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

The cell cycle regulator Aurora-A kinase presents an attractive target for cancer therapies, though its inhibition is also associated with toxic side effects. To gain a more nuanced understanding of Aurora-A function, we applied shotgun proteomics to identify 407 specific protein partners, including...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:The Journal of biological chemistry 2024-11, p.108000, Article 108000
Hauptverfasser: Prasath Damodaran, Arun, Gavard, Olivia, Gagné, Jean-Philippe, Rogalska, Malgorzata Ewa, Behera, Amit K., Mancini, Estefania, Bertolin, Giulia, Courtheoux, Thibault, Kumari, Bandana, Cailloce, Justine, Mereau, Agnès, Poirier, Guy G., Valcárcel, Juan, Gonatopoulos-Pournatzis, Thomas, Watrin, Erwan, Prigent, Claude
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung:The cell cycle regulator Aurora-A kinase presents an attractive target for cancer therapies, though its inhibition is also associated with toxic side effects. To gain a more nuanced understanding of Aurora-A function, we applied shotgun proteomics to identify 407 specific protein partners, including several splicing factors. Supporting a role in alternative splicing, we found that Aurora-A localizes to nuclear speckles, the storehouse of splicing proteins. Aurora-A interacts with and phosphorylates splicing factors both in vitro and in vivo, suggesting that it regulates alternative splicing by modulating the activity of these splicing factors. Consistently, Aurora-A inhibition significantly impacts the alternative splicing of 505 genes, with RNA motif analysis revealing an enrichment for Aurora-A interacting splicing factors. Additionally, we observed a significant positive correlation between the splicing events regulated by Aurora-A and those modulated by its interacting splicing factors. An interesting example is represented by CLK1 exon 4, which appears to be regulated by Aurora-A through SRSF3. Collectively, our findings highlight a broad role of Aurora-A in the regulation of alternative splicing.
ISSN:0021-9258
1083-351X
1083-351X
DOI:10.1016/j.jbc.2024.108000