LRP6 transduces a canonical Wnt signal independently of Axin degradation by inhibiting GSK3's phosphorylation of β-catenin

Christopher S. Cselenyi, Kristin K. Jernigan, Emilios Tahinci, Curtis A. Thorne, Laura A. Lee, Ethan Lee

Research output: Contribution to journalArticlepeer-review

154 Scopus citations

Abstract

Wnt/β-catenin signaling controls various cell fates in metazoan development and is misregulated in several cancers and developmental disorders. Binding of a Wnt ligand to its transmembrane coreceptors inhibits phosphorylation and degradation of the transcriptional coactivator β-catenin, which then translocates to the nucleus to regulate target gene expression. To understand how Wnt signaling prevents β-catenin degradation, we focused on the Wnt coreceptor low-density lipoprotein receptor-related protein 6 (LRP6), which is required for signal transduction and is sufficient to activate Wnt signaling when overexpressed. LRP6 has been proposed to stabilize β-catenin by stimulating degradation of Axin, a scaffold protein required for β-catenin degradation. In certain systems, however, Wnt-mediated Axin turnover is not detected until after β-catenin has been stabilized. Thus, LRP6 may also signal through a mechanism distinct from Axin degradation. To establish a biochemically tractable system to test this hypothesis, we expressed and purified the LRP6 intracellular domain from bacteria and show that it promotes β-catenin stabilization and Axin degradation in Xenopus egg extract. Using an Axin mutant that does not degrade in response to LRP6, we demonstrate that LRP6 can stabilize β-catenin in the absence of Axin turnover. Through experiments in egg extract and reconstitution with purified proteins, we identify a mechanism whereby LRP6 stabilizes β-catenin independently of Axin degradation by directly inhibiting GSK3's phosphorylation of β-catenin.

Original languageEnglish (US)
Pages (from-to)8032-8037
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number23
DOIs
StatePublished - Jun 10 2008
Externally publishedYes

Keywords

  • Axin
  • GSK3
  • LRP6
  • Wnt

ASJC Scopus subject areas

  • General

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