Preface -- List of contributing authors -- Table of Contents -- Introduction to Volume 1: Kallikrein-related Peptidases. Characterization, Regulation, and Interactions Within the Protease Web -- Bibliography -- 1 Genomic Structure of the KLK Locus -- 1.1 Introduction -- 1.2 Kallikreins in rodents -- 1.2.1 The mouse kallikrein gene family -- 1.2.2 The rat kallikrein gene family -- 1.3 Characterization and sequence analysis of the human KLK gene locus -- 1.3.1 Locus overview -- 1.3.2 Repeat elements and pleomorphism -- 1.4 Structural features of the human KLK genes and proteins -- 1.4.1 Common structural features -- 1.5 Sequence variations of human KLK genes -- 1.6 Regulation of KLK activity -- 1.6.1 At the mRNA level -- 1.6.2 Locus control of KLK expression -- 1.6.3 Epigenetic regulation of KLK gene expression -- 1.7 Isoforms and splice variants of human KLKs -- 1.8 Evolution of KLKs -- Bibliography -- 2 Single Nucleotide Polymorphisms in the Human KLK Locus and Their Implication in Various Diseases -- 2.1 Introduction -- 2.2 KLKSNPs - data-mining from SNPdb and 1000 Genomes -- 2.3 Functional annotations using web-based prediction tools -- 2.4 Experimentally validated functional KLK SNPs -- 2.5 KLKSNP haplotypes and tagging -- 2.6 Malignant and non-malignant diseases and association with KLK SNPs -- 2.6.1 Association studies on high-risk variants in KLK genes -- 2.6.2 Association studies on low-risk variants in KLK genes -- 2.7 Conclusions -- Bibliography -- 3 Evolution of Kallikrein-related Peptidases -- 3.1 Introduction -- 3.2 Basic elements of phylogenetic analysis -- 3.3 Evolutionary trends at the KLK locus -- 3.4 Evolution of the KLK1-KLK4 sublocus -- 3.4.1 KLK2 and KLK3 originate from a duplicated segment containing both KLK1 and KLK15.

3.4.2 A large number of KLK1 tandem repeats in the house mouse -- 3.4.3 The rat KLK1 sublocus consists of 10 large repeats -- 3.4.4 Four duplications of KLK1 and KLK15 in the dog -- 3.4.5 A large repeat containing KLK4 in the horse -- 3.5 KLK genes in non-mammalian species -- 3.6 General conclusions and remarks on the evolution of KLK genes -- Bibliography -- 4 Structural Aspects of Kallikrein-related Peptidases -- 4.1 Introduction -- 4.2 Individual KLK structures -- 4.2.1 Tissue kallikrein (KLK1) -- 4.2.2 Prostate specific antigen (PSA/KLK3) -- 4.2.3 Prostase (KLK4) -- 4.2.4 Stratum corneum tryptic enzyme (SCTE/KLK5) -- 4.2.5 Myelencephalon-specific protease or neurosin (MSP/KLK6) -- 4.2.6 Stratum corneum chymotryptic enzyme (SCCE/KLK7) -- 4.2.7 Neuropsin (KLK8) -- 4.2.8 Other mammalian KLK structures -- Bibliography -- 5 Molecular Recognition Properties of Kallikrein-related Peptidases on Synthetic and Endogenous Substrates -- 5.1 Introduction -- 5.2 Substrate specificities of individual kallikrein-related peptidases -- 5.2.1 The classical kallikreins (KLK1, KLK2, KLK3) -- 5.2.2 KLK4/KLK5/KLK7 -- 5.2.3 KLK6/KLK13/KLK14 -- 5.2.4 KLK8/KLK10/KLK12 -- 5.2.5 KLK9/KLK11/KLK15 -- Bibliography -- 6 Natural, Engineered and Synthetic Inhibitors of Kallikrein-related Peptidases -- 6.1 Introduction -- 6.2 KLK diversity -- 6.3 The KLK superfamily: Structure and catalytic mechanism -- 6.4 KLK inhibition: Rationale and mechanisms -- 6.5 Proteinaceous inhibitors -- 6.5.1 Kunitz domain inhibitors -- 6.5.2 Kazal domain inhibitors -- 6.5.3 Other canonical inhibitors -- 6.5.4 Serpins -- 6.6 Naturally occurring small molecule kallikrein inhibitors -- 6.7 Engineered KLK Inhibitors -- 6.7.1 Approaches to inhibitor design -- 6.7.2 Pharmacological challenges for therapeutic inhibitors -- 6.7.3 Serpins -- 6.7.4 Ecotin.

6.7.5 Sunflower Trypsin Inhibitor (SFTI) -- 6.7.6 Warhead inhibitors -- 6.8 Conclusions and outlook -- Acknowledgements -- Bibliography -- 7 Kallikrein-related Peptidases as Pharmaceutical Targets -- 7.1 Introduction -- 7.2 KLK disease markers as potential therapeutic targets -- 7.3 KLKs in oncology -- 7.3.1 Prostate cancer -- 7.3.2 Ovarian and pancreatic cancer -- 7.4 KLKs in inflammatory skin diseases -- 7.4.1 Kallikrein expressions and activities in skin -- 7.4.2 Netherton Syndrome as most relevant clinical model -- 7.4.3 Atopic dermatitis, the potential major indication for kallikrein targeting -- 7.4.4 Psoriasis and relevance of kallikreins -- 7.4.5 Other potential skin disorders with kallikrein involvement -- 7.5 KLKs in neurological disorders -- 7.5.1 Alzheimer's disease and dementia -- 7.5.2 Multiple sclerosis (MS) -- 7.6 Kallikrein inhibitors to treat human diseases -- 7.6.1 Design of KLK inhibitors and clinical development -- 7.6.2 KLK inhibitors in oncology -- 7.6.3 KLK inhibitors in dermatology -- 7.7 Conclusions and Outlook -- Bibliography -- 8 Expression of Kallikrein-related Peptidases under (Patho-)Physiological Conditions -- 8.1 Introduction -- 8.2 KLK expression in tissues and biological fluids under physiological conditions -- 8.2.1 KLKs in the central and peripheral nervous system -- 8.2.2 KLKs in the female reproductive system -- 8.2.3 KLKs in the male reproductive system -- 8.2.4 Cellular distribution of KLKs in the gastrointestinal system -- 8.2.5 KLKs in the skin and skin appendages -- 8.2.6 KLKs in the respiratory system -- 8.2.7 KLKs in the urinary system -- 8.2.8 KLKs in lymphatic and endocrine organs (adrenal glands, thyroid gland, parathyroid glands, pituitary gland) -- 8.2.9 KLKs in the cardiovascular system -- 8.2.10 KLKs in the skeletomuscular system.

8.3 Expression of KLKs in non-malignant diseases -- 8.3.1 Non-malignant diseases of the CNS -- 8.3.2 Inflammatory-related conditions -- 8.4 Expression of KLKs in cancer tissues -- 8.4.1 Cancers of the brain -- 8.4.2 Cancers of the female reproductive system -- 8.4.3 Cancers of the male reproductive system -- 8.4.4 Cancers of the gastrointestinal system -- 8.4.5 Cancers of the skin -- 8.4.6 Lung cancer -- 8.4.7 Cancers of the urinary system -- 8.5 Conclusion -- Abbreviations -- Bibliography -- 9 Kallikrein-related Peptidases within the Proteolytic Web -- 9.1 Introduction -- 9.2 KLKs as actors and targets during the initiation and amplification of extracellular proteolytic activity -- 9.2.1 The KLK-dependent KLK activome -- 9.2.2 Cross- and reciprocal activation of KLK and non-KLK proteases -- 9.2.3 Inactivation of protease inhibitors -- 9.3 KLKs in the termination of proteolytic activity -- 9.3.1 Proteolytic inactivation of (non-)KLK proteases -- 9.3.2 Processing of the uPA receptor -- 9.3.3 Disarming of the proteinase-activated receptors -- 9.4 Conclusion -- Bibliography -- 10 Kallikrein-Kinin Cascade: Bioregulation by Human Tissue Kallikrein 1 (hK1, KLK1) -- 10.1 Discovery of classical (true) tissue kallikrein and kinins -- 10.2 Cellular localization -- 10.3 Genomics and molecular structure -- 10.4 Inhibitors of hK1 -- 10.5 Modulation of membrane receptors -- 10.6 Epigenetic regulation -- 10.7 Kinin receptors and signaling -- 10.7.1 Receptor subtypes -- 10.7.2 Kinin receptor signaling -- 10.7.3 Regulation of kinin receptor signaling -- 10.8 Human disease -- 10.8.1 Hypertension and renal damage -- 10.8.2 Cardiac protection -- 10.8.3 Inflammation and neutrophil function -- 10.8.4 Cancer -- 10.8.5 Angiogenesis -- 10.9 Conclusion -- Abbreviations -- Bibliography.

11 Role of KLK4 in Dental Enamel Formation -- 11.1 Introduction -- 11.2 Early studies implicated proteases in dental enamel formation -- 11.3 Investigations of enamel proteases discovered KLK4 -- 11.4 KLK4 and amelogenesis imperfecta -- 11.5 Klk4 lacZ/lacZ mice -- 11.6 Other enamel specific genes -- 11.7 Role of KLK4 in enamel formation -- 11.8 Conclusion -- Bibliography -- 12 Kallikrein-related Peptidases and Semen -- 12.1 Introduction -- 12.2 Expression pattern and origin of seminal KLKs -- 12.3 Physiological function of seminal KLKs -- 12.3.1 Seminal coagulation and fibrinolytic balance -- 12.3.2 Sperm motility -- 12.3.3 Reproductive immune interactions -- 12.4 Proteolytic pathways of seminal KLKs -- 12.4.1 Role of seminal zinc -- 12.4.2 Role of seminal KLK inhibitors -- 12.4.3 Other inhibitory mechanisms of seminal KLKs -- 12.4.4 Seminal proteolytic activation cascade -- 12.5 Conclusions and outlook -- Abbreviations -- Bibliography -- 13 Kallikrein-related Peptidases and Inhibitors of the Skin -- 13.1 Introduction -- 13.2 KLKs in the epidermis -- 13.3 Desquamation -- 13.4 Regulation of protease activity -- 13.4.1 KLK activation -- 13.4.2 KLK inhibitors -- 13.5 Skin disorders -- 13.6 Conclusions and outlook -- Bibliography -- 14 Physiological and Pathophysiological Roles of Kallikrein-related Peptidases in the Central Nervous System -- 14.1 Introduction -- 14.2 KLK expression and roles in CNS physiology -- 14.2.1 KLK expression in the CNS -- 14.2.2 Physiological roles of KLKs in the CNS -- 14.2.3 Pathophysiological roles of KLKs in the CNS -- 14.3 Conclusions and outlook -- Acknowledgements -- Abbreviation -- Bibliography.

15 Kallikrein-related Peptidases (KLKs), Proteinase-mediated Signaling and Proteinase-activated receptors (PARs).