Regulation of actin by Rac and Phosphoinositides

描述(申请人提供)：几乎所有细胞都可以移动，运动性是 许多细胞正常运作的一个重要过程。细胞迁移也 导致许多疾病，包括癌症转移和动脉粥样硬化。 细胞通过产生片状脂膜来响应信号的移动，从而延长细胞的 细胞膜，附着并允许细胞向前拉。这一过程 没有肌动蛋白聚合就不会发生。细胞控制肌动蛋白 通过调节肌动蛋白上游离带刺末端的产生进行聚合 细丝。刺激细胞运动的信号最终是如何导致 具有自由带刺末端的肌动蛋白细丝的生成和肌动蛋白聚合 不知道。小的GTP结合蛋白rac1是一种重要的 导致细胞运动的许多信号转导途径。这些信号 由促进肌动蛋白聚合和片脂蛋白的rac1刺激 延期和依从性尚不清楚。协调的几个关键步骤 肌动蛋白聚合受磷脂酰肌醇-4，5-二磷酸调节 (Ptdlns-4，5-P2)。Rac1与磷脂酰肌醇-4-磷酸结合 5-激酶(PIP5Ks)，合成Ptdlns-4，5-P2的酶。RAC还 刺激Ptdlns-4，5-P2的合成。这一系列的发现表明 Rac1刺激的Ptdlns-4，5-P2的合成可能在细胞中起关键作用 能动性。当前提案的目标是检验这一假设。这个 Ptdlns-4，5-P2的多重功能阻碍了对它的研究 Ptdlns-4，5-P2既是信号分子又是底物。我们设计了一个 使我们能够确定Ptdlns-4，5-P2在 对rac1激活的反应并确定rac1如何调节Ptdlns-4，5-P2 级别。这些调查处于信号和信号之间的重要交汇点 转导和细胞生物学。我们的研究结果应该会产生 对信号转导通路如何调控肌动蛋白的重大新见解 聚合反应。我们应该更好地了解细胞是如何运动的，并推动 细胞生物学和信号转导领域。

DESCRIPTION (provided by applicant): Almost all cells can move and motility is an important process in the normal function of many cells. Cell migration also contributes to many diseases, including cancer metastasis and atherosclerosis. Cells move in response to signals by generating lamellipodia, which extend the cell membrane, adhere and allow the cell to pull itself forward. This process does not happen without actin polymerization. Cells control actin polymerization by regulating the creation of free barbed ends on actin filaments. How signals that stimulate cell motility ultimately result in the generation of actin filaments with free barbed ends and actin polymerization is not known. The small GTP-binding protein Rac1 is a critical intermediate in many signal transduction pathways that cause cell motility. The signals stimulated by Rac1 that promote actin polymerization and lamellipodial extension and adherence are not known. Several critical steps that coordinate actin polymerization are regulated by phosphatidylinositol-4,5-bisphosphate (Ptdlns-4,5-P2). Rac1 associates with the phosphatidylinositol-4-phosphate 5-kinases (PIP5Ks), the enzymes that synthesize Ptdlns-4,5-P2. Rac also stimulates Ptdlns-4,5-P2 synthesis. This confluence of findings suggests that Rac1-stimulated synthesis of Ptdlns-4,5-P2 may play a critical role in cell motility. The goal of the current proposal is to test this hypothesis. The study of Ptdlns-4,5-P2 has been hampered by the multiple functions of Ptdlns-4,5-P2 as both a signaling molecule and a substrate. We have devised approaches that will allow us to determine the function of Ptdlns-4,5-P2 in response to Rac1 activation and determine how Rac1 regulates Ptdlns-4,5 -P2 levels. These investigations are at an important junction between signal transduction and cell biology. The results of our studies should generate significant new insight into how signal transduction pathways regulate actin polymerization. We should understand better how cells move and advance the fields of cell biology and signal transduction.