Hedgehog Pathway
Pathway Description:
The Hedgehog pathway plays a critical role in both the patterning of the developing embryo and the maintenance of stem cell niches in adult tissues. Hedgehog family ligands, which include sonic, desert and indian hedgehog in vertebrates, require both cleavage, through autoprocessing, and lipid modification, involving cholesterol and palmitate, for secretion and proper diffusion to nearby cells. Patched, the receptor for hedgehog-family ligands, is normally bound to and represses the activity of another transmembrane protein called smoothened. In the absence of hedgehog, the Gli protein is tethered to microtubules via its association with Fused and Cos-2 proteins. Phosphorylation and cleavage of cytoplasmic Gli, by PKA, Slimb, and others, leads to repression of hedgehog target genes, which include cyclin D, cyclin E, Myc, and patched. Upon binding of hedgehog to patched, smoothened is activated and blocks the phosphorylation and cleavage of Gli which is now free to translocate to the nucleus and activate hedgehog target genes. Therefore, hedgehog family ligands switch Gli from being a transcriptional repressor to an activator. Patched and smoothened mutations result in aberrant hedgehog pathway activity and lead to tumorigenesis of a number of cancers including medulloblastomas and basal cell carcinomas.
Selected Reviews:
- Beachy PA, Karhadkar SS, Berman DM (2004) Tissue repair and stem cell renewal in carcinogenesis. Nature 432(7015), 324–31.
- Lum L, Beachy PA (2004) The Hedgehog response network: sensors, switches, and routers. Science 304(5678), 1755–9.
- Mann RK, Beachy PA (2004) Novel lipid modifications of secreted protein signals. Annu. Rev. Biochem. 73, 891–923.
- McMahon AP, Ingham PW, Tabin CJ (2003) Developmental roles and clinical significance of hedgehog signaling. Curr. Top. Dev. Biol. 53, 1–114.
- Pasca di Magliano M, Hebrok M (2003) Hedgehog signalling in cancer formation and maintenance. Nat. Rev. Cancer 3(12), 903–11.
created June 2006 • revised November 2006
