Lithium Inhibits Glycogen Synthase kinase-3 Activity and Mimics Wingless Signalling in Intact Cells

Curr Biol. 1996 Dec 1;6(12):1664-8. doi: 10.1016/s0960-9822(02)70790-2.

Abstract

Background: Exposing eukaryotic cells to lithium ions (Li+) during development has marked effects on cell fate and organization. The phenotypic consequences of Li+ treatment on Xenopus embryos and sporulating Dictyostelium are similar to the effects of inhibition or disruption, respectively, of a highly conserved protein serine/threonine kinase, glycogen synthase kinase-3 (GSK-3). In Drosophila, the GSK-3 homologue is encoded by zw3sgg, a segment-polarity gene involved in embryogenesis that acts downstream of wg. In higher eukaryotes, GSK-3 has been implicated in signal transduction pathways downstream of phosphoinositide 3-kinase and mitogen-activated protein kinases.

Results: We investigated the effect of Li+ on the activity of the GSK-3 family. At physiological doses, Li+ inhibits the activity of human GSK-3 beta and Drosophila Zw3Sgg, but has no effect on other protein kinases. The effect of Li+ on GSK-3 is reversible in vitro. Treatment of cells with Li+ inhibits GSK-3-dependent phosphorylation of the microtubule-associated protein Tau. Li+ treatment of Drosophila S2 cells and rat PC12 cells induces accumulation of cytoplasmic Armadillo/beta-catenin, demonstrating that Li+ can mimic Wingless signalling in intact cells, consistent with its inhibition of GSK-3.

Conclusions: Li+ acts as a specific inhibitor of the GSK-3 family of protein kinases in vitro and in intact cells, and mimics Wingless signalling. This reveals a possible molecular mechanism of Li+ action on development and differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors*
  • Calcium-Calmodulin-Dependent Protein Kinases / genetics
  • Cell Line
  • Drosophila Proteins*
  • Glycogen Synthase Kinase 3
  • Glycogen Synthase Kinases
  • Humans
  • Lithium Chloride / pharmacology*
  • Microtubule-Associated Proteins / antagonists & inhibitors*
  • Microtubule-Associated Proteins / genetics
  • PC12 Cells
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Proto-Oncogene Proteins / metabolism*
  • Rats
  • Signal Transduction / physiology*
  • Wnt1 Protein

Substances

  • Drosophila Proteins
  • Microtubule-Associated Proteins
  • Proto-Oncogene Proteins
  • Wnt1 Protein
  • wg protein, Drosophila
  • Glycogen Synthase Kinases
  • Protein-Serine-Threonine Kinases
  • Sgg protein, Drosophila
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Glycogen Synthase Kinase 3
  • Lithium Chloride