Regulation of cellular actin dynamics by FMNL subfamily formins

细胞迁移是由细胞前部突起的细胞突起启动的，如片状和丝状突起。这些结构是通过聚合肌动蛋白细丝构建的，肌动蛋白细丝的成核由不同的分子机器催化，例如哺乳动物中由15个成员组成的肌动蛋白核仁形成蛋白家族的成员。一些福尔马林，如mDia1或mDia2，已被证明定位和/或触发丝状伪足的形成，但这些似乎都不是这一过程所必需的。在寻找潜在的新的丝足调节因子的过程中，我们已经开始分析FMNL2(也称为FRL3)，它是福尔马林亚群中广泛表达的成员，以前曾与片状脂膜和丝足突起有关。初步工作表明，FMNL2结合了CDc42和rac1小GTP酶，并强烈聚集在突起的片状和丝状伪足的顶端。本项目旨在阐明FMNL2在细胞突起形成和细胞迁移中的确切功能。此外，我们将在体外分析FMNL2成核和/或延长肌动蛋白细丝的潜力，并在体外和体内研究Rho-GTP酶和其他相互作用伙伴对其调节的特性。

Cell migration is initiated by protrusion of cellular projections at the cell front, such as lamellipodia and filopodia. These structures are built by polymerising actin filaments, the nucleation of which is catalyzed by diverse molecular machines, for instance members of the formin family of actin nucleators, comprising 15 members in mammals. Some formins such as mDia1 or mDia2 have been shown to localize to and/or trigger the formation of filopodia, but neither of these appears essential for the process. In a search for potential new filopodial regulators, we have begun to analyse FMNL2 (also called FRL3), a widely expressed member of a subgroup of formins that have previously been implicated in the protrusion of both lamellipodia and filopodia. Preliminary work demonstrates that FMNL2 bind Cdc42 and Rac1 small GTPases, and strongly accumulates at the tips of protruding lamellipodia and filopodia. This project aims at elucidating the precise function of FMNL2 in the formation of cellular protrusions and cell migration. Furthermore, we will analyse the potential of FMNL2 to nucleate and/or elongate actin filaments in vitro, and characterise its regulation by Rho-GTPases and other interaction partners both in vitro and in vivo.