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. Wnt addiction of genetically defined cancers reversed by PORCN inhibition. Oncogene. 2015
• Nathan Harmston, et al. 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
• 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
• Li X, Yost HJ, Virshup DM, Seeling JM. Protein phosphatase 2A and its B56 regulatory subunit inhibit Wnt signaling in Xenopus. EMBO J. 2001
• Xu P, Virshup DM, Lee SH. B56-PP2A regulates motor dynamics for mitotic chromosome alignment. Journal of Cell Science. 2014
• Cheong JK et al. Casein kinase 1α-dependent feedback loop controls autophagy in RAS-driven cancers. Journal of Clinical Investigation. 2015
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
• Eide EJ et al. Control of mammalian circadian rhythm by CKIepsilon-regulated proteasome-mediated PER2 degradation. Mol Cell Biol. 2005
• Gallego et al., An opposite role for tau in circadian rhythms revealed by mathematical modeling. Proc. Natl. Acad. Sci. USA. 2006
• Min Zhou et al., (2015). A Period2 Phosphoswitch Regulates and Temperature Compensates Circadian Period. Molecular Cell. 2015
• Jonathan M Philpott, et al., Casein Kinase 1 dynamics underlie the PER2 circadian phosphoswitch. eLife. 2020
• Rajesh Narasimamurthy and David M Virshup. The phosphorylation switch that regulates ticking of the circadian clock. Molecular Cell. 2021