USP2a supports metastasis by tuning TGF-? signaling
Author:  Date:2018-02-27  Clicks:
Cell Rep. 2018 Feb 27;22(9):2442-2454. doi: 10.1016/j.celrep.2018.02.007.

USP2a Supports Metastasis by Tuning TGFSignaling.

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.

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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.


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

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