Andrew P. Kowalczyk, PhD
Department of Cell Biology
Department of Dermatology
Winship Cancer Institute
Office: 405M Whitehead Research Building
Emory University: Department of Cell Biology
615 Michael Street
Atlanta , GA 30322
- PhD in Physiology and Cell Biology, Albany Medical College, Albany, NY
- Postdoctoral Fellowship, Department of Pathology/Feinberg School of Medicine: Northwestern University
VE-cadherin is an endothelial adhesion molecule that plays key roles in the formation of blood vessels during both development and tumor angiogenesis. Similar to other classical cadherins, VE-cadherin mediates homophilic adhesion and associates with the actin cytoskeleton through interactions with armadillo family proteins, such as p120-catenin and beta-catenin. The catenins bind to the VE-cadherin tail and perform a multitude of cellular functions, including the regulation of adhesion and gene expression. We found that p120-catenin plays an unexpected role in regulating cadherin endocytosis. Current studies in the lab are designed to reveal the sequence determinants in the VE-cadherin tail that associate with clathrin adaptor proteins, and to define precisely how p120-catenin prevents these interactions to stabilize cadherins at the cell surface. In addition, we are using mouse genetic models to understand how VE-cadherin interactions with p120 regulate vascular development and tumor angiogenesis.
In parallel to our studies of cadherins in the vascular system, we are also investigating the role of cadherins in the autoimmune disease pemphigus vulgaris. Pemphigus vulgaris is a life-threatening autoimmune disease in which patients generate autoantibodies directed against a subset of desmosomal cadherins that are expressed in the outer layers of the skin. Desmosomes are cell-cell adhesive structures that mediate strong cell-cell adhesion. Various human diseases, both inherited and acquired, reveal critical roles for desmosomes in the normal function of both the heart and skin. Studies from our lab indicate that pemphigus antibodies cause endocytosis of desmogleins through a clathrin independent pathway. Using several approaches, we have found that we can prevent the loss of adhesion caused by pemphigus antibodies by either blocking Dsg3 endocytosis or by replenishing Dsg3 cell surface levels using adenoviral expression systems. These and other studies suggest that pemphigus is a disease of desmosome instability, and they highlight the need to understand how desmosomal cadherins are internalized and trafficked during desmosome disassembly.
The long term goal of our studies is to understand how the interface between membrane trafficking systems and cadherins is altered during disease states that are characterized by changes in adhesion. These pathologies include tumorigenesis, aberrant angiogenesis, and skin diseases such as pemphigus.
- View publications on Pubmed