Regulation of kallikrein-related peptidases in the skin – from physiology to diseases to therapeutic options

Jan Fischer; Ulf Meyer-Hoffert

doi:10.1160/TH12-11-0836

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2013; 110(03): 442-449
DOI: 10.1160/TH12-11-0836

Theme Issue Article

Schattauer GmbH

Regulation of kallikrein-related peptidases in the skin – from physiology to diseases to therapeutic options

Jan Fischer

¹Department of Dermatology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany

,

Ulf Meyer-Hoffert

¹Department of Dermatology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany

› Author Affiliations

Abstract

Summary

Kallikrein-related peptidases (KLKs) constitute a family of 15 highly conserved serine proteases, which show a tissue-specific expression profile. This made them valuable tumour expression markers. It became evident that KLKs are involved in many physiological processes like semen liquefaction and skin desquamation. More recently, we have learnt that they are involved in many pathophysiological conditions and diseases making them promising target of therapeutic intervention. Therefore, regulation of KLKs raised the interest of numerous reports. Herein, we summarise the current knowledge on KLKs regulation with an emphasis on skin-relevant KLKs regulation processes. Regulation of KLKs takes place on the level of transcription, on protease activation and on protease inactivation. A variety of protease inhibitors has been described to interact with KLKs including the irreversible serine protease inhibitors (SERPINs) and the reversible serine protease inhibitors of Kazal-type (SPINKs). In an attempt to integrate current knowledge, we propose that KLK regulation has credentials as targets for therapeutic intervention.

Keywords

Atopic dermatitis - rosacea - Netherton syndrome - LEKTI - proteinase activated receptor - LL-37

Full Text

References

References
1 Pavlopoulou A, Pampalakis G, Michalopoulos I. et al. Evolutionary history of tissue kallikreins. PLoS ONE 2010; 05: e13781.
2 Avgeris M, Mavridis K, Scorilas A. Kallikrein-related peptidase genes as promising biomarkers for prognosis and monitoring of human malignancies. Biol Chem 2010; 391: 505-511.
3 Veveris-Lowe TL, Lawrence MG, Collard RL. et al. Kallikrein 4 (hK4) and prostate-specific antigen (PSA) are associated with the loss of E-cadherin and an epithelial-mesenchymal transition (EMT)-like effect in prostate cancer cells. Endocr Relat Cancer 2005; 12: 631-643.
4 Oikonomopoulou K, Diamandis EP, Hollenberg MD. Kallikrein-related peptidases: proteolysis and signaling in cancer, the new frontier. Biol Chem 2010; 391: 299-310.
5 Dong Y, Tan OL, Loessner D. et al. Kallikrein-related peptidase 7 promotes multicellular aggregation via the alpha(5)beta(1) integrin pathway and paclitaxel chemoresistance in serous epithelial ovarian carcinoma. Cancer Res 2010; 70: 2624-2633.
6 Ekholm IE, Brattsand M, Egelrud T. Stratum corneum tryptic enzyme in normal epidermis: a missing link in the desquamation process?. J Invest Dermatol 2000; 114: 56-63.
7 Lundstrom A, Egelrud T. Stratum corneum chymotryptic enzyme: a proteinase which may be generally present in the stratum corneum and with a possible involvement in desquamation. Acta DermVenereol 1991; 71: 471-474.
8 Egelrud T. Desquamation in the stratums corneum. Acta DermVenereol 2000; 208: 44-45.
9 Stefansson K, Brattsand M, Ny A. et al. Kallikrein-related peptidase 14 may be a major contributor to trypsin-like proteolytic activity in human stratum corneum. Biol Chem 2006; 387: 761-768.
10 Eissa A, Amodeo V, Smith CR. et al. Kallikrein-related peptidase-8 (KLK8) is an active serine protease in human epidermis and sweat and is involved in a skin barrier proteolytic cascade. J Biol Chem 2011; 286: 687-706.
11 Lundwall A, Brattsand M. Kallikrein-related peptidases. Cell Mol Life Sci 2008; 65: 2019-2038.
12 Shaw JL, Diamandis EP. Distribution of 15 human kallikreins in tissues and biological fluids. Clin Chem 2007; 53: 1423-1432.
13 Komatsu N, Takata M, Otsuki N. et al. Expression and localisation of tissue kallikrein mRNAs in human epidermis and appendages. J Invest Dermatol 2003; 121: 542-549.
14 Komatsu N, Saijoh K, Toyama T. et al. Multiple tissue kallikrein mRNA and protein expression in normal skin and skin diseases. Br J Dermatol 2005; 153: 274-281.
15 Nylander-Lundqvist E, Back O, Egelrud T. IL-1 beta activation in human epidermis. J Immunol 1996; 157: 1699-1704.
16 Yao C, Karabasil MR, Purwanti N. et al. Tissue kallikrein mK13 is a candidate processing enzyme for the precursor of interleukin-1beta in the submandibular gland of mice. J Biol Chem 2006; 281: 7968-7976.
17 Yamasaki K, Schauber J, Coda A. et al. Kallikrein-mediated proteolysis regulates the antimicrobial effects of cathelicidins in skin. FASEB J 2006; 20: 2068-2080.
18 Yamasaki K, Di Nardo A, Bardan A. et al. Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. Nat Med 2007; 13: 975-980.
19 Meyer-Hoffert U, Schroder JM. Epidermal proteases in the pathogenesis of rosacea. J Investig Dermatol Symp Proc 2011; 15: 16-23.
20 Shaw JL, Diamandis EP. Regulation of human tissue kallikrein-related peptidase expression by steroid hormones in 32 cell lines. Biol Chem 2008; 389: 1409-1419.
21 Sa SM, Valdez PA, Wu J. et al. The effects of IL-20 subfamily cytokines on reconstituted human epidermis suggest potential roles in cutaneous innate defense and pathogenic adaptive immunity in psoriasis. J Immunol 2007; 178: 2229-2240.
22 Komatsu N, Saijoh K, Kuk C. et al. Aberrant human tissue kallikrein levels in the stratum corneum and serum of patients with psoriasis: dependence on phenotype, severity and therapy. Br J Dermatol 2007; 156: 875-883.
23 Voegeli R, Rawlings AV, Breternitz M. et al. Increased stratum corneum serine protease activity in acute eczematous atopic skin. Br J Dermatol 2009; 161: 70-77.
24 Voegeli R, Doppler S, Joller P. et al. Increased mass levels of certain serine proteases in the stratum corneum in acute eczematous atopic skin. Int J Cosmet Sci 2011; 33: 560-565.
25 Morizane S, Yamasaki K, Kabigting FD. et al. Kallikrein expression and cathelicidin processing are independently controlled in keratinocytes by calcium, vitamin D(3), and retinoic acid. J Invest Dermatol 2010; 130: 1297-1306.
26 Kawasaki S, Kawamoto S, Yokoi N. et al. Up-regulated gene expression in the conjunctival epithelium of patients with Sjogren's syndrome. Exp Eye Res 2003; 77: 17-26.
27 Yoon H, Blaber SI, Debela M. et al. A completed KLK activome profile: investigation of activation profiles of KLK9, 10, and 15. Biol Chem 2009; 390: 373-377.
28 Yoon H, Laxmikanthan G, Lee J. et al. Activation profiles and regulatory cascades of the human kallikrein-related peptidases. J Biol Chem 2007; 282: 31852-31864.
29 Beaufort N, Plaza K, Utzschneider D. et al. Interdependence of kallikrein-related peptidases in proteolytic networks. Biol Chem 2010; 391: 581-587.
30 Yoon H, Blaber SI, Li W. et al. Activation profiles of human kallikrein-related peptidases by matrix metalloproteinases. Biol Chem 2013; 394: 137-147.
31 Ohler A, Debela M, Wagner S. et al. Analyzing the protease web in skin: meprin metalloproteases are activated specifically by KLK4, 5 and 8 vice versa leading to processing of proKLK7 thereby triggering its activation. Biol Chem 2010; 391: 455-460.
32 Sales KU, Masedunskas A, Bey AL. et al. Matriptase initiates activation of epidermal pro-kallikrein and disease onset in a mouse model of Netherton syndrome. Nat Genet 2010; 42: 676-683.
33 Blaber M, Yoon H, Juliano MA. et al. Functional intersection of the kallikrein-related peptidases (KLKs) and thrombostasis axis. Biol Chem 2010; 391: 311-320.
34 Kanada KN, Nakatsuji T, Gallo RL. Doxycycline Indirectly Inhibits Proteolytic Activation of Tryptic Kallikrein-Related Peptidases and Activation of Cathelicidin. J Invest Dermatol 2012; 132: 1435-1442.
35 Monk E, Shalita A, Siegel DM. Clinical applications of non-antimicrobial tetracyclines in dermatology. Pharmacol Res 2011; 63: 130-145.
36 Memari N, Jiang W, Diamandis EP. et al. Enzymatic properties of human kallikrein-related peptidase 12 (KLK12). Biol Chem 2007; 388: 427-435.
37 Borgono CA, Michael IP, Shaw JL. et al. Expression and functional characterisation of the cancer-related serine protease, human tissue kallikrein 14. J Biol Chem 2007; 282: 2405-2422.
38 Bayes A, Tsetsenis T, Ventura S. et al. Human kallikrein 6 activity is regulated via an autoproteolytic mechanism of activation/inactivation. Biol Chem 2004; 385: 517-524.
39 Hachem JP, Houben E, Crumrine D. et al. Serine protease signaling of epidermal permeability barrier homeostasis. J Invest Dermatol 2006; 126: 2074-2086.
40 Goettig P, Magdolen V, Brandstetter H. Natural and synthetic inhibitors of kallikrein-related peptidases (KLKs). Biochimie 2010; 92: 1546-1567.
41 Kaiserman D, Whisstock JC, Bird PI. Mechanisms of serpin dysfunction in disease. Expert Rev Mol Med 2006; 08: 1-19.
42 Farshchian M, Kivisaari A, Ala-Aho R. et al. Serpin peptidase inhibitor clade A member 1 (SerpinA1) is a novel biomarker for progression of cutaneous squamous cell carcinoma. Am J Pathol 2011; 179: 1110-1119.
43 Hoffmann DC, Textoris C, Oehme F. et al. Pivotal role for alpha1-antichymotrypsin in skin repair. J Biol Chem 2011; 286: 28889-28901.
44 Krebs M, Uhrin P, Vales A. et al. Protein C inhibitor is expressed in keratinocytes of human skin. J Invest Dermatol 1999; 113: 32-37.
45 Zhang C, Li X, Lian X. et al. Immunolocalisation of protein C inhibitor in differentiation of human epidermal keratinocytes. Acta Histochem 2007; 109: 461-467.
46 Providence KM, Higgins PJ. PAI-1 expression is required for epithelial cell migration in two distinct phases of in vitro wound repair. J Cell Physiol 2004; 200: 297-308.
47 Chavanas S, Bodemer C, Rochat A. et al. Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome. Nat Genet 2000; 25: 141-142.
48 Comel M. Ichthyosis linearis circumflexa. Dermatologica 1949; 98: 133-136.
49 Netherton EW. A unique case of trichorrhexis nodosa; bamboo hairs. AMA Arch Derm 1958; 78: 483-487.
50 Bitoun E, Micheloni A, Lamant L. et al. LEKTI proteolytic processing in human primary keratinocytes, tissue distribution and defective expression in Netherton syndrome. Hum Mol Genet 2003; 12: 2417-2430.
51 Egelrud T, Brattsand M, Kreutzmann P. et al. hK5 and hK7, two serine proteinases abundant in human skin, are inhibited by LEKTI domain 6. Br J Dermatol 2005; 153: 1200-1203.
52 Descargues P, Deraison C, Bonnart C. et al. Spink5-deficient mice mimic Netherton syndrome through degradation of desmoglein 1 by epidermal protease hyperactivity. Nat Genet 2005; 37: 56-65.
53 Hachem JP, Wagberg F, Schmuth M. et al. Serine protease activity and residual LEKTI expression determine phenotype in Netherton syndrome. J Invest Dermatol 2006; 126: 1609-1621.
54 Briot A, Deraison C, Lacroix M. et al. Kallikrein 5 induces atopic dermatitis-like lesions through PAR2-mediated thymic stromal lymphopoietin expression in Netherton syndrome. J Exp Med 2009; 206: 1135-1147.
55 Briot A, Lacroix M, Robin A. et al. Par2 inactivation inhibits early production of TSLP, but not cutaneous inflammation, in Netherton syndrome adult mouse model. J Invest Dermatol 2010; 130: 2736-2742.
56 Furio L, Hovnanian A. When activity requires breaking up: LEKTI proteolytic activation cascade for specific proteinase inhibition. J Invest Dermatol 2011; 131: 2169-2173.
57 Mitsudo K, Jayakumar A, Henderson Y. et al. Inhibition of serine proteinases plasmin, trypsin, subtilisin A, cathepsin G, and elastase by LEKTI: a kinetic analysis. Biochemistry 2003; 42: 3874-3881.
58 Jayakumar A, Kang Y, Mitsudo K. et al. Expression of LEKTI domains 6-9' in the baculovirus expression system: recombinant LEKTI domains 6-9' inhibit trypsin and subtilisin A. Protein Expr Purif 2004; 35: 93-101.
59 Schechter NM, Choi EJ, Wang ZM. et al. Inhibition of human kallikreins 5 and 7 by the serine protease inhibitor lympho-epithelial Kazal-type inhibitor (LEKTI). Biol Chem 2005; 386: 1173-1184.
60 Kreutzmann P, Schulz A, Standker L. et al. Recombinant production, purification and biochemical characterisation of domain 6 of LEKTI: a temporary Kazal-type-related serine proteinase inhibitor. J Chromatogr B Analyt Technol Biomed Life Sci 2004; 803: 75-81.
61 Deraison C, Bonnart C, Lopez F. et al. LEKTI fragments specifically inhibit KLK5, KLK7, and KLK14 and control desquamation through a pH-dependent interaction. Mol Biol Cell 2007; 18: 3607-3619.
62 Borgono CA, Michael IP, Komatsu N. et al. A potential role for multiple tissue kallikrein serine proteases in epidermal desquamation. J Biol Chem 2007; 282: 3640-3652.
63 Fortugno P, Bresciani A, Paolini C. et al. Proteolytic activation cascade of the Netherton syndrome-defective protein, LEKTI, in the epidermis: implications for skin homeostasis. J Invest Dermatol 2011; 131: 2223-2232.
64 Fortugno P, Furio L, Teson M. et al. The 420K LEKTI variant alters LEKTI proteolytic activation and results in protease deregulation: implications for atopic dermatitis. Hum Mol Genet 2012; 21: 4187-4200.
65 Meyer-Hoffert U, Wu Z, Schroder JM. Identification of lympho-epithelial Kazal-type inhibitor 2 in human skin as a kallikrein-related peptidase 5-specific protease inhibitor. PLoS ONE 2009; 04: e4372.
66 Brattsand M, Stefansson K, Hubiche T. et al. SPINK9: A Selective, Skin-Specific Kazal-Type Serine Protease Inhibitor. J Invest Dermatol 2009; 129: 1656-1665.
67 Brannstrom K, Ohman A, von Pawel Rammingen U. et al. Characterisation of SPINK9, a KLK5-specific inhibitor expressed in palmo-plantar epidermis. Biol Chem 2012; 393: 369-377.
68 Reiss K, Meyer-Hoffert U, Fischer J. et al. Expression and regulation of murine SPINK12, a potential orthologue of human LEKTI2. Exp Dermatol 2011; 20: 905-910.
69 Meyer-Hoffert U, Wu Z, Kantyka T. et al. Isolation of SPINK6 in human skin: selective inhibitor of kallikrein-related peptidases. J Biol Chem 2010; 285: 32174-32181.
70 Kantyka T, Fischer J, Wu Z. et al. Inhibition of Kallikrein-related Peptidases by the Serine Protease Inhibitor of Kazal-type 6. Peptides 2011; 32: 1187-1192.
71 Lu H, Huang J, Li G. et al. Expression, purification and characterisation of recombinant human serine proteinase inhibitor Kazal-type 6 (SPINK6) in Pichia pastoris. Protein Expr Purif 2012; 82: 144-149.
72 Bennett K, Callard R, Heywood W. et al. New role for LEKTI in skin barrier formation: label-free quantitative proteomic identification of caspase 14 as a novel target for the protease inhibitor LEKTI. J Proteome Res 2010; 09: 4289-4294.
73 Fischer J, Koblyakova Y, Latendorf T. et al. Cross-Linking of SPINK6 by Transglutaminases Protects from Epidermal Proteases. J Invest Dermatol. 2013. epub ahead of print
74 Drenth JP, te Morsche R, Jansen JB. Mutations in serine protease inhibitor Kazal type 1 are strongly associated with chronic pancreatitis. Gut 2002; 50: 687-692.
75 Schalkwijk J, Wiedow O, Hirose S. The trappin gene family: proteins defined by an N-terminal transglutaminase substrate domain and a C-terminal four-disulphide core. Biochem J 1999; 340: 569-577.
76 Bonnart C, Deraison C, Lacroix M. et al. Elastase 2 is expressed in human and mouse epidermis and impairs skin barrier function in Netherton syndrome through filaggrin and lipid misprocessing. J Clin Invest 2010; 120: 871-882.
77 Franzke CW, Baici A, Bartels J. et al. Antileukoprotease inhibits stratum corneum chymotryptic enzyme. Evidence for a regulative function in desquamation. J Biol Chem 1996; 271: 21886-21890.
78 Delaria KA, Muller DK, Marlor CW. et al. Characterisation of placental bikunin, a novel human serine protease inhibitor. J Biol Chem 1997; 272: 12209-12214.
79 Bugge TH, List K, Szabo R. Matriptase-dependent cell surface proteolysis in epithelial development and pathogenesis. Front Biosci 2007; 12: 5060-5070.
80 Mukai S, Fukushima T, Naka D. et al. Activation of hepatocyte growth factor activator zymogen (pro-HGFA) by human kallikrein 1-related peptidases. Febs J 2008; 275: 1003-1017.
81 Swedberg JE, de Veer SJ, Harris JM. Natural and engineered kallikrein inhibitors: an emerging pharmacopoeia. Biol Chem 2010; 391: 357-374.