Axin-mediated CKI phosphorylation of β-catenin at Ser 45: A molecular switch for the Wnt pathway

Sharon Amit, Ada Hatzubai, Yaara Birman, Jens S. Andersen, Etti Ben-Shushan, Matthias Mann, Yinon Ben-Neriah*, Irit Alkalay

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

613 Scopus citations

Abstract

The Wnt pathway controls numerous developmental processes via the β-catenin - TCF/LEF transcription complex. Deregulation of the pathway results in the aberrant accumulation of β-catenin in the nucleus, often leading to cancer. Normally, cytoplasmic β-catenin associates with APC and axin and is continuously phosphorylated by GSK-3β, marking it for proteasomal degradation. Wnt signaling is considered to prevent GSK-3β from phosphorylating β-catenin, thus causing its stabilization. However, the Wnt mechanism of action has not been resolved. Here we study the regulation of β-catenin phosphorylation and degradation by the Wnt pathway. Using mass spectrometry and phosphopeptide-specific antibodies, we show that a complex of axin and casein kinase I (CKI) induces β-catenin phosphorylation at a single site: serine 45 (S45). Immunopurified axin and recombinant CKI phosphorylate β-catenin in vitro at S45; CKI inhibition suppresses this phosphorylation in vivo. CKI phosphorylation creates a priming site for GSK-3β and is both necessary and sufficient to initiate the β-catenin phosphorylation - degradation cascade. Wnt3A signaling and Dvl overexpression suppress S45 phosphorylation, thereby precluding the initiation of the cascade. Thus, a single, CKI-dependent phosphorylation event serves as a molecular switch for the Wnt pathway.

Original languageAmerican English
Pages (from-to)1066-1076
Number of pages11
JournalGenes and Development
Volume16
Issue number9
DOIs
StatePublished - 1 May 2002

Keywords

  • Axin
  • CKI
  • Ser 45 phosphorylation
  • Wnt regulation
  • β-Catenin

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