ERK-Smurf1-RhoA signaling is critical for TGFβ-drived EMT and tumor metastasis

  • Life Sci Alliance. 2022 Jun 2;5(10):e202101330. doi: 10.26508/lsa.202101330.
Jianzhong Zheng  1  2 ,  Zhiyuan Shi  1  2 ,  Pengbo Yang  3 ,  Yue Zhao  1  2 ,  Wenbin Tang  1  2 ,  Shaopei Ye  1  2 ,  Zuodong Xuan  1  2 ,  Chen Chen  1  2 ,  Chen Shao  2 ,  Qingang Wu  4  5 ,  Huimin Sun  6  7
Affiliations
  • 1. School of Medicine, Xiamen University, Xiamen, China.
  • 2. Department of Urology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
  • 3. Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, China.
  • 4. School of Medicine, Xiamen University, Xiamen, China [email protected] [email protected].
  • 5. Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
  • 6. The Central Lab of Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China [email protected] [email protected].
  • 7. The Key Laboratory for Endocrine Related Cancer Precision Medicine Of Xiamen, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
PMID: 35654587 DOI: 10.26508/lsa.202101330
Abstract

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.

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