Divergence of hedgehog signal transduction mechanism between Drosophila and mammals

Dev Cell. 2006 Feb;10(2):177-86. doi: 10.1016/j.devcel.2005.12.014.

Abstract

The Hedgehog (Hh) signaling pathway has conserved roles in development of species ranging from Drosophila to humans. Responses to Hh are mediated by the transcription factor Cubitus interruptus (Ci; GLIs 1-3 in mammals), and constitutive activation of Hh target gene expression has been linked to several types of human cancer. In Drosophila, the kinesin-like protein Costal2 (Cos2), which associates directly with the Hh receptor component Smoothened (Smo), is essential for suppression of the transcriptional activity of Ci in the absence of ligand. Another protein, Suppressor of Fused (Su(Fu)), exerts a weak negative influence on Ci activity. Based on analysis of functional and sequence conservation of Cos2 orthologs, Su(Fu), Smo, and Ci/GLI proteins, we find here that Drosophila and mammalian Hh signaling mechanisms have diverged, and that, in mouse cells, major Cos2-like activities are absent and the inhibition of the Hh pathway in the absence of ligand critically depends on Su(Fu).

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Cells, Cultured
  • Conserved Sequence
  • Drosophila / genetics*
  • Drosophila / metabolism*
  • Drosophila Proteins / chemistry
  • Drosophila Proteins / genetics*
  • Drosophila Proteins / metabolism*
  • Evolution, Molecular
  • Hedgehog Proteins
  • Humans
  • Kinesin / chemistry
  • Kinesin / genetics
  • Kinesin / metabolism
  • Mammals
  • Mice
  • Models, Biological
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Protein Structure, Tertiary
  • RNA Interference
  • Repressor Proteins / antagonists & inhibitors
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Sequence Homology, Amino Acid
  • Signal Transduction / genetics
  • Species Specificity
  • Trans-Activators / chemistry
  • Trans-Activators / genetics*
  • Trans-Activators / metabolism*

Substances

  • Drosophila Proteins
  • Hedgehog Proteins
  • Repressor Proteins
  • Su(fu) protein, Drosophila
  • Sufu protein, mouse
  • Trans-Activators
  • cos protein, Drosophila
  • hh protein, Drosophila
  • Kinesin