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Role of Protein Kinase D in Actin Remodeling and Cell Motiliy

蛋白激酶 D 在肌动蛋白重塑和细胞运动中的作用

基本信息

批准号：
8464147
负责人：
Peter Storz
金额：
$ 25.58万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2015-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The directed cell migration of tumor cells in response to a chemotactic stimulus is mediated by mechanisms that induce formation of free F-actin barbed-ends, extensions of existing filaments and actin branching at the leading edge, which results in membrane protrusion towards the stimulus. Key mediators of these processes are ADF/cofilin, which induces actin severing and barbed end formation, the actin nucleation factors of the WASp family and the Arp2/3 complex, which induce actin nucleation and dendritic branching, as well as Ena/VASP, which competes with the capping protein (CP). We made the striking observation that the serine/threonine kinase Protein Kinase D1 (PKD1) completely inhibits actin incorporation at barbed ends at the leading edge and that this results in the inhibition of actin-mediated directed cell migration. This proposal is designed to understand the impact of PKD1 on the key processes regulating actin turnover at the leading edge of migrating tumor cells. It is our hypothesis that PKD1 inhibits actin remodeling processes at multiple levels. Specifically we hypothesize that PKD1 mediates its effects through regulation of ADF/cofilin, the Arp2/3 complex and Ena/VASP. We propose that PKD1 impacts all these key-events to mediate its profound inhibitory effects observed on barbed end formation, actin incorporation and cell migration of tumor cells. Three Specific Aims will be investigated in this proposal: We will determine how PKD1 regulates ADF/cofilin activity (Specific Aim 1); identify how PKD1 regulates Arp2/3 functions (Specific Aim 2); and analyze how PKD1-mediated phosphorylation of VASP contributes to directed cell motility (Specific Aim 3). Successful completion of this proposal will identify novel functions for PKD1 in actin remodeling processes at the leading edge of motile tumor cells. This knowledge will be important for the development of novel strategies to inhibit tumor cell migration and invasion.

描述（由申请人提供）：肿瘤细胞响应趋化刺激的定向细胞迁移由诱导游离F-肌动蛋白倒钩末端形成、现有细丝延伸和肌动蛋白在前缘分支的机制介导，导致膜向刺激物突出。这些过程的关键介质是ADF/cofilin，其诱导肌动蛋白切断和倒刺末端形成，WASp家族的肌动蛋白成核因子和Arp 2/3复合物，其诱导肌动蛋白成核和树突状分支，以及Ena/VASP，其与加帽蛋白（CP）竞争。我们做了惊人的观察，丝氨酸/苏氨酸激酶蛋白激酶D1（PKD 1）完全抑制肌动蛋白掺入的倒钩末端的前沿，这导致抑制肌动蛋白介导的定向细胞迁移。该提案旨在了解PKD 1对调节迁移肿瘤细胞前沿肌动蛋白周转的关键过程的影响。我们的假设是PKD 1在多个水平上抑制肌动蛋白重塑过程。具体而言，我们假设PKD 1通过调节ADF/cofilin，Arp 2/3复合物和Ena/VASP介导其作用。我们认为PKD 1影响所有这些关键事件，以介导其对倒刺末端形成、肌动蛋白掺入和肿瘤细胞迁移的深刻抑制作用。本提案将研究三个具体目标：我们将确定PKD 1如何调节ADF/cofilin活性（具体目标1）;确定PKD 1如何调节Arp 2/3功能（具体目标2）;并分析PKD 1介导的VASP磷酸化如何有助于定向细胞运动（具体目标3）。成功完成这一建议将确定新的功能PKD 1肌动蛋白重塑过程中的运动肿瘤细胞的前沿。这些知识对于开发抑制肿瘤细胞迁移和侵袭的新策略将是重要的。