ERK3 Increases Snail Protein Stability by Inhibiting FBXO11-Mediated Snail Ubiquitination

Abstract

Simple Summary Several kinases are known to enhance the stability of the Snail protein, a key regulator of the epithelial-mesenchymal transition (EMT), by preventing its ubiquitination to induce the EMT process; however, the precise molecular mechanisms by which these kinases prevent Snail ubiquitination remain unclear. In this study, we found that the ERK3 kinase interacts with Snail and increases Snail protein stability by preventing ubiquitination in pancreatic cancer cells. Moreover, we found that ERK3 inhibits the binding of Snail to FBXO11, an E3 ubiquitin ligase that can induce Snail ubiquitination and degradation, resulting in increased Snail expression. Our findings suggest that the ERK3-Snail axis is a potential therapeutic target in pancreatic cancer.Abstract Snail is a key regulator of the epithelial-mesenchymal transition (EMT), the key step in the tumorigenesis and metastasis of tumors. Although induction of Snail transcription precedes the induction of EMT, the post-translational regulation of Snail is also important in determining Snail protein levels, stability, and its ability to induce EMT. Several kinases are known to enhance the stability of the Snail protein by preventing its ubiquitination; however, the precise molecular mechanisms by which these kinases prevent Snail ubiquitination remain unclear. Here, we identified ERK3 as a novel kinase that interacts with Snail and enhances its protein stability. Although ERK3 could not directly phosphorylate Snail, Erk3 increased Snail protein stability by inhibiting the binding of FBXO11, an E3 ubiquitin ligase that can induce Snail ubiquitination and degradation, to Snail. Importantly, functional studies and analysis of clinical samples indicated the crucial role of ERK3 in the regulation of Snail protein stability in pancreatic cancer. Therefore, we conclude that ERK3 is a key regulator for enhancing Snail protein stability in pancreatic cancer cells by inhibiting the interaction between Snail and FBXO11.