Tuesday, January 14, 2025
1/14/2025
Program Summary Our laboratory received continuous NIGMS funding since 2004 that allowed us to make substantial advances in our understanding of the mechanisms of the dynamic contacts between neighboring cells (adherens junctions) and between cells and the extracellular matrix (focal adhesions structures). In addition to holding animal cells together, these cell junctions communicate signals and control the stress placed upon cells. Over the past 16 years, we contributed important mechanistic discoveries toward an understanding of • how the cell-cell junctions connect cells in tissues to regulate tissue homeostasis that is crucial to providing the tissue barrier of epithelia, as well as cell migration and proliferation; and • how cell junctions initiate and maintain cell adhesion while regulating the organization of the underlying actin cytoskeleton by establishing a center for cell signaling and gene transcript regulation. We discovered how talin activates vinculin to stabilize focal adhesions and thereby suppress cell migration. Our high-resolution vinculin crystal structures, which we confirmed biochemically and in live cells, showed the auto-inhibitory intramolecular interactions that inactivate vinculin and thereby prevent vinculin from binding to the actin cytoskeleton. We also provided important insights into cell-cell junctions. Our high-resolution crystal and cryogenic electron microscopy structures of a-catenin, a crucial mediator of intercellular adhesions, revealed the mechanistic roles that its quaternary structures play in cell-cell adhesion and the formation of the dynamic link to the actin cytoskeleton. Significantly, our discoveries led to mechano-transduction studies of cell-cell and cell-matrix junctions on how cells sense and transmit forces. We recently discovered how lipid binding to vinculin, its cardiac isoform metavinculin, and to talin regulates focal adhesion turnover. This knowledge and expertise are the foundation for further discoveries that will additionally focus on the understudied role of the plasma membrane in cell adhesion. In the long run, we hope to fully understand cell adhesion by attaining a near-atomic structure of a “synthetic” cell junction. The regulation and dysregulation of cell junctions are fundamental to many biological processes such as development and cancer. Therefore, our proposed studies have both basic and potentially translational significance. The progress of our proposal relies heavily on obtaining purified proteins for structural and biochemical studies. We purchased our FPLCs over 20 years ago that are no longer functioning fully. The AKTA pure 25m system would be a two decades upgrade and provide exponentially faster progress on R35 GM139604.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).