Receptor seminar: Illuminating Notch and Wnt signaling mechanisms through protein engineering
Vincent C. Luca, PhD, Moffitt Cancer Center & University of South Florida
Illuminating Notch and Wnt signaling mechanisms through protein engineering
Host: Cecilia Sahlgren (firstname.lastname@example.org)
Coffee and sandwiches at 11:45
Human development is orchestrated by cell surface receptors that sense and respond to dynamic molecular signals. Among the ~20,000 protein-coding genes in the human genome, it has been determined that a remarkably small number of conserved signaling systems (Notch, Wnt, Shh, Jak/Stat, RTK, TGF-β, NF-κB) control the vast majority of cell fate decisions. In accord with their central importance in human biology, dysregulation of these “professional” developmental pathways contributes to the pathogenesis of congenital diseases and cancer.
My group integrates approaches in structural biology, cellular biology, and protein engineering to study developmental receptor signaling. We are particularly interested in understanding how mechanosensitive Notch receptors are activated by their ligands Jagged (Jag) and Delta-like (DLL). To approach this problem, we determined high-resolution structures of Notch receptor-ligand complexes, which provided insight into the roles of molecular tension and receptor glycosylation as regulatory mechanisms. We are now using various engineering strategies to develop targeted Notch agonists and antagonists as cancer drugs. In addition to our work on Notch, we are employing synthetic biology-based approaches to modulate Wnt signaling for applications in regenerative medicine. The collective goal of our research is to reprogram developmental signaling to pave the way for the development of next-generation therapies
Luca VC et al., Surrogate R-spondins for tissue-specific potentiation of Wnt Signaling. PlosOne 2020
Ming Q et al., Molecular engineering strategies for visualizing low-affinity protein complexes. Exp Biol Med (Maywood) 2019
Schneider et al., Inhibition of Delta-induced Notch signaling using fucose analogs. Nat Chem Biol 2018.
Highlighted: Notch signaling a sweet strategy. Nat Chem Biol 2018
Luca VC et al., 2017 Notch-Jagged complex structure implicates a catch bond in tuning ligand sensitivity. Science 2017
Highlighted: Signal Transduction: Notch Catches a Jagged edge. Nat Chem Biol 2017
Yan et al., Non-equivalence of Wnt and R-spondin ligands during Lgr5+ intestinal stem-cell self-renewal. Nature 2017
Highlighted: R-spondin is more than just Wnt’s Sidekick . Dev Cell 2017
Luca VC et al., Structural basis for Notch1 engagement of Delta-like 4. Science 2015