Monoubiquitination of p120-catenin is essential for TGFβ-induced epithelial-mesenchymal transition and tumor metastasis
Qingang Wu, Li Gao, Chengwen Wen, Taoling Zeng, Yuxi Fan, Chunyan Liu, Guofeng Fu, Changchuan Xie, Qi Lin, Liping Xie, Lei Huang, Pengpeng Pu, Zhong Ouyang, Hong‐Lin Chan, Tong‐Jin Zhao, Xiao Lei Chen, Guo Fu, Hongrui Wang
Abstract
Disassembly of intercellular junctions is a hallmark of epithelial-mesenchymal transition (EMT). However, how the junctions disassemble remains largely unknown. Here, we report that E3 ubiquitin ligase Smurf1 targets p120-catenin, a core component of adherens junction (AJ) complex, for monoubiquitination during transforming growth factor β (TGFβ)-induced EMT, thereby leading to AJ dissociation. Upon TGFβ treatment, activated extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylates T900 of p120-catenin to promote its interaction with Smurf1 and subsequent monoubiquitination. Inhibition of T900 phosphorylation or ubiquitination of p120-catenin abrogates TGFβ-induced AJ dissociation and consequent tight junction (TJ) dissociation and cytoskeleton rearrangement, hence markedly blocking lung metastasis of murine breast cancer. Moreover, the T900 phosphorylation level of p120-catenin is positively correlated with malignancy of human breast cancer. Hence, our study reveals the underlying mechanism by which TGFβ induces dissociation of AJs during EMT and provides a potential strategy to block tumor metastasis.