Characterization of Lamellipodin in Filopodia Dynamics

描述（由申请人提供）：细胞迁移需要在质膜处进行肌动蛋白重塑。肌动蛋白调控蛋白Ena/VASP家族是丝状足和板足动力学的关键调控因子，两者都是参与迁移的环境感知突起。这些蛋白质是第二信使途径的潜在汇聚点。Lamellipodin （Lpd）是最近在Gertler实验室发现的一种Ena/VASP配体。板足素（Lamellipodin, Lpd）分别靶向于板足的前缘和丝状足的尖端。Lpd表达下调会导致板足形成缺陷，并改变细胞内f -肌动蛋白的几何形状和含量。Lpd包含一个RA （RAS-association）域。RA结构域介导与小GTPases的RAS亚家族特定成员的结合。RAS信号可以诱导细胞极性和运动的改变，并驱动致癌转化。我们假设Lpd通过RAS蛋白信号传导到细胞骨架动力学。本研究的目标是阐明Lpd功能的潜在分子机制，通过解决Lpd通过调节肌动蛋白动力学（部分通过Ena/VASP蛋白）来传导RAS家族蛋白的信号来调节细胞迁移的一般假设。

DESCRIPTION (provided by applicant): Actin remodeling at the plasma membrane is required for cell migration. The Ena/VASP family of actin regulatory proteins are key regulators of filopodia and lamellipodia dynamics, both environment sensing protrusions involved in migration. These proteins are potential convergent points for second messenger pathways. Lamellipodin (Lpd) is an Ena/VASP ligand recently identified in the Gertler laboratory. Lamellipodin (Lpd) is discretely targeted to the leading edge of lamellipodia and the tips of filopodia. Knockdown of Lpd expression causes defects in lamellipodia formation and alters F-actin geometry and content with the cell. Lpd contains a RAS-association (RA) domain. RA domains mediate binding to specific members of the RAS subfamily of small GTPases. RAS signaling can induce changes in cell polarity and motility and drive oncogenic transformation. We hypothesize that Lpd couples signaling by RAS proteins to cytoskeletal dynamics. The goal of this proposal is to elucidate the underlying molecular mechanisms for Lpd function by addressing the general hypothesis that Lpd transduces signals from the RAS family proteins to regulate cell migration by regulating actin dynamics, in part via Ena/VASP proteins.