Your browser version may not work well with NCBI's Web applications. More information here...
1: Proc Natl Acad Sci U S A. 2008 Jun 10;105(23):8032-7. Epub 2008 May 28.
Related Articles, Links
Click here to read Click here to read
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.

Department of Cell and Developmental Biology, Vanderbilt University Medical Center, 465 21st Avenue South, U-4200 Learned Laboratory, Medical Research Building III, Nashville, TN 37232-8240, USA.

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.

Publication Types:
PMID: 18509060 [PubMed - indexed for MEDLINE]

PMCID: PMC2430354 [Available on 12/10/08]