Myosin-X and the molecular basis of filopodia function

描述（由申请人提供）：丝状伪足是指状细胞突起，假设其充当传感器，允许细胞与其环境接触并相互作用。丝状伪足在神经生长、血管生成、伤口愈合和听力等过程中起关键作用。结构相关的突起称为静纤毛，其功能是负责我们的听觉和平衡感的机械传感器，静纤毛组装或定位于它们的非常规肌球蛋白的缺陷会导致多种形式的人类耳聋。虽然丝状伪足、微绒毛和静纤毛的尖端都含有一种称为尖端复合体的特殊结构，但对尖端复合体的基本性质知之甚少，尽管它清楚地代表了细胞接触和相互作用的关键部位，这在这些突起的形成中也很重要。我们发现肌球蛋白-X（Myo 10）定位于丝状伪足的尖端并与整合素结合，这使我们假设Myo 10是丝状伪足尖端复合物的中心组分，并且尖端复合物是聚合、粘附和信号传导的专门位点。由于我们对丝状伪足尖端复合体知之甚少，特别是与深入研究的粘着结构（如局灶性粘连）相比，我们的目标是确定丝状伪足尖端复合体的基本性质，并确定其在丝状伪足粘附和信号传导中的作用。我们的具体目标 目的是：1）确定丝状伪足尖端复合体的组成和性质。2)可视化尖端复合物的形成和动力学，并研究其在细胞信号传导中的作用。3)确定丝状伪足尖端复合体在粘附和机械传导中的功能。通过对丝状伪足尖端复合体基本性质的界定，本研究将为丝状伪足尖端复合体的研究提供基础 了解人类健康和疾病背后的关键细胞生物学过程所需的信息。此外，Myo 10和丝状伪足尖端复合体的研究提供了一个模型系统，用于了解非常规肌球蛋白在静纤毛和其他基于肌动蛋白束的结构中的功能。

DESCRIPTION (provided by applicant): Filopodia are finger-like cellular protrusions hypothesized to act as sensors that allow cells to contact and interact with their environment. Filopodia are known or hypothesized to have key roles in processes such as nerve growth, angiogenesis, wound healing, and hearing. Structurally related protrusions known as stereocilia function as mechanosensors responsible for our senses of hearing and balance, and defects in the assembly of stereocilia, or in the unconventional myosins that localize to them, cause many forms of human deafness. Although the tips of filopodia, microvilli, and stereocilia all contain a specialized structure known as the tip complex, remarkably little is known about the basic properties of the tip complex, even though it clearly represents a key site of cell contact and interaction that is also important in the formation of these protrusions. Our discovery that myosin-X (Myo10) localizes to the tips of filopodia and binds to ¿-integrins has led us to hypothesize that Myo10 is a central component of the filopodial tip complex, and that the tip complex is a specialized site of polymerization, adhesion, and signaling. Since very little is known about the filopodial tip complex, especially in comparison to intensively studied adhesive structures such as focal adhesions, our objective is to determine the basic properties of the filopodial tip complex and define its roles in filopodial adhesion and signaling. Our specific aims are to: 1) Determine the composition and properties of the filopodial tip complex. 2) Visualize the formation and dynamics of the tip complex and investigate its role in cell signaling. 3) Determine the functions of the filopodial tip complex in adhesion and mechanotransduction. By defining the basic properties of the filopodial tip complex, this research will provide fundamental information needed to understand key cell biological processes underlying human health and disease. In addition, studies of Myo10 and the filopodial tip complex provide a model system for understanding the functions of unconventional myosins in stereocilia and other structures based on actin bundles.