Stability and association of Smoothened, Costal2 and Fused with Cubitus interruptus are regulated by Hedgehog

Nat Cell Biol. 2003 Oct;5(10):907-13. doi: 10.1038/ncb1052. Epub 2003 Oct 1.


The mechanisms involved in transduction of the Hedgehog (Hh) signal are of considerable interest to developmental and cancer biologists. Stabilization of the integral membrane protein Smoothened (Smo) at the plasma membrane is a crucial step in Hh signalling but the molecular events immediately downstream of Smo remain to be elucidated. We have shown previously that the transcriptional mediator Cubitus interruptus (Ci) is associated in a protein complex with at least two other proteins, the kinesin-like Costal2 (Cos2) and the serine-threonine kinase Fused (Fu). This protein complex governs the access of Ci to the nucleus. Here we show that, consequent on the stabilization of Smo, Cos2 and Fu are destabilized. Moreover, we find that the Cos2-Fu-Ci protein complex is associated with Smo in membrane fractions both in vitro and in vivo. We also show that Cos2 binding on Smo is necessary for the Hh-dependent dissociation of Ci from this complex. We propose that the association of the Cos2 protein complex with Smo at the plasma membrane controls the stability of the complex and allows Ci activation, eliciting its nuclear translocation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / physiology
  • Animals
  • Cell Membrane / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / embryology
  • Drosophila melanogaster / physiology
  • Embryonic Structures / cytology
  • Embryonic Structures / metabolism
  • Gene Expression Regulation, Developmental
  • Hedgehog Proteins
  • Kinesins / genetics
  • Kinesins / metabolism*
  • Macromolecular Substances
  • Protein Binding
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Signal Transduction / physiology
  • Smoothened Receptor
  • Transcription Factors
  • Transport Vesicles / metabolism


  • DNA-Binding Proteins
  • Drosophila Proteins
  • Hedgehog Proteins
  • Macromolecular Substances
  • Receptors, G-Protein-Coupled
  • Smoothened Receptor
  • Transcription Factors
  • ci protein, Drosophila
  • cos protein, Drosophila
  • smo protein, Drosophila
  • hh protein, Drosophila
  • fu protein, Drosophila
  • Protein Serine-Threonine Kinases
  • Kinesins