p190 RhoGAP Regulation and Function

描述（由申请方提供）：细胞迁移需要质膜上的肌动蛋白重塑。肌动蛋白调节蛋白的Ena/VASP家族是丝状伪足和板状伪足动力学的关键调节剂，这两种环境传感突起参与迁移。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实验室鉴定的Ena/VASP配体。片状伪足蛋白（Lpd）是离散的目标，以前缘的片状伪足和尖端的丝状伪足。Lpd表达的敲低导致板状伪足形成缺陷，并改变细胞中F-肌动蛋白的几何形状和含量。Lpd包含RAS关联（RA）结构域。RA结构域介导与小GTP酶的RAS亚家族的特定成员的结合。RAS信号可以诱导细胞极性和运动性的变化，并驱动致癌转化。我们假设LPD通过RAS蛋白将信号传导与细胞骨架动力学结合。该提案的目标是阐明LPD功能的潜在分子机制，通过解决LPD转导RAS家族蛋白的信号以通过调节肌动蛋白动力学（部分经由Ena/VASP蛋白）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.