Filopodia in Leukocyte and Endothelial Cell Function

Univ Of North Carolina Chapel Hill, Chapel Hill NC

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Abstract

Growing evidence indicates that the slender actin-based extensions known as filopodia play central roles in[unreadable] the cell biology underlying inflammation and angiogenesis. The initial contacts between leukocytes and[unreadable] endothelial cells during leukocyte rolling occur at the tips of filopodia-like structures and endothelial[unreadable] "pathfinder" cells appear to be guided by filopodia during angiogenesis. Despite these critical roles of[unreadable] filopodia in leukocytes and endothelial cells, the molecular mechanisms underlying filopodial extension,[unreadable] adhesion, and signaling are largely unknown. Our discovery that myosin-X (Myo10) is a core component of[unreadable] a putative filopodial tip complex, is involved in filopodia formation, and undergoes a novel form of motility in[unreadable] filopodia, gives us a powerful tool to investigate these questions. We therefore propose to:[unreadable] I. Determine the functional consequences of MyolO's interaction with integrins. Since Myo10 is an[unreadable] unconventional myosin whose tail includes a PERM domain that can binds to the cytoplasmic domains of pintegrins,[unreadable] we will test whether binding to this motor protein activates integrins. We will also test if Myo10[unreadable] binds to the leukocyte specific beta2-integrins and if Myo10 is required for complement-mediated phagocytosis.[unreadable] II. Analyze the functions of Myo10 in leukocytes and endothelial cells in processes such as[unreadable] filopodial extension, chemotaxis, and transendothelial migration using siRNA and a dominant negative[unreadable] construct. Although Myo10 is the MyTH-FERM myosin expressed in most vertebrate cells and a related[unreadable] myosin in lower organisms is required for filopodia formation, adhesion, and phagocytosis, almost nothing is[unreadable] known about the functions of this family of myosins in leukocytes and endothelial cells.[unreadable] III. Define the basic biochemical properties and components of the filopodial tip complex. Like the[unreadable] focal adhesion, the filopodial tip complex appears to function as a specialized site of cell adhesion, signaling,[unreadable] and actin polymerization, but currently very little is known about the molecular components and properties of[unreadable] the filopodial tip complex.[unreadable] This work is of great relevance to public health because it will investigate the fundamental cell biological[unreadable] mechanisms of inflammation and cell signaling that underlie cardiovascular disease and other serious[unreadable] human health problems.[unreadable]