KLK7

Last updated
KLK7
KLK7.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases KLK7 , PRSS6, SCCE, hK7, kallikrein related peptidase 7
External IDs OMIM: 604438 MGI: 1346336 HomoloGene: 37998 GeneCards: KLK7
Orthologs
SpeciesHumanMouse
Entrez

5650

23993

Ensembl

ENSG00000169035

ENSMUSG00000030713

UniProt

P49862
Q6DTY1

Q91VE3

RefSeq (mRNA)

NM_139277
NM_001207053
NM_001243126
NM_005046

NM_011872

RefSeq (protein)

NP_001193982
NP_001230055
NP_005037
NP_644806

NP_036002

Location (UCSC) Chr 19: 50.98 – 50.98 Mb Chr 7: 43.46 – 43.47 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Kallikrein-related peptidase 7 (KLK7) is a serine protease that in humans is encoded by the KLK7 gene. [5] [6] [7] [8] KLK7 was initially purified from the epidermis and characterised as stratum corneum chymotryptic enzyme (SCCE). [9] It was later identified as the seventh member of the human kallikrein family, which includes fifteen homologous serine proteases located on chromosome 19 (19q13). [10]

Contents

Gene

Alternative splicing of the KLK7 gene results in two transcript variants encoding the same protein. [8]

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. [11] [12]

Once active, KLK7 is able to cleave desmocollin and corneodesmosin. [13] 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. [14]

Both KLK5 and KLK14, other skin-expressed proteases, also cleave corneodesmosomal proteins. [13] KLK5 is able to undergo autoactivation, as well as activating KLK7 and KLK14, suggesting a KLK skin cascade is responsible for coordinating desquamation. [12]

KLK7 activity is regulated by a number of endogenous protein inhibitors including LEKTI, [15] [16] SPINK6, [17] elafin [18] and alpha-2-Macroglobulin-like 1. [19] Both Zn2+ and Cu2+ ions are also able to inhibit KLK7. [18]

KLK7 is a chymotrypsin-like serine protease, preferring to cleave proteins at the residues tyrosine, phenylalanine or leucine. [20] Analysis of peptide substrate hydrolysis indicates a strong preference for tyrosine at P1. [21]

Clinical significance

Skin disease

Dysregulation of KLK7 has been linked to several skin disorders including atopic dermatitis, [22] [23] psoriasis [24] and Netherton syndrome. [25] [26] 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, [27] breast, [28] pancreatic, [29] cervix, [30] and melanoma [31] cancers by excessive cleavage of cell junction proteins. It may also be underexpressed in lung cancer. [32]

Related Research Articles

<span class="mw-page-title-main">Stratum corneum</span> Outermost layer of the epidermis

The stratum corneum is the outermost layer of the epidermis. Consisting of dead tissue, it protects underlying tissue from infection, dehydration, chemicals and mechanical stress. It is composed of 15–20 layers of flattened cells with no nuclei and cell organelles.

<span class="mw-page-title-main">Desquamation</span> Medical condition

Desquamation occurs when the outermost layer of a tissue, such as the skin, is shed. The term is from Latin desquamare 'to scrape the scales off a fish'.

<span class="mw-page-title-main">Stratum granulosum</span> Cell layer in the epidermis

The stratum granulosum is a thin layer of cells in the epidermis lying above the stratum spinosum and below the stratum corneum. Keratinocytes migrating from the underlying stratum spinosum become known as granular cells in this layer. These cells contain keratohyalin granules, which are filled with histidine- and cysteine-rich proteins that appear to bind the keratin filaments together. Therefore, the main function of keratohyalin granules is to bind intermediate keratin filaments together.

Kallikreins are a subgroup of serine proteases, enzymes capable of cleaving peptide bonds in proteins. In humans, plasma kallikrein has no known paralogue, while tissue kallikrein-related peptidases (KLKs) encode a family of fifteen closely related serine proteases. These genes are localised to chromosome 19q13, forming the largest contiguous cluster of proteases within the human genome. Kallikreins are responsible for the coordination of various physiological functions including blood pressure, semen liquefaction and skin desquamation.

<span class="mw-page-title-main">Lamellar bodies</span> Secretory organelles

In cell biology, lamellar bodies are secretory organelles found in type II alveolar cells in the lungs, and in keratinocytes in the skin. They are oblong structures, appearing about 300-400 nm in width and 100-150 nm in length in transmission electron microscopy images. Lamellar bodies in the alveoli of the lungs fuse with the cell membrane and release pulmonary surfactant into the extracellular space.

<span class="mw-page-title-main">Netherton syndrome</span> Medical condition

Netherton syndrome is a severe, autosomal recessive form of ichthyosis associated with mutations in the SPINK5 gene. It is named after Earl W. Netherton (1910–1985), an American dermatologist who discovered it in 1958.

Corneocytes are terminally differentiated keratinocytes and compose most of the stratum corneum, the outermost layer of the epidermis. They are regularly replaced through desquamation and renewal from lower epidermal layers and are essential for its function as a skin barrier.

<span class="mw-page-title-main">KLK6</span> Protein-coding gene in the species Homo sapiens

Kallikrein-6 is a protein that in humans is encoded by the KLK6 gene. Kallikrein-6 is also referred to as neurosin, protease M, hK6, or zyme. It is a 223 amino acid sequence, derived from its 244 original form, which contains a 16 residue presignal and 5 residue activation peptide.

<span class="mw-page-title-main">Kallikrein-5</span> Protein-coding gene in the species Homo sapiens

Kallikrein-5, formerly known as stratum corneum tryptic enzyme (SCTE), is a serine protease expressed in the epidermis. In humans it is encoded by the KLK5 gene. This gene is one of the fifteen kallikrein subfamily members located in a cluster on chromosome 19. Its expression is up-regulated by estrogens and progestins. Alternative splicing results in multiple transcript variants encoding the same protein.

<span class="mw-page-title-main">LEKTI</span> Protein-coding gene in the species Homo sapiens

Lympho-epithelial Kazal-type-related inhibitor (LEKTI) also known as serine protease inhibitor Kazal-type 5 (SPINK5) is a protein that in humans is encoded by the SPINK5 gene.

<span class="mw-page-title-main">KLK11</span> Protein-coding gene in the species Homo sapiens

Kallikrein-11 is a protein that in humans is encoded by the KLK11 gene.

<span class="mw-page-title-main">Corneodesmosin</span> Protein-coding gene in the species Homo sapiens

Corneodesmosin is a protein that in humans is encoded by the CDSN gene.

<span class="mw-page-title-main">KLK13</span> Gene of the species Homo sapiens

Kallikrein-13 is a protein that in humans is encoded by the KLK13 gene.

<span class="mw-page-title-main">KLK8</span> Protein-coding gene in the species Homo sapiens

Kallikrein-8 is a protein that in humans is encoded by the KLK8 gene.

<span class="mw-page-title-main">KLK14</span> Protein-coding gene in the species Homo sapiens

Kallikrein-14 is a protein that in humans is encoded by the KLK14 gene.

Trichorrhexis invaginata is a distinctive hair shaft abnormality that may occur sporadically, either in normal hair or with other hair shaft abnormalities, or regularly as a marker for Netherton syndrome. The primary defect appears to be abnormal keratinization of the hair shaft in the keratogenous zone, allowing for intussusception of the fully keratinized and hard distal shaft into the incompletely keratinized and soft proximal portion of the shaft.

Term ''kallikrein 7 may refer to:

Serine protease inhibitor Kazal-type 6 (SPINK6) is a protein encoded by the SPINK6 gene in humans. It is a potent inhibitor of epidermal proteases involved in maintaining skin homeostasis, including KLK5, KLK7 and KLK14. SPINK6 is a member of a gene family cluster located on chromosome 5q33.1, which includes SPINK5 and SPINK9.

<span class="mw-page-title-main">LEKTI-2</span> Mammalian protein found in Homo sapiens

Lympho-epithelial Kazal-type related inhibitor 2 (LEKTI-2) is a protein encoded by the SPINK9 gene in humans. SPINK9 is a member of a gene family cluster located on chromosome 5q33.1, which includes SPINK5 and SPINK6. LEKTI-2 is an inhibitor of KLK5.

Stratum corneum chymotryptic enzyme is an enzyme. This enzyme catalyses the following chemical reaction

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000169035 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000030713 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Hansson L, Strömqvist M, Bäckman A, Wallbrandt P, Carlstein A, Egelrud T (July 1994). "Cloning, expression, and characterization of stratum corneum chymotryptic enzyme. A skin-specific human serine proteinase". The Journal of Biological Chemistry. 269 (30): 19420–19426. doi: 10.1016/S0021-9258(17)32185-3 . PMID   8034709.
  6. ↑ Lundwall A, Band V, Blaber M, Clements JA, Courty Y, Diamandis EP, et al. (June 2006). "A comprehensive nomenclature for serine proteases with homology to tissue kallikreins" (PDF). Biological Chemistry. 387 (6): 637–641. doi:10.1515/BC.2006.082. PMID   16800724. S2CID   436200.
  7. ↑ "Proceedings of the 1st International Symposium on Kallikreins, Lausanne, Switzerland, September 1-3 , 2005". Biological Chemistry. 387 (6): 635–824. June 2006. doi:10.1515/BC.2006.081. PMID   16800723. S2CID   83910246.
  8. 1 2 "Entrez Gene: KLK7 kallikrein-related peptidase 7".
  9. ↑ Lundström 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. doi: 10.2340/0001555571471474 . PMID   1685827.
  10. ↑ Yousef GM, Scorilas A, Magklara A, Soosaipillai A, Diamandis EP (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. 254 (1–2): 119–128. doi:10.1016/S0378-1119(00)00280-8. PMID   10974542.
  11. ↑ Sales KU, Masedunskas A, Bey AL, Rasmussen AL, Weigert R, List K, et al. (August 2010). "Matriptase initiates activation of epidermal pro-kallikrein and disease onset in a mouse model of Netherton syndrome". Nature Genetics. 42 (8): 676–683. doi:10.1038/ng.629. PMC   3081165 . PMID   20657595.
  12. 1 2 Brattsand M, Stefansson K, Lundh C, Haasum Y, Egelrud T (January 2005). "A proteolytic cascade of kallikreins in the stratum corneum". The Journal of Investigative Dermatology. 124 (1): 198–203. doi: 10.1111/j.0022-202X.2004.23547.x . PMID   15654974.
  13. 1 2 Caubet C, Jonca N, Brattsand M, Guerrin M, Bernard D, Schmidt R, et al. (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. 122 (5): 1235–1244. doi: 10.1111/j.0022-202X.2004.22512.x . PMID   15140227.
  14. ↑ Merleev AA, Le ST, Alexanian C, Toussi A, Xie Y, Marusina AI, et al. (August 2022). "Biogeographic and disease-specific alterations in epidermal lipid composition and single-cell analysis of acral keratinocytes". JCI Insight. 7 (16): e159762. doi:10.1172/jci.insight.159762. PMC   9462509 . PMID   35900871.
  15. ↑ Deraison C, Bonnart C, Lopez F, Besson C, Robinson R, Jayakumar A, et al. (September 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. PMC   1951746 . PMID   17596512.
  16. ↑ Egelrud T, Brattsand M, Kreutzmann P, Walden M, Vitzithum K, Marx UC, et al. (December 2005). "hK5 and hK7, two serine proteinases abundant in human skin, are inhibited by LEKTI domain 6". The British Journal of Dermatology. 153 (6): 1200–1203. doi:10.1111/j.1365-2133.2005.06834.x. PMID   16307658. S2CID   42775195.
  17. ↑ Meyer-Hoffert U, Wu Z, Kantyka T, Fischer J, Latendorf T, Hansmann B, et al. (October 2010). "Isolation of SPINK6 in human skin: selective inhibitor of kallikrein-related peptidases". The Journal of Biological Chemistry. 285 (42): 32174–32181. doi: 10.1074/jbc.M109.091850 . PMC   2952218 . PMID   20667819.
  18. 1 2 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". The Journal of Biological Chemistry. 271 (36): 21886–21890. doi: 10.1074/jbc.271.36.21886 . PMID   8702990.
  19. ↑ Galliano MF, Toulza E, Gallinaro H, Jonca N, Ishida-Yamamoto A, Serre G, Guerrin M (March 2006). "A novel protease inhibitor of the alpha2-macroglobulin family expressed in the human epidermis". The Journal of Biological Chemistry. 281 (9): 5780–5789. doi: 10.1074/jbc.m508017200 . PMID   16298998.
  20. ↑ Skytt A, Strömqvist M, Egelrud T (June 1995). "Primary substrate specificity of recombinant human stratum corneum chymotryptic enzyme". Biochemical and Biophysical Research Communications. 211 (2): 586–589. doi:10.1006/bbrc.1995.1853. PMID   7794273.
  21. ↑ Debela M, Magdolen V, Schechter N, Valachova M, Lottspeich F, Craik CS, et al. (September 2006). "Specificity profiling of seven human tissue kallikreins reveals individual subsite preferences". The Journal of Biological Chemistry. 281 (35): 25678–25688. doi: 10.1074/jbc.M602372200 . PMID   16740631.
  22. ↑ Komatsu N, Saijoh K, Kuk C, Liu AC, Khan S, Shirasaki F, et al. (June 2007). "Human tissue kallikrein expression in the stratum corneum and serum of atopic dermatitis patients". Experimental Dermatology. 16 (6): 513–519. doi:10.1111/j.1600-0625.2007.00562.x. PMID   17518992. S2CID   866377.
  23. ↑ Vasilopoulos Y, Cork MJ, Murphy R, Williams HC, Robinson DA, Duff GW, et al. (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. 123 (1): 62–66. doi: 10.1111/j.0022-202X.2004.22708.x . PMID   15191543.
  24. ↑ Ekholm E, Egelrud T (April 1999). "Stratum corneum chymotryptic enzyme in psoriasis". Archives of Dermatological Research. 291 (4): 195–200. doi:10.1007/s004030050393. PMID   10335915. S2CID   37395502.
  25. ↑ Descargues P, Deraison C, Bonnart C, Kreft M, Kishibe M, Ishida-Yamamoto A, et al. (January 2005). "Spink5-deficient mice mimic Netherton syndrome through degradation of desmoglein 1 by epidermal protease hyperactivity". Nature Genetics. 37 (1): 56–65. doi:10.1038/ng1493. PMID   15619623. S2CID   11404025.
  26. ↑ Descargues P, Deraison C, Prost C, Fraitag S, Mazereeuw-Hautier J, D'Alessio M, et al. (July 2006). "Corneodesmosomal cadherins are preferential targets of stratum corneum trypsin- and chymotrypsin-like hyperactivity in Netherton syndrome". The Journal of Investigative Dermatology. 126 (7): 1622–1632. doi: 10.1038/sj.jid.5700284 . PMID   16628198.
  27. ↑ Dong Y, Kaushal A, Brattsand M, Nicklin J, Clements JA (May 2003). "Differential splicing of KLK5 and KLK7 in epithelial ovarian cancer produces novel variants with potential as cancer biomarkers". Clinical Cancer Research. 9 (5): 1710–1720. PMID   12738725.
  28. ↑ Talieri M, Diamandis EP, Gourgiotis D, Mathioudaki K, Scorilas A (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. 91 (1): 180–186. doi:10.1160/TH03-05-0261. PMID   14691584. S2CID   5692357.
  29. ↑ Johnson SK, Ramani VC, Hennings L, Haun RS (May 2007). "Kallikrein 7 enhances pancreatic cancer cell invasion by shedding E-cadherin". Cancer. 109 (9): 1811–1820. doi:10.1002/cncr.22606. PMID   17354228. S2CID   8142528.
  30. ↑ Santin AD, Cane' S, Bellone S, Bignotti E, Palmieri M, De Las Casas LE, et al. (August 2004). "The serine protease stratum corneum chymotryptic enzyme (kallikrein 7) is highly overexpressed in squamous cervical cancer cells". Gynecologic Oncology. 94 (2): 283–288. doi:10.1016/j.ygyno.2004.05.023. PMID   15297163.
  31. ↑ Rezze GG, Fregnani JH, Duprat J, Landman G (March 2011). "Cell adhesion and communication proteins are differentially expressed in melanoma progression model". Human Pathology. 42 (3): 409–418. doi:10.1016/j.humpath.2010.09.004. PMID   21193224.
  32. ↑ Planque C, de Monte M, Guyetant S, Rollin J, Desmazes C, Panel V, et al. (April 2005). "KLK5 and KLK7, two members of the human tissue kallikrein family, are differentially expressed in lung cancer". Biochemical and Biophysical Research Communications. 329 (4): 1260–1266. doi:10.1016/j.bbrc.2005.02.100. PMID   15766562.

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