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KLK6 (kallikrein-related peptidase 6)

Written2019-04Paraskevi Karousi, Christos 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 KLK6, with data on DNA, protein, and where the gene is involved.

Keywords Kallikreins; KlK6; gastric cancer; colorectal cancer; breast cancer; ovarian cancer; laryngeal cancer.

(Note : for Links provided by Atlas : click)

Identity

Alias_namesPRSS9
PRSS18
protease, serine, 18
kallikrein 6 (neurosin, zyme)
Alias_symbol (synonym)Bssp
Klk7
neurosin
Other aliasBss
SP5
hK6
HGNC (Hugo) KLK6
LocusID (NCBI) 5653
Atlas_Id 41086
Location 19q13.41  [Link to chromosome band 19q13]
Location_base_pair Starts at 50958631 and ends at 50969673 bp from pter ( according to hg19-Feb_2009)  [Mapping KLK6.png]
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

 
  Graphic illustration of the KLK6 gene. Boxes denote exons and connecting lines represent introns. The coding sequences are colored in green, while 5' and 3' untranslated regions (UTRs) are shown in white. The numbers inside or outside boxes indicate lengths (nt) of exons and introns, respectively, while the numbers in parentheses indicate lengths (aa) of protein isoforms. Arrows mark the position of the start codons (ATG) and asterisks (*) mark the position of the stop codon (TGA). The figure is drawn in scale, except for the introns containing the (//) symbol. For each transcript, the splice variant number, the GenBank accession number and the protein isoform number are shown next to each transcript (Adamopoulos et al., 2017).
Description The KLK6 gene is located on 19q chromosome, has a total length of 11.043 nt, and consists of 7 exons and 6 introns.
Transcription KLK6 pre-mRNA is subjected to alternative splicing. Six (6) variants had previously been detected, while another 6 transcripts have recently been identified by our research group (Adamopoulos et al., 2017). Furthermore, one more variant is predicted, based on similarity to 50 ESTs. Each of them has a different exon and intron structure. The main variant (variant A) consists of 7 exons and 6 introns. The first 2 introns do not include coding regions and compose the 5UTR. The other 11 variants range from 3 to 7 exons and 2 to 6 introns, while some of them bare similarity to each other. The structures of all variants are clearly illustrated in Figure 1.
Pseudogene Not detected so far.

Protein

 
  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.
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).

Mutations

Note No mutations have been detected.

Implicated in

  
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).
  
  
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).
  
  
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).
  
  
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).
  
  
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).
  
  
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).
  

Bibliography

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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 
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
 

Citation

This paper should be referenced as such :
Karousi P, Kontos CK, Scorilas A
KLK6 (kallikrein-related peptidase 6);
Atlas Genet Cytogenet Oncol Haematol. in press
On line version : http://AtlasGeneticsOncology.org/Genes/KLK6ID41086ch19q13.html


External links

Nomenclature
HGNC (Hugo)KLK6   6367
Cards
AtlasKLK6ID41086ch19q13
Entrez_Gene (NCBI)KLK6  5653  kallikrein related peptidase 6
AliasesBssp; Klk7; PRSS18; PRSS9; 
SP59; hK6
GeneCards (Weizmann)KLK6
Ensembl hg19 (Hinxton)ENSG00000167755 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000167755 [Gene_View]  ENSG00000167755 [Sequence]  chr19:50958631-50969673 [Contig_View]  KLK6 [Vega]
ICGC DataPortalENSG00000167755
TCGA cBioPortalKLK6
AceView (NCBI)KLK6
Genatlas (Paris)KLK6
WikiGenes5653
SOURCE (Princeton)KLK6
Genetics Home Reference (NIH)KLK6
Genomic and cartography
GoldenPath hg38 (UCSC)KLK6  -     chr19:50958631-50969673 -  19q13.41   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)KLK6  -     19q13.41   [Description]    (hg19-Feb_2009)
GoldenPathKLK6 - 19q13.41 [CytoView hg19]  KLK6 - 19q13.41 [CytoView hg38]
ImmunoBaseENSG00000167755
Mapping of homologs : NCBIKLK6 [Mapview hg19]  KLK6 [Mapview hg38]
OMIM602652   
Gene and transcription
Genbank (Entrez)AF013988 AK314897 AY279383 AY318867 AY318868
RefSeq transcript (Entrez)NM_001012964 NM_001012965 NM_001319948 NM_001319949 NM_002774
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)KLK6
Cluster EST : UnigeneHs.79361 [ NCBI ]
CGAP (NCI)Hs.79361
Alternative Splicing GalleryENSG00000167755
Gene ExpressionKLK6 [ NCBI-GEO ]   KLK6 [ EBI - ARRAY_EXPRESS ]   KLK6 [ SEEK ]   KLK6 [ MEM ]
Gene Expression Viewer (FireBrowse)KLK6 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)5653
GTEX Portal (Tissue expression)KLK6
Human Protein AtlasENSG00000167755-KLK6 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ92876   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ92876  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ92876
Splice isoforms : SwissVarQ92876
PhosPhoSitePlusQ92876
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)KLK6
DMDM Disease mutations5653
Blocks (Seattle)KLK6
PDB (RSDB)1GVL    1L2E    1LO6    3VFE    4D8N   
PDB Europe1GVL    1L2E    1LO6    3VFE    4D8N   
PDB (PDBSum)1GVL    1L2E    1LO6    3VFE    4D8N   
PDB (IMB)1GVL    1L2E    1LO6    3VFE    4D8N   
Structural Biology KnowledgeBase1GVL    1L2E    1LO6    3VFE    4D8N   
SCOP (Structural Classification of Proteins)1GVL    1L2E    1LO6    3VFE    4D8N   
CATH (Classification of proteins structures)1GVL    1L2E    1LO6    3VFE    4D8N   
SuperfamilyQ92876
Human Protein Atlas [tissue]ENSG00000167755-KLK6 [tissue]
Peptide AtlasQ92876
HPRD04037
IPIIPI00023845   IPI00554738   IPI00896372   IPI00426071   
Protein Interaction databases
DIP (DOE-UCLA)Q92876
IntAct (EBI)Q92876
FunCoupENSG00000167755
BioGRIDKLK6
STRING (EMBL)KLK6
ZODIACKLK6
Ontologies - Pathways
QuickGOQ92876
Ontology : AmiGOserine-type endopeptidase activity  serine-type endopeptidase activity  protein binding  extracellular region  extracellular space  nucleolus  cytoplasm  mitochondrion  endoplasmic reticulum  central nervous system development  response to wounding  regulation of neuron projection development  protein autoprocessing  secretory granule  collagen catabolic process  tissue regeneration  hormone metabolic process  myelination  amyloid precursor protein metabolic process  regulation of cell differentiation  positive regulation of G protein-coupled receptor signaling pathway  
Ontology : EGO-EBIserine-type endopeptidase activity  serine-type endopeptidase activity  protein binding  extracellular region  extracellular space  nucleolus  cytoplasm  mitochondrion  endoplasmic reticulum  central nervous system development  response to wounding  regulation of neuron projection development  protein autoprocessing  secretory granule  collagen catabolic process  tissue regeneration  hormone metabolic process  myelination  amyloid precursor protein metabolic process  regulation of cell differentiation  positive regulation of G protein-coupled receptor signaling pathway  
NDEx NetworkKLK6
Atlas of Cancer Signalling NetworkKLK6
Wikipedia pathwaysKLK6
Orthology - Evolution
OrthoDB5653
GeneTree (enSembl)ENSG00000167755
Phylogenetic Trees/Animal Genes : TreeFamKLK6
HOGENOMQ92876
Homologs : HomoloGeneKLK6
Homology/Alignments : Family Browser (UCSC)KLK6
Gene fusions - Rearrangements
Fusion : FusionGDB19079    19080    2404   
Fusion : Fusion_HubARHGAP23--KLK6    KLK6--BAD    KLK6--KLK6    KLK6--SEPT4    PRSS3P2--KLK6   
Fusion : QuiverKLK6
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerKLK6 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)KLK6
dbVarKLK6
ClinVarKLK6
1000_GenomesKLK6 
Exome Variant ServerKLK6
ExAC (Exome Aggregation Consortium)ENSG00000167755
GNOMAD BrowserENSG00000167755
Varsome BrowserKLK6
Genetic variants : HAPMAP5653
Genomic Variants (DGV)KLK6 [DGVbeta]
DECIPHERKLK6 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisKLK6 
Mutations
ICGC Data PortalKLK6 
TCGA Data PortalKLK6 
Broad Tumor PortalKLK6
OASIS PortalKLK6 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICKLK6  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DKLK6
Mutations and Diseases : HGMDKLK6
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch KLK6
DgiDB (Drug Gene Interaction Database)KLK6
DoCM (Curated mutations)KLK6 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)KLK6 (select a term)
intoGenKLK6
NCG5 (London)KLK6
Cancer3DKLK6(select the gene name)
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM602652   
Orphanet
DisGeNETKLK6
MedgenKLK6
Genetic Testing Registry KLK6
NextProtQ92876 [Medical]
TSGene5653
GENETestsKLK6
Target ValidationKLK6
Huge Navigator KLK6 [HugePedia]
snp3D : Map Gene to Disease5653
BioCentury BCIQKLK6
ClinGenKLK6
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD5653
Chemical/Pharm GKB GenePA30156
Clinical trialKLK6
Miscellaneous
canSAR (ICR)KLK6 (select the gene name)
DataMed IndexKLK6
Probes
Litterature
PubMed105 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineKLK6
EVEXKLK6
GoPubMedKLK6
iHOPKLK6
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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