LAUSR

Snail is a key regulator of epithelial-mesenchymal transition (EMT) which is a major step in tumor metastasis. While the induction of Snail transcription precedes EMT, post-translational 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, 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.