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KLK14 (kallikrein-related peptidase 14)

Written2020-04Paraskevi Karousi, Andreas Scorilas, Christos K. Kontos
Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens, Greece / chkontos@biol.uoa.gr
This article is an update of :
2016-09Christos K. Kontos, Andreas Scorilas
Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Athens, Greece / ascorilas@biol.uoa.gr

Abstract Review on KLK14, with data on DNA, on the protein encoded, and where the gene is implicated.

Keywords Kallikreins; KLK14; Prostate cancer; Breast cancer; Ovarian cancer; Colon cancer; Non-small cell lung cancer; Chronic Lymphocytic Leukemia;

(Note : for Links provided by Atlas : click)

Identity

Alias (NCBI)KLK-L6
HGNC (Hugo) KLK14
HGNC Alias symbKLK-L6
HGNC Previous namekallikrein 14
LocusID (NCBI) 43847
Atlas_Id 41080
Location 19q13.41  [Link to chromosome band 19q13]
Location_base_pair Starts at 51077974 and ends at 51084210 bp from pter ( according to hg19-Feb_2009)  [Mapping KLK14.png]
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)

DNA/RNA

 
  Figure 1. Schematic representation of the KLK14 gene. Exons are shown as boxes and introns as connecting lines. The coding sequences are highlighted as red, while 5' and 3' untranslated regions (UTRs) are shown in white. Numbers inside or outside boxes indicate lengths (nt) of exons and introns, respectively, while numbers in parentheses indicate lengths (aa) of protein isoforms. Arrows (↓) show the position of the start codons (ATG) and asterisks (*) denote the position of the stop codons (TAA or TGA). Question marks (?) indicate undetermined 5' UTRs. The figure is drawn to scale, except for the introns containing the (//) symbol.
Description The KLK14 gene has a total length of 6,717 nt and consists of 8 exons and 7 intervening introns. The organization of the KLK14 gene is similar to that of the other KLK family members (Hooper et al., 2001; Yousef et al., 2001).
Transcription The KLK14 pre-mRNA is subjected to alternative splicing, generating nine splice variants, four of which are accessible via the Reference Sequence (RefSeq) database. Three of them (GenBank accession numbers: NM_001311182.2, NM_022046.6, and NM_001369775.2) encode the main protein isoform (Kurlender et al., 2005). These three splice variants differ only in their 5' and 3'-untranslated regions (UTRs). The fourth transcript (GenBank accession number: NR_163144.1) lacks exon 5 and does not have an open reading frame (ORF).
Three splice variants have been deposed in the Ensembl database, but only one of them shows a different exon combination, compared to the aforementioned transcripts; this transcript (Ensembl accession number: ENST00000391802.1) uses the same start codon as the predicted transcript and includes all other exons, leading to a protein isoform with distinct N-terminus, compared to the main isoform.
Recently, members of our research group have discovered four novel KLK14 transcripts and submitted their sequences to GenBank. Two out of them possess an ORF and, most likely, generate two respective protein isoforms. The first transcript (GenBank accession number: KY305101.1) resembles the one available in Ensembl, but lacks two exons within the coding sequence, leading to a protein isoform with a distinct C-terminus compared to the main one; the second one (GenBank accession number: KY305102.1) lacks three exons within the coding region and uses alternative splice sites in its 3' coding region, thus probably generating a short peptide of 30 amino acid residues. The 5'UTR of both these transcripts has not been determined. The other two transcripts (GenBank accession numbers: KY305104.1 and KY305105.1) have an intron retention, do not have any ORF and, most likely, represent nonsense-mediated mRNA decay candidates.
Another splice variant (GenBank accession number: XM_017026820.1) is predicted to be encoded by the KLK14 gene, based on automated sequence analysis of expressed sequence tags (ESTs). This splice variant probably uses a different translation start codon, lacks an exon within the coding sequence and uses alternative splice sites in its 3' coding region, in comparison with the aforementioned transcripts, generating a protein with distinct N- and C-termini, compared to the classical isoform precursor. Expression KLK14 mRNA is primarily expressed in the prostate, salivary gland, stomach, lung, spleen, uterus, thymus, liver, small intestine, and cerebellum while lower levels of expression are found in many other tissues. KLK14 mRNA expression is downregulated in malignant breast, testicular, prostatic, and ovarian tumors (Yousef et al., 2001).
Pseudogene Not identified so far.

Protein

 
  Figure 2. Alignment of amino acid sequences of the precursors of the KLK14 protein isoforms. The three amino acid residues (positions: 67, 11, and 204) constituting the catalytic triad that is required for protease activity are shown in red. The N-terminal signal peptide (positions: 1-18) is shown in blue. Substrate binding sites (positions: 198, 219, and 221) are shown in light blue, while the cleavage site of the precursor form (position: 25) is indicated in orange. Numbering of amino acid residue positions is based on the sequence of the main KLK14 isoform (isoform 1) precursor.
Description The precursor of the classical KLK14 isoform (isoform 1; GenBank accession numbers: NP_001298111.2, NP_001356704.1, and NP_071329.3) consists of 251 amino acid residues and has a molecular mass of 29.1 kDa. The N-terminal signal peptide comprises 18 amino acid residues. KLK14 is a secreted serine protease having dual activity, trypsin- and chymotrypsin-like, with a preference for cleavage after arginine residues (Felber et al., 2005; Rajapaksei and Takahashi, 2007). KLK14 protein is synthesized as inactive precursor zymogen that is cleaved at the position 25 during limited proteolysis to generate its active form (Borgono et al., 2007). Three amino acid residues (positions: 67, 111, and 204) constitute the catalytic triad that is required for protease activity. Three other amino acid residues (positions 198, 219, and 221) constitute the substrate-binding site. A recent study has suggested some specific amino acid residues as responsible for the ability of KLK14 to interact with other proteins (Asp189, Ser190, Gln192, and Trp211) (Solis-Calero and Carvalho, 2017).
KLK14 isoform 2 (Ensembl accession number: ENSP00000375678.1) consists of 267 amino acid residues and contains a distinct N-terminus, compared to isoform 1. KLK14 isoforms 3 and 4 (GenBank accession numbers: AQU42773.1 and AQU42774.1) share the same N-terminus as isoform 2 and consist of 125 and 30 amino acid residues, respectively. Additionally, another isoform, predicted to be generated by KLK14 splice variant X1 and composed of 179 amino acid residues, has distinct N- and C- termini, in comparison with the main KLK14 isoform precursor.
 
  Figure 3. Predicted models of the precursors of the KLK14 protein isoforms, using the I-TASSER server (Yang and Zhang, 2015). For each protein, only the 3D structure with the highest confidence score is presented. The RasMol 'Group' color scheme color codes residues by their position in a macromolecular chain. Each polypeptide is drawn as a smooth spectrum from blue through green, yellow and orange to red. Thus, the N-termini are colored blue and the C-termini are drawn in red.
Function Several human protein substrates for KLK14 have already been identified, including major components of the extracellular matrix such as collagens I-IV, fibronectin 1, kininogen 1, fibrinogen, plasminogen (PLG), vitronectin (VTN), and insulin-like growth factor-binding proteins 2 and 3 (IGFBP2 and IGFBP3) (Borgono et al., 2007; Felber et al., 2005; Kryza et al., 2020). Thus, this secreted cancer-related peptidase may be involved in several facets of tumor progression, including growth, invasion, and angiogenesis, as well as in arthritic disease via deterioration of cartilage (Borgono et al., 2007). Additionally, KLK14 is implicated in other physiological functions too, such as desquamation and activation of signaling molecules associated with inflammation and cancer (de Veer et al., 2012). In fact, this enzyme may be responsible for as much as 50% of the total trypsin-like activity in stratum corneum, thus suggesting an important role for this very efficient protease under normal and disease conditions in the skin (Stefansson et al., 2006). KLK14 can also directly cleave semenogelins I and II (SEMG1 and SEMG2), thus playing a major role in seminal clot liquefaction (Emami et al., 2008). In addition, active KLK14 is efficiently able to cleave C3, the point of convergence of the complement cascade, indicating a potential modulation of C3-mediated functions. Thus, it parcipates in the activation of the innate immune response (Oikonomopoulou et al., 2013). Members of the proteinase-activated receptor (PAR) family constitute also targets of KLK14; their activation upon cleavage by KLK14 leads to differential signaling and affects tissue function (Ramachandran et al., 2012). For instance, KLK14 acts on proteinase-activated receptor 2 (F2RL1 or PAR2) to induce MAPK3/ MAPK1 (ERK1/ERK2) signaling pathway in colon cancer ID: 5006> cells (Gratio et al., 2011). Besides its other actions, human KLK14 activates the KLK proteolytic cascade (Emami and Diamandis, 2008). Very recently, it has also been suggested that elevated KLK14 activity contributes at multiple levels the activation of the oncogenic hepatocyte growth factor ( HGF)/MET signaling in prostate cancer and other human malignancies (Reid et al., 2016).
Regarding the regulation of the enzymatic activity of KLK14, the serpins SERPINA1 (alpha-1 antitrypsin), SERPINF2 (alpha-2 antiplasmin), SERPINC1 (antithrombin III), SERPINA3 (alpha-1 antichymotrypsin) and SEPPINA12 (alpha-12), as well as SERPINE1 (plasminogen activator inhibitor-1) constitute inhibitors of this serine protease (Borgono et al., 2007; Felber et al., 2006; Ulbricht et al., 2018). Serine peptidase inhibitors, Kunitz type 1 SPINT1) and 2 (SPINT2), have been also shown to bind KLK14 (Solis-Calero and Carvalho, 2017). Moreover, citrate enhance KLK14 activity, whereas zinc ions exert inhibitory action on KLK14 (Borgono et al., 2007; Felber et al., 2006). Fragments of serine peptidase inhibitor Kazal type 5 (SPINK5; also known as LEKTI) specifically inhibit KLK14 as well as other KLKs, thus controlling desquamation through a pH-dependent interaction (Deraison et al., 2007). Moreover, transgenic mice bearing the human KLK14 gene and with Netherthon syndrome (SPINK5 deficiency) showed higher proteolytic activity in the granular layers and hair follicles, due to the higher KLK14 levels, as well as epidermal hyperproliferation and differentiation, downregulation of desmogleins 3 (DSG3) and 4 (DSG4), and IL36 family overexpression (Gouin et al., 2020).

Implicated in

  
Entity Prostate cancer
Note KLK14 is expressed by both benign and malignant glandular epithelial cells of the prostate (Hooper et al., 2001). However, KLK14 is significantly overexpressed in the majority of cancerous prostatic tissue specimens, as compared with their non-malignant counterparts. Moreover, KLK14 protein overexpression was associated with advanced stage, high tumor grade, and high Gleason score (≥7) (Rabien et al., 2008; Yousef et al., 2003b; Kryza et al., 2020). In addition, KLK14 expression was elevated in patients with castrate-resistant prostate cancer and patients with distant metastasis. KLK14 had higher proteolytic activity and was shown to regulate the MAPK pathway in LNCaP prostate cancer cells, promoting the migration and cohesion of these cells (Kryza et al., 2020).
Three common genetic variants in the KLK14 locus were shown to be associated with higher Gleason score (≥7). Two of them, namely rs17728459 and rs4802765, are both located upstream of the transcribed KLK14 region, whereas the third one (rs35287116) is located inside KLK14 coding region and accounts for a p.Gln33Arg substitution in the KLK14 signal peptide (Lose et al., 2012).
Prognosis High KLK14 levels predict biochemical relapse of prostate cancer patients, independently of other established prognostic factors (Rabien et al., 2008). Therefore, KLK14 has been suggested as a candidate novel marker for prostate cancer diagnosis and prognosis (Yousef et al., 2003b), as well as for the detection of cases at risk of disease progression, after radical prostatectomy (Rabien et al., 2008).
  
  
Entity Breast cancer
Note KLK14 mRNA overexpression was observed in malignant breast tumors in comparison with normal breast tissues and benign breast tumors (Fritzsche et al., 2006; Papachristopoulou et al., 2011). Moreover, KLK14 expression was shown to be upregulated upon treatment with androgens in BT-474 breast cancer cells (Paliouras and Diamandis, 2008). Additionally, serum KLK14 levels were elevated in 40% of patients with breast cancer (Borgono et al., 2003). Thus, KLK14 constitutes a potential diagnostic biomarker in breast cancer.
Prognosis KLK14 mRNA overexpression was associated with shorter overall (OS) and disease-free (DFS) survival intervals of breast cancer patients (Yousef et al., 2002). KLK14 mRNA overexpression was associated with high tumor grade and tumor volume, as well as with negative estrogen receptor status (Papachristopoulou et al., 2011). Accordingly, cytoplasmic KLK14 protein expression was significantly higher in invasive breast carcinomas than in normal breast tissue specimens. Moreover, KLK14 protein overexpression was associated with high histological grade and positive nodal status. However, it failed to predict patient outcome (Fritzsche et al., 2006). Moreover, KLK14 mRNA expression has been suggested as a biomarker for prediction of breast cancer patients' response to chemotherapy (Papachristopoulou et al., 2013).
  
  
Entity Ovarian cancer
Note KLK14 protein levels were higher in 40% of ovarian cancer tissues, as compared to normal ovarian tissues (Borgono et al., 2003) and this upregulation is probably mediated through an androgen receptor (Yousef et al., 2003a). Moreover, serum KLK14 levels were elevated in 65% of patients with ovarian cancer (Borgono et al., 2003). Thus, KLK14 constitutes a potential biomarker in ovarian cancer and a therapeutic target, as well (Borgono et al., 2003; Zhang et al., 2012).
Prognosis KLK14 mRNA upregulation was shown to be associated with longer DFS time intervals of ovarian cancer patients (Yousef et al., 2003a; Dettmar et al., 2018). KLK14 is considered to be involved in the malignant behavior of ovarian cancer cells (Zhang et al., 2012).
  
  
Entity Salivary gland cancer
Note Both pleomorphic adenoma and adenoid cystic carcinoma of the salivary glands showed elevated KLK14 expression than normal glands and mucoepidermoid carcinoma tissues. These observed differences in KLK14 protein levels imply that KLKs may aid in the differential diagnosis of salivary gland tumors. KLK14 is considered as a promising novel biomarker for salivary gland tumors (Hashem et al., 2010).
  
  
Entity Colon cancer
Note KLK14 mRNA expression can discriminate between colon cancer and adenoma tissues.
Prognosis KLK14 mRNA expression status is associated with shorter OS and DFS intervals of colon cancer patients. Therefore, KLK14 has been suggested as a biomarker of poor prognosis in colon cancer (Devetzi et al., 2013).
  
  
Entity Non-small cell lung cancer
Note KLK14 mRNA was reported to be upregulated in NSCL malignant tissues, compared to adjacent non-malignant tissues. Moreover, KLK14 mRNA was found to be related with tumor size, but this relation is marginal (Planque et al., 2008).
  
  
Entity Chronic lymphocytic leukemia
Note KLK14 mRNA overexpression is able to successfully distinguish patients with chronic lymphocytic leukemia (CLL) from non-leukemic population.
Prognosis Although not clearly associated to clinical staging or other prognostic factors including IGHV mutational status and CD38 expression, high KLK14 mRNA expression predicts poor overall survival of B-CLL patients. The unfavorable prognostic value of KLK14 mRNA positivity in peripheral blood mononuclear cells of B-CLL patients was shown to be independent of established prognostic factors of this hematological malignancy. As a result, KLK14 mRNA expression has been suggested as a prognostic biomarker of overall survival of B-CLL patients (Kontos et al., 2016).
  

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Citation

This paper should be referenced as such :
Karousi P, Scorilas A, Kontos CK
KLK14 (kallikrein-related peptidase 14);
Atlas Genet Cytogenet Oncol Haematol. in press
History of this paper:
Christos K Kontos, Andreas Scorilas. KLK14 (kallikrein-related peptidase 14). Atlas Genet Cytogenet Oncol Haematol. 2017;21(4):134-137.
http://documents.irevues.inist.fr/bitstream/handle/2042/68232/09-2016-KLK14ID41080ch19q13.pdf


External links

Nomenclature
HGNC (Hugo)KLK14   6362
Cards
AtlasKLK14ID41080ch19q13
Entrez_Gene (NCBI)KLK14  43847  kallikrein related peptidase 14
AliasesKLK-L6
GeneCards (Weizmann)KLK14
Ensembl hg19 (Hinxton)ENSG00000129437 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000129437 [Gene_View]  ENSG00000129437 [Sequence]  chr19:51077974-51084210 [Contig_View]  KLK14 [Vega]
ICGC DataPortalENSG00000129437
TCGA cBioPortalKLK14
AceView (NCBI)KLK14
Genatlas (Paris)KLK14
WikiGenes43847
SOURCE (Princeton)KLK14
Genetics Home Reference (NIH)KLK14
Genomic and cartography
GoldenPath hg38 (UCSC)KLK14  -     chr19:51077974-51084210 -  19q13.41   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)KLK14  -     19q13.41   [Description]    (hg19-Feb_2009)
GoldenPathKLK14 - 19q13.41 [CytoView hg19]  KLK14 - 19q13.41 [CytoView hg38]
ImmunoBaseENSG00000129437
genome Data Viewer NCBIKLK14 [Mapview hg19]  
OMIM606135   
Gene and transcription
Genbank (Entrez)AF283670 BC074904 BC074905 BC114614 KY305101
RefSeq transcript (Entrez)NM_001311182 NM_001369775 NM_022046
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)KLK14
Alternative Splicing GalleryENSG00000129437
Gene ExpressionKLK14 [ NCBI-GEO ]   KLK14 [ EBI - ARRAY_EXPRESS ]   KLK14 [ SEEK ]   KLK14 [ MEM ]
Gene Expression Viewer (FireBrowse)KLK14 [ Firebrowse - Broad ]
GenevisibleExpression of KLK14 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)43847
GTEX Portal (Tissue expression)KLK14
Human Protein AtlasENSG00000129437-KLK14 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9P0G3   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ9P0G3  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9P0G3
Splice isoforms : SwissVarQ9P0G3
Catalytic activity : Enzyme3.4.21.- [ Enzyme-Expasy ]   3.4.21.-3.4.21.- [ IntEnz-EBI ]   3.4.21.- [ BRENDA ]   3.4.21.- [ KEGG ]   [ MEROPS ]
PhosPhoSitePlusQ9P0G3
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)KLK14
DMDM Disease mutations43847
Blocks (Seattle)KLK14
SuperfamilyQ9P0G3
Human Protein Atlas [tissue]ENSG00000129437-KLK14 [tissue]
Peptide AtlasQ9P0G3
HPRD05844
IPIIPI00000700   
Protein Interaction databases
DIP (DOE-UCLA)Q9P0G3
IntAct (EBI)Q9P0G3
FunCoupENSG00000129437
BioGRIDKLK14
STRING (EMBL)KLK14
ZODIACKLK14
Ontologies - Pathways
QuickGOQ9P0G3
Ontology : AmiGOserine-type endopeptidase activity  serine-type endopeptidase activity  extracellular region  extracellular space  proteolysis  fertilization  secretory granule  negative regulation of G protein-coupled receptor signaling pathway  positive regulation of G protein-coupled receptor signaling pathway  epidermis morphogenesis  epidermis morphogenesis  cornification  seminal clot liquefaction  seminal clot liquefaction  
Ontology : EGO-EBIserine-type endopeptidase activity  serine-type endopeptidase activity  extracellular region  extracellular space  proteolysis  fertilization  secretory granule  negative regulation of G protein-coupled receptor signaling pathway  positive regulation of G protein-coupled receptor signaling pathway  epidermis morphogenesis  epidermis morphogenesis  cornification  seminal clot liquefaction  seminal clot liquefaction  
REACTOMEQ9P0G3 [protein]
REACTOME PathwaysR-HSA-6809371 [pathway]   
NDEx NetworkKLK14
Atlas of Cancer Signalling NetworkKLK14
Wikipedia pathwaysKLK14
Orthology - Evolution
OrthoDB43847
GeneTree (enSembl)ENSG00000129437
Phylogenetic Trees/Animal Genes : TreeFamKLK14
HOGENOMQ9P0G3
Homologs : HomoloGeneKLK14
Homology/Alignments : Family Browser (UCSC)KLK14
Gene fusions - Rearrangements
Fusion : QuiverKLK14
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerKLK14 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)KLK14
dbVarKLK14
ClinVarKLK14
MonarchKLK14
1000_GenomesKLK14 
Exome Variant ServerKLK14
GNOMAD BrowserENSG00000129437
Varsome BrowserKLK14
Genetic variants : HAPMAP43847
Genomic Variants (DGV)KLK14 [DGVbeta]
DECIPHERKLK14 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisKLK14 
Mutations
ICGC Data PortalKLK14 
TCGA Data PortalKLK14 
Broad Tumor PortalKLK14
OASIS PortalKLK14 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICKLK14  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DKLK14
Mutations and Diseases : HGMDKLK14
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch KLK14
DgiDB (Drug Gene Interaction Database)KLK14
DoCM (Curated mutations)KLK14 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)KLK14 (select a term)
intoGenKLK14
NCG6 (London) select KLK14
Cancer3DKLK14(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM606135   
Orphanet
DisGeNETKLK14
MedgenKLK14
Genetic Testing Registry KLK14
NextProtQ9P0G3 [Medical]
TSGene43847
GENETestsKLK14
Target ValidationKLK14
Huge Navigator KLK14 [HugePedia]
snp3D : Map Gene to Disease43847
BioCentury BCIQKLK14
ClinGenKLK14
Clinical trials, drugs, therapy
Protein Interactions : CTD43847
Pharm GKB GenePA30151
Clinical trialKLK14
Miscellaneous
canSAR (ICR)KLK14 (select the gene name)
HarmonizomeKLK14
DataMed IndexKLK14
Probes
Litterature
PubMed38 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineKLK14
EVEXKLK14
GoPubMedKLK14
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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