Hedgehog Signaling In Vertebrates

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• Pathway Key
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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 represses the activity of another transmembrane protein called smoothened, possibly by preventing its membrane association. In the Off-state, SUFU and COS2 sequester the microtubule-bound pool of the transcription factor Gli in the primary cilium. Gli can be phosphorylated by PKA, CKI, and GSK3 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 leads to activation and translocation of smoothened to the primary cilium. Its associated G-protein activity likely blocks inhibitory kinase action on Gli which is now 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. Importantly, activating mutations in patched are associated with Gorlin-syndrome and predisposes to basal cell carcinomas, medulloblastomas and rhabdomyosarcomas. In addition, smoothened inactivating mutations are also found in basal cell carcinomas and rare SuFu mutations in medulloblastomas, underscoring the involvement of this developmental pathway in human cancer.

Selected Reviews:

• 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.
• Varjosalo M, Taipale J (2007) Hedgehog signaling. J. Cell. Sci. 120(Pt 1), 3–6.
• Rubin LL, de Sauvage FJ (2006) Targeting the Hedgehog pathway in cancer. Nat Rev Drug Discov 5(12), 1026–33.
• 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.

CST would like to thank Dr. Hans Widlund, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, for contributing to this Hedgehog Signaling in Vertebrates diagram.