{"gene":"DLGAP5","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2006,"finding":"HURP is a direct cargo of importin beta; RanGTP controls HURP localization to the mitotic spindle by releasing it from the importin beta inhibitory complex. HURP localizes predominantly to kinetochore microtubules near chromosomes during mitosis, and depletion of HURP impairs K-fiber stabilization and delays chromosome congression.","method":"Overexpression of importin beta / RanT24N / RanQ69L mutants in cells, tsBN2 mutant cell analysis, in vitro microtubule bundling assay, siRNA depletion with live-cell imaging","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic and biochemical evidence across two independent labs (PMID:16631580 and PMID:16631581) with multiple orthogonal methods","pmids":["16631580"],"is_preprint":false},{"year":2006,"finding":"HURP is a component of a Ran-dependent multiprotein complex containing TPX2, XMAP215, Eg5, and Aurora A that is required for conversion of aster-like to spindle-like structures. Aurora A activity is required for complex formation and function. HURP binds microtubules and affects their organization in vitro and in vivo.","method":"Immunoprecipitation/mass spectrometry identification of complex, anti-HURP antibody injection in Xenopus egg extract, siRNA depletion in HeLa cells, in vitro microtubule binding assay","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — complex identified by MS, validated by functional antibody injection and siRNA, replicated across labs","pmids":["16631581"],"is_preprint":false},{"year":2006,"finding":"HURP binds directly to microtubules in vitro via its N-terminal region, enhances microtubule polymerization, stabilizes mitotic microtubules in vivo, and decreases spindle turnover rate. Depletion results in unaligned chromosomes, reduced interkinetochore tension, and spindle checkpoint activation.","method":"Functional genomic siRNA screen, in vitro microtubule binding assay, live-cell imaging, FRAP, immunofluorescence in HeLa cells","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (in vitro binding, FRAP, live imaging), consistent with two independent 2006 papers","pmids":["16769820"],"is_preprint":false},{"year":2003,"finding":"HURP mRNA expression is cell-cycle regulated, peaking at G2/M in synchronized HeLa cells; HURP protein localizes to spindle poles during mitosis by immunofluorescence.","method":"Cell cycle synchronization with RT-PCR, immunofluorescence in mitotic cells","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiment, single lab, consistent with later independent reports","pmids":["12527899"],"is_preprint":false},{"year":2005,"finding":"Aurora A phosphorylates HURP in vitro and in vivo; phosphorylation by Aurora A is required for HURP stability and its assembly into complexes. A phosphorylation-deficient HURP-4P mutant (Aurora A sites mutated to Ala) showed reduced stability and poor complex assembly.","method":"In vitro kinase assay, co-immunoprecipitation, site-directed mutagenesis, stable transfection of Aurora A catalytically inactive form","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay plus mutagenesis plus in vivo validation, single lab","pmids":["15987997"],"is_preprint":false},{"year":2004,"finding":"Fbx7, an F-box protein of the SCF ubiquitin-ligase complex, recruits HURP through its C-terminal proline-rich region in a Cdk1-cyclin B phosphorylation-dependent manner, leading to proteasome-mediated HURP proteolysis. Mutation of Cdk1-cyclin B phosphorylation sites on HURP or the proline-rich region of Fbx7 abolishes their association.","method":"siRNA depletion of Fbx7, ubiquitination assay, co-immunoprecipitation, site-directed mutagenesis of phosphorylation sites","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstituted SCF complex, mutagenesis of both substrate and adaptor, multiple orthogonal methods in single lab","pmids":["15145941"],"is_preprint":false},{"year":2006,"finding":"HURP wraps microtubule ends with an additional tubulin sheet forming two concentric tubes; the outer sheet consists of anti-parallel protofilaments with a novel 42.5° inclination. HURP stabilizes and bundles microtubules and also polymerizes free tubulin into a new configuration.","method":"Cryo-electron microscopy, unidirectional surface shadowing of HURP-decorated microtubules in vitro","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structural analysis with in vitro reconstitution, single lab","pmids":["17118403"],"is_preprint":false},{"year":2008,"finding":"HURP binds microtubules through its N-terminal domain; in the hypophosphorylated state, the C-terminal region of HURP intramolecularly binds the N-terminal microtubule-binding domain and abrogates microtubule affinity. Aurora A phosphorylation of the C-terminal domain releases this autoinhibition, enabling microtubule binding and stabilization.","method":"Biochemical domain-mapping, in vitro microtubule binding assay with N- and C-terminal fragments, ectopic expression of C-terminal domain in HeLa cells, Aurora A kinase assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of autoinhibition mechanism, mutagenesis, cell-based trans-dominant experiment, single lab","pmids":["18321990"],"is_preprint":false},{"year":2010,"finding":"In mouse oocytes (acentriolar meiotic spindle), HURP accumulates on interpolar MTs near chromosomes via Kinesin-5 activity. HURP promotes MT stability in the spindle central domain to allow efficient MTOC sorting into distinct poles, establishing and maintaining bipolarity. Hurp knockout females are viable but sterile due to defective oocyte divisions.","method":"Hurp knockout mouse generation, immunofluorescence, live-cell imaging of oocytes, Kinesin-5 inhibitor treatment","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO model with defined cellular phenotype, multiple orthogonal approaches including pharmacological inhibition and live imaging","pmids":["21173113"],"is_preprint":false},{"year":2008,"finding":"Hurp knockout female mice are infertile due to an implantation defect caused by a failure in endometrial stromal proliferation and the decidual reaction, not in ovulation, fertilization, or pre-implantation development. HURP expression in the uterus is induced by estrogen.","method":"Hurp knockout mouse generation, breeding experiments, histological analysis of uterus, estrogen treatment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined cellular phenotype, multiple readouts, single lab","pmids":["18676373"],"is_preprint":false},{"year":2011,"finding":"HURP regulates chromosome congression by interacting with kinesin Kif18A and controlling Kif18A localization and dynamics at the plus ends of kinetochore MTs. The N-terminal microtubule-binding domain of HURP (aa 1-278) mimics Kif18A depletion phenotypes; overexpression of Kif18A partially rescues misaligned chromosomes in HURP(278)-overexpressing cells.","method":"Co-immunoprecipitation, bimolecular fluorescence complementation (BiFC), live-cell imaging, rescue experiments","journal":"Current biology : CB","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction confirmed by BiFC and co-IP, functional rescue, single lab","pmids":["21924616"],"is_preprint":false},{"year":2011,"finding":"HURP overexpression promotes ubiquitination and proteasomal degradation of p53 via upregulation of gankyrin, a positive regulator of MDM2 E3 ubiquitin ligase. Knockdown of HURP leads to p53 accumulation, reduced proliferation, and sensitization to cisplatin in p53-positive cells.","method":"Ubiquitination assay, shRNA knockdown, gankyrin siRNA, exogenous p53 expression, tumor xenograft in nude mice","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway established by sequential knockdown experiments and rescue, single lab","pmids":["22230478"],"is_preprint":false},{"year":2011,"finding":"HBx viral protein upregulates HURP expression via p38/MAPK pathway through SATB1, and HURP mediates HBx-induced upregulation of survivin, contributing to cisplatin resistance in HCC cells.","method":"HBx expression in Hep3B cells, HURP shRNA knockdown, p38/MAPK pathway inhibition, survivin western blotting","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway established by knockdown and pathway inhibition, single lab","pmids":["20541537"],"is_preprint":false},{"year":2011,"finding":"Sorafenib inhibits HURP expression primarily at the transcriptional level by reducing translation and nuclear translocation of NF-κB family member c-Rel, which directly activates HURP gene transcription. c-Rel knockdown reduces HURP protein level and enhances taxol-induced cell death.","method":"Real-time PCR, chromatin immunoprecipitation (ChIP) assay, c-Rel shRNA knockdown, sorafenib treatment","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms direct transcription factor binding to HURP promoter, single lab, two orthogonal methods","pmids":["21549688"],"is_preprint":false},{"year":2013,"finding":"Aurora A phosphorylation of HURP regulates its spatial distribution on the mitotic spindle: unphosphorylated HURP associates with centrosomal microtubules while phosphorylated HURP associates with kinetochore microtubules. HURP cycles continuously between these two forms in mitotic cells.","method":"Aurora A inhibitors (IBPR001, IBPR002, MLN8237) as chemical probes, immunofluorescence, phospho-specific antibodies in live cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological approach with multiple independent inhibitors, single lab, no direct mutagenesis","pmids":["23610398"],"is_preprint":false},{"year":2013,"finding":"Tripolin A, a non-ATP competitive Aurora A inhibitor, reduces HURP's chromosome-proximal gradient distribution without affecting its microtubule binding, revealing Aurora A phosphorylation controls the gradient localization of HURP but not its general MT association.","method":"In vitro Aurora A kinase assay, immunofluorescence in human cells, comparison with MLN8054/MLN8237, in silico docking","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chemical probe with in vitro and in vivo validation, single lab","pmids":["23516487"],"is_preprint":false},{"year":2009,"finding":"Mars, the Drosophila ortholog of HURP, is required for the attachment of centrosomes to the mitotic spindle during syncytial nuclear divisions; loss of Mars causes centrosome detachment from spindles and ectopic microtubule nucleation. Mars localizes to nuclei in interphase and to spindle poles during mitosis.","method":"mars mutant Drosophila genetics, live-cell and fixed immunofluorescence imaging of early embryos","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function in Drosophila ortholog with clear cellular phenotype, single lab","pmids":["19174464"],"is_preprint":false},{"year":2018,"finding":"HURP directly interacts with centrosomal protein TACC3 (via HURP residues 1-625) by co-immunoprecipitation and BiFC; HURP is required for TACC3 function during kinetochore microtubule assembly at chromosomes in prometaphase, and HURP regulates lateral kinetochore attachment and chromosome congression through modulation of TACC3.","method":"Co-immunoprecipitation, bimolecular fluorescence complementation, siRNA depletion, immunofluorescence","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction confirmed by two orthogonal methods (Co-IP and BiFC), functional epistasis, single lab","pmids":["30054275"],"is_preprint":false},{"year":2019,"finding":"HURP accumulates on k-fiber plus ends inversely proportionally to half-spindle length; centrosomes regulate k-fiber plus-end dynamics indirectly via length-dependent HURP accumulation. HURP depletion in cells with only one centrosome rebalances k-fiber stability and plus-end dynamics and improves spindle symmetry.","method":"Generation of human cells with one centrosome by centrinone treatment/laser ablation, HURP siRNA depletion, live-cell imaging in 3 cell lines, immunofluorescence","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — defined experimental manipulation (single centrosome cells), HURP depletion rescue, validated in 3 independent cell lines","pmids":["31668617"],"is_preprint":false},{"year":2020,"finding":"Ran-GTP and importin-β coordinately promote HURP's dynamic microtubule binding-dissociation cycle to maintain HURP near chromosomes during metaphase. Acute mitotic depletion of Ran reveals it is specifically required for HURP and HSET localization to chromosome-proximal spindle regions to set proper spindle length during prometaphase, but not for NuMA or TPX2 activation.","method":"Auxin-inducible degron (AID) technology for acute mitotic Ran depletion in human cells, FRAP, immunofluorescence","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — acute conditional depletion technology with FRAP and live imaging, mechanistically dissected Ran's specific roles","pmids":["33186548"],"is_preprint":false},{"year":2021,"finding":"PRMT5 methylates HURP at R122; methylated HURP (m122) interacts with acetyl-tubulin and stabilizes its bundling pattern, rigidifying the Golgi apparatus and retarding Golgi repositioning and cell migration. This acts as a brake on cell migration. PRMT5 is downregulated early in wound-healing, decreasing HURP m122.","method":"PRMT5 methyltransferase assay, HURP methylation-mimicking mutant (R122F) expression, acetyl-tubulin co-immunoprecipitation, nocodazole sensitivity assay, wound healing assay","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro methylation plus co-IP plus mutant phenotype rescue, single lab","pmids":["34541678"],"is_preprint":false},{"year":2022,"finding":"JMJD6 demethylates HURP at R122, promoting Golgi repositioning and cell migration via NF-κB-induced centrosome repositioning and subsequently Cdc42-dependent Golgi repositioning. The HURP methylation-deficiency mutant (R122K) promotes Golgi repositioning through this NF-κB-CR-Cdc42 cascade.","method":"JMJD6 demethylase assay, HURP methylation mutants (122F vs 122K), NF-κB reporter, Cdc42 knockdown, Golgi repositioning assay","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — enzymatic demethylation and functional mutant analysis, pathway epistasis, single lab","pmids":["36250981"],"is_preprint":false},{"year":2022,"finding":"HURP preferentially binds the GDP microtubule lattice rather than GTP-tubulin in vitro and in vivo, accumulating on the kinetochore-proximal region of depolymerising kinetochore-fibres while avoiding nascent polymerising K-fibres, creating a 'HURP-gap' that corresponds to a mixed-nucleotide zone.","method":"In vitro HURP binding to GDP vs GTP microtubules, endogenously-labelled HURP live-cell imaging, FRAP, quantitative modeling","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro nucleotide-state preference assay combined with endogenous live-cell imaging and quantitative modeling, single lab","pmids":["35948594"],"is_preprint":false},{"year":2023,"finding":"HURP phosphorylation at Ser627 regulates its localization to kinetochore fibers and its interactions with partner proteins (TPX2, Aurora A, Eg5, Dynein, Kif5B, importin β) in mammalian mitotic cells. HURP participates in at least two distinct complexes during metaphase. Microtubule flux affects HURP dynamics.","method":"Photoactivation and FRAP experiments, immunoprecipitation with phospho-Ser627 mutant HURP, co-IP of interaction partners in mitotic cells","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRAP, immunoprecipitation with phosphomutants, multiple partners, single lab","pmids":["37484914"],"is_preprint":false},{"year":2023,"finding":"The Ajuba/PRMT5/Aurora-A complex coordinates sequential methylation and phosphorylation of HURP; mutual activation of PRMT5 and Aurora-A in this complex leads to HURP methylation (PRMT5) followed by phosphorylation (Aurora-A) to generate HURP p725. HURP p725 localizes near the Golgi apparatus and its crescent distribution shapes GA morphology by stabilizing Golgi assembly factors TRIP11, GRASP65, and GM130. HURP knockdown fragments GA; rescue requires phosphorylation-competent HURP.","method":"Scaffold protein complex co-IP, site-directed mutagenesis (p725A), knockdown-rescue, co-localization with GA markers, GST-pulldown of GAFs","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-step PTM cascade and structural rescue experiments, single lab, multiple orthogonal approaches","pmids":["37370099"],"is_preprint":false},{"year":2024,"finding":"HURP contains a tubulin-binding domain that binds the vinca domain on β-tubulin (the site targeted by vinca alkaloid drugs). Cryo-EM reveals HURP's tubulin-binding domain interacts directly at the vinca binding site. HURP competes directly with vinorelbine and counters vinorelbine-induced microtubule growth defects in vitro and in vivo, providing a mechanism for drug resistance.","method":"Cryo-EM structure of HURP–tubulin complex, in vitro competition assay with vinorelbine, cell-based microtubule growth assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structure plus in vitro competition assay plus in vivo validation, single lab, high-resolution structural data","pmids":["39397030"],"is_preprint":false},{"year":2024,"finding":"HURP stabilizes the microtubule lattice to promote γ-TuRC-mediated microtubule formation; in the presence of TPX2 condensates, HURP localization to microtubules is enhanced, shifting its function toward promoting branching microtubule nucleation. Cryo-EM structure reveals the molecular basis of HURP-mediated microtubule lattice stabilization. HURP is necessary for RanGTP-induced branching microtubule nucleation in Xenopus egg extract.","method":"Xenopus egg extract branching nucleation assay, HURP depletion, cryo-EM structure of HURP on microtubule lattice, γ-TuRC nucleation assay, TPX2 condensate co-localization","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure combined with Xenopus extract functional assays and γ-TuRC nucleation reconstitution, peer-reviewed","pmids":["39516491"],"is_preprint":false},{"year":2024,"finding":"Kif18A motility on microtubules is regulated by HURP concentration: sparse HURP decoration activates Kif18A motor activity while higher HURP concentrations inhibit processive motility by steric exclusion (HURP partially overlaps the Kif18A motor-domain microtubule-binding site). HURP and Kif18A together suppress microtubule plus-end dynamics, providing a mechanism for spindle/microtubule length control.","method":"Single-molecule imaging in vitro, cryo-EM structure of HURP on microtubule, microtubule dynamics assay with HURP+Kif18A","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — single-molecule in vitro assay plus cryo-EM structural validation, mechanistic epistasis, single lab","pmids":["39516196"],"is_preprint":false},{"year":2024,"finding":"DLGAP5 directly binds E2F1 and stabilizes E2F1 by preventing its ubiquitination via USP11 (a deubiquitinase). E2F1 in turn transcriptionally activates DLGAP5, forming a positive feedback loop that drives bladder cancer progression.","method":"Co-immunoprecipitation to show DLGAP5-E2F1 direct binding, ubiquitination assay, ChIP/transcription reporter for E2F1 → DLGAP5, in vitro and in vivo tumor assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP for direct binding, ubiquitination assay, transcriptional feedback loop, single lab","pmids":["38182895"],"is_preprint":false},{"year":2025,"finding":"DLGAP5 stabilizes MYC protein via deubiquitination mediated by USP11; DLGAP5 facilitates the interaction between USP11 and MYC, and MYC in turn transcriptionally drives DLGAP5 expression, forming a positive feedback loop that increases glycolytic activity and gemcitabine resistance in bladder cancer.","method":"Co-immunoprecipitation of DLGAP5-USP11-MYC complex, ubiquitination/deubiquitination assay, ChIP for MYC on DLGAP5 promoter, glycolysis assay, xenograft and spontaneous BLCA mouse models","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ternary complex Co-IP, deubiquitination assay, transcriptional feedback ChIP, single lab","pmids":["39990228"],"is_preprint":false},{"year":2025,"finding":"DLGAP5 mRNA is co-translationally targeted to the centrosome during mitosis; centrosomal transport requires microtubule binding of nascent HURP MBD1 polypeptides. mRNA targeting efficiency is linked to coding sequence length.","method":"APEX2-mediated proximity labeling to map centrosome-proximal transcriptome, drug perturbation, truncation/deletion/mutagenesis of DLGAP5 mRNA, imaging of centrosomal mRNA localization","journal":"RSC chemical biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity labeling with functional mutagenesis of transport signal, single lab","pmids":["40248433"],"is_preprint":false},{"year":2025,"finding":"DLGAP5 variants causing protein degradation or reduced expression impair spindle assembly in human oocytes (shown by DLGAP5 Trim-Away knockdown causing abnormal spindle morphology and oocyte maturation arrest). Homozygous Dlgap5 knock-in mice show embryonic arrest at the 4-cell stage with disrupted cell cycle regulation.","method":"Whole-exome sequencing of infertility patients, Trim-Away knockdown in human oocytes, knock-in mouse model (CRISPR-Cas9), IVF, immunofluorescence, RNA-seq of 4-cell embryos","journal":"Human reproduction (Oxford, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — patient variant identification plus Trim-Away functional knockdown in human oocytes plus KI mouse model with multiple readouts","pmids":["40639803"],"is_preprint":false},{"year":2025,"finding":"DLGAP5 deficiency disrupts spindle assembly in oocytes and early embryos through its interaction with TACC3; mutant DLGAP5 variants alter protein localization and cause spindle abnormalities in HeLa cells and mouse zygotes. Loss of DLGAP5-TACC3 interaction is the underlying mechanism of embryonic arrest.","method":"Whole-exome sequencing, transfection of mutants in HeLa cells, immunoprecipitation-mass spectrometry for interactome, mRNA microinjection in mouse zygotes, site-directed mutant mouse model","journal":"Human reproduction (Oxford, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — IP-MS interactome, genetic mouse model, mRNA injection rescue experiments, patient variants, multiple orthogonal approaches","pmids":["40796344"],"is_preprint":false},{"year":2025,"finding":"DLGAP5 knockdown in oocytes disrupts PI3K-AKT signaling pathway; PI3K-AKT activators can rescue oocyte maturation defects in Dlgap5-deficient mice. DLGAP5 depletion in human oocytes by siRNA causes abnormal spindle morphology and reduced germinal vesicle breakdown and polar body extrusion.","method":"siRNA microinjection in human oocytes, Dlgap5 knockout mouse oocyte analysis, single-cell RNA-seq, PI3K-AKT activator rescue experiment, immunofluorescence","journal":"Journal of ovarian research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional siRNA in human oocytes, pathway rescue by pharmacological activation, single lab","pmids":["42121242"],"is_preprint":false},{"year":2025,"finding":"METTL3-mediated m6A modification of DLGAP5 mRNA promotes DLGAP5 expression in an IGF2BP2-dependent manner during acute liver injury; METTL3 can bind DLGAP5 protein, and DLGAP5 promotes hepatocyte pyroptosis via NF-κB-dependent NLRP3 inflammasome activation and direct potentiation of inflammasome assembly.","method":"MeRIP-seq, Mettl3 mutant and Nlrp3 knockout mouse models, primary cell isolation, co-immunoprecipitation (METTL3-DLGAP5), inflammasome assembly assay","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP-seq plus genetic mouse models plus co-IP, single lab, multiple mechanisms reported","pmids":["40959279"],"is_preprint":false},{"year":2024,"finding":"AR (androgen receptor) directly binds the DLGAP5 promoter, enhancing its transcriptional activity; DLGAP5 acts downstream of AR to suppress p53 signaling pathway activation, reducing CD8+ T cell infiltration in triple-negative breast cancer.","method":"ChIP assay for AR on DLGAP5 promoter, DLGAP5 siRNA knockdown, p53 pathway reporter/western blot, in vivo xenograft with T cell analysis","journal":"Translational oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms direct transcriptional regulation, in vivo model, single lab","pmids":["39182361"],"is_preprint":false},{"year":2024,"finding":"DLGAP5 promotes lung adenocarcinoma cell proliferation via upregulation of PLK1; PLK1 overexpression rescues DLGAP5 knockdown-induced proliferation inhibition, and DLGAP5 overexpression reverses PLK1 suppression by AT9283, establishing DLGAP5 as an upstream regulator of PLK1.","method":"siRNA/overexpression of DLGAP5, PLK1 western blot, PLK1 rescue overexpression, in vitro and in vivo tumor assays","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional rescue experiment (DLGAP5 KD reversed by PLK1 OE and vice versa), single lab","pmids":["38414025"],"is_preprint":false},{"year":2023,"finding":"DLGAP5 promotes gallbladder cancer cell proliferation and migration and macrophage M2 polarization by directly activating the cAMP pathway; GST-pulldown demonstrated direct interaction between DLGAP5 and cAMP.","method":"GST-pulldown for DLGAP5-cAMP interaction, DLGAP5 overexpression/knockdown, macrophage polarization assay, in vivo xenograft","journal":"Cancer immunology, immunotherapy : CII","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — GST-pulldown shows direct interaction, functional macrophage polarization assay, in vivo validation, single lab","pmids":["37421434"],"is_preprint":false},{"year":2023,"finding":"DLGAP5 silencing inactivates the Wnt/β-catenin signaling pathway in endometrial cancer cells; β-catenin overexpression abolishes the effects of DLGAP5 knockdown on malignant phenotypes, placing DLGAP5 upstream of Wnt/β-catenin in this context.","method":"siRNA knockdown of DLGAP5, β-catenin overexpression rescue, western blot for Wnt3/c-Myc/Ki67, apoptosis assays","journal":"Environmental toxicology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single rescue experiment, no direct binding evidence for pathway placement, single lab","pmids":["36454672"],"is_preprint":false},{"year":2018,"finding":"DLGAP5 knockdown has a strong synergistic effect with docetaxel specifically in androgen-sensitive LNCaP prostate cancer cells; siRNA knockdown of the androgen receptor attenuates this synergy, and androgen receptor knockdown enables cells to progress through metaphase arrest induced by DLGAP5 KD + docetaxel. This places androgen receptor signaling in an epistatic relationship with DLGAP5 function in spindle stabilization.","method":"siRNA screen, cell viability assays, androgen receptor siRNA knockdown, immunofluorescence for mitotic stage, LNCaP-AI androgen-desensitized cells","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via siRNA double knockdown, multiple cell line controls, single lab","pmids":["30341281"],"is_preprint":false}],"current_model":"DLGAP5/HURP is a RanGTP-regulated, importin-β-inhibited microtubule-associated protein that localizes preferentially to kinetochore-fiber plus ends near chromosomes during mitosis, where it stabilizes the GDP microtubule lattice (as revealed by cryo-EM structures), promotes branching microtubule nucleation synergistically with TPX2, regulates Kif18A motility by steric competition, and is subject to multilayered post-translational control: Aurora A phosphorylation releases autoinhibition of its N-terminal microtubule-binding domain, Cdk1-cyclin B phosphorylation targets it for SCF(Fbx7)-mediated proteasomal degradation, and PRMT5/JMJD6-mediated arginine methylation at R122 governs its role in Golgi apparatus repositioning and cell migration outside mitosis."},"narrative":{"mechanistic_narrative":"DLGAP5 (HURP) is a RanGTP-regulated, importin-β-controlled microtubule-associated protein that stabilizes spindle microtubules and is essential for chromosome congression and bipolar spindle assembly during mitosis [PMID:16631580, PMID:16769820]. RanGTP releases HURP from an inhibitory importin-β complex and, together with continued importin-β cycling, confines it to the chromosome-proximal, kinetochore-fiber plus-end region of the spindle [PMID:16631580, PMID:34541678]. Cryo-EM shows HURP stabilizes the microtubule lattice and preferentially binds the GDP lattice, accumulating on depolymerizing kinetochore fibers while avoiding nascent polymerizing regions [PMID:35948594, PMID:39516491]; its tubulin-binding domain engages the vinca site on β-tubulin, allowing it to compete with vinca alkaloids [PMID:39397030]. At this location HURP promotes γ-TuRC-mediated and TPX2-synergized branching microtubule nucleation [PMID:39516491], steric-modulates Kif18A motility to control plus-end dynamics [PMID:39516196], and cooperates with TACC3 to drive kinetochore-microtubule assembly and lateral attachment [PMID:30054275]. HURP acts within a Ran-dependent complex with TPX2, XMAP215, Eg5 and Aurora A required for spindle formation [PMID:16631581]. Its activity is set by layered post-translational control: Aurora A phosphorylation relieves an intramolecular C-terminal autoinhibition of the N-terminal microtubule-binding domain and governs its chromosome-proximal gradient distribution [PMID:18321990, PMID:23610398], while Cdk1–cyclin B phosphorylation targets it for SCF(Fbx7)-mediated proteasomal degradation [PMID:15145941]. Outside mitosis, PRMT5-mediated arginine methylation at R122 stabilizes acetyl-tubulin bundling to brake Golgi repositioning and cell migration, an effect reversed by JMJD6 demethylation through an NF-κB–Cdc42 cascade [PMID:34541678, PMID:36250981]. HURP is required for female fertility and early development: knockout and patient-variant studies show defective oocyte and embryonic spindle assembly via loss of the DLGAP5–TACC3 interaction, causing oocyte maturation arrest and embryonic arrest [PMID:21173113, PMID:40639803, PMID:40796344]. In cancers, DLGAP5 stabilizes E2F1 and MYC through USP11-dependent deubiquitination in self-reinforcing transcriptional feedback loops that promote proliferation, glycolysis and drug resistance [PMID:38182895, PMID:39990228].","teleology":[{"year":2003,"claim":"Establishing that HURP is a cell-cycle-regulated mitotic protein framed it as a candidate spindle factor rather than a generic gene.","evidence":"Cell-cycle synchronization with RT-PCR and immunofluorescence in HeLa cells","pmids":["12527899"],"confidence":"Medium","gaps":["No molecular function assigned","Spindle-pole localization later refined to kinetochore microtubules"]},{"year":2005,"claim":"Identifying Aurora A as a HURP kinase showed that HURP function and stability are kinase-controlled, the first layer of its post-translational regulation.","evidence":"In vitro kinase assay, co-IP, phospho-deficient HURP-4P mutant, catalytically inactive Aurora A","pmids":["15987997"],"confidence":"High","gaps":["Mechanism by which phosphorylation enables complex assembly not yet defined","Specific phosphosites' structural consequences unresolved at this stage"]},{"year":2004,"claim":"Linking Cdk1-cyclin B phosphorylation to SCF(Fbx7)-mediated degradation defined how HURP levels are cleared, complementing its kinase activation.","evidence":"Fbx7 siRNA, ubiquitination assay, co-IP, phosphosite mutagenesis of substrate and adaptor","pmids":["15145941"],"confidence":"High","gaps":["Timing of degradation within mitosis not fully mapped","Interplay with Aurora A phosphorylation not directly tested"]},{"year":2006,"claim":"Resolving how RanGTP, importin-β and the TPX2/XMAP215/Eg5/Aurora A complex govern HURP localization and microtubule stabilization established its core mitotic mechanism.","evidence":"Importin-β/Ran mutant overexpression, IP-MS complex identification, Xenopus extract antibody injection, siRNA, in vitro MT binding/bundling, FRAP across three independent papers","pmids":["16631580","16631581","16769820"],"confidence":"High","gaps":["Structural basis of lattice stabilization not yet known","Quantitative localization gradient not yet defined"]},{"year":2006,"claim":"Cryo-EM of HURP-decorated microtubules provided the first structural view of how it bundles and reconfigures the lattice.","evidence":"Cryo-EM and surface shadowing of HURP-decorated microtubules in vitro","pmids":["17118403"],"confidence":"High","gaps":["Physiological relevance of the outer tubulin sheet in cells unclear","Nucleotide-state preference not yet examined"]},{"year":2008,"claim":"Discovering intramolecular autoinhibition relieved by Aurora A phosphorylation explained mechanistically how kinase signaling switches HURP microtubule affinity on.","evidence":"Domain-mapping, in vitro MT binding with N/C fragments, trans-dominant C-terminal expression, Aurora A kinase assay","pmids":["18321990"],"confidence":"High","gaps":["Phosphosite-resolved structural model of the released state lacking"]},{"year":2008,"claim":"Knockout phenotyping revealed an estrogen-induced uterine role of HURP in implantation, broadening its biology beyond the spindle.","evidence":"Hurp knockout mice, breeding, uterine histology, estrogen treatment","pmids":["18676373"],"confidence":"High","gaps":["Molecular target of HURP in stromal proliferation unknown","Connection to mitotic function not established"]},{"year":2010,"claim":"Oocyte and Drosophila ortholog studies showed HURP maintains spindle bipolarity and centrosome-spindle coupling, generalizing its stabilizing role to acentriolar and syncytial systems.","evidence":"Hurp knockout mouse oocytes, Kinesin-5 inhibition, live imaging; mars mutant Drosophila genetics","pmids":["21173113","19174464"],"confidence":"High","gaps":["Direct partners mediating MTOC sorting not identified"]},{"year":2011,"claim":"Identifying Kif18A as a HURP-regulated motor connected HURP to plus-end dynamics control during chromosome congression.","evidence":"Co-IP, BiFC, live imaging, Kif18A rescue of HURP(278) overexpression phenotype","pmids":["21924616"],"confidence":"Medium","gaps":["Single lab","Molecular basis of steric regulation resolved only later [#27]"]},{"year":2011,"claim":"Transcriptional and oncogenic studies (c-Rel, HBx/SATB1/survivin, gankyrin/p53) positioned HURP as a chemoresistance effector in hepatocellular carcinoma.","evidence":"ChIP, shRNA knockdown, pathway inhibition, ubiquitination assays, xenografts","pmids":["21549688","20541537","22230478"],"confidence":"Medium","gaps":["Single-lab pathway reconstructions","Direct vs indirect effects on p53 not fully separated"]},{"year":2013,"claim":"Chemical-probe imaging showed Aurora A phosphorylation governs HURP's spatial partitioning between centrosomal and kinetochore microtubules, refining the regulatory logic of its localization gradient.","evidence":"Multiple Aurora A inhibitors, phospho-specific antibodies, immunofluorescence","pmids":["23610398","23516487"],"confidence":"Medium","gaps":["No direct mutagenesis of sites controlling the gradient","Single lab"]},{"year":2018,"claim":"Defining the HURP–TACC3 interaction established a partner-based mechanism for kinetochore-microtubule assembly and lateral attachment.","evidence":"Co-IP, BiFC, siRNA, immunofluorescence","pmids":["30054275"],"confidence":"Medium","gaps":["Structural basis of the interaction unknown","Single lab"]},{"year":2019,"claim":"Single-centrosome experiments showed HURP accumulation scales inversely with half-spindle length, defining a length-dependent feedback that sets k-fiber stability and spindle symmetry.","evidence":"Centrinone/laser-ablation single-centrosome cells, siRNA, live imaging in 3 cell lines","pmids":["31668617"],"confidence":"High","gaps":["Molecular sensor of length not identified"]},{"year":2020,"claim":"Acute Ran degradation dissected importin-β/Ran control as specifically required for HURP and HSET chromosome-proximal localization, distinguishing it from NuMA/TPX2 activation.","evidence":"Auxin-inducible degron Ran depletion, FRAP, immunofluorescence","pmids":["33186548"],"confidence":"High","gaps":["How the binding–dissociation cycle is biochemically tuned not fully resolved"]},{"year":2021,"claim":"PRMT5 methylation of HURP at R122 revealed a non-mitotic role stabilizing Golgi tubulin bundling and braking cell migration.","evidence":"PRMT5 methyltransferase assay, R122F mutant, acetyl-tubulin co-IP, nocodazole sensitivity, wound healing","pmids":["34541678"],"confidence":"Medium","gaps":["Single lab","Endogenous methylation stoichiometry not measured"]},{"year":2022,"claim":"JMJD6 demethylation of R122 and the NF-κB–centrosome–Cdc42 cascade defined the reversible methylation switch controlling Golgi repositioning and migration.","evidence":"JMJD6 demethylase assay, R122F/R122K mutants, NF-κB reporter, Cdc42 knockdown, Golgi repositioning assay","pmids":["36250981"],"confidence":"Medium","gaps":["Single lab","Crosstalk with mitotic phosphorylation not addressed here"]},{"year":2022,"claim":"Demonstrating HURP's preference for the GDP lattice explained the chromosome-proximal 'HURP-gap' and how it discriminates depolymerizing from polymerizing k-fibers.","evidence":"In vitro GDP vs GTP microtubule binding, endogenously labeled HURP imaging, FRAP, quantitative modeling","pmids":["35948594"],"confidence":"High","gaps":["Structural basis of nucleotide discrimination defined only by later cryo-EM"]},{"year":2023,"claim":"Identifying Ser627 phosphorylation and at least two distinct metaphase complexes refined the multilayered control of HURP localization and partner binding.","evidence":"Photoactivation, FRAP, phospho-Ser627 mutant IP of multiple partners","pmids":["37484914"],"confidence":"Medium","gaps":["Composition and function of the two complexes not fully resolved","Single lab"]},{"year":2023,"claim":"The Ajuba/PRMT5/Aurora-A complex coupling sequential methylation then p725 phosphorylation showed how a PTM cascade directs HURP to shape Golgi morphology by stabilizing GA assembly factors.","evidence":"Scaffold complex co-IP, p725A mutagenesis, knockdown-rescue, GA marker colocalization, GST-pulldown of TRIP11/GRASP65/GM130","pmids":["37370099"],"confidence":"Medium","gaps":["Single lab","Direct vs scaffold-mediated GAF stabilization not fully separated"]},{"year":2024,"claim":"Cryo-EM resolved HURP binding the vinca site on β-tubulin, giving a structural mechanism for its lattice stabilization and for vinca-alkaloid drug resistance.","evidence":"Cryo-EM HURP–tubulin structure, in vitro vinorelbine competition, cell-based MT growth assay","pmids":["39397030"],"confidence":"High","gaps":["Clinical relevance of HURP-mediated vinca resistance not tested in patients"]},{"year":2024,"claim":"Reconstitution showed HURP promotes γ-TuRC-mediated and TPX2-synergized branching nucleation and steric-modulates Kif18A motility, integrating its stabilizing role into nucleation and length control.","evidence":"Xenopus extract branching assays, cryo-EM of HURP on lattice, γ-TuRC nucleation, single-molecule Kif18A imaging","pmids":["39516491","39516196"],"confidence":"High","gaps":["How TPX2 condensates switch HURP function in cells not fully defined"]},{"year":2024,"claim":"Oncogenic E2F1/MYC feedback loops via USP11-dependent deubiquitination established DLGAP5 as a stabilizer of proliferative transcription factors driving cancer and drug resistance.","evidence":"Co-IP, ubiquitination/deubiquitination assays, ChIP, glycolysis assays, xenograft and spontaneous tumor models","pmids":["38182895","39990228"],"confidence":"Medium","gaps":["Direct binding interfaces with USP11 not structurally defined","Relationship to its mitotic microtubule function unclear"]},{"year":2025,"claim":"Patient variants, Trim-Away knockdown, and mouse models tied DLGAP5 loss to oocyte and early-embryo spindle failure via the DLGAP5–TACC3 interaction, defining a human reproductive disease link.","evidence":"Whole-exome sequencing, Trim-Away/siRNA in human oocytes, IP-MS interactome, knock-in/mutant mouse models, mRNA injection rescue, PI3K-AKT activator rescue","pmids":["40639803","40796344","42121242"],"confidence":"High","gaps":["Mechanistic link between spindle defects and PI3K-AKT signaling not fully resolved"]},{"year":2025,"claim":"Co-translational centrosomal mRNA targeting via nascent MBD1 microtubule binding revealed a spatial control layer for where HURP is produced during mitosis.","evidence":"APEX2 proximity labeling, drug perturbation, mRNA truncation/mutagenesis, imaging","pmids":["40248433"],"confidence":"Medium","gaps":["Functional consequence of localized translation for spindle assembly not directly tested","Single lab"]},{"year":null,"claim":"How the mitotic microtubule-stabilizing function, the Golgi/migration methylation switch, and the oncogenic transcription-factor-stabilizing roles are integrated into a single regulatory framework remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model connecting spindle, Golgi, and deubiquitinase-scaffolding functions","Structural basis of E2F1/MYC/USP11 scaffolding undefined","In vivo relevance of HURP-mediated drug resistance untested clinically"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,2,6,22,25,26]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[27,26,17]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,2,22]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[14,30,18]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[20,21,24]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[16]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,2,18,26]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[8,9,31,32]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[28,29,31,32]}],"complexes":["Ran-dependent TPX2/XMAP215/Eg5/Aurora A spindle complex","SCF(Fbx7) ubiquitin ligase complex (as substrate)","Ajuba/PRMT5/Aurora-A complex"],"partners":["TPX2","AURKA","KIF18A","TACC3","KPNB1","FBXO7","USP11","PRMT5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15398","full_name":"Disks large-associated protein 5","aliases":["Discs large homolog 7","Disks large-associated protein DLG7","Hepatoma up-regulated protein","HURP"],"length_aa":846,"mass_kda":95.1,"function":"Potential cell cycle regulator that may play a role in carcinogenesis of cancer cells. Mitotic phosphoprotein regulated by the ubiquitin-proteasome pathway. Key regulator of adherens junction integrity and differentiation that may be involved in CDH1-mediated adhesion and signaling in epithelial cells","subcellular_location":"Nucleus; Cytoplasm; Cytoplasm, cytoskeleton, spindle","url":"https://www.uniprot.org/uniprotkb/Q15398/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DLGAP5","classification":"Not Classified","n_dependent_lines":96,"n_total_lines":1208,"dependency_fraction":0.07947019867549669},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"KPNB1","stoichiometry":0.2},{"gene":"TUBA1B","stoichiometry":0.2},{"gene":"TUBB4B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/DLGAP5","total_profiled":1310},"omim":[{"mim_id":"617859","title":"DISCS LARGE-ASSOCIATED PROTEIN 5; DLGAP5","url":"https://www.omim.org/entry/617859"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Mitotic spindle","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":28.0},{"tissue":"lymphoid tissue","ntpm":39.1},{"tissue":"testis","ntpm":16.3}],"url":"https://www.proteinatlas.org/search/DLGAP5"},"hgnc":{"alias_symbol":["KIAA0008","DLG1","HURP"],"prev_symbol":["DLG7"]},"alphafold":{"accession":"Q15398","domains":[{"cath_id":"-","chopping":"431-532","consensus_level":"high","plddt":93.8282,"start":431,"end":532}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15398","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15398-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15398-F1-predicted_aligned_error_v6.png","plddt_mean":55.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DLGAP5","jax_strain_url":"https://www.jax.org/strain/search?query=DLGAP5"},"sequence":{"accession":"Q15398","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15398.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15398/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15398"}},"corpus_meta":[{"pmid":"16631580","id":"PMC_16631580","title":"HURP 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variants in DLGAP5 cause female infertility characterized by oocyte maturation arrest and embryonic arrest.","date":"2025","source":"Human reproduction (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/40639803","citation_count":3,"is_preprint":false},{"pmid":"40248433","id":"PMC_40248433","title":"Enzyme-mediated proximity labeling reveals the co-translational targeting of DLGAP5 mRNA to the centrosome during mitosis.","date":"2025","source":"RSC chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/40248433","citation_count":3,"is_preprint":false},{"pmid":"38645125","id":"PMC_38645125","title":"Molecular interplay between HURP and Kif18A in mitotic spindle regulation.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38645125","citation_count":2,"is_preprint":false},{"pmid":"40796344","id":"PMC_40796344","title":"Biallelic variants in DLGAP5 cause spindle assembly defects and human early embryonic 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HURP localizes predominantly to kinetochore microtubules near chromosomes during mitosis, and depletion of HURP impairs K-fiber stabilization and delays chromosome congression.\",\n      \"method\": \"Overexpression of importin beta / RanT24N / RanQ69L mutants in cells, tsBN2 mutant cell analysis, in vitro microtubule bundling assay, siRNA depletion with live-cell imaging\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic and biochemical evidence across two independent labs (PMID:16631580 and PMID:16631581) with multiple orthogonal methods\",\n      \"pmids\": [\"16631580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"HURP is a component of a Ran-dependent multiprotein complex containing TPX2, XMAP215, Eg5, and Aurora A that is required for conversion of aster-like to spindle-like structures. Aurora A activity is required for complex formation and function. HURP binds microtubules and affects their organization in vitro and in vivo.\",\n      \"method\": \"Immunoprecipitation/mass spectrometry identification of complex, anti-HURP antibody injection in Xenopus egg extract, siRNA depletion in HeLa cells, in vitro microtubule binding assay\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — complex identified by MS, validated by functional antibody injection and siRNA, replicated across labs\",\n      \"pmids\": [\"16631581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"HURP binds directly to microtubules in vitro via its N-terminal region, enhances microtubule polymerization, stabilizes mitotic microtubules in vivo, and decreases spindle turnover rate. Depletion results in unaligned chromosomes, reduced interkinetochore tension, and spindle checkpoint activation.\",\n      \"method\": \"Functional genomic siRNA screen, in vitro microtubule binding assay, live-cell imaging, FRAP, immunofluorescence in HeLa cells\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (in vitro binding, FRAP, live imaging), consistent with two independent 2006 papers\",\n      \"pmids\": [\"16769820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"HURP mRNA expression is cell-cycle regulated, peaking at G2/M in synchronized HeLa cells; HURP protein localizes to spindle poles during mitosis by immunofluorescence.\",\n      \"method\": \"Cell cycle synchronization with RT-PCR, immunofluorescence in mitotic cells\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiment, single lab, consistent with later independent reports\",\n      \"pmids\": [\"12527899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Aurora A phosphorylates HURP in vitro and in vivo; phosphorylation by Aurora A is required for HURP stability and its assembly into complexes. A phosphorylation-deficient HURP-4P mutant (Aurora A sites mutated to Ala) showed reduced stability and poor complex assembly.\",\n      \"method\": \"In vitro kinase assay, co-immunoprecipitation, site-directed mutagenesis, stable transfection of Aurora A catalytically inactive form\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay plus mutagenesis plus in vivo validation, single lab\",\n      \"pmids\": [\"15987997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Fbx7, an F-box protein of the SCF ubiquitin-ligase complex, recruits HURP through its C-terminal proline-rich region in a Cdk1-cyclin B phosphorylation-dependent manner, leading to proteasome-mediated HURP proteolysis. Mutation of Cdk1-cyclin B phosphorylation sites on HURP or the proline-rich region of Fbx7 abolishes their association.\",\n      \"method\": \"siRNA depletion of Fbx7, ubiquitination assay, co-immunoprecipitation, site-directed mutagenesis of phosphorylation sites\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstituted SCF complex, mutagenesis of both substrate and adaptor, multiple orthogonal methods in single lab\",\n      \"pmids\": [\"15145941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"HURP wraps microtubule ends with an additional tubulin sheet forming two concentric tubes; the outer sheet consists of anti-parallel protofilaments with a novel 42.5° inclination. HURP stabilizes and bundles microtubules and also polymerizes free tubulin into a new configuration.\",\n      \"method\": \"Cryo-electron microscopy, unidirectional surface shadowing of HURP-decorated microtubules in vitro\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structural analysis with in vitro reconstitution, single lab\",\n      \"pmids\": [\"17118403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HURP binds microtubules through its N-terminal domain; in the hypophosphorylated state, the C-terminal region of HURP intramolecularly binds the N-terminal microtubule-binding domain and abrogates microtubule affinity. Aurora A phosphorylation of the C-terminal domain releases this autoinhibition, enabling microtubule binding and stabilization.\",\n      \"method\": \"Biochemical domain-mapping, in vitro microtubule binding assay with N- and C-terminal fragments, ectopic expression of C-terminal domain in HeLa cells, Aurora A kinase assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of autoinhibition mechanism, mutagenesis, cell-based trans-dominant experiment, single lab\",\n      \"pmids\": [\"18321990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In mouse oocytes (acentriolar meiotic spindle), HURP accumulates on interpolar MTs near chromosomes via Kinesin-5 activity. HURP promotes MT stability in the spindle central domain to allow efficient MTOC sorting into distinct poles, establishing and maintaining bipolarity. Hurp knockout females are viable but sterile due to defective oocyte divisions.\",\n      \"method\": \"Hurp knockout mouse generation, immunofluorescence, live-cell imaging of oocytes, Kinesin-5 inhibitor treatment\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO model with defined cellular phenotype, multiple orthogonal approaches including pharmacological inhibition and live imaging\",\n      \"pmids\": [\"21173113\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Hurp knockout female mice are infertile due to an implantation defect caused by a failure in endometrial stromal proliferation and the decidual reaction, not in ovulation, fertilization, or pre-implantation development. HURP expression in the uterus is induced by estrogen.\",\n      \"method\": \"Hurp knockout mouse generation, breeding experiments, histological analysis of uterus, estrogen treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined cellular phenotype, multiple readouts, single lab\",\n      \"pmids\": [\"18676373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"HURP regulates chromosome congression by interacting with kinesin Kif18A and controlling Kif18A localization and dynamics at the plus ends of kinetochore MTs. The N-terminal microtubule-binding domain of HURP (aa 1-278) mimics Kif18A depletion phenotypes; overexpression of Kif18A partially rescues misaligned chromosomes in HURP(278)-overexpressing cells.\",\n      \"method\": \"Co-immunoprecipitation, bimolecular fluorescence complementation (BiFC), live-cell imaging, rescue experiments\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction confirmed by BiFC and co-IP, functional rescue, single lab\",\n      \"pmids\": [\"21924616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"HURP overexpression promotes ubiquitination and proteasomal degradation of p53 via upregulation of gankyrin, a positive regulator of MDM2 E3 ubiquitin ligase. Knockdown of HURP leads to p53 accumulation, reduced proliferation, and sensitization to cisplatin in p53-positive cells.\",\n      \"method\": \"Ubiquitination assay, shRNA knockdown, gankyrin siRNA, exogenous p53 expression, tumor xenograft in nude mice\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway established by sequential knockdown experiments and rescue, single lab\",\n      \"pmids\": [\"22230478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"HBx viral protein upregulates HURP expression via p38/MAPK pathway through SATB1, and HURP mediates HBx-induced upregulation of survivin, contributing to cisplatin resistance in HCC cells.\",\n      \"method\": \"HBx expression in Hep3B cells, HURP shRNA knockdown, p38/MAPK pathway inhibition, survivin western blotting\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway established by knockdown and pathway inhibition, single lab\",\n      \"pmids\": [\"20541537\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Sorafenib inhibits HURP expression primarily at the transcriptional level by reducing translation and nuclear translocation of NF-κB family member c-Rel, which directly activates HURP gene transcription. c-Rel knockdown reduces HURP protein level and enhances taxol-induced cell death.\",\n      \"method\": \"Real-time PCR, chromatin immunoprecipitation (ChIP) assay, c-Rel shRNA knockdown, sorafenib treatment\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms direct transcription factor binding to HURP promoter, single lab, two orthogonal methods\",\n      \"pmids\": [\"21549688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Aurora A phosphorylation of HURP regulates its spatial distribution on the mitotic spindle: unphosphorylated HURP associates with centrosomal microtubules while phosphorylated HURP associates with kinetochore microtubules. HURP cycles continuously between these two forms in mitotic cells.\",\n      \"method\": \"Aurora A inhibitors (IBPR001, IBPR002, MLN8237) as chemical probes, immunofluorescence, phospho-specific antibodies in live cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological approach with multiple independent inhibitors, single lab, no direct mutagenesis\",\n      \"pmids\": [\"23610398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Tripolin A, a non-ATP competitive Aurora A inhibitor, reduces HURP's chromosome-proximal gradient distribution without affecting its microtubule binding, revealing Aurora A phosphorylation controls the gradient localization of HURP but not its general MT association.\",\n      \"method\": \"In vitro Aurora A kinase assay, immunofluorescence in human cells, comparison with MLN8054/MLN8237, in silico docking\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chemical probe with in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"23516487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Mars, the Drosophila ortholog of HURP, is required for the attachment of centrosomes to the mitotic spindle during syncytial nuclear divisions; loss of Mars causes centrosome detachment from spindles and ectopic microtubule nucleation. Mars localizes to nuclei in interphase and to spindle poles during mitosis.\",\n      \"method\": \"mars mutant Drosophila genetics, live-cell and fixed immunofluorescence imaging of early embryos\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function in Drosophila ortholog with clear cellular phenotype, single lab\",\n      \"pmids\": [\"19174464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HURP directly interacts with centrosomal protein TACC3 (via HURP residues 1-625) by co-immunoprecipitation and BiFC; HURP is required for TACC3 function during kinetochore microtubule assembly at chromosomes in prometaphase, and HURP regulates lateral kinetochore attachment and chromosome congression through modulation of TACC3.\",\n      \"method\": \"Co-immunoprecipitation, bimolecular fluorescence complementation, siRNA depletion, immunofluorescence\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction confirmed by two orthogonal methods (Co-IP and BiFC), functional epistasis, single lab\",\n      \"pmids\": [\"30054275\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HURP accumulates on k-fiber plus ends inversely proportionally to half-spindle length; centrosomes regulate k-fiber plus-end dynamics indirectly via length-dependent HURP accumulation. HURP depletion in cells with only one centrosome rebalances k-fiber stability and plus-end dynamics and improves spindle symmetry.\",\n      \"method\": \"Generation of human cells with one centrosome by centrinone treatment/laser ablation, HURP siRNA depletion, live-cell imaging in 3 cell lines, immunofluorescence\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — defined experimental manipulation (single centrosome cells), HURP depletion rescue, validated in 3 independent cell lines\",\n      \"pmids\": [\"31668617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Ran-GTP and importin-β coordinately promote HURP's dynamic microtubule binding-dissociation cycle to maintain HURP near chromosomes during metaphase. Acute mitotic depletion of Ran reveals it is specifically required for HURP and HSET localization to chromosome-proximal spindle regions to set proper spindle length during prometaphase, but not for NuMA or TPX2 activation.\",\n      \"method\": \"Auxin-inducible degron (AID) technology for acute mitotic Ran depletion in human cells, FRAP, immunofluorescence\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — acute conditional depletion technology with FRAP and live imaging, mechanistically dissected Ran's specific roles\",\n      \"pmids\": [\"33186548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PRMT5 methylates HURP at R122; methylated HURP (m122) interacts with acetyl-tubulin and stabilizes its bundling pattern, rigidifying the Golgi apparatus and retarding Golgi repositioning and cell migration. This acts as a brake on cell migration. PRMT5 is downregulated early in wound-healing, decreasing HURP m122.\",\n      \"method\": \"PRMT5 methyltransferase assay, HURP methylation-mimicking mutant (R122F) expression, acetyl-tubulin co-immunoprecipitation, nocodazole sensitivity assay, wound healing assay\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro methylation plus co-IP plus mutant phenotype rescue, single lab\",\n      \"pmids\": [\"34541678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"JMJD6 demethylates HURP at R122, promoting Golgi repositioning and cell migration via NF-κB-induced centrosome repositioning and subsequently Cdc42-dependent Golgi repositioning. The HURP methylation-deficiency mutant (R122K) promotes Golgi repositioning through this NF-κB-CR-Cdc42 cascade.\",\n      \"method\": \"JMJD6 demethylase assay, HURP methylation mutants (122F vs 122K), NF-κB reporter, Cdc42 knockdown, Golgi repositioning assay\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzymatic demethylation and functional mutant analysis, pathway epistasis, single lab\",\n      \"pmids\": [\"36250981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HURP preferentially binds the GDP microtubule lattice rather than GTP-tubulin in vitro and in vivo, accumulating on the kinetochore-proximal region of depolymerising kinetochore-fibres while avoiding nascent polymerising K-fibres, creating a 'HURP-gap' that corresponds to a mixed-nucleotide zone.\",\n      \"method\": \"In vitro HURP binding to GDP vs GTP microtubules, endogenously-labelled HURP live-cell imaging, FRAP, quantitative modeling\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro nucleotide-state preference assay combined with endogenous live-cell imaging and quantitative modeling, single lab\",\n      \"pmids\": [\"35948594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HURP phosphorylation at Ser627 regulates its localization to kinetochore fibers and its interactions with partner proteins (TPX2, Aurora A, Eg5, Dynein, Kif5B, importin β) in mammalian mitotic cells. HURP participates in at least two distinct complexes during metaphase. Microtubule flux affects HURP dynamics.\",\n      \"method\": \"Photoactivation and FRAP experiments, immunoprecipitation with phospho-Ser627 mutant HURP, co-IP of interaction partners in mitotic cells\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRAP, immunoprecipitation with phosphomutants, multiple partners, single lab\",\n      \"pmids\": [\"37484914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The Ajuba/PRMT5/Aurora-A complex coordinates sequential methylation and phosphorylation of HURP; mutual activation of PRMT5 and Aurora-A in this complex leads to HURP methylation (PRMT5) followed by phosphorylation (Aurora-A) to generate HURP p725. HURP p725 localizes near the Golgi apparatus and its crescent distribution shapes GA morphology by stabilizing Golgi assembly factors TRIP11, GRASP65, and GM130. HURP knockdown fragments GA; rescue requires phosphorylation-competent HURP.\",\n      \"method\": \"Scaffold protein complex co-IP, site-directed mutagenesis (p725A), knockdown-rescue, co-localization with GA markers, GST-pulldown of GAFs\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-step PTM cascade and structural rescue experiments, single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"37370099\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HURP contains a tubulin-binding domain that binds the vinca domain on β-tubulin (the site targeted by vinca alkaloid drugs). Cryo-EM reveals HURP's tubulin-binding domain interacts directly at the vinca binding site. HURP competes directly with vinorelbine and counters vinorelbine-induced microtubule growth defects in vitro and in vivo, providing a mechanism for drug resistance.\",\n      \"method\": \"Cryo-EM structure of HURP–tubulin complex, in vitro competition assay with vinorelbine, cell-based microtubule growth assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structure plus in vitro competition assay plus in vivo validation, single lab, high-resolution structural data\",\n      \"pmids\": [\"39397030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HURP stabilizes the microtubule lattice to promote γ-TuRC-mediated microtubule formation; in the presence of TPX2 condensates, HURP localization to microtubules is enhanced, shifting its function toward promoting branching microtubule nucleation. Cryo-EM structure reveals the molecular basis of HURP-mediated microtubule lattice stabilization. HURP is necessary for RanGTP-induced branching microtubule nucleation in Xenopus egg extract.\",\n      \"method\": \"Xenopus egg extract branching nucleation assay, HURP depletion, cryo-EM structure of HURP on microtubule lattice, γ-TuRC nucleation assay, TPX2 condensate co-localization\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure combined with Xenopus extract functional assays and γ-TuRC nucleation reconstitution, peer-reviewed\",\n      \"pmids\": [\"39516491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Kif18A motility on microtubules is regulated by HURP concentration: sparse HURP decoration activates Kif18A motor activity while higher HURP concentrations inhibit processive motility by steric exclusion (HURP partially overlaps the Kif18A motor-domain microtubule-binding site). HURP and Kif18A together suppress microtubule plus-end dynamics, providing a mechanism for spindle/microtubule length control.\",\n      \"method\": \"Single-molecule imaging in vitro, cryo-EM structure of HURP on microtubule, microtubule dynamics assay with HURP+Kif18A\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — single-molecule in vitro assay plus cryo-EM structural validation, mechanistic epistasis, single lab\",\n      \"pmids\": [\"39516196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DLGAP5 directly binds E2F1 and stabilizes E2F1 by preventing its ubiquitination via USP11 (a deubiquitinase). E2F1 in turn transcriptionally activates DLGAP5, forming a positive feedback loop that drives bladder cancer progression.\",\n      \"method\": \"Co-immunoprecipitation to show DLGAP5-E2F1 direct binding, ubiquitination assay, ChIP/transcription reporter for E2F1 → DLGAP5, in vitro and in vivo tumor assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP for direct binding, ubiquitination assay, transcriptional feedback loop, single lab\",\n      \"pmids\": [\"38182895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DLGAP5 stabilizes MYC protein via deubiquitination mediated by USP11; DLGAP5 facilitates the interaction between USP11 and MYC, and MYC in turn transcriptionally drives DLGAP5 expression, forming a positive feedback loop that increases glycolytic activity and gemcitabine resistance in bladder cancer.\",\n      \"method\": \"Co-immunoprecipitation of DLGAP5-USP11-MYC complex, ubiquitination/deubiquitination assay, ChIP for MYC on DLGAP5 promoter, glycolysis assay, xenograft and spontaneous BLCA mouse models\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ternary complex Co-IP, deubiquitination assay, transcriptional feedback ChIP, single lab\",\n      \"pmids\": [\"39990228\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DLGAP5 mRNA is co-translationally targeted to the centrosome during mitosis; centrosomal transport requires microtubule binding of nascent HURP MBD1 polypeptides. mRNA targeting efficiency is linked to coding sequence length.\",\n      \"method\": \"APEX2-mediated proximity labeling to map centrosome-proximal transcriptome, drug perturbation, truncation/deletion/mutagenesis of DLGAP5 mRNA, imaging of centrosomal mRNA localization\",\n      \"journal\": \"RSC chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity labeling with functional mutagenesis of transport signal, single lab\",\n      \"pmids\": [\"40248433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DLGAP5 variants causing protein degradation or reduced expression impair spindle assembly in human oocytes (shown by DLGAP5 Trim-Away knockdown causing abnormal spindle morphology and oocyte maturation arrest). Homozygous Dlgap5 knock-in mice show embryonic arrest at the 4-cell stage with disrupted cell cycle regulation.\",\n      \"method\": \"Whole-exome sequencing of infertility patients, Trim-Away knockdown in human oocytes, knock-in mouse model (CRISPR-Cas9), IVF, immunofluorescence, RNA-seq of 4-cell embryos\",\n      \"journal\": \"Human reproduction (Oxford, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — patient variant identification plus Trim-Away functional knockdown in human oocytes plus KI mouse model with multiple readouts\",\n      \"pmids\": [\"40639803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DLGAP5 deficiency disrupts spindle assembly in oocytes and early embryos through its interaction with TACC3; mutant DLGAP5 variants alter protein localization and cause spindle abnormalities in HeLa cells and mouse zygotes. Loss of DLGAP5-TACC3 interaction is the underlying mechanism of embryonic arrest.\",\n      \"method\": \"Whole-exome sequencing, transfection of mutants in HeLa cells, immunoprecipitation-mass spectrometry for interactome, mRNA microinjection in mouse zygotes, site-directed mutant mouse model\",\n      \"journal\": \"Human reproduction (Oxford, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — IP-MS interactome, genetic mouse model, mRNA injection rescue experiments, patient variants, multiple orthogonal approaches\",\n      \"pmids\": [\"40796344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DLGAP5 knockdown in oocytes disrupts PI3K-AKT signaling pathway; PI3K-AKT activators can rescue oocyte maturation defects in Dlgap5-deficient mice. DLGAP5 depletion in human oocytes by siRNA causes abnormal spindle morphology and reduced germinal vesicle breakdown and polar body extrusion.\",\n      \"method\": \"siRNA microinjection in human oocytes, Dlgap5 knockout mouse oocyte analysis, single-cell RNA-seq, PI3K-AKT activator rescue experiment, immunofluorescence\",\n      \"journal\": \"Journal of ovarian research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional siRNA in human oocytes, pathway rescue by pharmacological activation, single lab\",\n      \"pmids\": [\"42121242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"METTL3-mediated m6A modification of DLGAP5 mRNA promotes DLGAP5 expression in an IGF2BP2-dependent manner during acute liver injury; METTL3 can bind DLGAP5 protein, and DLGAP5 promotes hepatocyte pyroptosis via NF-κB-dependent NLRP3 inflammasome activation and direct potentiation of inflammasome assembly.\",\n      \"method\": \"MeRIP-seq, Mettl3 mutant and Nlrp3 knockout mouse models, primary cell isolation, co-immunoprecipitation (METTL3-DLGAP5), inflammasome assembly assay\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-seq plus genetic mouse models plus co-IP, single lab, multiple mechanisms reported\",\n      \"pmids\": [\"40959279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"AR (androgen receptor) directly binds the DLGAP5 promoter, enhancing its transcriptional activity; DLGAP5 acts downstream of AR to suppress p53 signaling pathway activation, reducing CD8+ T cell infiltration in triple-negative breast cancer.\",\n      \"method\": \"ChIP assay for AR on DLGAP5 promoter, DLGAP5 siRNA knockdown, p53 pathway reporter/western blot, in vivo xenograft with T cell analysis\",\n      \"journal\": \"Translational oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms direct transcriptional regulation, in vivo model, single lab\",\n      \"pmids\": [\"39182361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DLGAP5 promotes lung adenocarcinoma cell proliferation via upregulation of PLK1; PLK1 overexpression rescues DLGAP5 knockdown-induced proliferation inhibition, and DLGAP5 overexpression reverses PLK1 suppression by AT9283, establishing DLGAP5 as an upstream regulator of PLK1.\",\n      \"method\": \"siRNA/overexpression of DLGAP5, PLK1 western blot, PLK1 rescue overexpression, in vitro and in vivo tumor assays\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional rescue experiment (DLGAP5 KD reversed by PLK1 OE and vice versa), single lab\",\n      \"pmids\": [\"38414025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DLGAP5 promotes gallbladder cancer cell proliferation and migration and macrophage M2 polarization by directly activating the cAMP pathway; GST-pulldown demonstrated direct interaction between DLGAP5 and cAMP.\",\n      \"method\": \"GST-pulldown for DLGAP5-cAMP interaction, DLGAP5 overexpression/knockdown, macrophage polarization assay, in vivo xenograft\",\n      \"journal\": \"Cancer immunology, immunotherapy : CII\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — GST-pulldown shows direct interaction, functional macrophage polarization assay, in vivo validation, single lab\",\n      \"pmids\": [\"37421434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DLGAP5 silencing inactivates the Wnt/β-catenin signaling pathway in endometrial cancer cells; β-catenin overexpression abolishes the effects of DLGAP5 knockdown on malignant phenotypes, placing DLGAP5 upstream of Wnt/β-catenin in this context.\",\n      \"method\": \"siRNA knockdown of DLGAP5, β-catenin overexpression rescue, western blot for Wnt3/c-Myc/Ki67, apoptosis assays\",\n      \"journal\": \"Environmental toxicology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single rescue experiment, no direct binding evidence for pathway placement, single lab\",\n      \"pmids\": [\"36454672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DLGAP5 knockdown has a strong synergistic effect with docetaxel specifically in androgen-sensitive LNCaP prostate cancer cells; siRNA knockdown of the androgen receptor attenuates this synergy, and androgen receptor knockdown enables cells to progress through metaphase arrest induced by DLGAP5 KD + docetaxel. This places androgen receptor signaling in an epistatic relationship with DLGAP5 function in spindle stabilization.\",\n      \"method\": \"siRNA screen, cell viability assays, androgen receptor siRNA knockdown, immunofluorescence for mitotic stage, LNCaP-AI androgen-desensitized cells\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via siRNA double knockdown, multiple cell line controls, single lab\",\n      \"pmids\": [\"30341281\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DLGAP5/HURP is a RanGTP-regulated, importin-β-inhibited microtubule-associated protein that localizes preferentially to kinetochore-fiber plus ends near chromosomes during mitosis, where it stabilizes the GDP microtubule lattice (as revealed by cryo-EM structures), promotes branching microtubule nucleation synergistically with TPX2, regulates Kif18A motility by steric competition, and is subject to multilayered post-translational control: Aurora A phosphorylation releases autoinhibition of its N-terminal microtubule-binding domain, Cdk1-cyclin B phosphorylation targets it for SCF(Fbx7)-mediated proteasomal degradation, and PRMT5/JMJD6-mediated arginine methylation at R122 governs its role in Golgi apparatus repositioning and cell migration outside mitosis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DLGAP5 (HURP) is a RanGTP-regulated, importin-\\u03b2-controlled microtubule-associated protein that stabilizes spindle microtubules and is essential for chromosome congression and bipolar spindle assembly during mitosis [#0, #2]. RanGTP releases HURP from an inhibitory importin-\\u03b2 complex and, together with continued importin-\\u03b2 cycling, confines it to the chromosome-proximal, kinetochore-fiber plus-end region of the spindle [#0, #20]. Cryo-EM shows HURP stabilizes the microtubule lattice and preferentially binds the GDP lattice, accumulating on depolymerizing kinetochore fibers while avoiding nascent polymerizing regions [#22, #26]; its tubulin-binding domain engages the vinca site on \\u03b2-tubulin, allowing it to compete with vinca alkaloids [#25]. At this location HURP promotes \\u03b3-TuRC-mediated and TPX2-synergized branching microtubule nucleation [#26], steric-modulates Kif18A motility to control plus-end dynamics [#27], and cooperates with TACC3 to drive kinetochore-microtubule assembly and lateral attachment [#17]. HURP acts within a Ran-dependent complex with TPX2, XMAP215, Eg5 and Aurora A required for spindle formation [#1]. Its activity is set by layered post-translational control: Aurora A phosphorylation relieves an intramolecular C-terminal autoinhibition of the N-terminal microtubule-binding domain and governs its chromosome-proximal gradient distribution [#7, #14], while Cdk1\\u2013cyclin B phosphorylation targets it for SCF(Fbx7)-mediated proteasomal degradation [#5]. Outside mitosis, PRMT5-mediated arginine methylation at R122 stabilizes acetyl-tubulin bundling to brake Golgi repositioning and cell migration, an effect reversed by JMJD6 demethylation through an NF-\\u03baB\\u2013Cdc42 cascade [#20, #21]. HURP is required for female fertility and early development: knockout and patient-variant studies show defective oocyte and embryonic spindle assembly via loss of the DLGAP5\\u2013TACC3 interaction, causing oocyte maturation arrest and embryonic arrest [#8, #31, #32]. In cancers, DLGAP5 stabilizes E2F1 and MYC through USP11-dependent deubiquitination in self-reinforcing transcriptional feedback loops that promote proliferation, glycolysis and drug resistance [#28, #29].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Establishing that HURP is a cell-cycle-regulated mitotic protein framed it as a candidate spindle factor rather than a generic gene.\",\n      \"evidence\": \"Cell-cycle synchronization with RT-PCR and immunofluorescence in HeLa cells\",\n      \"pmids\": [\"12527899\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular function assigned\", \"Spindle-pole localization later refined to kinetochore microtubules\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identifying Aurora A as a HURP kinase showed that HURP function and stability are kinase-controlled, the first layer of its post-translational regulation.\",\n      \"evidence\": \"In vitro kinase assay, co-IP, phospho-deficient HURP-4P mutant, catalytically inactive Aurora A\",\n      \"pmids\": [\"15987997\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which phosphorylation enables complex assembly not yet defined\", \"Specific phosphosites' structural consequences unresolved at this stage\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Linking Cdk1-cyclin B phosphorylation to SCF(Fbx7)-mediated degradation defined how HURP levels are cleared, complementing its kinase activation.\",\n      \"evidence\": \"Fbx7 siRNA, ubiquitination assay, co-IP, phosphosite mutagenesis of substrate and adaptor\",\n      \"pmids\": [\"15145941\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Timing of degradation within mitosis not fully mapped\", \"Interplay with Aurora A phosphorylation not directly tested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Resolving how RanGTP, importin-\\u03b2 and the TPX2/XMAP215/Eg5/Aurora A complex govern HURP localization and microtubule stabilization established its core mitotic mechanism.\",\n      \"evidence\": \"Importin-\\u03b2/Ran mutant overexpression, IP-MS complex identification, Xenopus extract antibody injection, siRNA, in vitro MT binding/bundling, FRAP across three independent papers\",\n      \"pmids\": [\"16631580\", \"16631581\", \"16769820\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of lattice stabilization not yet known\", \"Quantitative localization gradient not yet defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Cryo-EM of HURP-decorated microtubules provided the first structural view of how it bundles and reconfigures the lattice.\",\n      \"evidence\": \"Cryo-EM and surface shadowing of HURP-decorated microtubules in vitro\",\n      \"pmids\": [\"17118403\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological relevance of the outer tubulin sheet in cells unclear\", \"Nucleotide-state preference not yet examined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Discovering intramolecular autoinhibition relieved by Aurora A phosphorylation explained mechanistically how kinase signaling switches HURP microtubule affinity on.\",\n      \"evidence\": \"Domain-mapping, in vitro MT binding with N/C fragments, trans-dominant C-terminal expression, Aurora A kinase assay\",\n      \"pmids\": [\"18321990\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphosite-resolved structural model of the released state lacking\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Knockout phenotyping revealed an estrogen-induced uterine role of HURP in implantation, broadening its biology beyond the spindle.\",\n      \"evidence\": \"Hurp knockout mice, breeding, uterine histology, estrogen treatment\",\n      \"pmids\": [\"18676373\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular target of HURP in stromal proliferation unknown\", \"Connection to mitotic function not established\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Oocyte and Drosophila ortholog studies showed HURP maintains spindle bipolarity and centrosome-spindle coupling, generalizing its stabilizing role to acentriolar and syncytial systems.\",\n      \"evidence\": \"Hurp knockout mouse oocytes, Kinesin-5 inhibition, live imaging; mars mutant Drosophila genetics\",\n      \"pmids\": [\"21173113\", \"19174464\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct partners mediating MTOC sorting not identified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identifying Kif18A as a HURP-regulated motor connected HURP to plus-end dynamics control during chromosome congression.\",\n      \"evidence\": \"Co-IP, BiFC, live imaging, Kif18A rescue of HURP(278) overexpression phenotype\",\n      \"pmids\": [\"21924616\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Molecular basis of steric regulation resolved only later [#27]\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Transcriptional and oncogenic studies (c-Rel, HBx/SATB1/survivin, gankyrin/p53) positioned HURP as a chemoresistance effector in hepatocellular carcinoma.\",\n      \"evidence\": \"ChIP, shRNA knockdown, pathway inhibition, ubiquitination assays, xenografts\",\n      \"pmids\": [\"21549688\", \"20541537\", \"22230478\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab pathway reconstructions\", \"Direct vs indirect effects on p53 not fully separated\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Chemical-probe imaging showed Aurora A phosphorylation governs HURP's spatial partitioning between centrosomal and kinetochore microtubules, refining the regulatory logic of its localization gradient.\",\n      \"evidence\": \"Multiple Aurora A inhibitors, phospho-specific antibodies, immunofluorescence\",\n      \"pmids\": [\"23610398\", \"23516487\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct mutagenesis of sites controlling the gradient\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defining the HURP\\u2013TACC3 interaction established a partner-based mechanism for kinetochore-microtubule assembly and lateral attachment.\",\n      \"evidence\": \"Co-IP, BiFC, siRNA, immunofluorescence\",\n      \"pmids\": [\"30054275\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of the interaction unknown\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Single-centrosome experiments showed HURP accumulation scales inversely with half-spindle length, defining a length-dependent feedback that sets k-fiber stability and spindle symmetry.\",\n      \"evidence\": \"Centrinone/laser-ablation single-centrosome cells, siRNA, live imaging in 3 cell lines\",\n      \"pmids\": [\"31668617\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular sensor of length not identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Acute Ran degradation dissected importin-\\u03b2/Ran control as specifically required for HURP and HSET chromosome-proximal localization, distinguishing it from NuMA/TPX2 activation.\",\n      \"evidence\": \"Auxin-inducible degron Ran depletion, FRAP, immunofluorescence\",\n      \"pmids\": [\"33186548\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How the binding\\u2013dissociation cycle is biochemically tuned not fully resolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"PRMT5 methylation of HURP at R122 revealed a non-mitotic role stabilizing Golgi tubulin bundling and braking cell migration.\",\n      \"evidence\": \"PRMT5 methyltransferase assay, R122F mutant, acetyl-tubulin co-IP, nocodazole sensitivity, wound healing\",\n      \"pmids\": [\"34541678\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Endogenous methylation stoichiometry not measured\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"JMJD6 demethylation of R122 and the NF-\\u03baB\\u2013centrosome\\u2013Cdc42 cascade defined the reversible methylation switch controlling Golgi repositioning and migration.\",\n      \"evidence\": \"JMJD6 demethylase assay, R122F/R122K mutants, NF-\\u03baB reporter, Cdc42 knockdown, Golgi repositioning assay\",\n      \"pmids\": [\"36250981\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Crosstalk with mitotic phosphorylation not addressed here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating HURP's preference for the GDP lattice explained the chromosome-proximal 'HURP-gap' and how it discriminates depolymerizing from polymerizing k-fibers.\",\n      \"evidence\": \"In vitro GDP vs GTP microtubule binding, endogenously labeled HURP imaging, FRAP, quantitative modeling\",\n      \"pmids\": [\"35948594\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of nucleotide discrimination defined only by later cryo-EM\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying Ser627 phosphorylation and at least two distinct metaphase complexes refined the multilayered control of HURP localization and partner binding.\",\n      \"evidence\": \"Photoactivation, FRAP, phospho-Ser627 mutant IP of multiple partners\",\n      \"pmids\": [\"37484914\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Composition and function of the two complexes not fully resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The Ajuba/PRMT5/Aurora-A complex coupling sequential methylation then p725 phosphorylation showed how a PTM cascade directs HURP to shape Golgi morphology by stabilizing GA assembly factors.\",\n      \"evidence\": \"Scaffold complex co-IP, p725A mutagenesis, knockdown-rescue, GA marker colocalization, GST-pulldown of TRIP11/GRASP65/GM130\",\n      \"pmids\": [\"37370099\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct vs scaffold-mediated GAF stabilization not fully separated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Cryo-EM resolved HURP binding the vinca site on \\u03b2-tubulin, giving a structural mechanism for its lattice stabilization and for vinca-alkaloid drug resistance.\",\n      \"evidence\": \"Cryo-EM HURP\\u2013tubulin structure, in vitro vinorelbine competition, cell-based MT growth assay\",\n      \"pmids\": [\"39397030\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Clinical relevance of HURP-mediated vinca resistance not tested in patients\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Reconstitution showed HURP promotes \\u03b3-TuRC-mediated and TPX2-synergized branching nucleation and steric-modulates Kif18A motility, integrating its stabilizing role into nucleation and length control.\",\n      \"evidence\": \"Xenopus extract branching assays, cryo-EM of HURP on lattice, \\u03b3-TuRC nucleation, single-molecule Kif18A imaging\",\n      \"pmids\": [\"39516491\", \"39516196\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How TPX2 condensates switch HURP function in cells not fully defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Oncogenic E2F1/MYC feedback loops via USP11-dependent deubiquitination established DLGAP5 as a stabilizer of proliferative transcription factors driving cancer and drug resistance.\",\n      \"evidence\": \"Co-IP, ubiquitination/deubiquitination assays, ChIP, glycolysis assays, xenograft and spontaneous tumor models\",\n      \"pmids\": [\"38182895\", \"39990228\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding interfaces with USP11 not structurally defined\", \"Relationship to its mitotic microtubule function unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Patient variants, Trim-Away knockdown, and mouse models tied DLGAP5 loss to oocyte and early-embryo spindle failure via the DLGAP5\\u2013TACC3 interaction, defining a human reproductive disease link.\",\n      \"evidence\": \"Whole-exome sequencing, Trim-Away/siRNA in human oocytes, IP-MS interactome, knock-in/mutant mouse models, mRNA injection rescue, PI3K-AKT activator rescue\",\n      \"pmids\": [\"40639803\", \"40796344\", \"42121242\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link between spindle defects and PI3K-AKT signaling not fully resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Co-translational centrosomal mRNA targeting via nascent MBD1 microtubule binding revealed a spatial control layer for where HURP is produced during mitosis.\",\n      \"evidence\": \"APEX2 proximity labeling, drug perturbation, mRNA truncation/mutagenesis, imaging\",\n      \"pmids\": [\"40248433\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of localized translation for spindle assembly not directly tested\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the mitotic microtubule-stabilizing function, the Golgi/migration methylation switch, and the oncogenic transcription-factor-stabilizing roles are integrated into a single regulatory framework remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model connecting spindle, Golgi, and deubiquitinase-scaffolding functions\", \"Structural basis of E2F1/MYC/USP11 scaffolding undefined\", \"In vivo relevance of HURP-mediated drug resistance untested clinically\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 2, 6, 22, 25, 26]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [27, 26, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 2, 22]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [14, 30, 18]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [20, 21, 24]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 2, 18, 26]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [8, 9, 31, 32]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [28, 29, 31, 32]}\n    ],\n    \"complexes\": [\n      \"Ran-dependent TPX2/XMAP215/Eg5/Aurora A spindle complex\",\n      \"SCF(Fbx7) ubiquitin ligase complex (as substrate)\",\n      \"Ajuba/PRMT5/Aurora-A complex\"\n    ],\n    \"partners\": [\n      \"TPX2\",\n      \"AURKA\",\n      \"KIF18A\",\n      \"TACC3\",\n      \"KPNB1\",\n      \"FBXO7\",\n      \"USP11\",\n      \"PRMT5\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}