KLK5 (Kallikrein-related peptidase 5)

2008-06-01   George M Yousef , Eleftherios P Diamandis 

Identity

HGNC
LOCATION
19q13.41
LOCUSID
ALIAS
KLK-L2,KLKL2,SCTE
FUSION GENES

DNA/RNA

Description

The KLK5 gene is approximately 9.5 Kb in length, consisting of 6 exons (5 of them are coding exons) and 5 introns.

Transcription

Five alternatively spliced variants have been identified for the KLK5 gene. These variants differ in the number and length of the 5 untranslated exons and/or the last two coding exons. Tissue-specific expression of these variants is regulated by multiple promoters located in the first exon of each isoform. KLK5 splice variants were found to be differentially expressed, at the mRNA level, in ovarian, breast and prostate cancers.

Pseudogene

None identified.

Proteins

Description

Full-length KLK5 is formed of 293 amino acids. It is composed of a signal peptide (29 amino acids), followed by an activation peptide (37 amino acids) and the mature chain (227 amino acids), with 4 potential N-linked glycosylation sites. The positions of the catalytic triad of serine proteases is conserved. KLK5 is synthesized as a full-length protein intracellularly. In the secretary pathway, the signal peptide is cleaved and the zymogen is released outside the cells. Upon activation, the propeptide is removed to generate the mature active protein. In serum and ascites fluid, in addition to the free (approximately 40 kDa) form, KLK5 forms complexes with alpha(1)-antitrypsin and alpha(2)-macroglobulin.

Expression

At the mRNA level, KLK5 is expressed in a variety of tissues, mainly the testis, brain, breast, thyroid and salivary glands. The KLK5 protein is expressed at higher levels in the skin, salivary gland, testis and female genital organs. KLK5 has also been identified in many biological fluids, including vaginal secretions, breast milk and seminal plasma. Many fetal tissues, including bone, skin, thymus and kidney also express KLK5.

Localisation

KLK5 is a secreted protein.

Function

KLK5 is a secreted serine protease. The physiological functions of KLK5 are not fully understood. The KLK5 protein was originally identified from a keratinocyte library and was purified from the stratum corneum of the human skin. It was found to have a trypsin-like enzymatic activity with strong preference for Arg over Lys in the P1 position. Evidence exists that it plays a role in skin desquamation. KLK5 can also digest extracellular matrix components, collagens type I, II, III, IV, fibronectin, and laminin, and can potentially release angiostatin from plasminogen, and "cystatin-like domain 3" from low molecular weight kininogen, and fibrinopeptide B and peptide beta15-42 from the B beta chain of fibrinogen. The KLK5 protein has been shown to activate another kallikrein, KLK7, and was found to be under steroid hormonal regulation in cancer cell lines. It has been recently shown that KLK5 is differentially expressed in a number of malignancies, including ovarian, breast and prostate cancers, but the mechanisms of its involvement in cancer have yet to be determined.

Homology

The human KLK5 protein sequence shares 40-70 % homology with other members of the human tissue kallikreins, and 70% identity with that of the mouse orthologue.

Mutations

Note

No germinal or somatic mutations are identified to be associated with cancer so far.

Implicated in

Entity name
Ovarian cancer
Disease
Higher KLK5 concentrations were found in the serum of 69% of patients with ovarian cancer. The KLK5 protein was found to be elevated in 55% of ovarian cancer tissues compared to normal. Also, KLK5 mRNA is significantly elevated in ovarian cancer, specially serous type. Ovarian cancer ascites contains higher levels, as compared to benign effusions and ascites from other cancer types. Two KLK5 splice variants are upregulated in ovarian cancer tissues compared to normal.
Prognosis
The KLK5 mRNA and protein are markers of unfavorable prognosis in ovarian cancer, being overexpressed in late stage and higher grade tumors, and associated with shorter DFS and OS. In addition, the KLK5 protein was shown to be an independent indicator of poor prognosis in patients with high-grade tumors and optimal debulking success.
Cytogenetics
No cytogenetic abnormalities are identified so far.
Hybrid gene
None identified.
Entity name
Breast cancer
Disease
Higher concentrations of KLK5 were found in the serum of 49% of patients with breast cancer. KLK5 splice variant 2 is downregulated in breast cancer compared to normal.
Prognosis
The KLK5 mRNA transcript was found to be an indicator of unfavorable prognosis, being overexpressed in node-positive patients with ER-negative tumors. It is independently associated with decreased DFS and OS, and it is an independent indicator of shorter DFS and OS in node-positive patients.
Cytogenetics
No cytogenetic abnormalities are identified so far.
Hybrid gene
None identified.
Entity name
Prostate cancer
Disease
KLK5 mRNA is downregulated in cancer vs normal prostatic tissues.
Prognosis
KLK5 mRNA is a favorable prognostic maker, with higher levels associated with low grade tumors and low Gleason score.
Cytogenetics
No cytogenetic abnormalities are identified so far.
Hybrid gene
None identified.
Entity name
Testicular cancer
Disease
KLK5 mRNA is downregulated in cancer vs normal testicular tissues.
Prognosis
KLK5 mRNA is a marker of favorable prognosis, overexpressed in smaller, early stage non-seminomas.
Cytogenetics
No cytogenetic abnormalities are identified so far.
Hybrid gene
None identified.
Entity name
Non-small cell lung carcinoma
Disease
Serum KLK5 levels are lower in lung cancer compared to normal and can be used as part of a multiparametric panel for diagnosis.
Prognosis
None identified.
Cytogenetics
No cytogenetic abnormalities are identified so far.
Hybrid gene
None identified.
Entity name
Urinary bladder carcinoma
Disease
None identified.
Prognosis
Increased expression of KLK5 was frequently observed in invasive tumors (pT2-pT4) compared with superficial tumors (pTa, pT1).
Cytogenetics
Copy number gain was observed in transitional cell carcinoma.
Hybrid gene
None identified.

Breakpoints

Note

None identified.

Bibliography

Pubmed IDLast YearTitleAuthors
127387252003Differential splicing of KLK5 and KLK7 in epithelial ovarian cancer produces novel variants with potential as cancer biomarkers.Dong Y et al
112373852001Human kallikrein gene 5 (KLK5) expression is an indicator of poor prognosis in ovarian cancer.Kim H et al
153617122004Differential expression of a human kallikrein 5 (KLK5) splice variant in ovarian and prostate cancer.Kurlender L et al
157136792005Biochemical and enzymatic characterization of human kallikrein 5 (hK5), a novel serine protease potentially involved in cancer progression.Michael IP et al
183165552008A multiparametric serum kallikrein panel for diagnosis of non-small cell lung carcinoma.Planque C et al
157665622005KLK5 and KLK7, two members of the human tissue kallikrein family, are differentially expressed in lung cancer.Planque C et al
168007442006Overexpression of the human tissue kallikrein genes KLK4, 5, 6, and 7 increases the malignant phenotype of ovarian cancer cells.Prezas P et al
175734182007Distribution of 15 human kallikreins in tissues and biological fluids.Shaw JL et al
174590522007Association of KLK5 overexpression with invasiveness of urinary bladder carcinoma cells.Shinoda Y et al
128905552003The human kallikrein protein 5 (hK5) is enzymatically active, glycosylated and forms complexes with two protease inhibitors in ovarian cancer fluids.Yousef GM et al
123859492002Differential expression of Kallikrein gene 5 in cancerous and normal testicular tissues.Yousef GM et al
127278432003Parallel overexpression of seven kallikrein genes in ovarian cancer.Yousef GM et al
121423802002Human kallikrein gene 5 (KLK5) expression by quantitative PCR: an independent indicator of poor prognosis in breast cancer.Yousef GM et al
156278842004The kallikrein gene 5 splice variant 2 is a new biomarker for breast and ovarian cancer.Yousef GM et al
147102252004Kallikrein gene downregulation in breast cancer.Yousef GM et al

Other Information

Locus ID:

NCBI: 25818
MIM: 605643
HGNC: 6366
Ensembl: ENSG00000167754

Variants:

dbSNP: 25818
ClinVar: 25818
TCGA: ENSG00000167754
COSMIC: KLK5

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000167754ENST00000336334Q9Y337
ENSG00000167754ENST00000391809Q9Y337
ENSG00000167754ENST00000593428Q9Y337
ENSG00000167754ENST00000594846M0QXX2

Expression (GTEx)

0
50
100
150
200
250
300
350

Pathways

PathwaySourceExternal ID
Developmental BiologyREACTOMER-HSA-1266738
KeratinizationREACTOMER-HSA-6805567
Formation of the cornified envelopeREACTOMER-HSA-6809371

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
170122592006Kallikrein-mediated proteolysis regulates the antimicrobial effects of cathelicidins in skin.127
151402272004Degradation of corneodesmosome proteins by two serine proteases of the kallikrein family, SCTE/KLK5/hK5 and SCCE/KLK7/hK7.84
156549742005A proteolytic cascade of kallikreins in the stratum corneum.64
171588872007A potential role for multiple tissue kallikrein serine proteases in epidermal desquamation.43
176255932008Activation of proteinase-activated receptor-2 by human kallikrein-related peptidases.41
166281982006Corneodesmosomal cadherins are preferential targets of stratum corneum trypsin- and chymotrypsin-like hyperactivity in Netherton syndrome.37
157136792005Biochemical and enzymatic characterization of human kallikrein 5 (hK5), a novel serine protease potentially involved in cancer progression.35
204241352010Blood biomarker levels to aid discovery of cancer-related single-nucleotide polymorphisms: kallikreins and prostate cancer.29
127387252003Differential splicing of KLK5 and KLK7 in epithelial ovarian cancer produces novel variants with potential as cancer biomarkers.25
165175952006Human tissue kallikrein 5 is a member of a proteolytic cascade pathway involved in seminal clot liquefaction and potentially in prostate cancer progression.24

Citation

George M Yousef ; Eleftherios P Diamandis

KLK5 (Kallikrein-related peptidase 5)

Atlas Genet Cytogenet Oncol Haematol. 2008-06-01

Online version: http://atlasgeneticsoncology.org/gene/41085/klk5