Figure 2.

Ciliary signaling pathways. (A–B) Hedgehog signaling pathway (A) In the absence of hedgehog (Hh) ligand the intraflagellar transport machinery moves the transcription factor glioma-associated oncogene (GLI) and suppressor of fused (SuFu) to the ciliary tip. Patched-1 (PTCH1) located in the surface of the ciliary membrane inhibits Smoothened (SMO), which is located in the cytoplasm, keeping GLI in an inactive form (GLI^R). The inactive transcription factor is transported back to the cell body and enters the nucleus where represses the expression of genes such as CCND1, N-MYC, GLI1, GLI2, and PATCH1. (B) Binding of ligand (Hh) to PTCH1 leads to the formation of oligomers, which are degraded in endosomes, reliving the repression of SMO, and causing its re-localization to the ciliary tip. SMO interacts with SuFu leading to the maturation of GLI into its active form (GLI^A). GLI^A is transported back to the cell body and enters the nucleus where activates transcription of target genes. (C, D) Canonical Wnt signaling pathway. (C) Without Wnt ligands, β-catenin is ubiquitinated and degraded by the proteasome. The initial events of this pathway are regulated by a destruction complex composed of casein kinase 1α (CK1α), glycogen synthase kinase 3β (GSK-3β), protein phosphatase 2A (PP2A), adenomatous polyposis coli (APC), and Axin 1. In the absence of β-catenin, the nuclear T cell-specific transcription factor/lymphoid enhancer factor-1 (TCF/LEF-1)-responsive elements are associated with transcriptional suppressors, such as Groucho (Gro) and Transducin-like enhancer of split-1 (TLE-1), keeping the pathway inactive. (D) When Wnt ligands bind the Frizzled (Fz) family receptors and its coreceptor low density lipoprotein receptor-related protein-5/6 (LRP5/6), Fz recruits Disheveled (Dvl) to inactivate the β-catenin destruction complex. Thus, β-catenin accumulates in the cytoplasm and translocates to the nucleus where replaces Gro/TLE, and acts as a transcriptional co-activator with TCF/LEF-1, inducing transcription of Wnt target genes. (E, F) Planar cell polarity signaling pathway. (E) In the absence of Wnt ligands the pathway is inactive. (F) When a signal is received by the Fz receptor a complex of proteins, including Dvl, is recruited at the plasma membrane. Dvl activates RHO-associated coiled-coil forming kinase (ROCK) and c-Jun N-terminal kinase (JUNK) in parallel, resulting in cytoskeletal organization and regulation of ciliogenesis. This figure was created using Servier Medical Art (available at https://smart.servier.com/).