Wingless Inactivates Glycogen Synthase kinase-3 via an Intracellular Signalling Pathway Which Involves a Protein Kinase C

EMBO J. 1996 Sep 2;15(17):4526-36.

Abstract

The Drosophila gene product Wingless (Wg) is a secreted glycoprotein and a member of the Wnt gene family. Genetic analysis of Drosophila epidermal development has defined a putative paracrine Wg signalling pathway involving the zeste-white 3/shaggy (zw3/sgg) gene product. Although putative components of Wg- (and by inference Wnt-) mediated signalling pathways have been identified by genetic analysis, the biochemical significance of most factors remains unproven. Here we show that in mouse 10T1/2 fibroblasts the activity of glycogen synthase kinase-3 (GSK-3), the murine homologue of Zw3/Sgg, is inactivated by Wg. This occurs through a signalling pathway that is distinct from insulin-mediated regulation of GSK-3 in that Wg signalling to GSK-3 is insensitive to wortmannin. Additionally, Wg-induced inactivation of GSK-3 is sensitive to both the protein kinase C (PKC) inhibitor Ro31-8220 and prolonged pre-treatment of 10T1/2 fibroblasts with phorbol ester. These findings provide the first biochemical evidence in support of the genetically defined pathway from Wg to Zw3/Sgg, and suggest a previously uncharacterized role for a PKC upstream of GSK-3/Zw3 during Wnt/Wg signal transduction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androstadienes / pharmacology
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors*
  • Culture Media, Conditioned
  • Drosophila / embryology
  • Drosophila / genetics
  • Drosophila Proteins*
  • Enzyme Inhibitors / pharmacology
  • Fibroblasts / metabolism
  • Glycogen Synthase Kinase 3
  • Glycogen Synthase Kinases
  • Mice
  • Polyenes / pharmacology
  • Protein Kinases / agonists
  • Protein Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Signal Transduction*
  • Sirolimus
  • Tetradecanoylphorbol Acetate / pharmacology
  • Wnt1 Protein
  • Wortmannin

Substances

  • Androstadienes
  • Culture Media, Conditioned
  • Drosophila Proteins
  • Enzyme Inhibitors
  • Polyenes
  • Proto-Oncogene Proteins
  • Wnt1 Protein
  • wg protein, Drosophila
  • Protein Kinases
  • Glycogen Synthase Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Glycogen Synthase Kinase 3
  • Tetradecanoylphorbol Acetate
  • Sirolimus
  • Wortmannin