Schistosoma mansoni receptor kinase 1 (SmRK1) is a divergent member of the TGFβ receptor family. Intracellular proteins that associate with these receptors are likely to play an important role in signaling. 14-3-3ε is a previously described cytoplasmic protein, which associates with both SmRK1 and the human type I TGFβ receptor (TβRI); overexpression of 14-3-3ε leads to enhanced TGFβ-mediated signaling by TβRI. We now describe the identification of S. mansoni eukaryotic translation initiation factor 2α subunit (eIF2α), through its interaction with SmRK1 in a yeast two-hybrid assay. S. mansoni eIF2α also interacts with human TGFβ receptors. Strongest association was demonstrated with kinase inactive receptors, particularly the type II TGFβ receptor (TβRII). Both TβRI and TβRII phosphorylate eIF2α in vitro, at sites other than the previously described eIF2α phosphorylation sites. EIF2α also modulates signaling by TGFβ receptors; however, in contrast to 14-3-3ε, eIF2α overexpression inhibits the TGFβ-driven response. These data suggest a novel function for eIF2α in the TGFβ signaling pathway. In addition, we have demonstrated an independent interaction between eIF2α and 14-3-3ε. Coexpression of 14-3-3ε with eIF2α leads to the abrogation of the inhibitory effect of eIF2α on TGFβ-mediated signaling. The interaction of these two regulatory proteins with each other and with the TGFβ receptors and their relative expression levels are likely to be important in fine-tuning the regulation of TGFβ signal transduction.