Professor David Virshup
Brief career history
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.
Regulation of Wnt signaling, with an emphasis on adult stem cell function 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 focused recently on Wnt biogenesis, understanding where in the stem cell niche Wnts come from in normal and disease states, and how we can therapeutically target all Wnts by drugging a key step in early Wnt biogenesis. This has led to development of a drug, ETC159, now in phase 1 clinical trials.
- Seeling JM et al. Regulation of β-catenin signaling by the B56 subunit of protein phosphatase 2A. Science. 1999 Mar 26;283(5410):2089-91.
- Yu J et al. WLS retrograde transport to the endoplasmic reticulum during Wnt secretion. Dev Cell. 2014 May 12;29(3):277-91. doi: 10.1016/j.devcel.2014.03.016. Epub 2014 Apr 24.
- Kabiri Z et al. Stroma provides an intestinal stem cell niche in the absence of epithelial Wnts. Development. 2014 Jun;141(11):2206-15.
- Kabiri Z et al., (2015). Wnts are dispensable for differentiation and self-renewal of adult murine hematopoietic stem cells. Blood. 2015 Aug 27;126(9):1086-94. doi: 10.1182/blood-2014-09-598540.
- Madan, B. et al., (2015) Wnt addiction of genetically defined cancers reversed by PORCN inhibition. Oncogene. 2016 Apr 28;35(17):2197-207. doi: 10.1038/onc.2015.280. Epub 2015 Aug 10.
- Madan, B. et al., (2016) USP6 Oncogene Promotes Wnt Signaling by Deubiquitylating Frizzleds. Proc. Natl. Acad. Sci. USA, 2016 May 24;113(21):E2945-54. doi: 10.1073/pnas.1605691113. Epub 2016 May 9.
Protein Phosphorylation regulated by PP2A and Casein Kinase 1
As a postdoctoral fellow, I discovered that a cellular 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, and identified novel targeting subunits, the B56 family, of protein phosphatase 2A. Over the following years we have studied the important of these subunits in determining PP2A substrate specificity and intracellular localization. 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.
- McCright B, Rivers AM, Audlin S, Virshup DM. The B56 family of protein phosphatase 2A (PP2A) regulatory subunits encodes differentiation-induced phosphoproteins that target PP2A to both nucleus and cytoplasm. J Biol Chem. 1996 Sep 6;271(36):22081-9.
- Li X, Yost HJ, Virshup DM, Seeling JM. Protein phosphatase 2A and its B56 regulatory subunit inhibit Wnt signaling in Xenopus. EMBO J. 2001 Aug 1;20(15):4122-31.
- Xu P, Virshup DM, Lee SH. B56-PP2A regulates motor dynamics for mitotic chromosome alignment. Journal of Cell Science. 2014 Nov 1;127(Pt 21):4567-73. doi: 10.1242/jcs.154609. Epub 2014 Sep 1.
- Cheong JK et al. Casein kinase 1α-dependent feedback loop controls autophagy in RAS-driven cancers. Journal of Clinical Investigation. 2015 Apr;125(4):1401-18. doi: 10.1172/JCI78018. Epub 2015 Mar 23.
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.
- Toh KL. An hPer2 Phosphorylation Site Mutation in Familial Advanced Sleep Phase Syndrome. Science. 2001 Feb 9;291(5506):1040-3.
- Eide EJ et al. Control of mammalian circadian rhythm by CKIepsilon-regulated proteasome-mediated PER2 degradation. Mol Cell Biol. 2005 Apr;25(7):2795-807.
- Gallego M, Eide EJ, Woolf MF, Virshup DM, Forger DB. An opposite role for tau in circadian rhythms revealed by mathematical modeling. Proc. Natl. Acad. Sci. USA. 2006 Jul 11;103(28):10618-23. Epub 2006 Jul 3.
- Min Zhou, Jae Kyoung Kim, Gracie Wee Ling Eng, Daniel B. Forger, David M. Virshup. (2015). A Period2 Phosphoswitch Regulates and Temperature Compensates Circadian Period. Molecular Cell. 2015 Oct 1;60(1):77-88. doi: 10.1016/j.molcel.2015.08.022.