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 research aims to understand the 3-dimensional architecture and dynamics of these junctions. We are trying to understand the mechanisms by which formation of the destruction complex enhances the phosphorylation of beta-catenin, and how beta-catenin serves as a scaffold to link the sequence-specific Tcfs to components of the general transcription machinery. We are attempting to biochemically reconstitute these complexes for mechanistic and structural studies.
As an Innovation Fund investigator, Weis’ lab is teaming with the lab of Georgios Skiniotis, Ph.D., to perform studies to obtain a 3-D structure of a major signaling complex in the Wnt pathway—a pathway implicated in cellular development and cancer. This complex is of particular interest because it is a major hub of Wnt activity—where various pathway components come together to form an organized scaffold. Understanding its assembly could lead to insights on how the pathway is regulated.