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| 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. |
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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.
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| 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. |
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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). |
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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). |
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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). |
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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). |
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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). |
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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). |
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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). |
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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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Expression and functional characterization of the cancer-related serine protease, human tissue kallikrein 14 |
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J Biol Chem 2007 Jan 26;282(4):2405-22 |
PMID 17110383 |
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LEKTI fragments specifically inhibit KLK5, KLK7, and KLK14 and control desquamation through a pH-dependent interaction |
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Thromb Haemost 2013 Apr;109(4):716-25 |
PMID 23224034 |
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Major role of human KLK14 in seminal clot liquefaction |
Emami N, Deperthes D, Malm J, Diamandis EP |
J Biol Chem 2008 Jul 11;283(28):19561-9 |
PMID 18482984 |
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Human kallikrein-related peptidase 14 (KLK14) is a new activator component of the KLK proteolytic cascade |
Emami N, Diamandis EP |
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PMID 18056261 |
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Enzymatic profiling of human kallikrein 14 using phage-display substrate technology |
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Biol Chem 2005 Mar;386(3):291-8 |
PMID 15843175 |
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Mutant recombinant serpins as highly specific inhibitors of human kallikrein 14 |
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PMID 16704423 |
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Expression of human Kallikrein 14 (KLK14) in breast cancer is associated with higher tumour grades and positive nodal status |
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PMID 16434994 |
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Transgenic Kallikrein 14 Mice Display Major Hair Shaft Defects Associated with Desmoglein 3 and 4 Degradation, Abnormal Epidermal Differentiation, and IL-36 Signature |
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Kallikrein-related peptidase 14 acts on proteinase-activated receptor 2 to induce signaling pathway in colon cancer cells |
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PMID 20155713 |
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Identification and characterization of KLK14, a novel kallikrein serine protease gene located on human chromosome 19q13 |
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PMID 11352573 |
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mRNA overexpression of kallikrein-related peptidase 14 (KLK14) is an independent predictor of poor overall survival in chronic lymphocytic leukemia patients |
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PMID 26351937 |
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The molecular function of kallikrein-related peptidase 14 demonstrates a key modulatory role in advanced prostate cancer |
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PMID 15878240 |
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The kallikrein 14 gene is down-regulated by androgen receptor signalling and harbours genetic variation that is associated with prostate tumour aggressiveness |
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Biol Chem 2012 Apr;393(5):403-12 |
PMID 22505522 |
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J Immunol 2013 Oct 1;191(7):3858-66 |
PMID 24014879 |
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Androgens act synergistically to enhance estrogen-induced upregulation of human tissue kallikreins 10, 11, and 14 in breast cancer cells via a membrane bound androgen receptor |
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Mol Oncol 2008 Apr;1(4):413-24 |
PMID 19383315 |
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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 |
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PMID 18627302 |
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High expression of KLK14 in prostatic adenocarcinoma is associated with elevated risk of prostate-specific antigen relapse |
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PMID 18497543 |
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In vitro evidence that KLK14 regulates the components of the HGF/Met axis, pro-HGF and HGF-activator inhibitor 1A and 1B |
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PMID 16800737 |
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PMID 29494334 |
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PMID 22505516 |
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