Vertebrate Smoothened Functions at the Primary Cilium

Nature. 2005 Oct 13;437(7061):1018-21. doi: 10.1038/nature04117. Epub 2005 Aug 31.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Caenorhabditis elegans / chemistry
  • Cell Line
  • Cilia / drug effects
  • Cilia / metabolism*
  • Dogs
  • Drosophila Proteins / chemistry
  • Embryo, Mammalian / metabolism
  • Embryo, Nonmammalian
  • Genes, Reporter / genetics
  • Mice
  • Mutation / genetics
  • Protein Sorting Signals / genetics
  • Protein Sorting Signals / physiology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, G-Protein-Coupled / antagonists & inhibitors
  • Receptors, G-Protein-Coupled / chemistry
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Signal Transduction
  • Smoothened Receptor
  • Veratrum Alkaloids / pharmacology
  • Vertebrates / embryology
  • Vertebrates / genetics
  • Vertebrates / metabolism*
  • Zebrafish / embryology
  • Zebrafish / genetics
  • Zebrafish / metabolism

Substances

  • Drosophila Proteins
  • Protein Sorting Signals
  • RNA, Messenger
  • Receptors, G-Protein-Coupled
  • Smo protein, mouse
  • Smoothened Receptor
  • Veratrum Alkaloids
  • smo protein, Drosophila
  • cyclopamine