The Hh pathway is controlled by two membrane proteins, Patched (Ptch), the Hh receptor, and Smoothened (Smo), a Class F G protein-coupled receptor (GPCR) which transduces the activation signal to downstream pathway components. In the absence of Hh ligand, Ptch inhibits signaling by Smo. Binding of Hh to Ptch triggers its internalization and degradation, thereby allowing Smo to accumulate and signal to intracellular effectors. Drosophila Smo appears to govern a sole canonical signal that culminates in activation of a Gli transcription factor, vertebrate Smo can activate two independent signaling arms. The canonical signal is dedicated to regulation of Hh target gene activation through Gli transcriptional effectors, and is thought to occur in a G protein-independent manner. Regulation of Gli phosphorylation by cyclic AMP (cAMP)-dependent protein kinase (PKA) is paramount to controlling transcriptional repressor and activator formation. Signaling from Smo to PKA and Sufu, a negative regulator of Gli activity, occurs in the PC and is dependent upon Smo interaction with the Ellis van Creveld Syndrome (Evc2) ciliary complex. Conversely, the noncanonical route utilizes Gαi to regulate cellular processes including metabolism, proliferation, Ca2+ flux and migration.

References

1.Arensdorf AM,et al. Trends Pharmacol Sci. 2016;37(1):62–72.