Signal transduction / 2nd ed.

Front Cover 1
Signal Transduction 4
Copyright Page 5
Contents 6
Preface 20
Notes 26
Chapter 1: Prologue: Signal Transduction, Origins, and Ancestors 30
Transduction, the word and its meaning: one dictionary, different points of view 30
Hormones, evolution, and history 31
The plasma membrane barrier 31
Protohormones 32
Protoendocrinologists 34
Hormones: a definition 39
What's in a name? 40
Neurotransmitters 41
Ergot 43
Receptors and ligands 45
References 46
Chapter 2: First Messengers 50
Hormones 54
Growth factors 54
Cytokines 55
Vasoactive agents 55
Neurotransmitters and neuropeptides 56
First messengers with intracellular receptors 56
Common aspects 57
Intracellular messengers 58
Binding of ligands to receptors 58
Binding heterogeneity 59
Measurement of binding affinity 59
K[sub(D)] and EC[sub(50)]: receptor binding and functional consequences 60
Spare receptors 61
Down-regulation of receptors 62
Discovery of the first second messenger, cAMP 63
References 64
Chapter 3: Receptors 66
Adrenaline (again) 66
α- and β-adrenergic receptors 67
Adrenergic receptor agonists and antagonists 67
Acetylcholine receptors 71
Acetylcholine 71
Cholinergic receptor subtypes 73
Nicotinic receptors 73
Muscarinic receptors 74
Nicotinic receptors are ion channels 75
Architecture of the nicotinic receptor 79
Other ligand-gated ion channels 83
The 7TM superfamily of G-protein-linked receptors 84
Categories of 7TM receptor 87
Receptor diversity: variation and specialization 88
Binding of low-molecular-mass ligands 90
Calcium sensors and metabotropic receptors 92
Proteinase-activated receptors (PARs) 94
The adhesion receptor subfamily 94
Frizzled 95
Receptor\u2013ligand interaction and receptor activation 95
A two-state equilibrium description of receptor activation 95
Receptor dimerization 98
Transmitting signals into cells 99
The receptor and the effector: one and the same or separate entities? 99
Mixing and matching receptors and effectors 100
Intracellular 7TM receptor domains and signal transmission 102
Adrenaline (yet again) 102
References 102
Chapter 4: GTP-binding Proteins and Signal Transduction 110
Nucleotides as metabolic regulators 110
ATP is not quite what it seems 111
GTP-binding proteins, G proteins, or GTPases 112
G proteins 112
The GTPase cycle: a monostable switch 113
Switching off activity: switching on GTPase 115
α-Subunits 117
α-Subunits determine G protein diversity 118
Sites on α-subunits that interact with the membrane and with other proteins 121
βγ-Subunits 123
β- and γ-subtypes 123
βγ-Subunits as signalling proteins 126
The G protein receptor kinase family 127
Receptor phosphorylation, down-regulation and pathway switching 127
Receptor mechanisms obviating G proteins 129
Monomeric GTP-binding proteins 130
Ras proteins discovered as oncogene products 130
Subfamilies of Ras 130
Structure 131
Post-translational modifications 134
GTPases everywhere! 135
Mutations of Ras that promote cancer 135
Functions of Ras 136
RasGAPs 137
RasGAP 137
Mechanism of GTPase activation 139
Guanine nucleotide exchange factors (GEFs) 140
Essay: Activation of G proteins without subunit unit dissociation 140
Pheromone-induced mating response in yeast 142
Monitoring subunit interactions in living cells by FRET 143
Constructing the mammalian β-adrenergic transduction system in insect cells 146
References 149
Chapter 5: Effector Enzymes Coupled to GTP Binding Proteins: Adenylyl Cyclase and Phospholipase C 160
Adenylyl cyclase 160
Cyclic AMP: the first second messenger 160
cAMP is formed from ATP 162
Adenylyl cyclase and its regulation 163
Structural organization of adenylyl cyclases 163
Regulation of adenylyl cyclase 165
ADP-ribosylation of βγ-subunits 175
Phospholipase C 176
First hints of a signalling role for inositol phospholipids 176
The phospholipase family 176
The isoenzymes of PLC 177
PLCδ: a prototype 179
Regulation of PLC 180
References 182
Chapter 6: The Regulation of Visual Transduction and Olfaction 188
Phototransduction 188
Sensitivity of photoreceptors 189
Photoreceptor mechanisms 190
Photoreceptor cells 192
Adaptation: calcium acts as a negative regulator 196
Photo-excitation of rhodopsin 199
Switching off the mechanism 200
Retinal, an inverse agonist? 201
Note on phototransduction in invertebrates 203
Olfaction 205
Olfactory receptor cells 206
Olfactory receptors 207
Transduction of olfactory signals 208
References 210
Chapter 7: Intracellular Calcium 214
A new second messenger is discovered 214
Calcium and evolution 216
Distinguishing Ca[sup(2+)] and Mg[sup(2+)] 217
Free, bound, and trapped Ca[sup(2+)] 218
Cytosol Ca[sup(2+)] is kept low 219
Extracellular calcium and activation 220
Using Ca[sup(2+)] ionophores to impose a rise in Ca[sup(2+)] 220
Sensing changes in intracellular Ca[sup(2+)] concentration 220
Ca[sup(2+)]-sensitive photoproteins 221
Fluorescent Ca[sup(2+)] indicators 221
Monitoring cytosol Ca[sup(2+)] in individual cells 223
Detecting and imaging subcellular Ca[sup(2+)] changes 224
Mechanisms that elevate cytosol Ca[sup(2+)] concentration 227
Ca[sup(2+)] release from intracellular stores, IP[sub(3)] and ryanodine receptors 229
Elevation of Ca[sup(2+)] by cyclic ADP-ribose and NAADP 233
Elevation of Ca[sup(2+)] by sphingosine-1-phosphate 235
Ca[sup(2+)] influx through plasma membrane channels 237
Replenishing depleted stores 238
Ca[sup(2+)] microdomains and global cellular signals 243
Ca[sup(2+)] signals in electrically excitable cells 243
Calcium signals in non-excitable cells 245
References 245
Chapter 8: Calcium Effectors 250
Calcium-binding by proteins 250
Polypeptide modules that bind Ca[sup(2+)] 253
Decoding Ca[sup(2+)] signals 253
Calmodulin and troponin C 254
Kinases regulated by calmodulin 255
Other Ca[sup(2+)]-calmodulin dependent enzymes 258
Calcium-dependent enzymes that are not regulated by calmodulin 262
Paradigms of calcium signalling 265
Triggering neurotransmitter secretion 265
Initiation of contraction in skeletal muscle 266
Smooth muscle contraction 268
References 268
Chapter 9: Phosphorylation and Dephosphorylation: Protein kinases A and C 272
Protein phosphorylation as a switch in cellular functioning 272
Cyclic AMP and the amplification of signals 274
Protein kinase A 275
Protein kinase A and the regulation of transcription 277
Activation of the CREB transcription factor 277
Attenuation of the cAMP response elements by dephosphorylation 279
Protein kinase A and the activation of ERK 279
Actions of cAMP not mediated by PKA 280
Epac, a guanine nucleotide exchange factor directly activated by cAMP 280
Protein kinase C 282
Discovery of phosphorylating activity independent cAMP 282
The protein kinase C family 283
Structural domains and activation of protein kinase C 284
The C1\u2013C4 regions 284
Activation of protein kinase C 288
Multiple sources of diacylglycerol and other lipids activate protein kinase C 288
Differential localization of PKC isoforms 289
Different types of PKC-binding proteins 290
Holding back the PKC response 292
A matter of life or death: PKC signalling complexes in the evasion of the fly-swat 293
Phorbol ester and inflammation 294
References 295
Chapter 10: Nuclear Receptors 302
First steps in the isolation of steroid hormones 302
Origins 302
Beginning again 303
The discovery of intracellular hormone receptors 303
Evidence for intracellular receptors 305
A superfamily of nuclear receptors 306
Orphan receptors and evolution 307
Nomenclature of nuclear receptors 310
Receptor structure and ligand binding 310
Ligand-binding domains are molecular switches 310
Activation of cytosol-resident receptors 311
DNA binding 313
Recognizing response elements 314
Activation and repression of transcription 316
Coactivators 316
Corepressors 317
Transrepression 318
Regulatory networks 318
Interaction with other signalling pathways 319
Phosphorylation 319
Phosphorylation may up- or down-regulate transcription 320
Ligand-independent activation 320
Non-transcriptional actions of nuclear receptors and their ligands 321
References 322
Chapter 11: Growth Factors: Setting the Framework 326
Viruses and tumours 327
The discovery of NGF \u2026 and EGF 328
Platelet-derived growth factor (PDGF) 332
Transforming growth factors (TGFα and TGFβ) 333
Problems with nomenclature 334
Essay: Cancer and transformation 335
Definitions 335
The essence of cancer 336
Alterations dictating malignancy 336
Genetic alterations at the basis of malignancy 337
Constructing cancer in a dish 338
References 340
Chapter 12: Signalling Pathways Operated by Receptor Protein Tyrosine Kinases 344
Introduction 344
Spotting phosphotyrosine 345
v-Src and other protein tyrosine kinases 346
Processes mediated through tyrosine phosphorylation 346
Tyrosine kinase-containing receptors 347
The ErbB receptor family and their ligands 347
Cross-linking of receptors causes activation 347
Assembly of receptor signalling complexes 352
Protein domains that bind phosphotyrosines and the assembly of signalling complexes 353
Branching of the signalling pathway 354
The PLCγ\u2013PKC signal transduction pathway 355
The Ras signalling pathway 356
From Ras to MAP kinase and the activation of transcription 363
Raf genes 364
Beyond ERK 366
Docking sites and a MAP kinase phosphorylation motif 366
Activation of protein kinases by ERKs 1 and 2 366
Activation of early response genes 371
Regulation of the cell cycle 372
Fine tuning the Ras-MAP kinase pathway: scaffold proteins 373
MAP kinase scaffold proteins discovered in yeast 373
KSR, a mammalian scaffold protein that regulates MAP kinase signalling 374
Other proteins that regulate MAP kinase pathways 377
Why are the signalling pathways so complicated? 377
Termination of the ERK response 378
The Ca[sup(2+)]\u2013calmodulin pathway 382
Activation of PI3-kinase 382
Direct phosphorylation of STAT transcription factors 382
A switch in receptor signalling: activation of ERK by 7TM receptors 383
Pathway switching mediated by receptor phosphorylation 383
Pathway switching by transactivation 385
Pathway switching, transactivation, and metastatic progression of colorectal cancer 386
References 391
Chapter 13: Signal Transduction to and from Adhesion Molecules 404
Adhesion molecules 405
Naming names 407
Immunoglobulin superfamily 407
ICAM 408
SIGLEC 409
Junctional adhesion molecules (JAMs) 411
Claudins 411
Occludin 412
Integrins 412
Inactive to primed 413
Primed to active 416
Cadherins 416
Selectins 421
Cartilage link proteins 424
Integrins, cell survival, and cell proliferation 426
Inside-out signalling and the formation of integrin adhesion complexes 426
Outside-in signalling from integrin adhesion complexes 427
Integrins and cell survival 429
Integrins and cell proliferation 432
References 438
Chapter 14: Adhesion Molecules in the Regulation of Cell Differentiation: Mainly About Wnt 446
Destabilization of adherens junctions causes cellular de-differentiation 446
Signalling through the canonical WNT pathway 448
Adenomatous polyposis coli (APC) and the localization of β-catenin 453
Take your partner: which way β-catenin? 455
The (β-catenin-dependent) canonical Wnt pathway 455
Wnt organizes the villous epithelium of the small intestine 463
Mutations of β-catenin, Axin, and APC in human cancers 466
Non-canonical signal transduction pathways 467
A role for cadherin in contact inhibition 467
Other examples of signalling through adhesion molecules 468
Cadherin in the central nervous system 468
JAM and the regulation of differentiation 468
Occludin interacts with the TGFβ type I receptor 468
Occludin prevents Raf-1-mediated cell transformation 469
References 471
Chapter 15: Activation of the Innate Immune System: the Toll-like Receptor 4 and Signalling through Ubiquitylation 480
Sensing the microbial universe 481
The toll receptor in Drosophila 482
Signalling through the TLR4 receptor 487
The TIRAP/MyD88 pathway 489
From TRAF6 to activation of NF-κB 489
From TRAF6 to activation of IRF-3 493
The IRF family of transcription factors 493
Some consequences of TLR4-induced gene transcription 495
Essay: Ubiquitylation and SUMOylation 496
Ubiquitylation 496
Ubiquitylation: a process involving three activities (but not necessarily three proteins) 496
63K or 48K conjugation 497
Two classes of E3-ubiquitin ligases 498
Ubiquitin-binding proteins 499
SUMO and sumoylation 499
Essay: The proteasome complex 500
The proteasome 501
20S particle 501
Proteasome activator (PA) subunits 503
References 506
Chapter 16: Traffic of White Blood Cells 512
Inflammation and leukocytes 512
Inflammatory mediators 512
Tumour necrosis factor-α, potential anti-tumour agent or inflammatory cytokine? 515
The family of TNF proteins and receptors 518
TNF-α and regulation of adhesion molecule expression in endothelial cells 518
Signalling via NF-κB 522
Chemokines and activation of integrins on leukocytes 523
The three-step process of leukocyte adhesion to endothelial cells 530
References 534
Chapter 17: Tyrosine Protein Kinases and Adaptive Immunity: TCR, BCR, Soluble Tyrosine Kinases and NFAT 542
The family of non-receptor protein tyrosine kinases 542
T-cell receptor signalling 544
More than one lymphocyte receptor must be engaged to ensure activation 544
PLCγ1 to NFAT 548
The PLCγ1 to NF-κB pathway 550
Down-regulation of the TCR response 550
Signalling through interferon receptors 552
Interferon-α receptor and STAT proteins 554
Alternative signalling pathways 555
Down-regulation of the JAK-STAT pathway 556
Oncogenes, malignancy, and signal transduction 559
Viral oncogenes 559
Non-viral oncogenes 560
Essay: Non-receptor protein tyrosine kinases and their regulation 561
References 567
Chapter 18: Phosphoinositide 3-Kinases, Protein Kinase B, and Signalling through the Insulin Receptor 572
Insulin receptor signalling; it took a little time to work out the details 572
Signalling through phosphoinositides 574
PI 3-kinase, PI(3,4)P[sub(2)] and PI(3,4,5)P[sub(3)] 575
A family of PI 3-kinases 576
Studying the role of PI 3-kinase 578
Protein kinase B and activation through PI(3,4,5)P[sub(2)] 579
Insulin: the role of IRS, PI 3-kinase, and PKB in the regulation of glycogen synthesis 583
From the insulin receptor to PKB 583
From PKB to glycogen synthase 586
The role of PI 3-kinase in activation of protein synthesis 588
Other processes mediated by the 3-phosphorylated inositol phospholipids 595
So, who did discover insulin? 596
References 598
Chapter 19: Protein Kinase C Revisited 606
PKC in cell transformation 606
The search for transcription factors that mediate phorbol ester effects 607
Regulation of cell polarity 614
Role of atypical PKC 614
References 623
Chapter 20: Signalling Through Receptor Serine/Threonine Kinases 628
The TGFβ family of growth factors 628
TGFβ receptors, type I and type II 629
TGFβ-mediated receptor activation 632
Accessory and pseudo receptors: betaglycan, endoglin, cripto, and BAMBI 634
Downstream signalling: Drosophila, Caenorhabitidis, and Smad 636
Smad proteins have multiple roles in signal transduction 637
Hetero-oligomeric complex formation 640
Nuclear import and export 641
Holding the TGFβ pathway in check 649
TGFβ: tumour suppressor and metastatic promoter? 652
References 661
Chapter 21: Protein Dephosphorylation and Protein Phosphorylation 670
Protein tyrosine phosphatases 671
Cytosolic PTPs 673
Transmembrane receptor-like PTPs 674
Tyrosine specificity and catalytic mechanism 674
PTPs in signal transduction 675
PTP1B, diabetes, and obesity 676
Redox regulation of PTP1B: reactive oxygen species as second messengers 679
SHP-1 and SHP-2 682
CD45 and the regulation of immune cell function 687
Regulating receptor PTPs 689
Dual specificity phosphatases 690
Regulation of MAP kinases by dual-specificity protein phosphatases (DS-MKP) 691
Physiological role of the dual-specificity MAP kinase phosphatases 694
PTEN, a dual-specificity phosphatase for phosphatidyl inositol lipids 697
Serine/threonine phosphatases 700
Classification of the serine/threonine phosphatases 701
Regulation of PPPs 704
PP1 in the regulation of glycogen metabolism 708
PP2B (calcineurin) 711
Dephosphorylation of NFAT: immunophilins show the way 712
References 718
Chapter 22: Notch 728
Notched wings, Morgan, and the gene theory 728
One gene, many alleles 731
Membrane components of the Notch pathway 732
Notch ligands (DSL proteins) 732
Notch receptors 732
Glycosylation of ligands and receptor 735
Activation of Notch 736
Both receptor and ligand trafficking are essential for Notch signalling 741
Notch and sensory progenitor cells of Drosophila; the importance of endocytosis 745
Development of mechanoreceptors on thorax and wing 746
Notch and the development of the bristle-containing sensory organ 749
Notch in the maintenance of an intestinal stem cell compartment 751
Cross-talk with other signal transduction pathways 751
References 759
Chapter 23: Targeting Transduction Pathways for Research and Medical Intervention 764
Chemotherapy 765
Cytotoxic antibiotics and antimetabolites 766
The purine pathway to chemotherapy 768
Good drugs and bad 768
Combination chemotherapy 769
Alternative targets for cancer therapy: towards a scientific rationale 771
Inhibiting the EGF family of receptor kinases 772
The antibody approach: trastuzumab 772
The tyrosine kinase inhibitor approach 774
Other signal transduction components targeted for therapeutic intervention 783
Towards a different approach in testing cancer drugs? 783
References 787
Chapter 24: Protein Domains and Signal Transduction 792
Modular structure of proteins 792
Structural domains 792
The evolution and shuffling of domains 793
Sequence homology and the acquisition of function 794
Domain function 795
The inventory of domains 796
Detection 796
Classification 796
Examples of domains with roles in signalling 797
Domains that bind oligopeptide motifs 797
Phosphoinositide-binding domains 803
Polypeptide modules that bind Ca[sup(2+)] 808
Zinc finger domains 810
Protein kinase domains 811
References 816
Index 820
A 820
B 821
C 822
D 824
E 825
F 826
G 826
H 827
I 828
J 829
K 829
L 829
M 830
N 830
O 832
P 832
Q 834
R 835
S 836
T 837
U 838
V 838
W 839
X 839
Y 839
Z 839