reporter assays in single lab with two orthogonal methods\",\n      \"pmids\": [\"14684163\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Drosophila homolog of RanBP10 acts as a negative regulator of JAK/STAT signaling by controlling nucleocytoplasmic transport of STAT92E, identified in a genome-wide RNAi screen.\",\n      \"method\": \"Genome-wide dsRNA-mediated RNAi screen in cultured Drosophila cells, STAT92E phosphorylation assay\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional RNAi screen with defined cellular readout but single method and identified in a large-scale screen rather than focused mechanistic study\",\n      \"pmids\": [\"16055650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"RanBP10 is a cytoplasmic guanine nucleotide exchange factor (GEF) for Ran; it binds beta-tubulin and associates with megakaryocyte microtubules. A point mutation in the candidate GEF domain abolishes exchange activity. RNAi-mediated loss of RanBP10 in cultured megakaryocytes disrupts microtubule organization.\",\n      \"method\": \"In vitro GEF activity assay, point mutagenesis of GEF domain, beta-tubulin co-immunoprecipitation, RNAi knockdown with microtubule organization readout\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro GEF assay with mutagenesis plus binding assay and functional RNAi in a single focused study with multiple orthogonal methods\",\n      \"pmids\": [\"18347012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"RanBP10 acts as a coactivator of the androgen receptor (AR): it enhances ligand-dependent AR transcriptional activity, forms a complex with AR, and shows additive effects with RanBPM on AR transactivation. RanBP10 also enhances glucocorticoid receptor but not estrogen receptor alpha transcriptional activity. RanBP10 forms homo-oligomers and hetero-oligomers with RanBPM and co-localizes with RanBPM in cytoplasm and nucleus.\",\n      \"method\": \"Luciferase reporter transcriptional assay, co-immunoprecipitation, co-localization by fluorescence microscopy\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus functional reporter assay with nuclear receptor specificity controls, single lab\",\n      \"pmids\": [\"18222118\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"RanBP10-deficient mice (gene-trap) show altered platelet shape (increased geometric axis ratio), disorders in microtubule filament numbers and localization in platelets, markedly prolonged bleeding time, and reduced platelet granule release (reduced CD62P and CD63 surface expression after PAR4 stimulation), establishing that RanBP10 is required for platelet discoid shape and degranulation in vivo.\",\n      \"method\": \"Gene-trap mouse knockout, ultrastructural analysis, flow cytometry, bleeding time assay, proplatelet formation assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout with multiple orthogonal phenotypic readouts (ultrastructure, flow cytometry, bleeding time) in a focused study\",\n      \"pmids\": [\"19801445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"RanBP10 interacts with PKCgamma and PKCdelta (identified by co-immunoprecipitation coupled to mass spectrometry) and with the D1 dopamine receptor. Overexpression of RanBP10 enhances basal D1 receptor phosphorylation and attenuates D1 receptor-stimulated cAMP accumulation; PKC inhibitors block the RanBP10-dependent increase in receptor phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation coupled to mass spectrometry, co-localization by immunofluorescence, cAMP accumulation assay, receptor phosphorylation assay, PKC inhibitor treatment\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-confirmed Co-IP plus functional signaling assays with pharmacological controls, single lab\",\n      \"pmids\": [\"20395553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"YPEL5 protein binds RanBP10 (and RanBPM) as identified by yeast two-hybrid, defining RanBP10 as part of a conserved Scorpin protein family alongside RanBPM.\",\n      \"method\": \"Yeast two-hybrid, comparative genomic analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single yeast two-hybrid without in-cell validation of RANBP10 interaction specifically\",\n      \"pmids\": [\"20580816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"RanBP10-null platelets show normal adhesion on collagen and von Willebrand factor under flow but impaired stable thrombus formation in vivo (ferric chloride model). Loss of RanBP10 leads to increased β1-tubulin protein driving α-monomers into polymerized microtubules; agonists fail to contract the peripheral marginal band or centralize granules in null platelets. Taxol-induced microtubule stabilization in wild-type platelets phenocopies the attenuated shape change, supporting RanBP10's role in inhibiting premature β1-tubulin polymerization.\",\n      \"method\": \"RanBP10-null mouse model, ferric chloride arterial thrombosis model, flow adhesion assay, aggregometry, Western blot for β1-tubulin, taxol pharmacological phenocopy\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout replicated across multiple orthogonal assays with pharmacological phenocopy, consistent with prior Blood 2009 study\",\n      \"pmids\": [\"22936655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Crystal structures of the IUS-SPRY domain of RanBP10 (and RanBPM) were determined, revealing a β-sandwich fold with conserved loops forming a shallow binding surface including two aspartates, a positive patch, and a tryptophan. The DDX-4 peptide (residues 228–247) binds this surface with a KD of ~13 μM; mutagenesis studies defined the interaction interface.\",\n      \"method\": \"X-ray crystallography, binding affinity measurement (KD), mutagenesis\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure plus mutagenesis and quantitative binding assay in single focused study\",\n      \"pmids\": [\"27622290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"miR-196a suppresses RANBP10 expression by binding its 3' UTR; higher RANBP10 expression impairs neuronal morphology, reduces β-tubulin polymerization, and worsens pathological aggregates in Huntington's disease model. Overexpression of RANBP10 exacerbates neuronal morphology deficits and intracellular transport impairment.\",\n      \"method\": \"3' UTR luciferase reporter assay, miRNA overexpression, RANBP10 overexpression/knockdown, neuronal morphology and transport assays in HD transgenic mouse model\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — 3' UTR reporter validation plus functional overexpression with multiple cellular readouts, single lab\",\n      \"pmids\": [\"28744327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RanBP10 forms a protein complex with karyopherin alpha2 (KPNA2) and dynein light chain DYNLT3 to facilitate HPV16 L2/vDNA transport towards mitotic chromatin during viral nuclear import, identified by label-free mass spectrometry and validated by biochemical and virological assays.\",\n      \"method\": \"Label-free mass spectrometry, biochemical co-immunoprecipitation, microscopy, functional virological infection assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS discovery with biochemical validation and functional virological assay, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"33974675\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RANBP10 was identified as an IDO2-binding protein (but not IDO1-binding) in a co-immunoprecipitation screen, implicating it as a potential mediator of IDO2's nonenzymatic proinflammatory function in autoimmune arthritis.\",\n      \"method\": \"Co-immunoprecipitation\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP identification without mechanistic follow-up for RANBP10 specifically\",\n      \"pmids\": [\"34965962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"RANBP10 suppresses the promoter activity of FBXW7, thereby increasing c-Myc protein stability in glioblastoma cells. Silencing FBXW7 in RANBP10-knockdown GBM cells partially rescues the proliferation/migration/invasion defects caused by RANBP10 loss, placing RANBP10 upstream of the FBXW7–c-Myc axis.\",\n      \"method\": \"Promoter-luciferase reporter assay, RANBP10 knockdown/overexpression, epistasis rescue by FBXW7 silencing, proliferation and invasion assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter reporter assay plus genetic epistasis (double knockdown rescue), single lab\",\n      \"pmids\": [\"34671019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"During human erythropoiesis, RANBP10 and RANBP9 form maturation stage-dependent distinct CTLH E3 ubiquitin ligase complexes; CRISPR-Cas9 inactivation of CTLH E3 assemblies (including RANBP10-containing complexes) causes defects in erythroid maturation, spontaneous/accelerated erythroid differentiation, and inefficient enucleation.\",\n      \"method\": \"Quantitative proteomics of in vitro human erythropoiesis, CRISPR-Cas9 knockout, enucleation and maturation assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomic stage mapping plus CRISPR functional validation, single lab, but RANBP10-specific effects not fully separated from RANBP9\",\n      \"pmids\": [\"36459484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"RANBP9 and RANBP10 (Scorpins) can each independently support formation of the CTLH E3 ubiquitin ligase complex and act as partial antagonists: acute overexpression of RANBP10 slows NSCLC cell proliferation and reshapes the cellular proteome and ubiquitylome, decreasing levels of proliferation-associated proteins including key DNA replication factors. A higher RANBP9/RANBP10 ratio correlates with greater proliferation.\",\n      \"method\": \"Inducible overexpression/loss-of-function cell lines, quantitative proteomics, ubiquitylome profiling, cell proliferation assays\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative proteomics and ubiquitylome with inducible functional cell lines, single lab\",\n      \"pmids\": [\"40883813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Crystal structures of CTLH-CRA domains of multiple CTLH complex subunits were determined; targeted perturbations of conserved CRA-CRA interface features allow engineered RanBP10 subunits to adopt non-native interaction partners, demonstrating that RanBP10's assembly specificity within the GID/CTLH E3 ligase ring is encoded by specific sequence and geometric features of its CRA domain.\",\n      \"method\": \"X-ray crystallography of CTLH-CRA domains, quantitative binding analyses, mutagenesis to reprogram pairing\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystal structure with mutagenesis and binding assay, but RanBP10 engineering is partial demonstration within a broader structural study\",\n      \"pmids\": [\"41948802\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"RanBP10 is a cytoplasmic scaffold protein that functions as a Ran-GEF (via a discrete GEF domain), binds β-tubulin to modulate non-centrosomal microtubule dynamics (particularly in megakaryocytes and platelets), acts as an integral subunit of the CTLH E3 ubiquitin ligase complex (where it can independently support complex assembly and antagonizes RANBP9 to regulate ubiquitylation output and cell proliferation), co-activates the androgen receptor through direct complex formation, suppresses FBXW7 promoter activity to stabilize c-Myc, regulates D1 dopamine receptor phosphorylation via PKC, and participates in HPV16 nuclear import by forming a transport complex with KPNA2 and DYNLT3.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"RANBP10 is a cytoplasmic multidomain scaffold protein that links Ran nucleotide exchange, microtubule regulation, and CTLH E3 ubiquitin ligase assembly across hematopoietic, neuronal, and proliferative contexts [#2, #4, #14]. It functions as a guanine nucleotide exchange factor for Ran through a discrete GEF domain whose activity is abolished by a single point mutation, and it binds β-tubulin to control non-centrosomal microtubule organization [#2]. In megakaryocytes and platelets this microtubule role is physiologically essential: loss of RANBP10 in mice distorts platelet discoid shape, disrupts microtubule filament number and localization, prolongs bleeding time, and impairs granule release and stable thrombus formation, in part by failing to restrain premature β1-tubulin polymerization [#4, #7]. RANBP10 is an integral subunit of the CTLH/GID E3 ubiquitin ligase complex, where it can independently nucleate complex assembly through CRA-domain interface features and acts as a partial antagonist of its paralog RANBP9, tuning ubiquitylation output and cell proliferation such that a higher RANBP9/RANBP10 ratio favors growth [#13, #14, #15]. Through its IUS-SPRY β-sandwich domain it engages partner peptides at a defined shallow binding surface and competes with RANBP9 for receptor tyrosine kinase MET binding without activating downstream Ras/Erk signaling [#0, #8]. RANBP10 additionally co-activates the androgen and glucocorticoid receptors via direct complex formation [#3], suppresses FBXW7 promoter activity to stabilize c-Myc in glioblastoma [#12], modulates D1 dopamine receptor phosphorylation through PKC [#5], and participates in HPV16 nuclear import by forming a transport complex with KPNA2 and DYNLT3 [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established that RANBP10, unlike its paralog RanBPM/RANBP9, binds the MET kinase domain via its SPRY domain but is a signaling-inert competitor that cannot couple to Sos or activate Ras/Erk, defining functional divergence within the Scorpin family.\",\n      \"evidence\": \"Co-IP, binding competition, and SRE-luciferase reporter assays in cell lines\",\n      \"pmids\": [\"14684163\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Physiological consequence of MET competition not shown in vivo\", \"Did not define which signaling outputs RANBP10 does control at MET\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"An ortholog screen implicated the RANBP10 family in negatively regulating JAK/STAT signaling by controlling nucleocytoplasmic transport of STAT, hinting at a transport-scaffolding role.\",\n      \"evidence\": \"Genome-wide dsRNA RNAi screen in Drosophila cells with STAT92E phosphorylation readout\",\n      \"pmids\": [\"16055650\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Drosophila homolog, not human RANBP10\", \"Direct molecular mechanism of STAT transport control not resolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined RANBP10's core biochemical identity as a cytoplasmic Ran-GEF that also binds β-tubulin and organizes microtubules, unifying nucleotide exchange and cytoskeletal functions.\",\n      \"evidence\": \"In vitro GEF assay with GEF-domain point mutant, β-tubulin co-IP, and RNAi in megakaryocytes\",\n      \"pmids\": [\"18347012\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"How Ran-GEF activity relates mechanistically to tubulin binding unclear\", \"Substrate/spatial regulation of the GEF activity not mapped\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed RANBP10 acts as a nuclear-receptor coactivator, enhancing androgen and glucocorticoid (but not estrogen) receptor transactivation and forming homo- and hetero-oligomers with RANBP9, extending its scaffold role into transcriptional control.\",\n      \"evidence\": \"Luciferase reporter assays, co-IP, and co-localization microscopy\",\n      \"pmids\": [\"18222118\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct vs indirect interaction with AR not distinguished\", \"Mechanism of coactivation (chromatin, transport) unresolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated in vivo that RANBP10 is required for platelet discoid shape, microtubule organization, hemostasis, and degranulation, validating the cytoskeletal function physiologically.\",\n      \"evidence\": \"Gene-trap knockout mouse with ultrastructure, flow cytometry, and bleeding time assays\",\n      \"pmids\": [\"19801445\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Did not separate GEF activity from tubulin binding for the phenotype\", \"Molecular basis of granule release defect not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected RANBP10 to GPCR signaling, showing it complexes with PKCγ/δ and the D1 dopamine receptor and promotes PKC-dependent receptor phosphorylation that attenuates cAMP signaling.\",\n      \"evidence\": \"Co-IP/mass spectrometry, immunofluorescence, cAMP and phosphorylation assays with PKC inhibitors\",\n      \"pmids\": [\"20395553\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether RANBP10 is a direct PKC substrate-presenting scaffold not established\", \"In vivo relevance in neurons not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Refined the platelet phenotype mechanistically, showing RANBP10 loss raises β1-tubulin and drives premature microtubule polymerization that blocks agonist-induced marginal band contraction and stable thrombus formation.\",\n      \"evidence\": \"RANBP10-null mouse with ferric chloride thrombosis, flow adhesion, aggregometry, β1-tubulin Western, and taxol phenocopy\",\n      \"pmids\": [\"22936655\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"How RANBP10 represses β1-tubulin levels mechanistically unclear\", \"Link between Ran-GEF activity and tubulin homeostasis untested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided the structural basis for partner recognition, defining the RANBP10 IUS-SPRY β-sandwich fold and its shallow conserved binding surface that engages partner peptides with micromolar affinity.\",\n      \"evidence\": \"X-ray crystallography, KD measurement, and interface mutagenesis\",\n      \"pmids\": [\"27622290\"],\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Endogenous SPRY-domain ligands beyond the test peptide not catalogued\", \"Structure of GEF and CRA domains not solved here\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Implicated RANBP10 dosage in neurodegeneration, showing miR-196a suppresses RANBP10 and that excess RANBP10 reduces β-tubulin polymerization and worsens neuronal morphology and transport in a Huntington's disease model.\",\n      \"evidence\": \"3'UTR luciferase reporter, miRNA and RANBP10 dosage manipulation, neuronal morphology/transport assays in HD mice\",\n      \"pmids\": [\"28744327\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct molecular target of RANBP10 in neurons not identified\", \"Causal contribution to human HD not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Expanded RANBP10's scaffold roles to viral nuclear import and oncogenic signaling, showing it forms a KPNA2/DYNLT3 transport complex for HPV16 nuclear entry and suppresses FBXW7 to stabilize c-Myc in glioblastoma.\",\n      \"evidence\": \"Mass spectrometry, co-IP, microscopy, virological assays (HPV16); promoter-luciferase and FBXW7-silencing epistasis with proliferation/invasion assays (GBM)\",\n      \"pmids\": [\"33974675\", \"34671019\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Whether RANBP10's CTLH/E3 or GEF activity drives these effects unknown\", \"Mechanism of FBXW7 promoter suppression undefined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed RANBP10 within the CTLH E3 ubiquitin ligase as a stage-specific subunit during erythropoiesis, with CTLH inactivation impairing erythroid maturation and enucleation.\",\n      \"evidence\": \"Quantitative proteomics of human erythropoiesis and CRISPR-Cas9 knockout with maturation/enucleation assays\",\n      \"pmids\": [\"36459484\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"RANBP10-specific effects not fully separated from RANBP9\", \"Ubiquitylation substrates in erythropoiesis not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established RANBP10 as an independent CTLH-assembly subunit and partial antagonist of RANBP9 whose overexpression reshapes the ubiquitylome to lower proliferation-associated and DNA replication factors, tying complex stoichiometry to growth control.\",\n      \"evidence\": \"Inducible cell lines, quantitative proteomics, ubiquitylome profiling, and proliferation assays in NSCLC\",\n      \"pmids\": [\"40883813\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Direct ubiquitylation substrates not definitively assigned to RANBP10\", \"Molecular basis of RANBP9 antagonism not structurally resolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined the structural code for RANBP10's incorporation into the GID/CTLH ring, showing CRA-domain interface features encode its assembly specificity, which can be reprogrammed by targeted mutagenesis.\",\n      \"evidence\": \"X-ray crystallography of CTLH-CRA domains with quantitative binding and pairing-reprogramming mutagenesis\",\n      \"pmids\": [\"41948802\"],\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"\",\n      \"gaps\": [\"Full CTLH ring architecture with RanBP10 not resolved\", \"Functional consequence of reprogrammed pairing in cells not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how RANBP10's distinct biochemical activities — Ran-GEF, β-tubulin/microtubule regulation, SPRY-mediated partner binding, and CTLH E3 ligase assembly — are integrated or differentially deployed across its many cellular contexts.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No study dissects which domain activity drives each phenotype\", \"Endogenous ubiquitylation substrates of RANBP10-CTLH unidentified\", \"Relationship between GEF activity and tubulin regulation untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2, 7]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 10]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2, 7]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [13, 14]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [4, 7]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"complexes\": [\n      \"CTLH/GID E3 ubiquitin ligase complex\",\n      \"KPNA2-DYNLT3 HPV16 nuclear import complex\"\n    ],\n    \"partners\": [\n      \"RANBP9\",\n      \"TUBB\",\n      \"MET\",\n      \"AR\",\n      \"PRKCG\",\n      \"KPNA2\",\n      \"DYNLT3\",\n      \"YPEL5\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}