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

Abstract

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.

Figure 1

eEF1A1 in protein synthesis. During protein-synthesis codon/anticodon matching leads to the binding of eEF1A1-aminoacyl-tRNA-GTP complex to the A-site of ribosome which contains the growing polypeptide chain at the P-site of ribosome. Following hydrolysis of GTP, eEF1A-tRNA-GDP complex leaves the ribosome. In order for additional translocation events to take place, the GDP must be exchanged for GTP, which is carried out by eEF1βγ.

Figure 2

Targeting of eEF1A1 is a novel mechanism in TGFβ signaling. Canonical TGFβ signaling pathway involves activation of Smad2 and Smad3 proteins (Smad pathway). There are numbers of TGFβ signaling pathways that do not involve direct activation of Smads (non-Smad pathway). These non-Smad pathways include MAPK, Rho-like GTPase and PI3K/Akt, as examples. Activation of Smad and non-Smad signaling cascade ultimately leads to the transcription activation of target genes. Recently, our study uncovered that eEF1A1 is phosphorylated by type I TGFβ receptor kinase, which leads to the direct regulation of protein synthesis, without involvement of transcriptional regulation.