KLK11 (Kallikrein-related peptidase 11)
2008-03-01 Liu-Ying Luo , Eleftherios P Diamandis AffiliationR&D Systems, Inc. 614 McKinley Place, N. E. Minneapolis, MN 55413, USA (LYL); Department of Pathology, Laboratory Medicine, Mount Sinai Hospital, 600 University Ave. Toronto, ON M5G 1X5, Canada (EPD)
Identity
HGNC
LOCATION
19q13.41
LOCUSID
ALIAS
PRSS20,TLSP
FUSION GENES
DNA/RNA
Description
The KLK11 gene is about 5.8 Kb in length, consisting of 6 exons and 5 introns.
Transcription
Three alternatively spliced variants have been described in the literature: including isoform 1, isoform 2, and isoform 3. Isoform 1 is preferentially expressed in the brain and it encodes a protein of 250 amino acids. Isoform 2 and isoform 3 are mainly expressed in the prostate. Compared to isoform 1, isoform 2 has additional 32 amino acids at the N-terminus and isoform 3 contains extra 25 amino acids inserted in the catalytic triad. Tissue-specific expression of these isoforms is regulated by multiple promoters that locate in the first exon of each isoform.
Pseudogene
Not identified so far
Proteins
Description
Full-length KLK11 is composed of a signal peptide (aa 1-50), a propeptide (aa 51-53), and a mature chain (aa 54-282). KLK11 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 propetide is removed to generate the mature active protein.
Expression
KLK11 is mainly expressed in epithelial tissues, such as stomach, trachea, and skin, with high levels in the brain and the prostate. KLK11 has also been identified in many biological fluids. Seminal plasma, containing an average of 15 μg/mL of KLK11, is the biological fluid reported to have the most abundant KLK11 so far. Other specimens, including serum, lactating milk, cerebrospinal fluid, and amniotic fluid, all have detectable amounts of KLK11.
Localisation
Secreted.
Function
The physiology functions of KLK11 and the mechanisms of its involvement in cancer have yet to be determined. Using positional scanning combinatorial tetrapeptide substrate library, it has revealed that KLK11 preferentially cleaves peptide bonds after methionine, arginine, and lysine. However, its physiology substrates remain unidentified. One hypothesis is that KLK11 may be part of a proteolytic cascade consisting of multiple kallikreins (KLKs). Since KLK11 is unable to autoactivate, in the cascade, it is likely that KLK11 is activated by upstream KLKs, then subsequently activate/inactaivate other downstream KLKs or other proteins. Accumulating experimental evidence is in accord with this hypothesis. It has been shown in in vitro experiments that, both KLK12 and KLK14 are able to activate KLK11. Another hypothesis is that KLK11 may be involved in the homeostasis of insulin growth factor. This hypothesis comes from the observation that KLK11 is able to degrade insulin growth factor binding protein 3 (IGFBP3) to facilitate the release of insulin growth factor. KLK11 enzymatic activity is mainly regulated by internal cleavage. In seminal plasma, about half the KLK11 is in the cleaved inactive form. Some abundant serine protease inhibitors present in the circulation or in seminal plasma, such as α1-antitrypsin, protein C inhibitor, α2-antiplasmin, and C1 inhibitor, fail to show rapid inhibition of KLK11.
Homology
Human KLK11 protein sequence shares 98% and 82% identity with that of chimpanzee and dog/bovine/mouse/rat, respectively.
Mutations
Note
No germinal or somatic mutations are identified to be associated with cancer so far.
Implicated in
Entity name
Prostate cancer
Disease
A number of investigations have been reported concerning the role of KLK11 as a potential diagnostic biomarker for prostate cancer (CaP). Prostate specific antigen (PSA) is currently the most widely used diagnostic marker for CaP. However, measuring PSA alone is lack of specificity, since some benign prostatic diseases, such as benign prostatic hyperplasia (BPH) and prostatitis, can also have increased serum PSA levels, whereas some CaP patients may have only mild elevation of PSA (4-10 ng/mL). To improve the specificity, a number of additional analyses, such as measuring the molecular forms of PSA, have been proposed. Patients with low free to total PSA ratios are considered to have higher risk of developing CaP. In spite of these efforts, false positive and false negative still occur and doctors frequently need to rely on prostate biopsy to make the final diagnosis. Some investigations have shown that measuring serum KLK11 concentrations may help discriminate CaP from BPH and reduce the number of unnecessary biopsies. Similar to PSA, serum KLK11 concentrations are elevated in the majority of CaP patients. However, compared to the BPH patients, the CaP patients tend to have lower serum KLK11 concentrations and lower KLK11 to total PSA ratios. In those patients that have less than 20% free PSA, measuring KLK11 to total PSA ratio identified 54% to have BPH. As such, it seems that KLK11 to total PSA ratio might be a complementary marker for free PSA percentage and combination of these two markers results in better specificity for CaP. KLK11 might not be superior to PSA in population screening. In a retrospective study, serum KLK11 or KLK11 to PSA ratio showed no advantage over PSA alone to differentiate CaP patients from noncancer individuals whose total PSA levels are in the range of 2.5 to 10 ng/mL.
Prognosis
Tissue expression levels of KLK11 may be used as a prognostic indicator for prostate cancer. Lower KLK11 mRNA levels have been found to be associated with higher tumor grade, tumor stage, and Gleason score, suggesting that KLK11 might be able to indicate the aggressiveness of prostate tumors.
Cytogenetics
No cytogenetic abnormalities are identified so far.
Hybrid gene
Not identified so far.
Entity name
Ovarian cancer
Disease
KLK11 has shown promise as a diagnostic biomarker for ovarian cancer. Earlier studies have revealed that serum KLK11 concentrations are elevated in the majority of ovarian cancer patients. Subsequent investigations further demonstrate that KLK11 is able to distinguish ovarian cancer cases from healthy controls. More importantly, it is less sensitive to benign ovarian diseases than is CA125, the most widely used diagnostic marker for ovarian cancer. Moreover, it has high temporal stability, which implies that it could be used in a longitudinal screening program for early detection.
Prognosis
Many investigations have clearly demonstrated that KLK11 has elevated protein levels in primary ovarian tumors than in normal tissue, benign or nonovarian metastatic tumors. In general, higher levels of KLK11 in ovarian tumor extracts are predictive of favorable outcome. They are more likely to be associated with early stage, responsive to chemotherapy, and longer progression free survival.
Cytogenetics
No cytogenetic abnormalities are identified so far.
Hybrid gene
Not identified so far.
Entity name
Lung cancer
Prognosis
The prognostic role of KLK11 has also been explored in lung cancer both at the mRNA and protein levels. With quantitative PCR, it has shown that KLK11 mRNA levels are lower in tumor tissues in comparison with adjacent normal counterparts. No significant correlation is identified with clinical stages, tumor status, and lymph node status. However, those patients with low KLK11 mRNA expression seem to have a significantly worse prognosis than those with high levels. At the protein level, serum KLK11 concentrations in non-small cell lung cancer patients are higher than in healthy controls and they are positively correlated with tumor stages.
Cytogenetics
No cytogenetic abnormalities are identified so far.
Hybrid gene
Not identified so far.
Breakpoints
Note
Not described so far.
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 12845660 | 2003 | Favorable prognostic value of tissue human kallikrein 11 (hK11) in patients with ovarian carcinoma. | Borgoño CA et al |
| 16740631 | 2006 | Specificity profiling of seven human tissue kallikreins reveals individual subsite preferences. | Debela M et al |
| 11782391 | 2002 | Human kallikrein 11: a new biomarker of prostate and ovarian carcinoma. | Diamandis EP et al |
| 17363527 | 2007 | Primary tumor levels of human tissue kallikreins affect surgical success and survival in ovarian cancer patients. | Dorn J et al |
| 18056261 | 2008 | Human kallikrein-related peptidase 14 (KLK14) is a new activator component of the KLK proteolytic cascade. Possible function in seminal plasma and skin. | Emami N et al |
| 16800745 | 2006 | Inhibition profiles of human tissue kallikreins by serine protease inhibitors. | Luo LY et al |
| 16467084 | 2006 | Purification and characterization of human kallikrein 11, a candidate prostate and ovarian cancer biomarker, from seminal plasma. | Luo LY et al |
| 17671125 | 2007 | Validation and characterization of human kallikrein 11 as a serum marker for diagnosis of ovarian carcinoma. | McIntosh MW et al |
| 17391064 | 2007 | Enzymatic properties of human kallikrein-related peptidase 12 (KLK12). | Memari N et al |
| 16911518 | 2006 | Multiple promoters regulate tissue-specific alternative splicing of the human kallikrein gene, KLK11/hippostasin. | Mitsui S et al |
| 10872828 | 2000 | A novel isoform of a kallikrein-like protease, TLSP/hippostasin, (PRSS20), is expressed in the human brain and prostate. | Mitsui S et al |
| 12736044 | 2003 | Quantitative analysis of hippostasin/KLK11 gene expression in cancerous and noncancerous prostatic tissues. | Nakamura T et al |
| 17905108 | 2007 | Is there a role for serum human tissue kallikrein in detection of prostate cancer? | Ochiai A et al |
| 16800740 | 2006 | Expression of the human kallikrein genes 10 (KLK10) and 11 (KLK11) in cancerous and non-cancerous lung tissues. | Planque C et al |
| 18316555 | 2008 | A multiparametric serum kallikrein panel for diagnosis of non-small cell lung carcinoma. | Planque C et al |
| 17487371 | 2007 | Kallikrein 11 expressed in human breast cancer cells releases insulin-like growth factor through degradation of IGFBP-3. | Sano A et al |
| 16870045 | 2006 | Decreased kallikrein 11 messenger RNA expression in lung cancer. | Sasaki H et al |
| 16800741 | 2006 | mRNA expression analysis of human kallikrein 11 (KLK11) may be useful in the discrimination of benign prostatic hyperplasia from prostate cancer after needle prostate biopsy. | Scorilas A et al |
| 15102682 | 2004 | Human kallikrein gene 11 (KLK11) mRNA overexpression is associated with poor prognosis in patients with epithelial ovarian cancer. | Shigemasa K et al |
| 15893744 | 2005 | Expression analysis and prognostic significance of human kallikrein 11 in prostate cancer. | Stavropoulou P et al |
| 16800743 | 2006 | Improved prostate cancer detection with a human kallikrein 11 and percentage free PSA-based artificial neural network. | Stephan C et al |
| 12727843 | 2003 | Parallel overexpression of seven kallikrein genes in ovarian cancer. | Yousef GM et al |
| 18056174 | 2007 | A multiparametric panel for ovarian cancer diagnosis, prognosis, and response to chemotherapy. | Zheng Y et al |
Other Information
Locus ID:
NCBI: 11012
MIM: 604434
HGNC: 6359
Ensembl: ENSG00000167757
Variants:
dbSNP: 11012
ClinVar: 11012
TCGA: ENSG00000167757
COSMIC: KLK11
RNA/Proteins
Expression (GTEx)
Protein levels (Protein atlas)
References
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 37971062 | 2024 | miR-1304 targets KLK11 to regulate gastric cancer cell proliferation through the mTOR signaling pathway. | 0 |
| 37971062 | 2024 | miR-1304 targets KLK11 to regulate gastric cancer cell proliferation through the mTOR signaling pathway. | 0 |
| 33420975 | 2021 | KLK11 acts as a tumor-inhibitor in laryngeal squamous cell carcinoma through the inactivation of Akt/Wnt/β-catenin signaling. | 2 |
| 34059001 | 2021 | KLK11 promotes the activation of mTOR and protein synthesis to facilitate cardiac hypertrophy. | 1 |
| 34067437 | 2021 | Kallikrein-11, in Association with Coiled-Coil Domain Containing 25, as a Potential Prognostic Marker for Cholangiocarcinoma with Lymph Node Metastasis. | 5 |
| 34697154 | 2021 | Kallikrein 11 Down-regulation in Breast Carcinoma: Correlation With Prognostic Parameters. | 2 |
| 33420975 | 2021 | KLK11 acts as a tumor-inhibitor in laryngeal squamous cell carcinoma through the inactivation of Akt/Wnt/β-catenin signaling. | 2 |
| 34059001 | 2021 | KLK11 promotes the activation of mTOR and protein synthesis to facilitate cardiac hypertrophy. | 1 |
| 34067437 | 2021 | Kallikrein-11, in Association with Coiled-Coil Domain Containing 25, as a Potential Prognostic Marker for Cholangiocarcinoma with Lymph Node Metastasis. | 5 |
| 34697154 | 2021 | Kallikrein 11 Down-regulation in Breast Carcinoma: Correlation With Prognostic Parameters. | 2 |
| 33015784 | 2020 | Diagnostic and prognostic values of KLK11 in nasopharyngeal carcinoma. | 1 |
| 33015784 | 2020 | Diagnostic and prognostic values of KLK11 in nasopharyngeal carcinoma. | 1 |
| 29874189 | 2018 | Novel splice variants of the human kallikrein-related peptidases 11 (KLK11) and 12 (KLK12), unraveled by next-generation sequencing technology. | 4 |
| 29975661 | 2018 | Activation and activity of glycosylated KLKs 3, 4 and 11. | 4 |
| 29874189 | 2018 | Novel splice variants of the human kallikrein-related peptidases 11 (KLK11) and 12 (KLK12), unraveled by next-generation sequencing technology. | 4 |
Citation
Liu-Ying Luo ; Eleftherios P Diamandis
KLK11 (Kallikrein-related peptidase 11)
Atlas Genet Cytogenet Oncol Haematol. 2008-03-01
Online version: http://atlasgeneticsoncology.org/gene/41077/klk11-(kallikrein-related-peptidase-11)
