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.

中文翻译：

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蛋白质组学研究确定了 Aurora-A 通过多种剪接因子介导的选择性剪接调节。


细胞周期调节因子 Aurora-A 激酶是癌症治疗的一个有吸引力的靶点，尽管其抑制也与毒副作用有关。为了更细致地了解 Aurora-A 功能，我们应用鸟枪法蛋白质组学鉴定了 407 个特异性蛋白质伴侣，包括几个剪接因子。支持选择性剪接中的作用，我们发现 Aurora-A 定位于核斑点，即剪接蛋白的仓库。Aurora-A 在体外和体内与剪接因子相互作用并磷酸化剪接因子，表明它通过调节这些剪接因子的活性来调节选择性剪接。一致地，Aurora-A 抑制显著影响 505 个基因的选择性剪接，RNA 基序分析显示 Aurora-A 相互作用剪接因子的富集。此外，我们观察到 Aurora-A 调节的剪接事件与受其相互作用剪接因子调节的剪接事件之间存在显著的正相关关系。一个有趣的例子是 CLK1 外显子 4，它似乎由 Aurora-A 到 SRSF3 调节。总的来说，我们的研究结果强调了 Aurora-A 在选择性剪接调节中的广泛作用。