Hedgehog stimulates maturation of Cubitus interruptus into a labile transcriptional activator

Nature. 1998 Dec 24-31;396(6713):749-53. doi: 10.1038/25533.

Abstract

In Drosophila, signalling by the protein Hedgehog (Hh) alters the activity of the transcription factor Cubitus interruptus (Ci) by inhibiting the proteolysis of full-length Ci (Ci-155) to its shortened Ci-75 form. Ci-75 is found largely in the nucleus and is thought to be a transcriptional repressor, whereas there is evidence to indicate that Ci-155 may be a transcriptional activator. However, Ci-155 is detected only in the cytoplasm, where it is associated with the protein kinase Fused (Fu), with Suppressor of Fused (Su(fu)), and with the microtubule-binding protein Costal-2. It is not clear how Ci-155 might become a nuclear activator. We show here that mutations in Su(fu) cause an increase in the expression of Hh-target genes in a dose-dependent manner while simultaneously reducing Ci-155 concentration by some mechanism other than proteolysis to Ci-75. Conversely, eliminating Fu kinase activity reduces Hh-target gene expression while increasing Ci-155 concentration. We propose that Fu kinase activity is required for Hh to stimulate the maturation of Ci-155 into a short-lived nuclear transcriptional activator and that Su(fu) opposes this maturation step through a stoichiometric interaction with Ci-155.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Cycle Proteins / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • DNA-Binding Proteins / metabolism*
  • Drosophila / embryology
  • Drosophila Proteins*
  • Hedgehog Proteins
  • Insect Proteins / genetics
  • Insect Proteins / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mutation
  • Protein-Serine-Threonine Kinases / metabolism*
  • Receptors, Cell Surface
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Signal Transduction
  • Transcription Factors / metabolism*
  • Ubiquitin-Protein Ligases*

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Drosophila Proteins
  • Hedgehog Proteins
  • Insect Proteins
  • Membrane Proteins
  • Receptors, Cell Surface
  • Repressor Proteins
  • Su(fu) protein, Drosophila
  • Transcription Factors
  • ci protein, Drosophila
  • ptc protein, Drosophila
  • slmb protein, Drosophila
  • hh protein, Drosophila
  • Ubiquitin-Protein Ligases
  • fu protein, Drosophila
  • Protein-Serine-Threonine Kinases
  • Cyclic AMP-Dependent Protein Kinases