Graduate Thesis Or Dissertation

Cytoskeletal regulation in cell motility and invasion

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  • Cell motility and invasion are important for development, immunity, wound healing, and tumor cell metastasis. Cells on two dimensional substrates migrate in three steps: protrusion of the front end, translocation of the cell body, and retraction of the rear end. For cells to migrate efficiently, these steps need to be well organized, and the actin cytoskeleton plays a critical role in each step. One of the actin structures important for cell motility is the stress fiber, a bundle of contractile actin filaments required for translocation of the cell body. Invasion or migration in three dimensional environments requires specialized actin rich membrane protrusions, called invadopodia, which regulate proteolytic activities that remodel the extracellular matrix for invasion. The purpose of this dissertation is to better understand the mechanisms regulating the actin cytoskeleton during cell motility and invasion. The first specific aim of this study was to elucidate the mechanism of how cysteine-rich protein 1 (CRP1) binds or bundles actin, and is localized to actin stress fibers. Using CRP1 mutants in cosedimentation assays and fluorescence microscopy, we showed that LIM1 and glycine-rich region 1 (GR1) of CRP1 are required for actin binding/bundling and localization to actin stress fibers. This is the first report of the function of the glycine-rich region, unique to CRPs, in regulating the cytoskeleton, and LIM1/GR1 as a stand alone actin binding/bundling domain. The second specific aim was to determine the role of calpain 2 in glioblastoma cell invasion. Using a calpain 2 knockdown cell line and cell permeable calpain inhibitors in transwell assays or scratch assays, we demonstrated that calpain 2 activity is required for glioblastoma cell invasion, but not migration. Using gelatin zymography, calpain 2 was shown to be important for maintaining the level of extracellular pro-MMP2 and MMP2. These data clearly demonstrate that calpain 2 is required for glioblastoma cell invasion via regulation of invadopodia associated MMP2. Overall, the work in this thesis has advanced our understanding of actin cytoskeletal regulation in stress fibers and invadopodia important for the extracellular matrix remodeling and tumor cell invasion.
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