Research

Cell Adhesion and Wnt signaling
Pamela Cowin, Ph.D.
Departments of Dermatology; Cell Biology

Beta-catenin and plakoglobin are closely related, bifunctional proteins that promote cell-cell adhesion at the plasma membrane and act as transcription factors in the nucleus. These two proteins have been shown, by an exciting convergence of the disciplines of cell and developmental biology, to play key roles in cancer. Plakoglobin and beta-catenin connect cadherins to the cytoskeleton, causing them to form the adhesive zippers of desmosomes and adherens junctions. An earlier focus of our lab was to clone the major desmosomal components and define the protein-protein interactions within these structures that are responsible for stable epithelial organization.

Currently, we are exploring the distinct roles of cytoplasmic plakoglobin and beta-catenin in Wnt signal transduction. Many cells communicate their positional co-ordinates by secreting Wnt proteins, which bind to receptors on the surface of neighboring cells. Binding of Wnt triggers a cascade of events that lead to the stabilization of cytoplasmic plakoglobin and beta-catenin. When elevated and activated in this manner, plakoglobin and beta-catenin enter the nucleus, form bipartite transcription factors with Lef/Tcf proteins and modulate the expression of an array of target genes encoding morphoregulatory proteins and cell-cycle regulators.

We study this signal transduction process in mammary gland and skin, elements of which undergo cyclical rounds of proliferation, differentiation and apoptosis, thus permitting experimentally induced changes in these important processes to be easily observed in vivo. We have shown that transgenic upregulation of beta-catenin induces extensive tumor formation in mammary gland. Overexpression of plakoglobin, in contrast suppresses proliferation in epidermis and hair. Thus despite their similarity in structure and adhesion-promoting function, plakoglobin and beta-catenin exert opposite effects on proliferation. Our studies are now focussed on defining the molecular basis for the contrasting roles of plakoglobin and beta-catenin in Wnt signaling.

Methods to establish primary cell cultures from these organs and to regraft modified cells back again are available. Thus we can harness cell and molecular approaches to study this question both in vitro and in vivo. Additionally, as many mouse mutants with defects in mammary gland and skin exist we can use genetics to decipher this signal transduction pathway.