PLK4 has emerged as a prime target for cancer therapeutics, and its overexpression is frequently observed in various types of human cancer. Recent studies have further revealed an unexpected oncogenic activity of PLK4 in regulating cancer cell migration and invasion. However, the molecular basis behind the role of PLK4 in these processes still remains only partly understood. Our previous work has demonstrated that an intact CEP85-STIL binding interface is necessary for robust PLK4 activation and centriole duplication. Here, we show that CEP85 and STIL are also required for directional cancer cell migration. Mutational and functional analyses reveal that the interactions between CEP85, STIL and PLK4 are essential for effective directional cell motility. Mechanistically, we show that PLK4 can drive the recruitment of CEP85 and STIL to the leading edge of cells to promote protrusive activity, and that downregulation of CEP85 and STIL leads to a reduction in ARP2 (also known as ACTR2) phosphorylation and reorganization of the actin cytoskeleton, which in turn impairs cell migration. Collectively, our studies provide molecular insight into the important role of the CEP85-STIL complex in modulating PLK4-driven cancer cell migration.This article has an associated First Person interview with the first author of the paper.

中文翻译：

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CEP85 和 STIL 之间的直接相互作用介导 PLK4 驱动的定向细胞迁移。

PLK4 已成为癌症治疗的主要靶点，其过度表达经常在各种类型的人类癌症中观察到。最近的研究进一步揭示了 PLK4 在调节癌细胞迁移和侵袭方面具有意想不到的致癌活性。然而，PLK4 在这些过程中作用背后的分子基础仍然只有部分了解。我们之前的工作表明，完整的 CEP85-STIL 结合界面对于 PLK4 的稳健激活和中心粒复制是必要的。在这里，我们证明 CEP85 和 STIL 也是癌细胞定向迁移所必需的。突变和功能分析表明，CEP85、STIL 和 PLK4 之间的相互作用对于有效的定向细胞运动至关重要。从机制上讲，我们表明 PLK4 可以驱动 CEP85 和 STIL 募集到细胞前缘，从而促进突出活性，并且 CEP85 和 STIL 的下调导致 ARP2（也称为 ACTR2）磷酸化和肌动蛋白重组的减少细胞骨架，进而损害细胞迁移。总的来说，我们的研究为 CEP85-STIL 复合物在调节 PLK4 驱动的癌细胞迁移中的重要作用提供了分子见解。本文有与该论文第一作者相关的第一人称采访。