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p38 Stabilizes Snail by Suppressing DYRK2-Mediated Phosphorylation That Is Required for GSK3β-βTrCP-Induced Snail Degradation

 Ki-Jun Ryu  ;  Sun-Mi Park  ;  Seung-Ho Park  ;  In-Kyu Kim  ;  Hyeontak Han  ;  Hyo-Jin Kim  ;  Seon-Hee Kim  ;  Keun-Seok Hong  ;  Hyemin Kim  ;  Minju Kim  ;  Sung-Jin Yoon  ;  Killivalavan Asaithambi  ;  Kon Ho Lee  ;  Jae-Yong Park  ;  Young-Sool Hah  ;  Hee Jun Cho  ;  Jong In Yook  ;  Jung Wook Yang  ;  Gyung-Hyuck Ko  ;  Gyemin Lee  ;  Yang Jae Kang  ;  Cheol Hwangbo  ;  Kwang Dong Kim  ;  Young-Jun Park  ;  Jiyun Yoo 
 Cancer Research, Vol.79(16) : 4135-4148, 2019 
Journal Title
 Cancer Research 
Issue Date
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 posttranslational 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 GSK3β-dependent Snail phosphorylation and βTrCP-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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2. College of Dentistry (치과대학) > Dept. of Oral Pathology (구강병리학교실) > 1. Journal Papers
Yonsei Authors
Yook, Jong In(육종인) ORCID logo https://orcid.org/0000-0002-7318-6112
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