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Sonnets: Three Volume Gift Set

Shakespeare's sonnets are thought to have been w见孙套却永艺练权ritten for 许打a private audience acros来自s several 局害燃比称固执鱼years, before being pu广卫blished in 1609.

  • 装帧 精装
  • ISBN 1906548005
  • 书名 Sonnets: Three Volume Gift Set
  • 页数 486页

简介

  Shakespeare's sonnets are thought to have been written for a private audien来自ce across several years, before being published in 1609360百科.

  条形码: 9781906548001

  William Shakespeare lived between 1552-1616, but his work endure衡于做s and is enjoyed the world over. --This text refers to the Audio Cassette edition.

  Shakespeare's sonnets are thought to have been written for a private audience across several years, before being published in 1609. The ver服学病些ses that compose the sonnets are often subversive, elusive, and int她逐染联接劳景响光imate, shaping an eroti统确普烧照回掌论艺喜c body of poetr界科行y in the pursuit of the depths and parameters of emotion. He seems to have planned contrasting 剂布度免衣布孙加series--bitter sequences of lust and recrimination h几儿今味aunted by a 扬合比评专married "d绍起危握仍察们石民路ark lady," lyrics praising yout皮概攻部校h and beauty addressed to a "fair youth," and allegorical contempla似天动二tions of Gre材致支达ek myth.

  Shakespeare's so保副位具龙把nnets are thought to have been written for a pr织员娘宜会胶领儿西兴指ivate audie何鲜带nce across several years, before being published in 1609. The verses that compose the sonnets are often subvers比决造均总入代杀万ive, elusive, and intimate, shaping an erotic body of poetry in the pursuit of the depths and parameters of emotion. He seems to have planned contrasting series--bitter sequences of lust and recrimination haunted by a married "dark lady," lyrics praising youth and beauty addressed to a "fair youth," and allegorical contemplations of Greek myth.

  Cover image

  Title page

  Table of Contents

  Copyright

  Contributors

  Preface

  VOLUME 1

  Chapter 1: Cell Signaling: Yesterday, Today, and Tomorrow

  Origins of Cell Signaling

  Enter Polypeptide Growth Factors

  Cell Signaling at the Molecular Level

  Lipid Signaling

  Cell Signaling Tomorrow

  PART I: INITIATION: EXTRACELLULAR AND MEMBRANE EVENTS

  Introduction

  Section A: Molecular Recognition

  Chapter 2: Structural and Energetic Basis of Molecular Recognition

  Introduction

  Principles of Binding

  Nonspecific Association with Membrane Surfaces

  Protein–Protein Interactions

  Prospects

  Chapter 3: Computational Genomics: Prediction of Protein Functional Linkages and Networks

  Introduction

  Approaches to Analyzing Protein Functions on a Genome-Wide Scale

  Current Issues and Future Prospects for Computing Functional Interactions

  Acknowledgments

  Chapter 4: Molecular Sociology

  Transmembrane Signaling Paradigms

  Structural Basis of Protein–Protein Recognition

  Conclusion

  Chapter 5: Free Energy Landscapes in Protein–Protein Interactions

  Introduction

  Thermodynamics of Protein–Protein Interactions

  Interaction Kinetics

  The Transition State

  Association of a Protein Complex

  Dissociation of a Protein Complex

  Summary

  Chapter 6: Antibody–Antigen Recognition and Conformational Changes

  Introduction

  Antibody Architecture

  Conformational Changes

  Conclusion

  Acknowledgments

  Chapter 7: Binding Energetics in Antigen–Antibody Interfaces

  Introduction

  Thermodynamic Mapping of Antigen–Antibody Interfaces

  Conclusions

  Chapter 8: Immunoglobulin–Fc Receptor Interactions

  Introduction

  IgG–Receptor Interactions

  IgE–Receptor Interactions

  Summary

  Chapter 9: Plasticity of Fc Recognition

  Introduction

  Structures of the Natural Fc Binding Domains

  The Consensus Binding Site on Fc

  Evolution of an Fc Binding Peptide

  Factors Promoting Plasticity

  Conserved and Functionally Important Molecular Interactions

  Conclusion

  Chapter 10: Ig-Superfold and Its Variable Uses in Molecular Recognition

  Introduction

  The Immunoglobulin Superfamily

  Ig-Superfold-Mediated Recognition

  Chapter 11: T-Cell Receptor/pMHC Complexes

  TCR Generation and Architecture

  Peptide Binding to MHC Class I and II

  TCR/pMHC Interaction

  Conclusions and Future Perspectives

  Acknowledgments

  Chapter 12: Mechanistic Features of Cell-Surface Adhesion Receptors

  Mechanosensory Mechanisms

  Cell–Cell Adhesions/Adherens Junctions

  T-Cell Costimulation

  Axon Guidance and Neural Development

  Conclusions

  Chapter 13: The Immunological Synapse

  Introduction

  Migration and the Immunological Synapse

  The Cytoskeleton and the Immunological Synapse

  The Role of Self MHCp in T-Cell Sensitivity to Foreign MHCp

  Integration of Adaptive and Innate Responses

  Summary

  Acknowledgments

  Chapter 14: NK Receptors

  Introduction

  Immunoreceptors

  Natural Killer Cells

  Ig-Type NK Receptors: KIR

  C-Type Lectin-Like NK Receptors: Ly49A

  C-Type Lectin-Like NK Receptors: NKG2D

  Chapter 15: Carbohydrate Recognition and Signaling

  Introduction

  Biological Roles of Carbohydrate Recognition

  Carbohydrate Structure and Diversity

  Lectins and Carbohydrate Recognition

  Carbohydrate-Mediated Signaling

  Conclusions

  Chapter 16: Rhinovirus–Receptor Interactions

  Chapter 17: HIV-1 Receptor Interactions

  Molecular Interactions

  Atomic Details

  Recognition in the Context of a Humoral Immune Response

  Chapter 18: Influenza Virus Neuraminidase Inhibitors

  Introduction

  Flu Virus: Role of NA

  Structure of NA

  Active Site

  Inhibitor Development

  Conclusion

  Acknowledgments

  Chapter 19: Signal Transduction and Integral Membrane Proteins

  Introduction

  Electrophysiology: Rapid Signal Transduction

  Mechanosensation: How Do We Feel?

  Active Transporters: Rapid Response and Energy Management

  Receptors: Gate Keepers for Cell Signaling

  Chapter 20: Structural Basis of Signaling Events Involving Fibrinogen and Fibrin

  Chapter 21: Structural Basis of Integrin Signaling

  Introduction

  Structure

  Quaternary Changes

  Tertiary Changes

  Tail Interactions

  Concluding Remarks

  Chapter 22: Structures of Heterotrimeric G Proteins and Their Complexes

  Introduction

  Gα Subunits

  Ga–Effector Interactions

  GTP Hydrolysis by Gα and Its Regulation by RGS Proteins

  Gβγ Dimers

  GPR/GoLoco Motifs

  Gα–GPCR Interactions

  Section B: Vertical Receptors

  Chapter 23: Structure and Function of G-Protein-Coupled Receptors: Lessons from the Crystal Structure of Rhodopsin

  Introduction

  Introduction to Rhodopsin: a Prototypical G-Protein-Coupled Receptor

  Molecular Structure of Rhodopsin

  Molecular Mechanism of Receptor Activation

  Chapter 24: Human Olfactory Receptors

  Chapter 25: Chemokines and Chemokine Receptors: Structure and Function

  Introduction

  Chemokine Structure and Function

  Chemokine Receptors

  Chapter 26: The Binding Pocket of G-Protein-Coupled Receptors for Biogenic Amines, Retinal, and Other Ligands

  Introduction

  The Binding Pocket of GPCRs

  A Role of the Second Extracellular Loop in Ligand Binding

  Acknowledgments

  Chapter 27: Glycoprotein Hormone Receptors: A Unique Paradigm for Ligand Binding and GPCR Activation

  Introduction

  Molecular Pathophysiology

  Structure Function Relationships of the Glycoprotein Hormone Receptors

  Conclusions and Perspectives

  Chapter 28: Protease-Activated Receptors

  Introduction

  Mechanism of Activation

  Protease-Activated Receptor Family

  Roles of PARs In Vivo

  Chapter 29: Constitutive and Regulated Signaling in Virus-Encoded 7TM Receptors

  Virus-Encoded Proteins Are Developed through Targeted Evolution In Vivo

  The Redundant Chemokine System Is an Optimal Target for Viral Exploitation

  Multiple Virus-Encoded 7TM Receptors

  Constitutive Signaling through Altered Pathways

  Viral Receptors Recognize Multiple Ligands with Variable Function

  Attempts To Identify the Function of Virus-Encoded Receptors In Vivo

  Chapter 30: Frizzleds as G-Protein-Coupled Receptors for Wnt Ligands

  Introduction

  Wnt Signaling

  Evidence for Frizzleds as G-Protein-Coupled Receptors

  Perspective

  Chapter 31: Agonist-Induced Desensitization and Endocytosis of G-Protein-Coupled Receptors

  Introduction

  General Processes of GPCR Regulation

  Mechanisms of GPCR Desensitization and Endocytosis

  Functional Consequences of GPCR Endocytosis

  Chapter 32: Functional Role(s) of Dimeric Complexes Formed from G-Protein-Coupled Receptors

  Acknowledgments

  Chapter 33: The Role of Chemokine Receptors in HIV Infection of Host Cells

  Introduction

  HIV Entry

  Coreceptor Use In Vivo

  Env Domains Involved in Coreceptor Interactions

  Coreceptor Domains Involved in HIV Infection

  Receptor Presentation and Processing

  Role of Signaling in HIV Infection

  Summary

  Acknowledgments

  Chapter 34: Chemotaxis Receptor in Bacteria: Transmembrane Signaling, Sensitivity, Adaptation, and Receptor Clustering

  Signaling at Periplasmic Ligand Binding Domain

  Signaling at the Cytoplasmic Domain

  Adaptation

  Clustering of the Chemoreceptor and Sensitivity

  Future Studies

  Acknowledgment

  Chapter 35: Overview: Function and Three-Dimensional Structures of Ion Channels

  Introduction

  Studies of Full-Length Ion Channels

  General Pore Features Revealed by Bacterial Channels

  Pore Helices: Electrostatic Aids to Permeation

  Open Channels

  Eukaryotic Ion Channels at High Resolution: Divide and Conquer

  Ion Channel Accessory Subunits: Soluble and Transmembrane

  The Future: Ion Channels as Electrosomes

  Chapter 36: How Do Voltage-Gated Channels Sense the Membrane Potential?

  Introduction

  The Voltage-Sensing Gating Particle

  S4 Is the Primary Voltage Sensor

  Physical Models of Activation: Turning a Screw through a Bolt

  Coupling Gating to S4 Voltage-Sensing Motions

  Chapter 37: Ion Permeation: Mechanisms of Ion Selectivity and Block

  Aqueous Pore

  Ion Selectivity

  Block

  Chapter 38: Agonist Binding Domains of Glutamate Receptors: Structure and Function

  Chapter 39: Nicotinic Acetylcholine Receptors

  Function

  Structure

  Chapter 40: Small Conductance Ca2+-Activated K+ Channels: Mechanism of Ca2+ Gating

  Introduction

  Clones Encoding SK Channels

  Biophysical and Pharmacological Profiles

  Mechanism of Ca2+-gating

  Pantophobiac After All

  Chapter 41: Regulation of Ion Channels by Direct Binding of Cyclic Nucleotides

  Introduction

  The Cyclic Nucleotide-Gated Channels

  Other Channels Directly Regulated by Cyclic Nucleotides

  Section C: Horizontal Receptors

  Chapter 42: Overview of Cytokine Receptors

  Chapter 43: Growth Hormone and IL-4 Families of Hormones and Receptors: The Structural Basis for Receptor Activation and Regulation

  Introduction

  The Growth Hormone Family of Hormones and Receptors

  Structural Basis for Receptor Homodimerization

  Hormone Specificity and Cross-Reactivity Determine Physiological Roles

  Hormone-Receptor Binding Sites

  Receptor–Receptor Interactions

  Hormone–Receptor Binding Energetics

  Biological Implications of Transient Receptor Dimerization

  A High-Affinity Variant of hGH (hGHv) Reveals an Altered Mode for Receptor Homodimerization

  Site1 and Site2 Are Structurally and Functionally Coupled

  IL-4 Hormone-Induced Receptor Activation

  IL-4–α-Chain Receptor Interface

  Binding of the γ-Chain Receptor

  Comparisons of IL-4 with GH (PRL)

  Concluding Remarks

  Chapter 44: Erythropoietin Receptor as a Paradigm for Cytokine Signaling

  Introduction

  Biochemical Studies Supporting Preformed Dimers

  Other Cytokine Receptor Superfamily Members

  Conclusions

  Acknowledgments

  Chapter 45: A New Paradigm of Cytokine Action Revealed by Viral IL-6 Complexed to gp130: Implications for GCSF Interaction with GCSFR

  Introduction

  Receptor/Ligand Interactions

  The gp130 System

  Viral Interleukin-6

  GCSF and GCSFR

  Structure of the Viral IL-6–gp130 Complex

  Site 1

  The Site 2 Interface

  The Site 3 Interface

  Implications of the vIL-6–gp130 Tetramer Structure for the Active GCSF–GCSFR Extracellular Signaling Complex

  Chapter 46: The Fibroblast Growth Factor (FGF) Signaling Complex

  Introduction

  FGF Polypeptides

  FGFR Tyrosine Kinases

  Heparan Sulfate

  Oligomeric FGF–FGFR–HS Signaling Complex

  Intracellular Signal Transduction by the FGFR Complex

  Chapter 47: Structure of IFN-γ and Its Receptors

  Chapter 48: Structure and Function of Tumor Necrosis Factor at the Cell Surface

  Introduction

  Structure of Tumor Necrosis Factor

  TNF Receptors

  Extracellular (Ligand Binding) Domains of TNF Family Receptors

  Ligand–Receptor Complexes

  Consequences of Ligand–Receptor Complex Formation

  Receptor Preassociation

  Conclusion

  Chapter 49: The Mechanism of NGF Suggested by the NGF–TrkA-D5 Complex

  Introduction

  Neurotrophins

  Trks

  NGF–TrkA-D5 Complex

  p75NTR

  Chapter 50: The Mechanism of VEGFR Activation Suggested by the Complex of VEGF–flt1-D2

  Introduction

  Heparin-Binding Domain of VEGF

  Receptor-Binding Domain of VEGF

  VEGF Receptors

  VEGF–flt1-D2 Complex

  Chapter 51: Receptor–Ligand Recognition in the TGFβ Family as Suggested by the Crystal Structures of BMP-2–BR-IAec and TGFβ3–TR-IIec

  Introduction

  Ligand and Receptor Structures

  Receptor–Ligand Complexes

  BMP-2–BR-IAec Complex

  Complex Formation with TGFβ Is Different than for BMP-2

  Chapter 52: Insulin Receptor Complex and Signaling by Insulin

  Introduction

  Insulin Receptor Domain Structure

  Binding Determinants of the IR

  Insulin Signaling to Glucose Transport

  Acknowledgment

  Chapter 53: Structure and Mechanism of the Insulin Receptor Tyrosine Kinase

  Introduction

  Structural/Mechanistic Studies

  Prospects

  Acknowledgment

  Chapter 54: What Does the Structure of Apo2L/TRAIL Bound to DR5 Tell Us About Death Receptors?

  Introduction

  Novel Features in the Structure of Apo2L/TRAIL

  Apo2L/TRAIL:DR5 structures

  Ligand-Independent Receptor Assembly

  Intracellular Consequences of Ligand Binding

  Conclusion

  Section D: Membrane Proximal Events

  Chapter 55: TNF Receptor Associated Factors

  Chapter 56: Assembly of Signaling Complexes for TNF Receptor Family Molecules

  Introduction

  Receptor Aggregation

  Raft Recruitment

  Ubiquitination

  Receptor Interactions

  Conclusions

  Chapter 57: Mechanisms of CD40 Signaling in the Immune System

  Introduction

  Signaling Pathways Triggered by CD40 Engagement

  CD40 Signaling Is Mediated by TRAF-Dependent and TRAF-Independent Pathways

  Chapter 58: Role of Lipid Domains in EGF Receptor Signaling

  Introduction

  Localization of the EGF Receptor to Lipid Rafts

  Rafts and EGF-Receptor-Mediated Signaling

  The EGF Receptor and Caveolin

  Summary

  Chapter 59: Structure and Function of B-Cell Antigen Receptor Complexes

  Introduction

  The Structure of the B Cell Antigen Receptor

  Initiation of BCR Signaling Is Controlled by Redox Regulation

  Chapter 60: Lipid-Mediated Localization of Signaling Proteins

  Introduction

  Protein Lipidation

  Summary

  Acknowledgments

  Chapter 61: G-Protein Organization and Signaling

  Introduction

  G-Protein Molecular Organization

  Structural Features of G Protein Activation

  Structural Determinants of Receptor–G-Protein Specificity

  Gα Interactions with Effector Molecules

  Gβγ Interactions with Effector Molecules

  Conclusions

  Chapter 62: JAK–STAT Signaling

  Introduction

  Cytokine Signaling Proteins

  JAK Structure and Localization

  STAT Structure and Function

  Inhibition of Cytokine Signaling

  Summary

  Acknowledgments

  Chapter 63: Organization of Photoreceptor Signaling Complexes

  INAD Organizes Signaling Complexes

  INAD-Signaling Complexes in Phototransduction

  Assembly, Targeting, and Anchoring of Signaling Complexes

  Signaling Complexes in Vertebrate Photoreceptors

  Chapter 64: Protein Localization in Negative Signaling

  Introduction

  The Role of CD28 and CTLA-4 in T-Cell Activation

  Expression and Localization of CTLA-4 and CD28: Consequences for Receptor Function

  Mechanisms of CTLA-4-Mediated Negative Signaling

  Conclusions

  Acknowledgments

  Chapter 65: Transmembrane Receptor Oligomerization

  Introduction

  Tyrosine Kinase-Containing Receptors

  Cytokine Receptors

  Guanylyl Cyclase-Containing Receptors

  Serine/Threonine Kinase-Containing Receptors

  Tumor Necrosis Factor Receptors

  Heptahelical Receptors (G-Protein-Coupled Receptors)

  Concluding Remarks

  PART II: TRANSMISSION: EFFECTORS AND CYTOSOLIC EVENTS

  PART II: Introduction

  Introduction to: Introduction

  Section A: Protein Phosphorylation

  Chapter 66: Eukaryotic Kinomes: Genomic Cataloguing of Protein Kinases and Their Evolution

  Introduction

  The Yeasts: Saccharomyces cerevisiae and Schizosaccharomyces pombe

  Nematodes: Caenorhabditis elegans

  Insects: Drosophila melanogaster

  Vertebrates: Homo sapiens

  Comparative Kinomics

  Coda

  Chapter 67: Modular Protein Interaction Domains in Cellular Communication

  Introduction

  Phosphotyrosine-Dependent Protein–Protein Interactions

  Interaction Domains: A Common Theme in Signaling

  Adaptors, Pathways, and Networks

  Evolution of a Phospho-Dependent Docking Protein

  Multisite Phosphorylation, Ubiquitination, and Switch-Like Responses

  Summary

  Acknowledgments

  Chapter 68: Structures of Serine/Threonine and Tyrosine Kinases

  Introduction

  Structures of Protein Kinases

  Structures of Inactive Protein Kinases

  Summary

  Chapter 69: Protein Tyrosine Kinase Receptor Signaling Overview

  Introduction

  PTK Subfamilies

  Mechanism of Activation

  Control of PTK Receptor Activity

  Cross-Talk Between Signaling Pathways

  PTK Receptors and Disease

  Acknowledgments

  Chapter 70: Signaling by the Platelet-Derived Growth Factor Receptor Family

  Introduction

  Platelet-Derived Growth Factors, Their Receptors, and Assembly of the PDGF Receptor Signaling Complex

  Some Aspects of Regulation of the PDGF Receptor-Initiated Signaling

  Chapter 71: EGF Receptor Family

  Introduction

  Domain Structure of ErbBs

  Subcellular Localization of ErbB Proteins

  ErbB-Induced Signaling Pathways

  Negative Regulatory Pathways

  Specificity of Signaling Through the ErbB Network

  ErbB Proteins and Pathological Conditions

  Chapter 72: IRS-Protein Scaffolds and Insulin/IGF Action

  IRS-Proteins: The Beginnings

  IRS-Proteins and Insulin Signaling

  IRS-Protein Structure and Function

  PI 3-Kinase Cascade

  IRS-Protein Signaling in Growth, Nutrition, and Longevity

  Interleukin-4 and IRS2 Signaling

  Heterologous Regulation of IRS-Protein Signals

  IRS2 and Pancreatic β-Cells

  Summary

  Chapter 73: Eph Receptors

  Introduction

  Ephs and Ephrins

  Eph Receptor Signaling Via Cytoplasmic Protein Tyrosine Kinases

  Eph Receptor Signaling Via Rho Family GTPases

  Effects on Cell Proliferation

  Eph Receptor Signaling through PDZ-Domain-Containing Proteins

  Eph Receptors and Cell Adhesion

  Ephrin Reverse Signaling

  EphrinB Reverse Signaling Via Phosphotyrosine

  EphrinB Reverse Signaling Via PDZ Domain Interactions

  Summary

  Chapter 74: Cytokine Receptor Superfamily Signaling

  Cytokine Receptor Superfamily Signaling

  Chapter 75: Negative Regulation of the JAK/STAT Signaling Pathway

  Introduction

  The Phosphatases

  STAT Phosphatases

  PIAS (Protein Inhibitors of Activated STATS)

  SOCS (Suppressors of Cytokine Signaling) Family

  Concluding Comments

  Acknowledgments

  Chapter 76: Activation of Oncogenic Protein Kinases

  Introduction

  Physiological Regulation of Protein Kinases

  Activation of Protein Kinases by Retroviruses

  Activation of Protein Kinases in Human Cancer

  Oncogenic Protein Kinases as Targets for Therapy

  Chapter 77: Protein Kinase Inhibitors

  Signal Transduction Therapy

  Protein Tyrosine Kinase Inhibitors

  SER/THR Kinase Inhibitors

  Chapter 78: Integrin Signaling: Cell Migration, Proliferation, and Survival

  Introduction

  Integrins Nucleate the Formation of Multi-Protein Complexes

  Cell Migration: A Paradigm for Studying Integrin Signaling

  Integrin Regulation of Cell Proliferation and Survival: Links to Cancer

  Concluding Remarks

  Acknowledgments

  Chapter 79: Downstream Signaling Pathways: Modular Interactions

  Introduction

  General Properties of Interaction Modules

  Roles in Signaling

  Prospects

  Chapter 80: Non-Receptor Protein Tyrosine Kinases in T-Cell Antigen Receptor Function

  Introduction

  T-Cell Antigen Receptor Structure

  Src PTKs

  Csk (c-Src PTK)

  ZAP-70/Syk PTKs

  Tec PTKs

  Summary

  Chapter 81: Cbl: A Physiological PTK Regulator

  Introduction

  Domains of Cbl Proteins

  Sli-1: A Negative Regulator of RPTKs

  PTK Downregulation by Polyubiquitylation

  Cbl-Deficient Mice

  Future Directions

  Chapter 82: TGFβ Signal Transduction

  Introduction

  The Smad Pathway

  Smads and the Ubiquitin–Proteasome System

  Smad-Independent Signaling Pathways

  Other Receptor Interacting Proteins

  Chapter 83: MAP Kinases

  Introduction

  The ERK Module

  Stress-Activated MAPKs, Part 1: SAPK/JNKs

  Stress-Activated MAPKs, Part 2: p38 MAPKs

  MAPKKs

  MAPKKKs

  MAPKKKKs

  Summary

  Acknowledgments

  Chapter 84: Cytoskeletal Regulation: Small G-Protein–Kinase Interactions

  Introduction

  p21-Activated Kinases

  Myotonic Dystrophy Kinase-Related Cdc42-Binding Kinase

  Rho-Associated Kinase (ROK)

  Acknowledgments

  Chapter 85: Recognition of Phospho-Serine/Threonine Phosphorylated Proteins

  Introduction

  14-3-3 Proteins

  FHA Domains

  WW Domains

  Leucine-Rich Repeats and WD40 Domains

  Concluding Remarks

  Acknowledgments

  Chapter 86: Role of PDK1 in Activating AGC Protein Kinase

  Introduction

  Mechanism of Activation of PKB

  PKB Is Activated by PDK1

  Activation of Other Kinases by PDK1

  Phenotype of PDK1 PKB- and S6K-Deficient Mice and Model Organisms

  Hydrophobic Motif of AGC Kinases

  Mechanism of Regulation of PDK1 Activity

  Structure of the PDK1 Catalytic Domain

  Concluding Remarks

  Acknowledgments

  Chapter 87: Regulation of Cell Growth and Proliferation in Metazoans by mTOR and the p70 S6 Kinase

  Introduction

  Functions of TOR

  Signaling from TOR

  Regulation of mTOR Activity (Fig. 2)

  Chapter 88: AMP-Activated Protein Kinase

  Introduction

  Structure of the AMPK Complex

  Regulation of the AMPK Complex

  Regulation in Intact Cells and Physiological Targets

  Medical Implications of the AMPK System

  Acknowledgments

  Chapter 89: Principles of Kinase Regulation

  Introduction

  Protein Kinase Structure

  General Principles of Control

  Regulatory Sites in Protein Kinase Domains

  Conclusions

  Chapter 90: Calcium/Calmodulin-Dependent Protein Kinase II

  Introduction

  Structure of CaMKII

  Regulation by Autophosphorylation

  Regulatory Roles of CaMKII in Neurons

  Chapter 91: Glycogen Synthase Kinase 3

  Introduction

  The Substrate Specificity of GSK3

  The Regulation of GSK3 Activity by Insulin and Growth Factors

  GSK3 as a Drug Target

  The Role of GSK3 in Embryonic Development

  GSK3 and Cancer

  Acknowledgments

  Chapter 92: Protein Kinase C: Relaying Signals from Lipid Hydrolysis to Protein Phosphorylation

  Introduction

  Protein Kinase C Family

  Regulation of Protein Kinase C

  Function of Protein Kinase C

  Summary

  Acknowledgments

  Chapter 93: The PIKK Family of Protein Kinases

  Introduction

  Overview of PIKK Family Members

  Overall Architecture of PIKK Family Proteins

  mTOR: A Key Regulator of Cell Growth

  DNA-PKcs: At the Heart of the DNA Nonhomologous End-Joining Machinery

  ATM and ATR: Signalers of Genome Damage

  SMG-1: A Regulator of Nonsense-Mediated mRNA Decay

  TRRAP: A Crucial Transcriptional Co-Activator

  PIKK Family Members as Guardians of Nucleic Acid Structure, Function, and Integrity?

  Acknowledgments

  Chapter 94: Histidine Kinases

  Chapter 95: Atypical Protein Kinases: The EF2/MHCK/ChaK Kinase Family

  Introduction

  Identification of an Atypical Family of Protein Kinases: EF2 Kinase, Myosin Heavy Chain Kinase and ChaK

  The Structure of the Atypical Kinase Domain Reveals Similarity to Classical Protein Kinases and to Metabolic Enzymes with ATP-Grasp Domains

  Substrate Specificity of Atypical Kinases

  Regulation of Atypical Kinases

  Functions of the Atypical Family of Protein Kinases

  Acknowledgments

  Chapter 96: Casein Kinase I and Regulation of the Circadian Clock

  Introduction

  double-time: A Casein Kinase I Homolog in Drosophila

  Casein Kinase I in the Mammalian Clock

  Casein Kinase I in the Neurospora Clock

  Similarities and Differences of CKI Function in Different Clock Systems

  Chapter 97: The Leucine-Rich Repeat Receptor Protein Kinases of Arabidopsis thaliana: A Paradigm for Plant LRR Receptors

  Introduction

  LRR Receptor Protein Kinases: The Genomic Point of View

  LRR Receptor Protein Kinases: The Functional View

  Summary

  Chapter 98: Engineering Protein Kinases with Specificity for Unnatural Nucleotides and Inhibitors

  Acknowledgments

  Section B: Protein Dephosphorylation

  Chapter 99: Overview of Protein Dephosporylation

  Chapter 100: Protein Serine/Threonine Phosphatases and the PPP Family

  Current Classification of Protein Serine/Threonine Phosphatases

  Background

  Evolution and Conserved Features of the PPP Family

  Catalytic Activities of the PPP Family Members

  Eukaryotic PPP Subfamilies

  Domain and Subunit Structure of PPP Family Members

  Medical Importance of the PPP Family

  Acknowledgments

  Chapter 101: The Structure and Topology of Protein Serine/Threonine Phosphatases

  Introduction

  Protein Serine/Threonine Phosphatases of the PPP Family

  Protein Serine/Threonine Phosphatases of the PPM Family

  Conclusions

  Chapter 102: Naturally Occurring Inhibitors of Protein Serine/Threonine Phosphatases

  Introduction

  Effects of Inhibitors in Cell-Based Experiments

  The Toxins Bind to the Active Sites of Protein Phosphatases

  Chemical Synthesis of Protein Phosphatase Inhibitors

  Microcystin Affinity Chromatography and Affinity Tagging

  Avoiding the Menace of Toxins in the Real World Outside the Laboratory

  Acknowledgments

  Chapter 103: Protein Phosphatase 1 Binding Proteins

  Introduction

  Protein Phosphatase 1 (PP1)

  PP1 Regulatory or Targeting Subunits

  Conclusions

  Acknowledgments

  Chapter 104: Role of PP2A in Cancer and Signal Transduction

  Introduction

  Structure of PP2A

  Subunit Interaction

  Association of PP2A with Cellular Proteins

  Alteration or Inhibition of PP2A Is Essential in Human Cancer Development

  Mutation of Aα and Aβ Isoforms in Human Cancer

  Differences between Aα and Aβ Subunits

  PP2A and Wnt Signaling

  PP2A and the MAP Kinase Pathway

  Summary

  Chapter 105: Serine/Threonine Phosphatase Inhibitor Proteins

  Introduction

  Protein Phosphatase 1 (PP1) Inhibitors

  I-1, DARPP-32, and Other Phosphorylation-Dependent Phosphatase Inhibitors

  Latent Phosphatase Complexes Activated by Inhibitor Phosphorylation

  Inhibitors of Type-2 Serine/Threonine Phosphatases

  Conclusions

  Acknowledgments

  Chapter 106: Calcineurin

  Introduction

  Enzymatic Properties

  Structure

  Regulation

  Distribution and Isoforms

  Functions

  Muscle Differentiation

  Conclusion

  Chapter 107: Protein Serine/Threonine-Phosphatase 2C (PP2C)

  Introduction

  Regulation of the Stress-Activated MAP Kinase Cascades

  Control of the CFTR Chloride Channel by PP2C

  Plant Hormone Abscisic Acid Signaling

  Fem-2: A Sex-Determining PP2C in Nematode

  Stress-Responsive PP2Cs in Bacillus subtilis

  Chapter 108: Overview of Protein Tyrosine Phosphatases

  Background

  Structural Diversity within the PTP Family

  The Classical PTPs

  The Dual Specificity Phosphatases (DSPs)

  Regulation of PTP Function

  Oxidation of PTPs in Tyrosine Phosphorylation-Dependent Signaling

  Substrate Specificity of PTPs

  PTPs and Human Disease

  Perspectives

  Acknowledgments

  Chapter 109: Protein Tyrosine Phosphatase Structure and Mechanisms

  Introduction

  Introduction to the Protein Tyrosine Phosphatase Family

  Structure

  Mechanism

  Regulation

  Acknowledgments

  Chapter 110: Bioinformatics: Protein Tyrosine Phosphatases

  Introduction to Bioinformatics

  Amino Acid Homology Among PTP Domains and Structure–Function Studies

  Identification of the Genomic Complement of PTPs

  Functional Aspects of PTPs in Health and Disease: Bioinformatics

  Chapter 111: PTP Substrate Trapping

  Introduction

  Original C→S and D→A Substrate-Trapping Mutants

  Second-Generation Trapping Mutants

  Accessory or Noncatalytic Site Contributions to Substrate Recognition

  New Twists on Trapping

  Other Applications of Substrate Trapping Mutants

  Chapter 112: Inhibitors of Protein Tyrosine Phosphatases

  Introduction

  Covalent PTP Modifiers

  Oxyanions as PTP Inhibitors

  pTyr Surrogates as PTP Inhibitors

  Bidentate PTP Inhibitors

  Other PTP Inhibitors

  Concluding Remarks

  Acknowledgment

  Chapter 113: Regulating Receptor PTP Activity

  Introduction

  Regulation by Dimerization

  Regulation by Phosphorylation

  Regulation by D2 Domain

  Chapter 114: CD45

  Introduction

  Structure

  Function

  Regulation

  Acknowledgment

  Chapter 115: Properties of the Cdc25 Family of Cell-Cycle Regulatory Phosphatases

  Introduction

  Physiological Functions of Cdc25

  Regulation of Cdc25

  Concluding Remarks

  Chapter 116: Cell-Cycle Functions and Regulation of Cdc14 Phosphatases

  Introduction

  The Cdc14 Phosphatase Subgroup of PTPs

  Budding Yeast Cdc14 is Essential for Exit from Mitosis

  Fission Yeast Cdc14 Coordinates Cytokinesis with Mitosis

  Potential Cell-Cycle Functions of Human Cdc14A and B

  Chapter 117: MAP Kinase Phosphatases

  Introduction

  MAPK Phosphatases in Yeast

  A MAPK Phosphatase in C. elegans

  MAPK Phosphatases in Drosophila melanogaster

  MAPK Phosphatases in Mammals

  Summary

  Chapter 118: SH2-Domain-Containing Protein–Tyrosine Phosphatases

  History and Nomenclature

  Structure, Expression, and Regulation

  Biological Functions of Shps

  Shp Signaling and Substrates

  Determinants of Shp Specificity

  Shps and Human Disease

  Summary and Future Directions

  Acknowledgments

  Chapter 119: Insulin Receptor PTP: PTP1B

  Introduction

  PTP1B as a Bona Fide IR Phosphatase

  PTP1B Gene Polymorphisms and Insulin Resistance

  Insulin-Mediated Modulation of PTP1B

  Genetic Evidence for Other PTP1B Substrates

  Concluding Remarks

  Chapter 120: Low-Molecular-Weight Protein Tyrosine Phosphatases

  Introduction

  Structures of LMW PTPases

  Catalytic Mechanism

  Inhibitors and Activators

  Substrate Specificity, Regulation, and Biological Role

  Acknowledgments

  Chapter 121: STYX/Dead-Phosphatases

  Introduction

  Gathering Styx: Structure Implies Function

  The Gratefully Undead: STYX/Dead-Phosphatases Mediate Phosphorylation Signaling

  Conclusions

  VOLUME 2

  PART II: TRANSMISSION: EFFECTORS AND CYTOSOLIC EVENTS (CONTINUED FROM VOLUME 1)

  Section C: Calcium Mobilization

  Chapter 122: Phospholipase C

  Introduction

  PLC Anatomy

  PLC Activation Mechanisms

  PLC Physiology

  Chapter 123: Inositol 1,4,5-trisphosphate 3-kinase and 5-phosphatase

  Introduction

  Type I InsP3 5-phosphatase

  InsP3 3-kinase

  Chapter 124: Cyclic ADP-ribose and NAADP

  Introduction

  Chapter 125: Sphingosine 1-phosphate

  Introduction

  Sphingolipid Metabolism

  Activation of SPHK

  Intracellular Target for SPP-mediated Ca2+ Release

  Concluding Remarks

  Acknowledgments

  Chapter 126: Voltage-gated Ca2+ Channels

  Introduction

  Physiological Roles of Voltage-gated Ca2+ Channels

  Ca2+ Current Types Defined by Physiological and Pharmacological Properties

  Molecular Properties of Ca2+ Channels

  Molecular Basis for Ca2+ Channel Function

  Ca2+ Channel Regulation

  Conclusion

  Chapter 127: Store-operated Ca2+ Channels

  Capacitative Calcium Entry

  Store-operated Channels

  Mechanism of Activation of Store-operated Channels

  Summary

  Chapter 128: Arachidonic Acid-regulated Ca2+ Channel

  Introduction

  Identification and Characterization of ARC Channels

  Specific Activation of ARC Channels by Low Agonist Concentrations

  Roles of ARC Channels and SOC/CRAC Channels in [Ca2+]i Signals: "Reciprocal Regulation"

  Conclusions and Implications

  Acknowledgments

  Chapter 129: IP3 Receptors

  Introduction

  Chapter 130: Ryanodine Receptors

  Function and Structure

  Activation of Ryanodine Receptor Ca2+ Release Channels

  Molecular Biology of Ryanodine Receptors

  Chapter 131: Intracellular Calcium Signaling

  The "Calcium Signaling Toolkit" and Calcium Homeostasis

  Multiple Channels and Messengers Underlie Ca2+ Increases

  Temporal Regulation of Ca2+ Signals

  Spatial Regulation of Ca2+ Signals

  Modulation of Ca2+ Signal Amplitude

  Ca2+ as a Signal within Organelles and in the Extracellular Space

  Chapter 132: Calcium Pumps

  Introduction

  Reaction Cycle of the SERCA and PMCA Pumps

  The SERCA Pump

  The PMCA Pump

  Genetic Diseases Evolving Defects of Calcium Pumps

  Chapter 133: Sodium/Calcium Exchange

  Introduction

  Two Families of PM Na+/Ca2+ Exchangers

  Modes of Operation of the Na+/Ca2+ Exchangers

  Regulation of NCX

  Inhibition of NCX

  Localization of the NCX

  Physiolo

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