“…In the absence of Hh ligands, Ptc blocks the activity of Smo and full-length Ci/Gli is phosphorylated by multiple kinases including PKA, CK1 and GSK3β, which targets it for Slimb/β-TRCP-mediated proteolysis to generate its repressor form (Ci R /Gli R ) [5]. In the presence of Hh, the Ptc inhibition of Smo is released through Hh binding to Ptc; Smo is phosphorylated by multiple kinases including PKA (Drosophila only), CK1 and Gprk2 kinases, which promotes its active conformation and changes its subcellular localization with Drosophila Smo accumulating on the cell surface and mammalian Smo accumulating in the primary cilium [6][7][8][9][10][11]. Ci/Gli phosphorylation and prote-olysis is blocked, leading to diminished Ci R /Gli R activity [12][13][14].…”