Phosphorylation of eIF4E promotes EMT and metastasis via translational control of SNAIL and MMP-3

Abstract

The progression of cancers from primary tumors to invasive and metastatic stages accounts for the overwhelming majority of cancer deaths. Understanding the molecular events which promote metastasis is thus critical in the clinic. Translational control is emerging as an important factor in tumorigenesis. The mRNA cap-binding protein eIF4E is an oncoprotein that plays an important role in cancer initiation and progression. eIF4E must be phosphorylated to promote tumor development. However, the role of eIF4E phosphorylation in metastasis is not known. Here, we show that mice in which eIF4E cannot be phosphorylated are resistant to lung metastases in a mammary tumor model, and that cells isolated from these mice exhibit impaired invasion. We also demonstrate that TGFβ induces eIF4E phosphorylation to promote translation of Snail and Mmp-3 mRNAs, and the induction of epithelial-to-mesenchymal transition (EMT). Furthermore, we describe a new model wherein EMT induced by TGFβ requires translational activation via the non-canonical TGFβ signaling branch acting through eIF4E phosphorylation.

Regulation of global and specific mRNA translation by the mTOR signaling pathway

“…58 Although phosphorylation of eIF4E does not have a major impact on global translation rates, it was found to stimulate the translation of a subset of mRNAs encoding proteins involved in survival (e.g., Mcl1) 59 and tumor invasion (e.g.,, Snail, MMP-3). 60,61 Translational regulation of Snail and MMP-3 mRNAs was found to promote epithelial-to-mesenchymal transition (EMT), pointing to a role for eIF4E phosphorylation in cancer metastasis. 60 However, the precise mechanisms by which eIF4E phosphorylation affects the translation of these transcripts remain to be determined.…”

“…60,61 Translational regulation of Snail and MMP-3 mRNAs was found to promote epithelial-to-mesenchymal transition (EMT), pointing to a role for eIF4E phosphorylation in cancer metastasis. 60 However, the precise mechanisms by which eIF4E phosphorylation affects the translation of these transcripts remain to be determined.…”

Dual Abrogation of Mnk and Mtor: A Novel Therapeutic Approach for the Treatment of Aggressive Cancers

“…MNK1 and MNK2 are serine/threonine protein kinases responsible for the phosphorylation of S209 on eIF4E [25]. The phosphorylation of eIF4E correlates with the increase in mesenchymal markers such as N-cadherin, fibronectin and vimentin, along with the acquisition of invasive properties [26].…”

Decreased eIF3e Expression Can Mediate Epithelial-to-Mesenchymal Transition through Activation of the TGFβ Signaling Pathway

“…Of note, although it may possess an IRES, SNAI1 translation is not maintained at the same level in A549 cells that harbor the eIF3e-targeting shRNA as in A549 cells that harbor the nontargeting shRNA. As it was recently shown that eIF4E phosphorylation is necessary for SNAI1 translation (37) and that eIF3e is necessary for eIF4E phosphorylation through the recruitment of MNK1 (38), we tested whether a decrease in eIF3e levels leads to a decrease in eIF4E phosphorylation. We examined the phosphorylation status of eIF4E and found that it is less phosphorylated in cells that have reduced eIF3e expression ( Supplementary Fig.…”