The establishment and maintenance of cell-cell adhesion is critical for normal cutaneous function, and the loss of cell adhesion is a hallmark feature of numerous skin diseases. Although significant progress has been made in identifying the molecular components of adhesive intercellular junctions, the detailed mechanisms by which intercellular junctions are assembled and regulated during cutaneous pathologies are still poorly understood. Members of the armadillo family of proteins are cytoplasmic components of adhesive junctions and link members of the cadherin family of cell adhesion molecules to the cytoskeleton. In addition, armadillo proteins play central roles in signaling pathways which regulate gene expression and tissue patterning. Recent evidence indicates that a new subfamily of armadillo proteins, termed the p120/plakophilin family, assemble into intercellular junctions in a variety of cutaneous cells. The focus of this proposal is p0071, a member of this p120/plakophilin subfamily of armadillo proteins. An interesting feature of p0071 is that this protein assembles into both actin and intermediate filament associated junctions, suggesting that p0071 may play a role in coordinating the assembly of different types of intercellular junctions. To understand how p0071 might play such roles requires a detailed understanding of the subcellular distribution of p0071 and the proteins within cells that function as p0071 binding partners. The central hypothesis of this proposal is that p0071 functions as a cadherin binding protein and plays a role in the assembly and turnover of both actin and intermediate filament associated intercellular junctions. The objectives of this proposal are to determine the subcellular distribution of p0071, identify p0071 binding partners, and elucidate the role of this protein in the assembly and turnover of adhesive intercellular junctions in both keratinocytes and dermal microvascular endothelial cells. The long-term goal of this work is to identify new molecules and cellular processes that might be targeted by therapeutic agents that could be used to facilitate epidermal wound healing or treat cutaneous pathologies which involve endothelial barrier dysfunction or angiogenesis.
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