Department of Biotechnology and Bioindustry Sciences, National Cheng Kung University, 1 University Rd., Tainan City 701, Taiwan, Republic of China; Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan, Republic of China.
Department of Biotechnology and Bioindustry Sciences, National Cheng Kung University, 1 University Rd., Tainan City 701, Taiwan, Republic of China.
Cell Rep. 2018 Feb 20;22(8):2160-2175. doi: 10.1016/j.celrep.2018.01.080.
In collective cell migration, directional protrusions orient cells in response to external cues, which requires coordinated polarity among the migrating cohort. However, the molecular mechanism has not been well defined. Drosophila border cells (BCs) migrate collectively and invade via the confined space between nurse cells, offering an in vivo model to examine how group polarity is organized. Here, we show that the front/back polarity of BCs requires Rap1, hyperactivation of which disrupts cluster polarity and induces misoriented protrusions and loss of asymmetry in the actin network. Conversely, hypoactive Rap1 causes fewer protrusions and cluster spinning during migration. A forward genetic screen revealed that downregulation of the Hippo (Hpo) pathway core components hpo or mats enhances the Rap1-induced migration defect and misdirected protrusions. Mechanistically, association of Rap1 with the kinase domain of Hpo suppresses its activity, which releases Hpo signaling-mediated suppression of F-actin elongation, promoting cellular protrusions in collective cell migration.
在集体细胞迁移中，定向突起使细胞对外部信号做出反应，这需要迁移群体中的协调极性。然而，其分子机制尚未得到很好的定义。果蝇缘细胞（BC）集体迁移并通过滋养细胞之间的受限空间侵入，提供了一个体内模型来研究如何组织群体极性。在这里，我们表明 BC 的前后极性需要 Rap1，其过度激活会破坏簇极性并诱导突起方向错误和肌动蛋白网络的不对称性丧失。相反，Rap1 活性不足会导致迁移过程中突起较少和簇旋转。正向遗传筛选显示，Hippo（Hpo）途径核心成分 hpo 或 mats 的下调增强了 Rap1 诱导的迁移缺陷和突起方向错误。在机制上，Rap1 与 Hpo 的激酶结构域结合会抑制其活性，从而释放 Hpo 信号转导介导的对 F-actin 延伸的抑制作用，促进集体细胞迁移中的细胞突起。
