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

Cselenyi CS, Jernigan KK, Tahinci E, Thorne CA, Lee LA, Lee E
Proc Natl Acad Sci U S A. 2008 105 (23): 8032-7

PMID: 18509060 · PMCID: PMC2430354 · DOI:10.1073/pnas.0803025105

Wnt/beta-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 beta-catenin, which then translocates to the nucleus to regulate target gene expression. To understand how Wnt signaling prevents beta-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 beta-catenin by stimulating degradation of Axin, a scaffold protein required for beta-catenin degradation. In certain systems, however, Wnt-mediated Axin turnover is not detected until after beta-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 beta-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 beta-catenin in the absence of Axin turnover. Through experiments in egg extract and reconstitution with purified proteins, we identify a mechanism whereby LRP6 stabilizes beta-catenin independently of Axin degradation by directly inhibiting GSK3's phosphorylation of beta-catenin.

MeSH Terms (27)

Adaptor Proteins, Signal Transducing Animals Axin Protein beta Catenin Cattle Cell Extracts Dishevelled Proteins Embryo, Nonmammalian Glycogen Synthase Kinase 3 Intracellular Space Low Density Lipoprotein Receptor-Related Protein-6 Mice Ovum Phosphoproteins Phosphorylation Proteasome Endopeptidase Complex Protein Processing, Post-Translational Protein Structure, Tertiary Receptors, LDL Recombinant Proteins Repressor Proteins Signal Transduction Thermodynamics Ubiquitin Wnt Proteins Xenopus Xenopus Proteins

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