Monoubiquitination of p120-catenin is essential for TGFβ-induced epithelial-mesenchymal transition and tumor metastasis
Monoubiquitination of p120-catenin is essential for TGFβ-induced epithelial-mesenchymal transition and tumor metastasis
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DOI：
10.1126/sciadv.aay9819
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发表时间：
2020-01
期刊：
影响因子：
13.6
通讯作者：
Qingang Wu;Gao-De Li;Chengwen Wen;Taoling Zeng;Yuxi Fan;Chunyan Liu;G. Fu;Changchuan Xie;Qi Lin;Liping Xie;Lei Huang;Pengpeng Pu;Zhong Ouyang;H. Chan;Tong-Jin Zhao;X. L. Chen;G. Fu;Hong-Rui Wang
中科院分区：
文献类型：
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作者：
Qingang Wu;Gao-De Li;Chengwen Wen;Taoling Zeng;Yuxi Fan;Chunyan Liu;G. Fu;Changchuan Xie;Qi Lin;Liping Xie;Lei Huang;Pengpeng Pu;Zhong Ouyang;H. Chan;Tong-Jin Zhao;X. L. Chen;G. Fu;Hong-Rui Wang
在TGFβ诱导的EMT中，p120-catenin的单泛素化控制粘附连接的解离。细胞间连接的破坏是上皮-间质转化（EMT）的标志。然而，这些连接是如何分解的，在很大程度上仍然未知。在此，我们报道了E3泛素连接酶Smurf 1靶向p120-catenin（粘附连接（AJ）复合物的核心组分），在转化生长因子β（TGFβ）诱导的EMT过程中进行单泛素化，从而导致AJ解离。在TGFβ处理后，活化的细胞外信号调节激酶1/2（ERK 1/2）磷酸化p120-连环蛋白的T900，以促进其与Smurf 1的相互作用和随后的单泛素化。抑制T900磷酸化或p120-catenin的泛素化可消除TGFβ诱导的AJ解离以及随之而来的紧密连接（TJ）解离和细胞骨架重排，从而显著阻断小鼠乳腺癌的肺转移。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TGFβ诱导AJ在EMT过程中解离的潜在机制，并提供了一种潜在的阻断肿瘤转移的策略。
Monoubiquitination of p120-catenin controls adherens junction dissociation in TGFβ-induced EMT. 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.