School of Medicine, Xiamen University, Xiamen, China.
Department of Urology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
Life Sci Alliance. 2022 Jun 2;5(10). doi: 10.26508/lsa.202101330. Print 2022 Oct.
Epithelial-mesenchymal transition (EMT) has fundamental roles in various biological processes. However, there are still questions pending in this fast-moving field. Here we report that in TGFβ-induced EMT, ERK-mediated Smurf1 phosphorylation is a prerequisite step for RhoA degradation and the consequent mesenchymal state achievement. Upon TGFβ treatment, activated ERK phosphorylates Thr223 of Smurf1, a member of HECT family E3 ligase, to promote Smurf1-mediated polyubiquitination and degradation of RhoA, thereby leading to cell skeleton rearrangement and EMT. Blockade of phosphorylation of Smurf1 inhibits TGFβ-induced EMT, and accordingly, dramatically blocks lung metastasis of murine breast cancer in mice. Hence, our study reveals an unknown role of ERK in TGFβ-induced EMT and points out a potential strategy in therapeutic intervention.
上皮-间充质转化 (EMT) 在各种生物学过程中起着重要作用。然而，在这个快速发展的领域仍有一些问题悬而未决。在这里，我们报告在 TGFβ诱导的 EMT 中，ERK 介导的 Smurf1 磷酸化是 RhoA 降解和随后获得间充质状态的必要步骤。在 TGFβ处理后，激活的 ERK 磷酸化 HECT 家族 E3 连接酶 Smurf1 的 Thr223，以促进 Smurf1 介导的 RhoA 多泛素化和降解，从而导致细胞骨架重排和 EMT。Smurf1 磷酸化的阻断抑制 TGFβ诱导的 EMT，并相应地，在小鼠中显著阻止了鼠乳腺癌的肺转移。因此，我们的研究揭示了 ERK 在 TGFβ诱导的 EMT 中的未知作用，并指出了一种潜在的治疗干预策略。
