Vertebrate Smoothened functions at the primary cilium
Vertebrate Smoothened functions at the primary cilium
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DOI：
10.1038/nature04117
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发表时间：
2005-10-13
期刊：
影响因子：
64.8
通讯作者：
Reiter, JF
中科院分区：
文献类型：
--
作者：
Corbit, KC;Aanstad, P;Reiter, JF
几种鞭毛内运输蛋白在意想不到的情况下参与哺乳动物刺猬（Hh）信号通路，这暗示了纤毛与Hh信号转导之间存在功能联系（1,2）。在此我们表明，哺乳动物平滑蛋白（Smo）这种对Hh信号传导至关重要的七跨膜蛋白在初级纤毛上表达。这种纤毛表达受Hh信号通路活性的调控；音猬因子或Smo中的激活突变促进其在纤毛上的定位，而Smo拮抗剂环巴胺则抑制其在纤毛上的定位。Smo向初级纤毛的转位依赖于一个保守的疏水碱性残基序列，该序列与先前在秀丽隐杆线虫中被证明是七跨膜蛋白纤毛定位所必需的结构域同源（4）。该结构域的突变不仅阻止纤毛定位，而且在培养细胞和斑马鱼胚胎中都消除了Smo的活性。因此，依赖于Hh的向纤毛的转位对Smo的活性至关重要，这表明Smo在初级纤毛上发挥作用。
The unanticipated involvement of several intraflagellar transport proteins in the mammalian Hedgehog (Hh) pathway has hinted at a functional connection between cilia and Hh signal transduction(1,2). Here we show that mammalian Smoothened (Smo), a seven-transmembrane protein essential for Hh signalling(3), is expressed on the primary cilium. This ciliary expression is regulated by Hh pathway activity; Sonic hedgehog or activating mutations in Smo promote ciliary localization, whereas the Smo antagonist cyclopamine inhibits ciliary localization. The translocation of Smo to primary cilia depends upon a conserved hydrophobic and basic residue sequence homologous to a domain previously shown to be required for the ciliary localization of seven-transmembrane proteins in Caenorhabditis elegans(4). Mutation of this domain not only prevents ciliary localization but also eliminates Smo activity both in cultured cells and in zebrafish embryos. Thus, Hh-dependent translocation to cilia is essential for Smo activity, suggesting that Smo acts at the primary cilium.