{"gene":"AURKC","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2007,"finding":"Homozygous single-nucleotide deletion (c.144delC) in AURKC results in premature translation termination, producing a truncated protein lacking the kinase domain, and causes male infertility by producing large-headed, multiflagellar, polyploid (tetraploid) spermatozoa due to failed meiosis.","method":"Genome-wide microsatellite scan, sequencing of AURKC coding sequence, flow cytometry for ploidy assessment","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — positional cloning plus sequencing with functional confirmation by ploidy analysis, replicated across multiple patients in multiple subsequent studies","pmids":["17435757"],"is_preprint":false},{"year":1998,"finding":"AURKC (STK13) encodes a serine/threonine protein kinase related to Drosophila Aurora and budding yeast Ipl1, mapping to human chromosome 19q13.3-ter; its cDNA was isolated from testis mRNA indicating testis-predominant expression.","method":"cDNA library screening, 5' RACE, somatic cell hybrid PCR, radiation hybrid mapping, FISH","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chromosomal localization and cloning with direct experimental methods, but no enzymatic or functional assays performed in this paper","pmids":["9799611"],"is_preprint":false},{"year":2018,"finding":"In mouse oocyte meiosis, AURKC is the predominant catalytic subunit of the chromosomal passenger complex (CPC); in the absence of AURKC, AURKA aberrantly localizes to chromosomes in a CPC-dependent manner, and AURKB negatively regulates AURKC activity to prevent aneuploidy. This inter-kinase regulation controls spindle length and chromosome segregation fidelity during meiosis I.","method":"Oocyte-specific single and double knockout mice (Aurkb and Aurkc KO), immunofluorescence localization, fecundity assays","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with double-KO mice plus direct localization experiments, multiple orthogonal readouts (spindle length, SAC, aneuploidy rates)","pmids":["30415701"],"is_preprint":false},{"year":2016,"finding":"Three macrozoospermia-associated AURKC mutations have distinct functional consequences: p.L49Wfs22 (c.144delC) is a loss-of-function allele that disrupts CPC localization; p.C229Y is a hypomorphic allele that cannot fully support meiotic cell-cycle progression; p.Y248* fails to localize and function within the CPC but retains cytoplasmic catalytic activity. All three cause metaphase chromosome misalignment and polyploidy via failure of AURKC-CPC function.","method":"Expression of mutant AURKC alleles in Aurkc-/- mouse oocytes, immunofluorescence for CPC localization, flow cytometry for ploidy, in vitro kinase assay","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro functional rescue system with mutagenesis, localization, ploidy, and kinase activity assays in a defined genetic background","pmids":["27106102"],"is_preprint":false},{"year":2017,"finding":"Haspin inhibition in late prometaphase I causes loss of interchromatid axis-localized AURKC, acceleration of meiosis I, and bypass of the spindle assembly checkpoint (SAC). In contrast, oocytes from Aurkc-/- mice (where AURKB is the sole CPC kinase) show no change in MI timing or MAD2 localization upon haspin inhibition, demonstrating that interchromatid axis-localized AURKB is not required for SAC activation and revealing a functional difference between AURKB and AURKC within the CPC.","method":"Haspin kinase inhibition in wild-type and Aurkc-/- mouse oocytes, immunofluorescence for AURKC, AURKB, MAD2 localization, live imaging for MI timing","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic null background combined with pharmacological inhibition and direct localization readouts in single lab, two orthogonal approaches","pmids":["28659416"],"is_preprint":false},{"year":2011,"finding":"Aberrantly expressed AURKC localizes to centromeric regions of mitotic chromosomes, decreases AURKB protein levels, and its kinase activity is required for increased cell proliferation, transformation, and migration. AURKC expression is transcriptionally repressed by PLZF, which is recruited to the AURKC promoter.","method":"AURKC-GFP overexpression in epithelial/cancer cell lines, kinase-dead mutant analysis, colony formation and migration assays, ChIP for PLZF at AURKC promoter, immunofluorescence","journal":"The Journal of pathology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple functional assays (localization, kinase-dead mutant, ChIP) in single lab, but overexpression system in somatic cells where AURKC is normally absent","pmids":["21710690"],"is_preprint":false},{"year":2011,"finding":"A splice-site mutation (c.436-2A>G) in AURKC causes skipping of exon 5, producing a truncated transcript, and combined with heterozygous c.144delC causes compound heterozygous AURKC loss of function leading to macrozoospermia.","method":"AURKC gene sequencing, RT-PCR of patient leukocyte transcripts demonstrating exon skipping","journal":"Molecular human reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct transcript analysis confirming splice defect, single case/family, no in vitro reconstitution","pmids":["21733974"],"is_preprint":false},{"year":2017,"finding":"AURKC physically interacts with IκBα and phosphorylates IκBα at Ser32, thereby activating NF-κB signaling in breast cancer cells; a small-molecule inhibitor (AKCI) that blocks the AURKC-IκBα protein-protein interaction induces G2/M arrest and inhibits migration, invasion, and tumor growth.","method":"Translocation-based cellular binding assay, identification of IκBα as AURKC binding partner, phosphorylation assay, small-molecule inhibitor (AKCI) treatment, NF-κB reporter assays, colony formation, xenograft tumor model","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — cellular binding assay and phosphorylation data plus functional readouts, but no reciprocal Co-IP or in vitro reconstitution; single lab","pmids":["29050234"],"is_preprint":false},{"year":2015,"finding":"Promoter CpG island hypomethylation is a key positive regulator of AURKC expression; demethylation with 5-aza-dC (but not the HDAC inhibitor TSA) elevates AURKC expression in cancer cell lines, and testis shows marked promoter hypomethylation consistent with high expression. PLZF-mediated repression only partially offsets AURKC expression even after demethylation, indicating that CpG methylation is the dominant regulatory mechanism.","method":"5-aza-dC and TSA pharmacological treatment, quantitative methylation analysis, RT-qPCR, TCGA dataset cross-validation, PLZF overexpression experiments","journal":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological demethylation plus cross-dataset validation, multiple cell lines, single lab","pmids":["25990457"],"is_preprint":false},{"year":2025,"finding":"AURKC interacts with and upregulates ERp57 protein in clear cell renal cell carcinoma; AURKC knockdown reduces CyclinD1, PCNA, and ERp57 levels and inhibits proliferation in vitro and tumor growth in vivo, while AURKC overexpression increases ERp57 and proliferation.","method":"Co-immunoprecipitation and colocalization (AURKC-ERp57 interaction), shRNA knockdown and overexpression in ccRCC cell lines, xenograft tumor mouse model, western blot for CyclinD1/PCNA/ERp57","journal":"Journal of Cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP/colocalization with KD/OE functional readouts, single lab, no mechanistic detail on how AURKC regulates ERp57","pmids":["39895780"],"is_preprint":false}],"current_model":"AURKC is a serine/threonine kinase that functions as the predominant catalytic subunit of the chromosomal passenger complex (CPC) during meiosis, where it is essential for accurate chromosome segregation and completion of meiosis I; loss-of-function mutations cause production of tetraploid, large-headed spermatozoa and male infertility, while in female meiosis AURKC competes with AURKA for CPC binding to control spindle length and is negatively regulated by AURKB to prevent aneuploidy; when aberrantly expressed in somatic/cancer cells, AURKC localizes to centromeric regions, reduces AURKB levels, phosphorylates IκBα to activate NF-κB, and promotes proliferation and transformation in a kinase-activity-dependent manner, with its testis-restricted normal expression maintained by promoter CpG methylation and PLZF-mediated transcriptional repression."},"narrative":{"mechanistic_narrative":"AURKC is a testis-predominant serine/threonine protein kinase of the Aurora family that acts as the principal catalytic subunit of the chromosomal passenger complex (CPC) during meiosis, where it is required for accurate chromosome segregation and completion of meiosis I [PMID:9799611, PMID:30415701]. In oocyte meiosis AURKC is the dominant CPC kinase: in its absence AURKA aberrantly loads onto chromosomes in a CPC-dependent manner, and AURKB negatively regulates AURKC to safeguard against aneuploidy, an inter-kinase balance that sets spindle length and segregation fidelity [PMID:30415701]. AURKC also performs a SAC-relevant function at the interchromatid axis that is not substituted by AURKB, marking a functional divergence between the two kinases within the CPC [PMID:28659416]. Loss of AURKC function causes male infertility (macrozoospermia): truncating, splice, and missense mutations disrupt CPC localization and meiotic progression, producing large-headed, multiflagellar, polyploid spermatozoa, with allele-specific severity ranging from null to hypomorphic [PMID:17435757, PMID:27106102, PMID:21733974]. AURKC is normally silenced outside the testis by promoter CpG methylation and PLZF-mediated transcriptional repression, with methylation the dominant control [PMID:21710690, PMID:25990457]. When aberrantly expressed in somatic and cancer cells, AURKC localizes to centromeres, lowers AURKB levels, and drives kinase-activity-dependent proliferation, transformation, and migration [PMID:21710690]; in breast cancer it binds and phosphorylates IκBα at Ser32 to activate NF-κB signaling [PMID:29050234].","teleology":[{"year":1998,"claim":"Established AURKC as a distinct Aurora/Ipl1-related serine/threonine kinase with testis-predominant expression, defining the gene and its likely germline-restricted role before any function was known.","evidence":"cDNA cloning from testis mRNA, RACE, and chromosomal mapping by radiation hybrid/FISH","pmids":["9799611"],"confidence":"Medium","gaps":["No enzymatic activity or substrate demonstrated","No cellular function or localization assayed"]},{"year":2007,"claim":"Linked AURKC loss directly to human disease, showing the kinase is essential for completion of meiosis in spermatogenesis.","evidence":"Positional cloning and sequencing identifying homozygous c.144delC, with flow-cytometric ploidy analysis of patient sperm","pmids":["17435757"],"confidence":"High","gaps":["Did not resolve at which meiotic step AURKC acts","No molecular mechanism for the polyploidy phenotype"]},{"year":2011,"claim":"Defined the transcriptional and oncogenic context of AURKC outside the germline, showing aberrant expression has transforming activity and is normally held off by PLZF.","evidence":"AURKC-GFP overexpression with kinase-dead controls, transformation/migration assays, and ChIP for PLZF at the promoter in cancer cell lines","pmids":["21710690"],"confidence":"Medium","gaps":["Overexpression system in cells where AURKC is normally absent","Mechanism by which AURKC lowers AURKB levels unresolved"]},{"year":2011,"claim":"Extended the allelic spectrum of AURKC infertility, showing compound heterozygous loss-of-function (splice defect plus c.144delC) also causes macrozoospermia.","evidence":"Gene sequencing and RT-PCR of patient transcripts demonstrating exon 5 skipping","pmids":["21733974"],"confidence":"Medium","gaps":["Single family","No in vitro reconstitution of the truncated protein"]},{"year":2015,"claim":"Identified the dominant regulatory mechanism restricting AURKC to the testis, showing promoter CpG methylation outweighs PLZF repression.","evidence":"5-aza-dC versus TSA pharmacological treatment, methylation quantitation, RT-qPCR, and TCGA cross-validation","pmids":["25990457"],"confidence":"Medium","gaps":["Does not establish which factors read the methylation state","Correlative for the testis methylation–expression link"]},{"year":2016,"claim":"Resolved how specific human mutations cause meiotic failure by assigning distinct molecular defects (null, hypomorphic, mislocalized-but-catalytic) to disease alleles.","evidence":"Rescue of Aurkc-/- mouse oocytes with mutant alleles, CPC localization imaging, ploidy flow cytometry, and in vitro kinase assays","pmids":["27106102"],"confidence":"High","gaps":["Substrate(s) of AURKC within the CPC not mapped","Cytoplasmic catalytic activity of p.Y248* of uncertain relevance"]},{"year":2017,"claim":"Established the inter-Aurora regulatory hierarchy in oocyte meiosis, defining AURKC as the predominant CPC kinase whose activity is restrained by AURKB to prevent aneuploidy.","evidence":"Single and double Aurkb/Aurkc oocyte knockouts, immunofluorescence localization, and fecundity/aneuploidy readouts","pmids":["30415701"],"confidence":"High","gaps":["Molecular basis of AURKB-to-AURKC negative regulation not defined","How spindle length is set downstream remains unclear"]},{"year":2017,"claim":"Distinguished AURKC from AURKB functionally within the CPC by showing AURKC at the interchromatid axis is required for SAC integrity whereas AURKB is not.","evidence":"Haspin inhibition in wild-type versus Aurkc-/- oocytes with MAD2/AURKC/AURKB imaging and live MI timing","pmids":["28659416"],"confidence":"High","gaps":["Substrate basis for the SAC requirement not identified","Tested only in mouse oocytes"]},{"year":2017,"claim":"Provided a molecular route for AURKC oncogenic signaling, identifying IκBα as a binding partner and substrate that links AURKC to NF-κB activation.","evidence":"Cellular binding assay, IκBα Ser32 phosphorylation, NF-κB reporters, and a PPI-blocking inhibitor in breast cancer cells and xenografts","pmids":["29050234"],"confidence":"Medium","gaps":["No reciprocal Co-IP or in vitro reconstitution of the interaction","Single lab"]},{"year":2025,"claim":"Extended AURKC's proliferative role to renal cancer through a candidate effector, ERp57.","evidence":"Co-IP/colocalization, shRNA knockdown and overexpression, and xenografts in ccRCC lines with CyclinD1/PCNA/ERp57 western blots","pmids":["39895780"],"confidence":"Low","gaps":["Single Co-IP without reciprocal validation","No mechanism for how AURKC regulates ERp57 levels","Single lab"]},{"year":null,"claim":"The direct meiotic substrates of AURKC within the CPC and the molecular mechanism by which AURKB negatively regulates AURKC remain undefined.","evidence":"","pmids":[],"confidence":"High","gaps":["No CPC substrate phosphorylation sites mapped for AURKC","Mechanism of inter-Aurora regulation unresolved","Structural model of AURKC within the CPC absent from the corpus"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,5,7]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[3,7]}],"localization":[{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[2,5]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[0,2,3]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[2,4]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7]}],"complexes":["chromosomal passenger complex (CPC)"],"partners":["AURKB","AURKA","NFKBIA","PLZF","ERP57"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UQB9","full_name":"Aurora kinase C","aliases":["Aurora 3","Aurora/IPL1-related kinase 3","ARK-3","Aurora-related kinase 3","Aurora/IPL1/Eg2 protein 2","Serine/threonine-protein kinase 13","Serine/threonine-protein kinase aurora-C"],"length_aa":309,"mass_kda":35.6,"function":"Serine/threonine-protein kinase component of the chromosomal passenger complex (CPC), a complex that acts as a key regulator of mitosis. 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. Also plays a role in meiosis and more particularly in spermatogenesis. Has redundant cellular functions with AURKB and can rescue an AURKB knockdown. Like AURKB, AURKC phosphorylates histone H3 at 'Ser-10' and 'Ser-28'. AURKC phosphorylates the CPC complex subunits BIRC5/survivin and INCENP leading to increased AURKC activity. Phosphorylates TACC1, another protein involved in cell division, at 'Ser-228'","subcellular_location":"Nucleus; Chromosome; Chromosome, centromere; Cytoplasm, cytoskeleton, spindle","url":"https://www.uniprot.org/uniprotkb/Q9UQB9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/AURKC","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/AURKC","total_profiled":1310},"omim":[{"mim_id":"603495","title":"AURORA KINASE C; AURKC","url":"https://www.omim.org/entry/603495"},{"mim_id":"258150","title":"SPERMATOGENIC FAILURE 1; SPGF1","url":"https://www.omim.org/entry/258150"},{"mim_id":"243060","title":"SPERMATOGENIC FAILURE 5; SPGF5","url":"https://www.omim.org/entry/243060"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"testis","ntpm":44.6}],"url":"https://www.proteinatlas.org/search/AURKC"},"hgnc":{"alias_symbol":["AurC","ARK3"],"prev_symbol":["STK13"]},"alphafold":{"accession":"Q9UQB9","domains":[{"cath_id":"3.30.200.20","chopping":"41-122","consensus_level":"high","plddt":92.7348,"start":41,"end":122},{"cath_id":"1.10.510.10","chopping":"127-297","consensus_level":"high","plddt":91.0089,"start":127,"end":297}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UQB9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UQB9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UQB9-F1-predicted_aligned_error_v6.png","plddt_mean":84.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=AURKC","jax_strain_url":"https://www.jax.org/strain/search?query=AURKC"},"sequence":{"accession":"Q9UQB9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UQB9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UQB9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UQB9"}},"corpus_meta":[{"pmid":"17435757","id":"PMC_17435757","title":"Homozygous mutation of AURKC yields large-headed polyploid spermatozoa and causes male infertility.","date":"2007","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17435757","citation_count":210,"is_preprint":false},{"pmid":"9799611","id":"PMC_9799611","title":"Cloning of STK13, a third human protein kinase related to Drosophila aurora and budding yeast Ipl1 that maps on chromosome 19q13.3-ter.","date":"1998","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9799611","citation_count":85,"is_preprint":false},{"pmid":"30415701","id":"PMC_30415701","title":"Genetic Interactions between the Aurora Kinases Reveal New Requirements for AURKB and AURKC during Oocyte Meiosis.","date":"2018","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/30415701","citation_count":62,"is_preprint":false},{"pmid":"21733974","id":"PMC_21733974","title":"A new AURKC mutation causing macrozoospermia: implications for human spermatogenesis and clinical diagnosis.","date":"2011","source":"Molecular human reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/21733974","citation_count":60,"is_preprint":false},{"pmid":"12438709","id":"PMC_12438709","title":"Search for the second Peutz-Jeghers syndrome locus: exclusion of the STK13, PRKCG, KLK10, and PSCD2 genes on chromosome 19 and the STK11IP gene on chromosome 2.","date":"2002","source":"Cytogenetic and genome research","url":"https://pubmed.ncbi.nlm.nih.gov/12438709","citation_count":45,"is_preprint":false},{"pmid":"21710690","id":"PMC_21710690","title":"Aberrantly expressed AURKC enhances the transformation and tumourigenicity of epithelial cells.","date":"2011","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/21710690","citation_count":36,"is_preprint":false},{"pmid":"23292864","id":"PMC_23292864","title":"Expression analysis of four testis-specific genes AURKC, OIP5, PIWIL2 and TAF7L in acute myeloid leukemia: a gender-dependent expression pattern.","date":"2013","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/23292864","citation_count":29,"is_preprint":false},{"pmid":"27106102","id":"PMC_27106102","title":"Characterization of macrozoospermia-associated AURKC mutations in a mammalian meiotic system.","date":"2016","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27106102","citation_count":23,"is_preprint":false},{"pmid":"25994570","id":"PMC_25994570","title":"Transcriptome analysis of the cancer/testis genes, DAZ1, AURKC, and TEX101, in breast tumors and six breast cancer cell lines.","date":"2015","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25994570","citation_count":19,"is_preprint":false},{"pmid":"30594972","id":"PMC_30594972","title":"Whole-exome sequencing identified a novel mutation of AURKC in a Chinese family with macrozoospermia.","date":"2018","source":"Journal of assisted reproduction and genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30594972","citation_count":19,"is_preprint":false},{"pmid":"19447663","id":"PMC_19447663","title":"[Function of aurora kinase C (AURKC) in human reproduction].","date":"2009","source":"Gynecologie, obstetrique & fertilite","url":"https://pubmed.ncbi.nlm.nih.gov/19447663","citation_count":18,"is_preprint":false},{"pmid":"27270838","id":"PMC_27270838","title":"Association of the AURKA and AURKC gene polymorphisms with an increased risk of gastric cancer.","date":"2016","source":"IUBMB life","url":"https://pubmed.ncbi.nlm.nih.gov/27270838","citation_count":17,"is_preprint":false},{"pmid":"26341096","id":"PMC_26341096","title":"Macrozoospermia: screening for the homozygous c.144delC mutation in AURKC gene in infertile men and estimation of its heterozygosity frequency in the Tunisian population.","date":"2015","source":"Journal of assisted reproduction and genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26341096","citation_count":17,"is_preprint":false},{"pmid":"21353399","id":"PMC_21353399","title":"[Confirmation of the high prevalence in Morocco of the homozygous mutation c.144delC in the aurora kinase C gene (AURKC) in the teratozoospermia with large-headed spermatozoa].","date":"2011","source":"Journal de gynecologie, obstetrique et biologie de la reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/21353399","citation_count":17,"is_preprint":false},{"pmid":"23273756","id":"PMC_23273756","title":"Sperm macrocephaly syndrome in a patient without AURKC mutations and with a history of recurrent miscarriage.","date":"2012","source":"Reproductive biomedicine online","url":"https://pubmed.ncbi.nlm.nih.gov/23273756","citation_count":13,"is_preprint":false},{"pmid":"28659416","id":"PMC_28659416","title":"Haspin inhibition reveals functional differences of interchromatid axis-localized AURKB and AURKC.","date":"2017","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/28659416","citation_count":11,"is_preprint":false},{"pmid":"32478938","id":"PMC_32478938","title":"Compound heterozygosity for novel AURKC mutations in an infertile man with macrozoospermia.","date":"2020","source":"Andrologia","url":"https://pubmed.ncbi.nlm.nih.gov/32478938","citation_count":11,"is_preprint":false},{"pmid":"35452930","id":"PMC_35452930","title":"High efficiency and related mechanism of Au(RC) nanoclusters on disaggregating Aβ fibrils.","date":"2022","source":"Journal of colloid and interface science","url":"https://pubmed.ncbi.nlm.nih.gov/35452930","citation_count":11,"is_preprint":false},{"pmid":"31455599","id":"PMC_31455599","title":"Macrozoospermia associated with mutations of AURKC gene: First case report in Latin America and literature review.","date":"2019","source":"Revista internacional de andrologia","url":"https://pubmed.ncbi.nlm.nih.gov/31455599","citation_count":9,"is_preprint":false},{"pmid":"25990457","id":"PMC_25990457","title":"Regulation of AURKC expression by CpG island methylation in human cancer cells.","date":"2015","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25990457","citation_count":8,"is_preprint":false},{"pmid":"37700958","id":"PMC_37700958","title":"A Case of Severe Teratozoospermia and Infertility Due to Homozygous Mutation c.144delC in the AURKC Gene.","date":"2023","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/37700958","citation_count":7,"is_preprint":false},{"pmid":"28930610","id":"PMC_28930610","title":"RPS6KA4/MIR1237 and AURKC promoter regions are differentially methylated in Wilms' tumor.","date":"2018","source":"Frontiers in bioscience (Elite 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obstetrics","url":"https://pubmed.ncbi.nlm.nih.gov/39133293","citation_count":4,"is_preprint":false},{"pmid":"30545223","id":"PMC_30545223","title":"Down-regulation of TSGA10, AURKC, OIP5 and AKAP4 genes by Lactobacillus rhamnosus GG and Lactobacillus crispatus SJ-3C-US supernatants in HeLa cell line.","date":"2018","source":"Klinicka onkologie : casopis Ceske a Slovenske onkologicke spolecnosti","url":"https://pubmed.ncbi.nlm.nih.gov/30545223","citation_count":3,"is_preprint":false},{"pmid":"39895780","id":"PMC_39895780","title":"AURKC Promotes Clear Cell Renal Cell Carcinoma Proliferation Through Upregulation of ERp57.","date":"2025","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/39895780","citation_count":1,"is_preprint":false},{"pmid":"29738175","id":"PMC_29738175","title":"[Idiopathic teratozoospermia is not correlated with c.144delC polymorphism in the AURKC gene in Sichuan].","date":"2017","source":"Zhonghua nan ke xue = National journal of andrology","url":"https://pubmed.ncbi.nlm.nih.gov/29738175","citation_count":0,"is_preprint":false},{"pmid":"41528256","id":"PMC_41528256","title":"A novel homozygous variant of AURKC causes macrozoospermia in a Chinese family.","date":"2026","source":"Systems biology in reproductive medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41528256","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.09.24.614706","title":"AUK3 is required for faithful nuclear segregation in the bloodstream form of  <i>Trypanosoma brucei</i>","date":"2024-09-26","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.24.614706","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":16313,"output_tokens":2798,"usd":0.045455,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10060,"output_tokens":3274,"usd":0.066075,"stage2_stop_reason":"end_turn"},"total_usd":0.11153,"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\": 2007,\n      \"finding\": \"Homozygous single-nucleotide deletion (c.144delC) in AURKC results in premature translation termination, producing a truncated protein lacking the kinase domain, and causes male infertility by producing large-headed, multiflagellar, polyploid (tetraploid) spermatozoa due to failed meiosis.\",\n      \"method\": \"Genome-wide microsatellite scan, sequencing of AURKC coding sequence, flow cytometry for ploidy assessment\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — positional cloning plus sequencing with functional confirmation by ploidy analysis, replicated across multiple patients in multiple subsequent studies\",\n      \"pmids\": [\"17435757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"AURKC (STK13) encodes a serine/threonine protein kinase related to Drosophila Aurora and budding yeast Ipl1, mapping to human chromosome 19q13.3-ter; its cDNA was isolated from testis mRNA indicating testis-predominant expression.\",\n      \"method\": \"cDNA library screening, 5' RACE, somatic cell hybrid PCR, radiation hybrid mapping, FISH\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chromosomal localization and cloning with direct experimental methods, but no enzymatic or functional assays performed in this paper\",\n      \"pmids\": [\"9799611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In mouse oocyte meiosis, AURKC is the predominant catalytic subunit of the chromosomal passenger complex (CPC); in the absence of AURKC, AURKA aberrantly localizes to chromosomes in a CPC-dependent manner, and AURKB negatively regulates AURKC activity to prevent aneuploidy. This inter-kinase regulation controls spindle length and chromosome segregation fidelity during meiosis I.\",\n      \"method\": \"Oocyte-specific single and double knockout mice (Aurkb and Aurkc KO), immunofluorescence localization, fecundity assays\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with double-KO mice plus direct localization experiments, multiple orthogonal readouts (spindle length, SAC, aneuploidy rates)\",\n      \"pmids\": [\"30415701\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Three macrozoospermia-associated AURKC mutations have distinct functional consequences: p.L49Wfs22 (c.144delC) is a loss-of-function allele that disrupts CPC localization; p.C229Y is a hypomorphic allele that cannot fully support meiotic cell-cycle progression; p.Y248* fails to localize and function within the CPC but retains cytoplasmic catalytic activity. All three cause metaphase chromosome misalignment and polyploidy via failure of AURKC-CPC function.\",\n      \"method\": \"Expression of mutant AURKC alleles in Aurkc-/- mouse oocytes, immunofluorescence for CPC localization, flow cytometry for ploidy, in vitro kinase assay\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro functional rescue system with mutagenesis, localization, ploidy, and kinase activity assays in a defined genetic background\",\n      \"pmids\": [\"27106102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Haspin inhibition in late prometaphase I causes loss of interchromatid axis-localized AURKC, acceleration of meiosis I, and bypass of the spindle assembly checkpoint (SAC). In contrast, oocytes from Aurkc-/- mice (where AURKB is the sole CPC kinase) show no change in MI timing or MAD2 localization upon haspin inhibition, demonstrating that interchromatid axis-localized AURKB is not required for SAC activation and revealing a functional difference between AURKB and AURKC within the CPC.\",\n      \"method\": \"Haspin kinase inhibition in wild-type and Aurkc-/- mouse oocytes, immunofluorescence for AURKC, AURKB, MAD2 localization, live imaging for MI timing\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic null background combined with pharmacological inhibition and direct localization readouts in single lab, two orthogonal approaches\",\n      \"pmids\": [\"28659416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Aberrantly expressed AURKC localizes to centromeric regions of mitotic chromosomes, decreases AURKB protein levels, and its kinase activity is required for increased cell proliferation, transformation, and migration. AURKC expression is transcriptionally repressed by PLZF, which is recruited to the AURKC promoter.\",\n      \"method\": \"AURKC-GFP overexpression in epithelial/cancer cell lines, kinase-dead mutant analysis, colony formation and migration assays, ChIP for PLZF at AURKC promoter, immunofluorescence\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple functional assays (localization, kinase-dead mutant, ChIP) in single lab, but overexpression system in somatic cells where AURKC is normally absent\",\n      \"pmids\": [\"21710690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A splice-site mutation (c.436-2A>G) in AURKC causes skipping of exon 5, producing a truncated transcript, and combined with heterozygous c.144delC causes compound heterozygous AURKC loss of function leading to macrozoospermia.\",\n      \"method\": \"AURKC gene sequencing, RT-PCR of patient leukocyte transcripts demonstrating exon skipping\",\n      \"journal\": \"Molecular human reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct transcript analysis confirming splice defect, single case/family, no in vitro reconstitution\",\n      \"pmids\": [\"21733974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"AURKC physically interacts with IκBα and phosphorylates IκBα at Ser32, thereby activating NF-κB signaling in breast cancer cells; a small-molecule inhibitor (AKCI) that blocks the AURKC-IκBα protein-protein interaction induces G2/M arrest and inhibits migration, invasion, and tumor growth.\",\n      \"method\": \"Translocation-based cellular binding assay, identification of IκBα as AURKC binding partner, phosphorylation assay, small-molecule inhibitor (AKCI) treatment, NF-κB reporter assays, colony formation, xenograft tumor model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — cellular binding assay and phosphorylation data plus functional readouts, but no reciprocal Co-IP or in vitro reconstitution; single lab\",\n      \"pmids\": [\"29050234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Promoter CpG island hypomethylation is a key positive regulator of AURKC expression; demethylation with 5-aza-dC (but not the HDAC inhibitor TSA) elevates AURKC expression in cancer cell lines, and testis shows marked promoter hypomethylation consistent with high expression. PLZF-mediated repression only partially offsets AURKC expression even after demethylation, indicating that CpG methylation is the dominant regulatory mechanism.\",\n      \"method\": \"5-aza-dC and TSA pharmacological treatment, quantitative methylation analysis, RT-qPCR, TCGA dataset cross-validation, PLZF overexpression experiments\",\n      \"journal\": \"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological demethylation plus cross-dataset validation, multiple cell lines, single lab\",\n      \"pmids\": [\"25990457\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"AURKC interacts with and upregulates ERp57 protein in clear cell renal cell carcinoma; AURKC knockdown reduces CyclinD1, PCNA, and ERp57 levels and inhibits proliferation in vitro and tumor growth in vivo, while AURKC overexpression increases ERp57 and proliferation.\",\n      \"method\": \"Co-immunoprecipitation and colocalization (AURKC-ERp57 interaction), shRNA knockdown and overexpression in ccRCC cell lines, xenograft tumor mouse model, western blot for CyclinD1/PCNA/ERp57\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP/colocalization with KD/OE functional readouts, single lab, no mechanistic detail on how AURKC regulates ERp57\",\n      \"pmids\": [\"39895780\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AURKC is a serine/threonine kinase that functions as the predominant catalytic subunit of the chromosomal passenger complex (CPC) during meiosis, where it is essential for accurate chromosome segregation and completion of meiosis I; loss-of-function mutations cause production of tetraploid, large-headed spermatozoa and male infertility, while in female meiosis AURKC competes with AURKA for CPC binding to control spindle length and is negatively regulated by AURKB to prevent aneuploidy; when aberrantly expressed in somatic/cancer cells, AURKC localizes to centromeric regions, reduces AURKB levels, phosphorylates IκBα to activate NF-κB, and promotes proliferation and transformation in a kinase-activity-dependent manner, with its testis-restricted normal expression maintained by promoter CpG methylation and PLZF-mediated transcriptional repression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"AURKC is a testis-predominant serine/threonine protein kinase of the Aurora family that acts as the principal catalytic subunit of the chromosomal passenger complex (CPC) during meiosis, where it is required for accurate chromosome segregation and completion of meiosis I [#1, #2]. In oocyte meiosis AURKC is the dominant CPC kinase: in its absence AURKA aberrantly loads onto chromosomes in a CPC-dependent manner, and AURKB negatively regulates AURKC to safeguard against aneuploidy, an inter-kinase balance that sets spindle length and segregation fidelity [#2]. AURKC also performs a SAC-relevant function at the interchromatid axis that is not substituted by AURKB, marking a functional divergence between the two kinases within the CPC [#4]. Loss of AURKC function causes male infertility (macrozoospermia): truncating, splice, and missense mutations disrupt CPC localization and meiotic progression, producing large-headed, multiflagellar, polyploid spermatozoa, with allele-specific severity ranging from null to hypomorphic [#0, #3, #6]. AURKC is normally silenced outside the testis by promoter CpG methylation and PLZF-mediated transcriptional repression, with methylation the dominant control [#5, #8]. When aberrantly expressed in somatic and cancer cells, AURKC localizes to centromeres, lowers AURKB levels, and drives kinase-activity-dependent proliferation, transformation, and migration [#5]; in breast cancer it binds and phosphorylates IκBα at Ser32 to activate NF-κB signaling [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established AURKC as a distinct Aurora/Ipl1-related serine/threonine kinase with testis-predominant expression, defining the gene and its likely germline-restricted role before any function was known.\",\n      \"evidence\": \"cDNA cloning from testis mRNA, RACE, and chromosomal mapping by radiation hybrid/FISH\",\n      \"pmids\": [\"9799611\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No enzymatic activity or substrate demonstrated\", \"No cellular function or localization assayed\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Linked AURKC loss directly to human disease, showing the kinase is essential for completion of meiosis in spermatogenesis.\",\n      \"evidence\": \"Positional cloning and sequencing identifying homozygous c.144delC, with flow-cytometric ploidy analysis of patient sperm\",\n      \"pmids\": [\"17435757\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve at which meiotic step AURKC acts\", \"No molecular mechanism for the polyploidy phenotype\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined the transcriptional and oncogenic context of AURKC outside the germline, showing aberrant expression has transforming activity and is normally held off by PLZF.\",\n      \"evidence\": \"AURKC-GFP overexpression with kinase-dead controls, transformation/migration assays, and ChIP for PLZF at the promoter in cancer cell lines\",\n      \"pmids\": [\"21710690\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression system in cells where AURKC is normally absent\", \"Mechanism by which AURKC lowers AURKB levels unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended the allelic spectrum of AURKC infertility, showing compound heterozygous loss-of-function (splice defect plus c.144delC) also causes macrozoospermia.\",\n      \"evidence\": \"Gene sequencing and RT-PCR of patient transcripts demonstrating exon 5 skipping\",\n      \"pmids\": [\"21733974\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single family\", \"No in vitro reconstitution of the truncated protein\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified the dominant regulatory mechanism restricting AURKC to the testis, showing promoter CpG methylation outweighs PLZF repression.\",\n      \"evidence\": \"5-aza-dC versus TSA pharmacological treatment, methylation quantitation, RT-qPCR, and TCGA cross-validation\",\n      \"pmids\": [\"25990457\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not establish which factors read the methylation state\", \"Correlative for the testis methylation–expression link\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolved how specific human mutations cause meiotic failure by assigning distinct molecular defects (null, hypomorphic, mislocalized-but-catalytic) to disease alleles.\",\n      \"evidence\": \"Rescue of Aurkc-/- mouse oocytes with mutant alleles, CPC localization imaging, ploidy flow cytometry, and in vitro kinase assays\",\n      \"pmids\": [\"27106102\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate(s) of AURKC within the CPC not mapped\", \"Cytoplasmic catalytic activity of p.Y248* of uncertain relevance\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established the inter-Aurora regulatory hierarchy in oocyte meiosis, defining AURKC as the predominant CPC kinase whose activity is restrained by AURKB to prevent aneuploidy.\",\n      \"evidence\": \"Single and double Aurkb/Aurkc oocyte knockouts, immunofluorescence localization, and fecundity/aneuploidy readouts\",\n      \"pmids\": [\"30415701\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of AURKB-to-AURKC negative regulation not defined\", \"How spindle length is set downstream remains unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Distinguished AURKC from AURKB functionally within the CPC by showing AURKC at the interchromatid axis is required for SAC integrity whereas AURKB is not.\",\n      \"evidence\": \"Haspin inhibition in wild-type versus Aurkc-/- oocytes with MAD2/AURKC/AURKB imaging and live MI timing\",\n      \"pmids\": [\"28659416\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate basis for the SAC requirement not identified\", \"Tested only in mouse oocytes\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Provided a molecular route for AURKC oncogenic signaling, identifying IκBα as a binding partner and substrate that links AURKC to NF-κB activation.\",\n      \"evidence\": \"Cellular binding assay, IκBα Ser32 phosphorylation, NF-κB reporters, and a PPI-blocking inhibitor in breast cancer cells and xenografts\",\n      \"pmids\": [\"29050234\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No reciprocal Co-IP or in vitro reconstitution of the interaction\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended AURKC's proliferative role to renal cancer through a candidate effector, ERp57.\",\n      \"evidence\": \"Co-IP/colocalization, shRNA knockdown and overexpression, and xenografts in ccRCC lines with CyclinD1/PCNA/ERp57 western blots\",\n      \"pmids\": [\"39895780\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP without reciprocal validation\", \"No mechanism for how AURKC regulates ERp57 levels\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct meiotic substrates of AURKC within the CPC and the molecular mechanism by which AURKB negatively regulates AURKC remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No CPC substrate phosphorylation sites mapped for AURKC\", \"Mechanism of inter-Aurora regulation unresolved\", \"Structural model of AURKC within the CPC absent from the corpus\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 5, 7]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"GO:0016301\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [2, 5]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [\"chromosomal passenger complex (CPC)\"],\n    \"partners\": [\"AURKB\", \"AURKA\", \"NFKBIA\", \"PLZF\", \"ERp57\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}