Regulation of the Hedgehog and Wingless Signalling Pathways by the F-box/WD40-repeat Protein Slimb

Nature. 1998 Jan 29;391(6666):493-6. doi: 10.1038/35154.

Abstract

Members of the Hedgehog (Hh) and Wnt/Wingless (Wg) families of secreted proteins control many aspects of growth and patterning during animal development. Hh signal transduction leads to increased stability of a transcription factor, Cubitus interruptus (Ci), whereas Wg signal transduction causes increased stability of Armadillo (Arm/beta-catenin), a possible co-factor for the transcriptional regulator Lef1/TCF. Here we describe a new gene, slimb (for supernumerary limbs), which negatively regulates both of these signal transduction pathways. Loss of function of slimb results in a cell-autonomous accumulation of high levels of both Ci and Arm, and the ectopic expression of both Hh- and Wg- responsive genes. The slimb gene encodes a conserved F-box/WD40-repeat protein related to Cdc4p, a protein in budding yeast that targets cell-cycle regulators for degradation by the ubiquitin/proteasome pathway. We propose that Slimb protein normally targets Ci and Arm for processing or degradation by the ubiquitin/proteasome pathway, and that Hh and Wg regulate gene expression at least in part by inducing changes in Ci and Arm, which protect them from Slimb-mediated proteolysis.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Animals, Genetically Modified
  • Armadillo Domain Proteins
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cloning, Molecular
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • DNA-Binding Proteins / metabolism
  • Drosophila / genetics
  • Drosophila Proteins*
  • F-Box Proteins*
  • GTP-Binding Proteins / chemistry
  • Gene Expression Regulation, Developmental
  • Hedgehog Proteins
  • Insect Proteins / chemistry
  • Insect Proteins / genetics
  • Insect Proteins / metabolism*
  • Male
  • Molecular Sequence Data
  • Mutation
  • Proto-Oncogene Proteins / metabolism*
  • Signal Transduction*
  • Trans-Activators*
  • Transcription Factors
  • Ubiquitin-Protein Ligases*
  • Ubiquitins / metabolism
  • Wings, Animal / embryology
  • Wnt1 Protein
  • beta-Transducin Repeat-Containing Proteins

Substances

  • ARM protein, Drosophila
  • Armadillo Domain Proteins
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Drosophila Proteins
  • F-Box Proteins
  • Hedgehog Proteins
  • Insect Proteins
  • Proto-Oncogene Proteins
  • Trans-Activators
  • Transcription Factors
  • Ubiquitins
  • Wnt1 Protein
  • beta-Transducin Repeat-Containing Proteins
  • ci protein, Drosophila
  • slmb protein, Drosophila
  • wg protein, Drosophila
  • hh protein, Drosophila
  • Ubiquitin-Protein Ligases
  • Cyclic AMP-Dependent Protein Kinases
  • GTP-Binding Proteins

Associated data

  • GENBANK/AF032878