Cellular Signaling in Health and Disease (eBook)

Preface 6
Contents 8
Part I: Metabolic Syndromes 19
Introduction 20
1.1 The Cellular Signaling Machinery Makes Homeostasis Possible 21
1.2 Inflammation Is Present in Diseases 21
1.3 Cholesterol Together with Inflammation Promotes Atherosclerosis 23
1.4 Signaling Pathways Responsible for Maintaining Cellular Homeostasis Are Uncovered and Explored 23
1.5 Biophysical Techniques Provide Detailed Information on the Three-Dimensional Structure of Macromolecules 24
1.6 Signaling Pathways Have Been Illuminated Through Intensive Efforts Spanning the Last 50 Years 25
1.7 Mutated, Misfolded Proteins Cause Cancer 26
1.8 The Microenvironment Is an Important Ingredient in Cancer Metastasis 27
1.9 Neurons Are Cells Highly Specialized for Long-Range Signaling 29
1.10 Amyloids Are an Essential Ingredient in Many Diseases 29
1.11 Reactive Oxygen and Nitrogen Species Carry Out Signaling in Ways That Contribute to Health and Disease 32
Further Reading 32
Energy Balance 35
2.1 Hormonal Signaling by the Endocrine Pancreas 37
2.2 In Response to Signals from the Pancreas, the Liver Maintains Glucose and Lipid Homeostasis 38
2.3 Energy in the Form of Lipids Is Stored and Released When Needed in Adipose Tissue 40
2.4 Adipose Tissue Functions as an Endocrine Organ 41
2.5 Ghrelin Released by Endocrine Cells in the Stomach Acts in Short-Term Feeding and Long-Term Energy Management 42
2.6 Satiation Signals Are Sent by Cells in the Gastrointestinal Tract 42
2.7 Brown Adipose Tissue Carries Out Adaptive (Diet-Induced and Cold-Induced, Nonshivering) Thermogenesis 43
2.8 Muscle Cells and beta-Oxidation 45
2.9 AMPK Is an Intracellular Energy Sensor and Regulator 47
2.10 AMPK Is Activated by Upstream Kinases and by Depleted Energy Supply as Indicated by Increased AMP/ATP Ratios 49
2.11 The Hypothalamic Network Provides Feedback Signals to Peripheral Tissues 51
2.12 Leptin Signaling and Regulation of Energy Balance in the Hypothalamus 53
2.13 Ghrelin Signaling and Regulation of Energy Balance in the Hypothalamus 55
Further Reading 56
Insulin Signaling and Type 2 Diabetes 60
3.1 Type 2 Diabetes Develops in a Series of Stages from Overnutrition 61
3.2 Adipose Tissue Functions as an Immune Organ 62
3.3 Metabolic Overload Occurs in Energy-Responsive Tissues 63
3.4 Signal Transduction Begins with the Insulin Receptor and Its Substrate Proteins 65
3.5 Phosphoinositide-3-OH Kinase (PI3K) and the PTEN Lipid Phosphatase 67
3.6 Activation of Protein Kinase B (PKB) and Protein Kinase C (PKC) 69
3.7 GLUT4 Transport Biomechanics and Regulation 71
3.8 The TOR Cassette Is the Downstream Target of Akt Signals 73
3.9 Feedback Regulation of Akt by TORC2 and IRS by TORC1/S6K 75
3.10 Insulin Resistance Develops from Inflammation and Metabolic Overload 75
3.11 Glucose-Stimulated Hormone Release by Pancreatic Islet Cells 78
3.12 KATP Channels and Their Regulation by Cellular Fuel Status 80
3.13 Islet beta-Cell Failure and Diabetic Complications 81
Further Reading 82
Metabolic Program Execution and Switching 86
4.1 Nuclear Receptors Are Ligand-Activated Transcription Factors 86
4.2 Nuclear Receptors Contain Five or Six Domains 88
4.3 The CAR Activates and Deactivates in a Manner Distinct from Other Nuclear Receptors 89
4.4 Peroxisome Proliferator-Activated Receptors Are Lipid Sensors and Effectors 90
4.5 Nuclear Receptors Require Coactivators and Corepressors 92
4.6 PGC-1 Scaffold Protein in Regulation of Lipid Homeostasis 95
4.7 FoxOs Mediate Survival, Metabolic, and Stress Responses 95
4.8 14-3-3 Protein Function as Small, Mobile Phosphoprotein Binding Modules 97
4.9 Gluconeogenesis in the Liver Is Stimulated by Glucagon and Repressed by Insulin 98
4.10 Catecholamine Signaling Targets PGC1alpha to Promote Diet-Induced Thermogenesis in Brown Adipose Tissue 100
4.11 Caloric Restriction Extends Lifespan by Activating Protective Stress Responses 101
4.12 SIRT1 Promotes Fatty Acid Oxidation in Liver and Skeletal Muscle 102
Further Reading 103
Cholesterol 106
5.1 Membrane Lipids Form Gels and Liquid States 106
5.2 Feedback Regulation of Cholesterol Synthesis by Insigs 109
5.3 Feedback Regulation of Cholesterol Synthesis by SREBPs 110
5.4 SREBPs, Liver X Receptors, and Farnesoid X Receptors Regulate Transcription 112
5.5 Lipoproteins Are Carriers of Cholesterol and Triglycerides 113
5.6 Apolipoproteins are Amphipathic, Lipid-Binding Constituents of the Lipoproteins 114
5.7 Cholesterol Comes in Two Forms - As a Sterol, i.e., as a Free Cholesterol (FC) Molecule, and as a Cholesterol Ester (CE) 117
5.8 ABC Transporters Export Cholesterol from Macrophages 118
Further Reading 119
Atherosclerosis 121
6.1 The Arterial Wall Consists of Three Layers 121
6.2 Cells Are Continually Subjected to Forces 123
6.3 Atherosclerotic Lesions Occur Preferentially in Regions of Disturbed Blood Flow 124
6.4 Cells Utilize Multiple Mechanotransduction Pathways That Convey Information About Blood Flow 126
6.5 Mechanotransduction Pathways Relay Information About Blood Flow to Endothelial Caveolae and Nitric Oxide Synthase 126
6.6 oxLDL Is Atherogenic and Acts in Opposition to eNOS and NO 127
6.7 Cell Adhesion Molecules and Chemokines Mediate Leukocyte Migration into Sites of Inflammation 129
6.8 Leukocyte Migration Occurs Through a Multistep Adhesion Cascade 131
6.9 Selectins Are Key Mediators of Leukocyte Tethering and Rolling 132
6.10 Slip and Catch Bonds Play Important Roles in Selectin-Mediated Rolling 133
6.11 Leukocyte Arrest Through the Joint Actions of Chemokines and Integrins 135
6.12 Epithelial Cell-to-Cell Adhesions Are Maintained by Junctional Complexes 137
6.13 Leukocytes Enter the Intima by Passing In-Between Epithelial Cells and by Passing Through Them 139
6.14 Rupture of the Fibrous Cap and Not the Lesion Itself Causes Thrombosis 140
Further Reading 142
Chronic Inflammation 145
7.1 The NF-kappaB Signaling Node Consists of IKKs, IkappaBs, and NF-kappaBs 146
7.2 Protein Ubiquitination Plays a Central Role in Cellular Signaling 149
7.3 TNFalpha Signaling Occurs Through Complex I and Complex II 151
7.4 Reactive Oxygen Species (ROS) Influences the Choice Between Survival and Death 152
7.5 Toll-like Receptor 4 Responds to Bacterial Lipopolysaccharides and Mammalian Lipids 153
7.6 Downstream and into the Nucleus with NF-kappaBs 155
7.7 Glucocorticoids Terminate Inflammatory Responses and Restore Homeostasis 156
7.8 LXRs and PPARgamma in Transrepression of Inflammation Through SUMOylation 157
7.9 The Local Microenvironment Is a Key Organizational Unit in Health and Disease 159
7.10 The Inflammatory Response Is a Biphasic One with Distinct Clear Up and Reconstruction Phases 160
7.11 Macrophages Are Inflammatory Cells with Key Roles in the Body’s Response to Infection and Injury 161
7.12 Fibroblasts Are Connective Tissue Cells 163
7.13 Mesenchymal Stem Cells Are Located Throughout the Body 164
Further Reading 164
Redox Signaling 168
8.1 Hydrogen Peroxide and Nitric Oxide Are Signaling Molecules 169
8.2 Nox Enzymes 170
8.3 Oxidation of Sulfhydryls and Hydrogen Peroxide Signaling 172
8.4 Nitric Oxide Synthases and Nitric Oxide Signaling 175
8.5 The Frank-Starlings Law and Excitation-Contraction Coupling 177
8.6 Transcriptional Regulation of the Metabolic Programs 179
8.7 Inappropriate S-Nitrosylation Contributes to Neurodegenerative Disorders 181
8.8 The Electron Transport Chain Can Generate Reactive Oxygen Species 183
Further Reading 185
Part II: Cancer 189
The Cell Cycle 190
9.1 The Cell Cycle Has Four Phases 193
9.2 Ubiquitin-Mediated Proteolysis Is a Key Part of the Cell Cycle Machinery 194
9.3 Several Families of Activators and Inhibitors Are Part of the Cell Cycle Engine 195
9.4 The Retinoblastoma Proteins and E2F Transcription Factors Are Downstream Cell Cycle Effectors at the G1/S Transition 196
9.5 Cell Cycle Effectors at the G2/M Transition 198
9.6 The SCF and APC/C Are Large Multisubunit Complexes 199
9.7 Mathematical Modeling Is an Essential Tool in Understanding Signaling Pathways and Networks 200
9.8 The Goldbeter Model of Entry and Exit from Mitosis 203
9.9 Multiple Positive and Negative Feedback Regulate the Progression Through the Cell Cycle 205
9.10 Multisite Phosphorylation Helps Ensure the Correct Ordering of Events 207
9.11 Traversing the Cell Cycle with the APC and SCF 207
Further Reading 208
Cell Cycle Checkpoints and DNA Damage Repair 212
10.1 The G1/S Checkpoint Pathway 213
10.2 Formation of IRIFs and Activation of ATM 214
10.3 Mediators Amplify the ATM Signal 216
10.4 Intra-S Phase and G2/M Checkpoints 217
10.5 Formation of SDSCs and Activation of ATR 218
10.6 Structure and Posttranslational Modifications of Checkpoint Proteins 219
10.7 p53 Structure and Function 221
10.8 Restoration of p53 Function by Second-Site Suppressors 223
10.9 Special Domains Mediate Protein-Protein Interactions and Chromatin Binding by Proteins that Function at the Apex of the Checkpoint and Repair Pathways 224
10.10 Base Excision Repair 225
10.11 Nucleotide Excision Repair 227
10.12 Mismatch Repair 227
10.13 Repair Proteins Diffuse Laterally in One-Dimension Along DNA 228
10.14 There Are Two Double-StrandBreak Repair Systems 229
10.15 The Mre11-Rad50-Nbs1 (MRN) Complex Is Involved in DNA Damage Sensing, Signaling, and Repair 231
10.16 Completing the Repair and Terminating the Checkpoint 232
Further Reading 233
Apoptosis and Senescence 237
11.1 Pathways to Apoptosis - Extrinsic and Intrinsic 238
11.2 Bcl2 Proteins Mediate the Apoptotic Balance 240
11.3 Sequestration and Release of Cytochrome c 242
11.4 Damage-Induced Apoptosis via p53 Transcription and Mitochondrial Actions 243
11.5 Cells That Are Healthy Do Not Have an Unlimited Capacity to Divide 244
11.6 Telomere Structure and Capping Proteins 244
11.7 Cancer Cells Increase Their Production of Telomerase, an Enzyme That Immortalizes the Cells 245
11.8 Regulation of Replicative Senescence by p53 and pRb 246
11.9 DNA Damage and Oncogene-Induced Senescence 247
11.10 A Model or Two of Oncogene-Induced Stress 248
11.11 p53 Undergoes Posttranslational Modifications Including Phosphorylation, Acetylation, and Ubiquitination at Multiple Sites 250
11.12 Heterochromatin Formation Provides a Route to Oncogene-Induced Senescence 251
11.13 The Retinoblastoma Protein Helps Establish the Senescent State by Mediating Heterochromatin Formation 253
Further Reading 254
Epigenetics 259
12.1 Nucleosomes and Chromatin Structure 260
12.2 Epigenetic Marks 261
12.3 DNA Methylation 263
12.4 Polycomb and Trithorax Group Proteins 264
12.5 Histone Acetylation and Deacetylation 264
12.6 Histone Methylation and Demethylation 265
12.7 Reading Out Histone Marks by Recognition Modules 266
12.8 Cooperative Actions by Histone Modification Enzymes and DNA Methyltransferases Can Silence Genes and Lead to Cancer 269
12.9 Recently Discovered Small Noncoding RNAs (ncRNAs) Regulate Gene Expression 270
12.10 Atomic-Level Studies of Dicer and Slicer Provide Crucial Insights into ncRNA Function 272
12.11 MicroRNAs and Cancer 274
12.12 Induced Pluripotent Stem Cells 276
Further Reading 277
Tumor Growth 281
13.1 Growth and Survival Signaling Pathways 281
13.2 Receptor Activation Leads to Recruitment of Molecular Adaptors to Docking Sites 283
13.3 Ras and Other Small GTPases Link Adaptors to Downstream Signaling Elements 285
13.4 Many of the Growth Signaling Proteins Function as Oncogenes 286
13.5 MAP Kinase Signaling Modules 288
13.6 The MAP Kinase Modules and Their Substrates Function as Dynamical Circuits 290
13.7 Active and Inactive Conformations of Protein Kinases 291
13.8 Oncogene Addiction 292
13.9 Target-Based Anticancer Therapies 293
13.10 Myc Protein Structure and Function 294
13.11 Phosphorylation and Polyubiquitination Sculpt Myc-Mediated Gene Transcription 295
13.12 Regulation of Cellular Growth by Ras, Erk, and Myc 296
13.13 Regulation of Cellular Proliferation by Myc 297
Further Reading 298
Tumor Metabolism 301
14.1 The Central Growth Network of the Cell Is Organized About the mTOR Cassette 302
14.2 AMPK Supplies a Gating Signal Indicative of Energy Balance 303
14.3 Cells Halt Growth in Response to Hypoxia and Other Cellular Stresses 303
14.4 Regulation of Cell Growth by Amino Acid Starvation Signaling to mTOR 305
14.5 Regulation of the Translation Initiation Complex by mTOR 306
14.6 Starvation and Autophagy 308
14.7 p53 Modulation of Metabolism Is One of Its Barrier Functions 310
14.8 The PTEN Tumor Suppressor Acts at the Plasma Membrane and in the Nucleus 312
14.9 Mutations and Disturbed Redox Balance Deactivate PTEN 313
14.10 HIF Transcription Factors Sense and Respond to Low Oxygen Conditions 314
14.11 HIFs Regulate Cellular Metabolism and Drive the Glycolytic Shift 316
14.12 Hexokinase II and Akt Drive the Glycolytic Shift and Prevent Apoptosis in Tumors 317
Further Reading 319
Metastasis 323
15.1 Tumor Growth and Metastasis Are Community Affairs 324
15.2 Macrophages and Fibroblasts Direct Invasion and Intravasation 326
15.3 The SDF-1/CXCR4 Axis Is a Central Participant in Metastasis 327
15.4 Focal Adhesions and Metastasic Migration 328
15.5 Receptor Cooperativity and Src Signaling 330
15.6 The Transforming Growth Factor-beta Pathway 332
15.7 TGF-beta Promotes Cytostasis 335
15.8 The Wnt Pathway 336
15.9 The Epithelial to Mesenchymal Transition 337
15.10 MicroRNAs and Transcription Repressors Jointly Regulate E-Cadherin Expression 339
15.11 MicroRNAs Act as Metastasis Repressors and Activators 341
15.12 Stem Cells and Cancer Stem Cells 341
15.13 Changing Views About Metastatic Spread 342
15.14 The Notch Pathway 343
15.15 The Hedgehog Pathway in Drosophila 345
15.16 The Hedgehog Pathway in Mammals 346
15.17 Bone Metastasis Is a Seed-and-Soil Exemplar 348
Further Reading 349
Part III: Neurodegeneration 353
Protein Folding, Misfolding, and Aggregation 354
16.1 Proteins Spontaneously Fold into Their Native State Based Solely on Their Primary Amino Acid Sequence 357
16.2 Protein Folding Can Be Described in Terms of an Energy Landscape Dominated by a Folding Funnel 358
16.3 Some Landscapes Are Smooth While Others Are Rugged 360
16.4 Proteins, Especially Those Involved in Signaling, Often Fold into Nonglobular, Extended Conformations 361
16.5 Dialysis-Related Amyloidosis Is Brought on by Partial Unfolding and Aggregation of beta-2 Microglobulin 363
16.6 beta Cell Failure and Amyloid Formation in Type 2 Diabetes Is Brought on by Amylin Misfolding and Aggregation 366
16.7 Some Proteins Have Native States That Are Metastable and Not at a Global Minimum in the Free Energy 366
16.8 beta-Sheet Conformational Variations Underlie the Prion Strains and Disease Potential 367
16.9 Strains and Transmissibility 370
16.10 General Observations on How Proteins Fold into Alternative Disease-Causing Structures Characterized by Cross-beta-Sheets 371
Further Reading 373
Alzheimer’s Disease 377
17.1 Generation of the Amyloid beta Protein 378
17.2 Removal Through Degradation and Clearance 381
17.3 Folding Physics, Metal Homeostasis, and Redox Chemistry 383
17.4 Normal Physiological Function of the Abeta Protein at the Synapse 384
17.5 Action of the Abeta Oligomers at the Synapse - Aberrant LTD 385
17.6 The Local Microenvironment Contains Neurons, Astrocytes, and Microglia 387
17.7 Microglia Respond to Amyloid Plaque Buildup by Mounting an Inflammatory Response 388
17.8 Inflammatory and Synaptic Cytokines Are Released by Microglia and Astrocytes 390
17.9 Tau Hyperphosphorylation and Formation of the Tangles 392
Further Reading 395
Chaperones, Endoplasmic Reticulum Stress, and the Unfolded Protein Response 398
18.1 The Cellular Complement of Molecular Chaperones 399
18.2 Hsp70 Structure and Function 400
18.3 Hsp90 Structure and Function 401
18.4 Heat Shock Factor 1 Is a Master Regulator of Protein Homeostasis 403
18.5 Folding, Processing, and Maturation of Membrane and Secreted Proteins 404
18.6 N-Linked Glycan Processing 406
18.7 The Unfolded Protein Response 408
18.8 ERAD and the Sec61 Translocon 411
18.9 The p97 Motor Protein Is a Molecular Chaperone Required for ERAD 412
Further Reading 414
Parkinson’s Disease 418
19.1 alpha-Synuclein Is a Presynaptic Protein 421
19.2 Abnormalities and Toxicity Result from alpha-Synuclein Misfolding and Aggregation 421
19.3 Oxidative Damage Is a Cause of alpha-Synuclein Aggregation and PD 422
19.4 Parkin Is an E3 Ubiquitin Ligase 423
19.5 Protein Carbonylation and UCH-L1 424
19.6 PINK1 Is a Neuroprotective Serine/Threonine Kinase 424
19.7 DJ-1 Protects Against Oxidative Stress 425
19.8 LRRK2 Is a ROCO Family Member and Mutations in This Protein Are Most Strongly Associated with PD 426
19.9 HtrA2/Omi Removes Misfolded Proteins 427
19.10 The Pathway Is Illuminated 428
19.11 Proteasome Organization 429
19.12 Cellular Garbage Collection and the Aggresomal - Autophagic Railway 431
19.13 Histone Deacetylase 6 Mediates Transport Along the Disposal Railway 432
Further Reading 433
Huntington’s Disease and Amyotrophic Lateral Sclerosis 438
20.1 Huntington’s Disease Is an Expanded PolyQ Repeat Disorder 439
20.2 The Structure of the Huntingtin Protein Is That of a Multipurpose Signaling Organizer 441
20.3 Synaptic Terminal Interactions Occur 441
20.4 Impaired Fast Axonal Transport Happens 443
20.5 Zippers, Aggregation, Fibrils, Inclusion Body Formation, and Toxicity 443
20.6 The Ubiquitin-Proteasome System Regulates Synaptic Transmission and This Function Is Impaired by Mutant Htt 445
20.7 Impaired Transcription: CBP and PGC-1 - and Mitochondrial Dysfunction 446
20.8 Structure and Folding of the Superoxide Dismutase Protein SOD1 447
20.9 SOD1 Mutations and Aggregation 448
20.10 Impaired Fast Axonal Transport and Retraction of Axons from Synapses 449
20.11 A Model for Amyotrophic Lateral Sclerosis 450
20.12 Acceleration of ALS Through Interactions Between Neurons and Other Cellular Residents of Its Microenvironment 451
20.13 PolyQs, Mutant SOD1, and Impaired ERAD 453
20.14 Mutations in Genes Other Than That for SOD1 Can Cause fALS 454
20.15 Interlocking Signaling Networks Underlie Health and Disease 456
Further Reading 457
Index 462