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中必不可少的，如伤口愈合、免疫反应和形态形成，并在癌症转移等病理过程中发挥重要作用。为了让细胞迁移，它们必须在几秒的时间尺度上主动和协调地重塑他们的肌动蛋白细胞骨架。肌动蛋白动力学的控制需要几十种蛋白质，但有两个关键成分是Arp2/3复合体和ADF/cofilin蛋白，前者在分支阵列中形成新的微丝，后者通过切断和增强解聚来促进肌动蛋白细丝的周转。长期以来，人们一直怀疑这两个因素是以一种协调的方式发挥作用，但这种协调的机制尚不清楚。我们实验室的最新数据表明，冠状蛋白是高度保守的WD-重复蛋白，在运动细胞的前沿具有独特的Arp2/3和cofilin活性的协调者功能。这项建议试图阐明这种协调的机制，并确定这种活动如何促进细胞迁移和癌症转移。为了实现这一目标，我们提出了四个具体的目标：1)Coron1B对Arp2/3功能的调节；2)Coron1B通过Slingshot磷酸酶调节Cofilin活性；3)Ser2磷酸化对Coron1B活性的时空调控；以及4)Coron1B和Coron1C的调节和功能的比较分析。

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.