Regulation of cellular actin dynamics by FMNL subfamily formins

细胞迁移是由细胞前部的突起开始的，如板足和丝状足。这些结构是由肌动蛋白细丝聚合而成的，其成核是由不同的分子机器催化的，例如，在哺乳动物中有15个成员的肌动蛋白成核者的formin家族成员。一些形成蛋白，如mDia1或mDia2，已经被证明定位和/或触发丝状足的形成，但它们似乎都不是这个过程所必需的。为了寻找潜在的新的丝状足调节因子，我们已经开始分析FMNL2（也称为FRL3）， FMNL2是一个广泛表达的形成蛋白亚群的成员，该亚群先前被认为与板足和丝状足的突出有关。初步研究表明，FMNL2结合Cdc42和Rac1小gtpase，并在突出的板足和丝状足的尖端强烈积累。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，我们将分析FMNL2在体外成核和/或延长肌动蛋白丝的潜力，并在体外和体内描述Rho-GTPases和其他相互作用伙伴对其的调节。

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.