USP2a Supports Metastasis by Tuning TGF-beta Signaling

Authors: Zhao, Yin; Wang, Xiaomeng; Wang, Qingqing; Deng, Yu; Li, Kang; Zhang, Man; Zhang, Qiang; Zhou, Jin; Wang, Hong-Yan; Bai, Peng; Ren, Yujie; Zhang, Ni; Li, Weina; Cheng, Yongbo; Xiao, Wuhan; Du, Hai-Ning; Cheng, Xiaoliang; Yin, Lei; Fu, Xiangning; Lin, Dandan; Zhou, Qianghui; Zhong, Bo

TGF-beta 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-beta-triggered signaling. USP2a interacts with TGFBR1 and TGFBR2 upon TGF-beta 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-beta-triggered signaling and metastasis. Our findings have characterized an essential role of USP2a as a potential target for treatment of metastatic cancers.

Volume: 22
Issue: 13
Pages: 2442 - 2454
Published Online: 2018
Full Text Link: http://dx.doi.org/10.1016/j.celrep.2018.02.007