# EIF4B Ser93 phosphorylation by ERK2 promotes epithelial-mesenchymal transition to drive colorectal cancer metastasis

## TL;DR

This study shows that phosphorylation of eIF4B at Ser93, driven by ERK2, promotes colorectal cancer metastasis through epithelial-mesenchymal transition.

## Contribution

The study identifies eIF4B Ser93 phosphorylation as a novel driver of CRC metastasis and a potential therapeutic target.

## Key findings

- eIF4B Ser93 phosphorylation is significantly increased in CRC and promotes cancer progression and metastasis.
- ERK2 directly phosphorylates eIF4B at Ser93, and inhibiting this phosphorylation enhances the efficacy of ERK2 inhibitors.
- Phosphorylated eIF4B enhances translation of mesenchymal markers by reducing its ubiquitination and degradation.

## Abstract

Colorectal cancer (CRC) is the third most common malignant tumor and the second leading cause of cancer-related mortality globally. Epithelial to mesenchymal transition (EMT) contributes to CRC metastasis and poor prognosis. Aberrant protein phosphorylation is implicated in CRC progression, warranting further investigation into its molecular mechanisms. Herein, we have identified significant alterations in protein phosphorylation associated with CRC through tandem mass tag (TMT) label-based phosphoproteomic analysis. The functions and enriched signaling pathways of these proteins were predominantly linked to the EMT process. Notably, the phosphorylation of eIF4B at Ser93 exhibited the most pronounced increase in CRC, a finding that was further validated in CRC tissues and cell lines by a newly generated antibody targeting eIF4B Ser93 phosphorylation. Phosphorylation of eIF4B Ser93 promoted CRC progression and metastasis both in vitro and in vivo. Mechanistically, eIF4B Ser93 phosphorylation decreased ubiquitination-mediated eIF4B degradation and enhanced its translation activity, through which it facilitated the translation of mesenchymal markers. Additionally, ERK2 directly phosphorylated eIF4B at Ser93, while inhibiting this phosphorylation is essential for the anti-cancer efficacy of the ERK2 inhibitor, Vx-11e. Together, the phosphorylation of eIF4B Ser93 driven by ERK2 promotes CRC growth and metastasis through the activation of EMT. Our findings indicate a novel therapeutic target and provide promising strategies for clinical intervention in human CRC.