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.

中文翻译：

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p120-catenin的单泛素化对于TGFβ诱导的上皮-间质转化和肿瘤转移至关重要。

细胞间连接的拆卸是上皮-间质转化（EMT）的标志。但是，如何解开路口仍然很未知。在这里，我们报道E3泛素连接酶Smurf1靶向p120-catenin（粘附连接（AJ）复合物的核心成分）在转化生长因子β（TGFβ）诱导的EMT期间进行单泛素化，从而导致AJ分离。经过TGFβ处理后，活化的细胞外信号调节激酶1/2（ERK1 / 2）使p120-catenin的T900磷酸化，从而促进其与Smurf1的相互作用以及随后的单泛素化。抑制p120-catenin的T900磷酸化或泛素化消除了TGFβ诱导的AJ分离和随之而来的紧密连接（TJ）分离和细胞骨架重排，从而显着阻断了鼠乳腺癌的肺转移。此外，p120-catenin的T900磷酸化水平与人乳腺癌的恶性程度呈正相关。因此，我们的研究揭示了在EMT期间TGFβ诱导AJ的解离的潜在机制，并提供了阻断肿瘤转移的潜在策略。