Mechanisms Directing Adherens Junctions and Actin Network Interactions

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DESCRIPTION (provided by applicant): The formation and stabilization of cell-cell adhesion complexes (adherens junctions) is essential for metazoan development, organogenesis and tissue homeostasis, and is also necessary for some pathophysiological conditions, for example wound healing. In contrast, loss of adherens junctions is a hallmark of cancer, leading to unrestricted cell proliferation and metastasis. Cell-cell adherens junctions require the proper assembly of multi-protein complexes at the plasma cell membrane. Here homotypic interactions between the calcium-binding ectodomains of single transmembrane pass cadherin receptors allows neighboring cells to bind to one another. The interactions of their cytoplasmic tail domains with ?-catenin, which in turn binds to ?-catenin, appears to direct the formation of adherens junctions, by inhibiting the production of lamellopodia. However, this ternary cadherin:??-catenin:??-catenin complex does not bind directly to the actin network, which is necessary for stabilizing these junctions and for tissue homeostasis. One thought is that local increases in the concentrations of ?-catenin at these complexes favors the formation of ?-catenin homodimers that then stabilize these complexes by directly binding to actin through a domain in their C-termini. By moving from crystal structures to biochemistry and then to biology, the proposed studies will define how adherens junctions are stabilized and control the organization of the actin cytoskeleton. Importantly, our studies will also lay the foundation for understanding how these controls are lost during tumor progression and may suggest new avenues for therapeutic intervention.