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Proteomic study identifies Aurora-A-mediated regulation of alternative splicing through multiple splicing factors

Arun Prasath Damodaran1, Olivia Gavard2, Jean-Philippe Gagné3

  • 1Univ Rennes, CNRS, Institut de Génétique et Développement de Rennes (IGDR) UMR6290, Équipe labellisée LNCC 2014, Rennes, France; RNA Biology Laboratory, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Frederick, Maryland, USA.

The Journal of Biological Chemistry
|November 17, 2024
PubMed

Insights

Aurora-A kinase regulates alternative splicing by interacting with and phosphorylating splicing factors. This finding reveals a broader role for Aurora-A beyond cell cycle control, impacting gene expression and offering new therapeutic avenues.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Genetics

Background:

  • Aurora-A kinase is a cell cycle regulator and a cancer therapy target.
  • Inhibition of Aurora-A kinase can cause toxic side effects.
  • Understanding Aurora-A kinase's full function is crucial for targeted cancer therapies.

Purpose of the Study:

  • To investigate the role of Aurora-A kinase in alternative splicing.
  • To identify protein partners of Aurora-A kinase involved in splicing.
  • To elucidate the mechanism by which Aurora-A kinase regulates alternative splicing.

Main Methods:

  • Shotgun proteomics was used to identify protein interactors of Aurora-A kinase.
  • Immunofluorescence was employed to determine Aurora-A kinase localization within the cell.
  • In vitro and in vivo assays were performed to study kinase activity and protein phosphorylation.
  • RNA sequencing and motif analysis were conducted to assess the impact of Aurora-A inhibition on alternative splicing.

Main Results:

  • 407 protein partners of Aurora-A kinase were identified, including several splicing factors.
  • Aurora-A kinase was found to localize to nuclear speckles, a hub for splicing proteins.
  • Aurora-A kinase interacts with and phosphorylates splicing factors, modulating their activity.
  • Inhibition of Aurora-A kinase affected alternative splicing in 505 genes, with enrichment for interacting splicing factors.
  • A positive correlation was observed between splicing events regulated by Aurora-A kinase and those modulated by its interacting splicing factors, exemplified by CLK1 exon 4 regulation via SRSF3.

Conclusions:

  • Aurora-A kinase plays a significant role in the regulation of alternative splicing.
  • The findings suggest Aurora-A kinase modulates gene expression through its impact on alternative splicing.
  • This study expands the known functions of Aurora-A kinase, offering new insights into cancer biology and potential therapeutic strategies.
Keywords:
Aurora-ACLK1RNASR proteincancercell cyclehnRNP proteinskinasemitosisproteomicssplicing

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