Cilia-mediated signaling pathways whose proper regulation is dependent on the proteasome and the structure of the proteasome. a–e SHH, PDGFRα, NOTCH, TGFβ, and canonical WNT signaling is transduced by primary cilia. a In the absence of the ligand SHH, SMO remains in cytoplasmic vesicles and is inhibited by PTCH1. As a result, GLI2 and GLI3 (forming a complex with SUFU) are phosphorylated most likely within the cilium and subsequently get proteolytically processed to their repressor forms (GLI2/3-R) by the proteasome at the ciliary base. In turn, GLI2/3-R translocate into the nucleus and represses the expression of SHH target genes. Importantly, GLI3 is the predominant repressor. When SHH binds to its receptor PTCH1, the SHH/PTCH1 complex leaves the cilium and PTCH1 is not able to inhibit the action of SMO any longer. Thereupon, SMO is transported into the cilium and converts the full-length forms of GLI2 and GLI3 (GLI2/3-FL) into their activator forms. In the course of this conversion process, SUFU dissociates from the complex enabling the GLI2 and GLI3 activator forms to induce SHH target gene expression. b In the ciliary membrane, PDGFRα is bound by its ligand PDGF-AA and subsequently becomes dimerized and phosphorylated. The phosphorylation of PDGFRα induces the activation of the MEK 1/2-ERK 1/2 and AKT/PKB signaling pathways. c Initiating NOTCH signaling, the extracellular domain of a NOTCH ligand (JAGGED or DELTA) binds to the NOTCH receptor which is located in the ciliary membrane. As a result, the NOTCH receptor undergoes a three-step cleavage and finally releases the NOTCH intracellular domain (NIC). NIC enters the nucleus and activates NOTCH target genes. d The receptors of the TGFβ pathway, TGFβ-RI and TGFβ-RII, are located at the ciliary base. When the TGFβ ligand binds to the receptors a heterotetrameric receptor complex composed of TGFβ-RI and TGFβ-RII is formed and activated. This activation results in the phosphorylation and activation of SMAD2 and SMAD3. The phosphorylated SMADs 2 and 3 associate with a co-SMAD called SMAD4. Afterwards, the complex consisting of SMAD2, 3, and 4 enters the nucleus and activates TGFβ target genes. e In the inactive state of the canonical WNT pathway, a destruction complex consisting of APC and AXIN triggers the phosphorylation of β-catenin by GSK3. After this phosphorylation event, β-catenin gets ubiquitinated and finally degraded. In the active state, WNT ligands bind to FRIZZLED and LRP receptors leading to the activation of DSH. DSH recruits the destruction complex to the plasma membrane, thereby interfering phosphorylation of β-catenin. Afterwards, β-catenin translocates into the nucleus and activates canonical WNT target gene expression. Primary cilia restrict canonical WNT signaling because the ciliary protein KIF3A is able to inhibit the phosphorylation of DSH. f The proteasome consists of the catalytic 20S subunit and two regulatory 19S subunits. The 20S subunit displays a cylindrical arrangement of four stacked heptameric rings. Each ring is composed of seven α and β subunits, respectively. Only three subunits (PSMB8-10) display a proteolytic activity equipping the proteasome with trypsin-like, chymotrypsin-like, and caspase-like abilities. The 19S subunit can be subdivided into two subcomplexes: a base complex (being constituted of six ATPases [PSMC1-6] and three non-ATPases [PSMD1, 2 and 4]) and a lid complex (consisting of nine non-ATPases [PSMD3, 6-8, 11-14, and SHFM1])