Proteolysis of the Hedgehog signaling effector Cubitus interruptus requires phosphorylation by Glycogen Synthase Kinase 3 and Casein Kinase 1

Cell. 2002 Mar 22;108(6):823-35. doi: 10.1016/s0092-8674(02)00664-5.

Abstract

The secreted signaling molecule Hedgehog regulates gene expression in target cells in part by preventing proteolysis of the full-length Cubitus interruptus (Ci-155) transcriptional activator to the Ci-75 repressor form. Ci-155 proteolysis depends on phosphorylation at three sites by Protein Kinase A (PKA). We show that these phosphoserines prime further phosphorylation at adjacent Glycogen Synthase Kinase 3 (GSK3) and Casein Kinase I (CK1) sites. Alteration of the GSK3 or CK1 sites prevents Ci-155 proteolysis and activates Ci in the absence of Hedgehog. Ci-155 proteolysis is also inhibited if cells lack activity of the Drosophila GSK3, Shaggy, previously implicated in Wingless signaling. Conversely, Ci-155 levels are reduced in Hedgehog-responding cells by overexpression of PKA and the Drosophila CK1, Double-time, a regulator of circadian rhythms.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Calcium-Calmodulin-Dependent Protein Kinases / genetics
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Casein Kinases
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Drosophila
  • Drosophila Proteins / metabolism*
  • Gene Expression Regulation, Enzymologic
  • Glycogen Synthase Kinase 3
  • Glycogen Synthase Kinases
  • Hedgehog Proteins
  • In Vitro Techniques
  • Molecular Sequence Data
  • Mutation
  • Phosphorylation
  • Protein Kinases / metabolism*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Signal Transduction / physiology
  • Transcription Factors
  • Wnt Proteins
  • Zebrafish Proteins*

Substances

  • DNA-Binding Proteins
  • Drosophila Proteins
  • Hedgehog Proteins
  • Proto-Oncogene Proteins
  • Transcription Factors
  • Wnt Proteins
  • Zebrafish Proteins
  • ci protein, Drosophila
  • hh protein, Drosophila
  • Protein Kinases
  • Glycogen Synthase Kinases
  • Casein Kinases
  • Protein-Serine-Threonine Kinases
  • Sgg protein, Drosophila
  • Cyclic AMP-Dependent Protein Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Glycogen Synthase Kinase 3