IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy.
Commun Biol. 2023 Oct 14;6(1):1044. doi: 10.1038/s42003-023-05411-y.
Little is known about the signaling network responsible for the organization of the perinuclear actin cap, a recently identified structure holding unique roles in the regulation of nuclear shape and cell directionality. In cancer cells expressing a constitutively active MET, we show a rearrangement of the actin cap filaments, which crash into perinuclear patches associated with spherical nuclei, meandering cell motility and inactivation of the mechano-transducer YAP1. MET ablation is sufficient to reactivate YAP1 and restore the cap, leading to enhanced directionality and flattened nuclei. Consistently, the introduction of a hyperactive MET in normal epithelial cells, enhances nuclear height and alters the cap organization, as also confirmed by TEM analysis. Finally, the constitutively active YAP1 mutant YAP5SA is able to overcome the effects of oncogenic MET. Overall, our work describes a signaling axis empowering MET-mediated YAP1 dampening and actin cap misalignment, with implications for nuclear shape and cell motility.
目前对于负责核周肌动蛋白帽（一种最近发现的结构，在调节核形状和细胞方向性方面具有独特作用）组织的信号网络知之甚少。在表达组成性激活 MET 的癌细胞中，我们观察到肌动蛋白帽纤维的重排，这些纤维会与与球形核相关的核周斑融合，使细胞运动蜿蜒曲折，并使机械转导因子 YAP1 失活。MET 消融足以重新激活 YAP1 并恢复帽结构，从而增强方向性和平整的核。一致地，在正常上皮细胞中引入超活性 MET 会增加核高度并改变帽结构，这也通过 TEM 分析得到证实。最后，组成性激活的 YAP1 突变体 YAP5SA 能够克服致癌 MET 的影响。总的来说，我们的工作描述了一个信号轴，赋予 MET 介导的 YAP1 抑制和肌动蛋白帽错位的能力，这对核形状和细胞运动具有重要意义。
