Characterization, regulation, and interactions within the protease web

1 - Preface [Seite 5]
2 - List of contributing authors [Seite 7]
3 - Table of Contents [Seite 11]
4 - Introduction to Volume 1: Kallikrein-related Peptidases. Characterization, Regulation, and Interactions Within the Protease Web [Seite 19]
4.1 - Bibliography [Seite 21]
5 - 1 Genomic Structure of the KLK Locus [Seite 23]
5.1 - 1.1 Introduction [Seite 23]
5.2 - 1.2 Kallikreins in rodents [Seite 24]
5.2.1 - 1.2.1 The mouse kallikrein gene family [Seite 25]
5.2.2 - 1.2.2 The rat kallikrein gene family [Seite 26]
5.3 - 1.3 Characterization and sequence analysis of the human KLK gene locus [Seite 27]
5.3.1 - 1.3.1 Locus overview [Seite 27]
5.3.2 - 1.3.2 Repeat elements and pleomorphism [Seite 29]
5.4 - 1.4 Structural features of the human KLK genes and proteins [Seite 30]
5.4.1 - 1.4.1 Common structural features [Seite 30]
5.5 - 1.5 Sequence variations of human KLK genes [Seite 31]
5.6 - 1.6 Regulation of KLK activity [Seite 32]
5.6.1 - 1.6.1 At the mRNA level [Seite 32]
5.6.2 - 1.6.2 Locus control of KLK expression [Seite 33]
5.6.3 - 1.6.3 Epigenetic regulation of KLK gene expression [Seite 35]
5.7 - 1.7 Isoforms and splice variants of human KLKs [Seite 36]
5.8 - 1.8 Evolution of KLKs [Seite 39]
5.9 - Bibliography [Seite 40]
6 - 2 Single Nucleotide Polymorphisms in the Human KLK Locus and Their Implication in Various Diseases [Seite 49]
6.1 - 2.1 Introduction [Seite 49]
6.2 - 2.2 KLKSNPs - data-mining from SNPdb and 1000 Genomes [Seite 50]
6.3 - 2.3 Functional annotations using web-based prediction tools [Seite 52]
6.4 - 2.4 Experimentally validated functional KLK SNPs [Seite 53]
6.5 - 2.5 KLKSNP haplotypes and tagging [Seite 54]
6.6 - 2.6 Malignant and non-malignant diseases and association with KLK SNPs [Seite 56]
6.6.1 - 2.6.1 Association studies on high-risk variants in KLK genes [Seite 57]
6.6.2 - 2.6.2 Association studies on low-risk variants in KLK genes [Seite 57]
6.7 - 2.7 Conclusions [Seite 89]
6.8 - Bibliography [Seite 89]
7 - 3 Evolution of Kallikrein-related Peptidases [Seite 97]
7.1 - 3.1 Introduction [Seite 97]
7.2 - 3.2 Basic elements of phylogenetic analysis [Seite 98]
7.3 - 3.3 Evolutionary trends at the KLK locus [Seite 98]
7.4 - 3.4 Evolution of the KLK1-KLK4 sublocus [Seite 100]
7.4.1 - 3.4.1 KLK2 and KLK3 originate from a duplicated segment containing both KLK1 and KLK15 [Seite 100]
7.4.2 - 3.4.2 A large number of KLK1 tandem repeats in the house mouse [Seite 103]
7.4.3 - 3.4.3 The rat KLK1 sublocus consists of 10 large repeats [Seite 105]
7.4.4 - 3.4.4 Four duplications of KLK1 and KLK15 in the dog [Seite 106]
7.4.5 - 3.4.5 A large repeat containing KLK4 in the horse [Seite 108]
7.5 - 3.5 KLK genes in non-mammalian species [Seite 110]
7.6 - 3.6 General conclusions and remarks on the evolution of KLK genes [Seite 111]
7.7 - Bibliography [Seite 112]
8 - 4 Structural Aspects of Kallikrein-related Peptidases [Seite 115]
8.1 - 4.1 Introduction [Seite 115]
8.2 - 4.2 Individual KLK structures [Seite 116]
8.2.1 - 4.2.1 Tissue kallikrein (KLK1) [Seite 116]
8.2.2 - 4.2.2 Prostate specific antigen (PSA/KLK3) [Seite 118]
8.2.3 - 4.2.3 Prostase (KLK4) [Seite 119]
8.2.4 - 4.2.4 Stratum corneum tryptic enzyme (SCTE/KLK5) [Seite 122]
8.2.5 - 4.2.5 Myelencephalon-specific protease or neurosin (MSP/KLK6) [Seite 124]
8.2.6 - 4.2.6 Stratum corneum chymotryptic enzyme (SCCE/KLK7) [Seite 126]
8.2.7 - 4.2.7 Neuropsin (KLK8) [Seite 128]
8.2.8 - 4.2.8 Other mammalian KLK structures [Seite 129]
8.3 - Bibliography [Seite 130]
9 - 5 Molecular Recognition Properties of Kallikrein-related Peptidases on Synthetic and Endogenous Substrates [Seite 135]
9.1 - 5.1 Introduction [Seite 135]
9.2 - 5.2 Substrate specificities of individual kallikrein-related peptidases [Seite 139]
9.2.1 - 5.2.1 The classical kallikreins (KLK1, KLK2, KLK3) [Seite 139]
9.2.2 - 5.2.2 KLK4/KLK5/KLK7 [Seite 143]
9.2.3 - 5.2.3 KLK6/KLK13/KLK14 [Seite 145]
9.2.4 - 5.2.4 KLK8/KLK10/KLK12 [Seite 147]
9.2.5 - 5.2.5 KLK9/KLK11/KLK15 [Seite 148]
9.3 - Bibliography [Seite 150]
10 - 6 Natural, Engineered and Synthetic Inhibitors of Kallikrein-related Peptidases [Seite 159]
10.1 - 6.1 Introduction [Seite 159]
10.2 - 6.2 KLK diversity [Seite 159]
10.3 - 6.3 The KLK superfamily: Structure and catalytic mechanism [Seite 159]
10.4 - 6.4 KLK inhibition: Rationale and mechanisms [Seite 161]
10.5 - 6.5 Proteinaceous inhibitors [Seite 162]
10.5.1 - 6.5.1 Kunitz domain inhibitors [Seite 162]
10.5.2 - 6.5.2 Kazal domain inhibitors [Seite 164]
10.5.3 - 6.5.3 Other canonical inhibitors [Seite 165]
10.5.4 - 6.5.4 Serpins [Seite 165]
10.6 - 6.6 Naturally occurring small molecule kallikrein inhibitors [Seite 166]
10.7 - 6.7 Engineered KLK Inhibitors [Seite 167]
10.7.1 - 6.7.1 Approaches to inhibitor design [Seite 168]
10.7.2 - 6.7.2 Pharmacological challenges for therapeutic inhibitors [Seite 168]
10.7.3 - 6.7.3 Serpins [Seite 168]
10.7.4 - 6.7.4 Ecotin [Seite 169]
10.7.5 - 6.7.5 Sunflower Trypsin Inhibitor (SFTI) [Seite 170]
10.7.6 - 6.7.6 Warhead inhibitors [Seite 171]
10.8 - 6.8 Conclusions and outlook [Seite 172]
10.9 - Acknowledgements [Seite 172]
10.10 - Bibliography [Seite 172]
11 - 7 Kallikrein-related Peptidases as Pharmaceutical Targets [Seite 179]
11.1 - 7.1 Introduction [Seite 179]
11.2 - 7.2 KLK disease markers as potential therapeutic targets [Seite 180]
11.3 - 7.3 KLKs in oncology [Seite 183]
11.3.1 - 7.3.1 Prostate cancer [Seite 183]
11.3.2 - 7.3.2 Ovarian and pancreatic cancer [Seite 185]
11.4 - 7.4 KLKs in inflammatory skin diseases [Seite 187]
11.4.1 - 7.4.1 Kallikrein expressions and activities in skin [Seite 187]
11.4.2 - 7.4.2 Netherton Syndrome as most relevant clinical model [Seite 188]
11.4.3 - 7.4.3 Atopic dermatitis, the potential major indication for kallikrein targeting [Seite 189]
11.4.4 - 7.4.4 Psoriasis and relevance of kallikreins [Seite 190]
11.4.5 - 7.4.5 Other potential skin disorders with kallikrein involvement [Seite 190]
11.5 - 7.5 KLKs in neurological disorders [Seite 191]
11.5.1 - 7.5.1 Alzheimer's disease and dementia [Seite 191]
11.5.2 - 7.5.2 Multiple sclerosis (MS) [Seite 191]
11.6 - 7.6 Kallikrein inhibitors to treat human diseases [Seite 192]
11.6.1 - 7.6.1 Design of KLK inhibitors and clinical development [Seite 192]
11.6.2 - 7.6.2 KLK inhibitors in oncology [Seite 194]
11.6.3 - 7.6.3 KLK inhibitors in dermatology [Seite 197]
11.7 - 7.7 Conclusions and Outlook [Seite 198]
11.8 - Bibliography [Seite 199]
12 - 8 Expression of Kallikrein-related Peptidases under (Patho-)Physiological Conditions [Seite 205]
12.1 - 8.1 Introduction [Seite 205]
12.2 - 8.2 KLK expression in tissues and biological fluids under physiological conditions [Seite 206]
12.2.1 - 8.2.1 KLKs in the central and peripheral nervous system [Seite 206]
12.2.2 - 8.2.2 KLKs in the female reproductive system [Seite 210]
12.2.3 - 8.2.3 KLKs in the male reproductive system [Seite 214]
12.2.4 - 8.2.4 Cellular distribution of KLKs in the gastrointestinal system [Seite 216]
12.2.5 - 8.2.5 KLKs in the skin and skin appendages [Seite 221]
12.2.6 - 8.2.6 KLKs in the respiratory system [Seite 225]
12.2.7 - 8.2.7 KLKs in the urinary system [Seite 225]
12.2.8 - 8.2.8 KLKs in lymphatic and endocrine organs (adrenal glands, thyroid gland, parathyroid glands, pituitary gland) [Seite 225]
12.2.9 - 8.2.9 KLKs in the cardiovascular system [Seite 229]
12.2.10 - 8.2.10 KLKs in the skeletomuscular system [Seite 229]
12.3 - 8.3 Expression of KLKs in non-malignant diseases [Seite 230]
12.3.1 - 8.3.1 Non-malignant diseases of the CNS [Seite 230]
12.3.2 - 8.3.2 Inflammatory-related conditions [Seite 233]
12.4 - 8.4 Expression of KLKs in cancer tissues [Seite 235]
12.4.1 - 8.4.1 Cancers of the brain [Seite 240]
12.4.2 - 8.4.2 Cancers of the female reproductive system [Seite 240]
12.4.3 - 8.4.3 Cancers of the male reproductive system [Seite 241]
12.4.4 - 8.4.4 Cancers of the gastrointestinal system [Seite 242]
12.4.5 - 8.4.5 Cancers of the skin [Seite 243]
12.4.6 - 8.4.6 Lung cancer [Seite 244]
12.4.7 - 8.4.7 Cancers of the urinary system [Seite 244]
12.5 - 8.5 Conclusion [Seite 245]
12.6 - Abbreviations [Seite 245]
12.7 - Bibliography [Seite 246]
13 - 9 Kallikrein-related Peptidases within the Proteolytic Web [Seite 269]
13.1 - 9.1 Introduction [Seite 269]
13.2 - 9.2 KLKs as actors and targets during the initiation and amplification of extracellular proteolytic activity [Seite 270]
13.2.1 - 9.2.1 The KLK-dependent KLK activome [Seite 270]
13.2.2 - 9.2.2 Cross- and reciprocal activation of KLK and non-KLK proteases [Seite 274]
13.2.3 - 9.2.3 Inactivation of protease inhibitors [Seite 278]
13.3 - 9.3 KLKs in the termination of proteolytic activity [Seite 278]
13.3.1 - 9.3.1 Proteolytic inactivation of (non-)KLK proteases [Seite 278]
13.3.2 - 9.3.2 Processing of the uPA receptor [Seite 279]
13.3.3 - 9.3.3 Disarming of the proteinase-activated receptors [Seite 280]
13.4 - 9.4 Conclusion [Seite 281]
13.5 - Bibliography [Seite 282]
14 - 10 Kallikrein-Kinin Cascade: Bioregulation by Human Tissue Kallikrein 1 (hK1, KLK1) [Seite 289]
14.1 - 10.1 Discovery of classical (true) tissue kallikrein and kinins [Seite 289]
14.2 - 10.2 Cellular localization [Seite 290]
14.3 - 10.3 Genomics and molecular structure [Seite 291]
14.4 - 10.4 Inhibitors of hK1 [Seite 294]
14.5 - 10.5 Modulation of membrane receptors [Seite 295]
14.6 - 10.6 Epigenetic regulation [Seite 295]
14.7 - 10.7 Kinin receptors and signaling [Seite 296]
14.7.1 - 10.7.1 Receptor subtypes [Seite 296]
14.7.2 - 10.7.2 Kinin receptor signaling [Seite 297]
14.7.3 - 10.7.3 Regulation of kinin receptor signaling [Seite 298]
14.8 - 10.8 Human disease [Seite 299]
14.8.1 - 10.8.1 Hypertension and renal damage [Seite 299]
14.8.2 - 10.8.2 Cardiac protection [Seite 301]
14.8.3 - 10.8.3 Inflammation and neutrophil function [Seite 301]
14.8.4 - 10.8.4 Cancer [Seite 304]
14.8.5 - 10.8.5 Angiogenesis [Seite 304]
14.9 - 10.9 Conclusion [Seite 305]
14.10 - Abbreviations [Seite 306]
14.11 - Bibliography [Seite 307]
15 - 11 Role of KLK4 in Dental Enamel Formation [Seite 313]
15.1 - 11.1 Introduction [Seite 313]
15.2 - 11.2 Early studies implicated proteases in dental enamel formation [Seite 313]
15.3 - 11.3 Investigations of enamel proteases discovered KLK4 [Seite 314]
15.4 - 11.4 KLK4 and amelogenesis imperfecta [Seite 315]
15.5 - 11.5 Klk4 lacZ/lacZ mice [Seite 315]
15.6 - 11.6 Other enamel specific genes [Seite 320]
15.7 - 11.7 Role of KLK4 in enamel formation [Seite 322]
15.8 - 11.8 Conclusion [Seite 325]
15.9 - Bibliography [Seite 325]
16 - 12 Kallikrein-related Peptidases and Semen [Seite 329]
16.1 - 12.1 Introduction [Seite 329]
16.2 - 12.2 Expression pattern and origin of seminal KLKs [Seite 330]
16.3 - 12.3 Physiological function of seminal KLKs [Seite 330]
16.3.1 - 12.3.1 Seminal coagulation and fibrinolytic balance [Seite 330]
16.3.2 - 12.3.2 Sperm motility [Seite 332]
16.3.3 - 12.3.3 Reproductive immune interactions [Seite 334]
16.4 - 12.4 Proteolytic pathways of seminal KLKs [Seite 336]
16.4.1 - 12.4.1 Role of seminal zinc [Seite 337]
16.4.2 - 12.4.2 Role of seminal KLK inhibitors [Seite 337]
16.4.3 - 12.4.3 Other inhibitory mechanisms of seminal KLKs [Seite 338]
16.4.4 - 12.4.4 Seminal proteolytic activation cascade [Seite 339]
16.5 - 12.5 Conclusions and outlook [Seite 340]
16.6 - Abbreviations [Seite 341]
16.7 - Bibliography [Seite 341]
17 - 13 Kallikrein-related Peptidases and Inhibitors of the Skin [Seite 347]
17.1 - 13.1 Introduction [Seite 347]
17.2 - 13.2 KLKs in the epidermis [Seite 349]
17.3 - 13.3 Desquamation [Seite 350]
17.4 - 13.4 Regulation of protease activity [Seite 351]
17.4.1 - 13.4.1 KLK activation [Seite 351]
17.4.2 - 13.4.2 KLK inhibitors [Seite 352]
17.5 - 13.5 Skin disorders [Seite 355]
17.6 - 13.6 Conclusions and outlook [Seite 358]
17.7 - Bibliography [Seite 359]
18 - 14 Physiological and Pathophysiological Roles of Kallikrein-related Peptidases in the Central Nervous System [Seite 367]
18.1 - 14.1 Introduction [Seite 367]
18.2 - 14.2 KLK expression and roles in CNS physiology [Seite 367]
18.2.1 - 14.2.1 KLK expression in the CNS [Seite 367]
18.2.2 - 14.2.2 Physiological roles of KLKs in the CNS [Seite 371]
18.2.3 - 14.2.3 Pathophysiological roles of KLKs in the CNS [Seite 377]
18.3 - 14.3 Conclusions and outlook [Seite 381]
18.4 - Acknowledgements [Seite 382]
18.5 - Abbreviation [Seite 382]
18.6 - Bibliography [Seite 382]
19 - 15 Kallikrein-related Peptidases (KLKs), Proteinase-mediated Signaling and Proteinase-activated receptors (PARs) [Seite 391]
19.1 - 15.1 Proteinases: shocktroops ofthe innate immune response [Seite 391]
19.2 - 15.2 Multiple mechanisms for proteinase-mediated signaling [Seite 392]
19.3 - 15.3 Proteinases and PAR-mediated signaling [Seite 394]
19.4 - 15.4 Linking PARs to the KLKs: the prostate connection [Seite 396]
19.5 - 15.5 Proteolytic cascades, KLKs and the innate immune response [Seite 397]
19.6 - 15.6 KLKs, other serine proteinases, PARs and inflammation [Seite 397]
19.7 - 15.7 KLKs, PARs and inflammation of the central nervous system and the skin [Seite 398]
19.8 - 15.8 KLKs, PARs and cancer [Seite 400]
19.9 - 15.9 KLKs and PARs: Therapeutic targets for inflammatory diseases, cancer and other disorders [Seite 401]
19.10 - 15.10 Blocking proteinase-mediated PAR activation: PAR-targeted blocking antibodies versus proteinase inhibitors [Seite 405]
19.11 - 15.11 Summary and outlook for the future [Seite 407]
19.12 - Acknowledgements [Seite 407]
19.13 - Bibliography [Seite 408]
20 - Index [Seite 417]