Motor Proteins, Cytoskeleton, and Cell Motility
Our research centers on determining the properties and roles of molecular motors. In the past several years it has become apparent that the myosin superfamily of actin-based motor proteins is much larger and far more diverse than previously realized, and in a recent genome based analysis we predicted 8 previously unrecognized myosin genes. Although the conventional myosins responsible for processes such as muscle contraction and cell division have been intensively studied for almost half a century, very little is known about the unconventional myosins. We are particularly interested in the cell and molecular biology of the unconventional myosins, since these molecules are hypothesized to underlie cellular phenomena ranging from organelle transport to signal transduction.
Our long range goals are to determine the molecular basis of processes such as organelle transport, cell crawling, and filopodial dynamics by characterizing the properties and functions of the motor proteins believed to power these movements. Much of our work has focused on brain myosin-V, a major component of brain that appears to power actin-based organelle transport in places such as the dendritic spine; loss of this myosin in mutant mice leads to seizures and death. We have also discovered a new member of the myosin-V family (Myo5c) and have implicated this myosin in the transport of a specific membrane compartment. Given that that Myo5c is a major class V myosin of secretory/epithelial tissues, we suspect that it powers actin-based organelle transport in many of the physiologically critical cells and tissues of the human body. We are also interested in devising improved motility assays that will allow us to reconstitute actin-based organelle transport so as to investigate mechanisms of motor regulation and docking.
We have also begun to characterize myosin-X, a newly discovered myosin that is characterized by the presence of multiple PH (pleckstrin homology) domains. Video microscopy and live cell imaging with GFP constructs indicate that myosin-X exhibits a striking localization to the tips of filopodia. More importantly, we have also discovered that myosin-X undergoes remarkable forward and rearward movements within filopodia and we are thus especially interested in investigating the properties and functions of this novel form of actin-based motility. We are currently investigating the roles of myosin-X in a variety of important processes including PI-3-kinase signaling, phagocytosis, filopodial dynamics, growth cone extension, tumor cell crawling, focal complex formation, and cell-cell signaling.