Role of p0071 in Cutaneous Intercellular Junctions

细胞间黏附的建立和维持是正常皮肤功能的关键，而细胞黏附的丧失是许多皮肤病的一个显著特征。尽管在鉴定黏附细胞间连接的分子组成方面已经取得了重大进展，但在皮肤病理过程中细胞间连接如何组装和调节的详细机制仍然知之甚少。Aradillo蛋白家族的成员是黏附连接的细胞质成分，并将细胞黏附分子中的钙粘素家族成员与细胞骨架联系起来。此外，螳螂蛋白在调节基因表达和组织模式的信号通路中发挥着核心作用。最近的证据表明，一个新的亚家族，被称为p120/普拉克亲和素家族，在各种皮肤细胞中组装成细胞间连接。这项提案的焦点是p0071，它是这个p120/Plakophlin亚家族中的一员。P0071的一个有趣的特征是，该蛋白可以组装成肌动蛋白和中间微丝相关的连接，这表明p0071可能在协调不同类型的细胞间连接的组装中发挥作用。要了解p0071如何发挥这样的作用，需要详细了解p0071的亚细胞分布和细胞内作为p0071结合伙伴的蛋白质。这一建议的中心假设是p0071作为钙粘附素结合蛋白发挥作用，并在肌动蛋白和中间丝相关的细胞间连接的组装和周转中发挥作用。本研究的目的是确定p0071的亚细胞分布，确定p0071的结合伙伴，并阐明该蛋白在角质形成细胞和真皮微血管内皮细胞中黏附连接的组装和周转中的作用。这项工作的长期目标是确定新的分子和细胞过程，这些分子和细胞过程可能是治疗药物的靶点，可以用于促进表皮伤口的愈合或治疗涉及内皮屏障功能障碍或血管生成的皮肤病理。

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.