| The hedgehog receptor patched is involved in cholesterol transport. | |
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MedLine Citation:
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PMID: 21931618 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: Sonic hedgehog (Shh) signaling plays a crucial role in growth and patterning during embryonic development, and also in stem cell maintenance and tissue regeneration in adults. Aberrant Shh pathway activation is involved in the development of many tumors, and one of the most affected Shh signaling steps found in these tumors is the regulation of the signaling receptor Smoothened by the Shh receptor Patched. In the present work, we investigated Patched activity and the mechanism by which Patched inhibits Smoothened. METHODOLOGY/PRINCIPAL FINDINGS: Using the well-known Shh-responding cell line of mouse fibroblasts NIH 3T3, we first observed that enhancement of the intracellular cholesterol concentration induces Smoothened enrichment in the plasma membrane, which is a crucial step for the signaling activation. We found that binding of Shh protein to its receptor Patched, which involves Patched internalization, increases the intracellular concentration of cholesterol and decreases the efflux of a fluorescent cholesterol derivative (BODIPY-cholesterol) from these cells. Treatment of fibroblasts with cyclopamine, an antagonist of Shh signaling, inhibits Patched expression and reduces BODIPY-cholesterol efflux, while treatment with the Shh pathway agonist SAG enhances Patched protein expression and BODIPY-cholesterol efflux. We also show that over-expression of human Patched in the yeast S. cerevisiae results in a significant boost of BODIPY-cholesterol efflux. Furthermore, we demonstrate that purified Patched binds to cholesterol, and that the interaction of Shh with Patched inhibits the binding of Patched to cholesterol. CONCLUSION/SIGNIFICANCE: Our results suggest that Patched may contribute to cholesterol efflux from cells, and to modulation of the intracellular cholesterol concentration. This activity is likely responsible for the inhibition of the enrichment of Smoothened in the plasma membrane, which is an important step in Shh pathway activation. |
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Authors:
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Michel Bidet; Olivier Joubert; Benoit Lacombe; Marine Ciantar; Rony Nehmé; Patrick Mollat; Lionel Brétillon; Hélène Faure; Robert Bittman; Martial Ruat; Isabelle Mus-Veteau |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2011-09-08 |
Journal Detail:
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Title: PloS one Volume: 6 ISSN: 1932-6203 ISO Abbreviation: PLoS ONE Publication Date: 2011 |
Date Detail:
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Created Date: 2011-09-20 Completed Date: 2012-02-03 Revised Date: 2012-04-26 |
Medline Journal Info:
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Nlm Unique ID: 101285081 Medline TA: PLoS One Country: United States |
Other Details:
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Languages: eng Pagination: e23834 Citation Subset: IM |
Affiliation:
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Université de Nice-Sophia Antipolis, CNRS-UMR 6543, Institute of Developmental Biology and Cancer, Nice, France. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Biological Transport / drug effects Cell Membrane / drug effects, metabolism Cholesterol / metabolism* Hedgehog Proteins / metabolism Humans Mice NIH 3T3 Cells Receptors, Cell Surface / genetics, metabolism* Receptors, G-Protein-Coupled / metabolism Saccharomyces cerevisiae / genetics Signal Transduction / drug effects Veratrum Alkaloids / pharmacology |
| Chemical | |
Reg. No./Substance:
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0/Hedgehog Proteins; 0/Receptors, Cell Surface; 0/Receptors, G-Protein-Coupled; 0/Smo protein, mouse; 0/Veratrum Alkaloids; 0/patched receptors; 4449-51-8/cyclopamine; 57-88-5/Cholesterol |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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