Professor,
Eppley Institute , Department
of Oral Biology, Courtesy Appointment - Department of Biochemistry &
Molecular BiologyB.S.- University of Minnesota, Microbiology
Ph.D.- University of Minnesota, Cell Biology
Research Summary
Our laboratory is interested in how cells interact with one another to form the three dimensional structure of a tissue. We are particularily interested in a family of proteins known as the cadherins. The cadherin family of proteins mediate the calcium-dependent interactions between cells that have been shown to be critical in cell sorting events that serve to form the various tissues during embryonic development. Cadherins are the transmembrane component of the adherens junction and interact homophilically in the extracellular space. The cytoplasmic domain of the cadherin interacts with a group of proteins called catenins that serve to link the cadherin to the cytoskeleton. Thus, the cadherin/catenin complex forms connections not only between two cells extracellularly but also coordinates cooperative cellular movements by linking together the cytoskeletal elements of two cells.
The projects in our laboratory are designed to study the structure and function of the cadherin/catenin complex. One project is to determine which domains of the catenins allow them to associate with cadherin and thus become part of an adherens junction. In addition, we are attempting to understand how the cadherin/catenin complex is associated with the cytoskeleton. Our approach is to engineer fragments of the catenins, transfect these into tissue culture cells and determine which protein-protein interactions are retained.
A second project is to unravel the signal transduction pathways involved in formation and activity of the cadherin/catenin adhesion complex. The catenins have been implicated in the wnt (or wingless) signaling pathway which also involves APC and the transcription factor, Lef-1. Wnt-1 and APC are both known tumor-associated proteins, thus, one hypothesis is that cadherin involvement in tumorigenesis may involve not only physical disruption of cellular interactions but also important signaling events.
A third project is designed to understand the role of cadherins in normal tissue morphogenesis using skin as a model system. Skin is a multi-layered tissue that is renewed on a daily basis. Renewal of the skin involves a precisely programed sequence of cell growth and differentiation events. Using cultures of primary human skin cells (keratinocytes) we have shown that cadherins regulate the differentiation pathway. Ongoing studies are designed to define the functions of and regulatory relationships among the various cadherins expressed in the skin.
A fourth project is to understand the role cadherins play in human breast cancer. Our hypothesis is that some breast cancer cells turn on the expression of an inappropriate cadherin. The expression of this molecule results in decreased cell-cell adhesion and increased cell motility and invasion. We have evidence that expression of N-cadherin by human breast cancer cells results in tumors that are highly aggressive.
Phone: 402-559-3892
FAX: 402-559-3888
E-mail:
Margaret Wheelock