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.
Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.