Phosphorylation of eukaryotic translation initiation factor 4G1 (eIF4G1) by protein kinase C{alpha} regulates eIF4G1 binding to Mnk1

Signal transduction through mitogen-activated protein kinases (MAPKs) is implicated in growth and proliferation control through translation regulation and involves posttranslational modification of translation initiation factors. For example, convergent MAPK signals to Mnk1 lead to phosphorylation of eukaryotic translation initiation factor 4E (eIF4E), which has been linked to malignant transformation. However, under-standing the compound effects of mitogenic signaling on the translation apparatus and on protein synthesis control remains elusive. This is particularly true for the central scaffold of the translation initiation apparatus and ribosome adaptor eIF4G. To unravel the effects of signal transduction to eIF4G on translation, we used specific activation of protein kinase C (PKC)-Ras-Erk signaling with phorbol esters. Phospho-proteomic and mutational analyses revealed that eIF4G1 is a substrate for PKC at Ser1186. We show that PKC activation elicits a cascade of orchestrated phosphorylation events that may modulate eIF4G1 structure and control interaction with the eIF4E kinase, Mnk1. In eukaryotes, protein synthesis is controlled mainly via re-strictive initiation. Translation initiation occurs upon recruit-ment of mRNAs to 40S ribosomal subunits. Conventionally, this requires eukaryotic translation initiation factor 4