Myosin-X is an unconventional myosin of the MyTH-FERM super class that is broadly expressed in vertebrate tissues. Although little is known about the functions of the MyTH-FERM myosins, mutations in one member of this group are the leading cause of hereditary deaf-blindness in children. We recently discovered that myosin-X undergoes a novel form of motility within filopodia, and we hypothesize that myosin-X is a component of a widespread but previously uncharacterized system for intracellular transport on actin-rich structures such as filopodia. Myosin-X also exhibits a remarkable localization to the tips of filopodia and overexpressing it leads to increased number and length of filopodia, suggesting that myosin-X functions in the largely unknown pathways regulating filopodial dynamics. Myosin-X also binds to integrins and one of its light chains is known to be dramatically down regulated in many tumors. Together these data strongly suggest that myosin-X and the novel form of motility associated with it play fundamental but largely unexplored roles in the basic cell biology underlying human health and disease. We propose to: I. Determine the fundamental properties, mechanisms, and regulation of this novel form of motility. II. Identify the structures and molecular cargo(s) transported by intrafilopodial motility. III. Use myosin-X as a marker to identify the components of a putative filopodial tip complex and determine if myosin-X is a component of signaling pathways that regulate filopodial dynamics. IV. Determine the functions of myosin-X in key cell biological processes such as phagocytosis, filopodial dynamics, and cell crawling. This research will determine the fundamental properties of a novel and previously uncharacterized form of motility that has critical implications for a host of important cell biological processes including integrin function, cell adhesion, filopodial dynamics, macrophage function, and nerve regrowth. The proposed research will thus answer critical questions about the basic cell biology underlying many human diseases including cancer, hereditary deafness, retinitis pigmentosa, and nerve injury.
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