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| Alignment of 4 out of the 8 isoforms of the KLK6 protein. The signal peptide, glycosylation site, catalytic triad, and disulfide bonds are marked on the main isoform (isoform 1). The other four isoforms that are not presented align only partially with the main isoform. |
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Description | Eight different isoforms of KLK6 protein have been detected, consisting of 244, 137, 120, 149, 42, 138 277, and 182 amino acid (aa) residues, respectively. The KLK6 gene encodes a single-chain pre-proenzyme, which is enzymatically inactive. After the removal of the signal peptide (16 aa) from the pre-proenzyme, an inactive proKLK is formed and secreted to the extracellular space, where it is finally transformed into the active KLK through further cleavage (Bayani & Diamandis, 2011). |
Expression | KLK6 is highly expressed in cerebral cortex, tonsil, spleen, esophagus, kidney, fallopian tube and breast. |
Localisation | KLK6 is mainly localized to nucleoplasm, nuclear membrane and cytokinetic bridge. |
Function | KLK6 is a serine protease, involved in proteolytic cascades. KLK6 has been suggested to be autoactivated or activate other proKLKs. When activated, serine proteases are usually regulated by binding to serpins (serine protease inhibitors), which prompts to their inactivation. A preference for Arg over Lys in the substrate P1 position and for Ser or Pro in the P2 position is detected in KLK6 substrate. Three amino acid residues (positions: 62, 106, and 197) constitute the catalytic triad in the main protein isoform (isoform 1, 244 aa) that is responsible for serine protease activity. An Asp residue at position 191 suggests a trypsin-like activity, while chymotrypsin activity is suggested by a loop similar to chymotrypsin 3D-structure. However, chymotrypsin activity is rejected by recent studies. KLK6 is activated against amyloid precursor protein, which is associated with Alzheimer's disease, myelin basic protein, and casein. Furthermore, it participates in the degradation of extracellular matrix (ECM) proteins, namely fibronectin, laminin, vitronectin, laminin and collagen. It is involved in alpha-synuclein degradation and in the inhibition of its polymerization. This fact demonstrates the potential role of KLK6 in Parkinson's disease. Furthermore, KLK6 plays a role in cancer invasion and metastasis (Bayani & Diamandis, 2011). |
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Entity | Gastric cancer |
Prognosis | KLK6 is overexpressed in gastric cancer tissues. Elevated expression of KLK6 is linked to lymphatic invasion and unfavorable patient prognosis and may be associated with pericellular proteolysis. KLK6 gene silencing successfully reduces tumor cell proliferation and invasion (Nagahara et al., 2005). |
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Entity | Non-Small Cell Lung Cancer (NSCLC) |
Prognosis | KLK6 expression is elevated in NSCLC tumor tissue and is involved in NSCLC development and progression. High KLK6 concentration is related to poor survival rates, and patients with KLK6 overexpression are characterized by unfavorable prognosis (Heuzé-Vourc'h et al., 2009). |
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Entity | Ovarian cancer |
Prognosis | KLK6 protein expression is elevated in ovarian cancer, in both tumor and surrounding stromal cells. KLK6 is more often overexpressed in serous ovarian carcinoma than in endometrioid and mucinous carcinomas. It has been found to be transcriptionally regulated by hormones; KLK6 represents a downstream molecule by which a hormone-related neoplasm initiates and invades through degradation of the extracellular matrix and interaction with angiogenic factors. Gene amplification is suggested as a possible mechanism of high KLK6 presence in ovarian tumors. KLK6 derived by stromal cells is associated with the aggressive ovarian neoplasm. Unique patterns of N-glycosylation of KLK6 have been found; parts of sialic acid on KLK6 are abundant, almost exclusively, in ovarian cancer cells. KLK6 has been suggested as a prognostic biomarker for ovarian cancer, and is applicable in every stage, including the early one. Furthermore, it can be used in combination with MUC16 (CA-125), KLK10 and KLK13, in a multivariate model with increased prognostic power (Ni et al., 2004; White et al., 2009; Kuzmanov et al., 2009; Seiz et al., 2012). |
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Entity | Breast Cancer |
Prognosis | In the majority of metastatic breast cancers, KLK6 is deregulated. The mechanism behind this deregulation is genomic DNA methylation. Specifically, KLK6 has a tumor-protective activity against breast cancer, which derives from KLK6 loss-of-function, due to hypermethylation of CpG dinucleotides. On the other hand, overexpression of KLK6 was related to demethylation of the CpG dinucleotides. Modulation of KLK6 expression could serve as a therapeutic target (Pampalakis and Sotiropoulou, 2006). |
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Entity | Skin cancer |
Prognosis | KLK6 has proved to induce early skin cancer through the development of skin inflammation. Deficiency of KLK6 is linked to the suppression of chemically-induced skin cancer. KLK6 suspends CDH1 (E-cadherin) expression and leads to accumulation of CTNNB1ID: 71> (beta-catenin). Moreover, it is involved in progression of skin cancer and migration of cancer cells in squamous skin tumors (Klucky et al., 2007). A role of KLK6 in neoplastic transformation and malignant progression in has been demonstrated, as well (Krenzer et al., 2011). |
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Entity | Colorectal cancer (CRC) |
Prognosis | KLK6 expression in CRC has been reported to be elevated when a mutation in KRAS oncogene, which is strongly related to CRC, is abundant. Its expression is also increased through caveolin 1 ( CAV1) activity. CAV1 is overexpressed in CRC and acts on the PI3K/AKT pathway, by decreasing the activity of negative regulatory phosphatases, such as PPA1 and PTPA (PP2A). This leads to KLK6 gene overexpression. KLK6 has proved to participate in invasion and KRAS-dependent migration (Henkhaus et al., 2008a). This occurs due to its serine protease-ability to degrade EMC components (collagen, laminin, fibronectin). KLK6 is also involved in proteolytic cascades leading to the activation of certain enzymes which are involved in pericellular proteolysis and subsequently, to tumor invasion. Proteolysis of ECM components leads to disruption of their interaction with cells and is associated with tumor cell growth and malignant transformation. KLK6 serves as a possible indicator in CRC. This is enhanced by the fact that a combined analysis of KLK6 and carcinoembryonic antigen (CEA) in lymph nodes is able to identify CRC patients with high risk of relapse (Henkhaus et al., 2008b; Ohlsson et al., 2012; Petraki et al., 2012). |
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Molecular cloning of novel transcripts of human kallikrein-related peptidases 5, 6, 7, 8 and 9 (KLK5 - KLK9), using Next-generation sequencing |
Adamopoulos PG, Kontos CK, Scorilas A |
Sci Rep 2017 Dec 11;7(1):17299 |
PMID 29229980 |
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The physiology and pathobiology of human kallikrein-related peptidase 6 (KLK6) |
Bayani J, Diamandis EP |
Clin Chem Lab Med 2011 Nov 3;50(2):211-33 |
PMID 22047144 |
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Kallikrein 6 is a mediator of K-RAS-dependent migration of colon carcinoma cells |
Henkhaus RS, Gerner EW, Ignatenko NA |
Biol Chem 2008 Jun;389(6):757-64 |
PMID 18627290 |
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Kallikrein 6 induces E-cadherin shedding and promotes cell proliferation, migration, and invasion |
Klucky B, Mueller R, Vogt I, Teurich S, Hartenstein B, Breuhahn K, Flechtenmacher C, Angel P, Hess J |
Cancer Res 2007 Sep 1;67(17):8198-206 |
PMID 17804733 |
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Expression and function of the kallikrein-related peptidase 6 in the human melanoma microenvironment |
Krenzer S, Peterziel H, Mauch C, Blaber SI, Blaber M, Angel P, Hess J |
J Invest Dermatol 2011 Nov;131(11):2281-8 |
PMID 21753781 |
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Differential N-glycosylation of kallikrein 6 derived from ovarian cancer cells or the central nervous system |
Kuzmanov U, Jiang N, Smith CR, Soosaipillai A, Diamandis EP |
Mol Cell Proteomics 2009 Apr;8(4):791-8 |
PMID 19088065 |
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Clinicopathologic and biological significance of kallikrein 6 overexpression in human gastric cancer |
Nagahara H, Mimori K, Utsunomiya T, Barnard GF, Ohira M, Hirakawa K, Mori M |
Clin Cancer Res 2005 Oct 1;11(19 Pt 1):6800-6 |
PMID 16203767 |
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High kallikrein-related peptidase 6 in non-small cell lung cancer cells: an indicator of tumour proliferation and poor prognosis |
Nathalie HV, Chris P, Serge G, Catherine C, Benjamin B, Claire B, Christelle P, Briollais L, Pascale R, Marie-Lise J, Yves C |
J Cell Mol Med 2009 Sep;13(9B):4014-22 |
PMID 19426157 |
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Characterisation of human kallikrein 6/protease M expression in ovarian cancer |
Ni X, Zhang W, Huang KC, Wang Y, Ng SK, Mok SC, Berkowitz RS, Ng SW |
Br J Cancer 2004 Aug 16;91(4):725-31 |
PMID 15305183 |
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Lymph node tissue kallikrein-related peptidase 6 mRNA: a progression marker for colorectal cancer |
Ohlsson L, Lindmark G, Israelsson A, Palmqvist R, Öberg Å, Hammarström ML, Hammarström S |
Br J Cancer 2012 Jun 26;107(1):150-7 |
PMID 22699826 |
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Multiple mechanisms underlie the aberrant expression of the human kallikrein 6 gene in breast cancer |
Pampalakis G, Sotiropoulou G |
Biol Chem 2006 Jun;387(6):773-82 |
PMID 16800739 |
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Evaluation and prognostic significance of human tissue kallikrein-related peptidase 6 (KLK6) in colorectal cancer |
Petraki C, Dubinski W, Scorilas A, Saleh C, Pasic MD, Komborozos V, Khalil B, Gabril MY, Streutker C, Diamandis EP, Yousef GM |
Pathol Res Pract 2012 Feb 15;208(2):104-8 |
PMID 22285222 |
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Stromal cell-associated expression of kallikrein-related peptidase 6 (KLK6) indicates poor prognosis of ovarian cancer patients |
Seiz L, Dorn J, Kotzsch M, Walch A, Grebenchtchikov NI, Gkazepis A, Schmalfeldt B, Kiechle M, Bayani J, Diamandis EP, Langer R, Sweep FC, Schmitt M, Magdolen V |
Biol Chem 2012 Apr;393(5):391-401 |
PMID 22505521 |
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Human kallikrein related peptidases 6 and 13 in combination withCA125 is a more sensitive test for ovarian cancer than CA125 alone |
White NM, Mathews M, Yousef GM, Prizada A, Fontaine D, Ghatage P, Popadiuk C, Dawson L, Doré JJ |
Cancer Biomark 2009;5(6):279-87 |
PMID 20037204 |
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