Smoothened Signaling Through a G-Protein Effector Network

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