Kallikrein-Related Peptidases, Volume 1: Characterization, Regulation, and Interactions Within the Protease Web

Kallikrein-related peptidases, Volume 1: Characterization, regulation, and interactions within the protease web......Page 4
Preface......Page 6
List of contributing authors......Page 8
Table of Contents......Page 12
Introduction to Volume 1: Kallikrein-related Peptidases. Characterization, Regulation, and Interactions Within the Protease Web......Page 20
Bibliography......Page 22
1.1 Introduction......Page 24
1.2 Kallikreins in rodents......Page 25
1.2.1 The mouse kallikrein gene family......Page 26
1.2.2 The rat kallikrein gene family......Page 27
1.3.1 Locus overview......Page 28
1.3.2 Repeat elements and pleomorphism......Page 30
1.4.1 Common structural features......Page 31
1.5 Sequence variations of human KLK genes......Page 32
1.6.1 At the mRNA level......Page 33
1.6.2 Locus control of KLK expression......Page 34
1.6.3 Epigenetic regulation of KLK gene expression......Page 36
1.7 Isoforms and splice variants of human KLKs......Page 37
1.8 Evolution of KLKs......Page 40
Bibliography......Page 41
2.1 Introduction......Page 50
2.2 KLK SNPs – data-mining from SNPdb and 1000 Genomes......Page 51
2.3 Functional annotations using web-based prediction tools......Page 53
2.4 Experimentally validated functional KLK SNPs......Page 54
2.5 KLK SNP haplotypes and tagging......Page 55
2.6 Malignant and non-malignant diseases and association with KLK SNPs......Page 57
Risk-associated KLK SNPs using candidate gene association studies......Page 58
Risk associated KLK SNPs using genome-wide association studies......Page 69
Fine-mapping studies on GWAS identified KLK SNPs......Page 88
Imputation – a new additional tool for fine-mapping studies......Page 89
Bibliography......Page 90
3.1 Introduction......Page 98
3.3 Evolutionary trends at the KLK locus......Page 99
3.4.1 KLK2 and KLK3 originate from a duplicated segment containing both KLK1 and KLK15......Page 101
3.4.2 A large number of KLK1 tandem repeats in the house mouse......Page 104
3.4.3 The rat KLK1 sublocus consists of 10 large repeats......Page 106
3.4.4 Four duplications of KLK1 and KLK15 in the dog......Page 107
3.4.5 A large repeat containing KLK4 in the horse......Page 109
3.5 KLK genes in non-mammalian species......Page 111
3.6 General conclusions and remarks on the evolution of KLK genes......Page 112
Bibliography......Page 113
4.1 Introduction......Page 116
4.2.1 Tissue kallikrein (KLK1)......Page 117
4.2.2 Prostate specific antigen (PSA/KLK3)......Page 119
4.2.3 Prostase (KLK4)......Page 120
4.2.4 Stratum corneum tryptic enzyme (SCTE/KLK5)......Page 123
4.2.5 Myelencephalon-specific protease or neurosin (MSP/KLK6)......Page 125
4.2.6 Stratum corneum chymotryptic enzyme (SCCE/KLK7)......Page 127
4.2.7 Neuropsin (KLK8)......Page 129
4.2.8 Other mammalian KLK structures......Page 130
Bibliography......Page 131
5.1 Introduction......Page 136
5.2.1 The classical kallikreins (KLK1, KLK2, KLK3)......Page 140
5.2.2 KLK4/KLK5/KLK7......Page 144
5.2.3 KLK6/KLK13/KLK14......Page 146
5.2.4 KLK8/KLK10/KLK12......Page 148
5.2.5 KLK9/KLK11/KLK15......Page 149
Bibliography......Page 151
6.3 The KLK superfamily: Structure and catalytic mechanism......Page 160
6.4 KLK inhibition: Rationale and mechanisms......Page 162
6.5.1 Kunitz domain inhibitors......Page 163
6.5.2 Kazal domain inhibitors......Page 165
6.5.4 Serpins......Page 166
6.6 Naturally occurring small molecule kallikrein inhibitors......Page 167
6.7 Engineered KLK Inhibitors......Page 168
6.7.3 Serpins......Page 169
6.7.4 Ecotin......Page 170
6.7.5 Sunflower Trypsin Inhibitor (SFTI)......Page 171
6.7.6 Warhead inhibitors......Page 172
Bibliography......Page 173
7.1 Introduction......Page 180
7.2 KLK disease markers as potential therapeutic targets......Page 181
7.3.1 Prostate cancer......Page 184
7.3.2 Ovarian and pancreatic cancer......Page 186
7.4.1 Kallikrein expressions and activities in skin......Page 188
7.4.2 Netherton Syndrome as most relevant clinical model......Page 189
7.4.3 Atopic dermatitis, the potential major indication for kallikrein targeting......Page 190
7.4.5 Other potential skin disorders with kallikrein involvement......Page 191
7.5.2 Multiple sclerosis (MS)......Page 192
7.6.1 Design of KLK inhibitors and clinical development......Page 193
7.6.2 KLK inhibitors in oncology......Page 195
7.6.3 KLK inhibitors in dermatology......Page 198
7.7 Conclusions and Outlook......Page 199
Bibliography......Page 200
8.1 Introduction......Page 206
8.2.1 KLKs in the central and peripheral nervous system......Page 207
8.2.2 KLKs in the female reproductive system......Page 211
8.2.3 KLKs in the male reproductive system......Page 215
8.2.4 Cellular distribution of KLKs in the gastrointestinal system......Page 217
8.2.5 KLKs in the skin and skin appendages......Page 222
8.2.8 KLKs in lymphatic and endocrine organs (adrenal glands, thyroid gland, parathyroid glands, pituitary gland)......Page 226
8.2.10 KLKs in the skeletomuscular system......Page 230
8.3.1 Non-malignant diseases of the CNS......Page 231
8.3.2 Inflammatory-related conditions......Page 234
8.4 Expression of KLKs in cancer tissues......Page 236
8.4.2 Cancers of the female reproductive system......Page 241
8.4.3 Cancers of the male reproductive system......Page 242
8.4.4 Cancers of the gastrointestinal system......Page 243
8.4.5 Cancers of the skin......Page 244
8.4.7 Cancers of the urinary system......Page 245
Abbreviations......Page 246
Bibliography......Page 247
9.1 Introduction......Page 270
Activation mechanism of the KLK precursors......Page 271
Methodologies applied to (pro-)KLKs production and activation assays......Page 272
KLK-induced activation of KLK precursors......Page 273
Proteases of the plasmin(ogen) system......Page 275
Matrix metalloproteinases......Page 276
Meprins......Page 277
Aminopeptidases......Page 278
9.3.1 Proteolytic inactivation of (non-)KLK proteases......Page 279
9.3.2 Processing of the uPA receptor......Page 280
9.3.3 Disarming of the proteinase-activated receptors......Page 281
9.4 Conclusion......Page 282
Bibliography......Page 283
10.1 Discovery of classical (true) tissue kallikrein and kinins......Page 290
10.2 Cellular localization......Page 291
10.3 Genomics and molecular structure......Page 292
10.4 Inhibitors of hK1......Page 295
10.6 Epigenetic regulation......Page 296
10.7.1 Receptor subtypes......Page 297
10.7.2 Kinin receptor signaling......Page 298
10.7.3 Regulation of kinin receptor signaling......Page 299
10.8.1 Hypertension and renal damage......Page 300
10.8.3 Inflammation and neutrophil function......Page 302
10.8.5 Angiogenesis......Page 305
10.9 Conclusion......Page 306
Abbreviations......Page 307
Bibliography......Page 308
11.2 Early studies implicated proteases in dental enamel formation......Page 314
11.3 Investigations of enamel proteases discovered KLK4......Page 315
11.5 Klk4lacZ/lacZ mice......Page 316
11.6 Other enamel specific genes......Page 321
11.7 Role of KLK4 in enamel formation......Page 323
Bibliography......Page 326
12.1 Introduction......Page 330
12.3.1 Seminal coagulation and fibrinolytic balance......Page 331
12.3.2 Sperm motility......Page 333
12.3.3 Reproductive immune interactions......Page 335
12.4 Proteolytic pathways of seminal KLKs......Page 337
12.4.2 Role of seminal KLK inhibitors......Page 338
12.4.3 Other inhibitory mechanisms of seminal KLKs......Page 339
12.4.4 Seminal proteolytic activation cascade......Page 340
12.5 Conclusions and outlook......Page 341
Bibliography......Page 342
13.1 Introduction......Page 348
13.2 KLKs in the epidermis......Page 350
13.3 Desquamation......Page 351
13.4.1 KLK activation......Page 352
13.4.2 KLK inhibitors......Page 353
13.5 Skin disorders......Page 356
13.6 Conclusions and outlook......Page 359
Bibliography......Page 360
14.2.1 KLK expression in the CNS......Page 368
14.2.2 Physiological roles of KLKs in the CNS......Page 372
Functional roles of KLKs in the modification of the CNS extracellular matrix......Page 375
Functional roles of KLKs in receptor activation......Page 377
KLKs in stroke......Page 378
KLKs in CNS trauma......Page 379
KLKs in neurodegenerative disorders......Page 380
KLKs in neuroinflammatory disorders......Page 381
14.3 Conclusions and outlook......Page 382
Bibliography......Page 383
15.1 Proteinases: shock troops of the innate immune response......Page 392
15.2 Multiple mechanisms for proteinase-mediated signaling......Page 393
15.3 Proteinases and PAR-mediated signaling......Page 395
15.4 Linking PARs to the KLKs: the prostate connection......Page 397
15.6 KLKs, other serine proteinases, PARs and inflammation......Page 398
15.7 KLKs, PARs and inflammation of the central nervous system and the skin......Page 399
15.8 KLKs, PARs and cancer......Page 401
15.9 KLKs and PARs: Therapeutic targets for inflammatory diseases, cancer and other disorders......Page 402
15.10 Blocking proteinase-mediated PAR activation: PAR-targeted blocking antibodies versus proteinase inhibitors......Page 406
Acknowledgements......Page 408
Bibliography......Page 409
Index......Page 418