USP2a Supports Metastasis by Tuning TGF-? Signaling.

TGF-? 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-?-triggered signaling. USP2a interacts with TGFBR1 and TGFBR2 upon TGF-? 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-?-triggered signaling and metastasis. Our findings have characterized an essential role of USP2a as a potential target for treatment of metastatic cancers.
Mesh Terms:
Amino Acid Sequence, Animals, Endopeptidases, Female, HEK293 Cells, Humans, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Neoplasm Metastasis, Phosphorylation, Polyubiquitin, Promoter Regions, Genetic, Receptor, Transforming Growth Factor-beta Type I, Receptor, Transforming Growth Factor-beta Type II, Signal Transduction, Smad Proteins, Transforming Growth Factor beta, Ubiquitin-Specific Proteases, Ubiquitination
Cell Rep
Date: Dec. 27, 2017
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