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KLK9 (kallikrein-related peptidase 9)

Written2016-09Panagiotis G. Adamopoulos, Andreas Scorilas
Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Athens. 157 01, Panepistimiopolis, Athens, Greece / ascorilas@biol.uoa.gr

Abstract Kallikreins (KLKs) represent the largest cluster of serine peptidases, which is composed of 15 members (KLK1-15). The human kallikrein-related peptidase 9 gene (KLK9), like the rest of the KLK genes, encodes for a trypsin-like serine peptidase. Serine peptidases are a group of protein-cleaving enzymes that contain a serine residue in their active site. Kallikreins constitute a subfamily of serine peptidases that cleave kininogen and release vasoactive peptides (kinins). The human KLK9 gene is located at 19q13.41 and consists of 5 exons and 4 intervening introns. Although KLK9 expression has been detected in various normal human tissues, differences in mRNA and protein expression levels have been observed. Like other KLKs, KLK9 is found differentially expressed in multiple human malignancies. Clinical studies regarding the KLK9 expression analysis in breast cancer tissues have demonstrated that KLK9 mRNA expression possesses significant prognostic ability and therefore could be a strong, independent marker of favorable prognosis in patients with breast cancer. In addition, the prognostic potential of the KLK9 mRNA expression levels in ovarian cancer has been clarified, since patients with KLK9-positive tumors demonstrate significantly longer progression-free and overall survival in comparison with KLK9-negative patients. Finally, KLK9 could serve as a prognostic biomarker for patients diagnosed with high-grade astrocytoma, as its expression level is associated with decreased survival of patients. Although the precise localization and structure of the KLK9 gene has now been fully characterized, its functional roles and connections to human diseases are still incompletely understood and merit further investigation.

Keywords Kallikreins; KLK9; KLK-L3; KLKL3; biomarker; proteolytic cascades; breast cancer; ovarian cancer; astrocytoma

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Identity

Other aliasKLK-L3
KLKL3
LocusID (NCBI) 284366
Atlas_Id 47324
Location 19q13.41  [Link to chromosome band 19q13]
Location_base_pair Starts at and ends at bp from pter
Local_order Telomere to centromere.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
Note The name of this gene is "kallikrein-related peptidase 9", while the name of its product is "kallikrein-9 precursor".

DNA/RNA

 
  Detailed structure of the annotated full-length mRNA transcript (NM_005551.4) of the KLK9 gene. The full-length KLK9 mRNA transcript is composed of 5 exons. Exons are depicted as boxes and introns as lines; gray and white boxes represent coding and non-coding exons, respectively. Numbers inside boxes and above lines indicate the length of each exon or intron in nucleotides. Finally, the translation start and stop codons are also shown.
Description The KLK9 gene consists of 5 exons and 4 intervening introns, spanning a region of 7081 bp genomic DNA.
Transcription A single mRNA transcript (NM_005551.4) of the KLK9 gene, with a total length of 1438 nucleotides, has been annotated. Expression of the KLK9 gene has been detected in various normal human tissues; still, differences in mRNA and protein expression levels have been observed. In particular, the highest mRNA levels of the KLK9 gene have been detected in stomach and vagina. In addition, KLK9 is expressed in high levels in the brain, cervix, esophagus, and fallopian tube, while normal expression levels are observed in breast, prostate, testis, thymus, thyroid, liver, lung, small intestine, spinal cord, and trachea (Shaw and Diamandis, 2007).
However, recent evidence derived from next-generation sequencing approaches has confirmed the existence of 10 novel alternative KLK9 transcripts (KLK9 v.2 -> v.11) that have already been submitted in GenBank® database (GenBank® accession numbers: KX571238 - KX571247 accordingly).
Pseudogene Not yet identified.

Protein

Description The protein encoded by the KLK9 gene is a kallikrein-related serine protease of 250 amino acid residues, with a calculated molecular mass of 25.6 kDa. Similar to other tissue kallikreins, the KLK9 protein is produced as a pre-proenzyme consisting of 250 amino acids, which is processed into a mature form with enzymatic activity (229 amino acids). In addition, KLK9 protein harbors a signal peptide of 19 amino acid residues and a 3-aa pro-segment (Yousef and Diamandis, 2000).
Localisation KLK9 is mainly localized in the cytoplasm.
Function Like the rest of the KLK genes, the KLK9 gene encodes for a trypsin-like serine peptidase. Serine peptidases are a group of protein-cleaving enzymes that contain a serine residue in their active site. Kallikreins constitute a subfamily of serine peptidases that cleave kininogen and release vasoactive peptides (kinins) (Schachter, 1980).
Homology Homology tests have demonstrated that human KLK9 protein shares the highest homology with human KLK11 (40%). In addition, KLK9 protein sequence is 38% homologous with the sequence of KLK5 and 33% homologous with the one of tissue kallikrein ( KLK1) (Yousef and Diamandis, 2000).

Mutations

Note No germinal or somatic mutations have been associated with cancer.

Implicated in

Note No cytogenetic abnormalities have been identified so far.
  
Entity Breast cancer
Prognosis Clinical studies regarding the expression analysis of the KLK9 gene in breast cancer tissues have demonstrated that KLK9 mRNA expression possesses strong prognostic ability. In particular, breast cancer patients with KLK9-positive tumors exhibit significantly longer disease-free survival (DFS) as well as overall survival (OS) compared to those who are KLK9-negative. As a result, mRNA overexpression of the KLK9 gene in breast tumors is found to be associated with increased DFS and OS leading to the conclusion that KLK9 mRNA levels could be a strong, independent marker of favorable prognosis in breast cancer (Yousef et al., 2003).
  
  
Entity Ovarian cancer
Prognosis Similar studies regarding the KLK9 mRNA expression analysis in ovarian tumor samples have clarified the prognostic potential of the KLK9 gene in ovarian cancer. KLK9 mRNA overexpression can serve as an independent favorable prognostic marker for ovarian cancer patients, since patients with KLK9-positive tumors demonstrated significantly longer progression-free and overall survival in comparison with KLK9-negative patients (Yousef et al., 2001).
  
  
Entity Astrocytoma
Prognosis KLK9 protein expression analysis in two distinct tissue microarrays containing grade III and IV astrocytoma samples revealed that increased KLK9 expression is associated with decreased survival of patients, thus suggesting its utility as a prognostic biomarker for patients diagnosed with high-grade astrocytoma (Drucker et al., 2015).
  

Bibliography

The prognostic value of the human kallikrein gene 9 (KLK9) in breast cancer
George M. Yousef, Andreas Scorilas, Terukazu Nakamura, Mohamed Abd Ellatif, Riccardo Ponzone, Nicoletta Biglia, Furio Maggiorotto, Riccardo Roagna, Piero Sismondi, and Eleftherios P. Diamandis
Breast Cancer Res Treat. 2003 Mar;78(2):149-58.
PMID 12725415
 
Distribution of 15 Human Kallikreins in Tissues and Biological Fluids
Julie L.V. Shaw and Eleftherios P. Diamandis
Clin Chem. 2007 Aug;53(8):1423-32.
PMID 17573418
 
Prognostic significance of multiple kallikreins in high-grade astrocytoma
Kristen L. Drucker, Caterina Gianinni, Paul A. Decker, Eleftherios P. Diamandis and Isobel A. Scarisbrick
BMC Cancer. 2015 Aug 1;15:565.
PMID 26231762
 
Kallikreins (kininogenases)A group of serine proteases with bioregulatory actions
Schachter, M.
Pharmacol Rev. 1979 Mar;31(1):1-17
PMID 94166
 

Citation

This paper should be referenced as such :
Panagiotis G Adamopoulos, Andreas Scorilas
KLK9 (kallikrein-related peptidase 9)
Atlas Genet Cytogenet Oncol Haematol. 2017;21(5):173-175.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/KLK9ID47324ch19q13.html


External links

Nomenclature
Cards
AtlasKLK9ID47324ch19q13.txt
Aliases
Genomic and cartography
Gene and transcription
RefSeq transcript (Entrez)
RefSeq genomic (Entrez)
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
BioGPS (Tissue expression)284366
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Protein Interaction databases
Ontologies - Pathways
Clinical trials, drugs, therapy
Miscellaneous
canSAR (ICR) (select the gene name)
Probes
Litterature
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed


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