The translation initiation factor eIF2 is hyperphosphorylated in melanoma cell lines

eIF2, a heterotrimeric protein constituted by alpha, beta and gamma subunits, is an essential factor involved in the initiation phase of eukaryotic translation. eIF2 is a G-protein that, in its active GTP-bound form, interacts with Met-tRNAi promoting its binding to the 40S ribosomal subunit and determining the correct localization on the start codon. The codon-anticodon interaction triggers GTP hydrolysis, whereby an inactive eIF2-GDP complex is released. eIF2 reactivation is catalyzed by the recycling factor eIF2B that allows GDP/GTP exchange. Because of its pivotal role in translation initiation, eIF2 is the main target of translational regulation mechanisms. Indeed, the recycling of the factor can be inhibited by the phosphorylation of its alpha subunit at Ser 51. In its phosphorylated form, eIF2 behaves as a competitive inhibitor of eIF2B, preventing GDP/GTP exchange and thereby reactivation of eIF2. eIF2 phosphorylation is triggered by various stress conditions, such as viral infection or nutrient deprivation, which lead to the activation of specific kinases (PKR, PERK, GCN2, HRI). In recent years, it has become increasingly evident that translational regulation plays an important role in tumorigenesis and tumor progression. In this study we analyzed the expression level and phosphorylation state of the alpha subunit of eIF2 in melanoma cell lines derived from primary tumours and invasive metastasis. While the amount of protein present remained roughly constant in the various cell lines, we observed a significant increase in the phosphorylation level of eIF2 alpha in metastatic cell lines compared to primary tumors. These data suggest that the stress kinases controlling eIF2 activity become activated upon tumor progression.