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KLK14 (kallikrein-related peptidase 14

Written2016-09Christos K. Kontos, Andreas Scorilas
Department of Biochemistry and Molecular Biology, National and Kapodistrian University of Athens, Athens, Greece /

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

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Other namesKLK-L6
HGNC (Hugo) KLK14
LocusID (NCBI) 43847
Atlas_Id 41080
Location 19q13.41  [Link to chromosome band 19q13]
Location_base_pair Starts at 51580752 and ends at 51587467 bp from pter ( according to hg19-Feb_2009)  [Mapping KLK14.png]
Local_order Telomere to centromere


Description The KLK14 gene has a total length of 6.700 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 he KLK14 gene is subjected to alternative splicing, generating two splice variants, which encode the same protein (Kurlender et al., 2005). These two splice variants differ only in their 3'-untranslated region (3'-UTR). One more splice variant is predicted to be encoded by the KLK14 gene, based on automatic sequence analysis of expressed sequence tags (ESTs). This splice variant uses the same start codon, but uses an alternate splice sites in the 3' coding region, in comparison with the aforementioned variants, generating a protein with a distinct C-terminus compared to the classical isoform precursor.
Pseudogene Not identified so far.


  Figure 2. Alignment of amino acid sequences of the precursors of the KLK14 protein isoforms. The three amino acid residues (positions: 83, 127, and 220) constituting the catalytic triad that is required for protease activity are shown in red. The N-terminal signal peptide (positions 1-34) is shown in light blue.
Description The classical KLK14 isoform (isoform 1) precursor consists of 267 amino acid residues and has a molecular mass of 29.1 kDa. The N-terminal signal peptide comprises 34 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 41 during limited proteolysis to generate its active form (Borgono et al., 2007). Three amino acid residues (positions: 83, 127, and 220) constitute the catalytic triad that is required for protease activity.
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).
Function Several human protein substrates for KLK14 have alreary been identified, including major components of the extracellular matrix such as collagens I-IV, fibronectin, laminin, kininogen, 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). 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), and SERPINA3 (alpha-1 antichymotrypsin), as well as SERPINE1 (plasminogen activator inhibitor-1) constitute inhibitors of this serine protease. Moreover, citrate enhance KLK14 activity, whereas zinc ions exert inhibitory action on KLK14 (Borgono et al., 2007; Felber et al., 2006). SPINK5 (LEKTI) fragments specifically inhibit KLK14 as well as other KLKs, thus controling desquamation through a pH-dependent interaction (Deraison et al., 2007)

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.
Prognosis Moreover, KLK14 protein overexpression was associated with advanced stage, high tumor grade, and high Gleason score (≥7) (Rabien et al., 2008; Yousef et al., 2003). Moreover, 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., 2003), as well as for the detection of cases at risk of disease progression after radical prostatectomy (Rabien et al., 2008).
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).
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).
Prognosis KLK14 mRNA overexpression was associated with high tumor grade and tumor volume, as well as with negative estrogen receptor (ER) 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). 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, while its prognostic utility is questionable. 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 is considered to be involved in the malignant behavior of ovarian cancer cells (Zhang et al., 2012). KLK14 protein levels were higher in 40% of ovarian cancer tissues, as compared to normal ovarian tissues. 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).
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 Chronic lymphocytic leukemia
Note KLK14 mRNA overexpression is able to successfully distinguish patients with chronic lymphocytic leukemia (CLL) from non-leukemic population.
Prognosis Furthermore, 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)


Expression and functional characterization of the cancer-related serine protease, human tissue kallikrein 14.
Borgono CA, Michael IP, Shaw JL, Luo LY, Ghosh MC, Soosaipillai A, Grass L, Katsaros D, Diamandis EP.
J Biol Chem 2007; 282: 2405-2422.
PMID 17110383
LEKTI fragments specifically inhibit KLK5, KLK7, and KLK14 and control desquamation through a pH-dependent interaction.
Deraison C, Bonnart C, Lopez F, Besson C, Robinson R, Jayakumar A, Wagberg F, Brattsand M, Hachem JP, Leonardsson G, Hovnanian A.
Mol Biol Cell 2007; 18: 3607-3619.
PMID 17596512
Major role of human KLK14 in seminal clot liquefaction.
Emami N, Deperthes D, Malm J, Diamandis EP.
J Biol Chem 2008; 283: 19561-19569.
PMID 18482984
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, Diamandis EP.
J Biol Chem 2008; 283: 3031-3041.
PMID 18056261
Enzymatic profiling of human kallikrein 14 using phage-display substrate technology.
Felber LM, Borgono CA, Cloutier SM, Kundig C, Kishi T, Ribeiro Chagas J, Jichlinski P, Gygi CM, Leisinger HJ, Diamandis EP, Deperthes D.
Biol Chem 2005; 386: 291-298.
PMID 15843175
Mutant recombinant serpins as highly specific inhibitors of human kallikrein 14.
Felber LM, Kundig C, Borgono CA, Chagas JR, Tasinato A, Jichlinski P, Gygi CM, Leisinger HJ, Diamandis EP, Deperthes D, Cloutier SM.
FEBS J 2006; 273: 2505-2514.
PMID 16704423
Expression of human Kallikrein 14 (KLK14) in breast cancer is associated with higher tumour grades and positive nodal status.
Fritzsche F, Gansukh T, Borgono CA, Burkhardt M, Pahl S, Mayordomo E, Winzer KJ, Weichert W, Denkert C, Jung K, Stephan C, Dietel M, Diamandis EP, Dahl E, Kristiansen G.
Br J Cancer 2006; 94: 540-547.
PMID 16434994
Kallikrein-related peptidase 14 acts on proteinase-activated receptor 2 to induce signaling pathway in colon cancer cells.
Gratio V, Loriot C, Virca GD, Oikonomopoulou K, Walker F, Diamandis EP, Hollenberg MD, Darmoul D.
Am J Pathol 2011; 179: 2625-2636.
PMID 21907696
Human kallikrein 14 (KLK14) expression in salivary gland tumors.
Hashem NN, Mara TW, Mohamed M, Zhang I, Fung K, Kwan KF, Daley TD, Diamandis EP, Darling MR.
Int J Biol Markers 2010; 25: 32-37.
PMID 20155713
Identification and characterization of KLK14, a novel kallikrein serine protease gene located on human chromosome 19q13.4 and expressed in prostate and skeletal muscle.
Hooper JD, Bui LT, Rae FK, Harvey TJ, Myers SA, Ashworth LK, Clements JA.
Genomics 2001; 73: 117-122.
PMID 11352573
mRNA overexpression of kallikrein-related peptidase 14 (KLK14) is an independent predictor of poor overall survival in chronic lymphocytic leukemia patients.
Kontos CK, Adamopoulos PG, Papageorgiou SG, Pappa V, Scorilas A.
Clin Chem Lab Med 2016; 54: 315-324.
PMID 26351937
A survey of alternative transcripts of human tissue kallikrein genes.
Kurlender L, Borgono C, Michael IP, Obiezu C, Elliott MB, Yousef GM, Diamandis EP.
Biochim Biophys Acta 2005; 1755: 1-14.
PMID 15878240
The kallikrein 14 gene is down-regulated by androgen receptor signalling and harbours genetic variation that is associated with prostate tumour aggressiveness.
Lose F, Lawrence MG, Srinivasan S, O'Mara T, Marquart L, Chambers S, Gardiner RA, Aitken JF, Spurdle AB, Batra J, Clements JA.
Biol Chem 2012; 393: 403-412.
PMID 22505522
Induction of complement C3a receptor responses by kallikrein-related peptidase 14.
Oikonomopoulou K, DeAngelis RA, Chen H, Diamandis EP, Hollenberg MD, Ricklin D, Lambris JD.
J Immunol 2013; 191: 3858-3866.
PMID 24014879
Significant alterations in the expression pattern of kallikrein-related peptidase genes KLK4, KLK5 and KLK14 after treatment of breast cancer cells with the chemotherapeutic agents epirubicin, docetaxel and methotrexate.
Papachristopoulou G, Talieri M, Scorilas A.
Tumour Biol 2013; 34: 369-378.
PMID 23086576
High expression of KLK14 in prostatic adenocarcinoma is associated with elevated risk of prostate-specific antigen relapse.
Rabien A, Fritzsche F, Jung M, Diamandis EP, Loening SA, Dietel M, Jung K, Stephan C, Kristiansen G.
Tumour Biol 2008; 29: 1-8.
PMID 18497543
Expression and enzymatic characterization of recombinant human kallikrein 14.
Rajapakse S, Takahashi T.
Zoolog Sci 2007; 24: 774-780.
PMID 18217483
Proteinase-activated receptors (PARs): differential signalling by kallikrein-related peptidases KLK8 and KLK14.
Ramachandran R, Eissa A, Mihara K, Oikonomopoulou K, Saifeddine M, Renaux B, Diamandis E, Hollenberg MD.
Biol Chem 2012; 393: 421-427.
PMID 22505524
In vitro evidence that KLK14 regulates the components of the HGF/Met axis, pro-HGF and HGF-activator inhibitor 1A and 1B.
Reid JC, Bennett NC, Stephens CR, Carroll ML, Magdolen V, Clements JA, Hooper JD.
Biol Chem 2016;
PMID 27533117
Kallikrein-related peptidase 14 may be a major contributor to trypsin-like proteolytic activity in human stratum corneum.
Stefansson K, Brattsand M, Ny A, Glas B, Egelrud T.
Biol Chem 2006; 387: 761-768.
PMID 16800737
Cloning of a new member of the human kallikrein gene family, KLK14, which is down-regulated in different malignancies.
Yousef GM, Magklara A, Chang A, Jung K, Katsaros D, Diamandis EP.
Cancer Res 2001; 61: 3425-3431.
PMID 11309303
Differential expression of the human kallikrein gene 14 (KLK14) in normal and cancerous prostatic tissues.
Yousef GM, Stephan C, Scorilas A, Ellatif MA, Jung K, Kristiansen G, Jung M, Polymeris ME, Diamandis EP.
Prostate 2003; 56: 287-292.
PMID 12858357
Effects of kallikrein-related peptidase 14 gene inhibition by small interfering RNA in ovarian carcinoma cells.
Zhang R, Shi H, Chen Z, Feng W, Zhang H, Wu K.
Mol Med Report 2012; 5: 256-259.
PMID 21993700
Non-combinatorial library screening reveals subsite cooperativity and identifies new high-efficiency substrates for kallikrein-related peptidase 14.
de Veer SJ, Swedberg JE, Parker EA, Harris JM.
Biol Chem 2012; 393: 331-341.
PMID 22505516


This paper should be referenced as such :
Kontos CK, Scorilas A
KLK14 (kallikrein-related peptidase 14;
Atlas Genet Cytogenet Oncol Haematol. in press
On line version :

External links

HGNC (Hugo)KLK14   6362
Entrez_Gene (NCBI)KLK14  43847  kallikrein related peptidase 14
GeneCards (Weizmann)KLK14
Ensembl hg19 (Hinxton)ENSG00000129437 [Gene_View]  chr19:51580752-51587467 [Contig_View]  KLK14 [Vega]
Ensembl hg38 (Hinxton)ENSG00000129437 [Gene_View]  chr19:51580752-51587467 [Contig_View]  KLK14 [Vega]
ICGC DataPortalENSG00000129437
TCGA cBioPortalKLK14
AceView (NCBI)KLK14
Genatlas (Paris)KLK14
SOURCE (Princeton)KLK14
Genetics Home Reference (NIH)KLK14
Genomic and cartography
GoldenPath hg19 (UCSC)KLK14  -     chr19:51580752-51587467 -  19q13.3-q13.4   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)KLK14  -     19q13.3-q13.4   [Description]    (hg38-Dec_2013)
EnsemblKLK14 - 19q13.3-q13.4 [CytoView hg19]  KLK14 - 19q13.3-q13.4 [CytoView hg38]
Mapping of homologs : NCBIKLK14 [Mapview hg19]  KLK14 [Mapview hg38]
Gene and transcription
Genbank (Entrez)AF283670 BC074904 BC074905 BC114614
RefSeq transcript (Entrez)NM_001311182 NM_022046
RefSeq genomic (Entrez)NC_000019 NC_018930 NT_011109 NW_004929415
Consensus coding sequences : CCDS (NCBI)KLK14
Cluster EST : UnigeneHs.283925 [ NCBI ]
CGAP (NCI)Hs.283925
Alternative Splicing GalleryENSG00000129437
Gene ExpressionKLK14 [ NCBI-GEO ]   KLK14 [ EBI - ARRAY_EXPRESS ]   KLK14 [ SEEK ]   KLK14 [ MEM ]
Gene Expression Viewer (FireBrowse)KLK14 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)43847
GTEX Portal (Tissue expression)KLK14
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ9P0G3 (Uniprot)
NextProtQ9P0G3  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ9P0G3
Splice isoforms : SwissVarQ9P0G3 (Swissvar)
Catalytic activity : Enzyme3.4.21.- [ Enzyme-Expasy ]   3.4.21.-3.4.21.- [ IntEnz-EBI ]   3.4.21.- [ BRENDA ]   3.4.21.- [ KEGG ]   
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)  
DMDM Disease mutations43847
Blocks (Seattle)KLK14
Human Protein AtlasENSG00000129437
Peptide AtlasQ9P0G3
Protein Interaction databases
IntAct (EBI)Q9P0G3
Ontologies - Pathways
Ontology : AmiGOserine-type endopeptidase activity  serine-type endopeptidase activity  extracellular space  proteolysis  fertilization  negative regulation of G-protein coupled receptor protein signaling pathway  positive regulation of G-protein coupled receptor protein signaling pathway  epidermis morphogenesis  extracellular exosome  seminal clot liquefaction  
Ontology : EGO-EBIserine-type endopeptidase activity  serine-type endopeptidase activity  extracellular space  proteolysis  fertilization  negative regulation of G-protein coupled receptor protein signaling pathway  positive regulation of G-protein coupled receptor protein signaling pathway  epidermis morphogenesis  extracellular exosome  seminal clot liquefaction  
NDEx NetworkKLK14
Atlas of Cancer Signalling NetworkKLK14
Wikipedia pathwaysKLK14
Orthology - Evolution
GeneTree (enSembl)ENSG00000129437
Phylogenetic Trees/Animal Genes : TreeFamKLK14
Homologs : HomoloGeneKLK14
Homology/Alignments : Family Browser (UCSC)KLK14
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerKLK14 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)KLK14
Exome Variant ServerKLK14
ExAC (Exome Aggregation Consortium)KLK14 (select the gene name)
Genetic variants : HAPMAP43847
Genomic Variants (DGV)KLK14 [DGVbeta]
DECIPHER (Syndromes)19:51580752-51587467  ENSG00000129437
CONAN: Copy Number AnalysisKLK14 
ICGC Data PortalKLK14 
TCGA Data PortalKLK14 
Broad Tumor PortalKLK14
OASIS PortalKLK14 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICKLK14 
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)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Genetic Testing Registry KLK14
NextProtQ9P0G3 [Medical]
Huge Navigator KLK14 [HugePedia]
snp3D : Map Gene to Disease43847
BioCentury BCIQKLK14
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD43847
Chemical/Pharm GKB GenePA30151
Clinical trialKLK14
canSAR (ICR)KLK14 (select the gene name)
PubMed33 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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