The Coordination of Cytoskeletal Dynamics by Coronins

描述（申请人提供）：细胞迁移是许多生理过程必不可少的，如伤口愈合，免疫反应和形态发生，并在病理过程中发挥重要作用，如癌症转移。为了使细胞迁移，它们必须在几秒的时间尺度上主动和协调地重塑其肌动蛋白细胞骨架。肌动蛋白动力学的控制需要数十种蛋白质，但两个关键成分是Arp2/3复合物，它在支链阵列中形成新丝，ADF/Cofilin蛋白通过切断和增强解聚来促进肌动蛋白丝的周转。长期以来，人们一直怀疑这两个因素以协调的方式起作用，但这种协调的机制尚不清楚。我们实验室最近的数据表明，作为高度保守的WD-repeat蛋白，Coronins在运动细胞的前沿具有Arp2/3和Cofilin活性协调者的独特功能。本研究旨在阐明这种协调的机制，并确定这种活性如何促进细胞迁移和癌症转移。为此，我们提出了四个具体目标：1)Coronin 1B对Arp2/3功能的调控；2)冠状蛋白1B通过Slingshot磷酸酶调控Cofilin活性；3) Ser2磷酸化对冠蛋白1B活性的时空调控；4)冠状蛋白1B与冠状蛋白1C调控及功能的比较分析。

DESCRIPTION (provided by applicant): Cell migration is essential for many physiological processes such as wound healing, immune response and morphogenesis, and plays a significant role in pathological processes such as cancer metastasis. In order for cells to migrate, they must actively and coordinately remodel their actin cytoskeleton on a time scale of seconds. The control of actin dynamics requires dozens of proteins, but two critical components are the Arp2/3 complex that nucleates new filaments in branched arrays and ADF/Cofilin proteins that promote actin filament turnover by severing and enhanced depolymerization. It has long been suspected that these two factors function in a coordinated manner, but the mechanism of this coordination was unknown. Recent data from our lab indicate that Coronins, highly conserved WD-repeat proteins, have a unique function as coordinators of Arp2/3 and Cofilin activity at the leading edge of motile cells. This proposal seeks to elucidate the mechanisms of this coordination and determine how this activity contributes to cell migration and cancer metastasis. To achieve this, we propose four specific aims: 1) The regulation of Arp2/3 function by Coronin 1B; 2) The regulation of Cofilin activity by Coronin 1B via the Slingshot phosphatases; 3) The spatial and temporal control of Coronin 1B activity by Ser2 phosphorylation; and 4) The comparative analysis of Coronin 1B and Coronin 1C regulation and function.