Protocadherin FAT1 binds Ena/VASP proteins and is necessary for actin dynamics and cell polarization
Protocadherin FAT1 binds Ena/VASP proteins and is necessary for actin dynamics and cell polarization
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DOI：
10.1038/sj.emboj.7600380
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发表时间：
2004-09-29
期刊：
影响因子：
11.4
通讯作者：
Holzman, LB
中科院分区：
文献类型：
--
作者：
Moeller, MJ;Soofi, A;Holzman, LB
细胞迁移需要细胞过程的整合，导致细胞极化和肌动蛋白动力学。先前使用果蝇遗传学工具的工作表明，原钙粘蛋白脂肪在决定组织平面细胞极性所必需的途径中起作用。在这里，我们确定哺乳动物脂肪1作为一个信号通路的近端元件，决定细胞极性在平面上的单层和定向肌动蛋白依赖的细胞运动。FAT 1定位于板状伪足、丝状伪足和微刺尖端的前缘，其中FAT 1直接与调节肌动蛋白聚合复合物的Ena/VASP蛋白相互作用。当靶向线粒体外小叶时，FAT 1胞质结构域招募足以诱导异位肌动蛋白聚合的肌动蛋白聚合机制的组分。在上皮细胞创伤模型中，FAT 1敲低降低了内源性VASP向前缘的募集，并导致板状脂质动力学受损、极化失败和细胞迁移减弱。FAT 1可能通过参与Ena/VASP依赖的细胞骨架动力学前沿调节和转导Ena/VASP独立的极性线索来调节细胞迁移。
Cell migration requires integration of cellular processes resulting in cell polarization and actin dynamics. Previous work using tools of Drosophila genetics suggested that protocadherin fat serves in a pathway necessary for determining cell polarity in the plane of a tissue. Here we identify mammalian FAT1 as a proximal element of a signaling pathway that determines both cellular polarity in the plane of the monolayer and directed actin-dependent cell motility. FAT1 is localized to the leading edge of lamellipodia, filopodia, and microspike tips where FAT1 directly interacts with Ena/VASP proteins that regulate the actin polymerization complex. When targeted to mitochondrial outer leaflets, FAT1 cytoplasmic domain recruits components of the actin polymerization machinery sufficient to induce ectopic actin polymerization. In an epithelial cell wound model, FAT1 knockdown decreased recruitment of endogenous VASP to the leading edge and resulted in impairment of lamellipodial dynamics, failure of polarization, and an attenuation of cell migration. FAT1 may play an integrative role regulating cell migration by participating in Ena/VASP-dependent regulation of cytoskeletal dynamics at the leading edge and by transducing an Ena/VASP-independent polarity cue.