APC Is Essential for Targeting Phosphorylated β-Catenin to the SCF^β-TrCP Ubiquitin Ligase

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• 作者：YunYun Su ; Chunjiang Fu ; Shinji Ishikawa ; Aless ; ra Stella ; Masayuki Kojima ; Kazuhisa Shitoh ; Emanuel M. Schreiber ; Billy W. Day ; Bo Liu
• 刊名：Molecular Cell
• 出版年：2008
• 出版时间：5 December 2008
• 年：2008
• 卷：32
• 期：5
• 页码：652-661
• 全文大小：933 K

文摘

Summary

Ubiquitin-dependent proteolysis is an important mechanism that suppresses the β-catenin transcription factor in cells without Wnt stimulation. A critical step in this regulatory pathway is to create a SCF^β-TrCP E3 ubiquitin ligase binding site for β-catenin. Here we show that the SCF^β-TrCP binding site created by phosphorylation of β-catenin is highly vulnerable to protein phosphatase 2A (PP2A) and must be protected by the adenomatous polyposis coli (APC) tumor suppressor protein. Specifically, phosphorylated β-catenin associated with the wild-type APC protein is recruited to the SCF^β-TrCP complex, ubiquitin conjugated, and degraded. A mutation in APC that deprives this protective function exposes the N-terminal phosphorylated serine/threonine residues of β-catenin to PP2A. Dephosphorylation at these residues by PP2A eliminates the SCF^β-TrCP recognition site and blocks β-catenin ubiquitin conjugation. Thus, by acting to protect the E3 ligase binding site, APC ensures the ubiquitin conjugation of phosphorylated β-catenin.