Signaling Pathways for Translation: Insulin and Nutrients(26 Progress in Molecular and Subcellular Biology)

The articles in the present volume are by major contributors to our under­ standing of signaling pathways affecting protein synthesis. They focus pri­ marily on two extracellular anabolic signals, although others are included as well. Insulin is one of the best-studied extracellular regulators of protein syn­ thesis. Several of the known pathways for regulation of protein synthesis were elucidated using insulin-dependent systems. Regulation of protein synthesis by amino acids, by contrast, is an emerging field that has recently received a great deal of attention. The dual role of amino acids as substrates for protein syn­ thesis and regulators of the overall process has only recently been recognized. Since amino acids serve as precursors for proteins, one might expect that with­ holding an essential amino acid would inhibit the elongation phase. Surpris­ ingly, research has shown that it is the initiation phase of protein synthesis that is restricted during amino acid starvation. Understanding the mechanisms by which the biosynthesis of proteins is reg­ ulated is important for several reasons. Protein synthesis consumes a major portion of the cellular ATP that is generated. Therefore, small changes in protein synthesis can have great consequences for cellular energy metabolism. Translation is also a major site for control of gene expression, since messenger RNAs differ widely in translational efficiency, and changes to the protein syn­ thesis machinery can differentially affect recruitment of individual mRNAs.

Table of Contents:
Insulin Signaling and the Control of PHAS-I Phosphorylation.- 1 Introduction.- 2 Mechanism of Translational Repression.- 3 PHAS Isoforms.- 4 Phosphorylation Sites in PHAS-I.- 5 Protein Kinases That Phosphorylate PHAS-I in Vitro.- 6 Control by Hormones, Nutrients, and cAMP.- References.- Insulin, Phorbol Ester and Serum Regulate the Elongation Phase of Protein Synthesis.- 1 Introduction.- 2 Structure and Function of EF-1 and EF-2.- 3 Modifications of EF-1 and EF-2.- 4 Regulation of Elongation by Insulin Via Multipotential S6 Kinase and EF-2 Kinase.- 5 Regulation of Elongation by Phorbol Ester Via Protein Kinase C.- 6 Regulation of Elongation during the Cell Cycle by Cdc2.- 7 Lack of Regulation of Elongation by Protein Kinase Casein Kinase II.- 8 Conclusions.- References.- Regulation of Protein Synthesis by Insulin Through IRS-1.- 1 Introduction.- 2 Materials and Methods.- 3 Results.- 4 Discussion.- References.- Regulation of Eukaryotic Initiation Factor eIF2B.- 1 Function and Structure of eIF2B.- 2 eIF2B Activity Can Be Regulated by the Phosphorylation of eIF2?.- 3 Regulation of eIF2B Activity in Vivo.- 4 Mechanisms Involved in the “Direct” Regulation of eIF2B Activity.- 5 Other Phosphorylation Sites in eIF2B.- 6 Other Inputs into the Control of eIF2B.- 7 Conclusions and Perspectives.- References.- The p70 S6 Kinase Integrates Nutrient and Growth Signals to Control Translational Capacity.- 1 Identification of the p70 S6 Kinase.- 2 Expression and Structure.- 3 Substrate Specificity and Selection.- 4 Cellular Function(s).- 5 Regulation of the p70 S6 Kinase.- 6 TOR Regulates Cell Function in Response to the Nutrient Milieu.- 7 p70 is Regulated by Multisite (Ser/Thr) Phosphorylation.- 8 RTK Recruitment of Type 1A PI-3 Kinases Activates p70 S6 Kinase.- 9 The Mechanism ofp70 Activation by PI-3 Kinase and the Role of PDK1.- 10 Candidate “p70 Thr412 Kinases”.- 11 Conclusion.- References.- Regulation of Translation Initiation by Amino Acids in Eukaryotic Cells.- 1 Introduction.- 2 Regulation by Amino Acids of met-tRNAi Binding to 40 S Ribosomal Subunits.- 3 Regulation of mRNA Binding to 40 S Ribosomal Subunits by Amino Acids.- 4 Is There Coordinated Regulation by Amino Acids of Translation Initiation and Elongation?.- 5 Summary.- References.