Figure 2.

Cilia-dependent regulation of the Hedgehog signaling pathway. Schematic representation of the Hedgehog pathway repression and activation, in the presence or absence of a ligand. In Panel “ON”, in the presence of ligand binding to PTCH1 receptor, SMO moves into the cilium, and PTCH1 is displaced outside. In the cilium, SMO inhibits SUFU, and it activates GLI transcription factors (GLIA), which, in turn, activate the expression of target genes. In contrast, in Panel “OFF”, in the absence of a ligand, PTCH1 receptor localizes at the primary cilium, and the 7-transmembrane domain protein SMO is in vesicles outside the cilium. GLI transcription factors are sequestered and suppressed by SUFU, and processed into their repressive forms (GLIR), thus repressing the expression of target genes. If the pathway is misregulated, “HYPER ON” (i.e., SMO, PTCH1 mutations, in medulloblastoma and basal cell carcinoma), the activation of the pathway throughout the cilium can induce tumorigenesis, and targeting of the cilium can turn off the pathway and reduce cell proliferation. On the other hand, if the misregulation of the pathway arises downstream (i.e., GLI2 mutations), the loss of the cilium can also boost medulloblastoma or basal cell carcinoma development, suggesting that the role of primary cilia in Hedgehog misregulation-driven cancers depends on the oncogenic alteration. GLI: GLI family zinc fingers; PTCH1: Patched-1; SMO: Smoothened; SUFU: Suppressor of Fused.