This is a competing renewal of a project focused on understanding the role of the cadherin/catenin complex in modulating cellular behavior that is relevant to tumorigenesis. In this grant period, we will expand our investigations into the mechanisms whereby cadherin complexes influence cell behavior by exploring crosstalk between cell-cell and cell-matrix interactions, since both types of adhesion are critical to cellular processes like migration and invasion. In particular, our studies will focus on how one member of the cadherin/catenin complex, Alpha-catenin, coordinates cell-cell adhesion with activity of invadopodia, a cell substrate adhesive structure that mediates invasion in tumor cells. Our overall hypothesis is that alpha-catenin plays a central role in coordinating cellular signals that regulate cell-cell and cell-matrix adhesion through its interactions with actin cytoskeletal components and signaling pathways. This hypothesis stems from strong preliminary evidence generated using an alpha-catenin-null human breast cancer cell line that undergoes remodeling of invadopodia in response to alpha-catenin re- expression.
Our specific aims are: 1) to determine if alpha-catenin interacts directly with components of invadopodia;2) to test the hypotheses that VASP function is important for maintenance of invadopodia and that expression of beta-catenin modulates VASP function;and 3) to define the role of alpha-catenin in regulating ERK signaling. Tumor formation and invasion are significant human health problems. The proposed research focuses on understanding how a cell coordinates changes in cell-cell and cell-matrix interactions as it becomes malignant. A basic understanding of tumor cell biology and the mechanisms involved in tumorigenesis will provide a basis for developing new methods for diagnosis and treatment. Studies proposed here will increase our understanding of cancer biology by identifying pathways involved in the cross talk between cell- cell and cell-matrix interactions and by characterizing signaling roles for beta-catenin, which is an understudied component of cellular junctions.
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