New insights into the functional mechanisms and clinical applications of the kallikrein-related peptidase family

Abstract 

The Kallikrein-related peptidase (KLK) family consists of fifteen conserved serine proteases that form the largest contiguous cluster of proteases in the human genome. While primarily recognized for their clinical utilities as potential disease biomarkers, new compelling evidence suggests that this family plays a significant role in various physiological processes, including skin desquamation, semen liquefaction, neural plasticity, and body fluid homeostasis. KLK activation is believed to be mediated through highly organized proteolytic cascades, regulated through a series of feedback loops, inhibitors, auto-degradation and internal cleavages. Gene expression is mainly hormone-dependent, even though transcriptional epigenetic regulation has also been reported. These regulatory mechanisms are integrated with various signaling pathways to mediate multiple functions. Dysregulation of these pathways has been implicated in a large number of neoplastic and non-neoplastic pathological conditions. This review highlights our current knowledge of structural/phylogenetic features, functional role and regulatory/signaling mechanisms of this important family of enzymes.

Keywords: Kallikrein-related peptidases, PSA, Proteolytic cascades, Skin desquamation, Semen liquefaction, Tumour growth, Tumour invasion, Angiogenesis, uPA signaling, PARs

Abbreviations: ACC, 7-amino-4-carbamoylmethylcoumarin, ACT, anti-chymotrypsin, AD, Alzheimer's disease, ADAMTS8, ADAM metallopeptidase with thrombospondin type 1 motif 8, ANF, atrial natriuretic factor, AI, amelogenesis imperfecta, AP, anti plasmin, APMSF, 4-amidino-phenyl-methane-sulfonyl fluoride, AT, antitrypsin, bFGF, basic fibroblast growth factor, B2R, human bradykinin B2 receptor, CAG, cancer-associated gene, cdk, cyclin-dependent kinase 7, CDSN, corneodesmosin, CNS, central nervous system, DSC, desmocollin, DSG, desmoglein, ECM, extracellular matrix, FN, fibronectin, FTD, frontotemporal dementia, FRET, fluorescence resonance energy transfer, HEK, human embryonic kidney, hCAP, human cathelicidin, hGH, human growth hormone, HRE, hormone response element, hsp, heat shock protein, IGF, insulin-like growth factor, IGFBP, IGF binding protein, IFN, interferon, IL, interleukin, KD, kallidin, KLK, kallikrein-related peptidase, KNRK, Kirsten virus-transformed normal rat kidney, LEKTI, lympho-epithelial Kazal-type inhibitor, LLP, low density lipoprotein, LK, low molecular weight kininogen, LMW, low molecular weight, LTP, long-term potentiation, MAPK, mitogen-activated protein kinase, MBP, myelin basic protein, MMP, matrix metalloproteinase, NS, Netherton syndrome, OLG, oligodendrocyte, PAI, plasminogen activator inhibitor, PAP, poly A polymerase, PAR, protease activated receptor, PCI, protein C inhibitor, PI, protease inhibitor, PKA, protein kinase A, PKC, protein kinase C, PS-SCL, positional scanning synthetic combinatorial library, PTHrp, parathyroid hormone-related peptide, SC, stratum corneum, Sg, seminogelin, siRNA, small interfering RNA, SLPI, secretory leukocyte protease inhibitor, SNP, single nucleotide polymorphism, SPINK, serine protease inhibitor Kazal-1, TGF, tumour growth factor, uPA, urokinase plasminogen activator, uPAR, urokinase plasminogen activator receptor, UTR, untranslated region, VEGF, vascular endothelial growth factor, VIP, vasoactive intestinal peptide