USP2a Supports Metastasis by Tuning TGF-β Signaling

Cell Reports
Yin ZhaoBo Zhong

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.

Citations

Apr 28, 2018·International Journal of Molecular Sciences·Laia CajaIsabel Fabregat
Oct 24, 2018·Cellular and Molecular Life Sciences : CMLS·Soo-Yeon Kim, Kwang-Hyun Baek
May 8, 2019·Cell Biochemistry and Function·Md Tariqul IslamHanchun Chen
Oct 22, 2020·Cell Death and Differentiation·Lyudmila KrassikovaErik Norberg
Aug 27, 2019·Biochimica Et Biophysica Acta. Reviews on Cancer·Ji ChengWenyi Wei
Nov 8, 2020·Cancers·Kamini Kaushal, Suresh Ramakrishna
Dec 19, 2020·Cell Death and Differentiation·Mohammed A BasarAchim Werner
Feb 4, 2021·International Journal of Molecular Sciences·Hiroshi Kitamura, Mayuko Hashimoto
May 1, 2021·International Journal of Molecular Sciences·Shiyao ChenHuchen Zhou
Aug 24, 2021·The Journal of Biological Chemistry·Fengwu ZhangYi Sun

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