Gene regulation at the RNA layer: RNA binding proteins in intercellular signaling networks

Transcriptional regulators are sometimes believed to be the only targets through which signal transduction pathways regulate gene expression. Although it is certainly true that many well-characterized intercellular signaling pathways operate by modifying the activity of specific transcription factors, an increasing body of evidence indicates that external signals can modulate gene expression by posttranscriptional mechanisms. RNA binding motifs are combined with other conserved domains, such as protein-interaction domains and consensus phosphorylation motifs, to allow gene expression to be regulated at the level of the RNA in response to extracellular signals. In this review, I discuss evidence that reveals how a particular family of RNA binding proteins, called signal transduction and activation of RNA (STAR) proteins, function in signaling and in the development of multicellular organisms. Furthermore, insulin and related growth factors regulate cell growth, at least in part, by moderating the activity of eukaryotic initiation factor 4E (eIF4E)-binding protein (4EBP), a protein that does not bind RNA directly but inhibits the activity of eIF4E, which is an mRNA cap-binding protein. I discuss the evidence linking insulin signaling to 4EBP phosphorylation. Finally, several other genes have been identified from invertebrate model organisms that encode RNA binding proteins and whose mutant phenotypes implicate them in intercellular signaling, but for which the mechanisms of function currently are unclear. The study of these and other similar genes is likely to uncover a diversity of roles for RNA binding proteins in signal transduction.