Regulation of actin by Rac and Phosphoinositides

描述（由申请人提供）：几乎所有细胞都可以移动，并且运动性很强。 这是许多细胞正常功能的重要过程。细胞迁移也 导致许多疾病，包括癌症转移和动脉粥样硬化。 细胞通过产生板状伪足来响应信号而移动，板状伪足延长了细胞的生长。 细胞膜，粘附并允许细胞将自己向前拉。这个过程 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自由倒钩末端的形成来聚合 细丝。刺激细胞运动的信号如何最终导致 产生具有自由倒刺末端的肌动蛋白丝和肌动蛋白聚合， 不知道。小的GTP结合蛋白Rac 1是一个关键的中间体， 导致细胞运动的许多信号转导途径。的信号 受促进肌动蛋白聚合和片状脂质体Rac 1刺激 扩展和粘附是未知的。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 （PtdIns-4，5-P2）。Rac 1与磷脂酰肌醇-4-磷酸结合 5-激酶（PIP 5 Ks），合成PtdIns-4，5-P2的酶。Rac也 刺激PtdIns-4，5-P2合成。这些研究结果表明， Rac 1刺激Ptdlns-4，5-P2的合成可能在细胞中起关键作用 能动性本提案的目的是检验这一假设。的 PtdIns-4，5-P2的研究受到了多功能的阻碍， PtdIns-4，5-P2作为信号分子和底物。我们设计了 方法，这将使我们能够确定Ptdlns-4，5-P2的功能， 响应Rac 1激活，并确定Rac 1如何调节Ptdlns-4，5-P2 程度.这些调查是在一个重要的交界处之间的信号 转导和细胞生物学。我们的研究结果应该会产生 对信号转导途径如何调节肌动蛋白重要新认识 聚合法我们应该更好地了解细胞是如何移动和推进的。 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.