Signaling Pathways for Translation, Softcover reprint of the original 1st ed. 2001
Insulin and Nutrients
Progress in Molecular and Subcellular Biology Series, Vol. 26

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.

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.- 4.1 Identification of Sites.- 4.2 Influence of Phosphorylation on the Electrophoretic Mobility of PHAS-I.- 4.3 Sites Involved in the Control of eIF4E Binding.- 4.4 Potential Mechanisms of Ordered Phosphorylation.- 5 Protein Kinases That Phosphorylate PHAS-I in Vitro.- 5.1 mTOR Protein.- 5.2 Protein Kinase C.- 5.3 Protein Kinase CK2.- 5.4 MAP Kinase.- 6 Control by Hormones, Nutrients, and cAMP.- 6.1 The Insulin Signaling Pathway.- 6.1.1 Insulin Receptor Substrate 1 (IRS-1).- 6.1.2 Phosphatidyl Inositol 3-OH Kinase (PI 3-kinase).- 6.1.3 Protein Kinase B.- 6.1.4 mTOR Phosphorylation.- 6.1.5 Tap42p and the ?4 Protein.- 6.2 Regulation of PHAS-I by a Nutrient-Sensing Pathway.- 6.3 Regulation of PHAS-I Dephosphorylation.- 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.- 2.1 Cell Lines.- 2.2 Measurement of Protein and DNA Synthesis.- 2.3 MAPK, p70S6K, PI3K and PKC Activity.- 2.4 Preparation of 32P-Labeled eIF4E and PHAS-I.- 2.5 MAPK Depletion.- 2.6 Northern Blot Analysis.- 2.7 eIF2B and GSK-3 Activity.- 3 Results.- 3.1 Both IR and IRS-1 Are Required for Stimulation of Translation by Insulin in 32D Cells.- 3.2 MAPK Activation Is Necessary But Not Sufficient for Insulin-Stimulated Protein Synthesis.- 3.3 SHP-2 Attenuates the IRS-1 Signal.- 3.4 The Insulin Signal to Protein Synthesis Proceeds Through PI3K.- 3.5 The mTOR Branch Downstream of PI3K Stimulates Growth-Regulated Translation.- 3.6 The PKC? Branch Downstream of PI3K Stimulates General Translation.- 3.7 General Protein Synthesis Is Correlated with Inhibition of GSK-3 and Activation of eIF2B.- 4 Discussion.- 4.1 Insulin Receptor and Insulin Receptor Substrate-1.- 4.2 GRB-2/SOS Binding to IRS-1.- 4.3 SHP-2 Binding to IRS-1.- 4.4 PI3K Binding to IRS-1.- 4.5 The Rapamycin-Sensitive Branch Involves PKB and mTOR.- 4.6 The Rapamycin-Insensitive Branch Proceeds Through PKC?.- 4.7 Glycogen Synthase Kinase-3 and eIF2B.- 4.8 Protein Synthesis and Cell Proliferation.- 4.9 Pathway from Insulin to General and Growth-Related Protein Synthesis.- References.- Regulation of Eukaryotic Initiation Factor eIF2B.- 1 Function and Structure of eIF2B.- 1.1 eIF2B Is a Guanine Nucleotide Exchange Factor.- 1.2 eIF2B Is a Heteropentameric Protein.- 1.3 eIF2B Is an Important Control Point for Translation Initiation.- 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.- 4.1 eIF2B May Be Regulated Allosterically and by Phosphorylation.- 4.2 eIF2B? Is a Substrate For GSK-3.- 4.3 Control of GSK-3 Activity.- 4.4 Regulation of Phosphorylation of the GSK-3 Site in eIF2B?.- 4.5 The Erk Pathway Can Also Modulate eIF2B Activity.- 5 Other Phosphorylation Sites in eIF2B.- 5.1 Phosphorylation of the Priming Site in eIF2B?.- 5.2 Phosphorylation Sites in eIF2B? in Vivo.- 5.3 Phosphorylation of eIF2B by Casein Kinases.- 5.4 Are Other Subunits of eIF2B Phosphorylated?.- 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).- 4.1 The p70 S6 Kinase Controls Expression of the Translational Apparatus by Regulating Initiation of 5? Terminal Oligopyrimidine Sequence mRNAs.- 4.2 The p70 S6 Kinase Coordinates Cell Division with Cell Growth.- 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 of p70 Activation by PI-3 Kinase and the Role of PDK1.- 10 Candidate “p70 Thr412 Kinases”.- 10.1 PDK1 As a p70 Thr412 Kinase.- 10.2 mTOR As a p70 Thr412 Kinase.- 10.3 A Novel Set of p70 Thr412 Kinases.- 11 Conclusion.- References.- Regulation of Translation Initiation by Amino Acids in Eukaryotic Cells.- 1 Introduction.- 1.1 Pathway of Translation Initiation.- 2 Regulation by Amino Acids of met-tRNAi Binding to 40 S Ribosomal Subunits.- 2.1 Regulation of met-tRNAi Binding in Saccharomyces cerevisiae.- 2.1.1 Regulation of GCN4 mRNA Translation by Amino Acids.- 2.1.2 Roles of eIF2 and eIF2B in Translational Regulation of Gcn4p Expression by Amino Acids.- 2.1.3 Gcn2p Is an eIF2? Kinase That Regulates Gcn4p Expression by Amino Acids.- 2.1.4 Model for the Translational Regulation of Gcn4p Expression by Amino Acids.- 2.2 Regulation of met-tRNAi Binding in Mammalian Cells.- 3 Regulation of mRNA Binding to 40 S Ribosomal Subunits by Amino Acids.- 3.1 Modulation of 4E-BP1 and S6K1 Phosphorylation by Amino Acids.- 3.2 Signaling Pathways for Leucine-Mediated Changes in Translation Initiation.- 4 Is There Coordinated Regulation by Amino Acids of Translation Initiation and Elongation?.- 5 Summary.- References.