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.
Zhao Y
1,
Wang X
1,
Wang Q
2,
Deng Y
3,
Li K
1,
Zhang M
1,
Zhang Q
1,
Zhou J
4,
Wang HY
4,
Bai P
4,
Ren Y
1,
Zhang N
3,
Li W
5,
Cheng Y
6,
Xiao W
7,
Du HN
4,
Cheng X
6,
Yin L
4,
Fu X
8,
Lin D
8,
Zhou Q
2,
Zhong B
9.
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
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