Regulation of protein stability by GSK3 mediated phosphorylation

Cell Cycle. 2009 Dec 15;8(24):4032-9. doi: 10.4161/cc.8.24.10111. Epub 2009 Dec 17.


Glycogen synthase kinase-3 (GSK3) plays important roles in numerous signaling pathways that regulate a variety of cellular processes including cell proliferation, differentiation, apoptosis and embryonic development. In the canonical Wnt signaling pathway, GSK3 phosphorylation mediates proteasomal targeting and degradation of beta-catenin via the destruction complex. We recently reported a biochemical screen that discovered multiple additional protein substrates whose stability is regulated by Wnt signaling and/or GSK3 and these have important implications for Wnt/GSK3 regulation of different cellular processes.(1) In this article, we also present a bio-informatics based screen for proteins whose stability may be controlled by GSK3 and beta-Trcp, the SCF E3 ubiquitin ligase that is responsible for beta-catenin degradation in the Wnt signaling pathway. Furthermore, we review various GSK3 regulated proteolysis substrates described in the literature. We propose that GSK3 phosphorylation dependent proteolysis is a widespread mechanism that the cell employs to regulate a variety of cell processes in response to signals.

MeSH terms

  • Animals
  • Glycogen Synthase Kinase 3 / metabolism*
  • Humans
  • Peptide Hydrolases / metabolism
  • Phosphorylation / physiology
  • Protein Stability*
  • Signal Transduction / physiology*
  • Ubiquitination / physiology
  • Wnt Proteins / metabolism*


  • Wnt Proteins
  • Glycogen Synthase Kinase 3
  • Peptide Hydrolases