Myosin-X and the molecular basis of filopodia function

描述（由申请人提供）：丝状足是指状的细胞突起，假设作为传感器，允许细胞与环境接触和相互作用。丝状足已知或假设在神经生长、血管生成、伤口愈合和听力等过程中起关键作用。被称为立体纤毛的结构相关的突出物作为机械传感器，负责我们的听觉和平衡感，而立体纤毛的组装缺陷，或定位于它们的非常规肌球蛋白的缺陷，导致了多种形式的人类耳聋。尽管丝状足、微绒毛和立体纤毛的尖端都含有一种被称为尖端复合体的特殊结构，但对尖端复合体的基本特性知之甚少，尽管它显然是细胞接触和相互作用的关键部位，在这些突起的形成中也很重要。我们发现肌球蛋白- x （Myo10）定位于丝状足的尖端，并与整合素结合，这使我们假设Myo10是丝状足尖端复合体的核心成分，而尖端复合体是聚合、粘附和信号传导的专门位点。由于对丝状尖端复合体知之甚少，特别是与已深入研究的黏附结构（如局灶黏附）相比，我们的目标是确定丝状尖端复合体的基本特性，并确定其在丝状黏附和信号传导中的作用。我们的具体目标

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.