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Phosphorylation of axin, a Wnt signal negative regulator, by glycogen synthase kinase-3beta regulates its stability

H Yamamoto1, S Kishida, M Kishida

  • 1Department of Biochemistry, Hiroshima University School of Medicine, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8551, Japan.

The Journal of Biological Chemistry
|April 10, 1999
PubMed

Insights

Axin stability is regulated by phosphorylation, which is influenced by GSK-3beta and Dvl. Wnt signaling down-regulates Axin via Dvl, impacting beta-catenin levels.

Area of Science:

  • Cellular Biology
  • Molecular Signaling
  • Protein Regulation

Background:

  • Axin is a key component of the beta-catenin destruction complex.
  • Glycogen synthase kinase-3beta (GSK-3beta) phosphorylates both Axin and beta-catenin.
  • The role of Axin phosphorylation in its own regulation was unclear.

Purpose of the Study:

  • To investigate the physiological significance of Axin phosphorylation by GSK-3beta.
  • To determine how Wnt signaling affects Axin stability.
  • To elucidate the role of Dvl in Axin regulation.

Main Methods:

  • Treatment of COS cells with GSK-3beta and protein phosphatase inhibitors.
  • Pulse-chase analyses to assess Axin stability.
  • In vitro kinase assays with Axin mutants and Dvl-1.
  • Wnt-3a stimulation in L cells and analysis of Dvl-1(DeltaPDZ) effects.

Main Results:

  • GSK-3beta inhibition decreased Axin levels, while phosphatase inhibition increased them.
  • Phosphorylated Axin is more stable; Axin mutants lacking phosphorylation sites have shorter half-lives.
  • Dvl-1 inhibited Axin phosphorylation by GSK-3beta in vitro.
  • Wnt-3a down-regulated Axin and increased beta-catenin; Dvl-1(DeltaPDZ) suppressed this Wnt effect.

Conclusions:

  • Axin phosphorylation by GSK-3beta is crucial for its protein stability.
  • Wnt signaling, mediated by Dvl, down-regulates Axin levels.
  • These findings reveal a regulatory mechanism for Axin stability and Wnt signaling.

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