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p38 Stabilizes Snail by Suppressing DYRK2-Mediated Phosphorylation That Is Required for GSK3 beta-beta TrCP-Induced Snail Degradation

Authors
Ryu, Ki-JunPark, Sun-MiPark, Seung-HoKim, In-KyuHan, HyeontakKim, Hyo-JinKim, Seon-HeeHong, Keun-SeokKim, HyeminKim, MinjuYoon, Sung-JinAsaithambi, KillivalavanLee, Kon HoPark, Jae-YongHah, Young-SoolCho, Hee JunYook, Jong InYang, Jung WookKo, Gyung-HyuckLee, GyeminKang, Yang JaeHwangbo, CheolKim, Kwang DongPark, Young-JunYoo, Jiyun
Issue Date
15-8월-2019
Publisher
AMER ASSOC CANCER RESEARCH
Citation
CANCER RESEARCH, v.79, no.16, pp.4135 - 4148
Indexed
SCIE
SCOPUS
Journal Title
CANCER RESEARCH
Volume
79
Number
16
Start Page
4135
End Page
4148
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/63510
DOI
10.1158/0008-5472.CAN-19-0049
ISSN
0008-5472
Abstract
Snail is a key regulator of epithelial-mesenchymal transition (EMT), which is a major step in tumor metastasis. Although the induction of Snail transcription precedes EMT, posttranslational regulation, especially phosphorylation of Snail, is critical for determining Snail protein levels or stability, subcellular localization, and the ability to induce EMT. To date, several kinases are known that enhance the stability of Snail by preventing its ubiquitination; however, the molecular mechanism(s) underlying this are still unclear. Here, we identified p38 MAPK as a crucial post-translational regulator that enhances the stability of Snail. p38 directly phosphorylated Snail at Ser107, and this effectively suppressed DYRK2-mediated Ser104 phosphorylation, which is critical for GSK3 beta-dependent Snail phosphorylation and beta TrCP-mediated Snail ubiquitination and degradation. Importantly, functional studies and analysis of clinical samples established a crucial role for the p38-Snail axis in regulating ovarian cancer EMT and metastasis. These results indicate the potential therapeutic value of targeting the p38-Snail axis in ovarian cancer. Significance: These findings identify p38 MAPK as a novel regulator of Snail protein stability and potential therapeutic target in ovarian cancer.
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