USP2a Supports Metastasis by Tuning TGF-β Signaling

Publication date: 27 February 2018
Source:Cell Reports, Volume 22, Issue 9
Author(s): 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
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.

Graphical abstract

Teaser

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.


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