Figure 2. Mammalian Hh signaling in primary cilia.

In the absence of Hh, Ptc localizes to the primary cilia and inhibits Smo ciliary accumulation. Gpr161, a ciliary localized GPCR, is required for PKA activation. Kif7 is localized at ciliary base and both Sufu and Kif 7 are required for Gli^R production. In the presence of Hh, Hh inhibits Ptc activity and promotes its ciliary removal depending on Smurf and, subsequently the accumulation of Smo into primary cilia depending on phosphorylation by CK1 and GRK2. Hh also promotes Gpr161 ciliary exit through Smo and β-arrestin. Smo is activated in the primary cilia by cholesterol and its derivatives oxysterols. Kif7, Gli and Sufu are localized at the ciliary tip where Gli^F is converted into Gli^A. The Evc1/Evc2 complex is localized near the ciliary base where it regulates Hh signal transduction downstream or in parallel to Smo in certain contexts. The nuclear import receptor Kapβ2 is required for Gli ciliary entry. See text for details.