KLK7

Kallikrein-related peptidase 7
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 2QXG​, 2QXH​, 2QXI​, 2QXJ​, 3BSQ​
Identifiers
Symbols	KLK7 ; PRSS6; SCCE; hK7
External IDs	OMIM: 604438 MGI: 1346336 HomoloGene: 37998 IUPHAR: 2377 ChEMBL: 2443 GeneCards: KLK7 Gene
EC number	3.4.21.117
Gene ontology Molecular function • serine-type endopeptidase activity • serine-type peptidase activity Cellular component • extracellular region • epidermal lamellar body Biological process • proteolysis • epidermis development • extracellular matrix disassembly • extracellular matrix organization Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	5650	23993
Ensembl	ENSG00000169035	ENSMUSG00000030713
UniProt	P49862	Q91VE3
RefSeq (mRNA)	NM_001207053	NM_011872
RefSeq (protein)	NP_001193982	NP_036002
Location (UCSC)	Chr 19: 50.98 – 50.98 Mb	Chr 7: 43.81 – 43.82 Mb
PubMed search

Kallikrein-related peptidase 7 (KLK7) is a serine protease that in humans is encoded by the KLK7 gene.^[1][2][3][4] KLK7 was initially purified from the epidermis and characterised as stratum corneum chymotryptic enzyme (SCCE).^[5] It was later identified as the seventh member of the human kallikrein family, which includes fifteen homologous serine proteases located on chromosome 19q13.^[6]

Gene

Alternative splicing of the KLK7 gene results in two transcript variants encoding the same protein.^[4]

Function

KLK7 is secreted as an inactive zymogen in the stratum granulosum layer of the epidermis, requiring proteolytic cleavage of the short N-terminal pro-region to liberate activated enzyme. This may be performed by KLK5 or matriptase, which are in vitro activators of KLK7.^[7][8]

Once active, KLK7 is able to cleave desmocollin and corneodesmosin.^[9] These proteins constitute the extracellular component of corneodesmosomes, intercellular cohesive structures which link the intermediate filaments of adjacent cells in the stratum corneum. Proteolysis of corneodesmosomes is required for desquamation, the shedding of corneocytes from the outer layer of the epidermis. This indicates a role for KLK7 in maintaining skin homeostasis.

Both KLK5 and KLK14, other skin-expressed proteases, also cleave corneodesmosomal proteins.^[9] KLK5 is able to undergo autoactivation, as well as activating KLK7 and KLK14, suggesting a KLK skin cascade is responsible for coordinating desquamation.^[8]

KLK7 activity is regulated by a number of endogenous protein inhibitors including LEKTI,^[10][11] SPINK6,^[12] elafin^[13] and alpha-2-Macroglobulin-like 1.^[14] Both Zn²⁺ and Cu²⁺ ions are also able to inhibit KLK7.^[13]

KLK7 is a chymotrypsin-like serine protease, preferring to cleave proteins at the residues tyrosine, phenylalanine or leucine.^[15] Analysis of peptide substrate hydrolysis indicates a strong preference for tyrosine at P1.^[16]

Clinical significance

Skin disease

Dysregulation of KLK7 has been linked to several skin disorders including atopic dermatitis,^[17][18] psoriasis^[19] and Netherton syndrome.^[20][21] These diseases are characterised by excessively dry, scaly and inflamed skin, due to a disruption of skin homeostasis and correct barrier function.

Cancer

Overexpression of KLK7 may provide a route for metastasis in ovarian,^[22] breast,^[23] pancreatic,^[24] cervix,^[25] and melanoma^[26] cancers by excessive cleavage of cell junction proteins. It may also be underexpressed in lung cancer.^[27]

References

1. Hansson L, Stromqvist M, Backman A, Wallbrandt P, Carlstein A, Egelrud T (Aug 1994). "Cloning, expression, and characterization of stratum corneum chymotryptic enzyme. A skin-specific human serine proteinase". J Biol Chem 269 (30): 19420–6. PMID 8034709.
2. Lundwall A, Band V, Blaber M, Clements JA, Courty Y, Diamandis EP, Fritz H, Lilja H, Malm J, Maltais LJ, Olsson AY, Petraki C, Scorilas A, Sotiropoulou G, Stenman UH, Stephan C, Talieri M, Yousef GM (Jun 2006). "A comprehensive nomenclature for serine proteases with homology to tissue kallikreins". Biol Chem 387 (6): 637–41. doi:10.1515/BC.2006.082. PMID 16800724.
3. Diamandis, Eleftherios P.; Deperthes, David; Lundwall, Åke (Jun 2006). "Proceedings of the 1st International Symposium on Kallikreins, Lausanne, Switzerland, September 1-3 , 2005". Biol Chem 387 (6): 635–824. doi:10.1515/BC.2006.081. PMID 16800723.
4. "Entrez Gene: KLK7 kallikrein-related peptidase 7".
5. Lundstrom A, Egelrud T. (1991). "Stratum-Corneum Chymotryptic Enzyme: a Proteinase Which May Be Generally Present in the Stratum-Corneum and with a Possible Involvement in Desquamation". Acta Dermato-Venereologica 71 (6): 471–474. PMID 1685827.
6. Yousef GM, Scorilas A, Magklara A, et al. (2000). "The KLK7 (PRSS6) gene, encoding for the stratum corneum chymotryptic enzyme is a new member of the human kallikrein gene family - genomic characterization, mapping, tissue expression and hormonal regulation.". Gene 254 (1-2): 119–28. doi:10.1016/S0378-1119(00)00280-8. PMID 10974542.
7. Katiuchia Uzzun Sales, Andrius Masedunskas, Alexandra L. Bey, Amber Rasmussen, Roberto Weigert, Karin List, Roman Szabo, Paul A. Overbeek, Thomas H. Bugge (2010). "Matriptase initiates epidermal prokallikrein activation and disease onset in a mouse model of Netherton syndrome". Nat. Genet. 42 (8): 676–683. doi:10.1038/ng.629. PMC 3081165. PMID 20657595.
8. Brattsand, M., Stefansson, K., Lundh, C., Haasum, Y., & Egelrud, T. (2005). "A proteolytic cascade of kallikreins in the stratum corneum.". Journal of Investigative Dermatology 124 (1): 198–203. doi:10.1111/j.0022-202X.2004.23547.x. PMID 15654974.
9. Caubet C, Jonca N, Brattsand M, et al. (2004). "Degradation of corneodesmosome proteins by two serine proteases of the kallikrein family, SCTE/KLK5/hK5 and SCCE/KLK7/hK7.". J. Invest. Dermatol. 122 (5): 1235–44. doi:10.1111/j.0022-202X.2004.22512.x. PMID 15140227.
10. Deraison, C., Bonnart, C., Lopez, F., Besson, C., Robinson, R., Jayakumar, A., Wagberg, F., Brattsand, M., Hachem, J. P., Leonardsson, G., & Hovnanian, A. (2007). "LEKTI fragments specifically inhibit KLK5, KLK7, and KLK14 and control desquamation through a pH-dependent interaction.". Molecular Biology of the Cell 18 (9): 3607–3619. doi:10.1091/mbc.e07-02-0124.
11. Egelrud T, Brattsand M, Kreutzmann P, Walden M, Vitzithum K, Marx UC, Forssmann WG, Mägert HJ. (2005). "hK5 and hK7, two serine proteinases abundant in human skin, are inhibited by LEKTI domain 6.". Br J Dermatol. 153 (6): 1200–1203. doi:10.1111/j.1365-2133.2005.06834.x.
12. Meyer-Hoffert U, Wu Z, Kantyka T, Fischer J, Latendorf T, Hansmann B, Bartels J, He Y, Gläser R, Schröder JM. (October 2010). "Isolation of SPINK6 in human skin: selective inhibitor of kallikrein-related peptidases.". J Biol Chem. 285 (42): 32174–81. doi:10.1074/jbc.M109.091850. PMC 2952218. PMID 20667819.
13. Franzke CW, Baici A, Bartels J, Christophers E, Wiedow O. (September 1996). "Antileukoprotease inhibits stratum corneum chymotryptic enzyme. Evidence for a regulative function in desquamation.". J Biol Chem. 271 (36): 21886–90. doi:10.1074/jbc.271.36.21886.
14. Galliano MF, Toulza E, Gallinaro H, Jonca N, Ishida-Yamamoto A, Serre G, Guerrin M. (November 2005). "A novel protease inhibitor of the alpha2-macroglobulin family expressed in the human epidermis.". J Biol Chem. 281 (9): 5780–5789. doi:10.1074/jbc.m508017200.
15. Skytt A, Strömqvist M, Egelrud T (1995). "Primary substrate specificity of recombinant human stratum corneum chymotryptic enzyme.". Biochem. Biophys. Res. Commun. 211 (2): 586–9. doi:10.1006/bbrc.1995.1853. PMID 7794273.
16. Debela M, Magdolen V, Schechter N, Valachova M, Lottspeich F, Craik CS, Choe Y, Bode W, Goettig P. (2006). "Specificity profiling of seven human tissue kallikreins reveals individual subsite preferences.". J Biol Chem. 281 (35): 25678–88. doi:10.1074/jbc.M602372200. PMID 16740631.
17. Komatsu N, Saijoh K, Kuk C, Liu AC, Khan S, Shirasaki F, Takehara K, Diamandis EP (Jun 2007). "Human tissue kallikrein expression in the stratum corneum and serum of atopic dermatitis patients". Exp Dermatol 16 (6): 513–519. doi:10.1111/j.1600-0625.2007.00562.x. PMID 17518992.
18. Vasilopoulos Y, Cork MJ, Murphy R, et al. (2004). "Genetic association between an AACC insertion in the 3'UTR of the stratum corneum chymotryptic enzyme gene and atopic dermatitis.". J. Invest. Dermatol. 123 (1): 62–6. doi:10.1111/j.0022-202X.2004.22708.x. PMID 15191543.
19. Ekholm E, Egelrud T (Apr 1999). "Stratum corneum chymotryptic enzyme in psoriasis". Arch of Dermatol Res 291 (4): 195–200. doi:10.1007/s004030050393. PMID 10335915.
20. Descargues P, Deraison C, Bonnart C, Kreft M, Kishibe M, Ishida-Yamamoto A, Elias P, Barrandon Y, Zambruno G, Sonnenberg A, Hovnanian A. (Jan 2005). "Spink5-deficient mice mimic Netherton syndrome through degradation of desmoglein 1 by epidermal protease hyperactivity". Nat Genet 37 (1): 56–65. doi:10.1038/ng1493. PMID 15619623.
21. Descargues P, Deraison C, Prost C, et al. (2006). "Corneodesmosomal cadherins are preferential targets of stratum corneum trypsin- and chymotrypsin-like hyperactivity in Netherton syndrome.". J. Invest. Dermatol. 126 (7): 1622–32. doi:10.1038/sj.jid.5700284. PMID 16628198.
22. Dong Y, Kaushal A, Brattsand M, et al. (2004). "Differential splicing of KLK5 and KLK7 in epithelial ovarian cancer produces novel variants with potential as cancer biomarkers". Clin. Cancer Res. 9 (5): 1710–20. PMID 12738725.
23. Talieri M, Diamandis EP, Gourgiotis D, Mathioudaki K, Scorilas A (2004). "Expression analysis of the human kallikrein 7 (KLK7) in breast tumors: a new potential biomarker for prognosis of breast carcinoma". Thromb Haemost 91 (1): 180–186. doi:10.1267/THRO04010180. PMID 14691584.
24. Johnson SK, Rarnani VC, Hennings L, Haun RS (2007). "Kallikrein 7 enhances pancreatic cancer cell invasion by shedding E-cadherin". Cancer 109 (9): 1811–1820. doi:10.1002/cncr.22606. PMID 17354228.
25. Santin AD, Cane' S, Bellone S, et al. (2004). "The serine protease stratum corneum chymotryptic enzyme (kallikrein 7) is highly overexpressed in squamous cervical cancer cells". Gynecol. Oncol. 94 (2): 283–8. doi:10.1016/j.ygyno.2004.05.023. PMID 15297163.
26. Rezze GG, Fregnani JHTG, Duprat J, Landman G (2011). "Cell adhesion and communication proteins are differentially expressed in melanoma progression model". Hum Pathol 42 (3): 409–418. doi:10.1016/j.humpath.2010.09.004. PMID 21193224.
27. Planque C, de Monte M, Guyetant S, et al. (2005). "KLK5 and KLK7, two members of the human tissue kallikrein family, are differentially expressed in lung cancer.". Biochem. Biophys. Res. Commun. 329 (4): 1260–6. doi:10.1016/j.bbrc.2005.02.100. PMID 15766562.

Further reading

• Gan L, Lee I, Smith R, et al. (2001). "Sequencing and expression analysis of the serine protease gene cluster located in chromosome 19q13 region.". Gene 257 (1): 119–30. doi:10.1016/S0378-1119(00)00382-6. PMID 11054574.
• Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
• Diamandis EP, Scorilas A, Kishi T, et al. (2004). "Altered kallikrein 7 and 10 concentrations in cerebrospinal fluid of patients with Alzheimer's disease and frontotemporal dementia.". Clin. Biochem. 37 (3): 230–7. doi:10.1016/j.clinbiochem.2003.11.012. PMID 14972646.
• Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
• Ishida-Yamamoto A, Deraison C, Bonnart C, et al. (2005). "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. 124 (2): 360–6. doi:10.1111/j.0022-202X.2004.23583.x. PMID 15675955.
• Yamasaki K, Schauber J, Coda A, et al. (2006). "Kallikrein-mediated proteolysis regulates the antimicrobial effects of cathelicidins in skin.". FASEB J. 20 (12): 2068–80. doi:10.1096/fj.06-6075com. PMID 17012259.
• Debela M, Hess P, Magdolen V, et al. (2007). "Chymotryptic specificity determinants in the 1.0 A structure of the zinc-inhibited human tissue kallikrein 7.". Proc. Natl. Acad. Sci. U.S.A. 104 (41): 16086–91. doi:10.1073/pnas.0707811104. PMC 2042166. PMID 17909180.

External links

• The MEROPS online database for peptidases and their inhibitors: S01.017