The main focus of the laboratory is to reveal mechanisms of adhesion between keratinocytes and vascular endothelial cells in the context of skin biology and disease. Our focus is on the function and regulation of the cadherin family of adhesion molecules. These molecules mediate cellular interactions and play key roles in the patterning of tissues during development and in the maintenance of tissue architecture in adults.
The Role of Cadherin Endocytosis in Cell Adhesion and Migration
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. Work from our group and others has shown that p120-catenin regulates cadherin turnover by inhibiting cadherin endocytosis (Fig. 1). Further, we found that p120-catenin occupies a unique endocytic motif (DEE) on the cadherin tail, and that dissociation of p120 exposes the endocytic signal to allow for cadherin endocytosis.
The identification of cadherin endocytosis motifs has allowed us to mutate those signals within the cadherin tail, and thereby test how cadherin endocytosis contributes to endothelial and epithelial cell function. Our work has shown that cadherins that are unable to undergo normal endocytosis suppress cell migration, suggesting that cadherin endocytosis plays a key role in cell motility during development and tumor cell metastasis. In fact, we have found that ubiquitination of the cadherin tail contributes to the loss of adhesion in models of Kaposi Sarcoma, an endothelial tumor. Ongoing studies in the lab are employing mouse genetic models and other approaches to determine how cadherin endocytosis contributes to adhesive plasticity and cell dynamics at a tissue level, and how these processes go awry in diseases associated with aberrant vascular leak and angiogenesis (Fig. 2).
Desmosomes: Cell Adhesion Structures Essential for Skin and Heart Function
Desmosomes are cell-cell adhesive contacts which are coupled to the keratin intermediate filament cytoskeleton (Fig. 3). The primary adhesion molecules in desmosomes are the desmosomal cadherins, desmogleins (Dsgs) and desmocollins (Dscs), which are linked to the intermediate filament cytoskeleton by desmosomal plaque proteins such as plakoglobin and desmoplakin. Desmosomes establish strong cell-cell adhesive interactions that serve to mechanically integrate adjacent epithelial cells. The functional importance of desmosomes is manifest in heart and skin diseases associated with desmosomal disorders. We are particularly interested in autoimmune and genetic diseases of desmosomes that cause skin fragility and alterations in epidermal differentiation. These human diseases highlight the importance of desmosomes in normal tissue function, and underscore the need to better understand how desmosomal proteins contribute to epithelial cell adhesion and signaling.
The basic biology of desmosome assembly is not well understood. Several morphological features of desmosomes provide guidelines for models of how the assembly of these structures might occur. Desmosomes are 0.5 micron rivet-like structures with remarkably compact protein packing, leading to their characteristic electron dense appearance when viewed by EM (Fig. 3). Thus, desmosomes represent a membrane microdomain characterized by both extensive clustering of components and by a size limitation that is regulated by unknown mechanisms. There are currently no comprehensive models that explain how desmosome assembly occurs, how plaque and desmosomal cadherin complexes become clustered, or how desmosomes are segregated into membrane domains of a relatively uniform size. We are currently focused on the recruitment of desmosomal proteins into lipid rafts as a fundamental mechanism governing desmosome formation and turnover. We use a variety of advanced imaging and biochemical approaches to understand how desmosomal proteins assemble into lipid raft membrane microdomains, and how this association regulates desmosome function in the context of mouse models and human diseases.