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.

Figure 1

Schematic representation of a kallikrein gene and protein. A) Kallikrein genes consist of 5 coding exons (blue boxes) of similar length and 4 introns (gray bar) with varying size. Red boxes represent the 5′ and 3′ UTRs. Roman numbers show intron phase. B) Kallikrein proteins are expressed as pre‐proenzymes. The amino‐terminal pre‐ (signal) sequence guides the enzyme to the endoplasmic reticulum for secretion. Proenzymes are activated extracellularly upon cleavage of the pro‐domain. H57, D102, and S195 are the amino acids of the catalytic triad.

Figure 2

Kallikrein locus conservation. Arrowheads indicate the approximate location of genes and their transcription direction. Green, “classical” kallikreins, Blue, newly discovered kallikreins, Black, pseudogenes, Red, non‐kallikreins. Figure is not to scale (modified from Elliott et al., 2006).

Figure 3

Antimicrobial function of kallikreins. KLK5 cleaves the inactive cathelicidin precursor (hCAP18) to the host cell activator LL‐37. Along with KLK7, KLK5 further breaks down the LL‐37 peptide to various antimicrobial peptides, namely KS‐30, KS‐22, LL‐29, RK‐31, and KR‐30. These peptides are consequently degraded to biologically inactive peptides. KLK‐mediated antimicrobial effect of cathelicidin is tightly regulated by a number of serine protease inhibitors, such as elafin and LEKTI (modified from Yamasaki et al., 2006).

Figure 4

Schematic representation of kallikrein signaling pathways. Kallikreins mediate uPA activation and subsequent conversion of plasminogen into active plasmin and cleavage of several downstream targets, such as fibrin and MMPs. Kallikreins cleave kininogen to kinin and induce a number of downstream targets including cAMP, NO, prostacyclin and cAMP. Kallikreins cleave and activate PARs at their extracellular N‐termini. Active PARs signal mainly through calcium signaling, Raf/Ras activation and cAMP inhibition. Kallikreins participate in ECM remodeling directly and/or indirectly through MMPs. For more information, please refer to our non‐standard abbreviations.

Figure 5

Schematic presentation of A) Kallikrein cascade in seminal plasma. KLK2 and 5 autoactivate and, in turn, activate pro‐KLK3. Activated KLK3 acts as an executor protease in the liquefaction of seminal clot and release of spermatozoa through processing of Sgl I/Sgl II and FN. The cascade is regulated by a number of negative and positive feedback loops, including internal cleavages, auto degradation, Zn2+, and endogenous inhibitors. B) Kallikrein cascade in skin. KLK5 autoactivates and activates KLK14 and 7, which, along with active KLK1, 6, and 13 function in skin desquamation through degradation of the corneodesmosomal proteins, i.e. desmogelin1 (DSG1), desmocollin1 (DSC1), and corneodesmosin (CDSN). Desquamation is regulated by of various serine protease inhibitors, such as SLPI, elafin, and certain LEKTI domains. For more definitions, please refer to our non‐standard abbreviations.