Fig. 2

A simplified schematic depiction of the canonical hedgehog (HH) signal transduction pathway within the primary cilium. a During the absence of the HH ligand the pathway is continuously repressed by PTCH and GPR161 located at the base of the primary cilium. In its unliganded state the HH receptor PTCH prevents SMO, the crucial GLI activator, from entering the plasma membrane of the primary cilium and thereby from executing its effector function (1). Furthermore, GPR161 increases cAMP levels, promoting the phosphorylation of the GLI transcription factors, which are sequestered in a repressive complex with SUFU and IFT proteins at the base of the primary cilium, by PKA and subsequently by GSK3β and CK1 (2). This phosphorylation leads to partial proteasomal degradation of GLI2 and GLI3 and repressor formation, predominantly GLI3R (3). Thereupon, GLI3R enters the nucleus and represses target gene transcription (4). b The binding of the HH ligand to its receptor PTCH is promoted by GAS1, BOC and CDO, whereas HHIP competes with PTCH for ligand binding (5). When HH binds to PTCH the repression of the pathway is relieved by internalization and lysosomal degradation of the receptor-ligand-complex (6). This allows SMO to enter the primary cilium (7) and to be activated by cholesterol, which triggers a conformational change (indicated by the schematic cholesterol structure in black and the asterisk (SMO*)). GPR161 whereas is removed from the plasma membrane (8). When SMO* and the SUFU-GLI complex co-localize at the tip of the primary cilium, upon the directed transport via IFT proteins along the microtubules, the GLI transcription factors are activated by SMO* and dissociate from the complex (9). The full-length activator forms of GLI2 and GLI3 enter the nucleus and drive target gene transcription (10)