Fig. 1. The canonical Hh signaling pathway.

(A) Hh signaling in Drosophila. In the absence of Hh (left), Ptc prevents Smo membrane localization and activation so that Smo is retained on intracellular vesicles. In this context, full-length Ci (yellow, indicating partial activity) is held in a microtubule-associated complex containing the kinesin-like protein Costal2 (Cos2), the kinase Fused (Fu), and Suppressor of Fused (Sufu), which promotes phosphorylation of Ci by PKA, GSK3, and CK1 and its partial proteasomal processing into a transcriptional repressor form (Ci_R, red). Binding of Hh to the receptor complex composed of Ptc and an Ihog co-receptor (Ihog or Boi, right) results in internalization of the ligand-receptor complex and phosphorylation and translocation of Smo to the plasma membrane, where it interacts with Cos2 to partially disrupt the microtubule-associated complex, leading to release of Ci and activation of the heterotrimeric G_i protein. Ci is subsequently converted into a fully active labile transcriptional activator (Ci_A, blue) by an unknown mechanism. (B) Hh signaling in vertebrates. Hh signaling in vertebrates is similar to Hh signaling in Drosophila, with the important distinction that signaling takes place on primary cilia. When a Hh ligand binds to the receptor complex formed by Ptc and an Ihog co-receptor (Cdo, Boc, or Gas1), Smo translocates to both the plasma membrane and to the primary cilium, where it regulates Gli processing and activation.