The long-term goal of this research is to investigate the cytoskeletal regulation of cell-cell and cell-matrix adhesion-mediated events and the mechanism by which this regulation is subverted in neoplastic disease. The adhesion of cells to one another Is essential for the establishment and maintenance of normal tissue architecture. As such cell-cell contacts not only have an essential function in normal cell growth and motility but are also involved in cases of dysregulation that occur during carcinogenesis and metastasis. Cells have several mechanisms for linking to their neighbors. These so-called """"""""cell junctions"""""""" consist of proteins that assemble into a variety of structures such as gap junctions, tight junctions, adherens junctions, desmosomes and hemidesmosomes, each with a different function. Despite their apparent stability, epithelial cell-cell junctions are highly dynamic regions of a cell that respond to cue from the extracellular environment. The morphological changes accompanying the response to these cues are mediated by the underlying actin cytoskeleton and their characteristics and integrity is controlled by kinases, phosphatases and small GTPases. A prominent phosphorylated protein that is reported to link cell-cell junctions to the actin cytoskeleton is vinculin. The role of vinculin at sites of adhesion to the matrix has been widely studied for many years, but the function of vinculin at sites of cell-cell contact remains largely unexplored. This proposal is directed towards answering this question. The hypothesis is that vinculin is an important regulator of epithelial cell junctions. This hypothesis will be tested and the role of vinculin dynamics and its phosphorylation in adherens and tight junction function will be examined. ? ? ?
| Peng, Xiao; Maiers, Jessica L; Choudhury, Dilshad et al. (2012) ?-Catenin uses a novel mechanism to activate vinculin. J Biol Chem 287:7728-37 |
| Nelson, Elke S; Folkmann, Andrew W; Henry, Michael D et al. (2011) Vinculin activators target integrins from within the cell to increase melanoma sensitivity to chemotherapy. Mol Cancer Res 9:712-23 |
| Peng, Xiao; Nelson, Elke S; Maiers, Jessica L et al. (2011) New insights into vinculin function and regulation. Int Rev Cell Mol Biol 287:191-231 |
| Peng, Xiao; Cuff, Laura E; Lawton, Cort D et al. (2010) Vinculin regulates cell-surface E-cadherin expression by binding to beta-catenin. J Cell Sci 123:567-77 |
| Wen, Kuo-Kuang; Rubenstein, Peter A; DeMali, Kris A (2009) Vinculin nucleates actin polymerization and modifies actin filament structure. J Biol Chem 284:30463-73 |
| Demali, Kris A; Jue, April L; Burridge, Keith (2006) IpaA targets beta1 integrins and rho to promote actin cytoskeleton rearrangements necessary for Shigella entry. J Biol Chem 281:39534-41 |
