Encyclopedia of Cell Biology 9780123944474, 0123944473

Table of contents :
FrontCover......Page 1
Encyclopedia of Cell Biology......Page 4
Dedication......Page 6
Editors-in-Chief......Page 8
Volume Editors......Page 10
Section Editors......Page 12
Contributors to Volume 1......Page 18
Contents of Volume 1......Page 22
Preface......Page 26
Cell Biology: An Overview......Page 28
Basic Molecular Components and Technology......Page 32
Nucleic Acid Synthesis/Breakdown......Page 33
Protein Synthesis and Degradation......Page 34
The Laws of Thermodynamics and Living Cells......Page 36
Gibbs Free Energy Changes are Additive......Page 37
Reaction Rate and Rate Constant......Page 38
Enzyme Kinetics......Page 39
Concerted and Sequential Models......Page 40
Noncovalent Interactions Play Key Roles in Mediating Functions of Biomacromolecules......Page 41
Effect of Molecular Crowding in Living Cells......Page 42
References......Page 43
Kinetics......Page 45
Cooperativity and Allosteric Regulation......Page 48
Transition State Analogs and Catalytic Antibodies......Page 49
Hammerhead......Page 50
The Ribosome......Page 53
Relevant Website......Page 54
Glossary......Page 55
Introduction......Page 56
Physical Structure of Nucleic Acid......Page 57
Chemical Modification of Nucleic Acids......Page 58
DNA Modification by Radiation......Page 59
Nucleic Acid Sequencing......Page 60
Sanger DNA Sequencing......Page 61
Library Preparation......Page 62
Data Analysis......Page 63
Future Directions......Page 64
References......Page 65
Further Reading......Page 66
The Phosphoramidite Approach......Page 67
The H-Phosphonate Approach......Page 71
The Chemical Synthesis of Oligoribonucleotides via the Phosphoramidite Approach......Page 72
The tert-butyldimethylsilyl group......Page 73
The 1-aryl-4-alkoxypiperidin-4-yl groups......Page 74
The 2-cyanoethyloxymethyl group......Page 75
The bis-(2-acetoxyethoxy)methyl group......Page 76
Photolithography with physical or digital masks......Page 77
Electrochemical arrays......Page 78
Gene assembly from DNA microarrays......Page 80
RNA microarrays......Page 81
References......Page 83
Overview of Expression Systems......Page 85
Bacterial Expression Systems......Page 87
Cell-Free Expression Systems......Page 89
Insect Expression Systems......Page 90
Mammalian Expression Systems......Page 91
References......Page 95
Relevant Websites......Page 96
Introduction......Page 97
The Protein Source......Page 98
Accountability......Page 99
Initial Steps......Page 100
Chromatography......Page 101
Ion-Exchange Chromatography......Page 102
Metabolite affinity chromatography......Page 103
A Final Word......Page 104
Relevant Websites......Page 105
The Move to Larger Proteins......Page 106
The Role of Separations Methodology......Page 107
Challenges and Limitations......Page 108
Mass Spectrometry......Page 109
Sequence Comparisons......Page 111
References......Page 113
Phosphorylation......Page 115
Glycosylation (N- and O-linked)......Page 116
Amidation......Page 117
Carbonylation......Page 118
See also......Page 119
References......Page 120
Relevant Websites......Page 121
Protein Structure: Motifs, Folds, and Domains......Page 122
Interaction and Binding Domains......Page 123
Structural Determination by Protein Crystallography and NMR Spectroscopy......Page 124
Bioinformatic Platforms......Page 125
Domains in Evolution: Modularity and Combinatorial Protein Structure......Page 126
References......Page 127
Fundamentals of NMR Structure Determination......Page 129
Intermolecular Distance Restraints......Page 130
Orientational Restraints......Page 131
Structural Proteomics of the Bacterial Phosphotransferase System......Page 132
Basis of PRE for the Study of Sparsely Populated States......Page 134
Basis of Lifetime Line Broadening and DEST......Page 135
References......Page 136
General Principles......Page 139
Protein Folding Mechanisms and the Search for the Native State Conformation......Page 140
Misfolding......Page 142
Disordered Proteins......Page 143
Related Diseases......Page 144
References......Page 145
Introduction......Page 146
Clearance Pathways of Aggregates – Cellular UPS......Page 147
Cellular Transfer of Aggregates on Toxic Fragments......Page 148
Symptoms and Treatments of the Disease......Page 149
See also......Page 150
References......Page 151
Further Reading......Page 152
Applications......Page 153
Binding sites......Page 154
Stability......Page 155
Site-selective conjugation......Page 156
References......Page 157
Metabolic Labeling......Page 159
Affinity Labeling......Page 161
Bioorthogonal Labeling......Page 162
Chemical Biology and Drug Development......Page 163
References......Page 164
Further Reading......Page 165
Introduction......Page 166
Evolution of Drug Design......Page 167
HTS......Page 168
Drug Design and Biologics......Page 169
References......Page 170
Relevant Website......Page 171
Antibodies for In Vitro Diagnosis, in Soluble (RIA), Surface-Bound (ELISA), Cell-Bound (Fluorescence-Activated Cell.........Page 172
Design of ‘Antibody Fragments’ for Unique Clinical Applications In Vivo......Page 173
Antibody Libraries: Construction, Display, and Selection......Page 174
Maturation......Page 175
Image-Guided Surgery: From Radioactive Image-Guided Surgery (RIGS) to Fluorescence Image-Guided Surgery (FIGS)......Page 176
Relevant Websites......Page 177
Why Lipidomics?......Page 178
Description of How the Components of the Lipidome Are Usually Analyzed......Page 179
Getting Started – Sample Preparation for Lipidomic Mass Spectrometry......Page 180
Tandem mass spectrometry......Page 181
Chromatography in combination with mass spectrometry......Page 182
Tissue-imaging mass spectrometry......Page 183
Fatty acyls......Page 184
Glycerolipids......Page 185
Prenol lipids......Page 186
Lipidomics Databases and Other Online Tools......Page 187
Tissue-Imaging Mass Spectrometry......Page 188
References......Page 189
Relevant Websites......Page 190
Introduction......Page 191
Synthesis of Phosphatidic Acid......Page 192
Synthesis of Non-Amine-Containing Phospholipids......Page 193
Synthesis of Amine-Containing Phospholipids......Page 195
Synthesis of Non-Amine-Containing Phospholipids......Page 197
Roles of Phospholipids in Cell Function......Page 200
References......Page 201
Relevant Websites......Page 203
Cholesteryl Esters......Page 204
Cholesterol Biosynthesis......Page 205
Regulation of Cholesterol Biosynthesis......Page 206
Cellular Cholesterol Homeostasis......Page 207
Cholesterol in Diseases......Page 208
Steroids......Page 209
References......Page 210
Glycoglycerolipids......Page 211
Glycophosphoglycerolipids......Page 213
Glycosphingolipids......Page 214
Glycosylated sterols......Page 215
Glycosylated prenols......Page 216
Sphingolipid Backbone Biosynthesis......Page 217
Glycan Headgroup Addition......Page 220
Analysis of Glycolipids by ‘Omic’ Technologies......Page 221
Perspective on the Future of Glycolipid Research......Page 222
References......Page 223
Relevant Websites......Page 224
Lipid Classification and Nomenclature......Page 225
The Primary Mammalian Signaling Lipids......Page 226
The Complexity of Lipid Signaling......Page 227
Intracellular Signaling Lipids Interact with Proteins......Page 229
References......Page 230
Relevant Websites......Page 231
Origins......Page 232
Membrane Electrostatics......Page 233
Membrane Subdomains......Page 234
Mechanisms that Modifies the Bulk Lipid Composition of Organelles......Page 235
Membrane Curvature......Page 236
References......Page 237
Relevant Website......Page 238
Formulation of the Lipid Raft Hypothesis......Page 239
The Basis of Membrane Protein Interaction with Rafts......Page 240
Detecting Rafts in Model Membranes......Page 242
Using Detergents to Detect Rafts in Cells: Rationale and Limitations......Page 243
Detecting Rafts in Cells Using Sterol Modification......Page 244
See also......Page 245
References......Page 246
Physical–Chemical Properties of the Cell Membrane and Physiological Solutions......Page 249
Electrical Properties of the Cell and Ohm’s Law......Page 251
Determinants of the Membrane Potential......Page 252
Electrochemical Driving Force for Ion Movement......Page 253
Relative Membrane Permeability......Page 254
Do Ion Concentrations Change When the Vm Changes?......Page 256
Passive Ion Transport via Selective, Facilitated Diffusion Ion Channels......Page 257
Passive Membrane Potential Changes......Page 260
Direct Measurements of Membrane Potential and Membrane Selectivity......Page 261
Quantifying Membrane and Ion Channel Selectivity Using Voltage-Clamp......Page 262
Caveats in Measuring Physiological Vm......Page 263
Physiological Values of Vm......Page 265
References......Page 266
Relevant Websites......Page 267
Results: Protein/Enzyme Assignments of the Four Mitochondrial Compartments with an Emphasis on the Outer Mitochondrial.........Page 268
‘Moonlighting’ Roles of the Mitochondrial Outer Membrane with Its Intracellular Neighbors......Page 269
Mitochondrial Endoplasmic Reticulum Interactions......Page 270
Cancer......Page 271
See also......Page 272
References......Page 273
Introduction......Page 275
Anatomy of a Neuron and Flow of Information......Page 276
Action Potentials......Page 277
Action Potential Propagation......Page 278
Postsynaptic Receptors/Ligand-Gated Ion Channels......Page 279
Allosteric Effectors......Page 280
References......Page 281
Protein......Page 283
CFTR and Protein Trafficking......Page 285
CFTR and Chloride Transport......Page 286
CFTR and Bicarbonate Transport......Page 288
Genetics......Page 290
Mutations affecting CFTR quantity......Page 291
Pharmacologic Approaches to Treat Patients with CF......Page 292
Relevant Websites......Page 293
Glycogen......Page 294
Starch......Page 295
Glycogen Synthesis......Page 296
Glycogen Degradation......Page 297
Starch Synthesis......Page 298
Starch Degradation......Page 299
Genetic Modification of Starch and Glycogen Metabolism......Page 300
References......Page 301
Core Protein Structure......Page 302
Cellular Functions of Proteoglycans in Health and Disease......Page 305
References......Page 308
Further Reading......Page 309
Structure and Cellular Metabolism......Page 310
Whole-Body Turnover of Hyaluronan......Page 312
Hyaluronan in Inflammatory Pathologies......Page 313
Hyaluronan in Cancer......Page 316
References......Page 317
Relevant Websites......Page 318
Glossary......Page 319
Substrates (Fuel) Availability......Page 320
Glucose transport and Its phosphorylation......Page 321
Regulation of glycogen synthesis......Page 322
Regulation of the glycolytic pathway......Page 323
Regulation of the pyruvate dehydrogenase complex......Page 324
Action of Glucagon......Page 325
Regulation of glycogen degradation......Page 326
See also......Page 327
Relevant Website......Page 328
Atomic Structures of Membrane Protein Complexes Responsible for Energization, That Is, Generation of the.........Page 329
Reaction Center of Anoxic Photosynthetic Bacteria......Page 330
Reaction Centers of Photosynthetic Plants, Algae, and Cyanobacteria......Page 331
Cytochrome b6f Complex in Oxygenic Photosynthesis Provides Electronic Connection between the Two Reaction Center Complexes......Page 332
The cytochrome b6f complex as a lipoprotein......Page 333
Pathways of proton uptake into the membrane......Page 334
The Mitochondrial Respiratory Chain......Page 335
Cytochrome bc1 Complex......Page 336
References......Page 337
Further Reading......Page 339
Glossary......Page 340
tRNA and genetic code......Page 341
Paralogous tRNA Genes/tRNA Isoacceptors......Page 344
Degenerative tRNAs in Mitochondria......Page 346
tRNA Aminoacylation......Page 347
Identify Element of tRNAs......Page 348
Proofreading of Aminoacyl-tRNAs......Page 350
tRNA in Translation......Page 351
tRNA in Translation Initiation......Page 352
tRNA in Elongation......Page 354
Surprising Number of Roles of tRNAs beyond Translation......Page 355
tRNA and GCN2 Pathway......Page 356
tRNAs for Cell Wall Synthesis......Page 357
tmRNAs......Page 358
Viral tRNA-Like Molecules......Page 359
tRNA and Human Diseases......Page 360
Mitochondrial tRNA and Human Diseases......Page 364
Therapeutics of tRNA-Related Diseases......Page 365
References......Page 366
Relevant Websites......Page 371
Shine–Dalgarno Sequence......Page 372
Cap......Page 373
AU-Rich Elements and Stem Loops in mRNA......Page 374
mRNA and Disease......Page 375
Further Reading......Page 376
Overview of Eukaryotic mRNA turnover......Page 377
Translation Elongation and mRNA Turnover......Page 378
The mRNA Cycle Hypothesis – From Polysome to p-Bodies (and Perhaps Back)......Page 379
Parting on Polysomes......Page 381
Perspectives......Page 382
References......Page 383
Introduction......Page 385
Dicer Cleaves Pre-miRNAs into miRNA–miRNA* Duplexes......Page 386
miRNAs Suppress Target mRNAs......Page 389
Alternative Biogenesis Pathways of miRNAs......Page 390
Nomenclature of miRNA......Page 391
References......Page 392
Relevant Website......Page 394
Biogenesis......Page 395
Nomenclature......Page 396
Predicting Prognosis and Response to Therapy......Page 397
miRNAs as a Target for Therapy......Page 398
IsomiRs......Page 399
LncRNAs......Page 400
References......Page 401
Relevant Websites......Page 405
From Aptamers to Riboswitches......Page 406
Ribozymes are Ubiquitous in Nature......Page 408
The glmS Ribozyme-Riboswitch......Page 411
References......Page 413
Interactions with mRNA......Page 415
Interactions with Initiation Factors......Page 416
Interactions with Initiator tRNA......Page 418
Peptide Bond Formation......Page 419
Interactions with Release Factors 1 and 2......Page 421
Interactions with Ribosome Recycling Factor......Page 423
References......Page 424
Introduction......Page 427
Functional Overview of Bacterial (C Family) and Eukaryotic (B Family) Replicative DNA Polymerases......Page 429
Sliding Clamps Are Conserved in All Cell Types......Page 431
Overview of Clamp Loader Mechanism......Page 432
Proposed Strand Exclusion Mechanism of Bacterial and Eukaryotic Replicative Helicases......Page 434
Eukaryotic Helicase Structure......Page 435
The Eukaryotic Primase......Page 436
The Primpol Primase......Page 437
The Eukaryotic RPA......Page 438
The Bacterial Replisome......Page 439
The Eukaryotic Replisome......Page 441
What Is Needed for the Future?......Page 442
References......Page 443
The End-Replication Problem......Page 449
Telomeric DNA......Page 450
Telomerase......Page 451
Telomerase Reverse Transcriptase......Page 452
Telomerase RNA......Page 453
References......Page 454
Relevant Website......Page 456
Introduction......Page 457
Proteins Associated with the Telomere......Page 458
Semiconservative Telomere Replication......Page 459
Recombination at Telomeres and ALT......Page 461
Telomeres in Cancer Cells......Page 462
Noncancer Telomere-Related Diseases......Page 463
References......Page 464
Perspective......Page 466
XPC-HR23B-CETN2......Page 467
TFIIH......Page 468
XPA-RPA......Page 469
Cockayne Syndrome......Page 470
References......Page 471
Relevant Website......Page 472
Basic Overview of the BER Pathway......Page 473
DNA Base Damage Recognition and Removal by DNA Glycosylases......Page 474
HhH DNA Glycosylases......Page 475
NEIL DNA Glycosylases......Page 476
Abasic Site Incision and Processing of DNA Strand Break Ends......Page 477
The Long-Patch BER Pathway......Page 478
Conclusions......Page 479
References......Page 480
Relevant Website......Page 481
Ligation......Page 482
Choice of DSB Repair Pathway......Page 483
NHEJ and Inhibitors......Page 484
References......Page 485
DSB Resection......Page 487
Rad51 Filament Assembly and Stability......Page 488
DNA Strand Invasion and Associated DNA Synthesis......Page 491
Synthesis-Dependent Strand Annealing......Page 492
Recombination and DNA Replication......Page 493
Recombination and Interstrand Cross-Link Repair......Page 494
Pathway Regulation and Crossover Control......Page 495
References......Page 496
Further Reading......Page 498
Core RNA Polymerase......Page 499
Bacterial RNA Polymerase Holoenzyme......Page 500
Initiation......Page 502
Elongation......Page 503
Termination......Page 505
Repression......Page 506
Activation......Page 507
Transcription and Regulation in Archaea......Page 508
References......Page 509
Further Reading......Page 511
Promoters and Transcription Factors......Page 512
Transcription Initiation and Elongation......Page 513
Chromatin......Page 514
Protein Biochemistry and Transcription In Vitro......Page 515
Some Outstanding Issues and Questions......Page 516
References......Page 517
Bacterial Enhancer Action......Page 519
Distant Promoter Activation Accompanied by DNA Looping......Page 520
Enhancer Action in Eukaryotes......Page 522
Conclusions......Page 523
References......Page 524
Relevant Websites......Page 525
The Chemistry of Splicing and the Architecture of the Intron......Page 526
The Spliceosome is Composed of snRNAs and Proteins......Page 527
Spliceosomes are Assembled from snRNPs on Introns......Page 529
The Active Site of the Spliceosome......Page 530
Alternative Splicing Creates Multiple Products from a Single Gene......Page 531
References......Page 532
Further Reading......Page 533
The Spliceosome......Page 534
Alternative Splicing......Page 536
Transcription, Chromatin Structure, and Splicing......Page 537
Diseases of the Spliceosome: Dysfunction Sheds Light on Function......Page 538
Splicing Mutations in Growth and Development......Page 539
References......Page 540
Introduction......Page 543
Temporal Regulation of Transgenes......Page 544
Homologous Recombination......Page 545
References......Page 546
Introduction......Page 548
Group I: dsDNA Viruses......Page 549
Group III: dsRNA Viruses......Page 550
Group V: (–) Strand RNA Viruses......Page 551
Group VI: (plus) Strand RNA Viruses with DNA Intermediates......Page 552
Gene Expression Strategies of RNA Viruses......Page 554
Relevant Website......Page 555
tRNA......Page 556
Ribosomes......Page 557
Cap-Dependent Protein Synthesis, the Predominant Pathway......Page 558
Other Initiation Events......Page 560
The Elongation Cycle......Page 561
Protein Synthesis Beyond the First Ribosome......Page 562
Global Regulation of Protein Synthesis......Page 563
References......Page 564
Glossary......Page 566
Nascent Polypeptides Possessing a Unique Signal Peptide Are Selectively Delivered to the ER Membrane......Page 567
The signal recognition particle (SRP) helps deliver a nascent polypeptide to the ER for co-translational translocation......Page 568
The Nascent Polypeptides Form Their Native Structures in the ER Lumen with the Help of Multiple Factors......Page 569
Glycan-Recognizing Molecular Chaperones Facilitate the Folding of Glycoproteins in the ER Lumen......Page 571
Improperly Folded Proteins Are Disposed Through the ER-Associated Degradation (ERAD) Pathway......Page 573
The Malfunctioning of Protein Folding in ER Are Known to Cause Folding Diseases......Page 574
References......Page 575
Mitochondrial Messenger RNAs......Page 576
Structural features of mitochondrial tRNAs......Page 577
Mitochondrial tRNA and aaRS in human disease......Page 578
Mitochondrial Ribosomes......Page 579
Mammalian mitochondrial system......Page 580
Polypeptide Chain Elongation......Page 581
Termination of Protein Synthesis and Ribosome Recycling in Mitochondria......Page 582
Future Directions......Page 583
Further Reading......Page 584
Relevant Websites......Page 585
The Proprotein Convertases......Page 586
General Properties......Page 587
PC1/3 Maturation in the Regulated Secretory Pathway......Page 588
Physiological Significance of PC1/3......Page 589
ProPC2 Maturation in the Regulated Secretory Pathway......Page 591
Physiological Significance of PC2......Page 592
Proprotein Convertase 5/6 (PCSK5)......Page 593
Summary and Conclusions......Page 594
References......Page 595
Glossary......Page 599
Introduction......Page 600
Identification of Protease Substrates......Page 601
Classical gel-based methods......Page 602
Gel-free methods (mass spectrometry-based)......Page 603
Negative Selection of N-termini by Combined Fractional Diagonal Chromatography (COFRADIC)......Page 605
Negative selection of N-terminal peptides by Terminal Amine Isotopic Labeling of Substrates (TAILS)......Page 606
Proteomic identification of protease cleavage site specificity......Page 607
Validation of Degradomic Data......Page 608
References......Page 610
Relevant Website......Page 612
Ubiquitin......Page 613
Ubiquitin-Conjugation System......Page 615
SUMO Family Members......Page 617
ISG15......Page 618
The 20S Core Particle: Structure and Catalytic Mechanism......Page 619
The 19S RPs: Structure and Function......Page 620
Assembly of the Proteasome......Page 621
The Proteasome......Page 622
References......Page 623
Further Reading......Page 626
Introduction......Page 627
Targeting and Entering the ER: The Beginning of a Perilous Journey......Page 628
The N-Glycosylation Quality Control Pathway......Page 630
ER Exit: The Continuation of a Productive Journey......Page 632
Location, location, location......Page 633
The fatty and sweet sides of destruction......Page 634
Getting Back Out: The Retro-Translocation of Misfolded Substrates......Page 635
At the End, the Proteasome......Page 636
References......Page 637
Introduction......Page 643
Cathepsins......Page 644
Cathepsins in the Immune Response......Page 645
Lipases......Page 646
Lysosomal Biogenesis and Its Regulation......Page 647
Endocytosis......Page 648
References......Page 649
Structure......Page 652
Substrate Profiles: Biological and Biomedical Implications......Page 653
ECM......Page 655
Transcriptional......Page 656
Natural Inhibitors......Page 657
Future Directions......Page 658
References......Page 659
Relevant Websites......Page 660
Introduction, Defining Characteristics and Phylogeny of A Disintegrin-Like and Metalloprotease Domain with Thrombospondin.........Page 661
Domain Organization and 3-Dimensional Structure......Page 663
ADAMTS13, vWF and Thrombotic Thrombocytopenic Purpura......Page 664
ADAMTS10, Tissue Microfibrils and Weill–Marchesani Syndrome......Page 665
ADAMTS Proteolysis of Versican as a Crucial Requirement for Normal Embryogenesis and Neural Function......Page 666
References......Page 667
Relevant Websites......Page 669
ADAM17, the TNFα Convertase......Page 670
ADAM17 is Crucial for EGFR Signaling......Page 671
ADAM17-Dependent EGFR Activation Protects the Skin and Intestinal Barrier......Page 672
ADAM17/TNFα and ADAM17/EGFR Signaling are Controlled by Upstream Regulators Called iRhoms......Page 673
ADAM10, A Crucial Regulator of Notch Signaling......Page 674
Other Substrates of ADAM10 and ADAM17......Page 675
Summary......Page 677
References......Page 679
Stem Region Accessory Domains......Page 681
The GPI-Anchored Serine Proteases......Page 682
The HAT/DESC Subfamily......Page 685
The Hepsin/TMPRSS Subfamily......Page 686
The Corin Subfamily......Page 687
References......Page 688
Amyloid Production......Page 692
Knockout Mice......Page 693
Prospects for Therapeutics......Page 694
Other Substrates......Page 695
Toward Structure Elucidation......Page 696
Prospects for Therapeutics......Page 697
References......Page 698
Relevant Websites......Page 700
Structure of Conventional Calpains......Page 701
The Smaller Regulatory Subunit, CAPNS1/30K......Page 702
Ca2plus: The Main Calpain Activator......Page 703
Relationship between Calpain and Caspases......Page 704
Central Nervous System......Page 705
Calpains in the Gastrointestinal Tract......Page 707
References......Page 708
Historical Background......Page 712
Cell-specific processing and trafficking......Page 713
Substrates......Page 714
Roles in immune responses......Page 715
Roles in gastric development and cancer......Page 716
Diagnostic and prognostic values in breast cancer......Page 717
Acknowledgments......Page 718
References......Page 719
Relevant Website......Page 721
Inhibition of Meprin Metalloproteases......Page 722
Meprin in Inflammation......Page 725
Meprin in Skin and Fibrosis......Page 726
References......Page 727
Tissue KLK......Page 730
Kallikrein-Related Peptidases......Page 731
See also......Page 733
References......Page 734
Further Reading......Page 735
Cystatins/Stefins......Page 737
Inhibitors of Apoptosis......Page 738
Regulation of inflammation and immunity......Page 739
Serpins......Page 740
Cysteine proteases......Page 741
Mechanism of Inhibition of MMPs......Page 742
Disease Aspects......Page 743
Relevant Website......Page 744
Platelet Production......Page 745
Platelet Structure and Function in Primary Hemostasis......Page 746
Propagation Phase......Page 747
Defects in platelet function......Page 748
Deep vein thrombosis – Overview......Page 749
Aging......Page 750
References......Page 751
Classical Pathway......Page 754
Lectin Pathway......Page 757
The Alternative Pathway......Page 759
References......Page 760
Relevant Websites......Page 762
Role of the Oral Cavity in Proteolysis......Page 763
Role of the Stomach in Proteolysis......Page 764
Role of the Small Intestine in Proteolysis......Page 765
Role of the Large Intestine in Proteolysis......Page 766
References......Page 767
Relevant Websites......Page 768
Glossary......Page 769
Inhibitors of Retroviral Proteases......Page 770
First generation of HIV-1 PR Inhibitors Approved as AIDS Drugs......Page 772
Emergence of Resistance to Clinical Inhibitors of HIV-1 PR......Page 773
Roads Not Taken – Inhibitors of HIV-1 PR That Did Not Become Drugs......Page 774
See also......Page 775
Relavant Website......Page 776
Overview of the system......Page 777
From angiotensinogen to Ang I: renin......Page 778
From Ang I to Ang II: ACE......Page 779
From Ang II to Ang-(1–7): ACE2......Page 780
Summary......Page 781
References......Page 782
Further Reading......Page 783
Caspases......Page 784
ADAM and AMAMTS Proteases......Page 785
Matrix Metalloproteinases......Page 786
Type II Transmembrane Trypsin-like Serine Proteases: Matriptase......Page 787
Concluding Remarks......Page 788
References......Page 789
The Lysosomal Compartment......Page 794
Autophagy......Page 795
Autophagy......Page 796
Amino acid signaling......Page 797
Gaucher disease......Page 798
Identification of the First Inborn Disease of the Lysosome......Page 799
Effects of Lysosomal Storage......Page 800
Coordination of Lysosomal Biogenesis and Autophagy – Revelations from Human Pathology......Page 801
Danon disease – an intrinsic disturbance of macroautophagy......Page 802
Energy metabolism in lysosomal diseases......Page 803
Action myoclonus-renal failure syndrome......Page 804
Deficiency of a Lysosomal Membrane Protein or Transporter......Page 805
Abnormal biogenesis of lysosomes is illustrated by Hermansky–Pudlak diseases (Type 1–9); Chédiak–Higashi disease and the.........Page 806
Lysosome-Related Organelles and the Osteoclast......Page 807
I-Cell Disease......Page 808
Cystinosis......Page 809
Modulating Substrate Biosynthesis (Substrate-Reduction Therapy)......Page 810
Hematopoietic Stem-Cell Transplantation......Page 811
Molecular therapy for Gaucher disease......Page 812
Therapeutic Stratagems for Lysosomal Diseases with Neurological Manifestations......Page 813
Gene Transfer......Page 814
(ii) Indirect use of vector-transduced autologous hematopoietic stem-cells which are re-infused......Page 815
Pathogenesis and Physiological Understanding......Page 816
References......Page 817
Introduction......Page 820
Physiology and Function of AT......Page 821
Mechanism of Deficiency in the Classical form of ATD......Page 822
Cellular Mechanisms of Liver Disease......Page 823
Cellular Responses to Misfolding of Mutant ATZ......Page 825
Therapies for ATD Liver Disease......Page 827
See also......Page 828
References......Page 829
FrontCover......Page 832
Encyclopedia of Cell Biology......Page 835
Editor-in-Chief......Page 837
Volume Editors......Page 839
Section Editors......Page 841
Contributors to Volume 2......Page 847
Contents of Volume 2......Page 853
Preface......Page 857
Cell Biology: An Overview......Page 859
Imaging the Cell......Page 863
Organelles......Page 864
Cytoskeleton and Motors......Page 865
Reference......Page 866
CryoEM Sample Consideration......Page 867
CryoEM Image Processing......Page 868
Resolution of CryoEM Density Maps......Page 869
CryoEM Model Building and Model Validation......Page 870
Identifying Different Populations Within a Heterogeneous Sample......Page 871
Conclusion......Page 873
References......Page 874
Relevant Website......Page 875
Scanning the Specimen......Page 876
Beam – Specimen Interactions......Page 877
A Brief History of SEM......Page 878
Labeling for SEM......Page 879
Merging SEM and TEM......Page 880
SEM of Subcellular Detail......Page 881
SEM and the Nuclear Envelope......Page 882
Further Reading......Page 883
Specimen Preparation Methods......Page 884
Microscopy......Page 886
Tomogram Reconstruction and 3D Image Analysis......Page 887
Techniques to Combine with Cryo-ET......Page 888
Examples......Page 889
Future Outlook......Page 890
References......Page 892
Relevant Websites......Page 893
Chemical Fixation......Page 894
Cryo-Immobilization and Freeze-Substitution......Page 896
Preembedding- and On-Section Labeling......Page 898
Whole Mount Labeling......Page 899
Freeze-Fracture Replica Labeling......Page 901
CLEM......Page 902
Immunogold Label Quantification and Labeling Specificity......Page 903
References......Page 904
Further Reading......Page 905
Orientation and Location of Region of Interest......Page 906
3D SEM Techniques......Page 907
Data Handling and Segmentation......Page 909
References......Page 911
Introduction – Fluorescent Proteins......Page 913
Fluorescent Proteins as Probes for Function......Page 914
Imaging Cells in Whole Organisms......Page 917
Technical Considerations for Live Imaging......Page 918
Looking Forward......Page 921
References......Page 922
Cell/Substrate Contact Regions......Page 924
TIR Combined with Polarization: Plasma Membrane Deformation......Page 925
TIR Combined with Fluorescence Recovery after Photobleaching and Fluorescence Resonance Energy Transfer (FRET)......Page 926
Prism-Based TIRF......Page 927
Suppression of Laser Interference Fringes......Page 928
TIRF versus Other Optical Sectioning Microscopies......Page 930
References......Page 931
Experimental Methods......Page 932
Discussion......Page 935
References......Page 936
Introduction......Page 938
STED Microscopy: General Principles......Page 939
Continuous-Wave STED Microscopy......Page 940
Time-Gated STED Microscopy......Page 941
Photobleaching and Resonant Scanning in STED Microscopy......Page 942
Biological Sample Preparation......Page 943
STED and GSDIM Applied to Biological Research......Page 944
References......Page 946
Relevant Websites......Page 947
Resolution Increase in SIM......Page 948
Band Separation/Unmixing......Page 951
Pixel Negative Values......Page 952
Centrosome Structure and Protein Domain Mapping......Page 953
Cytoskeleton Structure and Motor Proteins Organization......Page 954
Bacteria Structural and Functional Organization......Page 955
Live SIM......Page 956
SIM Image Alignment and Averaging......Page 957
References......Page 959
Relevant Website......Page 960
Correlation of Fluctuations of Concentration and Fluorescence......Page 961
Relationship between FCS and Fluorescence Photobleaching Measurements......Page 962
Instrumentation and Observation Volume......Page 963
Molecular Association Measured by Two-Color Cross-Correlation Spectroscopy......Page 964
Summary......Page 965
Acknowledgments......Page 966
References......Page 967
Fluorescence......Page 969
Measurement of Local Molecular Environment Parameters......Page 970
FRET Experiments......Page 971
Autofluorescence FLIM......Page 972
Ophthalmic FLIM......Page 973
Photon efficiency......Page 974
Live cell compatibility......Page 975
Time-domain FLIM by multidimensional TCSPC and laser scanning......Page 976
Time-domain wide-field FLIM by gated image intensifiers......Page 977
Time-domain data......Page 978
Latest Developments......Page 979
References......Page 980
The Localization Concept......Page 983
Experimental Requirements......Page 984
High-Speed LM......Page 985
SPT......Page 986
Future Trends/Avenues......Page 988
References......Page 989
Imaging Techniques Used to Perform IVM......Page 991
Imaging Tissue Architecture and Function In Vivo......Page 995
Imaging the Behavior of Individual Cells In Vivo......Page 1000
Imaging Subcellular Structures In Vivo......Page 1002
References......Page 1005
Light-Sensitive (Bio)molecules......Page 1009
Delivery of Light......Page 1011
Light-Sensitive Proteins to Control Cellular Excitability......Page 1012
Light-Gated Glutamate Receptors – Principles......Page 1013
References......Page 1015
Relevant Websites......Page 1017
Introduction......Page 1018
Morphology of the ER......Page 1019
Membrane Contact Sites of the ER with Other Organelles......Page 1021
Translocation and Membrane Embedding of ER Client Proteins......Page 1022
Protein Folding in the ER......Page 1023
Export from and Retrieval to the ER......Page 1025
ER Homeostasis......Page 1026
References......Page 1027
Further Reading......Page 1029
15degC Compartment......Page 1030
The p24 Protein Family......Page 1031
Rab1 and Rab2......Page 1032
Structure, Distribution, and Dynamics......Page 1033
Association with the Cytoskeleton......Page 1034
Transport Complexes......Page 1035
Sorting and Transport......Page 1037
Signaling......Page 1038
References......Page 1039
Further Reading......Page 1044
Transport through the Golgi......Page 1045
Glycosylation at the Golgi......Page 1048
Regulation of the Golgi Apparatus Structure and Function......Page 1049
Evolution of the Golgi Apparatus......Page 1050
References......Page 1051
Epithelial Cells Have Spatially Separated, Connected Endosomal Circuits......Page 1054
(Ultra)structure and Specialization......Page 1055
Regulation of Endosome Traffic......Page 1056
Phosphoinositides......Page 1057
Retrieval of Proteins from Endosomes to the Trans Golgi Network......Page 1058
Recycling from Early Endosomes to the Plasma Membrane......Page 1059
Conclusion and Perspectives......Page 1060
References......Page 1061
Biogenesis of the Multivesicular Body......Page 1063
The Late Endosome–Lysosome Network......Page 1065
Lysosome Enzymes and Lysosomal Membrane Proteins......Page 1066
Other Destinations: All Roads Do Not Lead to the Lysosomes......Page 1067
The Late Endosome: A Signaling Platform......Page 1068
References......Page 1069
Relevant Websites......Page 1072
Different Cell Types Employ Signaling Endosomes for Distinct Purposes......Page 1073
Endocytic Routes Specify Signaling Outcome......Page 1074
PIPs......Page 1079
Accessibility to Phosphatases......Page 1081
Transcription and Phosphorylation......Page 1082
Endocytosis and Implications in Cancer......Page 1083
References......Page 1084
Cell Type-Specific Secretory Lysosomes......Page 1087
Hematopoietic-Lineage Secretory Lysosomes......Page 1088
Biogenesis of Lysosomes and Secretory Lysosomes......Page 1090
Exocytosis of Secretory Lysosomes......Page 1091
Conclusions......Page 1092
References......Page 1093
Further Reading......Page 1096
Biogenesis and Transport of LROs......Page 1097
Genetic Diseases Associated with Defects in LRO Biogenesis and Transport......Page 1099
GS......Page 1101
References......Page 1103
Relevant Websites......Page 1104
Macroautophagy and Autophagosomes......Page 1105
Generation of the Autophagosomes: The Machinery......Page 1106
References......Page 1108
Relevant Websites......Page 1109
Photorespiration in Green Leaves......Page 1110
Glycolysis in Trypanosomes......Page 1111
Hydrogen peroxide metabolism – A simple respiratory pathway for which peroxisomes were named by Christian de Duve......Page 1112
The Glyoxylate Cycle and Glyoxylate Metabolism......Page 1114
Platelet activating factor......Page 1116
Metabolic Cooperation and Interaction with Other Organelles......Page 1117
Abundance and Adaptability......Page 1118
Gene Regulation......Page 1119
Peroxisome Division......Page 1121
Model 1: Formation from ER......Page 1123
Direct targeting and insertion of peroxisome membrane proteins into peroxisomes......Page 1124
Modification of the model: ER contribution to peroxisome membrane growth......Page 1125
Evidence for de novo formation in mutants......Page 1129
Remodeling, Random Turnover, and Selective Degradation......Page 1130
Human Disease and Peroxisomes......Page 1131
References......Page 1133
LD Proteins......Page 1135
LD Subpopulations......Page 1136
Biogenesis of LDs......Page 1137
Lipid Droplets and Disease......Page 1138
Further Reading......Page 1139
Mfn1 and Mfn2......Page 1141
Modulators of Mitofusin Proteins......Page 1143
Opa1, a Key Player in MIM Fusion......Page 1144
Key Players on the MOM in Drp1-Dependent Mitochondrial Fission: Mff, Mid49, and Mid51/MIEF1......Page 1146
Ganglioside-induced differentiation-associated protein 1 (GDAP1)......Page 1147
Sacsin......Page 1148
SUMOylation......Page 1149
Mfn1-, Mfn2-, and Opa1-Dependent Mitochondrial Fusion......Page 1150
Perspective......Page 1151
References......Page 1152
Synaptosomes......Page 1155
SVs......Page 1156
Physical Characteristics of SVs......Page 1157
Clathrin adaptor proteins......Page 1158
Loading with neurotransmitter......Page 1159
Kiss and run fusion......Page 1160
See also......Page 1161
References......Page 1162
Further Reading......Page 1163
The Physiological Role of EVs: From Waste Bin to Versatile Transporter of Biological Signals......Page 1164
EVs in Cross-Kingdom Communication......Page 1165
EV Biogenesis......Page 1166
EV-Based Biomarkers......Page 1168
EV-Based Vaccines and Therapeutics......Page 1169
References......Page 1170
Relevant Websites......Page 1172
Chromatin......Page 1173
Nuclear lamin......Page 1174
NPC......Page 1175
INM proteins......Page 1176
RanGTP gradient in interphase and mitosis......Page 1177
References......Page 1179
Nucleoporins (Nups)......Page 1181
Nucleocytoplasmic Transport......Page 1182
References......Page 1183
Elaioplast......Page 1186
Amyloplast......Page 1187
Chromoplast......Page 1188
Chloroplast functions......Page 1189
Photosynthesis and starch synthesis......Page 1190
Sun versus shade chloroplasts......Page 1191
Further Reading......Page 1192
Cargo Capture during Vesicle Formation......Page 1193
Regulation of COPII Biogenesis: The GTPase Cycle......Page 1194
Cellular Regulation of COPII Vesicle Biogenesis......Page 1195
Regulation of Vesicle Size......Page 1196
Vesicle Tethering......Page 1197
References......Page 1198
Introduction......Page 1201
En-Bloc Transfer of an N-Glycan to Protein......Page 1202
Unique Modification of Lysosomal Hydrolases......Page 1203
Maturation of N-Glycans During Transit Through Golgi Compartments......Page 1204
Man-6-P Receptors......Page 1205
Summary......Page 1206
Further Reading......Page 1207
Relevant Websites......Page 1208
Mucin-Type O-Glycans/O-GalNAc Glycans......Page 1209
O-Mannose Glycans......Page 1210
O-Glc Glycans......Page 1212
Proteoglycans/O-Xyl Glycans......Page 1213
References......Page 1214
Further Reading......Page 1215
A Crash Course in the Machinery Involved in Intra-Golgi Transport......Page 1216
SNARE complexes......Page 1217
The Cisternal Maturation Model......Page 1218
The Rim Progression Model Specifically Addresses Large Cargo Transport......Page 1220
Intercisternal Continuities. Is COPI No Longer Involved?......Page 1221
References......Page 1222
Modulating Constitutive Transport......Page 1225
Constitutive Transport via Endosomal Hubs......Page 1226
Lipid Rafts in Sorting and Transport......Page 1227
Ca2plus-dependent sorting and transport at the TGN......Page 1228
Rabs and SNAREs......Page 1229
References......Page 1230
Extent of the Regulation Network of the Secretory Pathway......Page 1233
Traffic Regulation in Response to Environmental Signals and Demands......Page 1234
The Conceptual Framework......Page 1235
Summary and Conclusions......Page 1236
References......Page 1237
Overview......Page 1238
Tour of Regulated Secretion......Page 1239
Protein hormones......Page 1241
Storage Inside the Cell......Page 1242
The Secretory Process......Page 1243
Constitutive Secretion......Page 1244
Relevant Websites......Page 1245
Biochemistry of Clathrin......Page 1246
CLCs......Page 1247
Clathrin Assembly and Disassembly......Page 1249
Receptor-mediated endocytosis......Page 1250
Endosome Roles......Page 1251
Non-membrane Traffic Roles for Mammalian CHC17 Clathrin......Page 1252
References......Page 1253
Further Reading......Page 1255
Carriers......Page 1256
Functions......Page 1257
Molecules......Page 1258
Molecules......Page 1259
Functions......Page 1260
References......Page 1261
Further Reading......Page 1262
Overview......Page 1263
Rab4 and the ‘Short-Loop’ Recycling Pathway......Page 1264
Rab11 in Cell Division......Page 1265
Other Rabs of the Endosomal Recycling Pathway......Page 1266
Intracellular Pathogens Subvert the Function of Rab GTPases......Page 1267
References......Page 1268
Biogenesis of MVBs and Cargo Sorting......Page 1270
Late Endosomes......Page 1272
Role of pH and Ion Concentrations in Endosomal Maturation......Page 1273
Role of Rab Proteins......Page 1274
Role of Cytoskeletal Elements and of Molecular Motors......Page 1275
References......Page 1277
Further Reading......Page 1279
Low Density Lipoprotein Biosynthesis......Page 1280
Receptor Structure......Page 1281
Endocytic-sorting signals......Page 1283
Disabled Homolog 2......Page 1284
The Autosomal Recessive Hypercholesterolemia Protein......Page 1285
Uncoupling of LDL from the Receptor in Endosomes......Page 1287
Selection of the LDL Receptor for Recycling to the Cell Surface......Page 1288
Cholesterol Overload Responses......Page 1289
Ubiquitin-Independent Downregulation of the LDL Receptor......Page 1290
Concluding Remarks......Page 1292
References......Page 1293
Relevant Websites......Page 1294
Introduction......Page 1295
Different Retrograde Pathways......Page 1296
Cargo Sorting and Budding......Page 1297
Cargo Sorting and Budding......Page 1298
Membrane Bending......Page 1299
Immunotherapy......Page 1300
References......Page 1301
Biosynthesis and Membrane Targeting of Rab Proteins......Page 1304
Structure and GTPase cycle of Rab Proteins......Page 1305
Packaging Cargo Proteins into Transport Vesicles......Page 1306
Ras Superfamily of G Proteins......Page 1307
Heterotrimeric G Proteins......Page 1308
References......Page 1309
Further Reading......Page 1311
Heterotetrameric Adaptor Complexes......Page 1312
AP1......Page 1313
AP3......Page 1314
GGAs......Page 1315
The EpsinR Family......Page 1316
PTB Domain Containing Family (DAB, ARH, and Numb)......Page 1317
The Adaptor Protein Network......Page 1318
References......Page 1319
SNAREs: Membrane Fusion Nanomachines......Page 1321
The Regulators of the SNARE Nanomachine......Page 1322
SNAREs: More than Fusogenic Proteins? The Case of the Longin v-SNAREs Sec22b and TI-VAMP/VAMP7......Page 1323
Conclusion......Page 1325
References......Page 1326
Relevant Websites......Page 1327
Early Acting ESCRTs......Page 1328
ESCRT-III and Vps4......Page 1329
Models of ESCRT Function......Page 1330
ESCRTs in Virus Budding......Page 1331
ESCRTs in Extracellular Vesicle Biogenesis......Page 1332
Activity at the Nuclear Envelope......Page 1333
References......Page 1334
The Assembly and Structure of Retromer......Page 1337
How Membrane Tubules are Stabilized......Page 1338
Recruitment of Retromer......Page 1339
Accessory Proteins that Modulate Retromer Function......Page 1340
The Physiological Processes That Depend on Retromer......Page 1343
Retromer and Disease......Page 1344
References......Page 1345
Interactions with Small GTPases and SNARE Proteins......Page 1347
Coiled-Coil Tethers......Page 1348
CATCHR Complexes......Page 1349
Conclusions......Page 1350
References......Page 1351
Further Reading......Page 1352
Role of BAR Proteins in Regulating NPF-Mediated Actin Assembly......Page 1353
BAR Domain Proteins as Regulators of Intracellular Transport......Page 1359
Role of BAR Proteins in Regulating Signaling......Page 1361
References......Page 1362
Glossary......Page 1365
Organelle Compartments the Spatial Restriction of Phosphoinositide Species and Organelle Identity......Page 1367
Endocytosis......Page 1369
Phosphoinositides in the Endosomal Compartment – Early Endosomes, Recycling Endosomes, and Late Endosomes......Page 1372
Phosphoinositides in Golgi Trafficking......Page 1374
Retrograde Trafficking from Endosomes to Golgi......Page 1375
Phosphoinositides in the Regulation of Autophagy......Page 1377
References......Page 1378
Hallmarks of FGF2 Membrane Translocation during Unconventional Secretion......Page 1382
PI(4,5)P2-Induced FGF2 Oligomerization and Membrane Pore Formation: A Transient Intermediate in FGF2 Membrane Translocation......Page 1384
Understanding the Regulation of IL-1beta Processing......Page 1385
Unconventional Secretion – What Is It Good for?......Page 1386
Future Perspectives......Page 1387
References......Page 1388
Introduction......Page 1390
ER Transmembrane Proteins Sense Misfolded Proteins to Activate UPR Signaling......Page 1391
IRE1 Is an Evolutionarily Conserved UPR Sensor......Page 1392
Chronic UPR Activation Causes Apoptosis in Mammalian Cells......Page 1393
The Role of the UPR in Human Health and Disease......Page 1394
Metabolic Syndrome Activates UPR Signaling......Page 1395
UPR Signaling Provides a Double-Edged Sword in Cancer......Page 1396
UPR Activation Is Associated with Neurodegenerative Diseases......Page 1397
References......Page 1398
Further Reading......Page 1400
Microtubule Structure......Page 1401
Cellular Functions of Microtubules......Page 1403
Regulation of Microtubule Structure and Mechanics by MAPs......Page 1405
Arrangement of Microtubules into Higher-Order Structures by MAPs......Page 1406
References......Page 1407
Relevant Websites......Page 1409
Introduction......Page 1410
Actin: Structural and Mechanical Properties......Page 1411
Bulk Solution Studies......Page 1414
G-Actin Binding Proteins......Page 1416
Barbed-End Trackers......Page 1419
Pointed End Binding Proteins......Page 1420
The WASP Homology 2 (WH2) Domain: A Versatile Module......Page 1421
Site-directed Branching of Actin Filaments by WASP Protein Family and Arp2/3 Complex......Page 1422
Actin Regulators in Adhesion Structures......Page 1423
Actin in the Nucleus? Potential Role of Actin in the Regulation of Gene Expression......Page 1426
References......Page 1427
Further Reading......Page 1430
Intermediate Filament Proteins Are Reliable Markers of Cellular Differentiation......Page 1431
Intermediate Filaments Can Be Assigned to Three Different Assembly Groups......Page 1432
Cytoplasmic Intermediate Filament Network Organization Is Determined by Interaction with Major Cellular Components.........Page 1434
Intermediate Filament Proteins Are Posttranslationally Modified......Page 1435
Intermediate Filaments Support Specialized Tissue Functions......Page 1436
Cytoplasmic Intermediate Filament Dysfunctions Cause Tissue-Specific Diseases......Page 1437
Highly Diverse Intermediate Filament Proteins Occur Throughout the Animal Kingdom......Page 1438
References......Page 1439
Relevant Websites......Page 1440
Septin Structure, Assembly, and Dynamics......Page 1441
Septins and the Actin Cytoskeleton......Page 1443
Septins and the Microtubule Cytoskeleton......Page 1446
References......Page 1447
Further Reading......Page 1449
Cytokinesis......Page 1450
Placement of the Z-ring at Mid-Cell......Page 1452
Segregation of Plasmids by Tubulin-Like TubZ......Page 1454
Organization of Intracellular Membrane Compartments......Page 1455
Conclusion......Page 1456
References......Page 1457
Relevant Websites......Page 1458
Myosin Structure and Organization......Page 1459
Class-1 Myosins......Page 1463
Class-5 Myosins......Page 1464
Class-8 and 11 Myosins......Page 1465
Summary and Perspectives......Page 1466
References......Page 1467
Relevant Websites......Page 1469
Discovery of Kinesin and Kinesin Superfamily Proteins......Page 1470
Molecular Phylogeny and Nomenclature of Kinesins......Page 1471
Depolymerizing Kinesins and Brain Wiring......Page 1473
Regulation of Kinesin by Signal Transduction......Page 1476
Autonomous Regulation of Kinesin Motility......Page 1478
References......Page 1479
Relevant Website......Page 1481
Cytoplasmic DHCs......Page 1482
Dynein Stepping Is Uncoordinated......Page 1483
The AAAplus Domains Power Dynein Motility......Page 1484
Force Generation......Page 1485
Transport of Cellular Cargoes......Page 1486
IFT Dynein......Page 1487
Molecular Arrangement in the Axoneme......Page 1488
Diversity of DHC Genes......Page 1489
Function of Axonemal Dynein HCs in Cilia......Page 1490
RS and Central Pair......Page 1492
Axonemal Dynein-Related Ciliopathies......Page 1493
References......Page 1494
Further Reading......Page 1498
Architecture and Dynamics of the Mitotic Spindle......Page 1499
Different Paths of Spindle Assembly......Page 1500
Microtubule Polymerization-Promoting Proteins......Page 1501
Poleward Microtubule Flux......Page 1502
Chromosome Congression......Page 1503
Spindle Disassembly and Cytokinesis......Page 1506
References......Page 1507
Relevant Websites......Page 1510
Structure of the Centrosome......Page 1511
Centriole Duplication......Page 1513
Centrosomes in Cell Division......Page 1515
The Centrosome in Development......Page 1517
Centrosome in Disease......Page 1518
Summary......Page 1519
References......Page 1520
Introduction......Page 1522
Structure of Cilia and Flagella......Page 1523
The Ciliary Membrane......Page 1525
Ciliogenesis......Page 1526
The anterograde IFT motor: Kinesin-2......Page 1527
The retrograde IFT motor: Cytoplasmic dynein 2......Page 1528
Cilium Disassembly and Length Maintenance......Page 1529
Diseases Caused by Defects in Cilia......Page 1530
Diseases Caused by Defective Motile Cilia......Page 1531
Diseases Caused by Defective Non-Motile Cilia......Page 1532
References......Page 1533
Relevant Websites......Page 1538
Sarcomere Contraction Is Driven by Sliding of Myosin and Actin Filaments......Page 1539
Calcium Release from the SR Activates Contraction......Page 1541
References......Page 1543
Further Reading......Page 1544
General Principles of Actin Polymerization-Driven Protrusion......Page 1545
Structure and Dynamics......Page 1548
Actin cytoskeleton......Page 1549
Behavior and Functions......Page 1550
Actin Dynamics......Page 1551
References......Page 1553
Basement Membranes......Page 1556
Laminins......Page 1557
Collagen IV......Page 1558
Other ECM Proteins Associated with Basement Membranes......Page 1559
Connective Tissue/Interstitium......Page 1560
Fibrillar Collagens......Page 1561
Matricellular Proteins......Page 1562
Conclusions......Page 1563
References......Page 1564
Relevant Websites......Page 1565
Integrating Classical Cadherin Adhesion with the Actin Cytoskeleton......Page 1566
Dynamic regulation of the junctional actin cytoskeleton......Page 1567
Junctional contractility and morphogenesis......Page 1568
Integrating IFs and Desmosomes......Page 1569
Linkages between MTs and Cell–Cell Junctions......Page 1570
MT-dependent cellular transport......Page 1571
References......Page 1572
Diversity of ECM Adhesions......Page 1575
The Integrin Adhesome......Page 1576
Geometric and Mechanical Sensory (Mechanosensing) Functions of ECM Adhesions......Page 1578
The Cross-Talk between the Cell and the ECM......Page 1579
References......Page 1580
Relevant Websites......Page 1581
Mesenchymal migration......Page 1582
ECM......Page 1585
Chemoattractant receptors......Page 1586
Microtubules......Page 1587
Front–back polarity......Page 1588
Embryonic Development......Page 1589
Autoimmune Disease......Page 1590
References......Page 1591
Regulation of the GTP-Binding/GTP-Hydrolytic Cycles of Rho GTPases......Page 1593
Rho GTPases and Their Roles in Regulating the Actin Cytoskeleton......Page 1595
Other Targets and Multiple Roles in Biology......Page 1597
Rho GTPases in Oncogenic Transformation......Page 1598
Rho GTPases in Mammalian Tumors......Page 1599
Key Points......Page 1600
References......Page 1601
Basic Principles of Cell Polarity and Common Mechanisms of Control......Page 1603
Polarity complexes......Page 1604
Initiating Cues of Polarization......Page 1605
Transcytosis and lumen formation......Page 1607
Molecular Basis......Page 1608
Loss of Cell Polarity and Disease......Page 1609
Conclusions......Page 1610
References......Page 1611
Further Reading......Page 1612
Introduction......Page 1613
Signaling to Actin Polymerization......Page 1614
Other Receptors and Signaling Pathways to Actin Polymerization......Page 1615
Linking Actin the Polymerization/Depolymerization Cycle with Vesicular Trafficking......Page 1616
Maturation of Phagosomes into Phagolysosomes......Page 1617
References......Page 1618
Functions of Macropinocytosis......Page 1620
Rac......Page 1621
Diacylglycerol......Page 1622
Actin and Myosin......Page 1623
References......Page 1624
Mechanisms of Phagocytosis......Page 1628
iNOS......Page 1629
Macrophage phagosome maturation......Page 1630
Neutrophil phagosome maturation......Page 1632
Autophagy and Xenophagy......Page 1633
Pyroptosis......Page 1634
Pathogen Subversion of Host Defense......Page 1635
References......Page 1636
Further Reading......Page 1637
Inactivation of Phagocytosis After Intimate Contact with Pathogens......Page 1638
Pathogens That Intimately Interact with Lysosomal Components......Page 1639
The Replication Vacuole 2: Manipulation of the Secretory Pathway to Support Bacterial Replication......Page 1640
Intimate Interaction with the Reticulum......Page 1641
Bypass and Exploitation of Host Autophagic Clearing of Microorganisms......Page 1642
References......Page 1644
Entry Mechanisms......Page 1646
Trigger......Page 1647
Bacterial attachment......Page 1648
Actin depolymerization and vacuole closure......Page 1649
Intravacuolar Bacteria......Page 1650
Cellular Responses to Bacterial Invasion......Page 1652
References......Page 1653
Exotoxins That Alter Signal Transduction......Page 1656
Exotoxins That Alter the Cytoskeleton......Page 1657
Exotoxins That Interfere with Intracellular Trafficking......Page 1658
References......Page 1659
Metabolomics......Page 1661
The Roles of the Microbiome......Page 1662
Birth and Infancy......Page 1663
Diet and Geographic Location......Page 1664
Antibiotics......Page 1665
Obesity......Page 1666
Cancer......Page 1667
References......Page 1668
The Virus Particle......Page 1671
Receptor Binding......Page 1672
Endocytosis and the Endosome Network......Page 1673
Intracellular Transport and Nuclear Import......Page 1676
Replication and Synthesis of Viral mRNAs......Page 1677
Virus Assembly and Release......Page 1678
References......Page 1679
Relevant Websites......Page 1680
Spherules produced by the Togaviridae and nodaviruses......Page 1681
Convoluted membranes and membrane webs generated by coronaviruses and flaviviruses......Page 1682
Host cell contribution to membrane rearrangements......Page 1684
The Nucleo-Cytoplasmic Large DNA Viruses Use Aggresomes to Generate Pericentriolar Factories......Page 1686
The DNA Viruses Generate Replication Compartments in the Nucleus......Page 1687
References......Page 1688
Overview......Page 1690
Gag Coordinates HIV Assembly......Page 1691
HIV Release and Maturation......Page 1694
Reverse Transcription......Page 1695
Humoral and Cellular Immunity......Page 1697
Drugs Interfering with HIV Replication......Page 1698
Conclusion......Page 1699
Further Reading......Page 1700
Prion Diseases......Page 1701
FFI......Page 1702
Structure......Page 1703
Neurotoxicity......Page 1704
References......Page 1705
Overview of C. elegans Pathogens......Page 1707
Immune Effectors......Page 1708
Caenopores......Page 1709
The p38 MAPK Pathway and Related Pathways......Page 1710
The DAF-2/DAF-16 Pathway......Page 1711
Conclusions and Perspectives......Page 1712
References......Page 1713
FrontCover......Page 1715
Encyclopedia of Cell Biology......Page 1718
Editors-in-Chief......Page 1720
Volume Editors......Page 1722
Section Editors......Page 1724
Contributors to Volume 3......Page 1730
Contents of Volume 3......Page 1738
Preface......Page 1742
Cell Biology: An Overview......Page 1744
The Signal Transduction Pathways......Page 1748
Cell Growth......Page 1749
Translation......Page 1750
Cell Cycle Progression......Page 1751
Functional Cell Biology of Immunity......Page 1752
Stem Cell Biology......Page 1753
Families of RTKs and Their Ligands......Page 1755
Signaling Downstream of RTKs......Page 1758
Internalization of RTKs......Page 1760
The PDGF Receptor Family......Page 1761
Met and Ron......Page 1762
Other RTKs......Page 1763
See also......Page 1764
References......Page 1765
Introduction......Page 1769
hGHR and Related Receptors......Page 1770
Beta Common Receptors......Page 1772
IL-7/TLSP Receptors......Page 1773
Shared Glycoprotein 130 Receptors......Page 1774
IL-1R3......Page 1775
IL-10/IL-22 Receptors......Page 1776
Type I IFN Receptors......Page 1777
Intracellular Signaling Complexes......Page 1778
References......Page 1779
Further Reading......Page 1783
Introduction......Page 1784
Function of TGF-beta Superfamily Signaling......Page 1785
TGF-beta Receptors......Page 1786
The SMADs......Page 1790
Pathway Modulation......Page 1791
TGF-beta Superfamily Signaling and Disease......Page 1793
References......Page 1794
Relevant Websites......Page 1797
Growth Factor Receptors and GPCRs......Page 1798
Association between G Proteins and Tubulin......Page 1799
References......Page 1800
Further Reading......Page 1802
Soluble GCs......Page 1803
pGCs......Page 1804
GCC......Page 1805
PDE......Page 1806
References......Page 1807
Structural Basis of Ligand–Receptor Interaction......Page 1808
Signal Transduction through TNFR Activation......Page 1809
Clinical Targeting of TNFSF and TNFRSF Members: Focusing on Cancer Immunotherapy......Page 1810
See also......Page 1811
References......Page 1812
DRs, a Subset of the TNF Receptor Family......Page 1814
DR Signaling is Mediated by Protein Interactions......Page 1815
Intrinsic Apoptotic Pathway......Page 1816
DR4 and DR5......Page 1817
TNFR1......Page 1818
p75NTR......Page 1819
References......Page 1820
Relevant Website......Page 1822
Intracellular Effectors of Signal Transduction – Transmembrane Receptors......Page 1823
Gene Regulatory Networks Controlled by the HH Pathway – The Glioma-Associated Transcription Factors......Page 1824
Noncanonical HH Signaling......Page 1826
Long-Range Transcriptional Regulation of the Mammalian SHH Gene – The ‘Zone of Polarizing Activity Regulatory Sequence’......Page 1827
Mutations in HH Pathway Components in Congenital Disease and Cancer......Page 1828
References......Page 1830
Wnt Proteins......Page 1833
Wnt Receptors: Frizzled and LRP5/6......Page 1834
Wnt Antagonists......Page 1835
The ‘Wnt-Off’ State: Keeping β-Catenin Levels Low......Page 1836
Formation of the Wnt-receptor signaling complex/signalosome......Page 1838
Nucleus Import......Page 1839
Nuclear Export......Page 1840
HATs......Page 1841
Conclusions......Page 1842
References......Page 1843
Relevant Website......Page 1845
Upstream Regulators of Hippo Signaling in D. melanogaster......Page 1846
The Hippo Pathway in Mammals......Page 1848
Upstream Regulators of Hippo Signaling in Mammals......Page 1849
Conclusions......Page 1851
References......Page 1852
Further Reading......Page 1853
Mechanisms......Page 1854
Pathology......Page 1856
References......Page 1858
A Brief History of the Discovery of SH Domains......Page 1859
SH3......Page 1860
Target Recognition Motifs......Page 1861
SH2......Page 1862
Target Recognition Motifs......Page 1863
Specificity and Promiscuity......Page 1864
Function......Page 1865
SH Domains and Diseases......Page 1866
References......Page 1867
Relevant Website......Page 1868
General Overview......Page 1869
The p38 Cascade......Page 1870
The ERK5 Cascade......Page 1871
Crosstalk with Other Signaling Cascades......Page 1872
MAPKs in Developmental Diseases......Page 1873
References......Page 1874
Class II PI3K......Page 1875
Akt......Page 1876
mTOR......Page 1877
Akt inactivation......Page 1879
PI3K/Akt/mTOR Signaling in Human Disorders......Page 1880
References......Page 1881
The Evolution of the JAK Family......Page 1883
Mechanism of Activation......Page 1888
STAT Proteins......Page 1889
Direct Kinase Inhibition by SOCS1 and SOCS3......Page 1891
Involvement of JAK Proteins in Human Disease......Page 1892
Involvement of SOCS Proteins in Human Disease......Page 1893
References......Page 1894
PLCδ family......Page 1900
PLCβ family......Page 1902
PLCγ family......Page 1903
PLCε1......Page 1904
PLCζ1......Page 1905
References......Page 1906
The EF-Hand Calcium-Binding Principle......Page 1908
CaM......Page 1909
Ca2plus Channels......Page 1910
Ca2plus Transporters......Page 1911
Calmodulin-Dependent Protein Kinases......Page 1912
References......Page 1914
Further Reading......Page 1916
History – Overview......Page 1917
Transport Signals and the Importin beta Superfamily: A Code......Page 1919
mRNA Export......Page 1921
Regulation of Transport......Page 1922
Nuclear Envelope......Page 1923
Translocons for Oversize Cargos......Page 1924
References......Page 1925
Cell–Cell Adhesion: The Essence of Multicellularity......Page 1928
Structural and Functional Diversity of Cell–Cell Junctions......Page 1929
The Cadherin Family and Diversity of AJs......Page 1930
Dynamic Connections between Cadherin and the Actin Cytoskeleton......Page 1931
Regulatory Elements of the Cadherin Adhesome......Page 1932
Cadherin and Embryonic Development......Page 1934
AJs in Disease......Page 1935
References......Page 1936
Introduction......Page 1939
Stiffness, Spacing, and Curvature......Page 1940
How Extracellular Signals Alter Adhesion to Matrix......Page 1941
Role of Cell–Matrix Adhesions in Pathological Processes: Fibrosis......Page 1942
References......Page 1943
Relevant Websites......Page 1945
Introduction......Page 1946
A Modular Signaling System......Page 1947
Principles of Collective Polarization......Page 1949
Feedback Control of Core Amplification......Page 1950
System Architecture......Page 1951
References......Page 1952
Chemotaxis......Page 1955
Migration in neural development......Page 1956
Activation of Rho GTPases......Page 1957
Lamellipodial migration......Page 1958
Overview......Page 1959
Collective Cell Migration......Page 1960
References......Page 1962
Blood Clotting and Inflammation......Page 1963
Formation of granulation tissue......Page 1966
The Phase of Tissue Remodeling......Page 1967
Parallels between Wound Healing and Cancer......Page 1968
Relevant Websites......Page 1969
EMT......Page 1970
EMT-Associated Cellular and Molecular Changes......Page 1971
Assembly of Invadopodia......Page 1972
Collective Cell Migration......Page 1973
Microtentacles......Page 1974
References......Page 1975
Introduction......Page 1977
Intermediate filaments......Page 1978
Microtubules......Page 1979
Kinesin......Page 1980
Regulation of motor proteins – Activation, inhibition, and cargo selectivity......Page 1981
Injury Changes Axon Structure and Axonal Transport to Initiate a Regeneration Program......Page 1982
Calcium influx transforms the injured axon to support regenerative growth......Page 1983
A protein kinase that can regulate both axon regeneration and Wallerian degeneration......Page 1984
Perspectives......Page 1985
References......Page 1986
Further Reading......Page 1988
mLST8 and Deptor are Common Components of mTORC1 and mTORC2......Page 1990
The Effect of Rapamycin on mTORC1 and mTORC2......Page 1991
Grb10 Is a Newly Identified mTORC1 Substrate......Page 1992
Growth factor-induced mTORC1 activation......Page 1993
Regulation of mTORC1 by stress granules......Page 1994
Regulation of mTOR Signaling by Amino Acids......Page 1995
mTORC1 Associates with Rheb on Lysosomal Membranes......Page 1996
Concluding Remarks......Page 1997
References......Page 1998
Nucleoli and Ribosome Subunit Biogenesis......Page 2001
Ribosomal DNA......Page 2004
Regulation of rDNA Expression......Page 2005
The Dynamic Nucleolus......Page 2006
Nucleolar Dynamics in Response to Transcriptional Inhibition and DNA Damage......Page 2007
Nucleoli and Viruses......Page 2010
Proteomic Studies on Nucleolar Architecture, Function, and Dynamics......Page 2011
Conclusion......Page 2012
References......Page 2013
Relevant Websites......Page 2016
Ribosomal proteins......Page 2017
P53-Independent Ribosome Stress......Page 2019
Nucleolar proteome dynamics......Page 2020
Kinase signaling in the nucleolus......Page 2021
Regulation of elongation......Page 2022
Protein quality control......Page 2023
Degradation of Defective Ribosomes......Page 2024
See also......Page 2025
References......Page 2026
Relevant Websites......Page 2027
Tightly Regulated by Oncogenes......Page 2028
Ribosomopathies Are Associated with Increased Cancer Risk......Page 2029
Non-ribosomal Functions of RPs Independent of the MDM2-p53 Pathway......Page 2030
p53 Activation Occurs in Response to Ribosome Biogenesis Inhibition......Page 2031
MDM2 Binds Ribosomal Proteins......Page 2032
References......Page 2033
Introduction......Page 2035
Cleavage and Folding of Precursor rRNA......Page 2036
rRNA Processing in Other Eukaryotes......Page 2038
rRNA Processing in Prokaryotes......Page 2040
Human Diseases Caused by rRNA Processing Defects......Page 2041
References......Page 2042
Ribosomal Pre-rRNA Processing......Page 2044
Nuclear Export of Pre-Ribosomal Particles......Page 2046
Cytoplasmic Maturation of the 60S Subunit......Page 2048
Cytoplasmic Maturation Events of the 40S Subunit......Page 2049
References......Page 2050
Further Reading......Page 2052
Relevant Websites......Page 2053
Discovery......Page 2054
Structure and mechanism......Page 2055
Type 4 Dicistroviridae IGR IRESs......Page 2056
Canonical eIFs......Page 2057
Critical analysis of cellular mRNA IRESs......Page 2060
See also......Page 2061
References......Page 2062
Relevant Website......Page 2063
NMD......Page 2064
NSD......Page 2065
NMD......Page 2066
NGD......Page 2067
mRNA Degradation Control by Short RNAs......Page 2068
Combined Action of Short RNAs and RBPs......Page 2070
References......Page 2071
The Extrinsic Pathway......Page 2074
The Intrinsic Pathway......Page 2075
Caspases......Page 2076
Lipids......Page 2077
The Bcl-2 family......Page 2078
Anti-apoptosis proteins of viral origin......Page 2079
References......Page 2080
Relevant Website......Page 2081
The Challenges of Being a Tumor Cell in its Primary Microenvironment......Page 2082
ROS As a Mediator of Anoikis......Page 2083
ROS as Cell Survival Factors......Page 2084
What Otto Warburg Said, How It Was Misinterpreted, and the Idea of Metabolic Coupling in Tumors......Page 2085
References......Page 2086
Mitochondria......Page 2088
Intrinsic apoptosis......Page 2089
Mitochondrial Control of Regulated Necrosis......Page 2090
MOMP......Page 2092
MPT......Page 2094
References......Page 2095
The TNF and TNFR Superfamilies......Page 2101
Structural Features of TNF, TNFR1, and TNFR2......Page 2102
TNF-Induced TNFR Signaling......Page 2103
TNFR-Induced NF-kappaB Activation......Page 2104
Regulation of TNF Signaling by Ubiquitin Ligases and Deubiquitinases......Page 2105
TNF-Induced Activation of MAPK Pathways......Page 2106
Impact of TNF Blockade in Inflammatory Diseases......Page 2107
References......Page 2108
Relevant Websites......Page 2110
Non-Apoptotic Functions......Page 2111
Effector Caspase Activation......Page 2113
Caspase Substrates......Page 2114
The Apoptosome (Intrinsic Apoptosis)......Page 2115
Pyroptosis......Page 2117
Necroptosis......Page 2118
References......Page 2119
Relevant Websites......Page 2120
Efferocytosis Is an Established Process That Is Rapidly Deployed in the Breast......Page 2121
Efferocytosis and Postpartum Breast Cancer......Page 2123
References......Page 2124
The Bcl-2 Family of Proteins: Classification and Structure......Page 2126
How Do Bcl-2 Family Proteins Regulate MOMP?......Page 2127
Physiology and Regulation of Bcl-2 Family Members......Page 2129
Bcl-2 Family Proteins and Cancer......Page 2131
Summary......Page 2132
References......Page 2133
Relevant Websites......Page 2136
RING, UBC, and UBA Domains......Page 2137
c-IAP1 (BIRC2) and c-IAP2 (BIRC3)......Page 2138
IAP proteins and NF-κB pathways......Page 2139
Cell death ligand driven apoptosis and necroptosis......Page 2140
Survivin (BIRC5)......Page 2141
IAP Antagonists......Page 2142
References......Page 2143
Unscheduled Entry into Mitosis......Page 2146
Mitotic Block......Page 2148
Concluding Remarks......Page 2149
References......Page 2150
Induction of Autophagy......Page 2151
Cargo Recognition......Page 2152
Recycling, an Integral Part of Autophagy......Page 2153
The Autophagic Cargo and Purpose of Its Degradation......Page 2154
Pathophysiology of Autophagy......Page 2155
References......Page 2156
Oncogenes and Tumor Suppressor Genes and Human Cancer......Page 2158
Number of mutations in a human cancer......Page 2159
Transcriptional regulation......Page 2160
Oncogenes, Tumor Suppressor Genes, and Cell Cycle Regulation......Page 2161
The PI3K pathway......Page 2162
Noonan syndrome......Page 2164
Neurofibromatosis......Page 2165
Oncogenes and Tumor Suppressor Genes in Diabetes......Page 2166
References......Page 2167
Relevant Websites......Page 2169
The Discovery of Regulators of the Cell Cycle......Page 2170
The Cyclin-Dependent Kinases......Page 2171
Functions of Cyclin-CDK in the Cell Cycle and Quiescence......Page 2172
Mutations of Cyclins and CDKs in Cancer......Page 2175
Beyond the Cell Cycle: Other Functions of Cyclins and CDKs......Page 2176
References......Page 2177
The Restriction Point......Page 2179
The Role of RB and p53 in Establishing the Restriction Point......Page 2182
References......Page 2183
Normal Function......Page 2184
Normal Function......Page 2185
D-type Cyclin/CDK4/6 assembly and nuclear import......Page 2186
Prognostic Significance of CDK Inhibitor Deregulation in Human Cancers......Page 2187
CIP/KIP Family......Page 2188
CDK Inhibitors as Predictors of Drug Response......Page 2189
References......Page 2191
Control and Significance of G1–S Phase Progression in Mammals......Page 2194
INK4a/ARF – a Dual Coding Locus in Mammals......Page 2195
INK4a/ARF – One Locus, Two Important Tumor Suppressors......Page 2196
ARF, a Multi-Faceted Tumor Suppressor......Page 2199
Regulation and Loss of INK4a/ARF in Cancer......Page 2200
INK4a/ARF in Aging......Page 2201
Conclusions......Page 2202
References......Page 2203
Relevant Websites......Page 2204
Replication Fork Formation......Page 2205
Replication Factories......Page 2206
ATM-related damage response......Page 2207
Chk1 and Chk2......Page 2208
Nuclear excision repair......Page 2209
MMR......Page 2210
Translesion DNA synthesis......Page 2211
Double-strand break repair......Page 2212
See also......Page 2213
References......Page 2214
Putting the CPC Together......Page 2216
CPC during the Approach to Mitosis......Page 2217
Spindle Assembly Checkpoint and Inter-Kinetochore Tension......Page 2218
CPC and Error Correction......Page 2219
Modified View of CPC Targeting......Page 2220
Conclusion......Page 2222
References......Page 2223
Introduction......Page 2225
Prophase......Page 2226
Metaphase......Page 2227
Cytokinesis......Page 2228
Membrane ingression......Page 2229
Membrane abscission......Page 2231
Mitosis As an Anticancer Drug Target......Page 2233
References......Page 2237
Relevant Website......Page 2240
The RhoA Pathway......Page 2241
Scaffolding Proteins: Anillin and Septins......Page 2242
The Role of Plk1......Page 2243
Vesicle Trafficking......Page 2244
Regulation of Aurora B by Cdk1......Page 2246
Temporal Regulation of Plk1......Page 2247
The Abscission Checkpoint......Page 2248
References......Page 2249
Ubiquitination......Page 2251
Deubiquitination......Page 2252
DUBs in the p53 Pathway......Page 2253
Involvement of p53 in Metabolism......Page 2254
References......Page 2256
What Defines Cellular Senescence?......Page 2258
Epigenetic Control of Senescence......Page 2259
Senescence in Cancer......Page 2260
Conclusion......Page 2262
References......Page 2263
Introduction......Page 2265
Chemical Defenses......Page 2266
Sensing Mechanisms......Page 2267
Innate Lymphoid Cells......Page 2268
Immunological Synapses......Page 2269
Lymphoid Tissues......Page 2272
See also......Page 2273
References......Page 2274
The TCR, a Tyrosine Kinase-Coupled Receptor......Page 2275
Subunit Composition, Stoichiometry, and Valency of the TCR......Page 2276
Properties of TCR Ligands......Page 2277
The Kinetic Model of T Cell Activation......Page 2278
How to Account for Specificity and Sensitivity of TCR Responses?......Page 2279
The Conformational Model of T Cell Activation......Page 2280
Signal Amplification and Diversification Module......Page 2281
Negative Regulation Modules......Page 2284
References......Page 2285
Further Reading......Page 2287
Initiation of Tfh Development......Page 2288
The GC......Page 2290
References......Page 2294
Introduction......Page 2297
Developmental and Epigenetic Regulation of V(D)J Recombination......Page 2298
Ordered Rearrangement of TCR and BCR Gene Segments......Page 2299
Posttranscriptional control......Page 2300
Allelic Exclusion......Page 2301
Transcription and epigenetic marks......Page 2302
Chromosomal organization......Page 2303
Regulation of Cleavage – 12/23 Restriction and Beyond......Page 2304
NHEJ pathway......Page 2305
DDR......Page 2307
The RAG recombinase: Domestication of a transposase......Page 2308
Body of evidence in humans......Page 2309
V(D)J Recombination and Immune Deficiency Disorders......Page 2310
References......Page 2311
Further Reading......Page 2313
Phenotypes of Memory T Cells......Page 2314
Tissue-Resident Memory......Page 2315
Different Phenotypes Characterize Different Viral Infections......Page 2316
Memory Inflation......Page 2317
Conclusions and Future Directions......Page 2318
Further Reading......Page 2319
Regulation of NFAT Activation......Page 2320
NFAT-Regulated Transcription......Page 2321
Thymoctyte Development and Positive Selection......Page 2322
Regulatory T Cells......Page 2323
References......Page 2324
Further Reading......Page 2326
Introduction......Page 2327
nfkb2 KO mice......Page 2328
relb KO mice......Page 2329
Role of NF-kappaB in Innate Immunity......Page 2330
Increased NF-kappaB Activity in Chronic Inflammatory Diseases......Page 2331
Human Immune Cell Viruses Use NF-kappaB for Replication and Pathogenesis......Page 2332
References......Page 2333
Relevant Websites......Page 2334
Discovery of Dendritic Cells......Page 2335
Classical MHC Class II Processing......Page 2336
Cross-Presentation......Page 2337
Autophagy......Page 2338
Plasmacytoid DCs......Page 2339
CD8plusCD11b- DCs......Page 2340
CD8-CD11bplus DCs......Page 2341
Langerhans cells and migratory DCs......Page 2342
Lymphoid Tissue DCs......Page 2343
Conclusions......Page 2344
References......Page 2345
Peripheral Tolerance......Page 2352
Regulatory T cells – a specialized cell type that regulate immune responses......Page 2353
Functions of CD28......Page 2354
CTLA-4 and CD28 Bind Same Ligands with Different Affinities......Page 2355
Cell biology of CTLA-4......Page 2356
Transendocytosis: cell biology at the heart of immune regulation......Page 2357
CTLA-4: a key mechanism of Treg suppression......Page 2358
Manipulation of CD28/CTLA-4 Pathway: Antagonist, Agonists, and Superagonists......Page 2359
References......Page 2360
Stromal Cell Regulation of Lymphocyte Migration......Page 2363
Initiation and Regulation of Adaptive Immune Responses by Stromal Cells......Page 2364
Regulation of Peripheral Tolerance by Stromal Cells......Page 2365
Initiation of Tissue Inflammation......Page 2366
Inflammatory Diseases......Page 2367
References......Page 2368
Role of CXCL12 in Homing to BM......Page 2371
Role of CXCL12 in HSC and HPC Maintenance within BM Niches......Page 2372
CXCL12 in HSC and HPC Mobilization......Page 2373
Role of CXCL12 in Maintenance of Neutrophils in BM......Page 2374
Role of CXCL12 in Maintenance of the B cell Lineage in BM......Page 2375
References......Page 2376
Introduction......Page 2379
Vascular Endothelium......Page 2380
Trafficking during T Lymphocyte Maturation......Page 2381
Trafficking during T Lymphocyte Immune Surveillance......Page 2382
Molecular Basis for Adhesion and Diapedesis......Page 2383
T Lymphocyte remodeling: Spreading, migration, probing, and piercing......Page 2384
Antigen presenting properties of endothelial cells......Page 2386
Emerging and Putative Roles for Endothelial Cell Ag Presentation......Page 2387
Roles for Endothelial Antigen Presentation in Pathology......Page 2388
T Lymphocyte ILP: Unique Ag-recognition sensory organelles......Page 2389
Stabilized ILP arrays function in signal amplification......Page 2390
Lessons learned from BEC-APC as unique planar APC......Page 2391
References......Page 2392
Introduction......Page 2397
Exclusion of Negative Regulators......Page 2398
Changes in Conformation and Accessibility of Intracellular Domains......Page 2400
TCRs as Mechanoreceptors......Page 2402
Quantity and Valency of Cognate pMHC Ligands......Page 2403
References......Page 2404
Forces Acting at Synapses......Page 2407
Imaging TCR-pMHC Interactions In Situ......Page 2408
Pulling Forces Enhance Discriminative Power of Peptide Recognition......Page 2411
References......Page 2412
Single-Cell Secretion......Page 2414
Cell Migration......Page 2416
Cell–Cell Communication......Page 2419
Medical Applications: Microtools as Part of an Integrated Workflow......Page 2420
Dissecting Biological Noise......Page 2421
References......Page 2422
Methods to Study T Cell Organization......Page 2424
T Cell Shape and Plasma Membrane Topology......Page 2425
Vesicle Trafficking......Page 2427
Signaling Complexes – The Central Supramolecular Activation Cluster......Page 2428
Signaling Organization Varies with T Cell Activation Conditions......Page 2429
References......Page 2430
Relevant Websites......Page 2433
Introduction......Page 2434
Structure of the Epithelial Layer......Page 2435
Epithelial Cell Types......Page 2436
Defense......Page 2437
Loss of Barrier Function in Disease......Page 2438
Perspective......Page 2439
References......Page 2440
Introduction......Page 2442
FcγR Activation by Immunoglobulin G (IgG)......Page 2443
The Phagocytic Synapse Model......Page 2444
Regulation of the Phagocytic Synapse by CD47......Page 2447
References......Page 2448
The Phagocyte NADPH Oxidase NOX2......Page 2449
Structure of the Cytosolic Components in Resting Cells......Page 2450
The ‘p47phox–p67phox–p40phox’ complex in resting cells......Page 2451
Assembly and Activation of the NADPH Oxidase Complex......Page 2452
Phosphorylation of p67phox and p40phox......Page 2453
References......Page 2454
CLRs......Page 2457
TLRs......Page 2459
NLRs......Page 2461
RLRs......Page 2465
AIM2-Like Receptors and Other Intracellular DNA Sensors......Page 2466
Role of Intracellular Organelles and Spatial Relocation......Page 2467
Combinatorial Sensing and PRR Crosstalk......Page 2468
Multiscale Regulation of Cytosolic Sensing Pathways......Page 2469
References......Page 2471
SR-Specific Domains Share Ancient Origins......Page 2474
Cell Biology of SRs: Endocytosis and Signaling......Page 2475
Transcriptional Control of SR Expression......Page 2477
Class B SRs Mediate Physiological Lipid Transport......Page 2478
Multiple SRs Mediate Clearance of Normal Self......Page 2479
SRs Collaborate with Other PRR Families to Fine-Tune Responses......Page 2480
SRs in Inflammatory Diseases: Innate Immunity to Modified Self......Page 2481
SRs in Cancer......Page 2482
References......Page 2483
Relevant Website......Page 2487
DCs in non-lymphoid organs......Page 2488
Growth Factors and DC Cultures......Page 2489
Human DC Development......Page 2490
Activation of innate lymphocytes......Page 2492
DC Maturation......Page 2493
DCs in Autoimmune Disease......Page 2494
References......Page 2495
Neutrophil Development......Page 2497
Tethering and Rolling......Page 2498
NETs......Page 2499
Low-Density Granulocytes......Page 2500
Papillon–Lefèvre syndrome......Page 2501
Rheumatoid Arthritis......Page 2502
References......Page 2503
The Splenic MZ and Its Macrophages......Page 2506
Metallophilic Macrophages......Page 2508
SIGN-R1/MARCO (MZ) Macrophages......Page 2509
Red Pulp Macrophages......Page 2510
SCMs......Page 2512
Medullary Macrophages......Page 2513
Conclusions......Page 2514
References......Page 2515
Members of the TNFRSF and CD4 T Cells......Page 2517
HVEM......Page 2518
OX40 and CD30......Page 2519
References......Page 2520
Determinants of Stem Cell Aging......Page 2523
Epigenetic Alterations......Page 2524
Extrinsic factors associated with satellite cell aging......Page 2525
Intrinsic modifications in aged satellite cells......Page 2526
HSCs......Page 2527
References......Page 2529
Enhancer Activation and Developmental Competence......Page 2532
Chromatin Remodeling......Page 2533
Epigenetic Signatures and Control of Nuclear Architecture in ESCs......Page 2535
Skeletal Muscle Stem Cells......Page 2536
Neural Stem Cells......Page 2537
References......Page 2538
Relevant Website......Page 2540
The Hair Follicle Stem Cell Populations – A Series of Specialized Compartments with Varying Cell Fate Competences......Page 2541
Signaling between Follicle Stem Cells and Their Microenvironment......Page 2542
A Unique Tissue-Specific Progenitor Cell Amid Cellular Neighbors......Page 2543
A Tissue with Functional Stem Cells but Poor Regenerative Capacity......Page 2544
The V-SVZ Neural Stem Cell Niche......Page 2545
SVZ Interactions......Page 2546
The Heart-Evidence for a Cardiac Stem Cell Niche?......Page 2547
Cell–cell Interactions......Page 2548
Juxtacrine and Paracrine Signaling......Page 2549
References......Page 2550
Terminology......Page 2554
Modes of Identification......Page 2555
Markers for the Identification of Cancer Stem Cells in Major Malignancies......Page 2556
Clinical Significance of Cancer Stem Cells......Page 2557
References......Page 2558
Hypoxia-Inducible Factor 1α and Glycolysis in Stem Cells......Page 2560
Fatty Acid Metabolism and Mitochondrial Function......Page 2561
Redox Homeostasis......Page 2562
Other Stem Cell Niches......Page 2563
References......Page 2564
New Tools to Provide Mechanistic Insights on Determining Cell Fates and Disease States......Page 2566
New Tools for Cell-Based Regenerative Therapy......Page 2567
References......Page 2568
Further Reading......Page 2569
FrontCover......Page 2570
Encyclopedia of Cell Biology......Page 2573
Editor-in-Chief......Page 2575
Volume Editors......Page 2577
Section Editors......Page 2579
Contributors to Volume 4......Page 2585
Contents of Volume 4......Page 2589
Preface......Page 2591
Cell Biology: An Overview......Page 2593
Systems Cell Biology: An OverviewSystems Cell Biology: An OverviewOverview | Systems Cell Biology: An Overview......Page 2597
Vertical Integration......Page 2598
Relevant Websites......Page 2599
Strategies for Chemotaxis......Page 2600
Temporal Sensing......Page 2601
Spatial Sensing......Page 2602
Signal Amplification and Sensitivity......Page 2603
Conclusions......Page 2604
Further Reading......Page 2605
Conceptual Models of Mechano-Chemical Control of Cell Motility and Shape......Page 2606
Detailed Biochemical Modeling......Page 2610
References......Page 2618
Relevant Websites......Page 2619
Stoichiometric Networks......Page 2620
Stoichiometry Matrix......Page 2621
Enzyme Response......Page 2622
Control Coefficients......Page 2623
Connectivity Theorems......Page 2624
Futile Cycles......Page 2625
Graphical Understanding of Feedback......Page 2627
Control Analysis......Page 2628
References......Page 2629
Further Reading......Page 2631
Dynamic Instability......Page 2632
Cellular Microtubule Dynamics and MAPs......Page 2634
Theoretical Framework for Microtubule Self-Assembly......Page 2636
References......Page 2638
Relevant Websites......Page 2639
Signal Amplification and Decision Making......Page 2640
Cellular Decisions Encoded in the Dynamics of Signaling......Page 2642
Robustness of Signaling Pathways......Page 2644
References......Page 2645
Further Reading......Page 2646
Cue-Dependent Cell Polarization......Page 2647
Breaking Symmetry......Page 2648
Inhibitory Interactions and Reinforcements in Polarity Regulation......Page 2650
References......Page 2651
Microscopic processes and parameters......Page 2652
Entry-Fusion-Exit Model......Page 2654
Regulation of the Microscopic Processes......Page 2655
Relation to Kinetics of Total Cargo Pool......Page 2656
References......Page 2657
Further Reading......Page 2658
Introduction......Page 2659
Constructing GRN Maps......Page 2660
Repression......Page 2661
Negative Feedback......Page 2662
Global Properties of GRNs......Page 2663
Modularity......Page 2664
References......Page 2666
Relevant Website......Page 2667
The Multiple Time and Spatial Scales Associated with Cellular Biology......Page 2668
Approaches for Linking Scales in Multiscale Models: ‘Top-Down’, ‘Bottom-Up,’ and ‘Middle-Out’......Page 2669
Assembling Multiscale Modeling......Page 2670
Software for Multiscale Modeling......Page 2671
Case Study I: Homeostasis in the Intestinal Crypt......Page 2672
Case Study II: Diabetic Retinopathy......Page 2673
References......Page 2674
Relevant Websites......Page 2675
Introduction......Page 2676
Composite hybrid ABM......Page 2677
EFA......Page 2678
Discussion......Page 2679
References......Page 2680
Relevant Website......Page 2681
State-of-the-Art in Cardiac Cell Modeling......Page 2682
Human Models of Cardiac Cell Electrophysiology......Page 2683
Modeling Variability in Cardiac Cell Electrophysiology......Page 2684
Whole Organ Cardiac Modeling......Page 2685
References......Page 2688
Relevant Website......Page 2690
Introduction......Page 2691
A Simple Mathematical Model Capturing the Resolution of Inflammation......Page 2692
Inflammatory Cytokines, TNF-Therapy......Page 2694
Inflammation and Progression to the Immune Response......Page 2695
References......Page 2696
Developmental Vasculogenesis......Page 2698
FGF receptors......Page 2700
FGFR signaling......Page 2701
VEGFR signaling......Page 2702
Tie signaling......Page 2703
FGF–VEGF–Ang–PDGF Networking......Page 2704
Hypoxic Induction of Angiogenesis......Page 2705
Destabilization of EC–EC Junctions......Page 2706
Migration and Proliferation......Page 2707
Sprout Fusion and Flow......Page 2708
Vessel Pruning......Page 2709
Arterial and Venous Vessels......Page 2710
References......Page 2711
Wound Healing and the Need for Modeling......Page 2713
Evaluation of Several Mathematical Approaches......Page 2714
References......Page 2717
Analyzing Cell Behavior......Page 2718
Particle-based models......Page 2719
Vertex-based models......Page 2720
Examples of Vertical Integration Studies......Page 2721
Differential-Adhesion Driven Cell Sorting......Page 2722
Vasculogenesis and Angiogenesis......Page 2723
Multiscale Modeling of Somitogenesis......Page 2724
Regulation of Root Growth by Auxin in Arabidopsis thaliana......Page 2725
References......Page 2727
Relevant Websites......Page 2729
Introduction......Page 2730
Identity of Adult NSCs......Page 2731
Cell Proliferation in the SVZ......Page 2732
Neuronal Differentiation in the Olfactory Bulb......Page 2733
Potential Applications......Page 2734
References......Page 2735
Further Reading......Page 2736
The Complex Nature of a Disease and Its Underlying (In Vitro) Molecular Networks......Page 2737
Tumor Microenvironment – A Biological Reality that Can Only Be Understood In Vivo and Using Global Integrative and.........Page 2738
Cancer Metastasis – A Showstopper for 1-Context-Only Studies/Theories......Page 2739
Principles of Network Biology......Page 2741
Tools to Study Networks at Multiple Levels of Biological Complexity......Page 2742
Computational Modeling – Understanding the Integrative Nature of Biological Networks......Page 2743
Development of a Global, Predictive Biological Model of Cell Behavior......Page 2745
References......Page 2746
Relevant Website......Page 2748
Genomics for Old and New Questions......Page 2749
Case Studies: New Genes for Old and New Functions......Page 2750
Gene Traffic......Page 2751
Gene Regulatory Networks......Page 2752
Perspectives......Page 2753
References......Page 2754
Evolution of High-Throughput Transcriptomic Technologies......Page 2756
Exploring the Interactive Transcriptome......Page 2758
Integrating Transcriptomics with Other Omics......Page 2759
References......Page 2760
Digestion of Proteins into Peptides......Page 2762
Data-dependent acquisition......Page 2763
Data-independent acquisition......Page 2764
Systems Biology Application for High-Throughput Proteomics......Page 2765
Organization of the proteome......Page 2766
Measuring dynamic proteomes......Page 2767
Central metabolism......Page 2768
References......Page 2769
Protein Phosphorylation......Page 2773
Phosphopeptide Enrichment......Page 2774
Large-Scale Phosphoproteomics Strategies......Page 2775
Phosphopeptide Fragmentation......Page 2776
PTM Cross Talk and PTM Coding......Page 2778
References......Page 2779
Methods to Map Interactomes......Page 2783
Mapping Protein–Protein Interactions......Page 2784
Mapping Protein–RNA Interactions......Page 2787
Mapping Protein-Small Molecule Interactions......Page 2788
Interaction Network Structure Reflects Biological Function......Page 2789
Interactome maps and human disease......Page 2790
Interactome maps, drugs, and drug targets......Page 2791
References......Page 2792
Metabolomics versus Metabolite Profiling......Page 2795
Conducting a Successful Metabolomics Study......Page 2796
Growth......Page 2797
Extract/Inactivate Enzymes......Page 2798
Analyze......Page 2799
GC–MS data......Page 2801
Using Metabolomics Data (What Good Is It?)......Page 2803
References......Page 2805
Overview......Page 2807
Integrating a Single Data Source with an Existing Interaction Network......Page 2808
Metabolic Networks......Page 2809
Methods for Integration of Data Types that Capture a Hierarchical Flow of Biological Information......Page 2810
References......Page 2812
Molecular-State Differences......Page 2814
Signaling Oscillations......Page 2815
Technical limitations......Page 2816
Measuring protein interactions and activity......Page 2817
Modeling and Analysis of Single-Cell Signaling Networks......Page 2818
Connecting Heterogeneity at Multiple Levels......Page 2819
References......Page 2820
Systematic Methods to Interrogate Genetic Perturbations and Map Phosphorylation-Dependent SignalingSystematic Methods to.........Page 2823
References......Page 2828
History......Page 2830
Cells......Page 2831
Perturbations......Page 2832
Assays......Page 2833
Instrumentation......Page 2834
High-Content Analysis......Page 2835
Feature extraction......Page 2836
Conclusion......Page 2838
References......Page 2839
Relevant Websites......Page 2840
Limitations of Manual Curation......Page 2841
Data Quality and Heterogeneity......Page 2842
Data Structure Standardization......Page 2843
Open Licenses......Page 2844
References......Page 2845
Relevant Websites......Page 2847
Horizontal Integration: Disease: Computational and Systems Cancer BiologyHorizontal Integration: Disease: Computational.........Page 2848
Integrative and Systems Biology Methodologies......Page 2849
Interactome Reverse Engineering......Page 2852
Regression Analysis......Page 2853
ARACNe and MINDy, a Case Study......Page 2854
Interrogating Pathways and Networks......Page 2855
References......Page 2856
Relevant Website......Page 2859
Genomics in Target and Drug Discovery......Page 2860
Proteomics and Metabolomics......Page 2861
Properties of Networks......Page 2862
References......Page 2863
Index......Page 2865