Translational connection of TGFβ signaling: Phosphorylation of eEF1A1 by TβR-I inhibits protein synthesis.

Transforming growth factor-β (TGFβ) signaling pathways regulate a wide array of cellular activities that are crucial for cell proliferation, apoptosis, migration and differentiation. TGFβ signaling pathways are initiated by ligand-activated TGFβ receptors, with type I TGFβ receptors (TβR-I) kinase being essential for phosphorylation of downstream targets. Until now, a prevalent view was that the TGFβ intracellular signaling targets would regulate transcription. Recently, we uncovered a novel TGFβ signaling pathway that exerts a direct regulatory effect on mRNA translation and protein synthesis. Eukaryotic elongation factor eEF1A1 is a GTP-binding protein that plays a central role in protein synthesis. By using a screening method for kinase substrate that was developed in our laboratory, we identified eEF1A1 as a novel substrate of TβR-I. This shed a new light on the convergence of TGFβ signaling and protein synthesis. We also showed phosphorylation of eEF1A1 at Ser300 by TβR-I prevents aa-tRNA binding to eEF1A1. As a consequence, TGFβ-dependent phosphorylation of eEF1A1 has an inhibitory effect on protein synthesis and cell proliferation. Therefore, we unveiled a novel regulatory mechanism of cellular proliferation by TGFβ at the translational level. Here we discuss this finding in the context of its potential role in the multiplicity of TGFβ signaling, and in the regulation of fundamental cellular functions, such as proliferation.