In keeping with the theme of receptor-ligand pleiotropy and cross-reactivity, we are attempting to make inroads into understanding the molecular basis of signaling in the Wnt/Frizzled and Notch systems, which are sometimes referred to as the Yin/Yang of developmental biology. These powerful receptor-ligand systems have so far eluded therapeutic control, and we aim to exploit structural information on Wnt and Notch complexes to engineer new therapeutic molecules as well as dissect basic developmental biology.
Wnts have diverse roles in governing cell fate, proliferation, migration, polarity, and death. In adults, Wnts function in homeostasis, cell fate determination and stem/progenitor self-renewal, and inappropriate activation of the Wnt pathway is implicated in a variety of cancers. Mammals encode 20 Wnts and 10 Frizzled receptors, yet the nature of Wnt/Fz specificity and its importance in function remains an elusive question. Furthermore, Wnts can signal through a variety of receptors to generate canonical (beta-catenin) or non-canonical downstream signals. While the intracellular signaling modules and their interactions have been well characterized, the nature of the extracellular structures and their interactions has remained almost a complete mystery. We have determined a structural basis for how Wnt engages a Frizzled receptor, and we continue to seek a higher level of understanding of this process in order to design Fz sub-type specific ligands. We hope that we can then utilize this information to carry out functional studies aimed at gleaning the role of specific Wnt/Fz pairs in different diseases, and to perhaps harness this system for therapeutic applications in regenerative medicine.
Similarly, Notch receptors see a diverse milieu of ligands (e.g. Jagged, Delta-like, etc) that control tissue growth and differentiation. Based on structural information for how Notch sees its ligands determined in this laboratory, we are now attempting to engineer Notch ligands to controllaby activate Notch signaling in a sub-type specific manner.