Molecular interactions, assembly, and signaling of vascular endothelial intercellular junctions.
The organization of cells within tissues and organs such as the skin requires cell-cell interactions that are highly specific and tightly regulated. These adhesive interactions also need to be integrated with cellular processes that control cell growth, differentiation and migration. The fundamental question that our laboratory seeks to understand is how cell-cell adhesion molecules are integrated with the cytoskeleton, and how this adhesion and signaling system is regulated in a manner that promotes tissue organization. We are focused on members of the cadherin family of cell-cell adhesion molecules, and on the proteins that interact with the cytoplasmic domains of cadherins. Cadherins are a family of cell-cell adhesion molecules that play important roles in development, wound healing, and in a variety of autoimmune and genetic skin diseases. We are particularly interested in how cadherins interact with a class of cytoplasmic proteins termed armadillo proteins. One project in the lab is to understand the specific functions of an armadillo family protein termed plakophilin-4 (p0071). We are studying how plakophilin-4 binds to cadherins, and how plakophilin-4 regulates cadherin-mediated adhesion. These studies utilize morphological approaches to determine the subcellular distribution of plakophilin-4 in fixed and living cells, and biochemical and genetic approaches to determine how plakophilin-4 interacts with other proteins involved in cell adhesion. A second project in the lab is designed to understand how dermal microvascular endothelial cells regulate cell surface levels of cadherins. We have found that under certain circumstances, endothelial cells rapidly internalize and degrade VE-cadherin through classical endocytic pathways involving lysosomal degradation. We are currently dissecting the pathway that VE-cadherin takes after internalization in order to understand the cellular machinery that regulates VE-cadherin cell surface levels. These studies are important because the down regulation of cadherins is associated with tumorigenesis, epithelial to mesenchymal transitions, and with the loss of endothelial barrier function during inflammatory conditions. Our long-term goal is to determine how membrane trafficking systems are integrated with cadherin based adhesive structures in endothelial cells, and how the interface between these two cellular systems is modulated during inflammation and angiogenesis.
