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Signaling Pathways for Translation : Insulin and Nutrients - Robert E. Rhoads

Signaling Pathways for Translation

Insulin and Nutrients

By: Robert E. Rhoads (Editor)

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Published: 17th July 2001
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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
Introductionp. 1
Mechanism of Translational Repressionp. 1
PHAS Isoformsp. 3
Phosphorylation Sites in PHAS-Ip. 5
Identification of Sitesp. 6
Influence of Phosphorylation on the Electrophoretic Mobility of PHAS-Ip. 6
Sites Involved in the Control of eIF4E Bindingp. 7
Potential Mechanisms of Ordered Phosphorylationp. 8
Protein Kinases That Phosphorylate PHAS-I in Vitrop. 10
mTOR Proteinp. 11
Protein Kinase Cp. 15
Protein Kinase CK2p. 16
MAP Kinasep. 16
Control by Hormones, Nutrients, and cAMPp. 17
The Insulin Signaling Pathwayp. 18
Insulin Receptor Substrate 1 (IRS-1)p. 18
Phosphatidyl Inositol 3-OH Kinase (PI 3-kinase)p. 18
Protein Kinase Bp. 19
mTOR Phosphorylationp. 20
p. 22
Regulation of PHAS-I by a Nutrient-Sensing Pathwayp. 23
Regulation of PHAS-I Dephosphorylationp. 25
Referencesp. 26
Insulin, Phorbol Ester and Serum Regulate the Elongation Phase of Protein Synthesis
Introductionp. 33
Structure and Function of EF-1 and EF-2p. 33
Modifications of EF-1 and EF-2p. 37
Regulation of Elongation by Insulin Via Multipotential S6 Kinase and EF-2 Kinasep. 39
Regulation of Elongation by Phorbol Ester Via Protein Kinase Cp. 42
Regulation of Elongation during the Cell Cycle by Cdc2p. 43
Lack of Regulation of Elongation by Protein Kinase Casein Kinase IIp. 44
Conclusionsp. 45
Referencesp. 45
Regulation of Protein Synthesis by Insulin Through IRS-1
Introductionp. 49
Materials and Methodsp. 52
Cell Linesp. 52
Measurement of Protein and DNA Synthesisp. 53
MAPK, p70(S6K), PI3K and PKC Activityp. 53
Preparation of (32)P-Labeled eIF4E and PHAS-Ip. 54
MAPK Depletionp. 54
Northern Blot Analysisp. 55
eIF2B and GSK-3 Activityp. 55
Resultsp. 55
Both IR and IRS-1 Are Required for Stimulation of Translation by Insulin in 32D Cellsp. 55
MAPK Activation Is Necessary But Not Sufficient for Insulin-Stimulated Protein Synthesisp. 56
SHP-2 Attenuates the IRS-1 Signalp. 57
The Insulin Signal to Protein Synthesis Proceeds Through PI3Kp. 59
The mTOR Branch Downstream of PI3K Stimulates Growth-Regulated Translationp. 62
The PKC$$ Branch Downstream of PI3K Stimulates General Translationp. 66
General Protein Synthesis Is Correlated with Inhibition of GSK-3 and Activation of eIF2Bp. 71
Discussionp. 77
Insulin Receptor and Insulin Receptor Substrate-1p. 77
GRB-2/SOS Binding to IRS-1p. 77
SHP-2 Binding to IRS-1p. 78
PI3K Binding to IRS-1p. 79
The Rapamycin-Sensitive Branch Involves PKB and mTORp. 79
The Rapamycin-Insensitive Branch Proceeds Through PKC$$p. 80
Glycogen Synthase Kinase-3 and eIF2Bp. 82
Protein Synthesis and Cell Proliferationp. 83
Pathway from Insulin to General and Growth-Related Protein Synthesisp. 84
Referencesp. 85
Regulation of Eukaryotic Initiation Factor eIF2B
Function and Structure of eIF2Bp. 95
eIF2B Is a Guanine Nucleotide Exchange Factorp. 95
eIF2B Is a Heteropentameric Proteinp. 95
eIF2B Is an Important Control Point for Translation Initiationp. 97
eIF2B Activity Can Be Regulated by the Phosphorylation of eIF2$$p. 97
Regulation of eIF2B Activity in Vivop. 98
Mechanisms Involved in the "Direct" Regulation of eIF2B Activityp. 100
eIF2B May Be Regulated Allosterically and by Phosphorylationp. 100
eIF2Be Is a Substrate For GSK-3p. 100
Control of GSK-3 Activityp. 102
Regulation of Phosphorylation of the GSK-3 Site in eIF2Bep. 104
The Erk Pathway Can Also Modulate eIF2B Activityp. 104
Other Phosphorylation Sites in eIF2Bp. 106
Phosphorylation of the Priming Site in eIF2Bep. 106
Phosphorylation Sites in eIF2Be in Vivop. 107
Phosphorylation of eIF2B by Casein Kinasesp. 107
Are Other Subunits of eIF2B Phosphorylated?p. 108
Other Inputs into the Control of eIF2Bp. 109
Conclusions and Perspectivesp. 110
p. 111
The p70 S6 Kinase Integrates Nutrient and Growth Signals to Control Translational Capacity
Identification of the p70 S6 Kinasep. 115
Expression and Structurep. 117
Substrate Specificity and Selectionp. 120
Cellular Function(s)p. 122
The p70 S6 Kinase Controls Expression of the Translational Apparatus by Regulating Initiation of 5' Terminal Oligopyrimidine Sequence mRNAsp. 122
The p70 S6 Kinase Coordinates Cell Division with Cell Growthp. 125
Regulation of the p70 S6 Kinasep. 127
TOR Regulates Cell Function in Response to the Nutrient Milieup. 128
p70 is Regulated by Multisite (Ser/Thr) Phosphorylationp. 132
RTK Recruitment of Type 1A PI-3 Kinases Activates p70 S6 Kinasep. 134
The Mechanism of p70 Activation by PI-3 Kinase and the Role of PDK1p. 135
Candidate "p70 Thr412 Kinases"p. 140
PDK1 As a p70 Thr412 Kinasep. 140
mTOR As a p70 Thr412 Kinasep. 141
A Novel Set of p70 Thr412 Kinasesp. 145
Conclusionp. 145
p. 146
Regulation of Translation Initiation by Amino Acids in Eukaryotic Cells
Introductionp. 155
Pathway of Translation Initiationp. 155
Regulation by Amino Acids of met-tRNAi Binding to 40 S Ribosomal Subunitsp. 157
Regulation of met-tRNAi Binding in Saccharomyces cerevisiaep. 157
Regulation of GCN4 mRNA Translation by Amino Acidsp. 157
Roles of eIF2 and eIF2B in Translational Regulation of Gcn4p Expression by Amino Acidsp. 159
Gcn2p Is an eIF2a Kinase That Regulates Gcn4p Expression by Amino Acidsp. 161
Model for the Translational Regulation of Gcn4p Expression by Amino Acidsp. 162
Regulation ofmet-tRNAi Binding in Mammalian Cellsp. 163
Regulation of mRNA Binding to 40 S Ribosomal Subunits by Amino Acidsp. 166
Modulation of 4E-BP1 and S6K1 Phosphorylation by Amino Acidsp. 168
Signaling Pathways for Leucine-Mediated Changes in Translation Initiationp. 172
Is There Coordinated Regulation by Amino Acids of Translation Initiation and Elongation?p. 174
Summaryp. 175
Referencesp. 177
Subject Indexp. 185
Table of Contents provided by Publisher. All Rights Reserved.

ISBN: 9783540417095
ISBN-10: 3540417095
Series: Progress in Molecular and Subcellular Biology
Audience: Professional
Format: Hardcover
Language: English
Number Of Pages: 186
Published: 17th July 2001
Publisher: Springer-Verlag Berlin and Heidelberg Gmbh & Co. Kg
Country of Publication: DE
Dimensions (cm): 23.5 x 15.5  x 1.27
Weight (kg): 0.47