Characterization, regulation, and interactions within the protease web (eBook)

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Viktor Magdolen, Technical UniversityMunich; Christian Sommerhoff and Hans Fritz, Ludwig Maximilian University, Munich; Manfred Schmitt, Technical UniversityMunich, Germany.

Preface 5
List of contributing authors 7
Table of Contents 11
Introduction to Volume 1: Kallikrein-related Peptidases. Characterization, Regulation, and Interactions Within the Protease Web 19
Bibliography 21
1 Genomic Structure of the KLK Locus 23
1.1 Introduction 23
1.2 Kallikreins in rodents 24
1.2.1 The mouse kallikrein gene family 25
1.2.2 The rat kallikrein gene family 26
1.3 Characterization and sequence analysis of the human KLK gene locus 27
1.3.1 Locus overview 27
1.3.2 Repeat elements and pleomorphism 29
1.4 Structural features of the human KLK genes and proteins 30
1.4.1 Common structural features 30
1.5 Sequence variations of human KLK genes 31
1.6 Regulation of KLK activity 32
1.6.1 At the mRNA level 32
1.6.2 Locus control of KLK expression 33
1.6.3 Epigenetic regulation of KLK gene expression 35
1.7 Isoforms and splice variants of human KLKs 36
1.8 Evolution of KLKs 39
Bibliography 40
2 Single Nucleotide Polymorphisms in the Human KLK Locus and Their Implication in Various Diseases 49
2.1 Introduction 49
2.2 KLKSNPs - data-mining from SNPdb and 1000 Genomes 50
2.3 Functional annotations using web-based prediction tools 52
2.4 Experimentally validated functional KLK SNPs 53
2.5 KLKSNP haplotypes and tagging 54
2.6 Malignant and non-malignant diseases and association with KLK SNPs 56
2.6.1 Association studies on high-risk variants in KLK genes 57
2.6.2 Association studies on low-risk variants in KLK genes 57
2.7 Conclusions 89
Bibliography 89
3 Evolution of Kallikrein-related Peptidases 97
3.1 Introduction 97
3.2 Basic elements of phylogenetic analysis 98
3.3 Evolutionary trends at the KLK locus 98
3.4 Evolution of the KLK1-KLK4 sublocus 100
3.4.1 KLK2 and KLK3 originate from a duplicated segment containing both KLK1 and KLK15 100
3.4.2 A large number of KLK1 tandem repeats in the house mouse 103
3.4.3 The rat KLK1 sublocus consists of 10 large repeats 105
3.4.4 Four duplications of KLK1 and KLK15 in the dog 106
3.4.5 A large repeat containing KLK4 in the horse 108
3.5 KLK genes in non-mammalian species 110
3.6 General conclusions and remarks on the evolution of KLK genes 111
Bibliography 112
4 Structural Aspects of Kallikrein-related Peptidases 115
4.1 Introduction 115
4.2 Individual KLK structures 116
4.2.1 Tissue kallikrein (KLK1) 116
4.2.2 Prostate specific antigen (PSA/KLK3) 118
4.2.3 Prostase (KLK4) 119
4.2.4 Stratum corneum tryptic enzyme (SCTE/KLK5) 122
4.2.5 Myelencephalon-specific protease or neurosin (MSP/KLK6) 124
4.2.6 Stratum corneum chymotryptic enzyme (SCCE/KLK7) 126
4.2.7 Neuropsin (KLK8) 128
4.2.8 Other mammalian KLK structures 129
Bibliography 130
5 Molecular Recognition Properties of Kallikrein-related Peptidases on Synthetic and Endogenous Substrates 135
5.1 Introduction 135
5.2 Substrate specificities of individual kallikrein-related peptidases 139
5.2.1 The classical kallikreins (KLK1, KLK2, KLK3) 139
5.2.2 KLK4/KLK5/KLK7 143
5.2.3 KLK6/KLK13/KLK14 145
5.2.4 KLK8/KLK10/KLK12 147
5.2.5 KLK9/KLK11/KLK15 148
Bibliography 150
6 Natural, Engineered and Synthetic Inhibitors of Kallikrein-related Peptidases 159
6.1 Introduction 159
6.2 KLK diversity 159
6.3 The KLK superfamily: Structure and catalytic mechanism 159
6.4 KLK inhibition: Rationale and mechanisms 161
6.5 Proteinaceous inhibitors 162
6.5.1 Kunitz domain inhibitors 162
6.5.2 Kazal domain inhibitors 164
6.5.3 Other canonical inhibitors 165
6.5.4 Serpins 165
6.6 Naturally occurring small molecule kallikrein inhibitors 166
6.7 Engineered KLK Inhibitors 167
6.7.1 Approaches to inhibitor design 168
6.7.2 Pharmacological challenges for therapeutic inhibitors 168
6.7.3 Serpins 168
6.7.4 Ecotin 169
6.7.5 Sunflower Trypsin Inhibitor (SFTI) 170
6.7.6 Warhead inhibitors 171
6.8 Conclusions and outlook 172
Acknowledgements 172
Bibliography 172
7 Kallikrein-related Peptidases as Pharmaceutical Targets 179
7.1 Introduction 179
7.2 KLK disease markers as potential therapeutic targets 180
7.3 KLKs in oncology 183
7.3.1 Prostate cancer 183
7.3.2 Ovarian and pancreatic cancer 185
7.4 KLKs in inflammatory skin diseases 187
7.4.1 Kallikrein expressions and activities in skin 187
7.4.2 Netherton Syndrome as most relevant clinical model 188
7.4.3 Atopic dermatitis, the potential major indication for kallikrein targeting 189
7.4.4 Psoriasis and relevance of kallikreins 190
7.4.5 Other potential skin disorders with kallikrein involvement 190
7.5 KLKs in neurological disorders 191
7.5.1 Alzheimer’s disease and dementia 191
7.5.2 Multiple sclerosis (MS) 191
7.6 Kallikrein inhibitors to treat human diseases 192
7.6.1 Design of KLK inhibitors and clinical development 192
7.6.2 KLK inhibitors in oncology 194
7.6.3 KLK inhibitors in dermatology 197
7.7 Conclusions and Outlook 198
Bibliography 199
8 Expression of Kallikrein-related Peptidases under (Patho-)Physiological Conditions 205
8.1 Introduction 205
8.2 KLK expression in tissues and biological fluids under physiological conditions 206
8.2.1 KLKs in the central and peripheral nervous system 206
8.2.2 KLKs in the female reproductive system 210
8.2.3 KLKs in the male reproductive system 214
8.2.4 Cellular distribution of KLKs in the gastrointestinal system 216
8.2.5 KLKs in the skin and skin appendages 221
8.2.6 KLKs in the respiratory system 225
8.2.7 KLKs in the urinary system 225
8.2.8 KLKs in lymphatic and endocrine organs (adrenal glands, thyroid gland, parathyroid glands, pituitary gland) 225
8.2.9 KLKs in the cardiovascular system 229
8.2.10 KLKs in the skeletomuscular system 229
8.3 Expression of KLKs in non-malignant diseases 230
8.3.1 Non-malignant diseases of the CNS 230
8.3.2 Inflammatory-related conditions 233
8.4 Expression of KLKs in cancer tissues 235
8.4.1 Cancers of the brain 240
8.4.2 Cancers of the female reproductive system 240
8.4.3 Cancers of the male reproductive system 241
8.4.4 Cancers of the gastrointestinal system 242
8.4.5 Cancers of the skin 243
8.4.6 Lung cancer 244
8.4.7 Cancers of the urinary system 244
8.5 Conclusion 245
Abbreviations 245
Bibliography 246
9 Kallikrein-related Peptidases within the Proteolytic Web 269
9.1 Introduction 269
9.2 KLKs as actors and targets during the initiation and amplification of extracellular proteolytic activity 270
9.2.1 The KLK-dependent KLK activome 270
9.2.2 Cross- and reciprocal activation of KLK and non-KLK proteases 274
9.2.3 Inactivation of protease inhibitors 278
9.3 KLKs in the termination of proteolytic activity 278
9.3.1 Proteolytic inactivation of (non-)KLK proteases 278
9.3.2 Processing of the uPA receptor 279
9.3.3 Disarming of the proteinase-activated receptors 280
9.4 Conclusion 281
Bibliography 282
10 Kallikrein-Kinin Cascade: Bioregulation by Human Tissue Kallikrein 1 (hK1, KLK1) 289
10.1 Discovery of classical (true) tissue kallikrein and kinins 289
10.2 Cellular localization 290
10.3 Genomics and molecular structure 291
10.4 Inhibitors of hK1 294
10.5 Modulation of membrane receptors 295
10.6 Epigenetic regulation 295
10.7 Kinin receptors and signaling 296
10.7.1 Receptor subtypes 296
10.7.2 Kinin receptor signaling 297
10.7.3 Regulation of kinin receptor signaling 298
10.8 Human disease 299
10.8.1 Hypertension and renal damage 299
10.8.2 Cardiac protection 301
10.8.3 Inflammation and neutrophil function 301
10.8.4 Cancer 304
10.8.5 Angiogenesis 304
10.9 Conclusion 305
Abbreviations 306
Bibliography 307
11 Role of KLK4 in Dental Enamel Formation 313
11.1 Introduction 313
11.2 Early studies implicated proteases in dental enamel formation 313
11.3 Investigations of enamel proteases discovered KLK4 314
11.4 KLK4 and amelogenesis imperfecta 315
11.5 Klk4 lacZ/lacZ mice 315
11.6 Other enamel specific genes 320
11.7 Role of KLK4 in enamel formation 322
11.8 Conclusion 325
Bibliography 325
12 Kallikrein-related Peptidases and Semen 329
12.1 Introduction 329
12.2 Expression pattern and origin of seminal KLKs 330
12.3 Physiological function of seminal KLKs 330
12.3.1 Seminal coagulation and fibrinolytic balance 330
12.3.2 Sperm motility 332
12.3.3 Reproductive immune interactions 334
12.4 Proteolytic pathways of seminal KLKs 336
12.4.1 Role of seminal zinc 337
12.4.2 Role of seminal KLK inhibitors 337
12.4.3 Other inhibitory mechanisms of seminal KLKs 338
12.4.4 Seminal proteolytic activation cascade 339
12.5 Conclusions and outlook 340
Abbreviations 341
Bibliography 341
13 Kallikrein-related Peptidases and Inhibitors of the Skin 347
13.1 Introduction 347
13.2 KLKs in the epidermis 349
13.3 Desquamation 350
13.4 Regulation of protease activity 351
13.4.1 KLK activation 351
13.4.2 KLK inhibitors 352
13.5 Skin disorders 355
13.6 Conclusions and outlook 358
Bibliography 359
14 Physiological and Pathophysiological Roles of Kallikrein-related Peptidases in the Central Nervous System 367
14.1 Introduction 367
14.2 KLK expression and roles in CNS physiology 367
14.2.1 KLK expression in the CNS 367
14.2.2 Physiological roles of KLKs in the CNS 371
14.2.3 Pathophysiological roles of KLKs in the CNS 377
14.3 Conclusions and outlook 381
Acknowledgements 382
Abbreviation 382
Bibliography 382
15 Kallikrein-related Peptidases (KLKs), Proteinase-mediated Signaling and Proteinase-activated receptors (PARs) 391
15.1 Proteinases: shocktroops ofthe innate immune response 391
15.2 Multiple mechanisms for proteinase-mediated signaling 392
15.3 Proteinases and PAR-mediated signaling 394
15.4 Linking PARs to the KLKs: the prostate connection 396
15.5 Proteolytic cascades, KLKs and the innate immune response 397
15.6 KLKs, other serine proteinases, PARs and inflammation 397
15.7 KLKs, PARs and inflammation of the central nervous system and the skin 398
15.8 KLKs, PARs and cancer 400
15.9 KLKs and PARs: Therapeutic targets for inflammatory diseases, cancer and other disorders 401
15.10 Blocking proteinase-mediated PAR activation: PAR-targeted blocking antibodies versus proteinase inhibitors 405
15.11 Summary and outlook for the future 407
Acknowledgements 407
Bibliography 408
Index 417