title: A potential role for multiple tissue kallikrein serine proteases in epidermal desquamation.
abstract: Desquamation of the stratum corneum is a serine protease-dependent 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 Ki 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) (Ki = 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, Ca2+ 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario M5G 1X5, Canada.
authors.forename: Carla A
authors.initials: CA
authors.lastname: Borgoño
authors.forename: Iacovos P
authors.initials: IP
authors.lastname: Michael
authors.forename: Nahoko
authors.initials: N
authors.lastname: Komatsu
authors.forename: Arumugam
authors.initials: A
authors.lastname: Jayakumar
authors.forename: Ravi
authors.initials: R
authors.lastname: Kapadia
authors.forename: Gary L
authors.initials: GL
authors.lastname: Clayman
authors.forename: Georgia
authors.initials: G
authors.lastname: Sotiropoulou
authors.forename: Eleftherios P
authors.initials: EP
authors.lastname: Diamandis
mesh_terms: D002352:Carrier Proteins / Q000502:physiology; D051183:Desmoglein 1 / Q000378:metabolism; D053492:Elafin / Q000502:physiology; D004817:Epidermis / Q000201:enzymology* / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D007610:Kallikreins / Q000037:antagonists & inhibitors / Q000502:physiology*; D010446:Peptide Fragments / Q000502:physiology; D053491:Proteinase Inhibitory Proteins, Secretory; D011994:Recombinant Proteins / Q000494:pharmacology; D053481:Secretory Leukocyte Peptidase Inhibitor / Q000502:physiology; D012697:Serine Endopeptidases / Q000502:physiology; D000074163:Serine Peptidase Inhibitor Kazal-Type 5; D015842:Serine Proteinase Inhibitors / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; C495297:DSG1 protein, human; D051183:Desmoglein 1; D053492:Elafin; D010446:Peptide Fragments; D053491:Proteinase Inhibitory Proteins, Secretory; D011994:Recombinant Proteins; C120650:SPINK5 protein, human; D053481:Secretory Leukocyte Peptidase Inhibitor; D000074163:Serine Peptidase Inhibitor Kazal-Type 5; D015842:Serine Proteinase Inhibitors; C470778:KLK13 protein, human; C425336:KLK14 protein, human; C400147:KLK5 protein, human; C103551:KLK6 protein, human; D007610:Kallikreins; D012697:Serine Endopeptidases