Sterols Ligands for Smoothened

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In the absence of Sonic hedgehog (Shh), Patched (Ptc, a receptor for Shh) inhibits signaling by Smoothened (Smo). In certain cancers, including medulloblastoma, the Shh pathway is activated, for example, by loss-of-function mutations in Ptc. However, defective Shh signaling is also associated with disease. Defects in sterol biosynthesis can lead to developmental phenotypes associated with Shh deficiency. Corcoran and Scott used a medulloblastoma cell line that was heterozygous for Ptc and completely deficient in p53 (PZp53 MED ) to understand the role that sterols play in Shh signaling in the signal-receiving cell. Using pharmacological inhibitors that blocked different steps in the biosynthesis of sterols, they determined that products of cholesterol metabolism, but not steroids, were required for the enhanced cell proliferation of PZp53 MED and induction of expression of an endogenous Shh-regulated gene, gli , and a Shh reporter gene. Addition of water-soluble cholesterol or specific oxysterol derivatives of cholesterol, of which 25-hydroxycholesterol was most potent, restored cell proliferation and Shh reporter gene expression in PZp53 MED cells in which cholesterol biosynthesis was blocked. Proliferation of medulloblastoma cells transfected to constitutively express Gli, which is downstream of Smo, was not reduced by inhibition of cholesterol synthesis. The authors proposed a model whereby Ptc, which is structurally similar to a cholesterol transporter, pumps sterols out of cells keeping Smo inactive. When Shh inhibits Ptc, then the sterol ligand of Smo accumulates and activates Smo. R. B. Corcoran, M. P. Scott, Oxysterols stimulate Sonic hedgehog signal transduction and proliferation of medulloblastoma cells. Proc. Natl. Acad. Sci. U.S.A. 103 , 8408-8413 (2006). [Abstract] [Full Text]