Originally based on a graduate course taught by the author, this true classic has once again been extensively updated to incorporate key new findings in biological signaling. With over half of the content re-written, plus 70 brand new and 50 revised figures, this is the most up-to-date textbook on signaling available anywhere.
Thanks to its clear structure, hundreds of illustrative drawings, as well as chapter introductions and newly added study questions, this text excels as a companion for a course on biological signaling, and equally as an introductory reference to the field for students and researchers. Generations of students and junior researchers have relied on ‘the Krauss’ to find their way through the bewildering complexity of biological signaling pathways.
Table of Content
Preface xxvii
1 Basics of Cell Signaling 1
1.1 Cell Signaling: Why, When, and Where? 1
1.2 Intercellular Signaling 3
1.3 Hormones in Intercellular Signaling 8
1.4 Intracellular Signaling: Basics 15
1.5 Molecular Tools for Intracellular Signaling 18
2 Structural Properties, Regulation and Posttranslational Modification of Signaling Proteins 27
2.1 Modular Structure of Signaling Proteins 27
2.2 Modular Signaling Complexes 31
2.3 Regulation of Signaling Enzymes by Effector Binding 34
2.4 Posttranslational Modifications (PTMs) in Cellular Signaling 36
2.5 Regulation by Protein Phosphorylation 51
2.6 Regulation by Protein Lysine Acetylation 55
2.7 Regulation by Protein Methylation 58
2.8 Ubiquitin Modification of Proteins 62
2.9 Lipidation of Signaling Proteins 90
Questions 99
References 100
3 Organization of Signaling 103
3.1 Scaffold Proteins 103
3.2 Signal Processing in Signaling Paths and Signaling Networks 108
3.3 Architecture of Signaling Pathways 113
Questions 127
References 127
4 The Regulation of Gene Expression 129
4.1 The Basic Steps of Gene Expression 129
4.2 The Components of the Eukaryotic Transcription Machinery 131
4.3 The Principles of Transcription Regulation 149
4.4 The Control of Transcription Factors 165
4.5 Chromatin Structure and Transcription Regulation 175
Questions 205
References 206
5 RNA Processing, Translational Regulation, and RNA Interference 209
5.1 Pre-m RNA Processing 209
5.2 Regulation at the Level of Translation 217
5.3 Regulation by RNA Silencing 229
Questions 247
References 248
6 Signaling by Nuclear Receptors 251
6.1 Ligands of Nuclear Receptors (NRs) 252
6.2 Principles of Signaling by Nuclear Receptors (NRs) 254
6.3 Structure of Nuclear Receptors (NRs) 257
6.4 Transcriptional Regulation by NRs 268
6.5 Regulation of Signaling by Nuclear Receptors 274
6.6 Subcellular Localization of NRs 280
6.7 Nongenomic Functions of NRs and their Ligands 284
Questions 289
References 289
7 G Protein-Coupled Signal Transmission Pathways 291
7.1 Transmembrane Receptors: General Structure and Classification 291
7.2 Structural Principles of Transmembrane Receptors 294
7.3 G Protein-Coupled Receptors 301
7.4 Regulatory GTPases 320
7.5 The Heterotrimeric G Proteins 327
7.6 Receptor-independent Functions of Heterotrimeric G Proteins 350
7.7 Effector Molecules of G Proteins 352
7.8 GPCR Signaling via Arrestin 363
Questions 365
References 366
8 Intracellular Messenger Substances: “Second Messengers” 369
8.1 General Properties of Intracellular Messenger Substances 369
8.2 Cyclic AMP 371
8.3 c GMP and Guanylyl Cyclases 375
8.4 Metabolism of Inositol Phospholipids and Inositol Phosphates 378
8.5 Storage and Release of Ca2+ 383
8.6 Functions of Phosphoinositides 392
8.7 Ca2+ as a Signal Molecule 394
8.8 Diacylglycerol as a Signal Molecule 401
8.9 Other Lipid Messengers: Ceramide, Sphingosine, and Lysophosphatidic Acid 401
8.10 The NO Signaling Molecule 404
Questions 414
References 415
9 Ser/Thr-Specific Protein Kinases and Protein Phosphatases 417
9.1 Classification, Structure, and Characteristics of Protein Kinases 417
9.2 Structure and Regulation of Protein Kinases 420
9.3 Protein Kinase A 431
9.4 The PI3 Kinase/Akt Pathway 439
9.5 Protein Kinase C 447
9.6 Ca2+/Calmodulin-Dependent Protein Kinases, Ca M Kinases 455
9.7 Ser/Thr-Specific Protein Phosphatases 461
Questions 469
References 470
10 Signal Transmission via Transmembrane Receptors with Tyrosine-Specific Protein Kinase Activity 473
10.1 Structure and Function of RTKs 474
10.2 Downstream Effector Proteins of RTKs 494
10.3 Nonreceptor Tyrosine-Specific Protein Kinases, Non-RTKs 507
10.4 Protein Tyrosine Phosphatases 519
Questions 532
References 533
11 Signal Transmission via Ras Proteins 535
11.1 The Ras Superfamily of Monomeric GTPases 535
11.2 GTPase-Activating Proteins (GAPs) of the Monomeric GTPases 539
11.3 Guanine Nucleotide Exchange Factors (GEFs) of the Monomeric GTPases 541
11.4 Guanine Nucleotide Dissociation Inhibitors (GDIs) 544
11.5 The Ras Family of Monomeric GTPases 545
11.6 Raf Kinase as an Effector of Signal Transduction by Ras Proteins 555
11.7 Further Ras Family Members: R-Ras, Ral, and Rap 561
11.8 Reception and Transmission of Multiple Signals by Ras Protein 562
11.9 The Further Branches of the Ras Superfamily 568
Questions 570
References 571
12 Intracellular Signal Transduction: The MAP Kinase Pathways 573
12.1 Organization and Components of MAPK Pathways 575
12.2 Regulation of MAPK Pathways by Protein Phosphatases and Inhibitor Proteins 579
12.3 Scaffolding in MAPK Signaling 583
12.4 The Major MAPK Pathways of Mammals 586
Questions 592
References 592
13 Membrane Receptors with Associated Tyrosine Kinase Activity 593
13.1 Cytokines and Cytokine Receptors 593
13.2 The Jak-STAT Pathway 608
13.3 T- and B-Cell Receptors 618
13.4 Signal Transduction via Integrins 623
Questions 628
References 629
14 Other Transmembrane Receptor Classes: Signaling by TGF-β Receptors, TNF Receptors, Toll Receptors, and Notch 631
14.1 Receptors with Intrinsic Ser/Thr Kinase Activity: The TGF-β Receptor and Smad Protein Signaling 631
14.2 Receptor Regulation by Intramembrane Proteolysis: The Notch Receptor 642
14.3 Tumor Necrosis Factor Receptor (TNFR) Superfamily 648
14.4 Toll-Like Receptor Signaling 653
Questions 658
References 659
15 Cell-Cycle Control by External Signaling Pathways 661
15.1 Principles of Cell-Cycle Control 661
15.2 Key Elements of the Cell-Cycle Apparatus 666
15.3 Regulation of the Cell Cycle by Proteolysis 681
15.4 G 1 Progression and S Phase Entry 684
15.5 Transit Through S Phase and M Phase 699
15.6 DNA Damage and DNA Replication Checkpoints 702
Questions 712
References 713
16 Malfunction of Signaling Pathways and Tumorigenesis: Oncogenes and Tumor Suppressor Genes 715
16.1 Basic Characteristics of Tumor Cells 715
16.2 Mutations in Cancer Cells 715
16.3 Common Physiologic Changes in Tumor Cells: The Hallmarks of Cancer 725
16.4 Signaling Proteins Mutated in Cancer: Oncogenes 729
16.5 Tumor Suppressor Genes: General Functions 741
16.6 Tumor Suppressors: Rb and ARF Proteins 743
16.7 Tumor Suppressor Protein p 53 747
16.8 Wnt/β-Catenin Signaling and the Tumor Suppressor APC 770
Questions 773
References 774
17 Apoptosis 777
17.1 Overview of Apoptotic Pathways 778
17.2 Caspases: Death by Proteolysis 779
17.3 The Family of Bcl-2 Proteins: Gatekeepers of Apoptosis 786
17.4 The Mitochondrial Pathway of Apoptosis 789
17.5 Death Receptor-Triggered Apoptosis 792
17.6 Links of Apoptosis to Cellular Signaling Pathways 795
Questions 799
References 799
Index 801
About the author
Gerhard Krauss is Professor of Biochemistry at the University of Bayreuth (Germany). His resarch is centered on the mechanism of interaction of DNA binding proteins and their target DNA. He is also a gifted teacher and textbook author, and for many years has been the head of the university education committee of the German Society of Biochemistry and Molecular Biology (GBM).
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