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

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 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 GSK3b-dependent Snail phosphorylation and bTrCP-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.

Convergent evolution of p38/MAPK activation in hormone resistant prostate cancer mediates pro-survival, immune evasive, and metastatic phenotypes

“…7E). These experiments suggest that p38 activation can promote a pro-metastatic, immune evasive phenotype by stabilizing Snail expression (Ryu et al, 2019) and leading to downstream PD-L1 upregulation. Together, our data suggest that p38 may provide a common mechanistic explanation for evolutionary convergence of cancer cell survival, metastasis, and immune evasion phenotypes in AR positive metastatic castration-resistant prostate cancer, which could be therapeutically targeted through p38 blockade to treat men with hormone therapy resistant prostate cancer (Fig.…”

Multiple functions of DYRK2 in cancer and tissue development

“…3B) [24]. In more recent study, Ryu et al [61] report that DYRK2-mediated Ser104 phosphorylation of SNAIL is effectively suppressed by p38 MAPK, resulting in p38-DYRK2-SNAIL axis regulates ovarian cancer EMT and metastasis.…”

The DYRK Family of Kinases in Cancer: Molecular Functions and Therapeutic Opportunities

“…In particular, mutual regulation has been described for SIAH2 and DYRK2 [ 151 ]; indeed, an increase in the SIAH2 protein has been observed in lung cancer tissue and linked to DYRK2 downregulation [ 135 ]. Besides the alterations to the cellular levels of DYRK2, changes in the substrate selectivity have been seen in relation to Snail in ovarian cancer, with DYRK2 phosphorylation prevented by the prior p38-mediated phosphorylation of Snail [ 152 ].…”