Monoubiquitination of p120-catenin is essential for TGFβ-induced epithelial-mesenchymal transition and tumor metastasis

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.

TOP2A promotes proliferation and metastasis of hepatocellular carcinoma regulated by miR-144-3p

“…At the same time, we noticed that cell-cell adherent junctions (AJS) were also significantly related to the high expression of TOP2A according to GSEA result ( Figure 4 A ). Numbers of studies have reported that EMT and AJS are closely related 22 , 23 . We then investigated the expression of EMT markers, such as N-cadherin, E-cadherin, Vimentin and Slug, using Western Blot in TOP2A knockdown cells.…”

“…In this pathway CDK1-Cyclin B1 complex plays an important role in promoting the G2/M phase transition. Particularly, CHK1 phosphorylation suppresses the formation of CDK1-CyclinB1 complex and blocks the progression of the cell cycle [21][22][23][24]. We found that knockdown and overexpression of TOP2A respectively promotes and inhibits the phosphorylation of CHK1.…”

ZEB2 facilitates peritoneal metastasis by regulating the invasiveness and tumorigenesis of cancer stem-like cells in high-grade serous ovarian cancers

“…Epithelial–mesenchymal (E–M) transition (EMT), a cellular remodelling programme in embryogenesis and tumorigenesis, contributes to tumour metastasis [ 11 , 12 ], therapy resistance and disease recurrence [ 13 , 14 ], during which cells lose epithelial apical–basal polarity and establish mesenchymal front–back polarity, decrease cell–cell adhesion and remodel cell–matrix adhesions as well as the cytoskeleton to acquire cell motility and invade the basement membrane [ 15 , 16 ]. When tumour cells are shed from the primary lesion into the peritoneal cavity, EMT, as an essential process orchestrated by a series of transcripts, induces cellular anoikis resistance and leads to the survival of malignant cells in ascites [ 17 ].…”

Application of two-dimensional difference gel electrophoresis to identify protein changes between center, margin, and adjacent non-tumor tissues obtained from non-small-cell lung cancer with adenocarcinoma or squamous cell carcinoma subtype

“…It is also interesting to note the association of semaphorins with the RhoA signaling pathway [ 95 , 96 ]. This signaling pathway is also involved in epithelial adherens junctions (AJs), indicated in our analysis, which are part of the mechanism binding epithelial cells together [ 97 ]. It is of interest that both molecules involved in AJs, MYL3 and TUBB, are upregulated in the tumor center, which may be important for AJs in this region.…”