{"gene":"AURKA","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":1997,"finding":"AURKA (BTAK) encodes a serine/threonine kinase localized on chromosome 20q13 with homology to yeast Ipl1 and Drosophila Aurora, both involved in chromosome segregation; the gene is amplified and overexpressed in breast tumor cell lines.","method":"cDNA cloning, sequence analysis, chromosomal mapping","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — foundational cloning and sequence work in a single lab; functional inference from homology, no direct enzymatic assay in this paper","pmids":["9174055"],"is_preprint":false},{"year":1997,"finding":"AURKA (Aik) protein is cell-cycle regulated, accumulates during G2/M and decreases after mitosis, localizes to the spindle pole from prophase through anaphase, and exhibits kinase activity (casein phosphorylation) enhanced at mitosis.","method":"Northern blot, Western blot, immunofluorescence, in vitro kinase assay with exogenous casein substrate","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (cell-cycle staging, immunofluorescence localization, in vitro kinase assay) in a single focused study","pmids":["9153231"],"is_preprint":false},{"year":1998,"finding":"Ectopic overexpression of AURKA (STK15/BTAK) in mouse NIH 3T3 cells and near-diploid human breast epithelial cells induces centrosome amplification, aneuploidy, and oncogenic transformation, defining AURKA as a centrosome-associated kinase whose overexpression drives chromosomal instability.","method":"Ectopic expression in mammalian cells, immunofluorescence, soft-agar transformation assay, FISH","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple cell-line models with defined phenotypic readouts; highly replicated in subsequent literature","pmids":["9771714"],"is_preprint":false},{"year":1999,"finding":"AURKA (Aurora2/Aik) associates with the cell cycle regulator Cdc20 in HeLa cells; Cdc20-associated kinase activity peaks in early M phase, identifying Cdc20 as an AURKA-interacting protein at mitotic spindle poles.","method":"Co-immunoprecipitation from HeLa cell extracts, kinase activity assay (MBP phosphorylation)","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single Co-IP experiment with kinase activity readout, single lab","pmids":["10377410"],"is_preprint":false},{"year":2000,"finding":"AURKA (Aurora2) is activated by phosphorylation of Threonine 288 within the activation loop; this phosphorylation increases enzymatic activity and can be catalyzed by PKA in vitro. Protein phosphatase 1 (PP1) dephosphorylates T288 and inactivates AURKA in vitro; in vivo T288 phosphorylation is induced by okadaic acid. Additionally, AURKA is degraded via the proteasome, and T288-phosphorylated AURKA may be targeted for mitotic degradation.","method":"In vitro kinase assay, site-directed mutagenesis (T288 substitution), phosphatase assay with PP1, okadaic acid treatment, proteasome inhibitor experiments","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro biochemical reconstitution with mutagenesis and multiple orthogonal methods in a single study","pmids":["11039908"],"is_preprint":false},{"year":2001,"finding":"AURKA (STK15) contains two functional PP1-binding sites; STK15 and PP1 interact in a cell-cycle-dependent manner peaking at mitosis. Activated STK15 phosphorylates PP1 and inhibits its phosphatase activity in vitro and in vivo. Conversely, PP1 dephosphorylates and inactivates STK15. Non-binding STK15 mutants are superphosphorylated but have reduced kinase activity, and cells expressing these mutants show aberrant chromosome alignment.","method":"Co-immunoprecipitation, in vitro kinase assay, in vitro phosphatase assay, site-directed mutagenesis of PP1-binding motifs, immunofluorescence for chromosome alignment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reciprocal biochemical assays with mutagenesis and cellular phenotypic validation, single lab with multiple orthogonal methods","pmids":["11551964"],"is_preprint":false},{"year":2013,"finding":"AURKA directly interacts with and phosphorylates HDM2 (MDM2) in vitro; this leads to P53 ubiquitination and attenuation of cisplatin-induced P53 activation in gastric cancer cells, promoting cell survival.","method":"Dual co-immunoprecipitation, in vitro kinase assay with recombinant AURKA and HDM2, ubiquitination assay, luciferase reporter for P53 activity","journal":"Clinical cancer research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of kinase-substrate relationship plus Co-IP and functional readouts, single lab with multiple orthogonal methods","pmids":["24240108"],"is_preprint":false},{"year":2014,"finding":"AURKA promotes STAT3 transcriptional activity through regulation of JAK2 expression and phosphorylation; overexpression of AURKA increases STAT3 Tyr705 phosphorylation and STAT3 nuclear translocation, whereas AURKA knockdown reduces these effects. Inhibition of JAK2 in the presence of AURKA overexpression abrogates AURKA-mediated STAT3 activation, establishing the AURKA-JAK2-STAT3 axis.","method":"siRNA knockdown, overexpression, immunofluorescence, luciferase reporter assay, JAK2-specific inhibitor (AZD1480), Western blot for phospho-STAT3","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological perturbations with multiple readouts, single lab","pmids":["24953013"],"is_preprint":false},{"year":2014,"finding":"SMAD4 binds to AURKA and induces its proteasomal degradation in a TGFβ-independent manner, thereby suppressing AURKA-mediated β-catenin/TCF transcriptional activity and metastatic phenotypes.","method":"Co-immunoprecipitation, overexpression and knockdown, luciferase reporter assay for β-catenin/TCF, colony formation, migration and invasion assays","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus functional rescue experiments in multiple cell lines, single lab","pmids":["25061104"],"is_preprint":false},{"year":2016,"finding":"In the nucleus, AURKA translocates from centrosomes and performs kinase-independent oncogenic functions by interacting with hnRNP K to form a transcriptional complex that shifts MYC promoter usage and activates MYC transcription, thereby enhancing breast cancer stem cell phenotype. Blocking AURKA nuclear localization inhibits this transactivating function.","method":"Co-immunoprecipitation, nuclear fractionation, ChIP/promoter assays, kinase-dead mutants, nuclear localization-blocking constructs, mammosphere assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods including Co-IP, kinase-dead mutants, and localization blocking experiments establishing kinase-independent nuclear function","pmids":["26782714"],"is_preprint":false},{"year":2018,"finding":"ARID1A occupies the AURKA gene promoter and negatively regulates AURKA transcription; loss of ARID1A results in enhanced AURKA transcription leading to persistent CDC25C activation and G2/M dysregulation, creating a synthetic lethal interaction exploitable therapeutically.","method":"ChIP assay, genetic knockout/knockdown, CDC25C activity assays, cell cycle analysis, xenograft models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP for promoter occupancy, genetic perturbations with mechanistic pathway placement, multiple orthogonal methods","pmids":["30097580"],"is_preprint":false},{"year":2018,"finding":"PRL-3 phosphatase interacts with AURKA and promotes its ubiquitination and proteasomal degradation by dephosphorylating FZR1, thereby activating the APC/C-FZR1 complex which targets AURKA.","method":"Co-immunoprecipitation, ubiquitination assay, phosphatase-dependent degradation assay, ectopic expression and knockdown, xenograft models","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic reconstitution identifying writer (APC/C-FZR1) and eraser (PRL-3-mediated dephosphorylation of FZR1) with multiple orthogonal methods","pmids":["30498084"],"is_preprint":false},{"year":2018,"finding":"AURKA directly phosphorylates SPOP at three sites, causing SPOP ubiquitination and degradation; SPOP in turn degrades AURKA via a feedback loop. AURKA-mediated SPOP degradation stabilizes androgen receptor (AR), ARv7, and c-Myc, driving castration-resistant prostate cancer progression.","method":"In vitro kinase assay identifying SPOP as direct AURKA substrate, co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (phospho-resistant SPOP), xenograft models","journal":"Cancers","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay establishing direct phosphorylation, mutagenesis (phospho-resistant mutant), and in vivo validation, single lab","pmids":["33158056"],"is_preprint":false},{"year":2019,"finding":"CEP41-mediated tubulin glutamylation of cilia activates AURKA and upregulates VEGFA/VEGFR2 expression through HIF1α during endothelial cell responses to shear stress or hypoxia, driving angiogenesis and cilia disassembly (deciliation).","method":"siRNA knockdown in human endothelial cells and zebrafish, immunofluorescence, Western blot, VEGF/HIF1α pathway analysis","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockdown in two model systems with pathway analysis, single lab","pmids":["31885126"],"is_preprint":false},{"year":2020,"finding":"AURKA kinase activity is required for the maintenance of ring-like aMTOC (acentriolar microtubule-organizing center) organization in mouse oocytes; inhibition of AURKA causes loss of aMTOC ring structure, CEP215 clustering at spindle poles, and shorter spindles with highly focused poles.","method":"Pharmacological AURKA inhibition in mouse oocytes (MI and MII stages), super-resolution microscopy, siRNA knockdown of Cep215","journal":"Reproduction (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological inhibition with direct imaging of aMTOC structural changes, single lab","pmids":["31895686"],"is_preprint":false},{"year":2021,"finding":"AURKA deletion in spermatogonia eliminates all developing germ cells (consistent with its mitotic role), while deletion in spermatocytes increases spermatocyte apoptosis, elevates abnormal sperm morphology, and increases progressive sperm motility with decreased PP1 activity in sperm lysate.","method":"Conditional knockout mice (Cre-lox in spermatogonia or spermatocytes), fertility assays, sperm motility analysis, PP1 activity assay","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO in vivo with multiple phenotypic readouts and biochemical (PP1 activity) validation, establishing multiple spermatogenic roles","pmids":["34518881"],"is_preprint":false},{"year":2022,"finding":"CBLC (an E3 ubiquitin ligase) interacts with the kinase domain of AURKA and stabilizes it by conjugating monoubiquitination and K11/K63-linked polyubiquitination, protecting AURKA from degrading K11/K48 polyubiquitination. CBLC depletion decreases AURKA half-life and delays AURKA accumulation/activation during mitotic entry.","method":"Co-immunoprecipitation and mass spectrometry, ubiquitination assays with linkage-specific analysis, cycloheximide chase (half-life), cell synchronization with thymidine block, Western blot","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Moderate — biochemical reconstitution of ubiquitination mechanism with linkage specificity, half-life assay, and functional mitotic entry readout, single lab with multiple orthogonal methods","pmids":["35149839"],"is_preprint":false},{"year":2023,"finding":"AURKA functionally interacts with mitochondrial ATP synthase subunits ATP5F1A and ATP5F1B (Complex V core subunits); disruption of this AURKA/ATP5F1A/ATP5F1B nexus triggers G0/G1 arrest accompanied by decreased glycolysis and mitochondrial respiration, with cell fate outcome dependent on the metabolic propensity of triple-negative breast cancer cells.","method":"Co-immunoprecipitation, pharmacological Complex V inhibition, AURKA abundance measurement, cell cycle analysis, Seahorse metabolic assays","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying interaction plus functional metabolic readouts, single lab","pmids":["37386025"],"is_preprint":false},{"year":2023,"finding":"AURKA directly interacts with and phosphorylates KEAP1, thereby activating NRF2 and its target gene transcription, suppressing ferroptosis in meningioma; FOXM1 transcriptionally induces AURKA expression in this context.","method":"Co-immunoprecipitation, in vitro kinase assay, NRF2 target gene reporter/Western blot, FOXM1 ChIP/promoter assay, mouse meningioma model","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and kinase assay establishing direct phosphorylation of KEAP1, supported by in vivo model, single lab","pmids":["38642502"],"is_preprint":false},{"year":2023,"finding":"The crystal structure of AURKA bound to a conserved helix (Helix-1) from CEP192 reveals a distinct binding site on AURKA that is different from the TPX2 binding site; disrupting the CEP192 Helix-1/AURKA interaction in cells causes mitotic defects, establishing the structural basis for centrosomal AURKA regulation distinct from spindle-microtubule regulation by TPX2.","method":"Crystal structure determination (X-ray crystallography), quantitative binding studies (ITC/SPR), cell-based mutation experiments with mitotic defect readout","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with quantitative binding measurements and functional cellular validation; establishes structural basis for CEP192-AURKA interaction","pmids":["37083534"],"is_preprint":false},{"year":2023,"finding":"AURKA interacts with DDX5 to form a transcriptional coactivator complex that induces transcription of the lncRNA TMEM147-AS1, which in turn sponges hsa-let-7b/7c-5p to upregulate AURKA in a positive feedback loop maintaining cisplatin resistance via lipophagy activation in ovarian cancer.","method":"Co-immunoprecipitation (AURKA-DDX5), ChIP/promoter analysis, lncRNA sponge assays, lipophagy assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP for complex formation plus transcriptional and functional assays, single lab","pmids":["37217070"],"is_preprint":false},{"year":2023,"finding":"CD73/NT5E directly interacts with AURKA (confirmed by co-IP and molecular docking) and inhibits AURKA ubiquitination; overexpression of CD73/NT5E stabilizes AURKA, downregulates p53 signaling, and regulates hepatic stellate cell activation and senescence in alcohol-related liver fibrosis.","method":"Co-immunoprecipitation, molecular docking, ubiquitination assay, mouse model of alcohol-related liver fibrosis","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP with ubiquitination assay and in vivo model, single lab","pmids":["36778123"],"is_preprint":false},{"year":2023,"finding":"TPX2 co-overexpression promotes AURKA nuclear accumulation in interphase, whereas AURKA overexpression alone is insufficient for nuclear accumulation. Nuclear export and proteasome activity also regulate nuclear AURKA levels. Nuclear AurkA driven by TPX2 co-overexpression promotes pro-tumorigenic processes in MCF10A mammospheres.","method":"Nuclear/cytoplasmic fractionation, live imaging, proteasome inhibition, co-overexpression experiments, mammosphere assay","journal":"Life science alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal localization methods with functional consequence in mammosphere model, single lab","pmids":["36797043"],"is_preprint":false},{"year":2023,"finding":"USP21 deubiquitinase directly interacts with AURKA (confirmed by co-IP and GST-pulldown) and deubiquitinates AURKA to restore its activity and stability; USP21 knockdown increases AURKA ubiquitination and suppresses laryngeal cancer cell proliferation, migration, and invasion.","method":"Co-immunoprecipitation, GST-pulldown, ubiquitination assay, knockdown experiments with rescue by AURKA overexpression","journal":"The Kaohsiung journal of medical sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assays (Co-IP and GST-pulldown) plus ubiquitination assay with functional rescue, single lab","pmids":["36919585"],"is_preprint":false},{"year":2021,"finding":"AURKA inhibition suppresses differentiation of THP-1 AML cells by repressing KDM6B (H3K27 demethylase) expression; AURKA and YY1 co-occupy the KDM6B promoter region. Alisertib-mediated AURKA inhibition dissociates this complex, upregulates KDM6B, and drives THP-1 differentiation into monocytes. This effect is blocked by the KDM6B inhibitor GSK-J4.","method":"ChIP (AURKA and YY1 at KDM6B promoter), alisertib treatment, flow cytometry for differentiation markers, KDM6B inhibitor epistasis","journal":"Molecules and cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for chromatin occupancy plus pharmacological epistasis establishing pathway, single lab","pmids":["29477140"],"is_preprint":false},{"year":2018,"finding":"AURKA promotes STAT3 activity through regulation of JAK2; pharmacological AURKA inhibition (MLN8237) decreases HDM2 protein levels, induces P53 transcriptional activity, and reduces cell survival in vitro and xenograft tumor growth in vivo in gastric cancer models.","method":"AURKA inhibitor (alisertib/MLN8237), siRNA, Western blot, xenograft model","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic perturbation with in vivo validation, already captured in the HDM2 entry; noting overlap with JAK2 axis (PMID 24953013)","pmids":["24240108"],"is_preprint":false},{"year":2021,"finding":"AURKA inhibition in Ewing's sarcoma cells induces apoptosis and ferroptosis through the NPM1/YAP1 axis; co-immunoprecipitation confirmed AURKA-NPM1 interaction, and AURKA inhibition disrupts this complex.","method":"Co-immunoprecipitation (AURKA-NPM1), pharmacological and siRNA AURKA inhibition, ferroptosis/apoptosis assays, xenograft model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus functional cell death assays and in vivo model, single lab","pmids":["38287009"],"is_preprint":false},{"year":2023,"finding":"HMMR interacts with AURKA and inhibits its ubiquitination-mediated degradation, elevating AURKA protein levels and subsequently activating the mTORC2/AKT pathway to drive prostate cancer progression; E2F1, upregulated by mTORC2/AKT, transcriptionally promotes HMMR expression, forming a positive feedback loop.","method":"Co-immunoprecipitation (HMMR-AURKA), ubiquitination assay, gain/loss-of-function experiments, mTOR inhibitor epistasis, in vivo xenograft","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP and ubiquitination assay identifying mechanism, supported by in vivo model, single lab","pmids":["36750558"],"is_preprint":false},{"year":2021,"finding":"AURKA promotes psoriasis-related inflammation by blocking autophagy-mediated suppression of the AIM2 inflammasome, acting through activation of the AKT/mTOR pathway; AURKA knockdown inhibits AIM2 inflammasome activation and enhances autophagy, while autophagy inhibition (3-MA) attenuates these effects.","method":"siRNA knockdown and overexpression, Western blot for inflammasome components (IL-1β, IL-18, caspase-1 p20), autophagy markers, AKT/mTOR phosphorylation assays, pharmacological inhibitors (PI-103, 3-MA)","journal":"Immunology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic perturbations with pharmacological epistasis placing AURKA in the AKT/mTOR-autophagy-AIM2 pathway, single lab","pmids":["34710506"],"is_preprint":false}],"current_model":"AURKA is a centrosome-associated serine/threonine kinase activated by T288 autophosphorylation (facilitated by cofactors including TPX2, CEP192, and Bora) and inactivated by PP1-mediated dephosphorylation; it localizes to spindle poles during mitosis to regulate centrosome maturation, spindle assembly, and chromosome segregation, and undergoes proteasomal degradation governed by ubiquitin ligases (APC/C-FZR1, CBLC) and deubiquitinases (USP21); beyond its catalytic mitotic roles, AURKA acts kinase-independently in the nucleus—driven by co-overexpression with TPX2—to transactivate oncogenes including MYC via hnRNP K interaction, and it phosphorylates diverse substrates (HDM2/MDM2 to suppress p53, KEAP1 to activate NRF2, SPOP to stabilize AR/c-Myc) and interacts with metabolic complexes (mitochondrial ATP synthase) to modulate energy metabolism and cell fate."},"narrative":{"mechanistic_narrative":"AURKA is a cell-cycle-regulated serine/threonine kinase that accumulates at G2/M and localizes to the spindle pole from prophase through anaphase, where it governs centrosome function and chromosome segregation [PMID:9153231]; its amplification and overexpression in tumors drives centrosome amplification, aneuploidy, and oncogenic transformation [PMID:9174055, PMID:9771714]. Catalytic activity is switched on by phosphorylation of Threonine 288 in the activation loop and switched off by PP1, with which AURKA forms a reciprocal regulatory loop—activated kinase phosphorylates and inhibits PP1, while PP1 dephosphorylates and inactivates the kinase [PMID:11039908, PMID:11551964]. Distinct cofactors engage AURKA at separable sites to direct its localized functions: a crystal structure of AURKA bound to CEP192 Helix-1 defines a centrosomal regulatory interface distinct from the TPX2 binding site [PMID:37083534], and TPX2 co-overexpression additionally drives AURKA into the interphase nucleus [PMID:36797043]. AURKA abundance is set by opposing ubiquitin machinery—the APC/C-FZR1 axis (modulated by PRL-3-mediated FZR1 dephosphorylation) and stabilizing/destabilizing E3 activity of CBLC, counterbalanced by the deubiquitinase USP21 [PMID:30498084, PMID:35149839, PMID:36919585]. Beyond mitosis, AURKA acts kinase-independently in the nucleus by partnering with hnRNP K to transactivate MYC and promote a cancer stem cell phenotype [PMID:26782714], and as a kinase it phosphorylates substrates that rewire tumor-relevant signaling: HDM2/MDM2 to suppress p53 [PMID:24240108], KEAP1 to activate NRF2 and suppress ferroptosis [PMID:38642502], and SPOP to stabilize androgen receptor and c-Myc [PMID:33158056]. It is also embedded in feedback circuits with metabolic and transcriptional regulators, including mitochondrial ATP synthase subunits that couple it to cell-cycle and metabolic fate [PMID:37386025].","teleology":[{"year":1997,"claim":"Established AURKA as a chromosome-segregation kinase homologous to yeast Ipl1/Drosophila Aurora and linked its amplification to breast cancer, framing it as a candidate oncogene.","evidence":"cDNA cloning, sequence/homology analysis and chromosomal mapping (20q13) in breast tumor cell lines","pmids":["9174055"],"confidence":"Medium","gaps":["No direct enzymatic assay in this study","Functional role inferred from homology only"]},{"year":1997,"claim":"Showed AURKA is cell-cycle regulated and spindle-pole-localized with mitotically enhanced kinase activity, placing it temporally and spatially within mitosis.","evidence":"Northern/Western blot, immunofluorescence and in vitro casein kinase assay across the cell cycle","pmids":["9153231"],"confidence":"High","gaps":["Physiological substrates not identified","Mechanism of activation not addressed"]},{"year":1998,"claim":"Demonstrated causally that AURKA overexpression drives centrosome amplification, aneuploidy, and transformation, establishing the oncogenic mechanism behind its amplification.","evidence":"Ectopic expression in NIH 3T3 and human breast epithelial cells with soft-agar transformation and FISH","pmids":["9771714"],"confidence":"High","gaps":["Did not define which catalytic substrates mediate centrosome amplification","In vivo relevance not tested here"]},{"year":2001,"claim":"Defined the activation switch (T288 autophosphorylation) and a reciprocal AURKA-PP1 antagonism that sets kinase activity and proper chromosome alignment.","evidence":"In vitro kinase/phosphatase assays, T288 and PP1-binding-site mutagenesis, okadaic acid, immunofluorescence","pmids":["11039908","11551964"],"confidence":"High","gaps":["Physiological kinase activating T288 in cells not fully resolved","Downstream mitotic substrates not enumerated"]},{"year":1999,"claim":"Identified Cdc20 as an early-mitotic AURKA-associated protein, linking the kinase to the mitotic regulatory machinery.","evidence":"Co-immunoprecipitation from HeLa extracts with MBP kinase activity readout","pmids":["10377410"],"confidence":"Medium","gaps":["Single Co-IP, no reciprocal validation","Functional consequence of the interaction not defined"]},{"year":2016,"claim":"Revealed a kinase-independent nuclear function in which AURKA partners hnRNP K to transactivate MYC, expanding AURKA biology beyond catalytic mitotic roles.","evidence":"Nuclear fractionation, Co-IP, ChIP/promoter assays, kinase-dead and localization-blocking mutants, mammosphere assays","pmids":["26782714"],"confidence":"High","gaps":["Structural basis of hnRNP K binding unknown","Determinants of nuclear import only partly defined"]},{"year":2022,"claim":"Mapped the ubiquitin economy controlling AURKA levels by identifying writers, erasers, and stabilizers acting on distinct ubiquitin linkages.","evidence":"Co-IP/MS, linkage-specific ubiquitination assays, cycloheximide chase and synchronization (CBLC, APC/C-FZR1/PRL-3, USP21)","pmids":["35149839","30498084","36919585"],"confidence":"High","gaps":["Relative contribution of each ligase across cell types unclear","Crosstalk between stabilizing and degrading linkages not fully resolved"]},{"year":2023,"claim":"Provided the structural basis for separable centrosomal versus spindle regulation by showing CEP192 Helix-1 binds AURKA at a site distinct from TPX2.","evidence":"X-ray crystallography, ITC/SPR binding measurements, cell-based interaction-disrupting mutations","pmids":["37083534"],"confidence":"High","gaps":["Conformational consequences of dual cofactor engagement not resolved","How localization-specific activation selects substrates unknown"]},{"year":2023,"claim":"Extended AURKA's substrate repertoire and feedback circuitry into tumor signaling and metabolism, defining KEAP1/NRF2, SPOP/AR-Myc, and ATP synthase as effector nodes.","evidence":"In vitro kinase assays, Co-IP, ubiquitination assays, Seahorse metabolic analysis and in vivo models (KEAP1, SPOP, HDM2, ATP5F1A/B)","pmids":["38642502","33158056","24240108","37386025"],"confidence":"Medium","gaps":["Many substrate interactions rest on single-lab Co-IP","Hierarchy among these effector pathways in vivo unclear"]},{"year":null,"claim":"How distinct localized cofactor-bound AURKA states select specific substrates and balance catalytic versus kinase-independent outputs remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking cofactor binding site to substrate choice","Structural basis for kinase-independent transcriptional functions undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,4,6,12,18]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[1,4,5,6,12,18]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[9,20]}],"localization":[{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[1,2,19]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[9,22]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1,14]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[17]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,2,4,5]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[9,24]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,2,12]}],"complexes":["APC/C-FZR1"],"partners":["TPX2","CEP192","PP1","CDC20","HNRNP K","MDM2","KEAP1","SPOP"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O14965","full_name":"Aurora kinase A","aliases":["Aurora 2","Aurora/IPL1-related kinase 1","ARK-1","Aurora-related kinase 1","Breast tumor-amplified kinase","Ipl1- and aurora-related kinase 1","Serine/threonine-protein kinase 15","Serine/threonine-protein kinase 6","Serine/threonine-protein kinase Ayk1","Serine/threonine-protein kinase aurora-A"],"length_aa":403,"mass_kda":45.8,"function":"Mitotic serine/threonine kinase that contributes to the regulation of cell cycle progression (PubMed:11039908, PubMed:12390251, PubMed:17125279, PubMed:17360485, PubMed:18615013, PubMed:26246606). Associates with the centrosome and the spindle microtubules during mitosis and plays a critical role in various mitotic events including the establishment of mitotic spindle, centrosome duplication, centrosome separation as well as maturation, chromosomal alignment, spindle assembly checkpoint, and cytokinesis (PubMed:14523000, PubMed:26246606). Required for normal spindle positioning during mitosis and for the localization of NUMA1 and DCTN1 to the cell cortex during metaphase (PubMed:27335426). Required for initial activation of CDK1 at centrosomes (PubMed:13678582, PubMed:15128871). Phosphorylates numerous target proteins, including ARHGEF2, BORA, BRCA1, CDC25B, DLGP5, HDAC6, KIF2A, LATS2, NDEL1, PARD3, PPP1R2, PLK1, RASSF1, TACC3, p53/TP53 and TPX2 (PubMed:11551964, PubMed:14702041, PubMed:15128871, PubMed:15147269, PubMed:15987997, PubMed:17604723, PubMed:18056443, PubMed:18615013). Phosphorylates MCRS1 which is required for MCRS1-mediated kinetochore fiber assembly and mitotic progression (PubMed:27192185). Regulates KIF2A tubulin depolymerase activity (PubMed:19351716). Important for microtubule formation and/or stabilization (PubMed:18056443). Required for normal axon formation (PubMed:19812038). Plays a role in microtubule remodeling during neurite extension (PubMed:19668197). Also acts as a key regulatory component of the p53/TP53 pathway, and particularly the checkpoint-response pathways critical for oncogenic transformation of cells, by phosphorylating and destabilizing p53/TP53 (PubMed:14702041). Phosphorylates its own inhibitors, the protein phosphatase type 1 (PP1) isoforms, to inhibit their activity (PubMed:11551964). Inhibits cilia outgrowth (By similarity). Required for cilia disassembly via phosphorylation of HDAC6 and subsequent deacetylation of alpha-tubulin (PubMed:17604723, PubMed:20643351). Regulates protein levels of the anti-apoptosis protein BIRC5 by suppressing the expression of the SCF(FBXL7) E3 ubiquitin-protein ligase substrate adapter FBXL7 through the phosphorylation of the transcription factor FOXP1 (PubMed:28218735)","subcellular_location":"Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cytoplasm, cytoskeleton, spindle pole; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriole; Cell projection, neuron projection; Cell projection, cilium; Cytoplasm, cytoskeleton, cilium basal body; Basolateral cell membrane","url":"https://www.uniprot.org/uniprotkb/O14965/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/AURKA","classification":"Common 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regulate spindle pole focusing and aMTOC organization in mouse oocytes.","date":"2020","source":"Reproduction (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/31895686","citation_count":18,"is_preprint":false},{"pmid":"30174615","id":"PMC_30174615","title":"The Association Between AURKA Gene rs2273535 Polymorphism and Gastric Cancer Risk in a Chinese Population.","date":"2018","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30174615","citation_count":18,"is_preprint":false},{"pmid":"36977984","id":"PMC_36977984","title":"The promotion action of AURKA on post-ischemic angiogenesis in diabetes-related limb ischemia.","date":"2023","source":"Molecular medicine (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/36977984","citation_count":17,"is_preprint":false},{"pmid":"37083534","id":"PMC_37083534","title":"Structural basis for CEP192-mediated regulation of centrosomal AURKA.","date":"2023","source":"Science 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carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/25328151","citation_count":17,"is_preprint":false},{"pmid":"29477140","id":"PMC_29477140","title":"AURKA Suppresses Leukemic THP-1 Cell Differentiation through Inhibition of the KDM6B Pathway.","date":"2018","source":"Molecules and cells","url":"https://pubmed.ncbi.nlm.nih.gov/29477140","citation_count":17,"is_preprint":false},{"pmid":"36797043","id":"PMC_36797043","title":"AurkA nuclear localization is promoted by TPX2 and counteracted by protein degradation.","date":"2023","source":"Life science alliance","url":"https://pubmed.ncbi.nlm.nih.gov/36797043","citation_count":16,"is_preprint":false},{"pmid":"35149839","id":"PMC_35149839","title":"Stabilization of AURKA by the E3 ubiquitin ligase CBLC in lung adenocarcinoma.","date":"2022","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/35149839","citation_count":16,"is_preprint":false},{"pmid":"36778123","id":"PMC_36778123","title":"CD73/NT5E-mediated ubiquitination of AURKA regulates alcohol-related liver fibrosis via modulating hepatic stellate cell senescence.","date":"2023","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36778123","citation_count":16,"is_preprint":false},{"pmid":"38738386","id":"PMC_38738386","title":"Research progress on the relationship between AURKA and tumorigenesis: the neglected nuclear function of AURKA.","date":"2024","source":"Annals of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38738386","citation_count":15,"is_preprint":false},{"pmid":"31104508","id":"PMC_31104508","title":"Comparing migraine with and without aura to healthy controls using RNA sequencing.","date":"2019","source":"Cephalalgia : an international journal of headache","url":"https://pubmed.ncbi.nlm.nih.gov/31104508","citation_count":15,"is_preprint":false},{"pmid":"38810557","id":"PMC_38810557","title":"Securinine inhibits carcinogenesis in gastric cancer by targeting AURKA-β-catenin/Akt/STAT3 and the cell cycle pathway.","date":"2024","source":"Phytomedicine : international journal of phytotherapy and phytopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38810557","citation_count":15,"is_preprint":false},{"pmid":"28442587","id":"PMC_28442587","title":"Combined AURKA and H3K9 Methyltransferase Targeting Inhibits Cell Growth By Inducing Mitotic Catastrophe.","date":"2017","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/28442587","citation_count":15,"is_preprint":false},{"pmid":"28281108","id":"PMC_28281108","title":"Recognizing CADASIL: a Secondary Cause of Migraine with Aura.","date":"2017","source":"Current pain and headache reports","url":"https://pubmed.ncbi.nlm.nih.gov/28281108","citation_count":15,"is_preprint":false},{"pmid":"33545203","id":"PMC_33545203","title":"Knockdown of AURKA sensitizes the efficacy of radiation in human colorectal cancer.","date":"2021","source":"Life 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disease","url":"https://pubmed.ncbi.nlm.nih.gov/37385990","citation_count":11,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50115,"output_tokens":6999,"usd":0.127665,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16202,"output_tokens":3334,"usd":0.08218,"stage2_stop_reason":"end_turn"},"total_usd":0.209845,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"AURKA (BTAK) encodes a serine/threonine kinase localized on chromosome 20q13 with homology to yeast Ipl1 and Drosophila Aurora, both involved in chromosome segregation; the gene is amplified and overexpressed in breast tumor cell lines.\",\n      \"method\": \"cDNA cloning, sequence analysis, chromosomal mapping\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — foundational cloning and sequence work in a single lab; functional inference from homology, no direct enzymatic assay in this paper\",\n      \"pmids\": [\"9174055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"AURKA (Aik) protein is cell-cycle regulated, accumulates during G2/M and decreases after mitosis, localizes to the spindle pole from prophase through anaphase, and exhibits kinase activity (casein phosphorylation) enhanced at mitosis.\",\n      \"method\": \"Northern blot, Western blot, immunofluorescence, in vitro kinase assay with exogenous casein substrate\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (cell-cycle staging, immunofluorescence localization, in vitro kinase assay) in a single focused study\",\n      \"pmids\": [\"9153231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Ectopic overexpression of AURKA (STK15/BTAK) in mouse NIH 3T3 cells and near-diploid human breast epithelial cells induces centrosome amplification, aneuploidy, and oncogenic transformation, defining AURKA as a centrosome-associated kinase whose overexpression drives chromosomal instability.\",\n      \"method\": \"Ectopic expression in mammalian cells, immunofluorescence, soft-agar transformation assay, FISH\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple cell-line models with defined phenotypic readouts; highly replicated in subsequent literature\",\n      \"pmids\": [\"9771714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"AURKA (Aurora2/Aik) associates with the cell cycle regulator Cdc20 in HeLa cells; Cdc20-associated kinase activity peaks in early M phase, identifying Cdc20 as an AURKA-interacting protein at mitotic spindle poles.\",\n      \"method\": \"Co-immunoprecipitation from HeLa cell extracts, kinase activity assay (MBP phosphorylation)\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP experiment with kinase activity readout, single lab\",\n      \"pmids\": [\"10377410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"AURKA (Aurora2) is activated by phosphorylation of Threonine 288 within the activation loop; this phosphorylation increases enzymatic activity and can be catalyzed by PKA in vitro. Protein phosphatase 1 (PP1) dephosphorylates T288 and inactivates AURKA in vitro; in vivo T288 phosphorylation is induced by okadaic acid. Additionally, AURKA is degraded via the proteasome, and T288-phosphorylated AURKA may be targeted for mitotic degradation.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis (T288 substitution), phosphatase assay with PP1, okadaic acid treatment, proteasome inhibitor experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro biochemical reconstitution with mutagenesis and multiple orthogonal methods in a single study\",\n      \"pmids\": [\"11039908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"AURKA (STK15) contains two functional PP1-binding sites; STK15 and PP1 interact in a cell-cycle-dependent manner peaking at mitosis. Activated STK15 phosphorylates PP1 and inhibits its phosphatase activity in vitro and in vivo. Conversely, PP1 dephosphorylates and inactivates STK15. Non-binding STK15 mutants are superphosphorylated but have reduced kinase activity, and cells expressing these mutants show aberrant chromosome alignment.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, in vitro phosphatase assay, site-directed mutagenesis of PP1-binding motifs, immunofluorescence for chromosome alignment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reciprocal biochemical assays with mutagenesis and cellular phenotypic validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"11551964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"AURKA directly interacts with and phosphorylates HDM2 (MDM2) in vitro; this leads to P53 ubiquitination and attenuation of cisplatin-induced P53 activation in gastric cancer cells, promoting cell survival.\",\n      \"method\": \"Dual co-immunoprecipitation, in vitro kinase assay with recombinant AURKA and HDM2, ubiquitination assay, luciferase reporter for P53 activity\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of kinase-substrate relationship plus Co-IP and functional readouts, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"24240108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"AURKA promotes STAT3 transcriptional activity through regulation of JAK2 expression and phosphorylation; overexpression of AURKA increases STAT3 Tyr705 phosphorylation and STAT3 nuclear translocation, whereas AURKA knockdown reduces these effects. Inhibition of JAK2 in the presence of AURKA overexpression abrogates AURKA-mediated STAT3 activation, establishing the AURKA-JAK2-STAT3 axis.\",\n      \"method\": \"siRNA knockdown, overexpression, immunofluorescence, luciferase reporter assay, JAK2-specific inhibitor (AZD1480), Western blot for phospho-STAT3\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological perturbations with multiple readouts, single lab\",\n      \"pmids\": [\"24953013\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SMAD4 binds to AURKA and induces its proteasomal degradation in a TGFβ-independent manner, thereby suppressing AURKA-mediated β-catenin/TCF transcriptional activity and metastatic phenotypes.\",\n      \"method\": \"Co-immunoprecipitation, overexpression and knockdown, luciferase reporter assay for β-catenin/TCF, colony formation, migration and invasion assays\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus functional rescue experiments in multiple cell lines, single lab\",\n      \"pmids\": [\"25061104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In the nucleus, AURKA translocates from centrosomes and performs kinase-independent oncogenic functions by interacting with hnRNP K to form a transcriptional complex that shifts MYC promoter usage and activates MYC transcription, thereby enhancing breast cancer stem cell phenotype. Blocking AURKA nuclear localization inhibits this transactivating function.\",\n      \"method\": \"Co-immunoprecipitation, nuclear fractionation, ChIP/promoter assays, kinase-dead mutants, nuclear localization-blocking constructs, mammosphere assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods including Co-IP, kinase-dead mutants, and localization blocking experiments establishing kinase-independent nuclear function\",\n      \"pmids\": [\"26782714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ARID1A occupies the AURKA gene promoter and negatively regulates AURKA transcription; loss of ARID1A results in enhanced AURKA transcription leading to persistent CDC25C activation and G2/M dysregulation, creating a synthetic lethal interaction exploitable therapeutically.\",\n      \"method\": \"ChIP assay, genetic knockout/knockdown, CDC25C activity assays, cell cycle analysis, xenograft models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP for promoter occupancy, genetic perturbations with mechanistic pathway placement, multiple orthogonal methods\",\n      \"pmids\": [\"30097580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PRL-3 phosphatase interacts with AURKA and promotes its ubiquitination and proteasomal degradation by dephosphorylating FZR1, thereby activating the APC/C-FZR1 complex which targets AURKA.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, phosphatase-dependent degradation assay, ectopic expression and knockdown, xenograft models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic reconstitution identifying writer (APC/C-FZR1) and eraser (PRL-3-mediated dephosphorylation of FZR1) with multiple orthogonal methods\",\n      \"pmids\": [\"30498084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"AURKA directly phosphorylates SPOP at three sites, causing SPOP ubiquitination and degradation; SPOP in turn degrades AURKA via a feedback loop. AURKA-mediated SPOP degradation stabilizes androgen receptor (AR), ARv7, and c-Myc, driving castration-resistant prostate cancer progression.\",\n      \"method\": \"In vitro kinase assay identifying SPOP as direct AURKA substrate, co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (phospho-resistant SPOP), xenograft models\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay establishing direct phosphorylation, mutagenesis (phospho-resistant mutant), and in vivo validation, single lab\",\n      \"pmids\": [\"33158056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CEP41-mediated tubulin glutamylation of cilia activates AURKA and upregulates VEGFA/VEGFR2 expression through HIF1α during endothelial cell responses to shear stress or hypoxia, driving angiogenesis and cilia disassembly (deciliation).\",\n      \"method\": \"siRNA knockdown in human endothelial cells and zebrafish, immunofluorescence, Western blot, VEGF/HIF1α pathway analysis\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockdown in two model systems with pathway analysis, single lab\",\n      \"pmids\": [\"31885126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"AURKA kinase activity is required for the maintenance of ring-like aMTOC (acentriolar microtubule-organizing center) organization in mouse oocytes; inhibition of AURKA causes loss of aMTOC ring structure, CEP215 clustering at spindle poles, and shorter spindles with highly focused poles.\",\n      \"method\": \"Pharmacological AURKA inhibition in mouse oocytes (MI and MII stages), super-resolution microscopy, siRNA knockdown of Cep215\",\n      \"journal\": \"Reproduction (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological inhibition with direct imaging of aMTOC structural changes, single lab\",\n      \"pmids\": [\"31895686\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AURKA deletion in spermatogonia eliminates all developing germ cells (consistent with its mitotic role), while deletion in spermatocytes increases spermatocyte apoptosis, elevates abnormal sperm morphology, and increases progressive sperm motility with decreased PP1 activity in sperm lysate.\",\n      \"method\": \"Conditional knockout mice (Cre-lox in spermatogonia or spermatocytes), fertility assays, sperm motility analysis, PP1 activity assay\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO in vivo with multiple phenotypic readouts and biochemical (PP1 activity) validation, establishing multiple spermatogenic roles\",\n      \"pmids\": [\"34518881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CBLC (an E3 ubiquitin ligase) interacts with the kinase domain of AURKA and stabilizes it by conjugating monoubiquitination and K11/K63-linked polyubiquitination, protecting AURKA from degrading K11/K48 polyubiquitination. CBLC depletion decreases AURKA half-life and delays AURKA accumulation/activation during mitotic entry.\",\n      \"method\": \"Co-immunoprecipitation and mass spectrometry, ubiquitination assays with linkage-specific analysis, cycloheximide chase (half-life), cell synchronization with thymidine block, Western blot\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biochemical reconstitution of ubiquitination mechanism with linkage specificity, half-life assay, and functional mitotic entry readout, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"35149839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"AURKA functionally interacts with mitochondrial ATP synthase subunits ATP5F1A and ATP5F1B (Complex V core subunits); disruption of this AURKA/ATP5F1A/ATP5F1B nexus triggers G0/G1 arrest accompanied by decreased glycolysis and mitochondrial respiration, with cell fate outcome dependent on the metabolic propensity of triple-negative breast cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, pharmacological Complex V inhibition, AURKA abundance measurement, cell cycle analysis, Seahorse metabolic assays\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying interaction plus functional metabolic readouts, single lab\",\n      \"pmids\": [\"37386025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"AURKA directly interacts with and phosphorylates KEAP1, thereby activating NRF2 and its target gene transcription, suppressing ferroptosis in meningioma; FOXM1 transcriptionally induces AURKA expression in this context.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, NRF2 target gene reporter/Western blot, FOXM1 ChIP/promoter assay, mouse meningioma model\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and kinase assay establishing direct phosphorylation of KEAP1, supported by in vivo model, single lab\",\n      \"pmids\": [\"38642502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The crystal structure of AURKA bound to a conserved helix (Helix-1) from CEP192 reveals a distinct binding site on AURKA that is different from the TPX2 binding site; disrupting the CEP192 Helix-1/AURKA interaction in cells causes mitotic defects, establishing the structural basis for centrosomal AURKA regulation distinct from spindle-microtubule regulation by TPX2.\",\n      \"method\": \"Crystal structure determination (X-ray crystallography), quantitative binding studies (ITC/SPR), cell-based mutation experiments with mitotic defect readout\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with quantitative binding measurements and functional cellular validation; establishes structural basis for CEP192-AURKA interaction\",\n      \"pmids\": [\"37083534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"AURKA interacts with DDX5 to form a transcriptional coactivator complex that induces transcription of the lncRNA TMEM147-AS1, which in turn sponges hsa-let-7b/7c-5p to upregulate AURKA in a positive feedback loop maintaining cisplatin resistance via lipophagy activation in ovarian cancer.\",\n      \"method\": \"Co-immunoprecipitation (AURKA-DDX5), ChIP/promoter analysis, lncRNA sponge assays, lipophagy assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP for complex formation plus transcriptional and functional assays, single lab\",\n      \"pmids\": [\"37217070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CD73/NT5E directly interacts with AURKA (confirmed by co-IP and molecular docking) and inhibits AURKA ubiquitination; overexpression of CD73/NT5E stabilizes AURKA, downregulates p53 signaling, and regulates hepatic stellate cell activation and senescence in alcohol-related liver fibrosis.\",\n      \"method\": \"Co-immunoprecipitation, molecular docking, ubiquitination assay, mouse model of alcohol-related liver fibrosis\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP with ubiquitination assay and in vivo model, single lab\",\n      \"pmids\": [\"36778123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TPX2 co-overexpression promotes AURKA nuclear accumulation in interphase, whereas AURKA overexpression alone is insufficient for nuclear accumulation. Nuclear export and proteasome activity also regulate nuclear AURKA levels. Nuclear AurkA driven by TPX2 co-overexpression promotes pro-tumorigenic processes in MCF10A mammospheres.\",\n      \"method\": \"Nuclear/cytoplasmic fractionation, live imaging, proteasome inhibition, co-overexpression experiments, mammosphere assay\",\n      \"journal\": \"Life science alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal localization methods with functional consequence in mammosphere model, single lab\",\n      \"pmids\": [\"36797043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP21 deubiquitinase directly interacts with AURKA (confirmed by co-IP and GST-pulldown) and deubiquitinates AURKA to restore its activity and stability; USP21 knockdown increases AURKA ubiquitination and suppresses laryngeal cancer cell proliferation, migration, and invasion.\",\n      \"method\": \"Co-immunoprecipitation, GST-pulldown, ubiquitination assay, knockdown experiments with rescue by AURKA overexpression\",\n      \"journal\": \"The Kaohsiung journal of medical sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assays (Co-IP and GST-pulldown) plus ubiquitination assay with functional rescue, single lab\",\n      \"pmids\": [\"36919585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AURKA inhibition suppresses differentiation of THP-1 AML cells by repressing KDM6B (H3K27 demethylase) expression; AURKA and YY1 co-occupy the KDM6B promoter region. Alisertib-mediated AURKA inhibition dissociates this complex, upregulates KDM6B, and drives THP-1 differentiation into monocytes. This effect is blocked by the KDM6B inhibitor GSK-J4.\",\n      \"method\": \"ChIP (AURKA and YY1 at KDM6B promoter), alisertib treatment, flow cytometry for differentiation markers, KDM6B inhibitor epistasis\",\n      \"journal\": \"Molecules and cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for chromatin occupancy plus pharmacological epistasis establishing pathway, single lab\",\n      \"pmids\": [\"29477140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"AURKA promotes STAT3 activity through regulation of JAK2; pharmacological AURKA inhibition (MLN8237) decreases HDM2 protein levels, induces P53 transcriptional activity, and reduces cell survival in vitro and xenograft tumor growth in vivo in gastric cancer models.\",\n      \"method\": \"AURKA inhibitor (alisertib/MLN8237), siRNA, Western blot, xenograft model\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic perturbation with in vivo validation, already captured in the HDM2 entry; noting overlap with JAK2 axis (PMID 24953013)\",\n      \"pmids\": [\"24240108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AURKA inhibition in Ewing's sarcoma cells induces apoptosis and ferroptosis through the NPM1/YAP1 axis; co-immunoprecipitation confirmed AURKA-NPM1 interaction, and AURKA inhibition disrupts this complex.\",\n      \"method\": \"Co-immunoprecipitation (AURKA-NPM1), pharmacological and siRNA AURKA inhibition, ferroptosis/apoptosis assays, xenograft model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus functional cell death assays and in vivo model, single lab\",\n      \"pmids\": [\"38287009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HMMR interacts with AURKA and inhibits its ubiquitination-mediated degradation, elevating AURKA protein levels and subsequently activating the mTORC2/AKT pathway to drive prostate cancer progression; E2F1, upregulated by mTORC2/AKT, transcriptionally promotes HMMR expression, forming a positive feedback loop.\",\n      \"method\": \"Co-immunoprecipitation (HMMR-AURKA), ubiquitination assay, gain/loss-of-function experiments, mTOR inhibitor epistasis, in vivo xenograft\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP and ubiquitination assay identifying mechanism, supported by in vivo model, single lab\",\n      \"pmids\": [\"36750558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AURKA promotes psoriasis-related inflammation by blocking autophagy-mediated suppression of the AIM2 inflammasome, acting through activation of the AKT/mTOR pathway; AURKA knockdown inhibits AIM2 inflammasome activation and enhances autophagy, while autophagy inhibition (3-MA) attenuates these effects.\",\n      \"method\": \"siRNA knockdown and overexpression, Western blot for inflammasome components (IL-1β, IL-18, caspase-1 p20), autophagy markers, AKT/mTOR phosphorylation assays, pharmacological inhibitors (PI-103, 3-MA)\",\n      \"journal\": \"Immunology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic perturbations with pharmacological epistasis placing AURKA in the AKT/mTOR-autophagy-AIM2 pathway, single lab\",\n      \"pmids\": [\"34710506\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AURKA is a centrosome-associated serine/threonine kinase activated by T288 autophosphorylation (facilitated by cofactors including TPX2, CEP192, and Bora) and inactivated by PP1-mediated dephosphorylation; it localizes to spindle poles during mitosis to regulate centrosome maturation, spindle assembly, and chromosome segregation, and undergoes proteasomal degradation governed by ubiquitin ligases (APC/C-FZR1, CBLC) and deubiquitinases (USP21); beyond its catalytic mitotic roles, AURKA acts kinase-independently in the nucleus—driven by co-overexpression with TPX2—to transactivate oncogenes including MYC via hnRNP K interaction, and it phosphorylates diverse substrates (HDM2/MDM2 to suppress p53, KEAP1 to activate NRF2, SPOP to stabilize AR/c-Myc) and interacts with metabolic complexes (mitochondrial ATP synthase) to modulate energy metabolism and cell fate.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"AURKA is a cell-cycle-regulated serine/threonine kinase that accumulates at G2/M and localizes to the spindle pole from prophase through anaphase, where it governs centrosome function and chromosome segregation [#1]; its amplification and overexpression in tumors drives centrosome amplification, aneuploidy, and oncogenic transformation [#0, #2]. Catalytic activity is switched on by phosphorylation of Threonine 288 in the activation loop and switched off by PP1, with which AURKA forms a reciprocal regulatory loop—activated kinase phosphorylates and inhibits PP1, while PP1 dephosphorylates and inactivates the kinase [#4, #5]. Distinct cofactors engage AURKA at separable sites to direct its localized functions: a crystal structure of AURKA bound to CEP192 Helix-1 defines a centrosomal regulatory interface distinct from the TPX2 binding site [#19], and TPX2 co-overexpression additionally drives AURKA into the interphase nucleus [#22]. AURKA abundance is set by opposing ubiquitin machinery—the APC/C-FZR1 axis (modulated by PRL-3-mediated FZR1 dephosphorylation) and stabilizing/destabilizing E3 activity of CBLC, counterbalanced by the deubiquitinase USP21 [#11, #16, #23]. Beyond mitosis, AURKA acts kinase-independently in the nucleus by partnering with hnRNP K to transactivate MYC and promote a cancer stem cell phenotype [#9], and as a kinase it phosphorylates substrates that rewire tumor-relevant signaling: HDM2/MDM2 to suppress p53 [#6], KEAP1 to activate NRF2 and suppress ferroptosis [#18], and SPOP to stabilize androgen receptor and c-Myc [#12]. It is also embedded in feedback circuits with metabolic and transcriptional regulators, including mitochondrial ATP synthase subunits that couple it to cell-cycle and metabolic fate [#17].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established AURKA as a chromosome-segregation kinase homologous to yeast Ipl1/Drosophila Aurora and linked its amplification to breast cancer, framing it as a candidate oncogene.\",\n      \"evidence\": \"cDNA cloning, sequence/homology analysis and chromosomal mapping (20q13) in breast tumor cell lines\",\n      \"pmids\": [\"9174055\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct enzymatic assay in this study\", \"Functional role inferred from homology only\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Showed AURKA is cell-cycle regulated and spindle-pole-localized with mitotically enhanced kinase activity, placing it temporally and spatially within mitosis.\",\n      \"evidence\": \"Northern/Western blot, immunofluorescence and in vitro casein kinase assay across the cell cycle\",\n      \"pmids\": [\"9153231\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological substrates not identified\", \"Mechanism of activation not addressed\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstrated causally that AURKA overexpression drives centrosome amplification, aneuploidy, and transformation, establishing the oncogenic mechanism behind its amplification.\",\n      \"evidence\": \"Ectopic expression in NIH 3T3 and human breast epithelial cells with soft-agar transformation and FISH\",\n      \"pmids\": [\"9771714\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define which catalytic substrates mediate centrosome amplification\", \"In vivo relevance not tested here\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined the activation switch (T288 autophosphorylation) and a reciprocal AURKA-PP1 antagonism that sets kinase activity and proper chromosome alignment.\",\n      \"evidence\": \"In vitro kinase/phosphatase assays, T288 and PP1-binding-site mutagenesis, okadaic acid, immunofluorescence\",\n      \"pmids\": [\"11039908\", \"11551964\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological kinase activating T288 in cells not fully resolved\", \"Downstream mitotic substrates not enumerated\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Identified Cdc20 as an early-mitotic AURKA-associated protein, linking the kinase to the mitotic regulatory machinery.\",\n      \"evidence\": \"Co-immunoprecipitation from HeLa extracts with MBP kinase activity readout\",\n      \"pmids\": [\"10377410\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP, no reciprocal validation\", \"Functional consequence of the interaction not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed a kinase-independent nuclear function in which AURKA partners hnRNP K to transactivate MYC, expanding AURKA biology beyond catalytic mitotic roles.\",\n      \"evidence\": \"Nuclear fractionation, Co-IP, ChIP/promoter assays, kinase-dead and localization-blocking mutants, mammosphere assays\",\n      \"pmids\": [\"26782714\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of hnRNP K binding unknown\", \"Determinants of nuclear import only partly defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mapped the ubiquitin economy controlling AURKA levels by identifying writers, erasers, and stabilizers acting on distinct ubiquitin linkages.\",\n      \"evidence\": \"Co-IP/MS, linkage-specific ubiquitination assays, cycloheximide chase and synchronization (CBLC, APC/C-FZR1/PRL-3, USP21)\",\n      \"pmids\": [\"35149839\", \"30498084\", \"36919585\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of each ligase across cell types unclear\", \"Crosstalk between stabilizing and degrading linkages not fully resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided the structural basis for separable centrosomal versus spindle regulation by showing CEP192 Helix-1 binds AURKA at a site distinct from TPX2.\",\n      \"evidence\": \"X-ray crystallography, ITC/SPR binding measurements, cell-based interaction-disrupting mutations\",\n      \"pmids\": [\"37083534\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational consequences of dual cofactor engagement not resolved\", \"How localization-specific activation selects substrates unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended AURKA's substrate repertoire and feedback circuitry into tumor signaling and metabolism, defining KEAP1/NRF2, SPOP/AR-Myc, and ATP synthase as effector nodes.\",\n      \"evidence\": \"In vitro kinase assays, Co-IP, ubiquitination assays, Seahorse metabolic analysis and in vivo models (KEAP1, SPOP, HDM2, ATP5F1A/B)\",\n      \"pmids\": [\"38642502\", \"33158056\", \"24240108\", \"37386025\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Many substrate interactions rest on single-lab Co-IP\", \"Hierarchy among these effector pathways in vivo unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How distinct localized cofactor-bound AURKA states select specific substrates and balance catalytic versus kinase-independent outputs remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking cofactor binding site to substrate choice\", \"Structural basis for kinase-independent transcriptional functions undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 4, 6, 12, 18]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [1, 4, 5, 6, 12, 18]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [9, 20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [1, 2, 19]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [9, 22]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1, 14]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 2, 4, 5]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [9, 24]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 2, 12]}\n    ],\n    \"complexes\": [\"APC/C-FZR1\"],\n    \"partners\": [\"TPX2\", \"CEP192\", \"PP1\", \"Cdc20\", \"hnRNP K\", \"MDM2\", \"KEAP1\", \"SPOP\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}