6 Regulation of Ribosomal Recruitment in Eukaryotes

The regulation of translation rates, the frequency with which a given mRNA is translated, plays a critical role in many fundamental biological processes, including cell growth (see Chapter 23), development (see Chapters 7 and 27), and the response to biological cues or environmental stresses (many chapters in this book). Dysregulation of translation may also be an important component in the transformation of cells (see Chapter 20). As discussed in other chapters, translation rates are primarily regulated at the initiation phase (see Chapter 2), a multistep process involving the recruitment of the 40S small ribosomal subunit to the 5′ end of an mRNA and the positioning of the ribosome at an initiation codon. This process requires the participation of a large number of initiation factors (see Chapter 2), including the eIF4 group, those proteins that interact directly with the 5′-untranslated region (UTR) of mRNA. Our current understanding of how the activity of the eIF4 initiation factors is regulated by intracellular signaling pathways is the subject of this chapter. The basic mechanism of ribosomal recruitment to mRNA in eukaryotes is conserved throughout evolution. For example, all eukaryotic organisms studied to date possess an eIF4F-like complex (for review, see Chapter 2), consisting of an mRNA cap-binding protein (eIF4E), a scaffolding protein (eIF4G), and an RNA helicase (eIF4A). An eIF4A cofactor, eIF4B, is also conserved in eukaryotes. However, different organisms appear to have devised very different methods to regulate the activity of these factors. Thus, in this chapter we also summarize our current under-standing...