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. Here we show that mammalian Smoothened (Smo), a seven-transmembrane protein essential for Hh signalling, 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. 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.
Pubmed ID: 16136078 RIS Download
Mesh terms: Amino Acid Motifs | Amino Acid Sequence | Animals | Caenorhabditis elegans | Cell Line | Cilia | Dogs | Drosophila Proteins | Embryo, Mammalian | Embryo, Nonmammalian | Genes, Reporter | Mice | Mutation | Protein Sorting Signals | RNA, Messenger | Receptors, G-Protein-Coupled | Signal Transduction | Smoothened Receptor | Veratrum Alkaloids | Vertebrates | Zebrafish
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