The Wnt pathway is an evolutionarily conserved signaling pathway present in all metazoans. During development, Wnt signaling coordinate the formation of tissues, organs, and limbs, and its misregulation leads to a variety of human disease states such as Alzheimer's and cancer. The Ethan Lee laboratory is interested in understanding the basic mechanism by which a Wnt signal is propagated and how this information is used to pattern the organism. They are also interested in how this information could be used in regenerative medicine and in the treatment of cancer. 

A major experimental approach in the Lee laboratory involves the use of Xenopus extracts and purified proteins to biochemically reconstitute Wnt signaling in vitro. Genome-scale screens, cultured mammalian cells, Xenopus embryos, Drosophila genetics (in collaboration with Dr. Laura Lee), and mouse studies are employed to compliment and extend our biochemical findings.

One of the major mysteries of this pathway is how a Wnt signal is propagated from the cell surface. Dr. Lee's laboratory has recently developed an in vitro system to study the mechanism of Wnt signal transduction from the plasma membrane. Towards this end, they have focused on understanding the mechanism of signaling from the co-receptor, LRP6, and the role of the membrane associated heterotrimeric G protein family members in Wnt signal transduction. Recently, lab members have taken a genome-scale screen to identify deubiquitinating enzyme (DUBs) and ubiquitin ligases (E3s) that regulate the Wnt pathway. They found that one of the E3 that they identified in this screen is required for Wnt signaling, and are currently characterizing its exact role in Wnt signaling and during Xenopus development.

Modern regenerative medicine is a field in which stem cells are manipulated to treat a variety of human diseases. Wnt signaling is one of a handful of molecular pathways critical to stem cells. Thus, agents that target Wnt signaling would be potentially useful for the treatment of cardiovascular disease, diabetes, neurodegeneration, and other disorders. Cancer stem cells (CSC) are fundamental to the initiation and maintenance of tumors. Failure to eradicate CSC (as is typical with conventional therapy) leaves behind a small reservoir of cells that drives relapse. Wnt inhibitors would be expected to specifically target this resistant CSC population. Using their Xenopus biochemical system, the Ethan Lee lab has recently identified a small molecule that potently inhibits the Wnt pathway. Current efforts are directed towards characterizing the molecular target of this small molecule.

NEWEST PUBLICATIONS

Regulation of dynein localization and centrosome positioning by Lis-1 and asunder during Drosophila spermatogenesis. 2012 Development 139: 2945-2954

XIAP monoubiquitylates Groucho/TLE to promote canonical Wnt signaling. 2012 Molecular Cell 45: 619-628

Screening for small molecule inhibitors of embryonic pathways: Sometimes you gotta crack a few eggs. 2012 Bioorganic & Medicinal Chemistry 20: 1869-1877

A biochemical screen for identification of small-molecule regulators of the Wnt pathway using Xenopus egg extracts. 2011 Journal of Biomolecular Screening 16: 995-1006