David M. Virshup
Professor of Pediatrics and of Oncological Sciences
B.A. Beloit College
M.D. Johns Hopkins University School of Medicine
david.virshup{at}hci.utah.edu
Research
My laboratory studies signal transduction in cancer. Our focus is two major regulators, protein kinases and protein phosphatases, and their role in colon cancer and sarcomas. Protein phosphorylation regulates virtually all intracellular processes, from signal transduction at the membrane to cell cycle progress to DNA replication in the nucleus.
Current projects include:
Regulation of Wnt signaling by protein phosphorylation. The WNT signaling pathway is critical for embryonic development, cell fate specification and is up-regulated in colorectal and other cancers. We study at a molecular level how the Wnt pathway is regulated, with a focus on how protein phosphorylation and dephosphorylation transmit signals from the cell membrane to the nucleus. Recent studies are expanding these molecular findings to animal models of cancer (see figures).
Regulators of sarcoma progression and metastasis. Our long term goals of this project are 1) to identify novel genes that regulate sarcoma progression and metastasis, 2) to test the roles and relevance of autocrine and paracrine signaling in sarcoma progression and metastasis, and 3) to validate the importance of these identified genes in a) animal models of sarcoma progression and metastasis and b) in clinical sarcomas.
Figure 1 (above): Luciferase imaging of mouse colon cancer. A. Luciferin imaging day 0 and day 10 after injection of 2*106 luc-neo tagged cells into subserosa of cecum of nude mouse. Established tumor shown in situ on day 10. outlined by light blue arrows. (Note the cecum is on the left side in mice) B. Luciferase imaging gives semi-quantitative measurement of tumor growth. In a separate experiment, mice with solitary lesions were serially imaged and photon output quantitated. This method will allow serial imaging of tumor response in a single mouse, adding significant statistical power to the studies.
Figrue 2 (below): Two-headed Xenopus
References
1. Swiatek W, Kang H, Garcia BA, Shabanowitz J, Coombs GS, Hunt DF, Virshup DM (2006) Negative Regulation of LRP6 Function by Casein Kinase I epsilon Phosphorylation. J Biol Chem. 2006 May 5;281(18):12233-41
2. Gallego M, Virshup DM (2005) Protein serine/threonine phosphatases: life, death, and sleeping. Curr Opin Cell Biol. 17:197-202
3. Eide EJ, Woolf MF, Kang H, Woolf P, Hurst W, Camacho F, Vielhaber EL, Giovanni A, Virshup DM (2005) Control of mammalian circadian rhythm by CKIepsilon-regulated proteasome-mediated PER2 degradation. Mol Cell Biol. 25:2795-807
4. Okamura H, Garcia-Rodriguez C, Martinson H, Qin J, Virshup DM, Rao A (2004) A conserved docking motif for CK1 binding controls the nuclear localization of NFAT1. Mol Cell Biol. 24:4184-95
5. Swiatek W, Tsai IC, Klimowski L, Pepler A, Barnette J, Yost HJ, Virshup DM (2004) Regulation of casein kinase I epsilon activity by Wnt signaling. J Biol Chem. 279:13011-7
6. Firulli BA, Howard MJ, McDaid JR, McIlreavey L, Dionne KM, Centonze VE, Cserjesi P, Virshup DM, Firulli AB (2003) PKA, PKC, and the protein phosphatase 2A influence HAND factor function: a mechanism for tissue-specific transcriptional regulation. Mol Cell. 12:1225-37
7. Li X, Scuderi A, Letsou A, Virshup DM (2002). B56-associated protein phosphatase 2A is required for survival and protects from apoptosis in Drosophila melanogaster. Mol Cell Biol. 22:3674-84
