Myosin-X and the molecular basis of filopodia function

描述(申请人提供)：丝状突起是指状细胞突起，假设作为传感器，允许细胞与其环境接触和互动。已知或假设丝状足在神经生长、血管生成、伤口愈合和听力等过程中具有关键作用。与结构相关的突起被称为立体纤毛，其功能是机械传感器，负责我们的听觉和平衡，以及立体纤毛组装的缺陷，或定位于它们的非传统肌球蛋白，导致许多形式的人类耳聋。尽管丝状伪足、微绒毛和立体纤毛的尖端都含有一种称为尖端复合体的特殊结构，但人们对尖端复合体的基本性质知之甚少，尽管它显然代表着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是重要的。我们的发现是肌球蛋白X(myosin-X，Myo10)定位于丝状伪足末端并与�-整合素结合，这使得我们假设Myo10是丝状伪足末端复合体的中心成分，而末端复合体是聚合、黏附和信号传递的专门部位。由于对丝状末端复合体的了解很少，特别是与广泛研究的粘连结构(如焦点粘连)相比，我们的目标是确定丝状末端复合体的基本性质，并确定其在丝状末端黏附和信号转导中的作用。我们的具体目标 目的是：1)测定丝状尖端复合体的组成和性质。2)可视化末端复合体的形成和动态，并研究其在细胞信号转导中的作用。3)确定丝状末端复合体在黏附和机械转导中的作用。通过定义丝轴尖端复合体的基本性质，这项研究将为 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，对Myo10和丝状末端复合体的研究为理解非传统肌球蛋白在立体纤毛和其他基于肌动蛋白束的结构中的功能提供了一个模型系统。

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.