Download Molecular regulation of the Wnt/ -catenin signaling pathway

David M. Virshup, M.D.
Professor and Director of the Program in Cancer and Stem Cell Biology
Duke-NUS Graduate Medical School Singapore
[email protected]
duke-nus.edu.sg
http://www.duke-nus.edu.sg/web/research_faculty_david.htm
Research Synopsis
The Virshup laboratory is interested in specific post-translational modifications that
control key regulatory pathways. Wnt signaling is a series of highly conserved
pathways important in stem cell maintenance, cell proliferation, development and
cancer. The Virshup laboratory studies Wnt signaling with a emphasis on the
posttranslational modifications of proteins that regulate these pathways and and
that control the fate of cells.
Project 1. Molecular regulation of the Wnt/-catenin signaling pathway
The Wnt/-catenin signaling pathway is critical in both cellular proliferation and
organismal development. My laboratory is interested in the kinases and phosphatases that
lie downstream of Wnt receptor activation. We have identified regulation of Casein
Kinase I, and several serine-threonine phosphatases as key events regulated by, and
regulating Wnt signaling. Diverse molecular, cellular and developmental approaches are
used to analyze these enzymes.
Project 2. Regulation of Wnt production
The connection between Wnt/β-catenin or “canonical” Wnt signaling and cancer is well
appreciated. Some cancers, such as colon cancer, have mutations in components of the
signaling pathway (i.e. adenomatous polyposis coli protein, “APC”, axin, and β-catenin).
In breast cancer and leukemias, cancer stem cell maintenance has been shown to depend
on Wnt signaling. Both β-catenin dependent and independent signaling pathways are
implicated in stem cell maintenance. In the more overtly Wnt dependent cancers, it is
clear that intervention at multiple points in the Wnt signaling pathway(s) is required for
effective treatment of a broad range of cancers. We are studying diverse aspects of Wnt
production and, using a cell based screen for inhibitors of Wnt signaling have identified
lead compound inhibitors throughout the entire pathway, with an emphasis on inhibitors
of secretion from Wnt expressing cells. These lead compounds have low toxicity and
significant efficacy on Wnt-stimulated signaling. A deeper understanding of Wnt
production, including further development of small molecules, may lead to useful cancer
chemotherapeutics.
Project 3. Circadian Rhythms
My lab has a longstanding interest in how our daily body clock, known as circadian
rhythms, are regulated in cells. We have previously dissected how the protein kinase
CKI controls rhythms by regulating the stability of the key circadian protein PER2. Now
I would like to study the physiologic and pathologic events that regulate phosphorylation
of PER2 and hence timing of the clock. Specific projects include, but are not limited to,
identification of the specific phosphatase holoenzyme that controls PER2 stability, and
analyzing the potential circadian regulation of the phosphatase in mammalian cells. These
phosphatases can themselves be key circadian regulators. Additional projects related to
circadian rhythms and cancer are possible as well. Methods used include measuring
circadian rhythms in cultured cells and mice.