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KLK13 (kallikrein-related peptidase 13)

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

Abstract Kallikreins (KLKs) constitute a family of 15 homologous secreted serine proteases (KLK1-15), which participate in numerous physiological procedures. All KLKs are encoded by the largest contiguous cluster of protease genes in the human genome (19q13.3-13.4). In specific, the human KLK13 gene spans a region of 8905 nucleotides, comprises 5 exons and 4 intervening introns and produces a single mRNA transcript that encodes KLK13 precursor protein. Like the rest of the KLK genes, KLK13 gene encodes for a trypsin-like serine peptidase, the functions of which are still unclear. KLK13 expression has been detected in a variety of human tissues and is found to be associated with several types of cancer. Evidence has showed that KLK13 can be an independent biomarker of favorable prognosis in breast cancer patients and may potentially be able to identify patients likely to benefit from hormonal treatment. In addition, major prognostic abilities of KLK13 have been confirmed in nonsmall cell lung cancer as well as gastric cancer, as patients with KLK13 overexpression demonstrated significantly longer overall (OS) and disease-free survival (DFS) accordingly. Although the precise localization and structure of the KLK13 gene has now been fully identified, its functional roles and implication mechanisms to human malignancies are still not conveniently understood and merit further investigation.

Keywords Kallikreins; KLK13; KLK-L4; KLKL4; biomarker; Proteolytic cascades

(Note : for Links provided by Atlas : click)

Identity

Alias_nameskallikrein 13
Alias_symbol (synonym)KLK-L4
Other aliasKLKL4
HGNC (Hugo) KLK13
LocusID (NCBI) 26085
Atlas_Id 41079
Location 19q13.33  [Link to chromosome band 19q13]
Location_base_pair Starts at 51559463 and ends at 51568367 bp from pter ( according to hg19-Feb_2009)  [Mapping KLK13.png]
Local_order Telomere to centromere
Note The name of this gene is "kallikrein-related peptidase 13". The name of its product is "kallikrein-13 precursor".

DNA/RNA

Description The human KLK13 gene is located on the chromosome 19q, spans a region of 8905 nucleotides and comprises 5 exons and 4 intervening introns. In addition, the lengths of the coding regions in each exon are 52, 187, 269, 137, and 189 nucleotides, respectively. (Yousef et al, 2000).
Transcription Only one mRNA transcript of the KLK13 gene has been annotated (NM_015596.1). This mRNA encodes for the kallikrein-13 precursor protein (NP_056411.1). In addition, evidence derived by automated computational analysis supports the existence of another transcript (XR_935788.1), which is predicted to be a non-coding transcript and therefore a candidate for nonsense-mediated mRNA decay (NMD). Like most members of the human kallikrein (KLK) gene family, KLK13 is expressed in a wide array of normal human tissues. In detail, KLK13 expression was detected at high levels in the esophagus and tonsil, while lower concentrations of KLK13 mRNA were confirmed in cervix, salivary gland, and vagina. In addition, even lower expression levels have been detected in various other adult and fetal tissues (Shaw and Diamandis, 2007).
In addition, next-generation sequencing approaches have revealed the existence of one novel alternatively spliced variant of KLK13 that has already been submitted in the GenBank® database (GenBank® accession number: KX595106) and is predicted to be non-coding, since it contains a premature stop codon.
Pseudogene None.

Protein

Description The protein encoded by the KLK13 gene is a kallikrein-related serine protease of 277 amino acid residues, with a calculated molecular mass of 30570 Da. Hydrophobicity and structural homology analysis showed that the amino-terminal region of the encoded protein is quite hydrophobic. In addition, evidence suggested that the amino acid segment 1-20 represents the signal peptide, while the segment 21-25 is the activation peptide. As a result, the active form of KLK13 starts from amino acid 26 (Yousef et al, 2000).
Expression High expression levels of KLK13 protein have been detected in mammary gland, prostate, salivary gland, testis, esophagus and tonsil, but lower expression levels have been found in many other human tissues (breast, kidney, skin, thyroid, trachea, ureter, and lung). In addition, KLK13 secretion in seminal plasma has been confirmed (Kapadia etl al, 2003) (Shaw and Diamandis, 2007).
Localisation Immunohistochemistry studies have demonstrated that KLK13 is generally located in the cytoplasm (Petraki et al, 2003). However, some nuclear staining of epithelial cells was also observed.
Function The function of the protein is still unclear. Like all members of the human kallikrein family, KLK13 is predicted to encode a secreted serine protease that is likely present in biological fluids. However, no suitable method for measuring KLK13 protein with high sensitivity and specificity has been established (Kapadia et al, 2003).
Homology KLK13 protein shares 51% amino acid sequence similarity with the TLSP and zyme genes, 49% with KLK5, 47% with KLK3 as well as 45% with KLK2. In addition, the classical catalytic triad of serine proteases is well conserved in the KLK13 (His108, Asp153, and Ser245) (Yousef et al, 2000).

Implicated in

  
Entity Breast cancer
Prognosis Clinical studies in breast tumour specimens have highlighted KLK13 as an independent favourable prognostic marker in breast cancer. Patients with positive KLK13 expression demonstrate a significantly longer disease-free survival (DFS) and overall survival (OS), as revealed by both univariate and multivariate Cox regression analyses. In addition, KLK13 expression positivity was detected more frequently in estrogen receptor (ER)-positive patients and was also significantly higher in patients over the age of 55 years. As a result, evidence supports that KLK13 can be an independent biomarker of favorable prognosis in breast cancer patients and may potentially be able to identify patients likely to benefit from hormonal treatment (Chang et al, 2002).
  
  
Entity Non-small cell lung cancer
Note In a recent study, KLK13 mRNA expression levels were assessed using a sensitive quantitative RT-PCR method in patients with non-small cell lung cancer (NSCLC), in order to investigate its prognostic potential in this type of malignancy. KLK13 was found significantly overexpressed in most cancerous tissues compared to the paired normal ones. Additionally, female patients demonstrated higher KLK13 expression levels than male patients.
Prognosis Regarding the prognostic abilities of KLK13 in NSCLC, patients characterized with overexpression of KLK13 survived significantly longer and therefore KLK13 expression is a favorable, independent prognostic indicator, in terms of overall survival (OS) (Gueugnon et al, 2015).
  
  
Entity Gastric cancer
Note The prognostic ability of KLK13 mRNA levels have also been studied in stomach cancer. In detail, after quantitative analysis of KLK13 expression profile was performed in numerous primary gastric carcinoma samples, using an ultra-sensitive (qRT-PCR) methodology, KLK13 expression was found to be downregulated in cancerous tissues, compared to their matching non-cancerous ones.
Prognosis Additionally, survival evaluation using Kaplan-Mayer curves revealed that patients overexpressing KLK13 demonstrate not only a significantly increased disease-free survival (DFS), having low risk of disease recurrences, but also a longer overall survival (OS). Thus, KLK13 can serve as a new favorable tumor biomarker for patients with gastric cancer (Konstantoudakis et al, 2010).
  
  
Entity Epithelial ovarian carcinoma
Prognosis The clinical value of KLK13 protein (KLK13) as a marker in ovarian cancer has been clarified. KLK13 levels were quantified in numerous ovarian tumor samples using an enzyme-linked immunosorbent assay (ELISA). After KLK13 concentration in ovarian tumor cytosols was identified, KLK13 levels were associated with various clinicopathological variables, progression-free survival (PFS) and overall survival (OS). Results indicated that patients with KLK13-positive tumor samples had a significantly longer PFS as well as OS in comparison with KLK13-negative patients. In addition to these findings, survival analysis using Kaplan-Mayer curves revealed a decreased relapse and death hazard in patients with KLK13-positive tumors (Scorilas et al, 2004).
  

Bibliography

Human Kallikrein 13: Production and Purification of Recombinant Protein and Monoclonal and Polyclonal Antibodies, and Development of a Sensitive and Specific Immunofluorometric Assay
Carl Kapadia, Albert Chang, Georgia Sotiropoulou, George M. Yousef, Linda Grass, Antoninus Soosaipillai, Xuekun Xing, David H.C. Howarth, and Eleftherios P. Diamandis
Clin Chem. 2003 Jan;49(1):77-86.
PMID 12507963
 
Human kallikrein gene 13 (KLK13) expression by quantitative RT-PCR: an independent indicator of favourable prognosis in breast cancer.
Chang A, Yousef GM, Scorilas A, Grass L, Sismondi P, Ponzone R, Diamandis EP.
Br J Cancer. 2002 May 6;86(9):1457-64.
PMID 11986781
 
Kallikrein-related peptidase 13: an independent indicator of favorable prognosis for patients with nonsmall cell lung cancer.
Gueugnon F, Barascu A, Mavridis K, Petit-Courty A, Marchand-Adam S, Gissot V, Scorilas A, Guyetant S, Courty Y.
Tumour Biol. 2015 Jul;36(7):4979-86.
PMID 25677900
 
Kallikrein-related peptidase 13 (KLK13) gene expressional status contributes significantly in the prognosis of primary gastric carcinomas.
Konstantoudakis G, Florou D, Mavridis K, Papadopoulos IN, Scorilas A.
Clin Biochem. 2010 Oct;43(15):1205-11.
PMID 20678496
 
Human kallikrein 13 expression in normal tissues: an immunohistochemical study.
Petraki CD, Karavana VN, Diamandis EP.
J Histochem Cytochem. 2003 Apr;51(4):493-501.
PMID 12642628
 
Human kallikrein 13 protein in ovarian cancer cytosols: a new favorable prognostic marker.
Scorilas A, Borgoño CA, Harbeck N, Dorn J, Schmalfeldt B, Schmitt M, Diamandis EP.
J Clin Oncol. 2004 Feb 15;22(4):678-85.
PMID 14966091
 
Distribution of 15 human kallikreins in tissues and biological fluids.
Shaw JL, Diamandis EP.
Clin Chem. 2007 Aug;53(8):1423-32.
PMID 17573418
 
Identification and characterization of KLK-L4, a new kallikrein-like gene that appears to be down-regulated in breast cancer tissues.
Yousef GM, Chang A, Diamandis EP.
J Biol Chem. 2000 Apr 21;275(16):11891-8.
PMID 10766816
 

Citation

This paper should be referenced as such :
Adamopoulos PG, Scorilas A
KLK13 (kallikrein-related peptidase 13);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/KLK13ID41079ch19q13.html


External links

Nomenclature
HGNC (Hugo)KLK13   6361
Cards
AtlasKLK13ID41079ch19q13
Entrez_Gene (NCBI)KLK13  26085  kallikrein related peptidase 13
AliasesKLK-L4; KLKL4
GeneCards (Weizmann)KLK13
Ensembl hg19 (Hinxton)ENSG00000167759 [Gene_View]  chr19:51559463-51568367 [Contig_View]  KLK13 [Vega]
Ensembl hg38 (Hinxton)ENSG00000167759 [Gene_View]  chr19:51559463-51568367 [Contig_View]  KLK13 [Vega]
ICGC DataPortalENSG00000167759
TCGA cBioPortalKLK13
AceView (NCBI)KLK13
Genatlas (Paris)KLK13
WikiGenes26085
SOURCE (Princeton)KLK13
Genetics Home Reference (NIH)KLK13
Genomic and cartography
GoldenPath hg19 (UCSC)KLK13  -     chr19:51559463-51568367 -  19q13.33   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)KLK13  -     19q13.33   [Description]    (hg38-Dec_2013)
EnsemblKLK13 - 19q13.33 [CytoView hg19]  KLK13 - 19q13.33 [CytoView hg38]
Mapping of homologs : NCBIKLK13 [Mapview hg19]  KLK13 [Mapview hg38]
OMIM605505   
Gene and transcription
Genbank (Entrez)AB108823 AB108824 AB451465 AL050220 AY923171
RefSeq transcript (Entrez)NM_015596
RefSeq genomic (Entrez)NC_000019 NC_018930 NT_011109 NW_004929415
Consensus coding sequences : CCDS (NCBI)KLK13
Cluster EST : UnigeneHs.165296 [ NCBI ]
CGAP (NCI)Hs.165296
Alternative Splicing GalleryENSG00000167759
Gene ExpressionKLK13 [ NCBI-GEO ]   KLK13 [ EBI - ARRAY_EXPRESS ]   KLK13 [ SEEK ]   KLK13 [ MEM ]
Gene Expression Viewer (FireBrowse)KLK13 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)26085
GTEX Portal (Tissue expression)KLK13
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9UKR3   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9UKR3  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9UKR3
Splice isoforms : SwissVarQ9UKR3
Catalytic activity : Enzyme3.4.21.- [ Enzyme-Expasy ]   3.4.21.-3.4.21.- [ IntEnz-EBI ]   3.4.21.- [ BRENDA ]   3.4.21.- [ KEGG ]   
PhosPhoSitePlusQ9UKR3
Domaine pattern : Prosite (Expaxy)TRYPSIN_DOM (PS50240)    TRYPSIN_HIS (PS00134)    TRYPSIN_SER (PS00135)   
Domains : Interpro (EBI)Peptidase_S1_PA    Peptidase_S1A    Trypsin_dom    TRYPSIN_HIS    TRYPSIN_SER   
Domain families : Pfam (Sanger)Trypsin (PF00089)   
Domain families : Pfam (NCBI)pfam00089   
Domain families : Smart (EMBL)Tryp_SPc (SM00020)  
Conserved Domain (NCBI)KLK13
DMDM Disease mutations26085
Blocks (Seattle)KLK13
SuperfamilyQ9UKR3
Human Protein AtlasENSG00000167759
Peptide AtlasQ9UKR3
HPRD05693
IPIIPI00007726   IPI00556343   IPI00556407   IPI00384324   
Protein Interaction databases
DIP (DOE-UCLA)Q9UKR3
IntAct (EBI)Q9UKR3
FunCoupENSG00000167759
BioGRIDKLK13
STRING (EMBL)KLK13
ZODIACKLK13
Ontologies - Pathways
QuickGOQ9UKR3
Ontology : AmiGOserine-type endopeptidase activity  serine-type endopeptidase activity  protein binding  extracellular region  extracellular space  cytoplasm  proteolysis  protein processing  hydrolase activity  secretory granule  extracellular exosome  
Ontology : EGO-EBIserine-type endopeptidase activity  serine-type endopeptidase activity  protein binding  extracellular region  extracellular space  cytoplasm  proteolysis  protein processing  hydrolase activity  secretory granule  extracellular exosome  
REACTOMEQ9UKR3 [protein]
REACTOME Pathways381426 [pathway]   6809371 [pathway]   
NDEx NetworkKLK13
Atlas of Cancer Signalling NetworkKLK13
Wikipedia pathwaysKLK13
Orthology - Evolution
OrthoDB26085
GeneTree (enSembl)ENSG00000167759
Phylogenetic Trees/Animal Genes : TreeFamKLK13
HOVERGENQ9UKR3
HOGENOMQ9UKR3
Homologs : HomoloGeneKLK13
Homology/Alignments : Family Browser (UCSC)KLK13
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerKLK13 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)KLK13
dbVarKLK13
ClinVarKLK13
1000_GenomesKLK13 
Exome Variant ServerKLK13
ExAC (Exome Aggregation Consortium)KLK13 (select the gene name)
Genetic variants : HAPMAP26085
Genomic Variants (DGV)KLK13 [DGVbeta]
DECIPHER (Syndromes)19:51559463-51568367  ENSG00000167759
CONAN: Copy Number AnalysisKLK13 
Mutations
ICGC Data PortalKLK13 
TCGA Data PortalKLK13 
Broad Tumor PortalKLK13
OASIS PortalKLK13 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICKLK13  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDKLK13
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch KLK13
DgiDB (Drug Gene Interaction Database)KLK13
DoCM (Curated mutations)KLK13 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)KLK13 (select a term)
intoGenKLK13
NCG5 (London)KLK13
Cancer3DKLK13(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM605505   
Orphanet
MedgenKLK13
Genetic Testing Registry KLK13
NextProtQ9UKR3 [Medical]
TSGene26085
GENETestsKLK13
Huge Navigator KLK13 [HugePedia]
snp3D : Map Gene to Disease26085
BioCentury BCIQKLK13
ClinGenKLK13
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD26085
Chemical/Pharm GKB GenePA30150
Clinical trialKLK13
Miscellaneous
canSAR (ICR)KLK13 (select the gene name)
Probes
Litterature
PubMed34 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineKLK13
EVEXKLK13
GoPubMedKLK13
iHOPKLK13
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Wed Apr 12 11:34:05 CEST 2017

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