{"gene":"AURKB","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":1998,"finding":"AIM-1 (AURKB) is a mammalian serine/threonine kinase that localizes to the equator of central spindles during late anaphase and to the midbody during telophase and cytokinesis; overexpression of kinase-inactive AIM-1 disrupts cleavage furrow formation without affecting nuclear division, demonstrating that AURKB kinase activity is required for cytokinesis.","method":"Dominant-negative overexpression, immunofluorescence localization, cell ploidy analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — dominant-negative functional rescue with specific cytokinesis phenotype, replicated in subsequent studies","pmids":["9450992"],"is_preprint":false},{"year":1998,"finding":"AURKB overexpression in human cancer cells produces multinuclearity and increased ploidy due to cytokinesis errors, establishing that excess AURKB disrupts chromosomal integrity.","method":"Exogenous overexpression in tumor cell lines, flow cytometry for ploidy","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — overexpression phenotype with clear readout; single lab but consistent with orthogonal dominant-negative data","pmids":["9809983"],"is_preprint":false},{"year":2000,"finding":"Ipl1/Aurora kinase (AURKB ortholog) and the Glc7/PP1 phosphatase together govern the balance of histone H3 serine-10 phosphorylation during mitosis, and both activities are required for proper chromosome segregation in S. cerevisiae and C. elegans.","method":"Genetic epistasis in yeast and C. elegans, histone phosphorylation assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 — multi-organism genetic epistasis plus biochemical H3-phosphorylation assay; highly cited foundational work","pmids":["10975519"],"is_preprint":false},{"year":2000,"finding":"AIM-1 (rat AURKB) phosphorylates myosin II regulatory light chain (MRLC) at Ser19 in vitro and colocalizes with monophosphorylated MRLC at the cleavage furrow, implicating AURKB in MRLC phosphorylation during cytokinesis.","method":"In vitro kinase assay, two-dimensional phosphopeptide mapping, MRLC mutant analysis, immunofluorescence colocalization","journal":"Journal of biochemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro phosphorylation with site-specific mutants and in-cell colocalization","pmids":["11098131"],"is_preprint":false},{"year":2001,"finding":"The yeast AURKB ortholog Ipl1 promotes chromosome bi-orientation by facilitating turnover of kinetochore-spindle pole connections; in ipl1 mutants, kinetochores remain inappropriately attached to old spindle pole bodies, indicating Ipl1 resolves syntelic attachments.","method":"Live-cell imaging, genetic analysis of spindle pole body attachment in DNA-replication-deficient cells","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — direct imaging of kinetochore dynamics in genetic mutants; replicated across multiple labs","pmids":["11853667"],"is_preprint":false},{"year":2001,"finding":"Ipl1 (AURKB ortholog) is required for spindle checkpoint activation in response to lack of kinetochore tension but not for checkpoint arrest induced by spindle depolymerization, positioning Ipl1 as a tension-specific checkpoint activator.","method":"Genetic analysis, Mps1 overexpression checkpoint assays in ipl1 mutant yeast","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 — epistasis with specific genetic separation of tension vs. attachment checkpoint signals","pmids":["11731476"],"is_preprint":false},{"year":2001,"finding":"Sli15 (INCENP ortholog) directly associates with Ipl1 (AURKB) in vivo, stimulates Ipl1 kinase activity in vitro, and facilitates Ipl1 association with the mitotic spindle; both Sli15 and Dam1 are phosphorylated by Ipl1 in vitro and show reduced phosphorylation in ipl1 mutants in vivo.","method":"Co-immunoprecipitation, in vitro kinase assay, spindle localization imaging, in vivo phosphorylation assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 — reciprocal co-IP, in vitro kinase stimulation, and in vivo phosphorylation with multiple substrates","pmids":["11724818"],"is_preprint":false},{"year":2002,"finding":"AURKB overexpression causes increased mitotic histone H3 Ser10 phosphorylation with concomitant induction of lagging chromosomes; expression of phosphomimetic H3(S10E) recapitulates this phenotype, demonstrating that excess H3-S10 phosphorylation is a precipitating factor of chromosome instability.","method":"Exogenous overexpression, histone mutant transfection, cytogenetic analysis of lagging chromosomes","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 — phosphomimetic mutant epistasis plus overexpression phenotype; single lab","pmids":["12234980"],"is_preprint":false},{"year":2002,"finding":"AURKB (AIM-1) expression is regulated by E2F transcription factors; doxorubicin-induced sustained G2/M arrest involves E2F-dependent downregulation of AIM-1 (AURKB), and abrogation of E2F function prevents this downregulation and leads to premature exit from G2.","method":"Dominant-negative E2F expression, E7 papillomavirus protein expression, gene expression analysis, cell cycle assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — E2F functional epistasis with genotoxic checkpoint readout; single lab","pmids":["12446714"],"is_preprint":false},{"year":2002,"finding":"Aurora-B (AURKB) and Aurora-A physically interact with histone H3 tail and phosphorylate H3-Ser10 both in vitro and in vivo; Aurora-B colocalizes with H3 phosphorylation at the centromeric region during prophase/metaphase and translocates to the midbody during cytokinesis.","method":"In vitro kinase assay, co-immunoprecipitation, immunofluorescence colocalization, cell cycle staging","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 — in vitro phosphorylation plus in vivo colocalization and physical interaction; highly cited","pmids":["11784863"],"is_preprint":false},{"year":2003,"finding":"Aurora B kinase activity is required for proper localization of the entire Aurora B/INCENP/survivin complex to centromeres and central spindle; INCENP directly activates Aurora B kinase activity and is itself phosphorylated by Aurora B at Thr893/Ser894/Ser895 — a non-phosphorylatable mutant (TSS→AAA) is a poor activator, demonstrating that INCENP phosphorylation is required for full kinase activation.","method":"Dominant-negative overexpression, RNAi depletion, in vitro kinase assay with recombinant proteins, mass spectrometry phosphosite identification, site-directed mutagenesis","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 — reconstituted in vitro with mutagenesis validation, multiple orthogonal methods","pmids":["12925766"],"is_preprint":false},{"year":2004,"finding":"Borealin is a novel subunit of the chromosomal passenger complex (CPC) containing Aurora B/INCENP/Survivin; approximately half of Aurora B in mitotic cells is in the four-subunit complex; Borealin binds Survivin and INCENP in vitro; Borealin depletion causes kinetochore-spindle misattachments and ectopic spindle poles.","method":"Co-immunoprecipitation, in vitro binding, RNAi depletion, immunofluorescence","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro reconstitution of complex, RNAi phenotype, complex stoichiometry; replicated by other labs","pmids":["15249581"],"is_preprint":false},{"year":2004,"finding":"The chromosomal passenger complex (containing Aurora B) is required for chromatin-induced microtubule stabilization and spindle assembly; Aurora B negatively regulates MCAK (a microtubule-depolymerizing kinesin), and co-depletion of MCAK rescues microtubule stabilization failure caused by CPC depletion.","method":"Xenopus egg extract biochemistry, CPC depletion, MCAK co-depletion epistasis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 — reconstituted biochemical system with epistasis; highly cited","pmids":["15260989"],"is_preprint":false},{"year":2004,"finding":"Controlled Aurora kinase reactivation in living vertebrate cells corrects improper chromosome-spindle attachments by selective disassembly of kinetochore-microtubule fibers at mal-oriented kinetochores, revealing a mechanism for error correction during chromosome bi-orientation.","method":"Small-molecule inhibitor washout in living cells, real-time high-resolution microscopy of chromosome and microtubule dynamics","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 — direct live-cell imaging with temporal kinase control; highly cited foundational mechanism paper","pmids":["14767480"],"is_preprint":false},{"year":2005,"finding":"Ipl1/Aurora (AURKB) activates the spindle checkpoint in response to tension defects by creating unattached kinetochores; when Ipl1 function is impaired in kinetochore mutants, kinetochore-microtubule attachments are restored and the checkpoint is silenced, demonstrating that Ipl1 converts syntelic tension defects into the unattached-kinetochore signal.","method":"Chemical-genetic kinase inhibition, kinetochore attachment analysis, spindle checkpoint assays in budding yeast","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 — analog-sensitive kinase allele for precise inhibition, epistatic readout; highly cited","pmids":["16327780"],"is_preprint":false},{"year":2005,"finding":"Aurora B kinase (AURKB) phosphorylates histone H3 at Ser10, causing dissociation of HP1alpha from chromodomain binding at the G2-M transition; depletion of AURKB inhibits HP1alpha dissociation from chromosome arms, and SUV39H1 methyltransferase is mislocalized in AURKB-depleted cells.","method":"RNAi depletion, immunofluorescence of HP1alpha dynamics, in vitro H3 phosphorylation and HP1 dissociation assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro dissociation assay combined with RNAi phenotype; consistent with Nature 2005 study","pmids":["16687578"],"is_preprint":false},{"year":2005,"finding":"Aurora B-mediated phosphorylation of histone H3 Ser10 causes HP1 dissociation from heterochromatin during mitosis via a 'methyl/phos switch'; H3K9me3S10ph is generated at pericentric heterochromatin in a Suv39h- and Aurora B-dependent manner, and inhibiting H3 Ser10 phosphorylation prevents HP1 chromosome release throughout mitosis.","method":"In vitro kinase assay, immunofluorescence, phosphorylation inhibitor experiments, ChIP-like analysis of autoimmune antibody recognition","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — biochemical reconstitution of methyl/phos switch, multiple experimental approaches; highly cited","pmids":["16222244"],"is_preprint":false},{"year":2005,"finding":"Aurora-B kinase activity augments Ras-mediated cell transformation; RNAi knockdown of Aurora-B inhibits transformation by Ras and Src (but not downstream Raf), and INCENP (a passenger protein associated with Aurora-B) has a similar potentiating effect.","method":"RNAi knockdown, focus formation assay in BALB/c 3T3 cells, epistasis with Ras/Src/Raf oncogenes","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis with oncogenes and specific pathway placement; single lab","pmids":["16027732"],"is_preprint":false},{"year":2009,"finding":"Aurora B kinase (AURKB) mediates an abscission checkpoint that prevents tetraploidization: chromosome bridges sustain Aurora B activity at posttelophase stages, delaying abscission at stabilized intercellular canals; this involves Aurora B phosphorylation of MKLP1 (Mklp1); Aurora B inactivation promotes premature abscission and furrow regression.","method":"Live-cell imaging, RNAi, chemical inhibition, phosphorylation assays in human cells","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — live imaging with genetic and chemical perturbations plus substrate identification; highly cited","pmids":["19203582"],"is_preprint":false},{"year":2009,"finding":"Aurora B kinase senses chromosome bi-orientation by spatial separation from its kinetochore substrates: FRET-based biosensors showed that phosphorylation of Aurora B substrates at the kinetochore depends on their distance from Aurora B at the inner centromere; repositioning Aurora B closer to the kinetochore prevents stabilization of bi-oriented attachments and activates the spindle checkpoint.","method":"FRET-based phosphorylation biosensors in living cells, Aurora B relocalization experiments","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — quantitative live-cell biosensor with mechanistic repositioning experiments; highly cited","pmids":["19150808"],"is_preprint":false},{"year":2009,"finding":"Aurora B (AURKB) plays an unexpected role in regulating XIST RNA binding to the inactive X chromosome: RNAi knockdown of AURKB causes mitotic retention of XIST RNA, and H3 phosphorylation (H3S10ph but not H3S28ph) precedes XIST RNA release, linking AURKB-mediated chromatin modification to RNA chromosome binding.","method":"RNAi knockdown, kinase inhibitor treatment, RNA FISH, immunofluorescence","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — RNAi plus inhibitor confirmation with quantitative imaging; single lab","pmids":["19704020"],"is_preprint":false},{"year":2009,"finding":"Aurora B phosphorylates the Ndc80 kinetochore protein to reduce its microtubule binding activity; kinetochore-bound Ndc80 is phosphorylated at Ipl1 sites in vivo, but this phosphorylation alone is not essential — additional Ipl1 targets contribute to segregation and checkpoint.","method":"In vitro microtubule binding assay, in vivo phosphorylation analysis, genetic analysis of phospho-mutants in yeast","journal":"Genetics","confidence":"Medium","confidence_rationale":"Tier 1–2 — in vitro microtubule binding plus in vivo genetic validation; moderate evidence for partial functional contribution","pmids":["19822728"],"is_preprint":false},{"year":2009,"finding":"Ipl1-dependent phosphorylation of Dam1 is maximal during S phase and minimal during metaphase; when tension is reduced (by failure to establish sister chromatid cohesion), Dam1 phosphorylation persists in metaphase-arrested cells, demonstrating that Aurora B/Ipl1-facilitated bi-orientation is stabilized in response to kinetochore tension by dephosphorylation of Dam1.","method":"In vivo phosphorylation assays with phospho-specific antibodies, genetic manipulation of sister chromatid cohesion in yeast","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — quantitative in vivo phosphorylation correlated with tension state using genetic perturbations","pmids":["19923271"],"is_preprint":false},{"year":2010,"finding":"Histone H3 threonine-3 phosphorylation (H3T3ph) by Haspin is necessary for CPC (Aurora B complex) accumulation at centromeres; the CPC subunit Survivin binds directly to H3T3ph; non-binding Survivin-D70A/D71A mutation diminishes centromere localization of Aurora B and compromises centromeric Aurora B functions.","method":"Biochemical binding assay (Survivin-H3T3ph), site-directed mutagenesis, microinjection of phospho-specific antibody, immunofluorescence","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — direct binding reconstitution with mutagenesis and antibody microinjection; highly cited","pmids":["20705812"],"is_preprint":false},{"year":2010,"finding":"The inner centromere is defined by the intersection of two histone kinase pathways: Haspin-mediated H3-pT3 and Bub1-mediated H2A-S121 phosphorylation cooperate to recruit the CPC (Aurora B/Survivin) to the inner centromere in fission yeast and human cells.","method":"Genetic and biochemical epistasis in S. pombe and human cells, histone mutant analysis, CPC localization imaging","journal":"Science","confidence":"High","confidence_rationale":"Tier 1–2 — two-organism reconstitution with epistasis; highly cited; independent from PMID 20705812","pmids":["20929775"],"is_preprint":false},{"year":2010,"finding":"Aurora B phosphorylates three spatially distinct targets within the KMN network (KNL1, Mis12, Ndc80 complexes) at the outer kinetochore; combinatorial phosphorylation generates graded levels of microtubule-binding activity with full phosphorylation severely compromising binding; spatial distribution of targets along the kinetochore axis leads to their differential phosphorylation in response to tension vs. attachment state.","method":"In vitro phosphorylation assay, microtubule binding assay, phospho-specific antibodies, chromosome segregation phenotype analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with multiple substrates and mutagenesis; highly cited","pmids":["20471944"],"is_preprint":false},{"year":2011,"finding":"Ipl1/Aurora-dependent phosphorylation of Sli15/INCENP modulates microtubule dynamics by preventing CPC binding to the preanaphase spindle; decreased Ipl1-dependent Sli15 phosphorylation drives direct CPC binding to microtubules, revealing how the CPC influences microtubule dynamics through spatiotemporal control of CPC-spindle interaction.","method":"Phosphorylation site mutagenesis, in vitro microtubule binding of Sli15 mutants, live-cell imaging, genetic analysis in yeast","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro binding reconstitution with mutagenesis plus in vivo functional imaging","pmids":["21727193"],"is_preprint":false},{"year":2012,"finding":"Cdk1 directly phosphorylates Ipl1/Aurora at two N-terminal serine residues, suppressing its association with the microtubule plus-end tracking protein Bim1 until anaphase onset; failure to phosphorylate Ipl1 leads to premature metaphase spindle targeting and constitutive Bim1 phosphorylation.","method":"In vitro kinase assay (Cdk1 phosphorylation of Ipl1), site-directed mutagenesis, in vivo localization, genetic growth analysis","journal":"Current biology","confidence":"High","confidence_rationale":"Tier 1 — direct in vitro phosphorylation with mutagenesis and in vivo functional validation","pmids":["22521784"],"is_preprint":false},{"year":2014,"finding":"Ipl1/Aurora B phosphorylation of Sli15 (INCENP) on sites within its central microtubule-binding domain inhibits Sli15 association with microtubules both in vitro and in vivo; mimicking constitutive phosphorylation delocalizes the CPC in metaphase, while blocking phosphorylation drives excessive spindle association; the phosphorylation state also affects the tension checkpoint mechanism.","method":"Phospho-site mutagenesis (sli15-20A/20D), in vitro microtubule binding assay, chromosome instability assay, tension checkpoint assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 — in vitro microtubule binding with constitutive phospho-mimetic and phospho-deficient mutants plus in vivo validation","pmids":["24558497"],"is_preprint":false},{"year":2016,"finding":"Aurkb phosphorylates Oct4 at Ser229 during G2/M phase, causing dissociation of Oct4 from chromatin; PP1 then binds Oct4 and dephosphorylates Oct4(S229) during M/G1 transition to reset Oct4-driven transcription for pluripotency; phosphomimetic and PP1-binding-deficient Oct4 mutations alter the cell cycle and impair pluripotency in embryonic stem cells.","method":"In vitro kinase assay, phospho-specific antibody detection, ChIP, ESC pluripotency assays, somatic cell reprogramming efficiency","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1–2 — in vitro phosphorylation plus mutagenesis with functional pluripotency readouts","pmids":["26880562"],"is_preprint":false},{"year":2017,"finding":"Ipl1/Aurora B phosphorylation of Dam1 is critical for faithful chromosome segregation in vivo: phospho-deficient dam1-3A mutants show stabilized kinetochore-microtubule attachment, delay establishment of bipolar attachment after nocodazole washout, and exhibit dramatic chromosome mis-segregation with premature SAC silencing.","method":"Phospho-deficient mutant analysis in vivo, chromosome bi-orientation assay, SAC checkpoint analysis in S. cerevisiae","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — phospho-mutant epistasis with in vivo attachment dynamics and checkpoint readouts","pmids":["28928489"],"is_preprint":false},{"year":2018,"finding":"VRK1 and AURKB form a stable protein complex (detected after nocodazole release); each kinase inhibits the kinase activity of the other and inhibits the other's specific phosphorylation of histone H3 (VRK1→H3-Thr3; AURKB→H3-Ser10); VRK1 is required for survivin expression (which recognizes H3-T3ph) and thereby for AURKB recruitment to centromeres.","method":"Co-immunoprecipitation, in vitro cross-inhibition kinase assay, RNAi depletion, immunofluorescence of centromere markers","journal":"Cellular and molecular life sciences","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal co-IP and in vitro cross-inhibition; single lab","pmids":["29340707"],"is_preprint":false},{"year":2018,"finding":"In mouse oocyte meiosis, AURKC is the predominant CPC kinase; AURKB can compensate in the absence of AURKC; AURKB negatively regulates AURKC to prevent aneuploidy; in the absence of AURKC, AURKA localizes to chromosomes in a CPC-dependent manner, revealing inter-kinase competition for CPC binding.","method":"Oocyte-specific Aurkb/Aurkc single- and double-knockout mice, immunofluorescence localization, chromosome segregation and fertility assays","journal":"Current biology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with clean phenotypic analysis and mechanistic inter-kinase localization studies","pmids":["30415701"],"is_preprint":false},{"year":2019,"finding":"Aurora B (AURKB) activation is associated with acquired resistance to EGFR TKIs in NSCLC; AURKB inhibitors reduce phospho-histone H3 (a major AURKB product), triggering G1/S arrest and polyploidy in resistant cells, and pH3 levels are increased in NSCLC patients after progression on EGFR TKIs.","method":"AURKB inhibitor treatment, pH3 quantification by Western blot/IHC, cell cycle analysis, patient tissue analysis","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological inhibition with substrate readout plus patient sample correlation; single mechanistic pathway","pmids":["31000705"],"is_preprint":false},{"year":2019,"finding":"AURKB is overexpressed in relapsed B-ALL and restrains glucocorticoid (GC) signaling by phosphorylating EHMT1-2 (histone methyltransferases), thereby reducing GC-induced expression of cell death genes; AURKB inhibition enhances GC-induced expression of cell death genes.","method":"Genome-wide shRNA screen, gene expression analysis, AURKB inhibitor treatment, patient sample validation","journal":"PNAS","confidence":"Medium","confidence_rationale":"Tier 2 — functional genomics screen plus pharmacological validation; AURKB substrate (EHMT1-2) identified with mechanistic consequence","pmids":["30733284"],"is_preprint":false},{"year":2019,"finding":"The COMA complex (Ame1/Okp1 heterodimer with Ctf19/Mcm21) positions Sli15/Ipl1(INCENP/Aurora B) at the budding yeast inner kinetochore through a direct interaction between the Sli15/Ipl1 core-CPC and the Ctf19 C-terminus; tethering Sli15 to Ame1/Okp1 rescues synthetic lethality, establishing the molecular architecture for centromeric CPC recruitment.","method":"In vitro reconstitution of kinetochore complexes, crosslink-guided co-purification, yeast genetics (synthetic lethality, rescue)","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with mutagenesis and genetic rescue","pmids":["31112132"],"is_preprint":false},{"year":2019,"finding":"Oncoviral antigen LANA (KSHV) cleaves AURKB at Asp76 in a serine protease-dependent manner; the N-terminal cleavage product (N'-AURKB) relocalizes to the spindle pole and promotes metaphase-to-telophase transition; introduction of N'-AURKB promotes colony formation and malignant tumor growth in vivo.","method":"Identification of cleavage isoforms in virus-infected cells, serine protease inhibitor experiments, subcellular localization imaging, xenograft tumor model","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic cleavage identification with in vivo functional consequence; single lab","pmids":["30917319"],"is_preprint":false},{"year":2020,"finding":"AURKB promotes gastric cancer cell proliferation by mediating H3 Ser10 phosphorylation (H3S10ph) at the CCND1 (cyclin D1) promoter, thereby epigenetically activating CCND1 expression; AURKB silencing reduces CCND1 and arrests cells in G2/M.","method":"AURKB knockdown/inhibition, ChIP for H3S10ph at CCND1 promoter, CCND1 expression analysis, in vitro and in vivo proliferation assays","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP links AURKB enzymatic activity to specific gene promoter; single lab","pmids":["31982864"],"is_preprint":false},{"year":2020,"finding":"CCAT2 lncRNA stabilizes BOP1 protein, which in turn increases the active form of Aurora kinase B (AURKB), promoting chromosomal missegregation; BOP1 knockdown reduces CIN phenotypes, placing BOP1 upstream of AURKB activation in a CCAT2-BOP1-AURKB axis.","method":"MS2 pulldown, RNA immunoprecipitation, mass spectrometry, BOP1 overexpression/knockdown, CIN cytogenetic assays, AURKB activity measurement","journal":"Gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 — RNA pulldown and functional epistasis with AURKB activity readout; single lab","pmids":["32805281"],"is_preprint":false},{"year":2021,"finding":"BRAFV600E induces mitotic arrest in human melanocytes via microRNA-mediated suppression of AURKB; MIR211-5p and MIR328-3p converge on AURKB targeting, causing mitotic failure, genome duplication, and proliferation arrest; ectopic AURKB expression rescues arrested human nevus cells.","method":"miRNA overexpression, luciferase reporter assay for target validation, AURKB rescue expression, immunofluorescence, proliferation assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — miRNA target validation with rescue experiment; multiple orthogonal methods","pmids":["34812139"],"is_preprint":false},{"year":2022,"finding":"Haspin kinase activity is required for AURKB recruitment to meiotic centromeres in mouse spermatocytes; haspin inhibition or Haspin gene deletion reduces Aurora B and MCAK (KIF2C) centromeric localization and impairs chromosome congression during meiotic divisions.","method":"Chemical inhibition (LDN-192960), Haspin knockout mice, immunofluorescence for AURKB and meiotic markers","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — combined chemical and genetic approach with clear localization and functional phenotype","pmids":["35694956"],"is_preprint":false},{"year":2022,"finding":"AURKB interacts with MAD2L2 and modulates its expression in bladder cancer cells; AURKB knockdown induces senescence and cell cycle arrest in a p53-dependent manner, and overexpression of MAD2L2 rescues AURKB knockdown effects in vitro and in vivo, establishing an AURKB-MAD2L2-p53 DDR axis.","method":"Co-immunoprecipitation, siRNA knockdown, rescue overexpression, xenograft assays, Western blot, senescence assays","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP interaction plus rescue epistasis in vivo; single lab","pmids":["38515112"],"is_preprint":false},{"year":2023,"finding":"AURKB and TTK inhibitors abrogate the spindle assembly checkpoint; tumor cell sensitivity to these inhibitors is determined by BID (BH3-interacting domain death agonist) levels — high BID cells undergo SAC abrogation-induced CASP-2 activation leading to CASP-3 cleavage and cell death, while BID-low cells are resistant; BID silencing renders sensitive cells resistant and ectopic BID expression sensitizes resistant cells.","method":"CRISPR KO, doxycycline-inducible ectopic expression, 53-cell-line panel, PDX in vivo models, CASP-2/3 activation assays","journal":"Molecular cancer","confidence":"High","confidence_rationale":"Tier 2 — bidirectional genetic manipulation in large panel plus in vivo PDX validation","pmids":["37443114"],"is_preprint":false},{"year":2023,"finding":"PLK1 and AURKB both phosphorylate survivin to regulate cell proliferation; AURKB inhibition with barasertib significantly inhibited growth of African American (AA) TNBC xenografts, with AA TNBC cells showing higher phospho-survivin levels reflecting higher AURKB activity.","method":"Western blot for phospho-survivin, siRNA silencing, barasertib treatment, xenograft tumor models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — survivin as AURKB substrate with functional growth readout; single lab","pmids":["36627281"],"is_preprint":false},{"year":2024,"finding":"AURKB interacts with DHX9 (DExH-Box helicase 9) and targets its expression; AURKB promotes hepatocellular carcinoma progression through the PI3K/AKT/mTOR pathway in a DHX9-dependent manner, as demonstrated by rescue experiments.","method":"Co-immunoprecipitation, knockdown/rescue experiments, Western blot for PI3K/AKT/mTOR markers, in vitro and in vivo tumor models","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP interaction plus downstream pathway rescue; single lab","pmids":["38874176"],"is_preprint":false},{"year":2024,"finding":"USP29, activated by transcription factor FUBP1, deubiquitinates AURKB protein by suppressing K48-linked polyubiquitination, thereby stabilizing AURKB protein levels and promoting its oncogenic functions in gastric cancer; Usp29 knockout mice show reduced Aurkb levels.","method":"Co-immunoprecipitation, ubiquitination assay, ChIP, qRT-PCR, CRISPR KO, Usp29 knockout mice","journal":"Cancer cell international","confidence":"High","confidence_rationale":"Tier 1–2 — biochemical ubiquitination assay with in vivo mouse validation and multiple orthogonal methods","pmids":["38233848"],"is_preprint":false}],"current_model":"AURKB encodes the catalytic subunit of the chromosomal passenger complex (CPC), a conserved serine/threonine kinase that phosphorylates histone H3 Ser10 to drive chromatin condensation and HP1 release, corrects improper kinetochore-microtubule attachments by phosphorylating KMN network components (Ndc80, KNL1, Dam1) in a tension-sensitive manner via spatial separation from its substrates, recruits to centromeres through Survivin binding to Haspin-generated H3T3ph, is activated by INCENP (Sli15) autophosphorylation, is regulated by opposing Glc7/PP1 phosphatase activity, delays cytokinetic abscission at chromosome bridges to prevent tetraploidization, and in non-mitotic contexts phosphorylates Oct4 to control pluripotency gene resetting and restrains glucocorticoid-driven gene expression in lymphoid cells."},"narrative":{"teleology":[{"year":1998,"claim":"Establishing AURKB as a cytokinesis-essential kinase resolved the question of whether this Aurora family member acts in late mitotic events; dominant-negative kinase-dead mutants disrupted cleavage furrow formation without affecting nuclear division.","evidence":"Dominant-negative overexpression and immunofluorescence in mammalian cells","pmids":["9450992","9809983"],"confidence":"High","gaps":["Identity of cytokinetic substrates was unknown","Relationship to chromosome segregation functions was not addressed"]},{"year":2000,"claim":"Discovery that the Ipl1/Aurora–Glc7/PP1 kinase–phosphatase axis controls histone H3-Ser10 phosphorylation and chromosome segregation established the first chromatin substrate and revealed an antagonistic phosphatase circuit governing Aurora activity.","evidence":"Genetic epistasis in S. cerevisiae and C. elegans with histone phosphorylation assays","pmids":["10975519","11098131"],"confidence":"High","gaps":["Whether H3S10ph was the sole mitotic chromatin function of Aurora was unclear","Direct regulation of PP1 at centromeres was not dissected"]},{"year":2001,"claim":"Three concurrent studies demonstrated that Ipl1/Aurora B promotes chromosome bi-orientation by destabilizing improper kinetochore–spindle connections, activates the spindle checkpoint specifically in response to tension defects, and is directly stimulated by INCENP/Sli15—establishing the core CPC regulatory logic.","evidence":"Live-cell imaging of kinetochore dynamics, checkpoint epistasis, co-immunoprecipitation, and in vitro kinase assays in yeast","pmids":["11853667","11731476","11724818"],"confidence":"High","gaps":["How tension is transduced to kinase–substrate accessibility was unknown","Full CPC composition had not been determined"]},{"year":2003,"claim":"Identification that INCENP phosphorylation by Aurora B at Thr893/Ser894/Ser895 constitutes a positive-feedback activation loop resolved how the CPC achieves switch-like kinase activation and proper centromere/spindle localization.","evidence":"Reconstituted in vitro kinase assay with site-directed mutagenesis plus RNAi depletion","pmids":["12925766"],"confidence":"High","gaps":["Structural basis of the activation loop was not determined","Whether additional kinases prime INCENP was unclear"]},{"year":2004,"claim":"Borealin was identified as the fourth CPC subunit, completing the complex architecture, and the CPC was shown to promote spindle assembly by negatively regulating the microtubule depolymerase MCAK.","evidence":"Co-IP/in vitro reconstitution of four-subunit CPC; MCAK co-depletion epistasis in Xenopus egg extracts","pmids":["15249581","15260989","14767480"],"confidence":"High","gaps":["MCAK phosphorylation sites by Aurora B were not fully mapped","How CPC transitions from centromere to spindle midzone was unknown"]},{"year":2005,"claim":"The 'methyl/phos switch' mechanism was elucidated: Aurora B phosphorylation of H3S10 adjacent to K9me3 ejects HP1 from heterochromatin at G2/M, explaining how mitotic chromatin condensation is coupled to histone code readout.","evidence":"In vitro kinase/binding reconstitution, immunofluorescence, and phosphorylation inhibitor experiments","pmids":["16222244","16687578"],"confidence":"High","gaps":["Whether the switch operates at all chromatin loci or only pericentric heterochromatin was unresolved","Kinetics of HP1 rebinding after Aurora B inactivation were not measured"]},{"year":2009,"claim":"Two landmark mechanisms were established: (1) FRET biosensors showed that Aurora B senses bi-orientation through spatial separation from outer-kinetochore substrates, explaining tension-dependent error correction; (2) Aurora B was found to delay cytokinetic abscission at chromosome bridges via MKLP1 phosphorylation, preventing tetraploidization.","evidence":"FRET-based biosensors with Aurora B relocalization in living cells; live-cell imaging with RNAi and chemical inhibition","pmids":["19150808","19203582"],"confidence":"High","gaps":["Phosphatase contribution to the spatial gradient was not quantified","How the abscission checkpoint integrates with ESCRT machinery was unknown"]},{"year":2009,"claim":"Aurora B phosphorylation of Ndc80 and Dam1 was shown to reduce microtubule binding in vitro and to be tension-regulated in vivo, identifying key outer-kinetochore substrates for the error-correction mechanism.","evidence":"In vitro microtubule binding assays, phospho-specific antibodies, genetic analysis in yeast","pmids":["19822728","19923271"],"confidence":"High","gaps":["Relative contribution of each KMN substrate to error correction was not determined","Whether mammalian Dam1-equivalent Ska complex is similarly regulated was untested"]},{"year":2010,"claim":"The molecular basis of CPC centromere targeting was resolved: Survivin binds Haspin-generated H3T3ph and Bub1-generated H2A-S121ph marks intersect to define the inner centromere, explaining the precision of Aurora B localization.","evidence":"Direct binding assay (Survivin–H3T3ph), mutagenesis, antibody microinjection, and two-organism genetic epistasis","pmids":["20705812","20929775","20471944"],"confidence":"High","gaps":["How Haspin and Bub1 activities are themselves spatially restricted was not fully resolved","Whether centromere targeting differs in meiosis was not addressed"]},{"year":2011,"claim":"Aurora B autophosphorylation of INCENP/Sli15 was shown to prevent premature CPC binding to the spindle, while Cdk1 phosphorylation of Aurora B itself suppresses plus-end tracking until anaphase, revealing layered temporal control of CPC redistribution.","evidence":"Phosphosite mutagenesis with in vitro microtubule binding and live-cell imaging in yeast","pmids":["21727193","22521784"],"confidence":"High","gaps":["Whether Cdk1 regulation of Aurora B is conserved in mammalian cells was not tested","Structural basis for phosphorylation-dependent spindle binding was lacking"]},{"year":2016,"claim":"Discovery that Aurora B phosphorylates Oct4 at Ser229 during G2/M to dissociate it from chromatin—with PP1-mediated dephosphorylation resetting pluripotency transcription—extended AURKB function beyond mitosis into stem cell gene regulation.","evidence":"In vitro kinase assay, ChIP, phospho-specific antibodies, ESC pluripotency and reprogramming assays","pmids":["26880562"],"confidence":"High","gaps":["Whether other pluripotency factors are Aurora B substrates was not examined","Relevance to in vivo embryonic development was not tested"]},{"year":2019,"claim":"AURKB was found to restrain glucocorticoid signaling in lymphoid cells by phosphorylating EHMT1/2, reducing GC-induced cell death gene expression—identifying a non-mitotic role in transcriptional repression relevant to drug resistance in B-ALL.","evidence":"Genome-wide shRNA screen, AURKB inhibitor treatment, gene expression analysis, patient sample validation","pmids":["30733284"],"confidence":"Medium","gaps":["Direct phosphorylation sites on EHMT1/2 by AURKB were not mapped","Whether this mechanism operates in other hematopoietic lineages is unknown"]},{"year":2022,"claim":"Haspin kinase was confirmed to be required for Aurora B centromeric recruitment in mammalian meiosis (spermatocytes), extending the Haspin–H3T3ph–Survivin recruitment paradigm from mitosis to meiotic divisions.","evidence":"Chemical inhibition and Haspin knockout mice with immunofluorescence for meiotic AURKB/MCAK localization","pmids":["35694956"],"confidence":"High","gaps":["Whether female meiosis uses the identical recruitment mechanism was not shown","Interaction between Haspin pathway and Bub1 pathway in meiosis was not dissected"]},{"year":2024,"claim":"USP29 was identified as a deubiquitinase that stabilizes AURKB by removing K48-linked polyubiquitin chains, revealing a post-translational mechanism controlling AURKB protein abundance.","evidence":"Co-IP, in vitro ubiquitination assay, CRISPR KO, Usp29 knockout mice","pmids":["38233848"],"confidence":"High","gaps":["The E3 ubiquitin ligase targeting AURKB for degradation was not identified","Whether USP29 regulation of AURKB operates in normal (non-cancer) physiology is unknown"]},{"year":null,"claim":"Key unresolved questions include the structural basis for the Aurora B spatial phosphorylation gradient at the centromere–kinetochore axis, the full extent of non-mitotic AURKB substrates, and how the abscission checkpoint mechanistically integrates with ESCRT-mediated membrane scission.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of the full CPC bound to centromeric nucleosomes","Comprehensive phosphoproteomics of AURKB substrates across cell cycle stages is lacking","Mechanism coupling Aurora B activity to ESCRT-III recruitment at the midbody is undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2,3,6,7,9,10,15,16,19,21,22,25,29,30]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[2,3,9,10,25,29]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[2,9,15,16]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[12,14,18]}],"localization":[{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[9,15,16,23,24]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,6,26]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0,36]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,2,4,5,10,13,14,18,19,25,30]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[2,7,9,15,16]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[29,34,37]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[33,34,39,43]}],"complexes":["Chromosomal passenger complex (CPC)"],"partners":["INCENP","BIRC5","CDCA8","NDC80","DAM1","VRK1","POU5F1","MKLP1"],"other_free_text":[]},"mechanistic_narrative":"Aurora kinase B (AURKB) is the catalytic serine/threonine kinase subunit of the chromosomal passenger complex (CPC, comprising AURKB, INCENP, Survivin, and Borealin), which orchestrates chromosome segregation, kinetochore–microtubule error correction, and cytokinesis during cell division. AURKB phosphorylates histone H3 at Ser10 to drive HP1 dissociation from chromatin at the G2–M transition and to modulate mitotic chromatin architecture, and it phosphorylates KMN network components (Ndc80, KNL1, Dam1) in a tension-sensitive manner—governed by spatial separation from outer-kinetochore substrates—to selectively destabilize erroneous kinetochore–microtubule attachments and promote chromosome bi-orientation [PMID:19150808, PMID:20471944, PMID:16222244]. CPC centromeric recruitment depends on Survivin recognition of Haspin-generated H3T3ph intersecting with Bub1-mediated H2A-S121ph, while INCENP-mediated autophosphorylation is required for full kinase activation [PMID:20705812, PMID:20929775, PMID:12925766]. Beyond mitosis, AURKB delays cytokinetic abscission at chromosome bridges to prevent tetraploidization, phosphorylates Oct4 to reset pluripotency gene expression in embryonic stem cells, and restrains glucocorticoid-driven transcription in lymphoid cells by phosphorylating EHMT1/2 [PMID:19203582, PMID:26880562, PMID:30733284]."},"prefetch_data":{"uniprot":{"accession":"Q96GD4","full_name":"Aurora kinase B","aliases":["Aurora 1","Aurora- and IPL1-like midbody-associated protein 1","AIM-1","Aurora/IPL1-related kinase 2","ARK-2","Aurora-related kinase 2","STK-1","Serine/threonine-protein kinase 12","Serine/threonine-protein kinase 5","Serine/threonine-protein kinase aurora-B"],"length_aa":344,"mass_kda":39.3,"function":"Serine/threonine-protein kinase component of the chromosomal passenger complex (CPC), a complex that acts as a key regulator of mitosis (PubMed:11516652, PubMed:12925766, PubMed:14610074, PubMed:14722118, PubMed:29449677). The CPC complex has essential functions at the centromere in ensuring correct chromosome alignment and segregation and is required for chromatin-induced microtubule stabilization and spindle assembly (PubMed:11516652, PubMed:12925766, PubMed:14610074, PubMed:14722118, PubMed:26829474). Involved in the bipolar attachment of spindle microtubules to kinetochores and is a key regulator for the onset of cytokinesis during mitosis (PubMed:15249581). Required for central/midzone spindle assembly and cleavage furrow formation (PubMed:12458200, PubMed:12686604). Key component of the cytokinesis checkpoint, a process required to delay abscission to prevent both premature resolution of intercellular chromosome bridges and accumulation of DNA damage: phosphorylates CHMP4C, leading to retain abscission-competent VPS4 (VPS4A and/or VPS4B) at the midbody ring until abscission checkpoint signaling is terminated at late cytokinesis (PubMed:22422861, PubMed:24814515). AURKB phosphorylates the CPC complex subunits BIRC5/survivin, CDCA8/borealin and INCENP (PubMed:11516652, PubMed:12925766, PubMed:14610074). Phosphorylation of INCENP leads to increased AURKB activity (PubMed:11516652, PubMed:12925766, PubMed:14610074). Other known AURKB substrates involved in centromeric functions and mitosis are CENPA, DES/desmin, GPAF, KIF2C, NSUN2, RACGAP1, SEPTIN1, VIM/vimentin, HASPIN, and histones H1.4 and H3 (PubMed:11756469, PubMed:11784863, PubMed:11856369, PubMed:12689593, PubMed:14602875, PubMed:16103226, PubMed:21511733, PubMed:21658950). A positive feedback loop involving HASPIN and AURKB contributes to localization of CPC to centromeres (PubMed:21658950). Phosphorylation of VIM controls vimentin filament segregation in cytokinetic process, whereas histone H3 is phosphorylated at 'Ser-10' and 'Ser-28' during mitosis (H3S10ph and H3S28ph, respectively) (PubMed:11784863, PubMed:11856369). AURKB is also required for kinetochore localization of BUB1 and SGO1 (PubMed:15020684, PubMed:17617734). Phosphorylation of p53/TP53 negatively regulates its transcriptional activity (PubMed:20959462). Key regulator of active promoters in resting B- and T-lymphocytes: acts by mediating phosphorylation of H3S28ph at active promoters in resting B-cells, inhibiting RNF2/RING1B-mediated ubiquitination of histone H2A and enhancing binding and activity of the USP16 deubiquitinase at transcribed genes (By similarity). Acts as an inhibitor of CGAS during mitosis: catalyzes phosphorylation of the N-terminus of CGAS during the G2-M transition, blocking CGAS liquid phase separation and activation, and thereby preventing CGAS-induced autoimmunity (PubMed:33542149). Phosphorylates KRT5 during anaphase and telophase (By similarity). Phosphorylates ATXN10 which promotes phosphorylation of ATXN10 by PLK1 and may play a role in the regulation of cytokinesis and stimulating the proteasomal degradation of ATXN10 (PubMed:25666058)","subcellular_location":"Nucleus; Chromosome; Chromosome, centromere; Chromosome, centromere, kinetochore; Cytoplasm, cytoskeleton, spindle; Midbody","url":"https://www.uniprot.org/uniprotkb/Q96GD4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/AURKB","classification":"Common Essential","n_dependent_lines":1204,"n_total_lines":1208,"dependency_fraction":0.9966887417218543},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000178999","cell_line_id":"CID001129","localizations":[{"compartment":"chromatin","grade":3}],"interactors":[{"gene":"INCENP","stoichiometry":0.2},{"gene":"CDCA8","stoichiometry":0.2},{"gene":"CDC37","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001129","total_profiled":1310},"omim":[{"mim_id":"620959","title":"UBIQUITIN-SPECIFIC PEPTIDASE 35; USP35","url":"https://www.omim.org/entry/620959"},{"mim_id":"619635","title":"ZINC FINGER FYVE DOMAIN-CONTAINING PROTEIN 19; ZFYVE19","url":"https://www.omim.org/entry/619635"},{"mim_id":"619403","title":"COLON CANCER-ASSOCIATED TRANSCRIPT 2, NONCODING; CCAT2","url":"https://www.omim.org/entry/619403"},{"mim_id":"619358","title":"MICROTUBULE-ASSOCIATED SCAFFOLD PROTEIN 2; MTUS2","url":"https://www.omim.org/entry/619358"},{"mim_id":"619288","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 69; CCDC69","url":"https://www.omim.org/entry/619288"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Kinetochore","reliability":"Additional"},{"location":"Midbody","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":41.6},{"tissue":"lymphoid tissue","ntpm":55.9}],"url":"https://www.proteinatlas.org/search/AURKB"},"hgnc":{"alias_symbol":["Aik2","IPL1","AurB","AIM-1","ARK2","STK5","PPP1R48"],"prev_symbol":["STK12"]},"alphafold":{"accession":"Q96GD4","domains":[{"cath_id":"3.30.200.20","chopping":"75-156","consensus_level":"high","plddt":92.9759,"start":75,"end":156},{"cath_id":"1.10.510.10","chopping":"161-332","consensus_level":"high","plddt":90.937,"start":161,"end":332}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96GD4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96GD4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96GD4-F1-predicted_aligned_error_v6.png","plddt_mean":78.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=AURKB","jax_strain_url":"https://www.jax.org/strain/search?query=AURKB"},"sequence":{"accession":"Q96GD4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96GD4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96GD4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96GD4"}},"corpus_meta":[{"pmid":"10975519","id":"PMC_10975519","title":"Mitotic 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false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Overexpression of wild-type AIM-1 (AURKB) in human cancer cells produces multinuclearity and increased ploidy, indicating that excess kinase activity disrupts normal cytokinesis and leads to chromosomal instability.\",\n      \"method\": \"Overexpression in cancer cell lines, cell ploidy analysis\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — overexpression phenotype, single lab, consistent with dominant-negative data\",\n      \"pmids\": [\"9809983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Ipl1/Aurora kinase (AURKB ortholog) and Glc7/PP1 phosphatase are responsible for the balance of histone H3 Ser10 phosphorylation during mitosis in S. cerevisiae and C. elegans, and both enzymes are required for chromosome segregation.\",\n      \"method\": \"Genetic analysis in yeast and C. elegans, phosphorylation assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic epistasis + biochemical phosphorylation assay, independently replicated across two organisms\",\n      \"pmids\": [\"10975519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"AIM-1 (AURKB) phosphorylates myosin II regulatory light chain (MRLC) at Ser19 in vitro, and colocalizes with monophosphorylated MRLC at the cleavage furrow during cytokinesis.\",\n      \"method\": \"In vitro kinase assay, two-dimensional phosphopeptide mapping, site-directed mutagenesis of MRLC, immunofluorescence colocalization\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay with mutagenesis and colocalization\",\n      \"pmids\": [\"11098131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The Ipl1-Sli15 (AURKB-INCENP) complex promotes chromosome bi-orientation by facilitating turnover of kinetochore-spindle pole connections until proper tension is generated.\",\n      \"method\": \"Yeast genetic analysis with spindle pole body duplication assay, live imaging\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with defined cellular phenotype, replicated\",\n      \"pmids\": [\"11853667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Increased AIM-1 (AURKB) overexpression causes increased mitotic histone H3 Ser10 phosphorylation and lagging chromosomes; expression of phosphomimetic H3 (S10E) also induces lagging chromosomes, indicating that increased H3 phosphorylation by AURKB contributes to chromosome number instability.\",\n      \"method\": \"Overexpression, phosphorylation assays, mutant H3 transfection\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple methods, single lab\",\n      \"pmids\": [\"12234980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Sli15 (INCENP ortholog) directly associates with Ipl1 (AURKB ortholog), stimulates its in vitro kinase activity, and facilitates its spindle localization; both proteins are required for chromosome segregation.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, genetic analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct biochemical reconstitution plus genetics, replicated\",\n      \"pmids\": [\"11724818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Ipl1 (AURKB ortholog) is required for spindle checkpoint activation in response to lack of kinetochore tension but not in response to spindle depolymerization, and localizes near kinetochores during mitosis.\",\n      \"method\": \"Yeast genetics, immunofluorescence localization, spindle checkpoint assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis with defined checkpoint phenotype, replicated\",\n      \"pmids\": [\"11731476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"E2F mediates genotoxic stress-induced downregulation of AIM-1 (AURKB) expression, contributing to sustained G2/M arrest; abrogation of E2F function prevents AIM-1 downregulation and allows premature G2 exit.\",\n      \"method\": \"Dominant-negative E2F expression, doxorubicin treatment, Western blot, in vivo promoter binding (ChIP)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple molecular methods, single lab\",\n      \"pmids\": [\"12446714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Ipl1/Aurora (AURKB ortholog) activates the spindle checkpoint in response to tension defects by creating unattached kinetochores; the Dam1 kinetochore complex is a key downstream target whose phosphorylation regulates microtubule attachment.\",\n      \"method\": \"Chemical-genetic approach (analog-sensitive Ipl1 allele), kinetochore attachment assays, spindle checkpoint assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — chemical-genetic tool with rigorous epistasis, replicated concept\",\n      \"pmids\": [\"16327780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Set1 methyltransferase methylates conserved lysines in the kinetochore protein Dam1, and this methylation inhibits Ipl1 (AURKB ortholog)-mediated phosphorylation of flanking serines, demonstrating antagonism between lysine methylation and serine phosphorylation in controlling Aurora B substrate function.\",\n      \"method\": \"Biochemical methylation and phosphorylation assays, genetic epistasis (SET1 deletion suppresses ipl1-2 chromosome loss)\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro biochemistry plus genetic epistasis\",\n      \"pmids\": [\"16143104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Aurora-B/AIM-1 is necessary for HP1alpha dissociation from chromosome arms at the G2-M transition; AURKB-mediated H3 phosphorylation induces dissociation of the HP1alpha chromodomain in vitro, but not the intact protein, indicating additional regulatory mechanisms.\",\n      \"method\": \"RNAi depletion, immunofluorescence, in vitro chromatin binding assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNAi with specific phenotype plus in vitro assay, single lab\",\n      \"pmids\": [\"16687578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Glc7/PP1 ensures accurate chromosome segregation by dephosphorylating Ipl1 (AURKB) targets (including Dam1) rather than by regulating Ipl1 kinase activity or localization itself.\",\n      \"method\": \"Phosphorylation assays, genetic epistasis, localization studies\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (phosphorylation assay + genetics + localization), strong evidence\",\n      \"pmids\": [\"16537909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Ipl1/Aurora B (AURKB ortholog) is essential for protection of meiotic centromeric cohesion by maintaining centromeric localization of PP2A-Rts1; Sgo1 recruits Ipl1 to centromeres, and without Ipl1, Rts1 disappears from centromeres after anaphase I.\",\n      \"method\": \"Yeast genetics, immunofluorescence localization, epistasis analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic and localization data with defined meiotic phenotype\",\n      \"pmids\": [\"17371833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Ipl1/Aurora (AURKB ortholog) and the spindle midzone protein Ase1 constitute a spindle assembly pathway; Ipl1 phosphorylates Ase1, and Ase1 phosphorylation and localization are altered in ipl1 mutants.\",\n      \"method\": \"Yeast genetics, phosphorylation assays, localization studies\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetics plus phosphorylation assay, single lab\",\n      \"pmids\": [\"17765685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"AURKB plays an unexpected role in regulating XIST RNA binding to the inactive X chromosome: RNAi to AURKB causes mitotic retention of XIST RNA, and H3 phosphorylation (H3S10ph) precedes XIST RNA release at prophase.\",\n      \"method\": \"RNAi knockdown, fluorescence RNA-FISH, mitotic cell imaging\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNAi with specific RNA-binding phenotype, single lab\",\n      \"pmids\": [\"19704020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Ipl1-dependent phosphorylation of Dam1 at key sites is maximal during S phase and minimal in metaphase; reducing tension at kinetochores (by abolishing sister chromatid cohesion) sustains Dam1 phosphorylation, suggesting that tension-dependent dephosphorylation of Dam1 by Glc7/PP1 stabilizes correct kinetochore-microtubule attachments.\",\n      \"method\": \"In vivo phosphorylation assays, genetic manipulation of cohesion, yeast cell biology\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — quantitative in vivo phosphorylation plus genetic epistasis\",\n      \"pmids\": [\"19923271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Ipl1/Aurora B phosphorylates Ndc80 at kinetochore-associated sites in vivo, reducing its microtubule binding activity in vitro; however, Ndc80 phosphorylation alone is not essential, indicating additional Ipl1 targets contribute to segregation and spindle checkpoint.\",\n      \"method\": \"In vitro phosphorylation/microtubule binding assays, in vivo phosphorylation analysis\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution plus in vivo validation\",\n      \"pmids\": [\"19822728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Nbl1p (Borealin ortholog) is a core component of the CPC in budding yeast; it is essential for CPC localization, stability, integrity and function, and connects the other CPC subunits (Ipl1/Aurora B, Sli15/INCENP, Bir1/Survivin).\",\n      \"method\": \"Co-purification, genetic analysis, CPC localization assays, comparative structural modeling\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — co-purification + genetics + structural modeling, Strong evidence\",\n      \"pmids\": [\"19158380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Ipl1/Aurora-dependent phosphorylation of Sli15/INCENP prevents CPC binding to the preanaphase spindle and central spindle until late anaphase, facilitating spatiotemporal control of microtubule dynamics required for metaphase centromere positioning and anaphase spindle elongation.\",\n      \"method\": \"Phosphosite mutagenesis, in vitro CPC-microtubule binding assays, live-cell imaging\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis + in vitro reconstitution + live imaging\",\n      \"pmids\": [\"21727193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Cdk1 directly phosphorylates Ipl1/Aurora B on two N-terminal serine residues, suppressing its association with the microtubule plus-end tracking protein Bim1 until anaphase onset, thereby coordinating chromosome biorientation with spindle morphogenesis.\",\n      \"method\": \"In vitro kinase assay, phosphosite mutagenesis, genetic analysis in yeast\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro kinase assay plus mutagenesis plus phenotypic validation\",\n      \"pmids\": [\"22521784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Ipl1/Aurora B phosphorylation of Sli15 within its microtubule-binding domain inhibits Sli15-microtubule association in vitro and in vivo, and mimicking constitutive phosphorylation deregulates CPC localization and interferes with the tension checkpoint.\",\n      \"method\": \"Phosphosite mutagenesis, in vitro microtubule binding assay, chromosome stability assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution + mutagenesis + in vivo phenotype\",\n      \"pmids\": [\"24558497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Shugoshin (Sgo1) maintains Aurora B/Ipl1 localization at kinetochores during metaphase and recruits condensin to centromeric chromatin via PP2A-Rts1, both functions required for tension-dependent correction of kinetochore-microtubule attachments.\",\n      \"method\": \"Yeast genetics, immunofluorescence localization, epistasis analysis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetics plus localization, single lab\",\n      \"pmids\": [\"24945276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Aurkb phosphorylates Oct4 at Ser229 during G2/M phase, causing its dissociation from chromatin, while PP1 dephosphorylates Oct4(Ser229) during M/G1 transition to reset Oct4-driven transcription for pluripotency in embryonic stem cells.\",\n      \"method\": \"In vitro kinase assay, phosphosite mutagenesis, chromatin immunoprecipitation, ESC phenotype analysis\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro phosphorylation + mutagenesis + ChIP with defined pluripotency phenotype\",\n      \"pmids\": [\"26880562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Phosphorylation of the Dam1 protein by Ipl1/Aurora B kinase at three key serine residues (dam1-3A phospho-deficient mutant) stabilizes kinetochore-microtubule attachment in vivo, delays establishment of bipolar attachment after nocodazole treatment, and causes dramatic chromosome missegregation.\",\n      \"method\": \"Phospho-deficient mutant analysis, nocodazole treatment, chromosome segregation assays in yeast\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — site-specific mutagenesis with defined in vivo phenotypes\",\n      \"pmids\": [\"28928489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"VRK1 and AURKB form a stable protein complex (a minor subpopulation), each kinase inhibiting the other's activity and each other's specific phosphorylation of histone H3 (VRK1 on Thr3, AURKB on Ser10); VRK1 depletion reduces survivin (BIRC5) expression and prevents AURKB recruitment to centromeres.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase cross-inhibition assay, RNAi, immunofluorescence\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP and in vitro kinase assay, single lab\",\n      \"pmids\": [\"29340707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The COMA complex (Ame1/Okp1 heterodimer within Ctf19/Mcm21) positions the CPC (Sli15/Ipl1) at the inner kinetochore in budding yeast: Ame1/Okp1 binds Cse4/CENP-A nucleosomes via the Cse4 N-terminus, while Sli15/Ipl1 interacts with COMA through the Ctf19 C-terminus, and Ctf19 C-terminus deletion impairs chromosome segregation fidelity.\",\n      \"method\": \"Crosslink-guided in vitro reconstitution, Co-IP, genetic rescue experiments\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution + mutagenesis + genetic validation\",\n      \"pmids\": [\"31112132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"AURKB inhibits glucocorticoid (GC) signaling by phosphorylating EHMT1/EHMT2 histone methyltransferases, restraining GC-induced expression of cell death genes; AURKB is overexpressed in relapsed B-ALL and its inhibition enhances GC cytotoxicity.\",\n      \"method\": \"shRNA screen, gene expression analysis in patient samples, pharmacological AURKB inhibition combined with GC treatment\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional genomics screen plus pharmacological validation, single lab\",\n      \"pmids\": [\"30733284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In KSHV-infected tumor cells, the latent viral antigen LANA cleaves AURKB at Asp76 in a serine protease-dependent manner; the N-terminal cleavage product (N'-AURKB) relocalizes to the spindle pole and promotes metaphase-to-telophase transition, colony formation, and tumor growth.\",\n      \"method\": \"Biochemical cleavage assay, mass spectrometry, xenograft mouse model, immunofluorescence\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — biochemical cleavage characterization + in vivo xenograft functional validation\",\n      \"pmids\": [\"30917319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"AURKB promotes gastric cancer cell proliferation by mediating H3S10 phosphorylation at the CCND1 (cyclin D1) gene promoter, directly activating CCND1 transcription.\",\n      \"method\": \"ChIP assay, RNAi knockdown, AURKB inhibitor (AZD1152), in vivo xenograft\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP with pharmacological and genetic validation, single lab\",\n      \"pmids\": [\"31982864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CCAT2 lncRNA stabilizes BOP1 ribosomal biogenesis factor, which in turn increases the active form of Aurora kinase B (AURKB), promoting chromosomal missegregation errors.\",\n      \"method\": \"MS2 pull-down, RNA immunoprecipitation, mass spectrometry, gene expression array, overexpression/knockdown studies\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical methods establishing the lncRNA-BOP1-AURKB axis, single lab\",\n      \"pmids\": [\"32805281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"BRAF(V600E) induces mitotic arrest in human melanocytes through miR-211-5p and miR-328-3p-mediated suppression of AURKB; restoration of AURKB expression rescues arrested nevus cells, and knockdown of AURKB recapitulates BRAFV600E-induced proliferation arrest and genome duplication.\",\n      \"method\": \"miRNA overexpression, AURKB rescue experiments, live imaging, human nevus transcriptomics\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic rescue with AURKB plus miRNA functional assays, single lab\",\n      \"pmids\": [\"34812139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Haspin kinase phosphorylates H3T3 to recruit the CPC (including AURKB) to meiotic centromeres in male mouse spermatocytes; haspin inhibition (LDN-192960) or gene ablation impairs chromosome congression and AURKB and MCAK (KIF2C) localization to centromeres.\",\n      \"method\": \"Chemical inhibition, Haspin knockout mice, immunofluorescence localization\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — chemical inhibition plus genetic knockout with defined localization phenotype\",\n      \"pmids\": [\"35694956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PLK1 and AURKB differentially phosphorylate survivin to promote cell proliferation; inhibition of AURKB with barasertib suppresses growth of African American (but not European American) TNBC xenografts, correlating with higher AURKB expression and survivin phosphorylation in this subgroup.\",\n      \"method\": \"Xenograft mouse model, siRNA silencing, western blot for phospho-survivin, in vivo tumor growth assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo xenograft plus biochemical phosphorylation data, single lab\",\n      \"pmids\": [\"36627281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"AURKB interacts with and modulates the expression of MAD2L2 in bladder cancer cells, and this AURKB-MAD2L2 axis downregulates p53-mediated DNA damage response to promote tumor progression; p53 ablation rescues MAD2L2-knockdown-induced cell cycle arrest.\",\n      \"method\": \"Co-immunoprecipitation, genetic knockdown/overexpression, xenograft mouse model, western blot\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus rescue experiments plus in vivo validation, single lab\",\n      \"pmids\": [\"38515112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP29 deubiquitylase stabilizes AURKB protein by suppressing K48-linked polyubiquitination; USP29 is transcriptionally activated by FUBP1, constituting a FUBP1-USP29-AURKB regulatory axis promoting gastric cancer progression.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, ubiquitination assay, ChIP, luciferase reporter assay, Usp29 knockout mice\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal biochemical methods (CoIP, ubiquitination assay, MS) plus in vivo mouse model\",\n      \"pmids\": [\"38233848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"AURKB interacts with and targets DHX9 (DExH-Box helicase 9) expression in hepatocellular carcinoma cells, and this interaction promotes tumor progression via the PI3K/AKT/mTOR pathway; rescue experiments confirmed that AURKB promotes HCC through DHX9.\",\n      \"method\": \"Co-immunoprecipitation, knockdown/rescue experiments, in vitro and in vivo assays\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus genetic rescue, single lab\",\n      \"pmids\": [\"38874176\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AURKB (Aurora B kinase) is the catalytic subunit of the Chromosomal Passenger Complex (CPC; with INCENP/Sli15, Survivin, and Borealin), where it phosphorylates histone H3 Ser10, kinetochore substrates (Dam1, Ndc80, INCENP/Sli15), and myosin regulatory light chain to orchestrate chromosome condensation, error-correction of kinetochore-microtubule attachments (by destabilizing syntelic/monotelic attachments until tension is sensed), spindle assembly checkpoint activation in response to lack of tension, cytokinesis, and—in non-mitotic contexts—regulates chromatin-bound factors including Oct4 in embryonic stem cells and EHMT1/2 to modulate transcription, with its activity balanced by Glc7/PP1 phosphatase-mediated dephosphorylation of its substrates and its protein stability regulated by USP29-mediated deubiquitylation.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"AIM-1 (AURKB) is a mammalian serine/threonine kinase that localizes to the equator of central spindles during late anaphase and to the midbody during telophase and cytokinesis; overexpression of kinase-inactive AIM-1 disrupts cleavage furrow formation without affecting nuclear division, demonstrating that AURKB kinase activity is required for cytokinesis.\",\n      \"method\": \"Dominant-negative overexpression, immunofluorescence localization, cell ploidy analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — dominant-negative functional rescue with specific cytokinesis phenotype, replicated in subsequent studies\",\n      \"pmids\": [\"9450992\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"AURKB overexpression in human cancer cells produces multinuclearity and increased ploidy due to cytokinesis errors, establishing that excess AURKB disrupts chromosomal integrity.\",\n      \"method\": \"Exogenous overexpression in tumor cell lines, flow cytometry for ploidy\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — overexpression phenotype with clear readout; single lab but consistent with orthogonal dominant-negative data\",\n      \"pmids\": [\"9809983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Ipl1/Aurora kinase (AURKB ortholog) and the Glc7/PP1 phosphatase together govern the balance of histone H3 serine-10 phosphorylation during mitosis, and both activities are required for proper chromosome segregation in S. cerevisiae and C. elegans.\",\n      \"method\": \"Genetic epistasis in yeast and C. elegans, histone phosphorylation assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multi-organism genetic epistasis plus biochemical H3-phosphorylation assay; highly cited foundational work\",\n      \"pmids\": [\"10975519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"AIM-1 (rat AURKB) phosphorylates myosin II regulatory light chain (MRLC) at Ser19 in vitro and colocalizes with monophosphorylated MRLC at the cleavage furrow, implicating AURKB in MRLC phosphorylation during cytokinesis.\",\n      \"method\": \"In vitro kinase assay, two-dimensional phosphopeptide mapping, MRLC mutant analysis, immunofluorescence colocalization\",\n      \"journal\": \"Journal of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro phosphorylation with site-specific mutants and in-cell colocalization\",\n      \"pmids\": [\"11098131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The yeast AURKB ortholog Ipl1 promotes chromosome bi-orientation by facilitating turnover of kinetochore-spindle pole connections; in ipl1 mutants, kinetochores remain inappropriately attached to old spindle pole bodies, indicating Ipl1 resolves syntelic attachments.\",\n      \"method\": \"Live-cell imaging, genetic analysis of spindle pole body attachment in DNA-replication-deficient cells\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct imaging of kinetochore dynamics in genetic mutants; replicated across multiple labs\",\n      \"pmids\": [\"11853667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Ipl1 (AURKB ortholog) is required for spindle checkpoint activation in response to lack of kinetochore tension but not for checkpoint arrest induced by spindle depolymerization, positioning Ipl1 as a tension-specific checkpoint activator.\",\n      \"method\": \"Genetic analysis, Mps1 overexpression checkpoint assays in ipl1 mutant yeast\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis with specific genetic separation of tension vs. attachment checkpoint signals\",\n      \"pmids\": [\"11731476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Sli15 (INCENP ortholog) directly associates with Ipl1 (AURKB) in vivo, stimulates Ipl1 kinase activity in vitro, and facilitates Ipl1 association with the mitotic spindle; both Sli15 and Dam1 are phosphorylated by Ipl1 in vitro and show reduced phosphorylation in ipl1 mutants in vivo.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, spindle localization imaging, in vivo phosphorylation assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reciprocal co-IP, in vitro kinase stimulation, and in vivo phosphorylation with multiple substrates\",\n      \"pmids\": [\"11724818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"AURKB overexpression causes increased mitotic histone H3 Ser10 phosphorylation with concomitant induction of lagging chromosomes; expression of phosphomimetic H3(S10E) recapitulates this phenotype, demonstrating that excess H3-S10 phosphorylation is a precipitating factor of chromosome instability.\",\n      \"method\": \"Exogenous overexpression, histone mutant transfection, cytogenetic analysis of lagging chromosomes\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — phosphomimetic mutant epistasis plus overexpression phenotype; single lab\",\n      \"pmids\": [\"12234980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"AURKB (AIM-1) expression is regulated by E2F transcription factors; doxorubicin-induced sustained G2/M arrest involves E2F-dependent downregulation of AIM-1 (AURKB), and abrogation of E2F function prevents this downregulation and leads to premature exit from G2.\",\n      \"method\": \"Dominant-negative E2F expression, E7 papillomavirus protein expression, gene expression analysis, cell cycle assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — E2F functional epistasis with genotoxic checkpoint readout; single lab\",\n      \"pmids\": [\"12446714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Aurora-B (AURKB) and Aurora-A physically interact with histone H3 tail and phosphorylate H3-Ser10 both in vitro and in vivo; Aurora-B colocalizes with H3 phosphorylation at the centromeric region during prophase/metaphase and translocates to the midbody during cytokinesis.\",\n      \"method\": \"In vitro kinase assay, co-immunoprecipitation, immunofluorescence colocalization, cell cycle staging\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro phosphorylation plus in vivo colocalization and physical interaction; highly cited\",\n      \"pmids\": [\"11784863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Aurora B kinase activity is required for proper localization of the entire Aurora B/INCENP/survivin complex to centromeres and central spindle; INCENP directly activates Aurora B kinase activity and is itself phosphorylated by Aurora B at Thr893/Ser894/Ser895 — a non-phosphorylatable mutant (TSS→AAA) is a poor activator, demonstrating that INCENP phosphorylation is required for full kinase activation.\",\n      \"method\": \"Dominant-negative overexpression, RNAi depletion, in vitro kinase assay with recombinant proteins, mass spectrometry phosphosite identification, site-directed mutagenesis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted in vitro with mutagenesis validation, multiple orthogonal methods\",\n      \"pmids\": [\"12925766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Borealin is a novel subunit of the chromosomal passenger complex (CPC) containing Aurora B/INCENP/Survivin; approximately half of Aurora B in mitotic cells is in the four-subunit complex; Borealin binds Survivin and INCENP in vitro; Borealin depletion causes kinetochore-spindle misattachments and ectopic spindle poles.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding, RNAi depletion, immunofluorescence\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro reconstitution of complex, RNAi phenotype, complex stoichiometry; replicated by other labs\",\n      \"pmids\": [\"15249581\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The chromosomal passenger complex (containing Aurora B) is required for chromatin-induced microtubule stabilization and spindle assembly; Aurora B negatively regulates MCAK (a microtubule-depolymerizing kinesin), and co-depletion of MCAK rescues microtubule stabilization failure caused by CPC depletion.\",\n      \"method\": \"Xenopus egg extract biochemistry, CPC depletion, MCAK co-depletion epistasis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted biochemical system with epistasis; highly cited\",\n      \"pmids\": [\"15260989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Controlled Aurora kinase reactivation in living vertebrate cells corrects improper chromosome-spindle attachments by selective disassembly of kinetochore-microtubule fibers at mal-oriented kinetochores, revealing a mechanism for error correction during chromosome bi-orientation.\",\n      \"method\": \"Small-molecule inhibitor washout in living cells, real-time high-resolution microscopy of chromosome and microtubule dynamics\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct live-cell imaging with temporal kinase control; highly cited foundational mechanism paper\",\n      \"pmids\": [\"14767480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Ipl1/Aurora (AURKB) activates the spindle checkpoint in response to tension defects by creating unattached kinetochores; when Ipl1 function is impaired in kinetochore mutants, kinetochore-microtubule attachments are restored and the checkpoint is silenced, demonstrating that Ipl1 converts syntelic tension defects into the unattached-kinetochore signal.\",\n      \"method\": \"Chemical-genetic kinase inhibition, kinetochore attachment analysis, spindle checkpoint assays in budding yeast\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — analog-sensitive kinase allele for precise inhibition, epistatic readout; highly cited\",\n      \"pmids\": [\"16327780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Aurora B kinase (AURKB) phosphorylates histone H3 at Ser10, causing dissociation of HP1alpha from chromodomain binding at the G2-M transition; depletion of AURKB inhibits HP1alpha dissociation from chromosome arms, and SUV39H1 methyltransferase is mislocalized in AURKB-depleted cells.\",\n      \"method\": \"RNAi depletion, immunofluorescence of HP1alpha dynamics, in vitro H3 phosphorylation and HP1 dissociation assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro dissociation assay combined with RNAi phenotype; consistent with Nature 2005 study\",\n      \"pmids\": [\"16687578\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Aurora B-mediated phosphorylation of histone H3 Ser10 causes HP1 dissociation from heterochromatin during mitosis via a 'methyl/phos switch'; H3K9me3S10ph is generated at pericentric heterochromatin in a Suv39h- and Aurora B-dependent manner, and inhibiting H3 Ser10 phosphorylation prevents HP1 chromosome release throughout mitosis.\",\n      \"method\": \"In vitro kinase assay, immunofluorescence, phosphorylation inhibitor experiments, ChIP-like analysis of autoimmune antibody recognition\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — biochemical reconstitution of methyl/phos switch, multiple experimental approaches; highly cited\",\n      \"pmids\": [\"16222244\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Aurora-B kinase activity augments Ras-mediated cell transformation; RNAi knockdown of Aurora-B inhibits transformation by Ras and Src (but not downstream Raf), and INCENP (a passenger protein associated with Aurora-B) has a similar potentiating effect.\",\n      \"method\": \"RNAi knockdown, focus formation assay in BALB/c 3T3 cells, epistasis with Ras/Src/Raf oncogenes\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with oncogenes and specific pathway placement; single lab\",\n      \"pmids\": [\"16027732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Aurora B kinase (AURKB) mediates an abscission checkpoint that prevents tetraploidization: chromosome bridges sustain Aurora B activity at posttelophase stages, delaying abscission at stabilized intercellular canals; this involves Aurora B phosphorylation of MKLP1 (Mklp1); Aurora B inactivation promotes premature abscission and furrow regression.\",\n      \"method\": \"Live-cell imaging, RNAi, chemical inhibition, phosphorylation assays in human cells\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — live imaging with genetic and chemical perturbations plus substrate identification; highly cited\",\n      \"pmids\": [\"19203582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Aurora B kinase senses chromosome bi-orientation by spatial separation from its kinetochore substrates: FRET-based biosensors showed that phosphorylation of Aurora B substrates at the kinetochore depends on their distance from Aurora B at the inner centromere; repositioning Aurora B closer to the kinetochore prevents stabilization of bi-oriented attachments and activates the spindle checkpoint.\",\n      \"method\": \"FRET-based phosphorylation biosensors in living cells, Aurora B relocalization experiments\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — quantitative live-cell biosensor with mechanistic repositioning experiments; highly cited\",\n      \"pmids\": [\"19150808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Aurora B (AURKB) plays an unexpected role in regulating XIST RNA binding to the inactive X chromosome: RNAi knockdown of AURKB causes mitotic retention of XIST RNA, and H3 phosphorylation (H3S10ph but not H3S28ph) precedes XIST RNA release, linking AURKB-mediated chromatin modification to RNA chromosome binding.\",\n      \"method\": \"RNAi knockdown, kinase inhibitor treatment, RNA FISH, immunofluorescence\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNAi plus inhibitor confirmation with quantitative imaging; single lab\",\n      \"pmids\": [\"19704020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Aurora B phosphorylates the Ndc80 kinetochore protein to reduce its microtubule binding activity; kinetochore-bound Ndc80 is phosphorylated at Ipl1 sites in vivo, but this phosphorylation alone is not essential — additional Ipl1 targets contribute to segregation and checkpoint.\",\n      \"method\": \"In vitro microtubule binding assay, in vivo phosphorylation analysis, genetic analysis of phospho-mutants in yeast\",\n      \"journal\": \"Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro microtubule binding plus in vivo genetic validation; moderate evidence for partial functional contribution\",\n      \"pmids\": [\"19822728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Ipl1-dependent phosphorylation of Dam1 is maximal during S phase and minimal during metaphase; when tension is reduced (by failure to establish sister chromatid cohesion), Dam1 phosphorylation persists in metaphase-arrested cells, demonstrating that Aurora B/Ipl1-facilitated bi-orientation is stabilized in response to kinetochore tension by dephosphorylation of Dam1.\",\n      \"method\": \"In vivo phosphorylation assays with phospho-specific antibodies, genetic manipulation of sister chromatid cohesion in yeast\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — quantitative in vivo phosphorylation correlated with tension state using genetic perturbations\",\n      \"pmids\": [\"19923271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Histone H3 threonine-3 phosphorylation (H3T3ph) by Haspin is necessary for CPC (Aurora B complex) accumulation at centromeres; the CPC subunit Survivin binds directly to H3T3ph; non-binding Survivin-D70A/D71A mutation diminishes centromere localization of Aurora B and compromises centromeric Aurora B functions.\",\n      \"method\": \"Biochemical binding assay (Survivin-H3T3ph), site-directed mutagenesis, microinjection of phospho-specific antibody, immunofluorescence\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct binding reconstitution with mutagenesis and antibody microinjection; highly cited\",\n      \"pmids\": [\"20705812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The inner centromere is defined by the intersection of two histone kinase pathways: Haspin-mediated H3-pT3 and Bub1-mediated H2A-S121 phosphorylation cooperate to recruit the CPC (Aurora B/Survivin) to the inner centromere in fission yeast and human cells.\",\n      \"method\": \"Genetic and biochemical epistasis in S. pombe and human cells, histone mutant analysis, CPC localization imaging\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — two-organism reconstitution with epistasis; highly cited; independent from PMID 20705812\",\n      \"pmids\": [\"20929775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Aurora B phosphorylates three spatially distinct targets within the KMN network (KNL1, Mis12, Ndc80 complexes) at the outer kinetochore; combinatorial phosphorylation generates graded levels of microtubule-binding activity with full phosphorylation severely compromising binding; spatial distribution of targets along the kinetochore axis leads to their differential phosphorylation in response to tension vs. attachment state.\",\n      \"method\": \"In vitro phosphorylation assay, microtubule binding assay, phospho-specific antibodies, chromosome segregation phenotype analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with multiple substrates and mutagenesis; highly cited\",\n      \"pmids\": [\"20471944\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Ipl1/Aurora-dependent phosphorylation of Sli15/INCENP modulates microtubule dynamics by preventing CPC binding to the preanaphase spindle; decreased Ipl1-dependent Sli15 phosphorylation drives direct CPC binding to microtubules, revealing how the CPC influences microtubule dynamics through spatiotemporal control of CPC-spindle interaction.\",\n      \"method\": \"Phosphorylation site mutagenesis, in vitro microtubule binding of Sli15 mutants, live-cell imaging, genetic analysis in yeast\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro binding reconstitution with mutagenesis plus in vivo functional imaging\",\n      \"pmids\": [\"21727193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Cdk1 directly phosphorylates Ipl1/Aurora at two N-terminal serine residues, suppressing its association with the microtubule plus-end tracking protein Bim1 until anaphase onset; failure to phosphorylate Ipl1 leads to premature metaphase spindle targeting and constitutive Bim1 phosphorylation.\",\n      \"method\": \"In vitro kinase assay (Cdk1 phosphorylation of Ipl1), site-directed mutagenesis, in vivo localization, genetic growth analysis\",\n      \"journal\": \"Current biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct in vitro phosphorylation with mutagenesis and in vivo functional validation\",\n      \"pmids\": [\"22521784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Ipl1/Aurora B phosphorylation of Sli15 (INCENP) on sites within its central microtubule-binding domain inhibits Sli15 association with microtubules both in vitro and in vivo; mimicking constitutive phosphorylation delocalizes the CPC in metaphase, while blocking phosphorylation drives excessive spindle association; the phosphorylation state also affects the tension checkpoint mechanism.\",\n      \"method\": \"Phospho-site mutagenesis (sli15-20A/20D), in vitro microtubule binding assay, chromosome instability assay, tension checkpoint assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro microtubule binding with constitutive phospho-mimetic and phospho-deficient mutants plus in vivo validation\",\n      \"pmids\": [\"24558497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Aurkb phosphorylates Oct4 at Ser229 during G2/M phase, causing dissociation of Oct4 from chromatin; PP1 then binds Oct4 and dephosphorylates Oct4(S229) during M/G1 transition to reset Oct4-driven transcription for pluripotency; phosphomimetic and PP1-binding-deficient Oct4 mutations alter the cell cycle and impair pluripotency in embryonic stem cells.\",\n      \"method\": \"In vitro kinase assay, phospho-specific antibody detection, ChIP, ESC pluripotency assays, somatic cell reprogramming efficiency\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — in vitro phosphorylation plus mutagenesis with functional pluripotency readouts\",\n      \"pmids\": [\"26880562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Ipl1/Aurora B phosphorylation of Dam1 is critical for faithful chromosome segregation in vivo: phospho-deficient dam1-3A mutants show stabilized kinetochore-microtubule attachment, delay establishment of bipolar attachment after nocodazole washout, and exhibit dramatic chromosome mis-segregation with premature SAC silencing.\",\n      \"method\": \"Phospho-deficient mutant analysis in vivo, chromosome bi-orientation assay, SAC checkpoint analysis in S. cerevisiae\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — phospho-mutant epistasis with in vivo attachment dynamics and checkpoint readouts\",\n      \"pmids\": [\"28928489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"VRK1 and AURKB form a stable protein complex (detected after nocodazole release); each kinase inhibits the kinase activity of the other and inhibits the other's specific phosphorylation of histone H3 (VRK1→H3-Thr3; AURKB→H3-Ser10); VRK1 is required for survivin expression (which recognizes H3-T3ph) and thereby for AURKB recruitment to centromeres.\",\n      \"method\": \"Co-immunoprecipitation, in vitro cross-inhibition kinase assay, RNAi depletion, immunofluorescence of centromere markers\",\n      \"journal\": \"Cellular and molecular life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP and in vitro cross-inhibition; single lab\",\n      \"pmids\": [\"29340707\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In mouse oocyte meiosis, AURKC is the predominant CPC kinase; AURKB can compensate in the absence of AURKC; AURKB negatively regulates AURKC to prevent aneuploidy; in the absence of AURKC, AURKA localizes to chromosomes in a CPC-dependent manner, revealing inter-kinase competition for CPC binding.\",\n      \"method\": \"Oocyte-specific Aurkb/Aurkc single- and double-knockout mice, immunofluorescence localization, chromosome segregation and fertility assays\",\n      \"journal\": \"Current biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with clean phenotypic analysis and mechanistic inter-kinase localization studies\",\n      \"pmids\": [\"30415701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Aurora B (AURKB) activation is associated with acquired resistance to EGFR TKIs in NSCLC; AURKB inhibitors reduce phospho-histone H3 (a major AURKB product), triggering G1/S arrest and polyploidy in resistant cells, and pH3 levels are increased in NSCLC patients after progression on EGFR TKIs.\",\n      \"method\": \"AURKB inhibitor treatment, pH3 quantification by Western blot/IHC, cell cycle analysis, patient tissue analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological inhibition with substrate readout plus patient sample correlation; single mechanistic pathway\",\n      \"pmids\": [\"31000705\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"AURKB is overexpressed in relapsed B-ALL and restrains glucocorticoid (GC) signaling by phosphorylating EHMT1-2 (histone methyltransferases), thereby reducing GC-induced expression of cell death genes; AURKB inhibition enhances GC-induced expression of cell death genes.\",\n      \"method\": \"Genome-wide shRNA screen, gene expression analysis, AURKB inhibitor treatment, patient sample validation\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional genomics screen plus pharmacological validation; AURKB substrate (EHMT1-2) identified with mechanistic consequence\",\n      \"pmids\": [\"30733284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The COMA complex (Ame1/Okp1 heterodimer with Ctf19/Mcm21) positions Sli15/Ipl1(INCENP/Aurora B) at the budding yeast inner kinetochore through a direct interaction between the Sli15/Ipl1 core-CPC and the Ctf19 C-terminus; tethering Sli15 to Ame1/Okp1 rescues synthetic lethality, establishing the molecular architecture for centromeric CPC recruitment.\",\n      \"method\": \"In vitro reconstitution of kinetochore complexes, crosslink-guided co-purification, yeast genetics (synthetic lethality, rescue)\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with mutagenesis and genetic rescue\",\n      \"pmids\": [\"31112132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Oncoviral antigen LANA (KSHV) cleaves AURKB at Asp76 in a serine protease-dependent manner; the N-terminal cleavage product (N'-AURKB) relocalizes to the spindle pole and promotes metaphase-to-telophase transition; introduction of N'-AURKB promotes colony formation and malignant tumor growth in vivo.\",\n      \"method\": \"Identification of cleavage isoforms in virus-infected cells, serine protease inhibitor experiments, subcellular localization imaging, xenograft tumor model\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic cleavage identification with in vivo functional consequence; single lab\",\n      \"pmids\": [\"30917319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"AURKB promotes gastric cancer cell proliferation by mediating H3 Ser10 phosphorylation (H3S10ph) at the CCND1 (cyclin D1) promoter, thereby epigenetically activating CCND1 expression; AURKB silencing reduces CCND1 and arrests cells in G2/M.\",\n      \"method\": \"AURKB knockdown/inhibition, ChIP for H3S10ph at CCND1 promoter, CCND1 expression analysis, in vitro and in vivo proliferation assays\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP links AURKB enzymatic activity to specific gene promoter; single lab\",\n      \"pmids\": [\"31982864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CCAT2 lncRNA stabilizes BOP1 protein, which in turn increases the active form of Aurora kinase B (AURKB), promoting chromosomal missegregation; BOP1 knockdown reduces CIN phenotypes, placing BOP1 upstream of AURKB activation in a CCAT2-BOP1-AURKB axis.\",\n      \"method\": \"MS2 pulldown, RNA immunoprecipitation, mass spectrometry, BOP1 overexpression/knockdown, CIN cytogenetic assays, AURKB activity measurement\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNA pulldown and functional epistasis with AURKB activity readout; single lab\",\n      \"pmids\": [\"32805281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"BRAFV600E induces mitotic arrest in human melanocytes via microRNA-mediated suppression of AURKB; MIR211-5p and MIR328-3p converge on AURKB targeting, causing mitotic failure, genome duplication, and proliferation arrest; ectopic AURKB expression rescues arrested human nevus cells.\",\n      \"method\": \"miRNA overexpression, luciferase reporter assay for target validation, AURKB rescue expression, immunofluorescence, proliferation assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — miRNA target validation with rescue experiment; multiple orthogonal methods\",\n      \"pmids\": [\"34812139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Haspin kinase activity is required for AURKB recruitment to meiotic centromeres in mouse spermatocytes; haspin inhibition or Haspin gene deletion reduces Aurora B and MCAK (KIF2C) centromeric localization and impairs chromosome congression during meiotic divisions.\",\n      \"method\": \"Chemical inhibition (LDN-192960), Haspin knockout mice, immunofluorescence for AURKB and meiotic markers\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — combined chemical and genetic approach with clear localization and functional phenotype\",\n      \"pmids\": [\"35694956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"AURKB interacts with MAD2L2 and modulates its expression in bladder cancer cells; AURKB knockdown induces senescence and cell cycle arrest in a p53-dependent manner, and overexpression of MAD2L2 rescues AURKB knockdown effects in vitro and in vivo, establishing an AURKB-MAD2L2-p53 DDR axis.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, rescue overexpression, xenograft assays, Western blot, senescence assays\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP interaction plus rescue epistasis in vivo; single lab\",\n      \"pmids\": [\"38515112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"AURKB and TTK inhibitors abrogate the spindle assembly checkpoint; tumor cell sensitivity to these inhibitors is determined by BID (BH3-interacting domain death agonist) levels — high BID cells undergo SAC abrogation-induced CASP-2 activation leading to CASP-3 cleavage and cell death, while BID-low cells are resistant; BID silencing renders sensitive cells resistant and ectopic BID expression sensitizes resistant cells.\",\n      \"method\": \"CRISPR KO, doxycycline-inducible ectopic expression, 53-cell-line panel, PDX in vivo models, CASP-2/3 activation assays\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — bidirectional genetic manipulation in large panel plus in vivo PDX validation\",\n      \"pmids\": [\"37443114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PLK1 and AURKB both phosphorylate survivin to regulate cell proliferation; AURKB inhibition with barasertib significantly inhibited growth of African American (AA) TNBC xenografts, with AA TNBC cells showing higher phospho-survivin levels reflecting higher AURKB activity.\",\n      \"method\": \"Western blot for phospho-survivin, siRNA silencing, barasertib treatment, xenograft tumor models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — survivin as AURKB substrate with functional growth readout; single lab\",\n      \"pmids\": [\"36627281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"AURKB interacts with DHX9 (DExH-Box helicase 9) and targets its expression; AURKB promotes hepatocellular carcinoma progression through the PI3K/AKT/mTOR pathway in a DHX9-dependent manner, as demonstrated by rescue experiments.\",\n      \"method\": \"Co-immunoprecipitation, knockdown/rescue experiments, Western blot for PI3K/AKT/mTOR markers, in vitro and in vivo tumor models\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP interaction plus downstream pathway rescue; single lab\",\n      \"pmids\": [\"38874176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP29, activated by transcription factor FUBP1, deubiquitinates AURKB protein by suppressing K48-linked polyubiquitination, thereby stabilizing AURKB protein levels and promoting its oncogenic functions in gastric cancer; Usp29 knockout mice show reduced Aurkb levels.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, ChIP, qRT-PCR, CRISPR KO, Usp29 knockout mice\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — biochemical ubiquitination assay with in vivo mouse validation and multiple orthogonal methods\",\n      \"pmids\": [\"38233848\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AURKB encodes the catalytic subunit of the chromosomal passenger complex (CPC), a conserved serine/threonine kinase that phosphorylates histone H3 Ser10 to drive chromatin condensation and HP1 release, corrects improper kinetochore-microtubule attachments by phosphorylating KMN network components (Ndc80, KNL1, Dam1) in a tension-sensitive manner via spatial separation from its substrates, recruits to centromeres through Survivin binding to Haspin-generated H3T3ph, is activated by INCENP (Sli15) autophosphorylation, is regulated by opposing Glc7/PP1 phosphatase activity, delays cytokinetic abscission at chromosome bridges to prevent tetraploidization, and in non-mitotic contexts phosphorylates Oct4 to control pluripotency gene resetting and restrains glucocorticoid-driven gene expression in lymphoid cells.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"AURKB (Aurora B kinase) is the catalytic subunit of the Chromosomal Passenger Complex (CPC), where it partners with INCENP/Sli15, Survivin, and Borealin to orchestrate chromosome condensation, error-correction of kinetochore–microtubule attachments, spindle assembly checkpoint signaling in response to tension defects, and cytokinesis [PMID:9450992, PMID:11853667, PMID:19158380]. AURKB phosphorylates kinetochore substrates including Dam1 and Ndc80 to destabilize improper attachments until biorientation generates tension, with the phosphatase Glc7/PP1 counteracting AURKB by dephosphorylating these substrates to stabilize correctly attached kinetochores [PMID:16327780, PMID:19822728, PMID:16537909, PMID:28928489]. During cytokinesis, AURKB phosphorylates myosin II regulatory light chain at the cleavage furrow, and its own localization is controlled by Cdk1-dependent phosphorylation of INCENP/Sli15 and Haspin-mediated H3T3 phosphorylation that recruits the CPC to centromeres [PMID:11098131, PMID:21727193, PMID:35694956]. Beyond mitosis, AURKB phosphorylates Oct4 to regulate pluripotency gene expression in embryonic stem cells and phosphorylates EHMT1/2 histone methyltransferases to modulate glucocorticoid-responsive transcription, while its protein stability is maintained by USP29-mediated deubiquitylation [PMID:26880562, PMID:30733284, PMID:38233848].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"The fundamental requirement of AURKB kinase activity for cytokinesis was established: kinase-inactive AURKB disrupted cleavage furrow formation while wild-type overexpression caused multinuclearity, framing AURKB as a mitotic kinase whose activity level must be precisely controlled.\",\n      \"evidence\": \"Overexpression of kinase-inactive and wild-type AIM-1 in human cancer cells with immunofluorescence and ploidy analysis\",\n      \"pmids\": [\"9450992\", \"9809983\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous substrates at the cleavage furrow not yet identified\", \"No loss-of-function data in mammalian cells at this stage\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identification of histone H3 Ser10 and myosin regulatory light chain as direct AURKB substrates linked the kinase to both chromosome condensation and the contractile ring, revealing its dual mitotic functions.\",\n      \"evidence\": \"Genetic analysis in yeast/C. elegans for H3S10ph balance; in vitro kinase assay with phosphopeptide mapping for MRLC\",\n      \"pmids\": [\"10975519\", \"11098131\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether H3S10ph is instructive for condensation or a readout remained debated\", \"MRLC phosphorylation by AURKB not yet shown to be essential in vivo\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"The discovery that INCENP/Sli15 directly binds and activates Ipl1/AURKB, and that AURKB is required for the spindle checkpoint response to tension loss (but not spindle depolymerization), established the CPC as a tension-sensing machine.\",\n      \"evidence\": \"Co-immunoprecipitation and in vitro kinase assay for INCENP-AURKB; yeast genetics and checkpoint assays for tension-specific checkpoint role\",\n      \"pmids\": [\"11724818\", \"11731476\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which tension is transduced to the kinase unknown\", \"Full composition of the CPC not yet resolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"AURKB was shown to promote chromosome biorientation by destabilizing improper kinetochore–spindle connections, establishing the error-correction paradigm that became central to the field.\",\n      \"evidence\": \"Yeast genetic analysis with spindle pole body duplication assay and live imaging\",\n      \"pmids\": [\"11853667\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the critical kinetochore phospho-substrates not yet determined\", \"How biorientation feeds back to suppress AURKB activity unclear\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Dam1 was identified as a key kinetochore target through which AURKB detaches kinetochores to activate the spindle checkpoint, and methylation–phosphorylation antagonism on Dam1 revealed a chromatin-level regulatory logic for controlling attachment stability.\",\n      \"evidence\": \"Chemical-genetic analog-sensitive Ipl1 allele; biochemical methylation/phosphorylation assays with genetic epistasis\",\n      \"pmids\": [\"16327780\", \"16143104\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Metazoan equivalent of Dam1 regulation not established\", \"Whether methylation-phosphorylation switch is conserved beyond yeast unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"The opposing phosphatase Glc7/PP1 was shown to ensure segregation fidelity by dephosphorylating AURKB substrates (not by regulating AURKB itself), and AURKB-dependent H3S10 phosphorylation was linked to HP1α dissociation at the G2-M transition.\",\n      \"evidence\": \"Phosphorylation assays and genetic epistasis in yeast; RNAi plus in vitro chromatin binding in mammalian cells\",\n      \"pmids\": [\"16537909\", \"16687578\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How PP1 is spatially targeted to oppose AURKB at kinetochores not resolved\", \"HP1α release requires factors beyond H3S10ph alone\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Ndc80 was identified as an additional AURKB kinetochore substrate whose phosphorylation weakens microtubule binding, while Borealin/Nbl1 was established as an essential CPC scaffolding subunit, completing the four-subunit CPC model and revealing substrate redundancy in error correction.\",\n      \"evidence\": \"In vitro phosphorylation/microtubule binding for Ndc80; co-purification and genetics for Borealin/Nbl1; in vivo Dam1 phosphorylation dynamics\",\n      \"pmids\": [\"19822728\", \"19158380\", \"19923271\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of functionally important kinetochore substrates still not delineated\", \"Structural basis of CPC assembly not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"AURKB's autoregulatory phosphorylation of INCENP/Sli15 was shown to prevent premature CPC–microtubule binding, explaining how the CPC relocalizes from centromeres to the spindle midzone at anaphase onset.\",\n      \"evidence\": \"Phosphosite mutagenesis, in vitro CPC–microtubule binding assays, live-cell imaging\",\n      \"pmids\": [\"21727193\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphatase(s) responsible for reversing Sli15 phosphorylation at anaphase not identified\", \"Mechanism of midzone targeting beyond microtubule binding unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Cdk1 was found to directly phosphorylate AURKB N-terminal residues, preventing its association with Bim1 until anaphase, thus integrating cell-cycle control with AURKB localization and function.\",\n      \"evidence\": \"In vitro kinase assay, phosphosite mutagenesis, yeast genetic analysis\",\n      \"pmids\": [\"22521784\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Cdk1 regulation of AURKB is conserved in metazoa not tested\", \"Other cell-cycle kinases that regulate AURKB not systematically explored\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"AURKB was shown to have a non-mitotic role: phosphorylation of Oct4 at Ser229 during G2/M evicts Oct4 from chromatin, with PP1-mediated dephosphorylation resetting pluripotency-associated transcription, revealing AURKB as a regulator of stem cell gene expression.\",\n      \"evidence\": \"In vitro kinase assay, phosphosite mutagenesis, ChIP, ESC phenotypic analysis\",\n      \"pmids\": [\"26880562\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other pluripotency factors are AURKB substrates not examined\", \"Relevance to in vivo embryonic development not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Multiple studies expanded AURKB's functional repertoire: the COMA inner-kinetochore complex was shown to position the CPC via Ctf19-Sli15 interaction; AURKB phosphorylation of EHMT1/2 was found to restrain glucocorticoid-induced gene expression; and KSHV LANA-mediated cleavage of AURKB generated a gain-of-function fragment promoting tumorigenesis.\",\n      \"evidence\": \"Crosslink-guided reconstitution and genetics for COMA-CPC; shRNA screen with pharmacological validation for EHMT1/2; biochemical cleavage assay with xenograft for LANA-AURKB\",\n      \"pmids\": [\"31112132\", \"30733284\", \"30917319\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether COMA-CPC positioning is conserved in human kinetochores unknown\", \"Full spectrum of AURKB chromatin substrates in interphase not mapped\", \"LANA cleavage mechanism and in vivo relevance beyond KSHV tumors unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Haspin kinase–mediated H3T3 phosphorylation was shown to recruit the CPC (including AURKB) to meiotic centromeres in mouse spermatocytes, extending the Haspin-CPC recruitment pathway from mitosis to meiosis.\",\n      \"evidence\": \"Chemical inhibition (LDN-192960) and Haspin knockout mice with immunofluorescence\",\n      \"pmids\": [\"35694956\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Haspin is the sole H3T3 kinase in meiosis not excluded\", \"Functional consequences for meiotic chromosome segregation fidelity not fully quantified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"AURKB protein stability was found to be regulated by USP29-mediated removal of K48-linked polyubiquitin chains, within a FUBP1→USP29→AURKB axis that promotes gastric cancer progression, adding a post-translational stability control layer to AURKB regulation.\",\n      \"evidence\": \"Co-IP, mass spectrometry, ubiquitination assay, ChIP, Usp29 knockout mice\",\n      \"pmids\": [\"38233848\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ubiquitin ligase(s) targeting AURKB for degradation not identified in this study\", \"Whether this axis operates in normal (non-cancer) physiology untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis for how mechanical tension at kinetochores regulates the AURKB-PP1 phosphorylation balance, the complete catalogue of interphase AURKB substrates that mediate its transcriptional roles, and whether the COMA-based CPC inner-kinetochore recruitment mechanism identified in yeast is conserved at human centromeres.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Structural/biophysical mechanism of tension sensing not resolved\", \"Complete interphase substrate repertoire unknown\", \"Conservation of inner-kinetochore CPC recruitment pathway in mammals unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 3, 5, 9, 10, 17, 23, 24, 27]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [2, 3, 9, 17, 20, 23]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [2, 5, 7, 11, 13, 22, 26, 32]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 3, 14, 19]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [15, 23, 29]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 2, 4, 7, 9, 16, 17, 19, 20, 24]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [2, 5, 11, 15, 29]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [35]}\n    ],\n    \"complexes\": [\n      \"Chromosomal Passenger Complex (CPC)\"\n    ],\n    \"partners\": [\n      \"INCENP\",\n      \"BIRC5\",\n      \"CDCA8\",\n      \"VRK1\",\n      \"USP29\",\n      \"NDC80\",\n      \"POU5F1\",\n      \"MAD2L2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"Aurora kinase B (AURKB) is the catalytic serine/threonine kinase subunit of the chromosomal passenger complex (CPC, comprising AURKB, INCENP, Survivin, and Borealin), which orchestrates chromosome segregation, kinetochore–microtubule error correction, and cytokinesis during cell division. AURKB phosphorylates histone H3 at Ser10 to drive HP1 dissociation from chromatin at the G2–M transition and to modulate mitotic chromatin architecture, and it phosphorylates KMN network components (Ndc80, KNL1, Dam1) in a tension-sensitive manner—governed by spatial separation from outer-kinetochore substrates—to selectively destabilize erroneous kinetochore–microtubule attachments and promote chromosome bi-orientation [PMID:19150808, PMID:20471944, PMID:16222244]. CPC centromeric recruitment depends on Survivin recognition of Haspin-generated H3T3ph intersecting with Bub1-mediated H2A-S121ph, while INCENP-mediated autophosphorylation is required for full kinase activation [PMID:20705812, PMID:20929775, PMID:12925766]. Beyond mitosis, AURKB delays cytokinetic abscission at chromosome bridges to prevent tetraploidization, phosphorylates Oct4 to reset pluripotency gene expression in embryonic stem cells, and restrains glucocorticoid-driven transcription in lymphoid cells by phosphorylating EHMT1/2 [PMID:19203582, PMID:26880562, PMID:30733284].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Establishing AURKB as a cytokinesis-essential kinase resolved the question of whether this Aurora family member acts in late mitotic events; dominant-negative kinase-dead mutants disrupted cleavage furrow formation without affecting nuclear division.\",\n      \"evidence\": \"Dominant-negative overexpression and immunofluorescence in mammalian cells\",\n      \"pmids\": [\"9450992\", \"9809983\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of cytokinetic substrates was unknown\", \"Relationship to chromosome segregation functions was not addressed\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Discovery that the Ipl1/Aurora–Glc7/PP1 kinase–phosphatase axis controls histone H3-Ser10 phosphorylation and chromosome segregation established the first chromatin substrate and revealed an antagonistic phosphatase circuit governing Aurora activity.\",\n      \"evidence\": \"Genetic epistasis in S. cerevisiae and C. elegans with histone phosphorylation assays\",\n      \"pmids\": [\"10975519\", \"11098131\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether H3S10ph was the sole mitotic chromatin function of Aurora was unclear\", \"Direct regulation of PP1 at centromeres was not dissected\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Three concurrent studies demonstrated that Ipl1/Aurora B promotes chromosome bi-orientation by destabilizing improper kinetochore–spindle connections, activates the spindle checkpoint specifically in response to tension defects, and is directly stimulated by INCENP/Sli15—establishing the core CPC regulatory logic.\",\n      \"evidence\": \"Live-cell imaging of kinetochore dynamics, checkpoint epistasis, co-immunoprecipitation, and in vitro kinase assays in yeast\",\n      \"pmids\": [\"11853667\", \"11731476\", \"11724818\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How tension is transduced to kinase–substrate accessibility was unknown\", \"Full CPC composition had not been determined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification that INCENP phosphorylation by Aurora B at Thr893/Ser894/Ser895 constitutes a positive-feedback activation loop resolved how the CPC achieves switch-like kinase activation and proper centromere/spindle localization.\",\n      \"evidence\": \"Reconstituted in vitro kinase assay with site-directed mutagenesis plus RNAi depletion\",\n      \"pmids\": [\"12925766\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the activation loop was not determined\", \"Whether additional kinases prime INCENP was unclear\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Borealin was identified as the fourth CPC subunit, completing the complex architecture, and the CPC was shown to promote spindle assembly by negatively regulating the microtubule depolymerase MCAK.\",\n      \"evidence\": \"Co-IP/in vitro reconstitution of four-subunit CPC; MCAK co-depletion epistasis in Xenopus egg extracts\",\n      \"pmids\": [\"15249581\", \"15260989\", \"14767480\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"MCAK phosphorylation sites by Aurora B were not fully mapped\", \"How CPC transitions from centromere to spindle midzone was unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"The 'methyl/phos switch' mechanism was elucidated: Aurora B phosphorylation of H3S10 adjacent to K9me3 ejects HP1 from heterochromatin at G2/M, explaining how mitotic chromatin condensation is coupled to histone code readout.\",\n      \"evidence\": \"In vitro kinase/binding reconstitution, immunofluorescence, and phosphorylation inhibitor experiments\",\n      \"pmids\": [\"16222244\", \"16687578\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the switch operates at all chromatin loci or only pericentric heterochromatin was unresolved\", \"Kinetics of HP1 rebinding after Aurora B inactivation were not measured\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Two landmark mechanisms were established: (1) FRET biosensors showed that Aurora B senses bi-orientation through spatial separation from outer-kinetochore substrates, explaining tension-dependent error correction; (2) Aurora B was found to delay cytokinetic abscission at chromosome bridges via MKLP1 phosphorylation, preventing tetraploidization.\",\n      \"evidence\": \"FRET-based biosensors with Aurora B relocalization in living cells; live-cell imaging with RNAi and chemical inhibition\",\n      \"pmids\": [\"19150808\", \"19203582\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphatase contribution to the spatial gradient was not quantified\", \"How the abscission checkpoint integrates with ESCRT machinery was unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Aurora B phosphorylation of Ndc80 and Dam1 was shown to reduce microtubule binding in vitro and to be tension-regulated in vivo, identifying key outer-kinetochore substrates for the error-correction mechanism.\",\n      \"evidence\": \"In vitro microtubule binding assays, phospho-specific antibodies, genetic analysis in yeast\",\n      \"pmids\": [\"19822728\", \"19923271\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of each KMN substrate to error correction was not determined\", \"Whether mammalian Dam1-equivalent Ska complex is similarly regulated was untested\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"The molecular basis of CPC centromere targeting was resolved: Survivin binds Haspin-generated H3T3ph and Bub1-generated H2A-S121ph marks intersect to define the inner centromere, explaining the precision of Aurora B localization.\",\n      \"evidence\": \"Direct binding assay (Survivin–H3T3ph), mutagenesis, antibody microinjection, and two-organism genetic epistasis\",\n      \"pmids\": [\"20705812\", \"20929775\", \"20471944\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Haspin and Bub1 activities are themselves spatially restricted was not fully resolved\", \"Whether centromere targeting differs in meiosis was not addressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Aurora B autophosphorylation of INCENP/Sli15 was shown to prevent premature CPC binding to the spindle, while Cdk1 phosphorylation of Aurora B itself suppresses plus-end tracking until anaphase, revealing layered temporal control of CPC redistribution.\",\n      \"evidence\": \"Phosphosite mutagenesis with in vitro microtubule binding and live-cell imaging in yeast\",\n      \"pmids\": [\"21727193\", \"22521784\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Cdk1 regulation of Aurora B is conserved in mammalian cells was not tested\", \"Structural basis for phosphorylation-dependent spindle binding was lacking\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Discovery that Aurora B phosphorylates Oct4 at Ser229 during G2/M to dissociate it from chromatin—with PP1-mediated dephosphorylation resetting pluripotency transcription—extended AURKB function beyond mitosis into stem cell gene regulation.\",\n      \"evidence\": \"In vitro kinase assay, ChIP, phospho-specific antibodies, ESC pluripotency and reprogramming assays\",\n      \"pmids\": [\"26880562\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other pluripotency factors are Aurora B substrates was not examined\", \"Relevance to in vivo embryonic development was not tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"AURKB was found to restrain glucocorticoid signaling in lymphoid cells by phosphorylating EHMT1/2, reducing GC-induced cell death gene expression—identifying a non-mitotic role in transcriptional repression relevant to drug resistance in B-ALL.\",\n      \"evidence\": \"Genome-wide shRNA screen, AURKB inhibitor treatment, gene expression analysis, patient sample validation\",\n      \"pmids\": [\"30733284\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct phosphorylation sites on EHMT1/2 by AURKB were not mapped\", \"Whether this mechanism operates in other hematopoietic lineages is unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Haspin kinase was confirmed to be required for Aurora B centromeric recruitment in mammalian meiosis (spermatocytes), extending the Haspin–H3T3ph–Survivin recruitment paradigm from mitosis to meiotic divisions.\",\n      \"evidence\": \"Chemical inhibition and Haspin knockout mice with immunofluorescence for meiotic AURKB/MCAK localization\",\n      \"pmids\": [\"35694956\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether female meiosis uses the identical recruitment mechanism was not shown\", \"Interaction between Haspin pathway and Bub1 pathway in meiosis was not dissected\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"USP29 was identified as a deubiquitinase that stabilizes AURKB by removing K48-linked polyubiquitin chains, revealing a post-translational mechanism controlling AURKB protein abundance.\",\n      \"evidence\": \"Co-IP, in vitro ubiquitination assay, CRISPR KO, Usp29 knockout mice\",\n      \"pmids\": [\"38233848\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The E3 ubiquitin ligase targeting AURKB for degradation was not identified\", \"Whether USP29 regulation of AURKB operates in normal (non-cancer) physiology is unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis for the Aurora B spatial phosphorylation gradient at the centromere–kinetochore axis, the full extent of non-mitotic AURKB substrates, and how the abscission checkpoint mechanistically integrates with ESCRT-mediated membrane scission.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of the full CPC bound to centromeric nucleosomes\", \"Comprehensive phosphoproteomics of AURKB substrates across cell cycle stages is lacking\", \"Mechanism coupling Aurora B activity to ESCRT-III recruitment at the midbody is undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2, 3, 6, 7, 9, 10, 15, 16, 19, 21, 22, 25, 29, 30]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [2, 3, 9, 10, 25, 29]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [2, 9, 15, 16]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [12, 14, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [9, 15, 16, 23, 24]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 6, 26]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0, 36]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 2, 4, 5, 10, 13, 14, 18, 19, 25, 30]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [2, 7, 9, 15, 16]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [29, 34, 37]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [33, 34, 39, 43]}\n    ],\n    \"complexes\": [\n      \"Chromosomal passenger complex (CPC)\"\n    ],\n    \"partners\": [\n      \"INCENP\",\n      \"BIRC5\",\n      \"CDCA8\",\n      \"NDC80\",\n      \"DAM1\",\n      \"VRK1\",\n      \"POU5F1\",\n      \"MKLP1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}