In multicellular organisms, cells need to communicate with one another to ensure proper tissue and organ development, and to prevent diseases such as cancer. My lab studies an essential but poorly understood aspect of this process: how signals are transmitted from the outside of the cell across the membrane to the cell interior. We are tackling this problem from an interdisciplinary perspective, drawing on protein and lipid biochemistry, cell biology, physiology, embryology, and a range of related approaches.
A better understanding of cell-cell communication will allow us to understand at a molecular level how tissues and organs develop. It will also help us to design better therapies for birth defects, cancers, and other diseases.
Current research in my lab focuses on:
- Signal transduction in the Hedgehog cascade, which controls the development of nearly all of our tissues and organs and is mutated in several widespread cancers. Surprisingly, we know nearly nothing about how some of the most critical steps in this pathway operate. We are approaching this question by merging in vitro biochemistry, biophysics, and structural biology with in vivo cellular and organismal functional readouts. Our studies have provided foundational insights into how Hedgehog signals are received and transmitted across the membrane. In turn, these insights are helping us develop innovative strategies to control this pathway in cancer and degenerative disorders.
- Signaling pathways in the primary cilium. The primary cilium is a tiny antenna-shaped membrane protrusion that is critical to Hedgehog and a range of other signaling pathways controlling the nervous, cardiovascular, and musculoskeletal systems. We are using novel live cell fluorescent activity reporters to dissect the signaling events that unfold within this tiny organelle.
- How lipids and kinases influence signal transduction. Our work on Hedgehog has led to new principles regarding how lipids can bind to and activate membrane receptors, and how membrane receptors can signal to kinases. We are now using these principles to unravel the signaling mechanisms in a variety of other signaling pathways, including G protein-coupled receptor cascades critical throughout human health and physiology.
Left: A 2.8 Å crystal structure of SMOOTHENED (green), the main signal transducer in the Hedgehog pathway, bound to cholesterol ligands (yellow) and trapped in an active state by a conformation-specific nanobody (NbSmo8, orange)(Desphande et al, Nature 2019). Right: Hedgehog signaling in the primary cilium. SMOOTHENED (magenta) controls protein kinase A (PKA, green) via an unprecedented mechanism - it directly binds and inactivates PKA by physically blocking the enzyme’s active site (Arveseth et al, PLOS Biol 2021; Happ et al, biorxiv 2021). The cilium is marked by SMOOTHENED staining (magenta), and the nucleus is marked by Hoechst staining (blue).