Role of p0071 in Cutaneous Intercellular Junctions

细胞间粘连的建立和维持对正常皮肤功能至关重要，而细胞粘连的丧失是许多皮肤病的标志特征。尽管在确定粘附细胞间连接的分子成分方面取得了重大进展，但在皮肤病变期间细胞间连接组装和调节的详细机制仍然知之甚少。犰狳蛋白家族成员是黏附连接的细胞质成分，并将细胞黏附分子钙粘蛋白家族成员连接到细胞骨架上。此外，犰狳蛋白在调节基因表达和组织模式的信号通路中起着核心作用。最近的证据表明，犰狳蛋白的一个新的亚家族，称为p120/嗜plakophilin家族，在各种皮肤细胞中组装成细胞间连接。该提案的重点是p0071，它是犰狳蛋白p120/plakophilin亚家族的成员。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丝相关连接，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的亚细胞分布以及细胞内作为p0071结合伙伴的蛋白质。该提案的中心假设是p0071作为钙粘蛋白结合蛋白，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，并阐明该蛋白在角化细胞和真皮微血管内皮细胞中粘附性细胞间连接的组装和转换中的作用。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被治疗剂靶向，用于促进表皮伤口愈合或治疗涉及内皮屏障功能障碍或血管生成的皮肤病变。

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.