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Cell Rep. 2018 Feb 27;22(9):2442-2454. doi: 10.1016/j.celrep.2018.02.007.

USP2a Supports Metastasis by Tuning TGF-β Signaling.

Author information

1
Medical Research Institute, School of Medicine, Wuhan University, Wuhan 430071, China; College of Life Sciences, Wuhan University, Wuhan 430072, China.
2
College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, China.
3
Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
4
College of Life Sciences, Wuhan University, Wuhan 430072, China.
5
Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
6
Wuhan Qlife Lab, Co., Wuhan 430074, China.
7
Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China.
8
Cancer Center, Renmin Hospital of Wuhan University, Wuhan 430060, China.
9
Medical Research Institute, School of Medicine, Wuhan University, Wuhan 430071, China; College of Life Sciences, Wuhan University, Wuhan 430072, China. Electronic address: zhongbo@whu.edu.cn.

Abstract

TGF-β has been demonstrated to promote tumor metastasis, and the regulatory mechanisms are poorly understood. Here, we report the role of USP2a in promoting metastasis by facilitating TGF-β-triggered signaling. USP2a interacts with TGFBR1 and TGFBR2 upon TGF-β stimulation and removes K33-linked polyubiquitin chains from Lys502 of TGFBR1, promoting the recruitment of SMAD2/3. Simultaneously, TGFBR2 phosphorylates Ser207/Ser225 of USP2a, leading to the disassociation of SMAD2/3 from TGFBR1. The phosphorylation of USP2a and SMAD2 is positively correlated in human tumor biopsies, and USP2a is hyper-phosphorylated in lung adenocarcinomas with lymph node invasion. Depletion or pharmacologic inhibition of USP2a dampens TGF-β-triggered signaling and metastasis. Our findings have characterized an essential role of USP2a as a potential target for treatment of metastatic cancers.

KEYWORDS:

SMAD2/3; TGF-β; TGFBR1/2; USP2a; epithelial-to-mesenchymal transition; metastasis; phosphorylation; signaling transduction; ubiquitination

PMID:
29490279
DOI:
10.1016/j.celrep.2018.02.007
[Indexed for MEDLINE]
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