p190 RhoGAP Regulation and Function

描述(申请人提供)：细胞迁移需要肌动蛋白在质膜上的重塑。Ena/Vasp家族的肌动蛋白调节蛋白是丝状足纲和片状脂体动态的关键调节因子，这两个环境感知突起都参与了迁移。这些蛋白质是第二信使通路的潜在聚合点。LamelLipodin(LPD)是Gertler实验室新近发现的一种Ena/Vasp配体。片脂蛋白(LPD)的靶点是片脂的前缘和丝状伪足的尖端。LPD表达下调会导致板脂形成缺陷，并改变F-肌动蛋白的几何构型和细胞内的含量。LPD包含RAS关联(RA)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信号可以诱导细胞的极性和运动性的改变，并驱动致癌转化。我们假设LPD通过RAS蛋白将信号与细胞骨架动力学联系起来。这项建议的目的是阐明LPD功能的潜在分子机制，通过解决这一普遍假设，即LPD通过部分通过Ena/Vasp蛋白调节肌动蛋白动态来传递来自RAS家族蛋白的信号来调节细胞迁移。

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.