AURKC

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).

1. 1998 Medium

   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

   PMID:9799611

   Open questions at the time

   • No enzymatic activity or substrate demonstrated
   • No cellular function or localization assayed
2. 2007 High

   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

   PMID:17435757

   Open questions at the time

   • Did not resolve at which meiotic step AURKC acts
   • No molecular mechanism for the polyploidy phenotype
3. 2011 Medium

   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

   PMID:21710690

   Open questions at the time

   • Overexpression system in cells where AURKC is normally absent
   • Mechanism by which AURKC lowers AURKB levels unresolved
4. 2011 Medium

   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

   PMID:21733974

   Open questions at the time

   • Single family
   • No in vitro reconstitution of the truncated protein
5. 2015 Medium

   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

   PMID:25990457

   Open questions at the time

   • Does not establish which factors read the methylation state
   • Correlative for the testis methylation–expression link
6. 2016 High

   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

   PMID:27106102

   Open questions at the time

   • Substrate(s) of AURKC within the CPC not mapped
   • Cytoplasmic catalytic activity of p.Y248* of uncertain relevance
7. 2017 High

   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

   PMID:30415701

   Open questions at the time

   • Molecular basis of AURKB-to-AURKC negative regulation not defined
   • How spindle length is set downstream remains unclear
8. 2017 High

   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

   PMID:28659416

   Open questions at the time

   • Substrate basis for the SAC requirement not identified
   • Tested only in mouse oocytes
9. 2017 Medium

   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

   PMID:29050234

   Open questions at the time

   • No reciprocal Co-IP or in vitro reconstitution of the interaction
   • Single lab
10. 2025 Low

    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

    PMID:39895780

    Open questions at the time

    • Single Co-IP without reciprocal validation
    • No mechanism for how AURKC regulates ERp57 levels
    • Single lab

• The direct meiotic substrates of AURKC within the CPC and the molecular mechanism by which AURKB negatively regulates AURKC remain undefined.
• 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