Receptor modifications in Hedgehog regulation

The Hedgehog (Hh) signaling pathway is one of the highly conserved signaling cascades that control cell growth, cell fate, and pattern formation in species ranging from Drosophila to human. Smoothened (Smo), a G-proteincoupled- receptor (GPCR) family protein, serves as a core component to tranduce Hh signal across the cell membrane. Studying how the activity of Smo is regulated is a key to understand how Hh morphegen gradiant differentially induces target gene expression during normal animal development as well as how abnormal Hh signaling activity contributes to various human diseases. In this chapter, we focus on the regulation of Smo by its posttranslational modifications. By reviewing our current knowledge on how Hh ligands dynamically induce phosphorylation and ubiquitination of Smo and how these modifications coordinatedly modulate Smo function and downstream signaling events, we hope to inspire future exploration of comprehensive mechanisms underlying the regulation of Smo.