Hedgehog Signaling Pathway
The evolutionarily conserved Hedgehog pathway plays a critical role in a time and position-dependent fashion during development by regulating patterning and maintenance of proliferative niches. Proper secretion and gradient diffusion of the vertebrate Hedgehog-family ligands, including Sonic, Desert, and Indian Hedgehog, all require autoprocessive cleavage as well as cholesterol and palmitate lipid modifications. In the receiving cell in the absence of Hedgehog ligand (off-state), the Patched receptor is associated with Smoothened, a G-coupled transmembrane protein, and prevents its membrane incorporation from endosomes. Further, the Hedgehog Off-state allows SuFu and COS2 (Kif7 in vertebrates) to sequester the microtubule-bound pool of the Gli transcription factor within the primary cilium, thereby allowing its phosphorylation by PKA, CK1, and GSK-3. This results in β-TrCP-mediated degradation of Gli activators (Gli1 and Gli2 in mammals) or the generation of repressor-Gli (Gli3 or truncated-Ci in Drosophila) in the conserved pathway that collectively leads to repression of Hedgehog target genes. In the on-state, Hedgehog binding sequesters the co-receptor Ihog to Patched that permits β-arrestin to freely facilitate incorporation of Smoothened to the primary cilium membrane. In the primary cilium, Smoothened’s associated G protein activity relieves Gli from microtubule association, enables nuclear translocation, and activation of Hedgehog/Gli target genes including Cyclin D, Cyclin E, Myc, and Patched. Consequently, the conserved action of Hedgehog ligands is to switch the Gli factors from transcriptional repressors into activators and allow for well-coordinated bursts of transcriptional events. Loss-of-function Patched mutations are associated with Gorlin syndrome and predisposes to basal cell carcinomas, medulloblastomas, and rhabdomyosarcomas. In addition, researchers have found activating mutations of Smoothened in basal cell carcinomas and rare SuFu mutations in medulloblastomas, underscoring the involvement of this developmental pathway in cancer; consequently, significant interest is focused on targeting this pathway for therapeutic purposes.
- Beachy PA, Hymowitz SG, Lazarus RA, Leahy DJ, Siebold C (2010) Interactions between Hedgehog proteins and their binding partners come into view. Genes Dev. 24(18), 2001–12.
- Eaton S (2008) Multiple roles for lipids in the Hedgehog signalling pathway. Nat. Rev. Mol. Cell Biol. 9(6), 437–45.
- Hui CC, Angers S (2011) Gli proteins in development and disease. Annu. Rev. Cell Dev. Biol. 27, 513–37.
- Ingham PW, Nakano Y, Seger C (2011) Mechanisms and functions of Hedgehog signalling across the metazoa. Nat. Rev. Genet. 12(6), 393–406.
- Ng JM, Curran T (2011) The Hedgehog's tale: developing strategies for targeting cancer. Nat. Rev. Cancer 11(7), 493–501.
- Oh EC, Katsanis N (2012) Cilia in vertebrate development and disease. Development 139(3), 443–8.
- Theunissen JW, de Sauvage FJ (2009) Paracrine Hedgehog signaling in cancer. Cancer Res. 69(15), 6007–10.
- Wilson CW, Chuang PT (2010) Mechanism and evolution of cytosolic Hedgehog signal transduction. Development 137(13), 2079–94.
We would like to thank Dr. Hans Widlund, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, for contributing to this diagram.
created June 2006
revised December 2012