5 Protein Kinases That Phosphorylate eIF2 and eIF2B, and Their Role in Eukaryotic Cell Translational Control

Translational initiation in eukaryotes is a complex process involving many components, described in detail in other chapters of this volume (see, e.g., Merrick and Hershey; Trachsel; Jackson), This chapter presents a review of the current state of knowledge concerning the regulation of initiation, concentrating on the mechanisms by which the activity of initiation factor eIF2 is controlled by reversible protein phosphorylation. In recent years, it has become clear that the phosphorylation of the smallest (α)-subunit of eIF2 is a widely used mechanism of translational control in many organisms, and we now know of several physiologically important situations where eIF2α kinases are activated or inhibited. In most situations, in vivo translation is limited by the rate of initiation, although the precise stage at which this limitation occurs probably varies depending on the circumstances. A rate-limiting step in initiation when protein synthesis is relatively rapid occurs at the level of binding of messenger RNAs to 43S preinitiation complexes (Sonenberg 1993). This process involves the least abundant initiation factor in the cell, the cap-binding protein eIF4E, as well as other components of the eIF4F complex; its regulation is discussed by Sonenberg (this volume). In contrast, under a variety of conditions of cellular stress, the binding of initiator Met-tRNA i to the 40S ribosomal subunit, catalyzed by initiation factor eIF2, can become the rate-limiting step. Examples of stresses that have this effect are hemin deprivation of reticulocytes (London et al. 1976; Chen et al. 1994), nutrient limitation (Pain 1994; Hinnebusch, this volume), heat shock (Panniers...