1. Academic Validation
  2. The hedgehog receptor patched is involved in cholesterol transport

The hedgehog receptor patched is involved in cholesterol transport

  • PLoS One. 2011;6(9):e23834. doi: 10.1371/journal.pone.0023834.
Michel Bidet 1 Olivier Joubert Benoit Lacombe Marine Ciantar Rony Nehmé Patrick Mollat Lionel Brétillon Hélène Faure Robert Bittman Martial Ruat Isabelle Mus-Veteau
Affiliations

Affiliation

  • 1 Université de Nice-Sophia Antipolis, CNRS-UMR 6543, Institute of Developmental Biology and Cancer, Nice, France.
Abstract

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.

Figures
我们的 Cookie 政策

我们使用 Cookies 和类似技术以提高网站的性能和提升您的浏览体验,部分功能也使用 Cookies 帮助我们更好地理解您的需求,为您提供相关的服务。 如果您有任何关于我们如何处理您个人信息的疑问,请阅读我们的《隐私声明》