An Interview With Nicholas Tolwinski "I was interested in the subject of cellular polarity, or how cells know direction" more

The Wingless signaling pathway plays crucial roles in development and disease. Misregulation causes growth abnormalities in organisms as diverse as worms and humans and is responsible for tumorigenesis in adults. Owing to the ubiquity and importance of this pathway, it has been the focus of much research over the past 20 years, and many of the genes and components are now understood in some detail. However, the manner in which these components are arranged in a pathway that connects activity at the cell surface with a transcriptional response in the nucleus remains controversial.

The basic model of Wingless signaling is shown below. In the absence of Wg ligand, a complex composed of Axin, APC, and the kinase GSK3 phosphorylate and target Armadillo (Beta-catenin) for degradation. Upon Wg binding, the complex is recruited to the membrane where Axin is degraded leading to the release of Arm from cytoplasmic repression. Arm then enters the nucleus, where it activates transcription.

[Enlarge Image]

This laboratory will focus on several aspects of Wg signaling in development. One interesting property of Armadillo is that it is both a transcriptional activator of the Wg pathway and a structural protein in adherens junctions. Is there a possible relationship between the roles of Armadillo in signaling and adhesion? This is one of the more interesting and long-standing questions in the Wnt field, namely what is the advantage of using a structural component of junctions as a transcriptional activator? Further, the coincidence of an oncogene having adhesive properties suggests a link between tumorigenesis and metastasis. By using genetic and cell biological methods, it should be possible to follow the regulation of junction assembly and disassembly in development.

Other projects will involve developing genetic strategies to study the interactions of the various known components, as well as the isolation of novel pathway components. Further, the role that Armadillo plays in the nucleus will be addressed in detail.