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

Content Provider	PubMed Central
Author	Cselenyi, Christopher S. Jernigan, Kristin K. Tahinci, Emilios Thorne, Curtis A. Lee, Laura A. Lee, Ethan
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.
Related Links	http://dx.doi.org/10.1073/pnas.0803025105
Ending Page	8037
Page Count	6
Starting Page	8032
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	23
Volume Number	105
Language	English
Publisher	National Academy of Sciences
Publisher Date	2008-06-10
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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