hK5 and hK7, two serine proteinases abundant in human skin, are inhibited by LEKTI domain 6

Egelrud, Torbjörn; Brattsand, Maria; Kreutzmann, Peter; Walden, Michael; Vitzithum, Klaus; Marx, Ute C.; Forssmann, Wolf‐Georg; Mägert, Hans-Jürgen

doi:10.1111/j.1365-2133.2005.06834.x

Cited by 113 publications

(112 citation statements)

References 27 publications

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“…Previous studies have shown pancreatic ELA2 zymogen activation by trypsin cleavage (17). As KLK5, a trypsin-like protease directly inhibited by LEKTI, is hyperactive in LEKTI-deficient epidermis (15,(18)(19)(20), we tested the effect of KLK5 on pro-ELA2 activation. Coincubation of pro-ELA2 with KLK5 led to a 4-fold increase in elastolytic activity compared with pro-ELA2 basal activity ( Figure 2A).…”

Section: Ela2 Is a New Epidermal Protease Which Is Hyperactive In Lekmentioning

confidence: 99%

Elastase 2 is expressed in human and mouse epidermis and impairs skin barrier function in Netherton syndrome through filaggrin and lipid misprocessing

Bonnart¹,

Deraison²,

Lacroix³

et al. 2010

J. Clin. Invest.

120

123

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The human epidermis serves 2 crucial barrier functions: it protects against water loss and prevents penetration of infectious agents and allergens. The physiology of the epidermis is maintained by a balance of protease and antiprotease activities, as illustrated by the rare genetic skin disease Netherton syndrome (NS), in which impaired inhibition of serine proteases causes severe skin erythema and scaling. Here, utilizing mass spectrometry, we have identified elastase 2 (ELA2), which we believe to be a new epidermal protease that is specifically expressed in the most differentiated layer of living human and mouse epidermis. ELA2 localized to keratohyalin granules, where it was found to directly participate in (pro-)filaggrin processing. Consistent with the observation that ELA2 was hyperactive in skin from NS patients, transgenic mice overexpressing ELA2 in the granular layer of the epidermis displayed abnormal (pro-)filaggrin processing and impaired lipid lamellae structure, which are both observed in NS patients. These anomalies led to dehydration, implicating ELA2 in the skin barrier defect seen in NS patients. Thus, our work identifies ELA2 as a major new epidermal protease involved in essential pathways for skin barrier function. These results highlight the importance of the control of epidermal protease activity in skin homeostasis and designate ELA2 as a major protease driving the pathogenesis of NS.

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Section: Ela2 Is a New Epidermal Protease Which Is Hyperactive In Lekmentioning

confidence: 99%

Elastase 2 is expressed in human and mouse epidermis and impairs skin barrier function in Netherton syndrome through filaggrin and lipid misprocessing

Bonnart¹,

Deraison²,

Lacroix³

et al. 2010

J. Clin. Invest.

120

123

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“…hK3/PSA has been shown to rapidly hydrolyze the seminal vesicle proteins semenogelin I and II, resulting in liquefaction of the ejaculated seminal plasma clot (14), whereas hK2 (15,16) and hK4 (17) apparently activate pro-hK3/PSA in vitro, suggesting a physiological regulatory mechanism. hK4 and hK8 seem to be important for tooth development and neural plasticity, like their putative murine or porcine orthologs enamel matrix serine proteinase and neuropsin (18 -20), and hK5 and hK7 as well as hK14 are involved in skin desquamation and inflammatory processes (21,22).…”

mentioning

confidence: 99%

Specificity Profiling of Seven Human Tissue Kallikreins Reveals Individual Subsite Preferences

Debela

Magdolen

Schechter

et al. 2006

Journal of Biological Chemistry

133

121

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Human tissue kallikreins (hKs) form a family of 15 closely related (chymo)trypsin-like serine proteinases. These tissue kallikreins are expressed in a wide range of tissues including the central nervous system, the salivary gland, and endocrine-regulated tissues, such as prostate, breast, or testis, and may have diverse physiological functions. For several tissue kallikreins, a clear correlation has been established between expression and different types of cancer. For example, the prostate-specific antigen (PSA or hK3) serves as tumor marker and is used to monitor therapy response. Using a novel strategy, we have cloned, expressed in Escherichia coli or in insect cells, refolded, activated, and purified the seven human tissue kallikreins hK3/PSA, hK4, hK5, hK6, hK7, hK10, and hK11. Moreover, we have determined their extended substrate specificity for the nonprime side using a positional scanning combinatorial library of tetrapeptide substrates. hK3/PSA and hK7 exhibited a chymotrypsin-like specificity preferring large hydrophobic or polar residues at the P1 position. In contrast, hK4, hK5, and less stringent hK6 displayed a trypsin-like specificity with strong preference for P1-Arg, whereas hK10 and hK11 showed an ambivalent specificity, accepting both basic and large aliphatic P1 residues. The extended substrate specificity profiles are in good agreement with known substrate cleavage sites but also in accord with experimentally solved (hK4, hK6, and hK7) or modeled structures. The specificity profiles may lead to a better understanding of human tissue kallikrein functions and assist in identifying their physiological protein substrates as well as in designing more selective inhibitors.The tissue kallikreins constitute a subgroup of the chymotrypsin-like serine proteinase family S1A of clan PA(S) (1). They are highly homologous to the "true tissue kallikrein" K1, which is encoded in mammals, for example, by the human KLK1 or the mouse Klk1 genes (2). The 15 human KLK genes code for the classical tissue kallikreins hK1, hK2, and the prostate-specific antigen (PSA, 5 hK3) as well as for the 12 more recently discovered so-called new tissue kallikreins, hK4 to hK15, named in chronological order of their characterization (3-7). These genes share common characteristics such as a similar exon/intron organization and encode single-chain pre-proproteinases, which consist of a signal peptide, a generally short, 4 -9-residue-long pro-peptide (only hK5 harbors a rather long propeptide of 37 residues), and a chymotrypsin-or trypsin-like catalytic domain ( Fig. 1) with amino acid sequence identity of about 80% for the classical and 40% among the new tissue kallikreins, respectively (8, 9). According to phylogenetic analyses, hK1, hK2, and hK3 form a subgroup of particularly closely related proteinases, whereas the tissue kallikreins hK4-hK15 diverge into several subgroups, namely hK4/hK5/hK7, hK6/ hK13/hK14, hK8/hK10/hK12, and hK9/hK11/hK15 (2, 10). In Table 1, the 15 human tissue kallikreins are listed together with their s...

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“…Subsequently KLK5 activates other trypsin-like KLKs and chymotrypsin-like KLK7 by proteolytic release of the amino-terminal propeptide. Although most of the 15 kallikreins are expressed in skin (16), KLK5 and KLK7 are highly expressed in differentiated keratinocytes (17).…”

mentioning

confidence: 99%

Kallikrein-related Peptidase-7 Regulates Caspase-14 Maturation during Keratinocyte Terminal Differentiation by Generating an Intermediate Form

Yamamoto

Miyai

Matsumoto

et al. 2012

Journal of Biological Chemistry

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hK5 and hK7, two serine proteinases abundant in human skin, are inhibited by LEKTI domain 6

Cited by 113 publications

References 27 publications

Elastase 2 is expressed in human and mouse epidermis and impairs skin barrier function in Netherton syndrome through filaggrin and lipid misprocessing

Elastase 2 is expressed in human and mouse epidermis and impairs skin barrier function in Netherton syndrome through filaggrin and lipid misprocessing

Specificity Profiling of Seven Human Tissue Kallikreins Reveals Individual Subsite Preferences

Kallikrein-related Peptidase-7 Regulates Caspase-14 Maturation during Keratinocyte Terminal Differentiation by Generating an Intermediate Form

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