Proteases and proteomics: Cutting to the core of human skin pathologies

Proteomics - Clinical Applications

Volumn 8, Issue 5-6, 2014, Pages 389-402

  de Veer, Simon J ^a,b,c   Furio, Laetitia ^a,b   Harris, Jonathan M ^c   Hovnanian, Alain ^a,b,d  

^a UNIVERSITÉ PARIS DESCARTES   (France)

^b IMAGINE INSTITUTE   (France)

^c QUEENSLAND UNIVERSITY OF TECHNOLOGY   (Australia)

^d HÔPITAL NECKER ENFANTS MALADES   (France)

Author keywords

Epidermis; Inflammation; Keratinocyte; Permeability barrier; Therapeutic target

Indexed keywords

CATHELICIDIN ANTIMICROBIAL PEPTIDE LL 37; CYCLIC AMP; DIPEPTIDYL PEPTIDASE I; FILAGGRIN; INACTIVE RHOMBOID PROTEIN; INTERLEUKIN 36 RECEPTOR INHIBITOR ANTAGONIST; INTERLEUKIN RECEPTOR; INTERSTITIAL COLLAGENASE; LYMPHOEPITHELIAL KAZAL TYPE INHIBITOR; MATRIPTASE; PROTEINASE; PROTEINASE INHIBITOR; STEFIN A; UNCLASSIFIED DRUG; PEPTIDE HYDROLASE;

ADAM17 GENE; ATOPIC DERMATITIS; CSTA GENE; CTSC GENE; ENZYME SPECIFICITY; EPIDERMOLYSIS BULLOSA HEREDITARIA; EXTRACELLULAR MATRIX; FLG GENE; GENE EXPRESSION REGULATION; HUMAN; ICHTHYOSIS; IL36RN GENE; IMMUNOCOMPETENT CELL; IRRITABLE COLON; KERATINOCYTE; LYMPHOCYTIC INFILTRATION; MMP1 GENE; NETHERTON DISEASE; NONHUMAN; NUCLEOTIDE SEQUENCE; PAPILLON LEFEVRE SYNDROME; PATHOGENESIS; PERMEABILITY BARRIER; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN CLEAVAGE; PROTEIN EXPRESSION; PROTEOMICS; PSORS1 GENE; PUSTULAR PSORIASIS; REVIEW; RHBDF2 GENE; ROSACEA; SKIN DISEASE; SKIN PERMEABILITY; SKIN STRUCTURE; SPINK5 GENE; ST14 GENE; TRANSCRIPTOMICS; TYLOSIS; ANIMAL; ENZYMOLOGY; GENE EXPRESSION PROFILING; GENETICS; METABOLISM; PATHOLOGY; PROCEDURES;

ANIMALS; GENE EXPRESSION PROFILING; GENE EXPRESSION REGULATION, ENZYMOLOGIC; HUMANS; PEPTIDE HYDROLASES; PROTEASE INHIBITORS; PROTEOMICS; SKIN DISEASES;

EID: 84902081116     PISSN: 18628346     EISSN: 18628354     Source Type: Journal    
DOI: 10.1002/prca.201300081     Document Type: Review

References (102)

1. Rochat, A., Kobayashi, K., Barrandon, Y., Location of stem cells of human hair follicles by clonal analysis. Cell 1994, 76, 1063-1073.
2. Jones, P. H., Harper, S., Watt, F. M., Stem cell patterning and fate in human epidermis. Cell 1995, 80, 83-93.
3. Koster, M. I., Kim, S., Mills, A. A., DeMayo, F. J., Roop, D. R., p63 is the molecular switch for initiation of an epithelial stratification program. Genes Dev. 2004, 18, 126-131.
4. Rangarajan, A., Talora, C., Okuyama, R., Nicolas, M. et al., Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. EMBO J. 2001, 20, 3427-3436.
5. Fuchs, E., Green, H., Changes in keratin gene expression during terminal differentiation of the keratinocyte. Cell 1980, 19, 1033-1042.
6. Manabe, M., Sanchez, M., Sun, T. T., Dale, B. A., Interaction of filaggrin with keratin filaments during advanced stages of normal human epidermal differentiation and in ichthyosis vulgaris. Differentiation 1991, 48, 43-50.
7. Steven, A. C., Steinert, P. M., Protein composition of cornified cell envelopes of epidermal keratinocytes. J. Cell Sci. 1994, 107(Pt 2), 693-700.
8. Elias, P. M., Friend, D. S., The permeability barrier in mammalian epidermis. J. Cell Biol. 1975, 65, 180-191.
9. Lundstrom, A., Egelrud, T., Cell shedding from human plantar skin in vitro: evidence of its dependence on endogenous proteolysis. J. Invest. Dermatol. 1988, 91, 340-343.
10. Toomes, C., James, J., Wood, A. J., Wu, C. L. et al., Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis. Nat. Genet. 1999, 23, 421-424.
11. Turk, D., Janjic, V., Stern, I., Podobnik, M. et al., Structure of human dipeptidyl peptidase I (cathepsin C): exclusion domain added to an endopeptidase framework creates the machine for activation of granular serine proteases. EMBO J. 2001, 20, 6570-6582.
12. Meade, J. L., de Wynter, E. A., Brett, P., Sharif, S. M. et al., A family with Papillon-Lefevre syndrome reveals a requirement for cathepsin C in granzyme B activation and NK cell cytolytic activity. Blood 2006, 107, 3665-3668.
13. Pham, C. T., Ivanovich, J. L., Raptis, S. Z., Zehnbauer, B., Ley, T. J., Papillon-Lefevre syndrome: correlating the molecular, cellular, and clinical consequences of cathepsin C/dipeptidyl peptidase I deficiency in humans. J. Immunol. 2004, 173, 7277-7281.
14. Chavanas, S., Bodemer, C., Rochat, A., Hamel-Teillac, D. et al., Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome. Nat. Genet. 2000, 25, 141-142.
15. Hausser, I., Anton-Lamprecht, I., Severe congenital generalized exfoliative erythroderma in newborns and infants: a possible sign of Netherton syndrome. Pediatr. Dermatol. 1996, 13, 183-199.
16. Judge, M. R., Morgan, G., Harper, J. I., A clinical and immunological study of Netherton's syndrome. Br. J. Dermatol. 1994, 131, 615-621.
17. Briot, A., Deraison, C., Lacroix, M., Bonnart, C. 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.
18. Descargues, P., Deraison, C., Bonnart, C., Kreft, M. et al., Spink5-deficient mice mimic Netherton syndrome through degradation of desmoglein 1 by epidermal protease hyperactivity. Nat. Genet. 2005, 37, 56-65.
19. Descargues, P., Deraison, C., Prost, C., Fraitag, S. et al., Corneodesmosomal cadherins are preferential targets of stratum corneum trypsin- and chymotrypsin-like hyperactivity in Netherton syndrome. J. Invest. Dermatol. 2006, 126, 1622-1632.
20. Yang, T., Liang, D., Koch, P. J., Hohl, D. et al., Epidermal detachment, desmosomal dissociation, and destabilization of corneodesmosin in Spink5-/- mice. Genes Dev. 2004, 18, 2354-2358.
21. Deraison, C., Bonnart, C., Lopez, F., Besson, C. 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.
22. Ishida-Yamamoto, A., Deraison, C., Bonnart, C., Bitoun, E. et al., LEKTI is localized in lamellar granules, separated from KLK5 and KLK7, and is secreted in the extracellular spaces of the superficial stratum granulosum. J. Invest. Dermatol. 2005, 124, 360-366.
23. Bonnart, C., Deraison, C., Lacroix, M., Uchida, Y. 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.
24. Furio, L., de Veer, S., Jaillet, M., Briot, A. et al., Transgenic kallikrein 5 mice reproduce major cutaneous and systemic hallmarks of Netherton syndrome. J. Exp. Med., 2014, doi:10.1084/jem.20131797.
25. Basel-Vanagaite, L., Attia, R., Ishida-Yamamoto, A., Rainshtein, L. et al., Autosomal recessive ichthyosis with hypotrichosis caused by a mutation in ST14, encoding type II transmembrane serine protease matriptase. Am. J. Hum. Genet. 2007, 80, 467-477.
26. Alef, T., Torres, S., Hausser, I., Metze, D. et al., Ichthyosis, follicular atrophoderma, and hypotrichosis caused by mutations in ST14 is associated with impaired profilaggrin processing. J. Invest. Dermatol. 2009, 129, 862-869.
27. List, K., Szabo, R., Wertz, P. W., Segre, J. et al., Loss of proteolytically processed filaggrin caused by epidermal deletion of Matriptase/MT-SP1. J. Cell Biol. 2003, 163, 901-910.
28. Sales, K. U., Masedunskas, A., Bey, A. L., Rasmussen, A. L. 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.
29. Charles, R. P., Guitard, M., Leyvraz, C., Breiden, B. et al., Postnatal requirement of the epithelial sodium channel for maintenance of epidermal barrier function. J. Biol. Chem. 2008, 283, 2622-2630.
30. Blaydon, D. C., Nitoiu, D., Eckl, K. M., Cabral, R. M. et al., Mutations in CSTA, encoding Cystatin A, underlie exfoliative ichthyosis and reveal a role for this protease inhibitor in cell-cell adhesion. Am. J. Hum. Genet. 2011, 89, 564-571.
31. Krunic, A. L., Stone, K. L., Simpson, M. A., McGrath, J. A., Acral peeling skin syndrome resulting from a homozygous nonsense mutation in the CSTA gene encoding Cystatin A. Pediatr. Dermatol. 2013, 30, e87-e88.
32. Pavlovic, S., Krunic, A. L., Bulj, T. K., Medenica, M. M. et al., Acral peeling skin syndrome: a clinically and genetically heterogeneous disorder. Pediatr. Dermatol. 2012, 29, 258-263.
33. Blaydon, D. C., Biancheri, P., Di, W. L., Plagnol, V. et al., Inflammatory skin and bowel disease linked to ADAM17 deletion. N. Engl. J. Med. 2011, 365, 1502-1508.
34. Franzke, C. W., Cobzaru, C., Triantafyllopoulou, A., Loffek, S. et al., Epidermal ADAM17 maintains the skin barrier by regulating EGFR ligand-dependent terminal keratinocyte differentiation. J. Exp. Med. 2012, 209, 1105-1119.
35. Blaydon, D. C., Etheridge, S. L., Risk, J. M., Hennies, H. C. et al., RHBDF2 mutations are associated with tylosis, a familial esophageal cancer syndrome. Am. J. Hum. Genet. 2012, 90, 340-346.
36. Zettl, M., Adrain, C., Strisovsky, K., Lastun, V., Freeman, M., Rhomboid family pseudoproteases use the ER quality control machinery to regulate intercellular signaling. Cell 2011, 145, 79-91.
37. Maretzky, T., McIlwain, D. R., Issuree, P. D., Li, X. et al., iRhom2 controls the substrate selectivity of stimulated ADAM17-dependent ectodomain shedding. Proc. Natl. Acad. Sci. USA 2013, 110, 11433-11438.
38. Etheridge, S. L., Brooke, M. A., Kelsell, D. P., Blaydon, D. C., Rhomboid proteins: a role in keratinocyte proliferation and cancer. Cell Tissue Res. 2013, 351, 301-307.
39. Varki, R., Sadowski, S., Uitto, J., Pfendner, E., Epidermolysis bullosa. II. Type VII collagen mutations and phenotype-genotype correlations in the dystrophic subtypes. J. Med. Genet. 2007, 44, 181-192.
40. Hovnanian, A., Duquesnoy, P., Amselem, S., Blanchet-Bardon, C. et al., Exclusion of linkage between the collagenase gene and generalized recessive dystrophic epidermolysis bullosa phenotype. J. Clin. Invest. 1991, 88, 1716-1721.
41. Titeux, M., Pendaries, V., Tonasso, L., Decha, A. et al., A frequent functional SNP in the MMP1 promoter is associated with higher disease severity in recessive dystrophic epidermolysis bullosa. Hum. Mutat. 2008, 29, 267-276.
42. Kern, J. S., Gruninger, G., Imsak, R., Muller, M. L. et al., Forty-two novel COL7A1 mutations and the role of a frequent single nucleotide polymorphism in the MMP1 promoter in modulation of disease severity in a large European dystrophic epidermolysis bullosa cohort. Br. J. Dermatol. 2009, 161, 1089-1097.
43. Suarez-Farinas, M., Dhingra, N., Gittler, J., Shemer, A. et al., Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune activation compared with extrinsic atopic dermatitis. J. Allergy Clin. Immunol. 2013, 132, 361-370.
44. Elias, P. M., Hatano, Y., Williams, M. L., Basis for the barrier abnormality in atopic dermatitis: outside-inside-outside pathogenic mechanisms. J. Allergy Clin. Immunol. 2008, 121, 1337-1343.
45. Ellinghaus, D., Baurecht, H., Esparza-Gordillo, J., Rodriguez, E. et al., High-density genotyping study identifies four new susceptibility loci for atopic dermatitis. Nat. Genet. 2013, 45, 808-812.
46. Palmer, C. N., Irvine, A. D., Terron-Kwiatkowski, A., Zhao, Y. et al., Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat. Genet. 2006, 38, 441-446.
47. Weidinger, S., Illig, T., Baurecht, H., Irvine, A. D. et al., Loss-of-function variations within the filaggrin gene predispose for atopic dermatitis with allergic sensitizations. J. Allergy Clin. Immunol. 2006, 118, 214-219.
48. Fortugno, P., Furio, L., Teson, M., Berretti, 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.
49. Janssens, M., van Smeden, J., Gooris, G. S., Bras, W. et al., Increase in short-chain ceramides correlates with an altered lipid organization and decreased barrier function in atopic eczema patients. J. Lipid Res. 2012, 53, 2755-2766.
50. Howell, M. D., Kim, B. E., Gao, P., Grant, A. V. et al., Cytokine modulation of atopic dermatitis filaggrin skin expression. J. Allergy Clin. Immunol. 2007, 120, 150-155.
51. Soumelis, V., Reche, P. A., Kanzler, H., Yuan, W. et al., Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat. Immunol. 2002, 3, 673-680.
52. Kezic, S., O'Regan, G. M., Yau, N., Sandilands, A. et al., Levels of filaggrin degradation products are influenced by both filaggrin genotype and atopic dermatitis severity. Allergy 2011, 66, 934-940.
53. Hachem, J. P., Man, M. Q., Crumrine, D., Uchida, Y. et al., Sustained serine proteases activity by prolonged increase in pH leads to degradation of lipid processing enzymes and profound alterations of barrier function and stratum corneum integrity. J. Invest. Dermatol. 2005, 125, 510-520.
54. Elder, J. T., Bruce, A. T., Gudjonsson, J. E., Johnston, A. et al., Molecular dissection of psoriasis: integrating genetics and biology. J. Invest. Dermatol. 2010, 130, 1213-1226.
55. Ellis, C. N., Gorsulowsky, D. C., Hamilton, T. A., Billings, J. K. et al., Cyclosporine improves psoriasis in a double-blind study. JAMA 1986, 256, 3110-3116.
56. Snowden, J. A., Heaton, D. C., Development of psoriasis after syngeneic bone marrow transplant from psoriatic donor: further evidence for adoptive autoimmunity. Br. J. Dermatol. 1997, 137, 130-132.
57. Nair, R. P., Stuart, P. E., Nistor, I., Hiremagalore, R. et al., Sequence and haplotype analysis supports HLA-C as the psoriasis susceptibility 1 gene. Am. J. Hum. Genet. 2006, 78, 827-851.
58. Marrakchi, S., Guigue, P., Renshaw, B. R., Puel, A. et al., Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis. N. Engl. J. Med. 2011, 365, 620-628.
59. Lande, R., Gregorio, J., Facchinetti, V., Chatterjee, B. et al., Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 2007, 449, 564-569.
60. Nestle, F. O., Conrad, C., Tun-Kyi, A., Homey, B. et al., Plasmacytoid predendritic cells initiate psoriasis through interferon-alpha production. J. Exp. Med. 2005, 202, 135-143.
61. Morizane, S., Yamasaki, K., Muhleisen, B., Kotol, P. F. et al., Cathelicidin antimicrobial peptide LL-37 in psoriasis enables keratinocyte reactivity against TLR9 ligands. J. Invest. Dermatol. 2012, 132, 135-143.
62. Sorensen, O. E., Follin, P., Johnsen, A. H., Calafat, J. et al., Human cathelicidin, hCAP-18, is processed to the antimicrobial peptide LL-37 by extracellular cleavage with proteinase 3. Blood 2001, 97, 3951-3959.
63. Yamasaki, K., Schauber, J., Coda, A., Lin, H. et al., Kallikrein-mediated proteolysis regulates the antimicrobial effects of cathelicidins in skin. FASEB J. 2006, 20, 2068-2080.
64. Duk, J. M., van Voorst Vader, P. C., ten Hoor, K. A., Hollema, H. et al., Elevated levels of squamous cell carcinoma antigen in patients with a benign disease of the skin. Cancer 1989, 64, 1652-1656.
65. Wiedow, O., Schroder, J. M., Gregory, H., Young, J. A., Christophers, E., Elafin: an elastase-specific inhibitor of human skin. Purification, characterization, and complete amino acid sequence. J. Biol. Chem. 1990, 265, 14791-14795.
66. Komatsu, N., Saijoh, K., Kuk, C., Shirasaki, F. 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.
67. Steinhoff, M., Buddenkotte, J., Aubert, J., Sulk, M. et al., Clinical, cellular, and molecular aspects in the pathophysiology of rosacea. J. Investig. Dermatol. Symp. Proc. 2011, 15, 2-11.
68. Yamasaki, K., Gallo, R. L., Rosacea as a disease of cathelicidins and skin innate immunity. J. Investig. Dermatol. Symp. Proc. 2011, 15, 12-15.
69. Yamasaki, K., Di Nardo, A., Bardan, A., Murakami, M. et al., Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. Nat. Med. 2007, 13, 975-980.
70. Yamasaki, K., Kanada, K., Macleod, D. T., Borkowski, A. W. et al., TLR2 expression is increased in rosacea and stimulates enhanced serine protease production by keratinocytes. J. Invest. Dermatol. 2011, 131, 688-697.
71. Sulk, M., Seeliger, S., Aubert, J., Schwab, V. D. et al., Distribution and expression of non-neuronal transient receptor potential (TRPV) ion channels in rosacea. J. Invest. Dermatol. 2012, 132, 1253-1262.
72. Schwab, V. D., Sulk, M., Seeliger, S., Nowak, P. et al., Neurovascular and neuroimmune aspects in the pathophysiology of rosacea. J. Investig. Dermatol. Symp. Proc. 2011, 15, 53-62.
73. Lund, L. R., Romer, J., Bugge, T. H., Nielsen, B. S. et al., Functional overlap between two classes of matrix-degrading proteases in wound healing. EMBO J. 1999, 18, 4645-4656.
74. Tran, K. T., Lamb, P., Deng, J. S., Matrikines and matricryptins: implications for cutaneous cancers and skin repair. J. Dermatol. Sci. 2005, 40, 11-20.
75. Martins, V. L., Caley, M., O'Toole, E. A., Matrix metalloproteinases and epidermal wound repair. Cell Tissue Res. 2013, 351, 255-268.
76. Oestreicher, J. L., Walters, I. B., Kikuchi, T., Gilleaudeau, P. et al., Molecular classification of psoriasis disease-associated genes through pharmacogenomic expression profiling. Pharmacogenomics J. 2001, 1, 272-287.
77. Bowcock, A. M., Shannon, W., Du, F., Duncan, J. et al., Insights into psoriasis and other inflammatory diseases from large-scale gene expression studies. Hum. Mol. Genet. 2001, 10, 1793-1805.
78. Sugiura, H., Ebise, H., Tazawa, T., Tanaka, K. et al., Large-scale DNA microarray analysis of atopic skin lesions shows overexpression of an epidermal differentiation gene cluster in the alternative pathway and lack of protective gene expression in the cornified envelope. Br. J. Dermatol. 2005, 152, 146-149.
79. Nomura, I., Gao, B., Boguniewicz, M., Darst, M. A. et al., Distinct patterns of gene expression in the skin lesions of atopic dermatitis and psoriasis: a gene microarray analysis. J. Allergy Clin. Immunol. 2003, 112, 1195-1202.
80. Nomura, I., Goleva, E., Howell, M. D., Hamid, Q. A. et al., Cytokine milieu of atopic dermatitis, as compared to psoriasis, skin prevents induction of innate immune response genes. J. Immunol. 2003, 171, 3262-3269.
81. Guttman-Yassky, E., Suarez-Farinas, M., Chiricozzi, A., Nograles, K. E. et al., Broad defects in epidermal cornification in atopic dermatitis identified through genomic analysis. J. Allergy Clin. Immunol. 2009, 124, 1235-1244 e1258.
82. Guttman-Yassky, E., Lowes, M. A., Fuentes-Duculan, J., Zaba, L. C. et al., Low expression of the IL-23/Th17 pathway in atopic dermatitis compared to psoriasis. J. Immunol. 2008, 181, 7420-7427.
83. Gudjonsson, J. E., Ding, J., Johnston, A., Tejasvi, T. et al., Assessment of the psoriatic transcriptome in a large sample: additional regulated genes and comparisons with in vitro models. J. Invest. Dermatol. 2010, 130, 1829-1840.
84. Suarez-Farinas, M., Li, K., Fuentes-Duculan, J., Hayden, K. et al., Expanding the psoriasis disease profile: interrogation of the skin and serum of patients with moderate-to-severe psoriasis. J. Invest. Dermatol. 2012, 132, 2552-2564.
85. Carlen, L. M., Sanchez, F., Bergman, A. C., Becker, S. et al., Proteome analysis of skin distinguishes acute guttate from chronic plaque psoriasis. J. Invest. Dermatol. 2005, 124, 63-69.
86. Howell, M. D., Fairchild, H. R., Kim, B. E., Bin, L. et al., Th2 cytokines act on S100/A11 to downregulate keratinocyte differentiation. J. Invest. Dermatol. 2008, 128, 2248-2258.
87. Broccardo, C. J., Mahaffey, S. B., Strand, M., Reisdorph, N. A., Leung, D. Y., Peeling off the layers: skin taping and a novel proteomics approach to study atopic dermatitis. J. Allergy Clin. Immunol. 2009, 124, 1113-1115.
88. Broccardo, C. J., Mahaffey, S., Schwarz, J., Wruck, L. et al., Comparative proteomic profiling of patients with atopic dermatitis based on history of eczema herpeticum infection and Staphylococcus aureus colonization. J. Allergy Clin. Immunol. 2011, 127, 186-193.
89. Piruzian, E., Bruskin, S., Ishkin, A., Abdeev, R. et al., Integrated network analysis of transcriptomic and proteomic data in psoriasis. BMC Syst. Biol. 2010, 4, 41.
90. Schilling, O., Overall, C. M., Proteome-derived, database-searchable peptide libraries for identifying protease cleavage sites. Nat. Biotechnol. 2008, 26, 685-694.
91. Kleifeld, O., Doucet, A., auf dem Keller, U., Prudova, A. et al., Isotopic labeling of terminal amines in complex samples identifies protein N-termini and protease cleavage products. Nat. Biotechnol. 2010, 28, 281-288.
92. Tholen, S., Biniossek, M. L., Gansz, M., Gomez-Auli, A. et al., Deletion of cysteine cathepsins B or L yields differential impacts on murine skin proteome and degradome. Mol. Cell. Proteomics 2013, 12, 611-625.
93. Tholen, S., Biniossek, M. L., Gansz, M., Ahrens, T. D. et al., Double deficiency of cathepsins B and L results in massive secretome alterations and suggests a degradative cathepsin-MMP axis. Cell. Mol. Life Sci. 2014, 71, 899-916.
94. Becker-Pauly, C., Barre, O., Schilling, O., Auf dem Keller, U. et al., Proteomic analyses reveal an acidic prime side specificity for the astacin metalloprotease family reflected by physiological substrates. Mol. Cell. Proteomics 2011, 10, M111 009233.
95. Jefferson, T., Auf dem Keller, U., Bellac, C., Metz, V. V. et al., The substrate degradome of meprin metalloproteases reveals an unexpected proteolytic link between meprin beta and ADAM10. Cell. Mol. Life Sci. 2013, 70, 309-333.
96. Bennett, K., Callard, R., Heywood, W., Harper, J. 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, 9, 4289-4294.
97. Bennett, K., Heywood, W., Di, W. L., Harper, J. et al., The identification of a new role for LEKTI in the skin: the use of protein 'bait' arrays to detect defective trafficking of dermcidin in the skin of patients with Netherton syndrome. J. Proteomics 2012, 75, 3925-3937.
98. Auf dem Keller, U., Prudova, A., Eckhard, U., Fingleton, B., Overall, C. M., Systems-level analysis of proteolytic events in increased vascular permeability and complement activation in skin inflammation. Sci. Signal. 2013, 6, rs2.
99. Harris, J. L., Backes, B. J., Leonetti, F., Mahrus, S. et al., Rapid and general profiling of protease specificity by using combinatorial fluorogenic substrate libraries. Proc. Natl. Acad. Sci. USA 2000, 97, 7754-7759.
100. de Veer, S. J., Swedberg, J. E., Parker, E. A., Harris, J. M., Non-combinatorial library screening reveals subsite cooperativity and identifies new high efficiency substrates for kallikrein-related peptidase 14. Biol. Chem. 2012, 393, 331-341.
101. Swedberg, J. E., Nigon, L. V., Reid, J. C., de Veer, S. J. et al., Substrate-guided design of a potent and selective kallikrein-related peptidase inhibitor for kallikrein 4. Chem. Biol. 2009, 16, 633-643.
102. O'Donoghue, A. J., Eroy-Reveles, A. A., Knudsen, G. M., Ingram, J. et al., Global identification of peptidase specificity by multiplex substrate profiling. Nat. Methods 2012, 9, 1095-1100.