Desquamation of the stratum corneum is a serine proteasedependent process. Two members of the human tissue kallikrein (KLK) family of (chymo)tryptic-like serine proteases, KLK5 and KLK7, are implicated in desquamation by digestion of (corneo)desmosomes and inhibition by desquamation-related serine protease inhibitors (SPIs). However, the epidermal localization and specificity of additional KLKs also supports a role for these enzymes in desquamation. This study aims to delineate the probable contribution of KLK1, KLK5, KLK6, KLK13, and KLK14 to desquamation by examining their interactions, in vitro, with: 1) colocalized SPI, lympho-epithelial Kazal-type-related inhibitor (LEKTI, four recombinant fragments containing inhibitory domains 1-6 (rLEKTI(1-6)), domains 6 -8 and partial domain 9 (rLEKTI(6 -9)), domains 9 -12 (rLEKTI(9 -12)), and domains 12-15 (rLEKTI(12-15)), secretory leukocyte protease inhibitor, and elafin and 2) their ability to digest the (corneo)desmosomal cadherin, desmoglein 1. KLK1 was not inhibited by any SPI tested. KLK5, KLK6, KLK13, and KLK14 were potently inhibited by rLEKTI(1-6), rLEKTI(6 -9), and rLEKTI(9 -12) with K i values in the range of 2.3-28.4 nM, 6.1-221 nM, and 2.7-416 nM for each respective fragment. Only KLK5 was inhibited by rLEKTI(12-15) (K i ‫؍‬ 21.8 nM). No KLK was inhibited by secretory leukocyte protease inhibitor or elafin. Apart from KLK13, all KLKs digested the ectodomain of desmoglein 1 within cadherin repeats, Ca 2؉ binding sites, or in the juxtamembrane region. Our study indicates that multiple KLKs may participate in desquamation through cleavage of desmoglein 1 and regulation by LEKTI. These findings may have clinical implications for the treatment of skin disorders in which KLK activity is elevated.As the outermost layer of the skin, the stratum corneum functions as the body's main protective barrier against physical and chemical damage, dehydration, and microbial pathogens. Inter-corneocyte cohesion within the stratum corneum depends primarily on corneodesmosomes, structurally modified desmosomes (1-3). Akin to classical desmosomes, corneodesmosomes maintain tissue integrity and mediate cell adhesion via calcium-dependent interactions between two families of desmosomal cadherins, the desmogleins (DSG1-4) 2 and desmocollins 1-3 (4, 5). The most abundant isoforms in the stratum corneum include DSG1, DSG4, and desmocollin-1 (6, 7). As specialized desmosomes, corneodesmosomes also contain a unique glycoprotein constituent, corneodesmosin (3).During normal stratum corneum desquamation, the most superficial corneocytes are shed from the skin surface. This process requires proteolysis of the corneodesmosomal adhesion molecules DSG1 (8, 9), desmocollin-1 (10), and corneodesmosin (11) likely mediated by both trypsin-like and chymotrypsin-like serine proteases (9, 12). To date, serine protease activity in the stratum corneum has been attributed to human tissue kallikreins (KLK; encoded by KLK genes (EC 3.4.21)), a subgroup of 15 secreted serine proteases with (chymo)trypsi...

Kallikrein-related peptidases constitute a single family of 15 (chymo)trypsin-like proteases (KLK1-15) with pleiotropic physiological roles. Aberrant regulation of KLKs has been associated with diverse diseases such as hypertension, renal dysfunction, skin disorders, inflammation, neurodegeneration, and cancer. Recent studies suggested that coordinated activation and regulation of KLK activity are achieved via a complex network of interactions referred to as the "KLK activome." However, it remains to be validated whether these hypothetical KLK activation cascade pathways are operative in vivo. In addition, KLKs have emerged as versatile signaling molecules. In summary, KLKs represent attractive biomarkers for clinical applications and potential therapeutic targets for common human pathologies.

Protease M expression (mRNA) may be a useful marker in the detection of primary mammary carcinomas, as well as primary ovarian cancers. Other medical applications are also likely, based on sequence relatedness to trypsin and PSA.