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Regulatory Pathways

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david.virshup@duke-nus.edu.sg

David Virshup

 

David Virshup, MD, is the inaugural Director of the Program in Cancer and Stem Cell Biology at the newly established Duke-NUS Graduate Medical School in Singapore. Until July, 2007, he was an investigator at the Huntsman Cancer Institute, and the first Willard Snow Hansen Presidential Professor of Cancer Research at the University of Utah. While spending the majority of his time on laboratory-based research, he is also a practicing pediatric hematologist/oncologist. His laboratory studies protein phosphorylation, a key signaling mechanism, and its effects on circadian rhythms and cell proliferation. Virshup received his medical degree from Johns Hopkins University School of Medicine in 1981. He completed his clinical training in Pediatrics and Pediatric Hematology/Oncology at Johns Hopkins. His research training was in the departments of Pediatrics, Cell Biology and Anatomy, and Molecular Biology and Genetics at Johns Hopkins.
 
Wnt signaling is a highly conserved pathway important in stem cell maintenance, cell proliferation, cancer and development. The Virshup laboratory studies the Wnt signaling pathways with a emphasis on the protein kinases and phosphatases that are regulated by Wnt, and that control the fate of cells.

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/b-catenin signaling pathway
The Wnt/b-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 CKIe 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.

Full details of David's current lab members can be found on his Duke-NUS website.

Stewart J, James J, McCluggage GW, McQuaid S, Arthur K, Boyle D, Mullan P, McArt D, Yan B, Irwin G, Harkin DP, Zhengdeng L, Ong CW, Yu J, Virshup DM, Salto-Tellez M. Analysis of wntless (WLS) expression in gastric, ovarian, and breast cancers reveals a strong association with HER2 overexpression. Mod Pathol. 2015 Mar;28(3):428-36. doi: 10.1038/modpathol.2014.114. Epub 2014 Sep 26. PubMed PMID: 25258105. Link
Xu P, Virshup DM, Lee SH. B56-PP2A regulates motor dynamics for mitotic chromosome alignment. J Cell Sci. 2014 Nov 1;127(21):4567-73. doi: 10.1242/jcs.154609. Epub 2014 Sep 1. PubMed PMID: 25179604. Link
Low IC, Loh T, Huang Y, Virshup DM, Pervaiz S. Ser70 phosphorylation of Bcl-2 by selective tyrosine nitration of PP2A-B56δ stabilizes its antiapoptotic activity. Blood. 2014 Oct 2;124(14):2223-34. doi: 10.1182/blood-2014-03-563296. Epub 2014 Jul 31. PubMed PMID: 25082878. Link
Asad M, Wong MK, Tan TZ, Choolani M, Low J, Mori S, Virshup D, Thiery JP, Huang RY. FZD7 drives in vitro aggressiveness in Stem-A subtype of ovarian cancer via regulation of non-canonical Wnt/PCP pathway. Cell Death Dis. 2014 Jul 17;5:e1346. doi: 10.1038/cddis.2014.302. PubMed PMID: 25032869; PubMed Central PMCID: PMC4123093. Link
Zhu Y, Demidov ON, Goh AM, Virshup DM, Lane DP, Bulavin DV. Phosphatase WIP1 regulates adult neurogenesis and WNT signaling during aging. J Clin Invest. 2014 Jul;124(7):3263-73. doi: 10.1172/JCI73015. Epub 2014 Jun 9. PubMed PMID: 24911145; PubMed Central PMCID: PMC4071391. Link
MacDonald BT, Hien A, Zhang X, Iranloye O, Virshup DM, Waterman ML, He X. Disulfide bond requirements for active Wnt ligands. J Biol Chem. 2014 Jun 27;289(26):18122-36. doi: 10.1074/jbc.M114.575027. Epub 2014 May 19. PubMed PMID: 24841207; PubMed Central PMCID: PMC4140276. Link
Kabiri Z, Greicius G, Madan B, Biechele S, Zhong Z, Zaribafzadeh H, Edison, Aliyev J, Wu Y, Bunte R, Williams BO, Rossant J, Virshup DM. Stroma provides an intestinal stem cell niche in the absence of epithelial Wnts. Development. 2014 Jun;141(11):2206-15. PubMed PMID: 24821987. Link
Yu J, Chia J, Canning CA, Jones CM, Bard FA, Virshup DM. 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. PubMed PMID: 24768165. Link
Yim DG, Ghosh S, Guy GR, Virshup DM. Casein kinase 1 regulates Sprouty2 in FGF-ERK signaling. Oncogene. 2015 Jan 22;34(4):474-84. doi: 10.1038/onc.2013.564. Epub 2014 Jan 27. PubMed PMID: 24469046. Link
David M. Virshup and Shirish Shenolikar. (2009). From Promiscuity to Precision: Protein Phosphatases get a Makeover. Molecular Cell. 33: 537-545 (IF: 13.2)
Gary S. Coombs, Tracy M. Covey, and David M. Virshup. (2008) Wnt Signaling in Development and Disease: Past, Present and Future. Current Drug Targets. 9: 513-531 (IF: 4.0)
Gallego M, Virshup DM. (2007) Post-translational modifications regulate the ticking of the circadian clock. Nature Reviews Mol Cell Biol. 8:139-48. (IF: 31.9)
W Luo, A Peterson, B A Garcia, G Coombs, B Kofahl, R Heinrich, J Shabanowitz, D F. Hunt, H. J Yost, and DM Virshup. (2007) Protein phosphatase 1 regulates assembly and function of the ?- catenin degradation complex. EMBO Journal. 26, 1511-1521. (IF: 8.7)
I-C Tsai, J Amack, Z-H Gao, Vi Band, H. J Yost, DM Virshup. (2007). A Wnt-CKI?-Rap1 Pathway Regulates Gastrulation by Modulating SIPA1L1, a Rap GTPase Activating Protein. Developmental Cell, 12, 335-347. (IF: 12.4)
Forester CM, Maddox J, Louis JV, Goris J, Virshup DM. (2007) Control of mitotic exit by PP2A regulation of Cdc25C and Cdk1. Proc Natl Acad Sci U S A. 104:19867-72. (IF: 9.6)