The hedgehog receptor patched is involved in cholesterol transport.
The hedgehog receptor patched is involved in cholesterol transport.
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DOI：
10.1371/journal.pone.0023834
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Mus-Veteau I
中科院分区：
文献类型：
--
作者：
Bidet M;Joubert O;Lacombe B;Ciantar M;Nehmé R;Mollat P;Brétillon L;Faure H;Bittman R;Ruat M;Mus-Veteau I
Sonic hedgehog（Shh）信号在胚胎发育期间的生长和模式化中起着至关重要的作用，并且在成人的干细胞维持和组织再生中也起着关键作用。异常的Shh通路激活参与许多肿瘤的发展，并且在这些肿瘤中发现的最受影响的Shh信号传导步骤之一是Shh受体Patched对信号受体Smoothened的调节。在目前的工作中，我们研究了修补活动和修补抑制Smoothened的机制。使用众所周知的小鼠成纤维细胞NIH 3 T3的Shh响应细胞系，我们首先观察到细胞内胆固醇浓度的增强诱导质膜中的Smoothened富集，这是信号传导激活的关键步骤。我们发现Shh蛋白与其受体Patched的结合，涉及Patched内化，增加了胆固醇的细胞内浓度，并减少了荧光胆固醇衍生物（BODIPY-胆固醇）从这些细胞中的流出。用Shh信号传导的拮抗剂环巴胺处理成纤维细胞抑制Patched表达并减少BODIPY-胆固醇流出，而用Shh途径激动剂SAG处理增强Patched蛋白表达和BODIPY-胆固醇流出。我们还表明，在酵母S。酿酒酵母导致BODIPY-胆固醇流出的显著增加。此外，我们证明，纯化的补丁结合胆固醇，和Shh与补丁的相互作用抑制补丁胆固醇的结合。我们的研究结果表明，修补可能有助于胆固醇流出细胞，并调节细胞内胆固醇浓度。这种活性可能是抑制Smoothened在质膜中富集的原因，这是Shh途径激活的重要步骤。
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. 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. 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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影响因子：
4.6
作者：
Khaliullina, Helena;Panakova, Daniela;Eaton, Suzanne
通讯作者：
Eaton, Suzanne
DOI：
10.1002/ajmg.c.30243
发表时间：
2010-02-15
影响因子：
3.1
作者：
Haas, Dorothea;Muenke, Maximilian
通讯作者：
Muenke, Maximilian
影响因子：
4.8
作者：
Infante, Rodney E.;Abi-Mosleh, Lina;Goldstein, Joseph L.
通讯作者：
Goldstein, Joseph L.
影响因子：
4.8
作者：
Davis, HR;Zhu, LJ;Altmann, SW
通讯作者：
Altmann, SW
影响因子：
56.9
作者：
Altmann, SW;Davis, HR;Graziano, MP
通讯作者：
Graziano, MP