Phosphorylation of β-Catenin by AKT Promotes β-Catenin Transcriptional Activity

Dexing Fang,David Hawke,Yanhua Zheng,Yan Xia,Jill Meisenhelder,Heinz Nika,Gordon B Mills,Ryuji Kobayashi,Tony Hunter,Zhimin Lu

doi:10.1074/jbc.m611871200

Abstract

Increased transcriptional activity of beta-catenin resulting from Wnt/Wingless-dependent or -independent signaling has been detected in many types of human cancer, but the underlying mechanism of Wnt-independent regulation is poorly understood. We have demonstrated that AKT, which is activated downstream from epidermal growth factor receptor signaling, phosphorylates beta-catenin at Ser552 in vitro and in vivo. AKT-mediated phosphorylation of beta-catenin causes its disassociation from cell-cell contacts and accumulation in both the cytosol and the nucleus and enhances its interaction with 14-3-3zeta via a binding motif containing Ser552. Phosphorylation of beta-catenin by AKT increases its transcriptional activity and promotes tumor cell invasion, indicating that AKT-dependent regulation of beta-catenin plays a critical role in tumor invasion and development.

Highlights

Repeats of ␤-catenin [5]. ␤-Catenin is phosphorylated in its N-terminal domain by GSK-3␤, which leads to its degradation via the ubiquitin/proteasome pathway mediated by SKP1/CUL1/F-box E3 ligase (6 –11)
Gain of function mutations in ␤-catenin, including N-terminal mutations that lead to stabilization of the protein or loss of function mutations in proteins that participate in the regulated turnover of ␤-catenin, such as the tumor suppressor adenomatous polyposis coli (APC), result in up-regulation of ␤-catenin protein levels, increasing its transcriptional activity
AKT Phosphorylates ␤-Catenin at Ser552 in Vitro and in Vivo—We previously showed that epidermal growth factor (EGF) stimulation results in translocation of ␤-catenin into the nucleus and increased transcriptional activity without altering its stability and phosphorylation level by GSK-3␤ [16]

Summary

Introduction

Repeats of ␤-catenin [5]. ␤-Catenin is phosphorylated in its N-terminal domain by GSK-3␤, which leads to its degradation via the ubiquitin/proteasome pathway mediated by SKP1/CUL1/F-box E3 ligase (6 –11). AKT phosphorylates ␤-catenin at Ser552, which leads to its disassociation from cell-cell contacts, increases its binding to 14-3-3␨ and its transcriptional activity and enhances invasion by tumor cells. AKT Phosphorylates ␤-Catenin at Ser552 in Vitro and in Vivo—We previously showed that EGF stimulation results in translocation of ␤-catenin into the nucleus and increased transcriptional activity without altering its stability and phosphorylation level by GSK-3␤ [16].

Results

Conclusion