Current Research and Scholarly Interests
Our laboratory studies molecular interactions that underlie the establishment and maintenance of cell and tissue structure. Our principal areas of interest are the architecture and dynamics of intercellular adhesion junctions, signaling pathways that govern cell fate determination, and determinants of cell polarity. We also have a long-standing interest in carbohydrate-based cellular recognition and adhesion. We take a strongly reductionist approach to these problems by reconstituting macromolecular assemblies with purified components in order to analyze them using biochemical, biophysical and structural methods. Mechanistic models derived from these studies are tested in cell culture systems.
Several distinct intercellular junctions connect epithelial cells. Two of these, the adherens junction and the desmosome, contain cadherin cell adhesion molecules. The extracellular regions of these transmembrane proteins mediate intercellular binding, while their cytoplasmic domains are linked to the actin- (adherens junction) or intermediate filament- (desmosome) based cytoskeletons. In this way the cytoskeletons of cells comprising a tissue are linked, imparting particular morphologies and mechanical strength to the tissue. The dynamics of these complex assemblies underlie changes in cell and tissue architecture that occur during development and in many cancers. Our goal is to understand the architecture and dynamics of these junctions at a molecular level. A major current focus is in understanding how mechanical force regulates these assemblies by altering molecular conformation, how different junctional components alter force responsiveness, and different intercellular junctions communicate. We are also studying the interplay between cell adhesion and the development and maintenance of apical-basal polarity. Finally, we are examining how cell-cell junctional proteins have changed during metazoan evolution as part of the development of more complex tissue architectures.
The Wnt signaling pathway controls cell fate determination during embryogenesis and in the normal renewal of tissues in the adult. Moreover, dysregulation of the pathway drives progression of many cancers. In the Wnt/beta-catenin pathway, Wnt protein binding to cell surface receptors leads to activation of target genes by beta-catenin. In the absence of a Wnt signal, non-junctional beta-catenin is bound in a multiprotein “destruction complex”, where it is phosphorylated and targeted for degradation by the ubiquitin/proteosome pathway. Binding of a Wnt to cell surface receptors prevents beta-catenin destruction. We are biochemically reconstituting these complexes for mechanistic and structural studies. Our goals are to determine the mechanism of beta-catenin destruction in the absence of a Wnt signal, and how Wnt binding to receptors turns off beta-catenin destruction.