eIf2α-regulated translation modulates the early adhesion of mesenchymal-like cells

Abstract

ABSTRACTCellular invasion is a complex process that requires several interdependent biological mechanisms, which are initiated by changes in adhesion that establish a morphology favorable for migration. Hence, the regulation of adhesion potential is a rate-limiting step in metastasis. Our previous work revealed that de novo translation is necessary to regulate the adhesion of mesenchymal-like cells; however, the underlying translational regulatory mechanism and the identity of newly synthesized proteins needed for the adhesion process remain unidentified. Here, we describe a translational regulatory mechanism that modulates mesenchymal cell adhesion. We observed a drastic decrease in translation during the initial phase of adhesion, followed by a reprogramming of the translatome, characterized by an orchestrated wave of mRNA translation that increases the expression of specific proteins involved in adhesion. We observed that phosphorylation of eukaryotic translation initiation factor 2 subunit alpha (eIF2α), which inhibits general translation initiation, was drastically increased at the beginning of cell adhesion. As adhesion progressed, the selective increase in the translation of adhesion-related mRNAs intensified as eIF2α phosphorylation gradually decreased over time in mensenchymal cells, but not in epithelial cells. Taken together, we have identified a translational regulatory mechanism specifically affecting the adhesion process of mesenchymal cells, as well as metastatic cells that have undergone epithelial-to-mesenchymal transition.One sentence summaryTranslation regulates mesenchymal cell adhesion