Abstract
Disruption of the Hedgehog (HH) signaling pathway underlies an increasingly large array of different human tumors. Consistent with the important role HH plays in cancer, the tumor burden of patients treated with a novel HH inhibitor was dramatically reduced in a recent clinical trial. This drug binds directly to and antagonizes activity of the seven-transmembrane protein Smoothened (SMO), attenuating downstream signaling events that remain largely unknown. While functional studies of SMO signaling have provided a basic roadmap of information flow following ligand stimulation, the exact routes of signaling, and how they communicate with each other and with other signaling pathways, are not well characterized. We recently demonstrated that one route of SMO-mediated signal transduction involves activation of the heterotrimeric guanine nucleotide binding protein (G-protein) Gαi, suggesting that SMO can signal, at least in part, as a canonical G-protein-coupled receptor (GPCR). In this chapter, we discuss structural, functional, and mechanistic aspects of SMO signaling that relate to its function as a GPCR, and provide insight into how G-protein-dependent signaling might impact HH pathway activity.
