Inter-junctional signaling in epithelial junctional complex

Each cell-cell contact integrates many individual junctions of several functionally and structurally different types. These junctions must be coordinately remodeled during morphogenetic changes. The long-term goal of our project is to define the mechanisms of this coordination. In the current funding cycle of our grant, we study the interplay between adhesive extracellular module and actin-binding intracellular module of adherens junctions (AJs). These junctions consist of the transmembrane adhesive receptor, cadherin, that interacts with the actin cytoskeleton through proteins called catenins. We discovered a remarkable binding process – the cooperative binding of α-catenin to actin filaments. This process is likely to regulate the strength of the cadherin adhesive interface. We also found that the same process bundles the actin filaments attached to the junction and that the resulting bundle promotes the assembly of another junction, called nectin junction (NJ). Our preliminary data suggests that this assembly is based on the specific recognition of this bundle by the NJ protein, afadin. This and other data, outlined in our proposal, suggest a new hypothesis that the actin-binding proteins of NJs, tight junctions, and desmosomes recognize the local actin filament organization produced by AJs and that this recognition coordinates the assembly and dynamics of all junctions in the cell-cell contact. This study will not only explore this conceptually new type of cell signaling, but also will lay the foundation for understanding the role of this signaling in complex morphogenetic processes.