The phosphorylation of eukaryotic initiation factor 2: a principle of translational control in mammalian cells.
In eukaryotic cells, protein biosynthesis is controlled at the level of polypeptide chain initiation. During the initiation process, eukaryotic initiation factor 2 (eIF-2) catalyzes the binding of Met-tRNAf and GTP to the 40S ribosomal subunit. In a later step, eIF-2 is released from the ribosomal initiation complex, most likely as an eIF-2.GDP complex, and another initiation factor termed eIF-2B is necessary to recycle eIF-2 by displacing GDP by GTP. In rabbit reticulocytes, inhibition of protein synthesis is accompanied by the phosphorylation of the alpha-subunit of eIF-2, a process that does not render eIF-2 inactive, but prevents it from being recycled by eIF-2B. First described in rabbit reticulocytes as inhibitors of translation, two distinct eIF-2 alpha kinases are known: the haemin-controlled kinase (termed HCI) and the double-stranded RNA-activated kinase (termed DAI). eIF-2 alpha phosphorylation appears to be a reversible control mechanism since corresponding phosphatases have been described. Recent reports indicate a correlation between eIF-2 alpha phosphorylation and the inhibition of protein synthesis in several mammalian cell types under a range of physiological conditions. In this review, the physical and functional features of the known eIF-2 alpha kinases are described with respect to their role in mammalian cells and the mode of activation by cellular signals. Furthermore, the possible impact of the eIF-2/eIF-2B ratio and of the subcellular compartmentation of these factors (and the eIF-2 alpha kinases) on mammalian protein synthesis is discussed.
Sarre
T F
TF
Institut für Biologie III, Freiburg, F.R.G.
D000818:Animals; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D005786:Gene Expression Regulation; D006168:Guinea Pigs; D051379:Mice; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011494:Protein Kinases / Q000502:physiology; D011500:Protein Synthesis Inhibitors / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D019892:eIF-2 Kinase
D015852:Eukaryotic Initiation Factor-2; D011500:Protein Synthesis Inhibitors; D011494:Protein Kinases; D019892:eIF-2 Kinase