Monoubiquitination of p120-catenin is essential for TGFβ-induced epithelial-mesenchymal transition and tumor metastasis
Open Access
- 24 January 2020
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Advances
- Vol. 6 (4), eaay9819
- https://doi.org/10.1126/sciadv.aay9819
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.Funding Information
- National Natural Science Foundation of China (31970742)
- National Natural Science Foundation of China (U1605222)
- National Key Research and Development Project of China (2016YFC1302400)
This publication has 42 references indexed in Scilit:
- Multiplex Genome Engineering Using CRISPR/Cas SystemsScience, 2013
- aV integrins and TGF‐β‐induced EMT: a circle of regulationJournal of Cellular and Molecular Medicine, 2012
- A p120 Catenin Isoform Switch Affects Rho Activity, Induces Tumor Cell Invasion, and Predicts Metastatic DiseaseOnline Journal of Public Health Informatics, 2008
- Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype?Nature Reviews Cancer, 2007
- Non-Smad TGF-β signalsJournal of Cell Science, 2005
- Serine and Threonine Phospho-Specific Antibodies to p120-CateninHybridoma and Hybridomics, 2004
- Regulation of Cell Polarity and Protrusion Formation by Targeting RhoA for DegradationScience, 2003
- Smad-dependent and Smad-independent pathways in TGF-β family signallingNature, 2003
- Molecular Cloning of the Human p120ctnCatenin Gene (CTNND1): Expression of Multiple Alternatively Spliced IsoformsGenomics, 1998
- The E-cadherin Complex Contains the src Substrate p120Experimental Cell Research, 1995