KLK7

Gene

Alternative splicing of the KLK7 gene results in two transcript variants encoding the same protein.

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.

Once active, KLK7 is able to cleave desmocollin and corneodesmosin. 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. For example, KLK7 expression is highly downregulated at acral surfaces where desquamation is delayed and the epidermis is thick.

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

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

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

Clinical significance

Skin disease

Dysregulation of KLK7 has been linked to several skin disorders including atopic dermatitis, psoriasis and Netherton syndrome. 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, breast, pancreatic, cervix, and melanoma cancers by excessive cleavage of cell junction proteins. It may also be underexpressed in lung cancer.

References

References

1. (August 2022). "Biogeographic and disease-specific alterations in epidermal lipid composition and single-cell analysis of acral keratinocytes". JCI Insight.
2. (July 1994). "Cloning, expression, and characterization of stratum corneum chymotryptic enzyme. A skin-specific human serine proteinase". The Journal of Biological Chemistry.
3. (June 2006). "A comprehensive nomenclature for serine proteases with homology to tissue kallikreins". Biological Chemistry.
4. (June 2006). "Proceedings of the 1st International Symposium on Kallikreins, Lausanne, Switzerland, September 1-3, 2005". Biological Chemistry.
5. "Entrez Gene: KLK7 kallikrein-related peptidase 7".
6. (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.
7. (August 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.
8. (June 2007). "Human tissue kallikrein expression in the stratum corneum and serum of atopic dermatitis patients". Experimental Dermatology.
9. (April 1999). "Stratum corneum chymotryptic enzyme in psoriasis". Archives of Dermatological Research.
10. (January 2005). "Spink5-deficient mice mimic Netherton syndrome through degradation of desmoglein 1 by epidermal protease hyperactivity". Nature Genetics.
11. (May 2003). "Differential splicing of KLK5 and KLK7 in epithelial ovarian cancer produces novel variants with potential as cancer biomarkers". Clinical Cancer Research.
12. (January 2004). "Expression analysis of the human kallikrein 7 (KLK7) in breast tumors: a new potential biomarker for prognosis of breast carcinoma". Thrombosis and Haemostasis.
13. (August 2004). "The serine protease stratum corneum chymotryptic enzyme (kallikrein 7) is highly overexpressed in squamous cervical cancer cells". Gynecologic Oncology.
14. (March 2011). "Cell adhesion and communication proteins are differentially expressed in melanoma progression model". Human Pathology.
15. (August 2010). "Matriptase initiates activation of epidermal pro-kallikrein and disease onset in a mouse model of Netherton syndrome". Nature Genetics.
16. (January 2005). "A proteolytic cascade of kallikreins in the stratum corneum". The Journal of Investigative Dermatology.
17. (May 2004). "Degradation of corneodesmosome proteins by two serine proteases of the kallikrein family, SCTE/KLK5/hK5 and SCCE/KLK7/hK7". The Journal of Investigative Dermatology.
18. (September 2007). "LEKTI fragments specifically inhibit KLK5, KLK7, and KLK14 and control desquamation through a pH-dependent interaction". Molecular Biology of the Cell.
19. (December 2005). "hK5 and hK7, two serine proteinases abundant in human skin, are inhibited by LEKTI domain 6". The British Journal of Dermatology.
20. (October 2010). "Isolation of SPINK6 in human skin: selective inhibitor of kallikrein-related peptidases". The Journal of Biological Chemistry.
21. (September 1996). "Antileukoprotease inhibits stratum corneum chymotryptic enzyme. Evidence for a regulative function in desquamation". The Journal of Biological Chemistry.
22. (March 2006). "A novel protease inhibitor of the alpha2-macroglobulin family expressed in the human epidermis". The Journal of Biological Chemistry.
23. (July 2004). "Genetic association between an AACC insertion in the 3'UTR of the stratum corneum chymotryptic enzyme gene and atopic dermatitis". The Journal of Investigative Dermatology.
24. (July 2006). "Corneodesmosomal cadherins are preferential targets of stratum corneum trypsin- and chymotrypsin-like hyperactivity in Netherton syndrome". The Journal of Investigative Dermatology.
25. (June 1995). "Primary substrate specificity of recombinant human stratum corneum chymotryptic enzyme". Biochemical and Biophysical Research Communications.
26. (September 2006). "Specificity profiling of seven human tissue kallikreins reveals individual subsite preferences". The Journal of Biological Chemistry.
27. (April 2005). "KLK5 and KLK7, two members of the human tissue kallikrein family, are differentially expressed in lung cancer". Biochemical and Biophysical Research Communications.