期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 105, 期 23, 页码 8032-8037出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0803025105
关键词
axin; GSK3; LRP6; Wnt
资金
- NCI NIH HHS [T32 CA09592, T32 CA009592, P50 CA095103, P50 CA95103] Funding Source: Medline
- NIDDK NIH HHS [5 T32 DK007563] Funding Source: Medline
- NIGMS NIH HHS [5 T32 GM007347, 1 R01 GM081635-01, R01 GM081635, T32 GM007347] Funding Source: Medline
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 Writ signaling prevents beta-catenin degradation, we focused on the Writ coreceptor low-density lipoprotein receptor-related protein 6 (LRP6), which is required for signal transduction and is sufficient to activate Writ signaling when overexpressed. LRP6 has been proposed to stabilize beta-catenin by stimulating degradation of Axin, a scaffold protein required for p-catenin degradation. In certain systems, however, Wnt-mediated Axin turnover is not detected until after p-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 P-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.
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