FIGURE 1.

Canonical activation of HH-GLI signaling. In absence of the HH ligand (A), PTCH inhibits SMO, and therefore GLI2 and GLI3 are phosphorylated by PKA, CK1 and GSK3β, which create binding sites for the E3 ubiquitin ligase β-TrCP. GLI3 and GLI2 undergo partial proteasome degradation, leading to the formation of repressor forms (GLI3/2^R), that translocate into the nucleus where they inhibit the transcription of HH target genes. Upon HH ligand binding (B), the repression of SMO by PTCH is relieved, allowing accumulation and activation of SMO. Thus, SMO promotes a signaling cascade that ultimately leads to translocation of full length (FL) activated forms of GLI (GLI^A) into the nucleus, where they induce transcription of HH target genes. CK1, caseine kinase 1; GLI2/3^R, GLI2/3 repressors; GLI^A, GLI activators; GLI^FL, GLI full length; GSK3β, glycogen synthase kinase 3β; Hh, Hedgehog; PKA, protein kinase A; PTCH, Patched; SMO, Smoothened; SUFU, Suppressor of Fused.