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USP2a Supports Metastasis by Tuning TGF-β Signaling

Authors :
Yin Zhao
Xiaomeng Wang
Qingqing Wang
Yu Deng
Kang Li
Man Zhang
Qiang Zhang
Jin Zhou
Hong-Yan Wang
Peng Bai
Yujie Ren
Ni Zhang
Weina Li
Yongbo Cheng
Wuhan Xiao
Hai-Ning Du
Xiaoliang Cheng
Lei Yin
Xiangning Fu
Dandan Lin
Qianghui Zhou
Bo Zhong
Source :
Cell Reports, Vol 22, Iss 9, Pp 2442-2454 (2018)
Publication Year :
2018
Publisher :
Elsevier, 2018.

Abstract

Summary: 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. : Zhao et al. find that USP2a deconjugates K33-linked ubiquitination of TGFBR1 at Lys502 and is phosphorylated at Ser207/Ser225 by TGFBR2 after TGF-β stimulation. This allows R-SMAD recruitment to and subsequent disassociation from the TGFBR1/2 receptor complex. Keywords: USP2a, TGF-β, epithelial-to-mesenchymal transition, metastasis, ubiquitination, phosphorylation, SMAD2/3, TGFBR1/2, signaling transduction

Subjects

Subjects :
Biology (General)
QH301-705.5

Details

Language :
English
ISSN :
22111247
Volume :
22
Issue :
9
Database :
Directory of Open Access Journals
Journal :
Cell Reports
Publication Type :
Academic Journal
Accession number :
edsdoj.9a96e218d9e8425c88acf8e3af3908ca
Document Type :
article
Full Text :
https://doi.org/10.1016/j.celrep.2018.02.007