Hedgehog Signaling In Vertebrates

• 
• Description
• Reviews
• Key
• Download PDF
• Product Pathways

Search this pathway for protein information from PhosphoSitePlus^®, our expert-curated knowledge base of protein phosphorylation and other post-translational modifications.

Pathway Description:

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 and cholesterol as well as palmitate lipid modifications. In the absence of Hedgehog ligand in the receiving cell (Off-state), the receptor for Hedgehog-family ligands, Patched, is normally bound to and prevents membrane association of Smoothened, a G-coupled transmembrane protein. In the Off-state, SuFu and COS2 (Kif7 in vertebrates) sequester the microtubule-bound pool of the transcription factor Gli in the primary cilium. Gli can be phosphorylated by PKA, CKI, and GSK-3 resulting in β-TrCP-mediated degradation of Gli activators (Gli1 and Gli2 in mammals) or in the conserved pathway generation of repressor-Gli (Gli3 or truncated-Ci in Drosophila), which leads to repression of Hedgehog target genes. In the On-state, Hedgehog binding to Patched enables β-arrestin mediated translocation of Smoothened to the primary cilium where its associated G protein activity inhibits suppressive kinase action on Gli, leaving Gli free to translocate to the nucleus and activate Hedgehog target genes, including Cyclin D, Cyclin E, Myc, and Patched. Consequently, the conserved action of Hedgehog ligands is to switch the Gli-factors from being transcriptional repressors to activators. Loss of function mutations in Patched are associated with Gorlin-syndrome and predisposes to basal cell carcinomas, medulloblastomas, and rhabdomyosarcomas. In addition, activating mutations in Smoothened are found in basal cell carcinomas and rare SuFu mutations in medulloblastomas, underscoring the involvement of this developmental pathway in human cancer.

Selected Reviews:

• Briscoe J, Briscoe J (2009) Making a grade: Sonic Hedgehog signalling and the control of neural cell fate. EMBO J. 28(5), 457–65.
• Eaton S (2008) Multiple roles for lipids in the Hedgehog signalling pathway. Nat. Rev. Mol. Cell Biol. 9(6), 437–45.
• Fuccillo M, Joyner AL, Fishell G (2006) Morphogen to mitogen: the multiple roles of hedgehog signalling in vertebrate neural development. Nat. Rev. Neurosci. 7(10), 772–83.
• Goetz SC, Ocbina PJ, Anderson KV (2009) The primary cilium as a Hedgehog signal transduction machine. Methods Cell Biol. 94, 199–222.
• Theunissen JW, de Sauvage FJ (2009) Paracrine Hedgehog signaling in cancer. Cancer Res. 69(15), 6007–10.
• Wang Y, McMahon AP, Allen BL (2007) Shifting paradigms in Hedgehog signaling. Curr. Opin. Cell Biol. 19(2), 159–65.
• Wilson CW, Chuang PT (2006) New "hogs" in Hedgehog transport and signal reception. Cell 125(3), 435–8.

We would like to thank Dr. Hans Widlund, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, for contributing to this diagram.