David Virshup, M.D., is Director of the Programme in Cancer and Stem Cell Biology (CSCB) and Professor at Duke-NUS Medical School and is jointly appointed as Professor of Pediatrics at Duke University in North Carolina.
Dr. Virshup received his B.A. magna cum laude from Beloit College, majoring in chemistry. He received his M.D. from Johns Hopkins University in Baltimore, followed by clinical residency in Pediatrics and a fellowship in Pediatric Hematology/Oncology. He credits his research training and mentoring to William Zinkham, Vann Bennett, and Tom Kelly in the departments of Pediatrics, Cell Biology and Anatomy, and Molecular Biology and Genetics, all at Hopkins. Dr. Virshup established his first independent laboratory at the University of Utah in Salt Lake City, where over the course of 17 years he rose to Professor of Pediatrics and Oncological Sciences with an endowed chair as an investigator at the Huntsman Cancer Institute. He moved to Duke-NUS in Singapore in 2007 to help establish CSCB.
He has been elected to several honorific societies including the American Society for Clinical Investigation (ASCI), the American Association for the Advancement of Science (AAAS) and the Association of American Physicians (AAP). He is board certified in both Pediatrics and Pediatric Hematology/Oncology in the USA.
His research has focused on signal transduction, with an emphasis on both Wnt signaling and circadian rhythms. Early work examined the roles of Protein Phosphatase 2A and Casein Kinase 1 play in these processes. In Singapore, studies of phosphorylation of the PERIOD protein lead to the elucidation of the phosphoswitch model controlling circadian clock speed. In addition, his laboratory collaborated to develop a small molecule inhibitor of Wnt secretion, ETC-159, a drug now in human clinical trials.
A full list of publications from the Virshup lab can be viewed on Google Scholar and ORCID
Regulation of Wnt signaling, with an emphasis on Wnt delivery and therapeutic targeting
Our laboratory discovered in the late 1990s that specific targeting subunits of Protein Phosphatase 2A (PP2A) regulated β-catenin degradation in the Wnt pathway, a finding that led to fruitful studies of how phosphorylation regulates Wnt/β-catenin signaling downstream of the membrane. Because multiple Wnts and Wnt-regulated pathways are aberrantly regulated in cancer, my lab has recently focused on Wnt biogenesis, delivery and targets.
Major projects in Wnt signaling include:
- Understanding where in the stem cell niche Wnts come from in both normal and disease states.
- Therapeutic targeting of Wnt secretion by drugging the enzyme PORCN, a key step in early Wnt biogenesis. This has led to development of a drug, ETC159, now in clinical trials.
- Exploiting PORCN inhibitors to understand Wnt target genes in cancer and stem cells.
Selected References
- Kabiri Z et al. Stroma provides an intestinal stem cell niche in the absence of epithelial Wnts. Development. (2014)
- Madan, B. et al., (2015) Wnt addiction of genetically defined cancers reversed by PORCN inhibition. Oncogene. (2016)
- Nathan Harmston, et al., (2020) “Widespread repression of gene expression in cancer by a Wnt/β-catenin/MAPK pathway.” Cancer Research (2020).
- Kaur, A, et al., WNT inhibition creates a BRCA-like state in Wnt-addicted cancer. EMBO Molecular Medicine (2021)
- Nygaard, R., et al., Structural basis of WLS/Evi-mediated Wnt transport and secretion Cell (2021).
Protein Phosphorylation regulated by PP2A and Casein Kinase 1
As a postdoctoral fellow, I discovered that protein phosphatase, PP2A could activate eukaryotic DNA replication in a model system by site-specific dephosphorylation. Early in my independent research career at the University of Utah, my laboratory identified casein kinase 1 as the counter-regulator of PP2A. We continue to study the role of PP2A and Casein Kinase 1 family members in cancer-related cellular processes, most notably in circadian rhythms and Wnt signaling.
Selected References
Regulation of Circadian Rhythms by Protein Phosphorylation
Casein Kinase 1 was shown to regulate circadian rhythms in Drosophila. We extended these findings to humans and mice, showing that casein kinase 1 regulates the PERIOD proteins by controlling their ubiquitin-mediated degradation as well as nucleocytoplasmic shuttling. A collaboration with Daniel Forger, a mathematician who build realistic models of the molecular clock, has been instrumental in providing counter-intuitive insights. Our current work on phosphorylation in circadian rhythms focuses on a phosphoswitch mechanism that regulates the stability of the PER2 protein, a central regulator of clock timing.
Selected References